Nitrogen-containing spiro compound as well as preparation method and application thereof

Abstract

The invention discloses an orexin receptor antagonist and application thereof. Specifically, the invention discloses a compound as shown in a formula (I), and a stereoisomer, a tautomer, a crystal form, a pharmaceutically acceptable salt, a hydrate, a solvate or a prodrug thereof. The compound provided by the invention is an orexin receptor antagonist and can be used for preparing medicines for treating and / or preventing diseases related to orexin.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of medicine, in particular to a kind of compound containing nitrogen spiro ring and its preparation method and application. BACKGROUND

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

[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 wake-up time of rodents injected with orexin in the abdominal cavity is prolonged (Piper et al. J. Neurosci. 2000 12.726-730), and OX2R damage or mutation 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 two receptors can be regulated to regulate wakefulness and sleep. 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]

[0010] wherein,

[0011] n is 0, 1, 2 or 3;

[0012] 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;

[0013] 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;

[0014] L1is selected from the group consisting of C(O), S(O)2, S(O);

[0015] 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 ;

[0016] 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;

[0017] 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 substituents;

[0018] R b is 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.

[0019] In another preferred embodiment, the heteroaryl is an aromatic cyclic group having 1, 2, 3, or 4 heteroatoms selected from N, O, or S in the ring backbone.

[0020] In another preferred embodiment, the heteroaryl is a monocyclic or fused ring.

[0021] In another preferred embodiment, each of a, d, a', and d' is independently 1, 2, or 3.

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

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

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

[0025] In another preferred embodiment, e is 1, 2, or 3.

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

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

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

[0029] In another preferred embodiment, e' is 1, 2, or 3.

[0030] In another preferred embodiment, each of a and b, a' and b', d and e, d' and e' is independently not simultaneously 0.

[0031] In another preferred embodiment, 1≤a+b≤3.

[0032] In another preferred embodiment, 1≤d+e≤3.

[0033] In another preferred embodiment, 1≤a'+b'≤3.

[0034] In another preferred embodiment, 1≤d'+e'≤3.

[0035] 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.

[0036] 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.

[0037] 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;

[0038] 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.

[0039] In a preferred embodiment, Ar2is substituted or unsubstituted selected from the group consisting of 5-6 membered heteroaryl, benzo 5-6 membered heteroaryl;

[0040] 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.

[0041] 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;

[0042] 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.

[0043] In another preferred embodiment, Ar2is substituted with 2 or 3 R b substituted, and one R b substituted at the para position of Ar2, R b is F, Cl or Br.

[0044] In one preferred embodiment, the compound has the structure of Formula (II):

[0045]

[0046] wherein n, d, e, d', e', R1, L1, Ar1and Ar2are as defined above.

[0047] In another preferred embodiment, the compound has the structure of Formula (III):

[0048]

[0049] wherein m is 0, 1, 2, 3 or 4;

[0050] n, d, e, d', e', L1, R1, R a , Ar2are as defined above.

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

[0052]

[0053] 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 ;

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

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

[0056]

[0057]

[0058] wherein n, m, d, e, d', e', L1, R1, R a , R b are as defined above.

[0059] In another preferred embodiment, the compound has the structure of Formula (VI):

[0060]

[0061] wherein n, d, e, d', e', L1, R1, R b are as defined above.

[0062] In another preferred embodiment, the compound has the structure of formula (VII):

[0063]

[0064] wherein n, d, e, d', e', R1, R b are as defined above.

[0065] In another preferred embodiment, the compound has the structure of formula (VII): is selected from the group consisting of:

[0066]

[0067] wherein is the point of attachment to Ar2or L1.

[0068] In another preferred embodiment, the N atom attached to Ar2is not located at the ortho position of the spiro carbon atom.

[0069] In another preferred embodiment, the compound has the structure of formula (VII): is selected from the group consisting of:

[0070] wherein is the point of attachment to Ar2or L1.

[0071] In a preferred embodiment, the compound is selected from the group consisting of:

[0072]

[0073]

[0074]

[0075]

[0076]

[0077]

[0078]

[0079]

[0080]

[0081]

[0082]

[0083]

[0084]

[0085]

[0086] The second aspect of the present invention provides a pharmaceutical composition comprising:

[0087] (i) the compound according to the first aspect of the present invention, its stereoisomer, tautomer, crystalline form, pharmaceutically acceptable salt, hydrate, solvate or prodrug; and

[0088] (ii) pharmaceutically acceptable carriers, adjuvants or vehicles.

[0089] The third aspect of the present invention is a use of the compound according to the first aspect of the present invention, its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs, or the pharmaceutical composition according to the second aspect of the present invention, characterized in that it is used for preparing a medicament for treating and / or preventing diseases related to orexin;

[0090] Preferably, the orexin-related disease is selected from the group consisting of sleep-wake cycle disorders, insomnia, restless legs syndrome, jet lag, restless sleep, depression, Alzheimer's disease, sleep disorders secondary to the following diseases: neurotic disorders, mania, depression, bipolar disorder, schizophrenia, pain syndrome, fibromyalgia, neuropathic pain, tension, Parkinson's disease, Tourette syndrome, anxiety, delirium, dementia, overweight or obesity, conditions associated with overweight or obesity, insulin resistance, type II diabetes, hyperlipidemia, gallstones, angina pectoris, hypertension, dyspnea, tachycardia, infertility, sleep apnea, back and joint pain, varicose veins, osteoarthritis, hypertension, tachycardia, arrhythmia, angina pectoris, acute heart failure, ulcers, irritable bowel syndrome, diarrhea, and gastroesophageal reflux.

[0091] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features described in detail below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be listed here one by one. DETAILED DESCRIPTION

[0092] 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.

[0093] Terminology

[0094] 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".

[0095] 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.

[0096] 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" refers to a cycloalkyl group containing 3-8 (e.g., 3, 4, 5, 6, 7, or 8) carbon atoms, preferably C 3-6 cycloalkyl. Cycloalkyl groups can be monocyclic, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or the like, or can be in the form of a bicyclic ring, such as a fused, bridged, or spirocyclic ring.

[0097] As used herein, the term "alkoxy" refers to -O-alkyl, wherein examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, isopropoxy, tert-butoxy, and the like.

[0098] As used herein, the term "hydroxyalkyl" refers to an alkyl group containing one or more hydroxyl groups, and the definition of alkyl is as described above. Examples of hydroxyalkyl groups include, but are not limited to, -CH2OH, -CH2CH2OH, -CH2CH2CH2OH, and the like.

[0099] As used herein, the "halogen" refers to F, Cl, Br, I, and isotopes thereof, including but not limited to F, 18 F, Cl, 32 Cl, Br, I.

[0100] As used herein, the term "nitro" refers to -NO2.

[0101] As used herein, the term "cyano" refers to -CN.

[0102] As used herein, the term "haloalkyl" refers to a group in which one or more hydrogen atoms in the alkyl group described above are replaced by the same or different halogen atoms. 1-6 "Alkyl" is preferably a halogenated C 1-4 Examples of alkyl and halogenated alkyl groups include, but are not limited to, -CH2Cl, -CH2CF3, -CH2CCl3, perfluoroalkyl groups (eg, -CF3-, -CF2CF3), and the like.

[0103] As used herein, the term "aryl" refers to an aromatic cyclic hydrocarbon group (including monocyclic, bicyclic or polycyclic groups), for example, "C 6-12 "Aryl" refers to an aromatic cyclic hydrocarbon group with 6-12 (6, 7, 8, 9, 10, 11 or 12) ring carbon atoms. Among them, it contains two or more aromatic rings (such as bicyclic rings, etc.), and the aromatic rings of the aryl group can be connected by a single bond (such as biphenyl) or fused (such as naphthalene, anthracene, etc.). Examples of aryl groups (especially monocyclic and bicyclic groups) include but are not limited to: phenyl, biphenyl or naphthyl. The aryl group can be fused with the heterocyclic group through a single bond or any two adjacent ring carbon atoms, for example: benzotetrahydrofuranyl, chromanyl, benzodioxanyl, wait.

[0104] As used herein, the term "heteroaryl" refers to an aromatic cyclic group (including monocyclic, bicyclic or polycyclic groups) whose ring backbone 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, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyrazinyl, thienyl, furanyl, pyranyl, pyridinyl, pyrrolyl, pyrazolyl, pyrimidinyl, quinolinyl, isoquinolinyl, benzofuranyl, benzothienyl, benzothiopyranyl, benzimidazolyl, benzoxazolyl, benzoxadiazolyl, benzothiazolyl, benzothiadiazolyl, benzopyranyl, indolyl, isoindolyl, triazolyl, triazinyl, quinoxalinyl, purinyl, quinazolinyl, quinolizinyl, naphthyridinyl, pteridinyl, carbazolyl, aza Base, diazepine Acridinium, etc.

[0105] In the present invention, the alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl and other groups include substituted alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl and the like unless otherwise specified, and the substituents include but are not limited to halogen, hydroxyl, cyano, acyl, sulfonyl, ester, sulfinyl, alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, acyl, ester and the like.

[0106] As used herein, the term "substituted" means that one or more hydrogen atoms on a particular group are replaced with a particular substituent. The particular substituents are those described in the foregoing or those substituents that appear in the various embodiments. Unless otherwise indicated, a substituted group can have one substituent at any available substitutable position, and the substituent can be selected from a particular group, which can be the same or different at each occurrence. Those skilled in the art will appreciate that combinations of substituents that are not chemically feasible or that are not stable are not intended within the scope of the application.

[0107] Unless otherwise indicated, the groups described herein are optionally substituted with a substituent selected from the group consisting of D, halogen, cyano, nitro, hydroxy, amino, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, 3-12 membered heterocyclyl, C3-C8cycloalkyl, 5-10 membered heteroaryl, and C6-C10aryl. 12 Cycloalkyl, 5-10 membered heteroaryl, and C6-C 10 Aryl.

[0108] "Optionally" as used herein means that the subsequently described event or circumstance can or can not occur, and this description includes instances where the event or circumstance occurs, as well as instances where it does not.

[0109] Abbreviations

[0110]

[0111]

[0112] Active ingredient

[0113] As used herein, "a compound of the application" refers to a compound of Formula (I), and also includes stereoisomers thereof, optical isomers thereof, pharmaceutically acceptable salts thereof, crystalline forms thereof, isotopic derivatives thereof, prodrugs thereof, metabolites thereof, solvates thereof, or hydrates thereof.

[0114] Unless otherwise indicated, the structural formulae described herein are intended to include all stereoisomers (such as cis-trans isomers, enantiomeric, diastereomeric, and conformational isomers): the R, S configuration about asymmetric centers; the (Z), (E) configuration about double bonds; and the like. Thus, individual stereochemical isomers and mixtures thereof (e.g., enantiomeric, diastereomeric, and conformational mixtures) of the compounds of the application are within the scope of the application.

[0115] The compounds of the present application can contain geometric isomers, one or more chiral carbon atoms, and therefore can exist in stereoisomeric forms. Geometric isomers refer to the non-enantiomeric isomers of a compound that differ only in the arrangement of atoms in space. This restriction is usually due to the presence of a functional group in the organic compound structure that cannot rotate freely, such as a C=C double bond, a C=N double bond, a C=S double bond, a N=N double bond, a heterocycle, or a cycloalkane. Organic molecules containing such isomers, such as alkenes, azo compounds, cycloalkanes, etc., are considered geometric isomers, with the cis- referring to the same ligand being in the adjacent position, and the trans- referring to the same ligand being in the opposite position. Each chiral carbon atom can be defined as (R)- or (S)- based on the stereochemistry. The present application is intended to include all possible isomers, as well as their racemates and optically pure forms. The preparation of the compounds of the present application can select a racemate, a geometric isomer, a chiral isomer, a diastereomeric isomer, or an enantiomeric isomer as a starting material or intermediate. The optically active isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, such as crystallization and chiral chromatography.

[0116] Conventional techniques for preparing / isolating individual optical isomers (i.e., geometric isomers and chiral isomers) include chiral synthesis from appropriate geometric precursors or optically pure precursors, or resolution of racemates (or racemates of salts or derivatives) using, for example, chiral high-performance liquid chromatography.

[0117] If a synthesis of a specific stereoisomer of a compound of the present application is desired, it can be prepared by asymmetric synthesis, or derivatized with a chiral auxiliary, the resulting stereomixture separated, and the chiral auxiliary removed to yield the pure geometric monomer, chiral monomer, or mixed stereomonomer. If the molecule contains a geometric isomeric center, the pure geometric isomers can be purified by column chromatography (normal phase silica gel column or reverse phase high-performance liquid chromatography preparation); 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 derivatized with an appropriate optically active acid or base to form a diastereomeric salt, which can then be separated by conventional means, such as fractional crystallization or chromatography, to yield the pure enantiomer.

[0118] The present application also includes isotopically-labeled compounds (i.e., isotopic derivatives), which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the predominant atomic mass or mass number. Examples of isotopes that can be suitably substituted into the compounds of the present application include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulphur, fluorine, and chlorine, such as 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. The isotopic derivatives of the compounds of the present invention are all within the scope of protection of the present invention. 3 H-labeled compounds and 14 C-labeled compounds are useful in drug and substrate tissue distribution studies. 3 H) and carbon-14 (i.e. 14 The preparation and detection of C) labeled compounds are relatively easy and are the first choice among isotopes. In addition, heavier isotope substitutions such as deuterium, i.e. 2 H, due to its excellent metabolic stability, has advantages in certain therapeutics, such as increasing half-life in vivo or reducing dosage, and therefore, may be preferred in certain situations. Isotopically labeled compounds can be prepared using conventional methods by replacing readily available isotopically labeled reagents with non-isotopic reagents using the protocols disclosed in the examples.

[0119] As used herein, the term "pharmaceutically acceptable salt" includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0120] "Pharmaceutically acceptable acid addition salts" refer to salts formed with inorganic or organic acids that retain the biological effectiveness of the free base without the side effects. Inorganic acid salts include, but are not limited to, hydrochlorides, hydrobromides, sulfates, nitrates, and phosphates; organic acid salts include, but are not limited to, formate, acetate, 2,2-dichloroacetate, trifluoroacetate, propionate, hexanoate, octanoate, decanoate, undecylenate, glycolate, gluconate, lactate, sebacate, adipate, glutarate, malonate, oxalate, maleate, succinate, fumarate, tartrate, citrate, palmitate, stearate, oleate, cinnamate, laurate, malate, glutamate, pyroglutamate, aspartate, benzoate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, alginate, ascorbate, salicylate, 4-aminosalicylate, and naphthalene disulfonate. These salts can be prepared by methods known in the art.

[0121] "Pharmaceutically acceptable base addition salt" refers to salts of the free acids that retain the biological effectiveness and non-toxicity of the free acids and that are formed with inorganic or organic bases. 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 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 salts can be prepared by methods known in the art.

[0122] Metabolites of the compounds of Formula (I), and pharmaceutically acceptable salts thereof, as well as all prodrugs of the compounds of Formula (I), and pharmaceutically acceptable salts thereof, are also within the scope of the application. Prodrugs are any covalently bonded compounds, which release the parent drug in vivo upon metabolism or hydrolysis. Typically, the release occurs through a simple chemical or enzymatic reaction, but a prodrug can also be a bioprecursor, which provides the drug moiety in vivo upon some biochemical reaction. Prodrugs are often active drugs in their own right, and can be designed to improve the delivery, distribution, absorption, metabolism, and / or excretion of the parent drug. A thorough discussion is provided in the literature: e.g., H. Bundgaard, Design of Prodrugs (Elsevier, 1985); idem, Advanced Drug Delivery Reviews 8: 1-38 (1992); idem, Chemical Approaches to the Delivery of Drugs (Plenum, 1987); and idem, Trends in Synthetic Medicinal Chemistry 2: 335-343 (1988); all of which are incorporated herein by reference.

[0123] As used herein, the term "solvate" means a complex of a compound of Formula (I) with solvent molecules in specific ratios.

[0124] As used herein, the term "hydrate" means a complex of a compound of Formula (I) with water molecules in specific ratios.

[0125] As described herein, the compounds of the application can be substituted with any number of substituents or functional groups to expand the scope of the application. Generally, the term "substituted" means substituted with the indicated substituent group in place of a hydrogen radical. When a particular structure is substituted with multiple instances of a particular substituent, each occurrence of the substituent group can be the same or different. As used herein, the term "substituted" includes all permissible substituents. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic organic radicals. As used herein, heteroatoms such as nitrogen can have hydrogen substituents and / or any permissible substituents of the

[0126] Pharmaceutical composition and administration method

[0127] Since the compound of the present application can selectively inhibit orexin receptor 2 (OX2R) and is useful for treating diseases such as sleep-wake cycle disorder, insomnia, restless leg syndrome, jet lag, depression, Alzheimer's disease, etc., the compound of the present application and its stereoisomer, its optical isomer, its pharmaceutically acceptable salt, its crystal form, its isotope derivative, its prodrug, its metabolite, its solvate or its hydrate, and a pharmaceutical composition containing the compound of the present application as a main active ingredient can be used for preventing and / or treating (stabilizing, alleviating or curing) diseases related to orexin (sleep-wake cycle disorder, insomnia, restless leg syndrome, jet lag, depression, Alzheimer's disease, etc.).

[0128] 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 an 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.

[0129] The "pharmaceutically acceptable carrier" means one or more compatible solid or liquid filler or gel materials, which are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components of the composition can be blended with the compound of the present application and among themselves without significantly reducing the efficacy of the compound. Examples of the pharmaceutically acceptable carrier include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyhydric alcohols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as Tween ), wetting agents (such as sodium dodecyl sulfate), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0130] The administration method of the compound or pharmaceutical composition of the present application is not particularly limited, and representative administration methods include, but are not limited to, oral, parenteral (intravenous, intramuscular or subcutaneous).

[0131] ​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 excipients as (a) fillers or extenders, e.g., starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, e.g., hydroxymethylcellulose, alginic acid, gelatin, polyvinylpyrrolidone, sucrose, and acacia; (c) humectants, 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) absorption accelerators, e.g., quaternary ammonium compounds; (g) moisturizing agents, e.g., glycerol and sorbitol; (h) respiration accelerators, e.g., high-oleic acid cottonseed oil; and (i) lubricants, e.g., magnesium stearate, calcium stearate, stearic acid, glyceryl monostearate, sodium stearyl fumarate, and talc. In the case of capsules, tablets, and pills, the dosage forms can also comprise buffering agents.

[0132] Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, e.g., enteric coatings and other materials well known in the art. They can optionally contain opacifying agents, and can also be of a composition that they release the active compound or compounds in a certain part of the digestive tract. 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.

[0133] Liquid dosage forms for oral administration include pharmaceutically-acceptable emulsions, solutions, suspensions, syrups, and 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- butanediol, dimethylformamide, and the like, as well as mixtures thereof.

[0134] Besides such inert diluents, the composition can also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0135] Suspensions, in addition to the active compounds, can contain suspending agents, as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, and sodium carbomate, among others.

[0136] Compositions for parenteral injection can contain 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 excipients include water, ethanol, polyols and suitable mixtures thereof.

[0137] Dosage forms of the compounds of the present application for topical administration include ointments, powders, patches, 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.

[0138] The compounds of the present application can be administered alone or in combination with other pharmaceutically acceptable compounds.

[0139] 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 administered simultaneously, separately or sequentially with the compounds of the present application for the prevention and / or treatment of orexin-related diseases.

[0140] In using the pharmaceutical composition, a safe and effective amount of the compounds of the present application is administered to a mammal (e.g., human) in need of treatment, wherein the amount is pharmaceutically effective for administration, and the amount is typically 1-2000 mg, preferably 20-500 mg, per day for a 60 kg body weight. Of course, the specific dose will also take into account a variety of factors such as the type of administration, the patient's health status, and the like, which are within the skill of the skilled medical practitioner.

[0141] Preparation method

[0142] 1. When L1 is C(O), the general preparation method is as follows

[0143] 1.1 Preparation method 1

[0144]

[0145] Step 1:

[0146] In DMF, the aromatic carboxylic acid (Ar1-L1-OH) is reacted with oxalyl chloride to obtain the corresponding acyl chloride (Ar1-L1-Cl);

[0147] In dichloromethane, the above acyl chloride is reacted with the mono-Boc-protected spiro-biamine compound A using N-N-diisopropylethylamine (DIEA) as a base to obtain the corresponding amide compound B.

[0148] or

[0149] The compound A' obtained in step 1' is subjected to deprotection reaction in trifluoroacetic acid and dichloromethane system to obtain compound C', which is directly used in the next step.

[0150] Step 2:

[0151] The compound C obtained in step 1 is subjected to deprotection reaction in trifluoroacetic acid and dichloromethane system to obtain compound C, which is directly used in the next step.

[0152] Step 3:

[0153] The compound C obtained in step 2 and Ar2 halide (Ar2-X, wherein X is halogen) are subjected to SNAr reaction at high temperature 120°C in the presence of cesium carbonate as base and DMF as solvent, and purification to obtain compound I, which is used for biological test.

[0154] 1.2. Preparation method 2

[0155]

[0156] Step 1':

[0157] The compound A' obtained in step 1' is subjected to SNAr reaction at high temperature 120°C in the presence of cesium carbonate as base and DMF as solvent and compound A' and Ar2 halide (Ar2-X, wherein X is halogen) to obtain compound B'.

[0158] Step 2':

[0159] The compound B obtained in step 1' is subjected to deprotection reaction in trifluoroacetic acid and dichloromethane system to obtain compound C, which is directly used in the next step.

[0160] Step 3':

[0161] The aromatic carboxylic acid (Ar1-L1-OH) is subjected to reaction with oxalyl chloride in dichloromethane to obtain the corresponding acyl chloride (Ar1-L1-Cl);

[0162] The above acyl chloride (Ar1-L1-Cl) is subjected to reaction with compound C' in dichloromethane in the presence of N-N-diisopropyl ethylamine (DIEA) as base to obtain candidate molecule I, which is directly used for biological test.

[0163] or

[0164] The aromatic carboxylic acid (Ar1-COOH) is subjected to condensation reaction with compound C' in the presence of HATU as condensing agent, DMF as solvent and N-N-diisopropyl ethylamine (DIEA) as base to obtain candidate molecule I, which is directly used for biological test.

[0165] 2. When L1 is S(O)2, the general preparation method is as follows:

[0166]

[0167] Step 1':

[0168] The SNAr reaction of the mono-Boc-protected spiro-biamine compound A' and Ar2 halide (Ar2-X, wherein X is halogen) is directly carried out at high temperature 120°C with cesium carbonate as base and DMF as solvent, and compound B' is obtained after purification.

[0169] Step 2':

[0170] The deprotection reaction of compound B' obtained in Step 1' is carried out in a trifluoroacetic acid and dichloromethane system, and compound C' is obtained and directly used in the next step.

[0171] Step 3":

[0172] The reaction of compound C' with sulfonyl chloride (Ar1-L1-Cl) is carried out in tetrahydrofuran as solvent, and candidate molecule I is obtained and directly used for biological testing.

[0173] The main advantages of the present application are:

[0174] 1. The OX2R antagonists of the present application have high selectivity for OX2R.

[0175] 2. Compared with the oral positive control, SD rats show higher blood drug concentration, higher exposure and higher bioavailability after oral administration of the OX2R antagonists of the present application.

[0176] 3. Compared with the oral positive control, SD rats show higher drug concentration in the brain and higher brain-blood ratio after oral administration of the OX2R antagonists of the present application.

[0177] The present application will be further described in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present application and not used to limit the scope of the present application. The experimental methods in the following examples are generally carried out according to conventional conditions or according to the conditions recommended by the manufacturers. Unless otherwise specified, percentages and parts are weight percentages and weight parts.

[0178] Example 001

[0179] 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-yl)phenyl methanone

[0180]

[0181] First step

[0182]

[0183] 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 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) and use directly in the next step.

[0184] Second step

[0185]

[0186] 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 at room temperature overnight. Concentrate the reaction directly and purify by column. Purify the crude product by medium pressure liquid chromatography (MPLC, PE / EtOAc = 0-50%) to give 001-03 (90 mg, 51% yield) as a colorless oil.

[0187] Second step

[0188]

[0189] Dissolve 001-03 (90 mg, 2224.19 μmol) in DCM (5 mL), add trifluoroacetic acid (TFA, 11 mL) and stir the reaction at room temperature for 2 h. TLC shows the reaction is complete. Concentrate the reaction directly to give 001-04 (256 mg, TFA salt) as a light yellow oil. Use the product directly in the next step.

[0190] Third step

[0191]

[0192] To a solution of 001-04 (68 mg, 163.72 pmol, 1 eq), 2 (32.32 mg, 163.72 pmol, 1 eq) and Cs2C03(221.59 mg, 4491.15 pmol, 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 mixture, 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 pre-HPLC (acetonitrile-water system) to give the product 001 (18.4 mg, 27.6% yield for two steps) as a white solid.

[0193] MS (ESI, m / z): 408.3 [M+H] + .

[0194] 1 H NMR (300 MHz, DMSO) d 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)

[0195] Example 002

[0196] Preparation of compound 002: (6-(4,6-dimethylpyrimidin-2-yl)-2,6-diazaspiro[3.4]-6- octane (2-fluoro-6-2H-l,2,3-triazol-2-yl)phenyl methyl ketone

[0197]

[0198] First step

[0199]

[0200] To a solution of 001-04 (68 mg, 163.72 pmol, 1 eq), 2 (32.32 mg, 163.72 pmol, 1 eq) and Cs2C03(221.59 mg, 4491.15 pmol, 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 mixture, 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 pre-HPLC (acetonitrile-water system) to give the product 001 (18.4 mg, 27.6% yield for two steps) as a white solid.

[0201] MS (ESI, m / z): 319.22 [M+H] + .

[0202] Second Step

[0203]

[0204] 002-02 (161 mg, 505.62 μmol, 1 eq) was dissolved in DCM (5 mL), after adding TFA (1 mL), the reaction was stirred at room temperature for 1 h. TLC showed that the reaction was completed. The reaction solution was directly concentrated to obtain light yellow oil 002-03 (176 mg, TFA salt). The product was directly used in the next step.

[0205] Third Step

[0206]

[0207] 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. Liquid chromatography-mass spectrometry showed that the reaction was completed. Water (15 mL) was added to the reaction solution, 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 obtain the crude product. The crude product was purified by prep-HPLC (acetonitrile-water) to obtain white solid product 002 (108.5 mg, 49.9% yield for two steps).

[0208] MS (ESI, m / z): 408.2 [M+H] + .

[0209] 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)

[0210] Example 003

[0211] Preparation of compound 003: 8-(4,6-dimethylpyrimidin-2-yl)-2,8-diazaspiro[5.5]undecan-2-yl)(2-fluoro-6-2H-1,2,3-triazol-2-yl)phenyl methyl ketone

[0212]

[0213] First step

[0214]

[0215] 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, combined the organic phase 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 yellow oil.

[0216] MS (ESI, m / z): 344.28 [M-100].

[0217] Second step

[0218]

[0219] 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 yellow oil. The product was used directly for the next step.

[0220] Third step

[0221]

[0222] 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. The LC-MS showed that 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 give the crude product. The crude product was purified by prep-HPLC integration to give white solid 003 (89.4 mg, 41.2% yield for 3 steps).

[0223] MS (ESI, m / z): 450.3 [M+H] + .

[0224] 1 H 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)

[0225] Example 004

[0226] 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 methyl ketone

[0227]

[0228] First step

[0229]

[0230] 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 allowed to react at room temperature overnight. The reaction was directly concentrated to give the crude product. The crude product was purified by MPLC (petroleum ether / ethyl acetate = 0-50%, SiO2) to give colorless oil 004-02 (140 mg, yield 76%).

[0231] MS (ESI, m / z): 416.21 [M+H] + .

[0232] Second Step

[0233]

[0234] 004-02 (140 mg, 336.96 umol) was dissolved in DCM (5 mL), and TFA (2 mL) was added. The reaction was stirred at room temperature for 2 h. TLC showed the reaction was complete. The reaction was directly concentrated to give 004-03 (256 mg, TFA salt) as a light yellow oil. The product was used directly in the next step.

[0235] Third Step

[0236]

[0237] 004-03 (106.26 mg, 336.96 umol, 1 eq), 2 (48.05 mg, 336.96 umol, 1 eq) and Cs2CO3 (329.36 mg, 1.01 umol, 3 eq) were dissolved in DMF (3 mL). The reaction was heated at 120 °C under argon for 1.5 h. TLC showed the reaction was complete. Water (15 mL) was added to the reaction, and it was extracted with EtOAc (25 mL) three 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 integration to give the product 005 (72.6 mg, 51% yield for two steps) as a white solid.

[0238] MS (ESI, m / z): 422.28 [M+H] + .

[0239] 1 H NMR (300 MHz, DMSO) δ 8.15 (s, 2H), 7.83-7.81 (m, 1H), 7.70-7.63 (m, 1H),

[0240] 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)

[0241] Example 005

[0242] 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

[0243]

[0244] First Step

[0245]

[0246] 005-01 (158.73 mg, 0.7 mmol, 1 eq), 2 (100 mg, 0.7 mmol, 1 eq) and Cs2CO3 (685.52 mg, 2.1 mmol, 3 eq) were dissolved in DMF (3 mL), the reaction was heated at 120 °C for 2 h. TLC 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 (petroleum ether / ethyl acetate = 0-20%) to get white solid 005-02 (170 mg, yield 73.0%).

[0247] MS (ESI, m / z): 333.22 [M+H] + .

[0248] Second Step

[0249]

[0250] 005-02 (190 mg, 511.36 μmol, 1 eq) was dissolved in DCM (5 mL), after adding TFA (1 mL), the reaction was stirred at room temperature for 1 h. TLC showed the reaction was completed. The reaction was directly concentrated to get yellowish oil 005-03 (256 mg, TFA salt). The product was directly used for the next step.

[0251] Third Step

[0252]

[0253] 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. Mass spectrometry 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 (50 mL), dried and concentrated to get the crude product. The crude product was purified by prep-HPLC integration to get white solid product 005 (37.0 mg, 2 steps yield 17.2%).

[0254] MS (ESI, m / z): 422.3 [M+H] + .

[0255] 1H 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)

[0256] Example 006

[0257] Example 006: Preparation of (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 methanone

[0258]

[0259] First Step

[0260]

[0261] Dissolve 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). Stir the reaction at room temperature for 12 h. The reaction is complete by mass spectrometry. Add water (15 mL) to the reaction and extract with EtOAc (25 mL) three times. Combine the organic layers and wash with saturated brine (25 mL), dry and concentrate to give the crude product. Purify the crude product by MPLC (petroleum ether / ethyl acetate = 0-50%) to give 006-02 (165 mg, 88.2% yield) as colorless oil. MS (ESI, m / z): 410.28 [M+23]

[0262] Second Step

[0263]

[0264] Dissolve 006-3 (165 mg, 425.90 μmol, 1 eq) in DCM (3 mL), add TFA (1 mL) and stir the reaction at room temperature for 1 h. TLC shows the reaction is complete. Concentrate the reaction directly to give 006-03 (170 mg, TFA salt) as light yellow oil. Use the product directly in the next step.

[0265] Third Step

[0266]

[0267] To a solution of 006-03 (170 mg, 423.60 pmol, 1 eq), 2 (60.40 mg, 423.60 pmol, 1 eq) and Cs2C03 (690.09 mg, 2.12 mmol, 3 eq) in DMF (2 mL) was heated at 120 °C for 2 h. 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 006 (66 mg, 39.4% yield for 2 steps) as a white solid.

[0268] MS (ESI, m / z): 394.29 [M+H] + .

[0269] Example 007

[0270] 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

[0271]

[0272] First step

[0273]

[0274] To a solution of 007-01 (80.00 mg, 403.50 pmol, 1 eq), 2 (57.53 mg, 403.50 pmol, 1 eq) and Cs2C03 (394.40 mg, 1.21 mmol, 3 eq) in DMF (2 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 = 0-30%) to give 007-02 (150 mg, 96.2% yield) as a colorless oil.

[0275] Second step

[0276]

[0277] To a solution of 007-02 (150 mg, 387.17 pmol, 1 eq) in DCM (3 mL) was added TFA (1 mL) and stirred at room temperature for 1 h. TLC showed the reaction was completed. The reaction was directly concentrated to give 007-03 (155 mg, TFA salt) as a light yellow oil. The product was used directly for the next step.

[0278] Third Step

[0279]

[0280] 007-03 (155 mg, 486.96 umol, 1 eq), 1 (100.88 mg, 486.96 umol, 1 eq), HATU (222.19 mg, 584.35 umol, 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 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 white solid 007 (12.2 mg, 6.1% yield for 2 steps).

[0281] MS (ESI, m / z): 394.3 [M+H] + .

[0282] Example: 008

[0283] 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

[0284]

[0285] First Step

[0286]

[0287] 008-01 (95.70 mg, 482.71 umol, 1 eq), 1 (100 mg, 482.71 umol, 1 eq), HATU (220.25 mg, 579.25 umol, 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 completed 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 get the crude product. The crude product was purified by MPLC (petroleum ether / ethyl acetate = 0-50%) to get colorless oil 008-02 (171 mg, yield 91.4%). MS (ESI, m / z): 388.31 [M+H] +

[0288] Second Step

[0289]

[0290] 008-02 (171 mg, 441.39 pmol, 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 a light yellow oil. The product was used directly in the next step.

[0291] Third Step

[0292]

[0293] 008-03 (177 mg, 441.04 pmol, 1 eq), 2 (62.89 mg, 441.04 pmol, 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 and concentrated to give the crude product. The crude product was purified by prep-HPLC to give 008 (44 mg, 25.3% yield over 2 steps) as a white solid.

[0294] MS (ESI, m / z): 394.3 [M+H] + .

[0295] Example 009

[0296] Compound 009: Preparation of (2-(4,6-dimethylpyrimidin-2-yl)-2,8- diazaspiro[4.5]-8-decan(2-fluoro-6-2H-l,2,3-triazol-2-yl)phenyl methanone

[0297]

[0298] First Step

[0299]

[0300] 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.

[0301] MS (ESI, m / z): 347.35 [M+H] + .

[0302] Second Step

[0303]

[0304] 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.

[0305] Third Step

[0306]

[0307] 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 the product 009 (108.3 mg, 45.3% yield for 2 steps) as a white solid.

[0308] MS (ESI, m / z): 436.3 [M+H] + .

[0309] 1H 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)

[0310] Example 010

[0311] 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

[0312]

[0313] First step

[0314]

[0315] 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 at room temperature for 12 h. TLC shows the reaction is complete. Add water (15 mL) to the reaction and extract with EtOAc (25 mL) for 3 times, combine the organic phase and wash with saturated brine (25 mL), dry and concentrate to get the crude product. Purify the crude product with MPLC (PE / EtOAc = 0-30%) to get 010-02 (200 mg, yield 96.7%) as light yellow oil. MS (ESI, m / z): 452.20 [M+H] + .

[0316] Second step

[0317]

[0318] Dissolve 010-02 (200 mg, 465.66 μmol, 1 eq) in DCM (2 mL), add TFA (2 mL) and stir the reaction at room temperature for 1 h. TLC shows the reaction is complete. Concentrate the reaction directly to get 010-03 (200 mg, TFA salt) as light yellow oil. Use the product directly for the next step.

[0319] Third step

[0320]

[0321] 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.

[0322] MS (ESI, m / z): 436.2 [M+H] + .

[0323] 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)

[0324] Example 011

[0325] 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

[0326]

[0327] First step

[0328]

[0329] 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%).

[0330] MS (ESI, m / z): 347.3 [M+H] + , 291.2 [M-55] +

[0331] Second step

[0332]

[0333] 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.

[0334] Third step

[0335]

[0336] 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 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 for 1 time, dried over anhydrous Na2SO4, concentrated under reduced pressure to obtain the crude product. The crude product was separated by high pressure preparation to obtain product 011 6.2 mg. MS (ESI, m / z): 436.3 [M+H] + .

[0337] Example 012

[0338] 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

[0339]

[0340] First step

[0341]

[0342] 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 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 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%).

[0343] Second step

[0344]

[0345] Compound 012-02 (67.1 mg, 140.51 μmol, 1.0 eq) was dissolved in 2 mL of DCM, and then 2 mL of TFA was added. The reaction was stirred at 80 °C 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 012-03 (48.3 mg) was directly used in the next reaction.

[0346] Step 3

[0347]

[0348] 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 of DMF, and the reaction system was placed in a 120 °C oil bath for stirring for about 2 h. The reaction process 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, and then extracted with EtOAc (20 mL) for 3 times. The combined organic phase was 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 012 33.7 mg. MS (ESI, m / z): 450.3 [M+H] + .

[0349] Example 013

[0350] 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

[0351]

[0352] Step 1

[0353]

[0354] 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 at 25 °C for 16 h, 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 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 obtain compound 013-02 (colorless oil, 76.5 mg, yield 100%).

[0355] Second step

[0356]

[0357] Compound 013-02 (76.5 mg, 160.20 μmol, 1.0 eq) was dissolved in 2 mL DCM, 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, it was concentrated under reduced pressure to obtain residue 013-03 (55.0 mg) which was directly used in the next step reaction.

[0358] Third step

[0359]

[0360] 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 DMF, the reaction system was placed in a 120 °C oil bath and stirred for about 2 h, the reaction process was monitored by liquid chromatography. After the reaction was completed and cooled to room temperature, 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 separated by high pressure preparation to obtain product 013 32.0 mg. MS (ESI, m / z): 450.3 [M+H] + .

[0361] Example 014

[0362] 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

[0363]

[0364] First step

[0365]

[0366] Compound 014-01 (50.0 mg, 153.92 μmol, 1.0 eq), 2 (22.0 mg, 153.92 μmol, 1.0 eq), Cs2CO3(150.5 mg, 461.75 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 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, 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 014-02 (colorless oil, 47.2 mg, yield 77.7%).

[0367] Second step

[0368]

[0369] 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, heated to 80 °C and stirred for about 2 h, and the reaction process was monitored by TLC. After the reaction was completed, the residue 014-03 (31.2 mg) was obtained by concentration under reduced pressure and directly used in the next step.

[0370] Third step

[0371]

[0372] 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), DIEA (79.4 mg, 614.47 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 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 for 1 time, dried over anhydrous Na2SO4, 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] + .

[0373] Example 015

[0374] 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

[0375]

[0376] First step

[0377]

[0378] 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 to 2 mL 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 completed and cooled to room temperature, 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 obtain compound 015-02 (colorless oil, 147.5 mg, yield 69.4%).

[0379] Second step

[0380]

[0381] 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 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 015-03 (106.6 mg) was directly used in the next reaction.

[0382] Step 3

[0383]

[0384] 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, 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 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 015 24.7 mg, purity 98.0%, MS (ESI, m / z): 450.3 [M+H] + .

[0385] Example 016

[0386] 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

[0387]

[0388] Step 1

[0389]

[0390] Compound 016-01 (90.0 mg, 374.46 pmol, 1.0 eq), 1 (77.6 mg, 374.46 pmol, 1.0 eq), HATU (170.9 mg, 449.35 pmol, 1.2 eq), DIEA (242.0 mg, 1.87 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, the organic phase was combined and washed with about 50 mL of saturated brine once, dried over anhydrous Na2S04, 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 016-02 (colorless oil, 36.2 mg, yield 22.5%). MS (ESI, m / z): 374.26 [M-55].

[0391] Second step

[0392]

[0393] Compound 016-02 (36.2 mg, 84.28 pmol, 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 016-03 (27.8 mg) was directly used in the next step reaction.

[0394] Third step

[0395]

[0396] Compound 016-03 (27.8 mg, 84.40 pmol, 1.0 eq), 2 (12.0 mg, 84.40 pmol, 1.0 eq) and Cs2C03(82.8 mg, 253.20 pmol, 3.0 eq) were added to 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 once, dried over anhydrous Na2S04, 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] + .

[0397] Example 017

[0398] 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

[0399]

[0400] First step

[0401]

[0402] 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 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 017-02 (colorless oil, 121.1 mg, yield 71.2%). MS (ESI, m / z): 424.26

[0403] [M-100+Na].

[0404] Second step

[0405]

[0406] Compound 017-02 (121.1 mg, 301.66 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 017-03 (90.9 mg) was directly used in the next step reaction.

[0407] Third step

[0408]

[0409] 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 into 2 mL DMF at 25 °C, the reaction system was placed in a 120 °C oil bath for stirring reaction 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 separated by high-pressure preparation to obtain product 017 24.4 mg, purity 99.0%, MS (ESI, m / z): 408.3 [M+H] + .

[0410] 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).

[0411] Example 018

[0412] 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

[0413]

[0414] First step

[0415]

[0416] 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 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 018-02 (colorless oil, 107.7 mg, yield 81.5%), MS (ESI, m / z): 277.28 [M-55].

[0417] Second step

[0418]

[0419] 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.

[0420] Third step

[0421]

[0422] 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] + .

[0423] Example 019

[0424] 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

[0425]

[0426] First step

[0427]

[0428] 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].

[0429] Second step

[0430]

[0431] 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.

[0432] Third step

[0433]

[0434] 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 Preparation of compound 019 + .

[0435] Example 020

[0436] 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

[0437]

[0438] First step

[0439]

[0440] Compound 020-01 (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 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 phases were combined and washed with about 50 mL of saturated brine once, dried over anhydrous Na2S04, 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 020-02 (colorless oil, 167.3 mg, yield 100.0%). MS (ESI, m / z): 374.28 [M-55].

[0441] Second step

[0442]

[0443] 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 used directly in the next reaction.

[0444] Step 3

[0445]

[0446] 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 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, which was then extracted 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 020 26.6 mg. MS (ESI, m / z): 436.3 [M+H] + .

[0447] 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).

[0448] Example 021

[0449] 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

[0450]

[0451] First Step

[0452]

[0453] 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 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 021-02 (colorless oil, 86.3 mg, yield 58.7%).

[0454] Second Step

[0455]

[0456] Compound 021-02 (86.3 mg, 207.72 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 021-03 (65.5 mg) was directly used in the next step reaction.

[0457] Third Step

[0458]

[0459] Compound 021-03 (65.5 mg, 207.70 umol, 1.0 eq), 2 (29.6 mg, 207.70 umol, 1.0 eq) and Cs2CO3 (203.0 mg, 623.11 umol, 3.0 eq) were dissolved in 2 mL DMF, the reaction system was placed in a 120 °C oil bath for stirring reaction 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 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 product 021 28.2 mg, purity 99.0%, MS (ESI, m / z): 422.3 [M+H] + .

[0460] 1 H NMR (300 MHz, CDCl3) 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).

[0461] Example 022

[0462] 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

[0463]

[0464] First step

[0465]

[0466] Compound 022-01 (80.0 mg, 353.48 μmol, 1.0 eq), 2 (50.4 mg, 352.48 μmol, 1.0 eq), and Cs2CO3 (346.6 mg, 1.06 mmol, 3.0 eq) were dissolved in 2 mL of DMF at 25°C. The reaction system was stirred in an oil bath at 120°C for approximately 2 hours. The reaction progress was monitored by liquid chromatography-mass spectrometry. After cooling to room temperature, the reaction solution was added with approximately 20 mL of water. The mixture was then extracted three times with EtOAc (20 mL). The organic phases were combined and washed once with approximately 50 mL of saturated brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by MPLC using a gradient elution with 0%-30% ethyl acetate / petroleum ether. The resulting fractions were concentrated under reduced pressure to remove the solvent, yielding compound 022-02 (74.0 mg, 63.0% yield).

[0467] Step 2

[0468]

[0469] Compound 022-01 (74.0 mg, 222.59 μmol, 1.0 eq) was dissolved in 2 mL of DCM at 25°C. 1 mL of TFA was added and the mixture was stirred for approximately 2 hours. The reaction progress was monitored by TLC. After completion of the reaction, the solvent was removed by concentration under reduced pressure, and the residue 022-02 (51.7 mg) was used directly in the next reaction.

[0470] Step 3

[0471]

[0472] 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), and DIEA (143.8 mg, 1.11 mmol, 5.0 eq) were dissolved in 2 mL of DMF at 25°C. The reaction system was stirred for 16 hours, and the reaction progress was monitored by liquid chromatography-mass spectrometry. After completion of the reaction, approximately 20 mL of water was added to the reaction solution, followed by extraction three times with EtOAc (20 mL). The organic phases were combined and washed once with approximately 50 mL of saturated brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude product. The crude product was dissolved in methanol and subjected to high-pressure preparative separation to obtain 28.3 mg of product 022. MS (ESI, m / z): 422.3 [M+H] + .

[0473] Example 023

[0474] 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

[0475]

[0476] First step

[0477]

[0478] 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 of 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 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, 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 023-02 (colorless oil, 137.9 mg, yield 81.0%). MS (ESI, m / z): 346.27 M-5.

[0479] Second step

[0480]

[0481] 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 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, and the residue 023-03 (103.5 mg) was directly used in the next step reaction.

[0482] Third step

[0483]

[0484] 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 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 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 product 023 72.6 mg.

[0485] MS (ESI, m / z): 408.3 [M+H] + .

[0486] 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).

[0487] Example 024

[0488] 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

[0489]

[0490] First step

[0491]

[0492] 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 of DMF, the reaction system was stirred at 25 °C 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%-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.

[0493] Second step

[0494]

[0495] 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 at 25 °C 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 024-03 (94.4 mg) was directly used in the next step reaction.

[0496] Third step

[0497]

[0498] 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 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 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] + .

[0499] Example 025

[0500] 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

[0501]

[0502] First step

[0503]

[0504] 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%).

[0505] Second step

[0506]

[0507] 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.

[0508] Third step

[0509]

[0510] 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] + .

[0511] Example 026

[0512] 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

[0513]

[0514] First step

[0515]

[0516] 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%).

[0517] Second step

[0518]

[0519] 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.

[0520] Third step

[0521]

[0522] 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 and stirred 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 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] + .

[0523] Example 027

[0524] 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

[0525]

[0526] First step

[0527]

[0528] 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), and DIEA (215.1 mg, 1.66 mmol, 5.0 eq) were dissolved in 2 mL of DMF at 25°C. The reaction system was stirred for 16 hours, with the reaction progress monitored by liquid chromatography-mass spectrometry. After completion of the reaction, approximately 20 mL of water was added to the reaction solution, followed by extraction three times with EtOAc (20 mL). The organic phases were combined and washed once with approximately 50 mL of saturated brine, dried over anhydrous NaSO, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by MPLC using a gradient elution method of 0%-30% ethyl acetate / petroleum ether. The resulting fractions were concentrated under reduced pressure to remove the solvent, affording compound 027-02 (colorless oil, 115 mg, 80.4% yield). MS (ESI, m / z): 330.32 [M+H-100].

[0529] Step 2

[0530]

[0531] Compound 027-02 (115 mg, 267.75 μmol, 1.0 eq) was dissolved in 2 mL of DCM at 25°C. 1 mL of TFA was added and the mixture was stirred for approximately 2 hours. The reaction progress was monitored by TLC. After completion of the reaction, the solvent was removed by concentration under reduced pressure, and the residue 027-03 (88.2 mg) was used directly in the next reaction.

[0532] Step 3

[0533]

[0534] Compounds 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 at 25°C. The reaction system was stirred in an oil bath at 120°C for approximately 2 h. The reaction progress was monitored by liquid chromatography-mass spectrometry. After cooling to room temperature, the reaction solution was added with approximately 20 mL of water. The mixture was then extracted three times with EtOAc (20 mL). The organic phases were combined and washed once with approximately 50 mL of saturated brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude product. The crude product was dissolved in methanol and subjected to high-pressure preparative separation to yield 65 mg of product 027. MS (ESI, m / z): 436.3 [M+H]. + .

[0535] Example 028

[0536] 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

[0537]

[0538] First step

[0539]

[0540] Compound 028-01 (90.0 mg, 374.46 umol, 1.0 eq), 2 (53.4 mg, 374.46 umol, 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, 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 028-02 (colorless oil, 132 mg, yield 100.0%).

[0541] Second step

[0542]

[0543] Compound 028-02 (132 mg, 380.97 umol, 1.0 eq) was dissolved in 2 mL of DCM, 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 028-03 (93.8 mg) was directly used in the next step reaction.

[0544] Third step

[0545]

[0546] 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 sent to high pressure preparation separation to obtain the product 028 35 mg. MS (ESI, m / z): 436.3 [M+H] + .

[0547] Example 029

[0548] 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

[0549]

[0550] First step

[0551]

[0552] 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 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 029-02 (colorless oil, 117 mg, yield 81.2%).

[0553] Second step

[0554]

[0555] Compound 029-02 (117 mg, 337.68 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 029-03 (83.2 mg) was directly used in the next reaction.

[0556] Third step

[0557]

[0558] 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 at 25 °C 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 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 the product was separated by high-pressure preparation to obtain 029-03 (20 mg). MS (ESI, m / z): 436.3 [M+H] + .

[0559] Example 030

[0560] 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

[0561]

[0562] First step

[0563]

[0564] Compound 030-01 (100.0 mg, 441.85 μmol, 1.0 eq), 2 (63.0 mg, 441.85 μmol, 1.0 eq), and Cs2CO3 (431.9 mg, 1.33 mmol, 3.0 eq) were added to 2 mL of DMF at 25°C. The reaction system was stirred in an oil bath at 120°C for approximately 2 hours. The reaction progress was monitored by liquid chromatography-mass spectrometry. After cooling to room temperature, the reaction solution was added with approximately 20 mL of water. The mixture was then extracted three times with EtOAc (20 mL). The organic phases were combined, washed once with approximately 50 mL of saturated brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by MPLC using a gradient elution with 0%-30% ethyl acetate / petroleum ether. The resulting fractions were concentrated under reduced pressure to remove the solvent, yielding compound 030-02 (a colorless oil, 124 mg, 84.4% yield).

[0565] Step 2

[0566]

[0567] Compound 030-02 (124 mg, 372.99 μmol, 1.0 eq) was dissolved in 2 mL of DCM at 25°C. 1 mL of TFA was added and the mixture was stirred for approximately 2 hours. The reaction progress was monitored by TLC. After completion of the reaction, the solvent was removed by concentration under reduced pressure, and the residue 030-03 (86 mg) was used directly in the next reaction.

[0568] Step 3

[0569]

[0570] 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), and DIEA (239.2 mg, 1.85 mmol, 5.0 eq) were dissolved in 2 mL of DMF at 25°C. The reaction system was stirred for 16 hours, and the reaction progress was monitored by liquid chromatography-mass spectrometry. After completion of the reaction, approximately 20 mL of water was added to the reaction solution, followed by extraction three times with EtOAc (20 mL). The organic phases were combined and washed once with approximately 50 mL of saturated brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude product. The crude product was dissolved in methanol and subjected to high-pressure preparative separation to obtain 73 mg of product 030. MS (ESI, m / z): 422.3 [M+H] + .

[0571] 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).

[0572] Example 031

[0573] 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

[0574]

[0575] First step

[0576]

[0577] Compound 031-01 (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 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 Na2S04, 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 031-02 (colorless oil, 115 mg, yield 80.4%). MS (ESI, m / z): 330.32

[0578] [M + H - 100].

[0579] Second step

[0580]

[0581] Compound 031-02 (115 mg, 267.75 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 031-03 (88.2 mg) was directly used in the next reaction.

[0582] Third step

[0583]

[0584] 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, and the reaction system was placed in a 120 °C oil bath and stirred 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 031 65 mg. MS (ESI, m / z): 500.3, 502.2 [M+H] + .

[0585] 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).

[0586] Example 032

[0587] 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

[0588]

[0589] 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%).

[0590] MS (ESI, m / z): 447.3 [M+H] +

[0591] Example 033

[0592] 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

[0593]

[0594] 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%).

[0595] MS (ESI, m / z): 438.2 [M+1] + , 897.3 [2M+23] +

[0596] Example 034

[0597] Method for synthesis of compound 034 as above

[0598]

[0599] Example 035

[0600] 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

[0601]

[0602] First step

[0603]

[0604] 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, 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 once, and then dried over anhydrous Na2SO4, and then 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%).

[0605] Second step

[0606]

[0607] Compound 035-02 (117 mg, 324.55 μmol, 1.0 eq) was dissolved in 2 mL of DCM, 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 concentration under reduced pressure, and the residue 035-03 (84.5 mg) was directly used in the next step reaction.

[0608] Third step

[0609]

[0610] Compound 035-03 (84.5 mg, 324.52 umol, 1.0 eq), 1 (67.2 mg, 324.52 umol, 1.0 eq), HATU (148.1 mg, 389.42 umol, 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] + .

[0611] Example 036

[0612] 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

[0613]

[0614] First step

[0615]

[0616] Compound 036-01 (90.0 mg, 423.94 umol, 1.0 eq), 2 (60.5 mg, 423.94 umol, 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].

[0617] Second step

[0618]

[0619] Compound 036-02 (25.4 mg, 79.77 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 036-03 (17.4 mg) was used directly in the next reaction.

[0620] Step 3

[0621]

[0622] 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 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 product 036 2 mg with a purity of 97.0%, MS (ESI, m / z): 408.3 [M+H] + .

[0623] Example 037

[0624] 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

[0625]

[0626] Step 1

[0627]

[0628] Compound 037-01 (100.0 mg, 393.12 umol, 1.0 eq), 1 (81.4 mg, 393.12 umol, 1.0 eq), HATU (179.4 mg, 471.75 umol, 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, 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%).

[0629] Second step

[0630]

[0631] Compound 037-02 (15 mg, 33.82 umol, 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 037-03 (10.0 mg) was directly used in the next step reaction.

[0632] Third step

[0633]

[0634] Compound 037-03 (10.0 mg, 29.12 umol, 1.0 eq), 2 (4.2 mg, 29.12 umol, 1.0 eq) and Cs2CO3 (28.5 mg, 87.36 umol, 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 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] + .

[0635] Example 038

[0636] 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

[0637]

[0638] First step

[0639]

[0640] 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 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 038-02 (colorless oil, 22.0 mg, yield 16.6%).

[0641] Second step

[0642]

[0643] 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, and 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 in the next step reaction.

[0644] Third step

[0645]

[0646] 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 for 1 time, 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] + .

[0647] Example 039

[0648] 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

[0649]

[0650] First step

[0651]

[0652] 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 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 039-02 (colorless oil, 170 mg, yield 97.8%), MS (ESI, m / z): 390.31 M-5.

[0653] Second step

[0654]

[0655] Compound 039-02 (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 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 039-03 (131.8 mg) was used directly in the next reaction.

[0656] Step 3

[0657]

[0658] 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, 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, 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 039 134 mg, purity 96.0%, MS (ESI, m / z): 452.4 [M+H] + .

[0659] 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).

[0660] Example 040

[0661] 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

[0662]

[0663] First step

[0664]

[0665] 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 at 25 °C, and the reaction system was placed in a 120 °C oil bath for stirring reaction 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, and then extracted with EtOAc (30 mL) for 3 times, and then the organic phase was combined and washed with about 80 mL of saturated brine for 1 time, and then dried with anhydrous Na2SO4, and then 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 040 88 mg, purity 97.2%, MS (ESI, m / z): 548.2 [M+H] + .

[0666] The following compounds were synthesized by the same method as above

[0667]

[0668]

[0669]

[0670]

[0671]

[0672]

[0673]

[0674]

[0675]

[0676]

[0677]

[0678]

[0679]

[0680] Example 135

[0681] 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

[0682]

[0683] First step

[0684]

[0685] 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 at 25 °C, and the reaction system was placed in an 80 °C oil bath and stirred for about 24 h. The reaction process was monitored by liquid chromatography. After cooling to room temperature, about 30 mL of water was added to the reaction solution, and then extracted with EtOAc (30 mL) for 3 times. 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] + .

[0686] The following compounds were synthesized by the same method as above

[0687]

[0688] Example 139

[0689] Preparation of compound 139: 7-(4,6-dimethylpyrimidin-2-yl)-2-((methoxyphenyl)sulfonyl)-2,7-diazaspiro[3,5]nonane

[0690]

[0691] First step

[0692]

[0693] Compound 006-03 (50.0 mg, 215.21 umol, 1.0 eq), 5 (44.5 mg, 215.21 umol, 1.0 eq), Et3N (65.3 mg, 645.63 umol, 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, 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 139 14 mg. MS (ESI, m / z): 403.3 [M+H] + .

[0694] The following compounds were synthesized by the same method as above

[0695]

[0696]

[0697]

[0698]

[0699]

[0700]

[0701]

[0702] Example 194

[0703] Compound 194: Preparation of (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

[0704]

[0705] Compound 194-01 (100.0 mg, 525.87 μmol, 1.0 eq), DMF (3.8 mg, 52.59 μmol, 0.1 eq) was 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, 1 mL KOH solution was added to quench the reaction 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 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] + .

[0706] The following compounds were synthesized by the same method

[0707]

[0708] Test Example 1: Determination of the inhibitory activity of the compound on OX1 & PFSK-1 (OX2) receptors

[0709] 1. Cell information

[0710] SEQ ID NO Cell No. Final Cells / 25 μl / well 1 OX1-CHO 12000.00 2 PFSK-1 (OX2) 12000.00

[0711] 1.1 This study uses stably transfected 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.

[0712] 1.2. OX1-CHO cell lines are cultured in F12 medium containing 10% fetal bovine serum and 0.2 mg / mL Hygromycin B, and PFSK-1 (OX2) is cultured in 1640 medium containing 10% fetal bovine serum, and the culture temperature is 37°C, and the carbon dioxide concentration is 5%.

[0713] 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 cells are detached from the dish bottom, add about 5 mL of 37°C pre-warmed complete medium. Gently pipette the cell suspension to dissociate the aggregated cells. Transfer the cell suspension to a sterile centrifuge tube and centrifuge at 1000 rpm for 5 min.

[0714] 1.4. To maintain the physiological activity of the cells, the experimental cell confluency is controlled at about 80%.

[0715] 2. Experimental Procedure

[0716] 2.1 Cell Plating: Digest and collect OX1 & PFSK-1 (OX2)-CHO cells, count after resuspension, then seed into 384-well cell plates at a seeding density of 1.2 x 105cells / 25 μL / well. Then place the cell plates in a 37°C, 5% CO2 incubator for about 16-20 h; 4

[0717] 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 to 1x loading buffer with Assay buffer, and place at room temperature for use;

[0718] 2.3 Remove the medium in the cell plates, quickly add 35 μL of 1x loading buffer to each well, and after centrifugation, place the cell plates in a 37°C incubator in the dark for 120 min;

[0719] 2.4 Prepare working solutions of positive compounds and test compounds, and transfer 5 μL to the corresponding cell wells, and place in a 37°C incubator in the dark for 30 min;

[0720] 2.5 Prepare agonist, and transfer 20 μL / well to the 384-well compound source plate;

[0721] 2.6 Place the cell plates, source plate, and gun head in the corresponding positions of the FLIPR instrument, use the FLIPR Tetra to add 10 μL of the diluted compounds in step 5 to each experimental well, and collect data at a wavelength of 515 nm-575 nm.

[0722] 2.7 Plot the signal value against the compound concentration, and use the non-linear regression method of GraphPad Prism software to curve fit IC 50

[0723] 3. Data Analysis​​

[0724] 1) Z' factor = 1 - 3 * (SD Max + SD Min) / (AVG Max - AVG Min);

[0725] 2) CV Max = (SD Max / AVG Max) * 100%;

[0726] 3) CV Min = (SD Min / AVG Min) * 100%;

[0727] 4) S / B = Signal / Background;

[0728] 5) Compound IC50 was calculated using GraphPad nonlinear fit equation 50 :

[0729] Y = Bottom + (Top - Bottom) / (1 + 10^((LogIC 50 -X) * HillSlope))

[0730] 6) % Inhibition equation:

[0731]

[0732] Average of positive control.

[0733] Average of negative control (DMSO). 4. Test results:

[0734] Wherein, the positive compound is Seltorexant, and the structure is as follows:

[0735]

[0736]

[0737] Note 1: The positive control has a slight deviation in each test result, and each time is 1 positive control and multiple test molecules are detected together.

[0738] Note 2: Selectivity ratio = Inhibition activity of molecule on OX1R (nM) / Inhibition activity of molecule on OX2R (nM)

[0739] 5. Experimental conclusion

[0740] The compound of the present application has good inhibition effect on OX2R, and the effect is obviously better than that on OX1R, indicating that the compound of the present application has excellent OX2R selectivity.

[0741] Test Example 2: Pharmacokinetic experiment evaluation

[0742] 1. Purpose of the study

[0743] The pharmacokinetic behavior of the compound of the present application was studied in SD rats orally administered with the compound.

[0744] 2. Formulation prescription

[0745] Injection administration: 1.00 mg of the test drug was weighed into 2.00 mL of 20% hydroxypropyl-β-cyclodextrin (HPCD), and a solution or suspension with a concentration of 0.500 mg / mL was obtained after mixing.

[0746] Oral administration: 5.00 mg of the test drug was weighed into 10.00 mL of 20% hydroxypropyl-β-cyclodextrin (HPCD), and a solution or suspension with a concentration of 0.500 mg / mL was obtained after mixing.

[0747] 3. Drug administration and sample collection

[0748] Five SD rats were selected and randomly divided into two groups, three for oral administration and two for injection administration,

[0749] Plasma samples were collected at 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after administration.

[0750] 4. Data processing

[0751] LCMS / MS was used for quantitative analysis of biological samples, and pharmacokinetic software was used for calculation of pharmacokinetic parameters.

[0752] 5. Test results

[0753]

[0754] 6. Experimental conclusion

[0755] 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.

[0756] Test Example 3: Determination of drug concentration of the test drug in rat brain tissue

[0757] Four SD rats were selected and administered with the test drug by gavage, and two animals were randomly euthanized at 0.5 hours and 2 hours after administration, respectively, to collect plasma and brain tissue samples. LCMS / MS was used for quantitative analysis of biological samples.

[0758]

[0759] Note 1: Brain / plasma ratio = individual brain concentration (ng / g) / individual plasma concentration (ng / mL)

[0760] Experimental Conclusion:

[0761] As can be seen from the above table, compared with the oral administration of the positive control Seltorexant, the rats have higher drug concentration and brain-blood ratio in the brain tissue after oral administration of the compound of the present application, indicating that the compound of the present application has more excellent blood-brain barrier permeability.

[0762] All documents mentioned in the present application are incorporated herein by reference as if each document were individually incorporated by reference. In addition, it is to be understood that the application can be carried out by specifically different embodiments and that each disclosed embodiment can be implemented with or without the corresponding benefits claimed.

Claims

1. A compound of Formula (I), stereoisomers, tautomers, crystalline forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs 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; L1 is 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.

2. The compound, stereoisomer, tautomer, crystalline form, pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, of claim 1, wherein, each R1 is independently selected from the group consisting of H, hydroxyl, methyl, hydroxymethyl, -C(O)CF3, -N(CH3)2, or two R1 on the same carbon together form =O.

3. The compound, stereoisomer, tautomer, crystalline form, pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, of claim 1, wherein, said Ar1 is 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.

4. The compound, stereoisomer, tautomer, crystalline form, pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, of claim 1, wherein, said R a selected from the group consisting of H, D, C 1-4 alkyl, C 1-3 alkoxy, halogen, cyano, -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.

5. The compound of claim 1, stereoisomers, tautomers, crystalline forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof, wherein, said Ar2 is substituted or unsubstituted group selected from the group consisting of 5-6 membered heteroaryl, benzo 5-6 membered heteroaryl; Preferably, said Ar2 is 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, benzimidazole, benzopyridine, benzopyrimidine, benzopyrazine.

6. The compound of claim 1, stereoisomer, tautomer, crystalline form, pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, 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.

7. The compound of claim 1, stereoisomer, tautomer, crystalline form, pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, wherein, said compound has a structure of Formula (II): wherein n, d, e, d', e', R1, L1, Ar1 and Ar2 are defined in claim 1.

8. The compound of claim 1, stereoisomer, tautomer, crystalline form, pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, wherein, said compound is selected from the group consisting of:

9. A pharmaceutical composition, characterized by, said composition comprises: (i) a compound of any one of claims 1-8, stereoisomers, tautomers, crystalline forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof; and (ii) a pharmaceutically acceptable carrier, adjuvant or excipient.

10. Use of a compound according to any one of claims 1 to 8, a stereoisomer, a tautomer, a crystalline form, a pharmaceutically acceptable salt, a hydrate, a solvate or a prodrug thereof, or a pharmaceutical composition according to 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 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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