NMDA receptor antagonist and use thereof

Abstract

The present invention relates to a NMDA receptor antagonist and a use thereof. The NMDA receptor antagonist of the present invention is a compound of formulas II and III below, or a pharmaceutically acceptable salt, an enantiomer, a diastereomer, a tautomer, a solvate, an isotopic substituent, a polymorphic substance, a prodrug or a metabolite thereof. The present invention also provides a pharmaceutical composition comprising these compounds, and a use of these compounds in treating or preventing NMDA receptor-mediated diseases.

Description

NMDA receptor antagonists and uses thereof Technical Field

[0001] The present invention relates to NMDA receptor antagonists and uses thereof. Background Art

[0002] Glutamate is a neurotransmitter that regulates excitatory synaptic transmission in the mammalian brain. The glutamate system plays an important role in synaptic plasticity, learning, memory, etc. N-methyl-D-aspartate (NMDA) receptor is the most important type of ionotropic glutamate receptor and is also a ligand-gated ion channel. NMDA receptor (NMDAR) is a tetramer composed of multiple subunits. Most natural NMDARs discovered so far are composed of two GluN1 and two GluN2 (or GluN3). The characteristics of NMDAR depend on the subtype of GluN2 or GluN3. NMDARs with different GluN2 subtypes have different ion permeability, Mg 2+ There are great differences in blocking sensitivity, antagonist sensitivity, agonist affinity and channel kinetic properties.

[0003] As a transmembrane ion channel protein, the NMDA receptor has a complex molecular structure. Its various subunits are specific in brain region distribution and pharmacological characteristics. They exhibit dynamic changes during different developmental periods, participating in numerous physiological activities and providing a molecular basis for complex neural activity, thereby ensuring the normal functioning of neural networks. The integration, localization, recycling, and distribution of NMDARs within and outside synapses are dependent on the regulation of neural activity and are considered key factors in synaptic plasticity. Disruptions in their functional homeostasis are highly correlated with numerous brain diseases, such as depression, schizophrenia, and epilepsy. NMDA receptor targets can be used to treat these diseases.

[0004] In addition, because NMDA plays a key role in synaptic plasticity and excitotoxic neurotoxicity, its dysfunction is also highly correlated with a variety of neurodegenerative diseases that lead to cognitive impairment, such as Alzheimer's disease, Parkinson's disease, and Huntington's disease. NMDA receptor antibodies produced by human autoimmunity can interfere with the normal function of NMDA receptors, leading to schizophrenia symptoms and anti-NMDA receptor encephalitis. NMDAR has potential targets for the development of such diseases. Therefore, NMDA receptor targets are expected to be used in new rapid antidepressants for schizophrenia, anti-epileptic, Alzheimer's disease, Parkinson's disease, Huntington's disease, and anti-NMDA receptor encephalitis. In addition, they can also be used for anesthesia, sedation, analgesia, and itching (for human or animal use). Summary of the Invention

[0005] The purpose of the present invention is to provide an NMDA receptor antagonist and its use.

[0006] The compounds of the present invention are NMDA receptor antagonists. Therefore, the compounds of the present invention, their pharmaceutically acceptable salts, enantiomers, diastereomers, tautomers, solvates, isotope substitutions, polymorphs, prodrugs or metabolites can be used to modulate the activity of NMDA receptors, thereby being useful for treating and / or preventing NMDA receptor-mediated diseases. The compounds of the present invention have NMDAR-mediated current inhibition activity. Good in vivo pharmacodynamics, such as antidepressant, analgesic and antipruritic efficacy. And have excellent in vivo safety (e.g., no significant toxic effect dose (NOAEL) is higher), do not have hallucinogenic side effects, and will not induce psychotomimetic behavior. At the same time, the invention compounds also have excellent pharmacokinetic properties (e.g., good in vivo metabolic stability, excellent oral absorption drug exposure and good oral absorption bioavailability).

[0007] In a first aspect of the present invention, there is provided a compound of the following formula II, or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, isotope-substituted product, polymorph, prodrug or metabolite thereof:

[0008] Where,

[0009] X is -O- or -CH2-;

[0010] E is -O- or -CH2-;

[0011] A is -NR a - or -CH2-;

[0012] B is -NR a - or -CH2-;

[0013] R a Selected from H and C 1-6 alkyl;

[0014] D is -O- or -CH2-;

[0015] Y is selected from substituted or unsubstituted 6-14 membered aryl, substituted or unsubstituted 5-14 membered heteroaryl and substituted or unsubstituted C 1-6 Alkyl, Y is optionally substituted by 1, 2, 3, 4 or 5 R1, each R1 is independently selected from deuterium, cyano, C 1-3 alkyl, halogen, 5-14 membered heteroaryl optionally substituted by 1, 2, 3, 4 or 5 halogens, and 6-14 membered aryl optionally substituted by 1, 2, 3, 4 or 5 halogens, the 5-14 membered heteroaryl including 1, 2, 3 or 4 heteroatoms selected from N, O and S;

[0016] Z is selected from H, hydroxyl, C 1-6 Alkyl and C 1-6alkoxy;

[0017] R2 is selected from deuterium, C 1-3 Alkyl or halogen;

[0018] R3 is selected from deuterium, C 1-3 Alkyl or halogen;

[0019] m is 0, 1, 2, or 3;

[0020] o is 0, 1, 2, or 3;

[0021] The chiral carbon atom at position 1 is in S configuration or R configuration;

[0022] The chiral carbon atom at position 2 is in S configuration or R configuration;

[0023] Provided that the compound of formula II is not the following compounds and their salts: (4aR,8aS)-4α-(2-thienyl)octahydro-2H-benzo[b][1,4]oxazine, (4aR,8aR)-4α-(2-chloro-3-thienyl)octahydro-2H-benzo[b][1,4]oxazine, (4aS,8aR)-4α-(2-thienyl)octahydro-2H-benzo[b][1,4]oxazine, (4aR,8aS)-4α-(3-methyl-2-thienyl)octahydro-2H-benzo[b][1,4]oxazine, (4aR,8aR)-4α-(4-methyl-3-thienyl)octahydro-2H-benzo[b][1,4]oxazine, (4aR,8aR)-4 α-(3-chlorophenyl)octahydro-2H-benzo[b][1,4]oxazine, (4aS,8aS)-4α-(3-chlorophenyl)octahydro-2H-benzo[b][1,4]oxazine, (4aR,8aR)-4α-(2-chlorophenyl)octahydro-2H-benzo[b][1,4]oxazine, (4aS,8aS)-4α-(2-chlorophenyl)octahydro-2H-benzo[b][1,4]oxazine, 4a-phenyloctahydro-2H-benzo[b][1,4]oxazine, 4a-(2-methoxyphenyl)octahydro-2H-benzo[b][1,4]oxazine, 4a-(3-fluorophenyl)octahydro-2H-benzo[b][1,4]oxazine, 4a-(4-fluorophenyl)octahydro-2 H-benzo[b][1,4]oxazine, 4a-(2,3-difluorophenyl)octahydro-2H-benzo[b][1,4]oxazine, 4a-(2-fluorophenyl)octahydro-2H-benzo[b][1,4]oxazine, 6-methyl-4a-phenyloctahydro-2H-benzo[b][1,4]oxazine, 6-ethyl-4a-phenyloctahydro-2H-benzo[b][1,4]oxazine, 4a-(3-chlorophenyl)octahydro-2H-benzo[b][1,4]oxazine, 4a-(3-methylphenyl)octahydro-2H-benzo[b][1,4]oxazine, 4a-(2-chlorophenyl)octahydro-2H-benzo[b][1,4]oxazine, 4a-(4-chlorophenyl)octahydro-2H-benzo[b][1,4]oxazine [1,4]oxazine, 4a-(4-methylphenyl)octahydro-2H-benzo[b][1,4]oxazine, 4a-(3-(trifluoromethyl)phenyl)octahydro-2H-benzo[b][1,4]oxazine, 8-methyl-4a-phenyloctahydro-2H-benzo[b][1,4]oxazine, 5-methyl-4a-phenyloctahydro-2H-benzo[b][1,4]oxazine, 7-methyl-4a-phenyloctahydro-2H-benzo[b][1,4]oxazine, 4-methyl-4a-phenyloctahydro-2H-benzo[b][1,4]oxazine, 3,3-dimethyl-5a-phenyldecahydrobenzo[b][1,4]olanzapine, 4a-(3-methoxyphenyl)octahydro-2H-benzo[b][1,4]oxazine, 4a-(3-(trifluoromethoxy)phenyl)octahydro-2H-benzo[b][1,4]oxazine, 4a-(4-(trifluoromethyl)phenyl)octahydro-2H-benzo[b][1,4]oxazine, 4a-(2,6-dimethylphenyl)octahydro-2H-benzo[b][1,4]oxazine, 4a-(4-(tert-butyl)phenyl)octahydro-2H-benzo[b][1,4]oxazine, 4a-(2,3-dichlorophenyl)octahydro-2H-benzo[b][1,4]oxazine, 4a-(2-isopropylphenyl)octahydro-2H-benzo[b][1,4]oxazine, 4a-(2,5-dimethylphenyl)octahydro-2H-benzo[b][1,4 ]oxazine, 4a-(2-chloro-3-fluorophenyl)octahydro-2H-benzo[b][1,4]oxazine, 4a-(3,4-difluorophenyl)octahydro-2H-benzo[b][1,4]oxazine, 6,6-dimethyl-4a-phenyloctahydro-2H-benzo[b][1,4]oxazine, 4a-(2-chloro-5-fluorophenyl)octahydro-2H-benzo[b][1,4]oxazine, 4α-(3-ethoxyphenyl)octahydro-2H-benzo[b][1,4]oxazine, 4α-(2-chloro-4-methoxyphenyl)octahydro-2H-benzo[b][1,4]oxazine, 4a-(2-chloro-6-fluorophenyl)octahydro-2H-benzo[b][1,4]oxazine.

[0024] In a second aspect of the present invention, a salt crystal form of Compound 2 is provided, selected from the following salt crystal forms A, B, C, D, E, F, L and M,

[0025] The X-ray powder diffraction pattern of hydrochloride form A has characteristic peaks at the following 2θ angles: 14.44°±0.20°, 17.16°±0.20°, 20.59°±0.20° and 23.38°±0.20°;

[0026] The X-ray powder diffraction pattern of the phosphate crystal form B has characteristic peaks at the following 2θ angles: 5.48°±0.20°, 18.48°±0.20°, 22.49°±0.20° and 22.92°±0.20°;

[0027] The X-ray powder diffraction pattern of the mesylate salt form C has characteristic peaks at the following 2θ angles: 8.05°±0.20°, 14.37±0.20°, 16.18°±0.20°, 18.49°±0.20°, 22.65±0.20°;

[0028] The X-ray powder diffraction pattern of the mesylate salt form D has characteristic peaks at the following 2θ angles: 12.13°±0.20°, 14.80°±0.20°, 20.54°±0.20°, 23.37°±0.20° and 26.09°±0.20°;

[0029] The X-ray powder diffraction pattern of the mesylate salt form E has characteristic peaks at the following 2θ angles: 14.81°±0.20°, 16.30°±0.20°, 18.60°±0.20° and 22.75°±0.20°;

[0030] The X-ray powder diffraction pattern of the formate salt form F has characteristic peaks at the following 2θ angles: 11.35°±0.20°, 13.53°±0.20° and 23.76°±0.20°;

[0031] The X-ray powder diffraction pattern of the oxalate salt form L has characteristic peaks at the following 2θ angles: 9.44°±0.20°, 11.11°±0.20°, 15.61°±0.20°, 19.42°±0.20° and 26.30°±0.20°;

[0032] The X-ray powder diffraction pattern of the pamoate salt form M has characteristic peaks at the following 2θ angles: 5.44°±0.20°, 6.49°±0.20°, 10.75°±0.20° and 21.01°±0.20°.

[0033] The third aspect of the present invention provides a salt crystal form of compound 3, selected from the following salt crystal forms G, H, I, J, K, N and O,

[0034] The X-ray powder diffraction pattern of hydrochloride form G has characteristic peaks at the following 2θ angles: 6.18°±0.20°, 11.42°±0.20°, 12.45°±0.20°, 20.02°±0.20° and 23.41°±0.20°;

[0035] The X-ray powder diffraction pattern of the hydrochloride salt form H has characteristic peaks at the following 2θ angles: 6.64°±0.20°, 13.12°±0.20°, 13.31°±0.20°, 21.83°±0.20° and 23.06°±0.20°;

[0036] The X-ray powder diffraction pattern of the phosphate crystal form I has characteristic peaks at the following 2θ angles: 5.94°±0.20°, 12.29°±0.20°, 13.34°±0.20° and 17.99°±0.20°;

[0037] The X-ray powder diffraction pattern of the mesylate salt form J has characteristic peaks at the following 2θ angles: 14.75°±0.20°, 15.81°±0.20° and 21.89°±0.20°;

[0038] The X-ray powder diffraction pattern of the formate salt form K has characteristic peaks at the following 2θ angles: 11.92°±0.20°, 15.15°±0.20° and 24.04°±0.20°;

[0039] The X-ray powder diffraction pattern of the oxalate salt form N has characteristic peaks at the following 2θ angles: 6.20°±0.20°, 7.49°±0.20°, 12.25°±0.20°, 12.47°±0.20°, 16.36°±0.20° and 23.43°±0.20°;

[0040] The X-ray powder diffraction pattern of the pamoate salt form O has characteristic peaks at the following 2θ angles: 6.18°±0.20°, 9.41°±0.20°, 11.10°±0.20°, 15.59°±0.20° and 26.25°±0.20°.

[0041] A fourth aspect of the present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and:

[0042] (i) the compound of the first aspect of the present invention, its pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, isotope-substituted product, polymorph, prodrug or metabolite, and a pharmaceutically acceptable carrier; or

[0043] (ii) a crystalline salt of Compound 2 according to the second aspect of the present invention; or

[0044] (iii) The salt crystal form of Compound 3 according to the third aspect of the present invention.

[0045] The fifth aspect of the present invention provides the use of the compound described in the first aspect of the present invention, its pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, isotope substitution, polymorph, prodrug or metabolite, the salt crystal form of compound 2 described in the second aspect of the present invention, the salt crystal form of compound 3 described in the third aspect of the present invention, or the pharmaceutical composition described in the fourth aspect of the present invention in the preparation of a medicament for treating or preventing NMDA receptor-mediated diseases, or in the preparation of an anesthetic or analgesic.

[0046] In one or more embodiments, the NMDA receptor-mediated disease is selected from the group consisting of cerebral ischemia, traumatic brain injury, infarction, stroke, Alzheimer's disease, Parkinson's disease, Huntington's disease, depression, anxiety, bipolar disorder, schizophrenia, autism, epilepsy, anti-NMDA receptor encephalitis, neuropathic pain, anorexia, sleep disorders, itch-related diseases, and other nervous system events or neurodegeneration caused by NMDA receptor activation.

[0047] In one or more embodiments, the NMDA receptor-mediated disease is depression, schizophrenia, or epilepsy.

[0048] In one or more embodiments, the sleep disorder-related disease is insomnia, sleep apnea syndrome, atypical sleep cycle rhythm disorder or Down syndrome.

[0049] In one or more embodiments, the NMDA receptor-mediated disorder is pain or pruritus. BRIEF DESCRIPTION OF THE DRAWINGS

[0050] FIG1 is an XRPD pattern of Compound 2 hydrochloride Form A.

[0051] Figure 2 is a superimposed DSC and TGA graph of Compound 2 Hydrochloride Form A.

[0052] FIG3 is an XRPD pattern of Compound 2 Phosphate B Crystalline Form.

[0053] FIG4 is a DSC and TGA overlay of Compound 2 Phosphate Form B.

[0054] FIG5 is an XRPD pattern of Compound 2 mesylate salt Form C.

[0055] FIG6 is a superimposed diagram of DSC and TGA of Compound 2 mesylate Form C.

[0056] FIG7 is an XRPD pattern of Compound 2 mesylate salt Form D.

[0057] FIG8 is a DSC spectrum of Compound 2 mesylate salt Form D.

[0058] FIG9 is a TGA spectrum of Compound 2 mesylate salt Form D.

[0059] Figure 10 is the XRPD pattern of Compound 2 mesylate E crystal form

[0060] FIG11 is a DSC spectrum of Compound 2 mesylate salt Form E.

[0061] Figure 12 is the TGA spectrum of Compound 2 mesylate salt Form E.

[0062] FIG13 is an XRPD pattern of Compound 2 formate salt Form F.

[0063] FIG14 is an overlay of DSC and TGA images of Compound 2 formate salt Form F.

[0064] FIG15 is an XRPD pattern of Compound 2 oxalate L crystal form.

[0065] FIG16 is an XRPD pattern of Compound 2 Pamoate M Crystalline Form.

[0066] FIG17 is an XRPD pattern of Compound 3 hydrochloride Form G.

[0067] FIG18 is a superimposed diagram of DSC and TGA of Compound 3 hydrochloride Form G.

[0068] FIG19 is an XRPD pattern of Compound 3 hydrochloride Form H.

[0069] FIG20 is a superimposed diagram of DSC and TGA of Compound 3 hydrochloride Form H.

[0070] Figure 21 is the XRPD pattern of Compound 3 Phosphate Form I.

[0071] Figure 22 is a superimposed DSC and TGA graph of Compound 3 Phosphate Form I.

[0072] FIG23 is an XRPD pattern of Compound 3 mesylate salt Form J.

[0073] FIG24 is a superimposed DSC and TGA graph of Compound 3 mesylate Form J.

[0074] Figure 25 is the XRPD pattern of Compound 3 formate salt Form K.

[0075] Figure 26 is a superimposed DSC and TGA graph of Compound 3 formate Form K.

[0076] Figure 27 is the XRPD pattern of Compound 3 oxalate salt Form N.

[0077] Figure 28 is the XRPD pattern of Compound 3 Pamoate Form O.

[0078] FIG29 shows the antidepressant results of the forced swimming test of Compound 1 and Compound 2 hydrochloride A crystal form.

[0079] FIG30 shows the antidepressant results of the forced swimming test of Compound 2 mesylate salt Form C.

[0080] FIG31 shows the antidepressant results of the forced swimming test of Compound 3 hydrochloride Form G and a comparative compound.

[0081] FIG32 shows the antidepressant results of compound 34 hydrochloride in the forced swimming test.

[0082] FIG33 is the open field test result of Compound 2 hydrochloride Form A.

[0083] FIG34 is the open field test result of Compound 2 mesylate salt Form C.

[0084] FIG35 is the open field test result of Compound 3 hydrochloride G crystal form.

[0085] FIG36 shows the open field test results of compound 34 hydrochloride.

[0086] FIG37 shows the results of the prepulse inhibition experiment of Compound 2 mesylate salt Form C. DETAILED DESCRIPTION

[0087] To facilitate understanding of the features and effects of the present invention by those skilled in the art, the following provides a general description and definition of the terms and expressions used in the specification and claims. Unless otherwise indicated, all technical and scientific terms used herein have the ordinary meanings as understood by those skilled in the art regarding the present invention. In the event of conflict, the definitions in this specification shall prevail.

[0088] The theories or mechanisms described and disclosed herein, whether correct or incorrect, should not limit the scope of the present invention in any way, that is, the present invention can be implemented without being limited by any specific theory or mechanism.

[0089] Herein, “comprising,” “including,” “containing” and similar terms encompass the meanings of “consisting essentially of” and “consisting of,” for example, when “A comprises B and C” is disclosed herein, “A consists essentially of B and C” and “A consists of B and C” should be deemed to have been disclosed herein.

[0090] Throughout this document, all features, such as values, amounts, amounts, and concentrations, specified in numerical ranges or percentage ranges are provided for simplicity and convenience only. Accordingly, the description of numerical ranges or percentage ranges should be considered to encompass and specifically disclose all possible subranges and individual values ​​within those ranges (including integers and fractions).

[0091] In this document, unless otherwise specified, percentage refers to mass percentage and ratio refers to mass ratio.

[0092] Herein, when describing embodiments or examples, it should be understood that they are not intended to limit the present invention to these embodiments or examples. On the contrary, all alternatives, modifications and equivalents of the methods and materials described herein are encompassed within the scope defined by the claims.

[0093] In this document, for the sake of brevity, not all possible combinations of the various technical features in each embodiment or example are described. Therefore, as long as there are no contradictions in the combination of these technical features, the various technical features in each embodiment or example can be combined in any way, and all possible combinations should be considered to be within the scope of this specification.

[0094] I. Terminology

[0095] As used herein, "alkyl" refers to a straight or branched monovalent saturated hydrocarbon radical with a specified number of carbon atoms. In some embodiments, alkyl is one having 1 to 6 carbon atoms ("C1-C6 alkyl"), including alkyl groups containing 6 carbon atoms (C6 alkyl), 5 carbon atoms (C5 alkyl), 4 carbon atoms (C4 alkyl), 3 carbon atoms (C3 alkyl), 2 carbon atoms (C2 alkyl), 1 carbon atom (C1 alkyl), or an alkyl group within the range of any of the above-mentioned carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, etc. Unless otherwise specified, alkyl groups may be optionally substituted with a suitable substituent.

[0096] As used herein, "alkoxy" refers to an alkyl-O- group, wherein alkyl is as defined above.

[0097] As used herein, "aryl" or "Ar" refers to an aromatic carbocyclic group having a single ring (e.g., phenyl) or multiple (e.g., fused) rings (e.g., naphthyl or anthracenyl), wherein each of the multiple rings may or may not be aromatic, and at least one of the multiple rings is aromatic. For aryl groups having multiple rings, they may be attached to the parent structure on the aromatic ring or on the non-aromatic ring. In some embodiments, aryl groups having multiple rings are attached to the parent structure on the aromatic ring. In some embodiments, aryl groups are 6-14 membered aryl groups (i.e., aryl groups containing 6 to 14 ring carbon atoms), preferably 6-10 membered aryl groups. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, phenanthrenyl, anthracenyl, indenyl, azulenyl, biphenyl, biphenylene, and fluorenyl. Unless otherwise specified, aryl groups may optionally be substituted with suitable substituents.

[0098] As used herein, "heteroaryl" refers to a group containing 5-14, preferably 5-10 ring atoms, and having at least one aromatic ring. The ring atoms contained in the heteroaryl group are carbon atoms and 1-3 heteroatoms selected from O, N and S (including oxidized forms of heteroatoms). In the present invention, preferred heteroaryl groups are heteroaryl groups containing N or S atoms, more preferably 5-membered heteroaryl groups containing S atoms. Examples of heteroaryl groups include, but are not limited to, triazolyl, thienyl, furyl, pyranyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, isoindolyl, indolyl, benzimidazolyl and pyrazolopyrimidinyl. Unless otherwise specified, the heteroaryl group may be optionally substituted by a suitable substituent.

[0099] As used herein, "oxo" refers to =0.

[0100] As used herein, "halogen" includes F, Cl, Br, and I.

[0101] As used herein, "hydroxy" refers to -OH.

[0102] As used herein, the terms "moiety," "moiety," "chemical moiety," "group," and "chemical group" refer to specific segments or functional groups in a molecule. A chemical moiety is generally considered to be a chemical entity embedded in or attached to a molecule.

[0103] English letters are used herein to designate specific crystal forms. English letters preceding and following the term "crystal form" denote the same crystal form and are used interchangeably. For example, "Crystal Form A" and "Crystal Form A" denote the same crystal form designated A. Those skilled in the art will also appreciate that in the methods described below, the functional groups of the intermediate compounds may need to be protected by appropriate protecting groups. Such functional groups include hydroxyl, amino, thiol, and carboxylic acid. Suitable hydroxyl-protecting groups include trialkylsilyl or diarylalkylsilyl (e.g., tert-butyldimethylsilyl, tert-butyldiphenylsilyl, or trimethylsilyl), tetrahydropyranyl, and benzyl. Suitable amino, amidino, and guanidino-protecting groups include tert-butyloxycarbonyl and benzyloxycarbonyl. Suitable thiol-protecting groups include -C(O)-R" (wherein R" is an alkyl, aryl, or aralkyl group), p-methoxybenzyl, and trityl. Suitable carboxyl-protecting groups include alkyl esters, aryl esters, and aralkyl esters.

[0104] Protecting groups can be introduced and removed according to standard techniques known to those skilled in the art and as described herein. The use of protecting groups is described in detail in Greene, TW and PGM Wuts, Protective Groups in Organi Synthesis, (1999), 4th Ed., Wiley. Protecting groups can also be polymeric resins.

[0105] As used herein, " subject " can be people, non-human primates, mammals, rats, mice, cattle, horses, pigs, sheep, goats, dogs, cats etc.Subject may be suspected of having or suffering from neurodegenerative disorders, such as NMDA receptor-mediated diseases, including cerebral ischemia, traumatic brain injury, infarction, stroke, Alzheimer's disease, Parkinson's disease, Huntington's chorea, depression, anxiety, manic-depressive disorder, schizophrenia, autism, epilepsy, anti-NMDA receptor encephalitis, neuropathic pain, psychosis, anorexia, sleep disorders (such as insomnia, sleep apnea syndrome, atypical sleep cycle rhythm disorder or Down syndrome) or pruritus related diseases.Subject may also be suspected of having or suffering from other nervous system events or neurodegeneration caused by NMDA receptor activation.

[0106] “Mammals” include: humans; domesticated animals, such as laboratory animals, household pets (e.g., cats, dogs, pigs, cows, sheep, goats, horses, rabbits) and zoo animals (e.g., tigers, monkeys, bears, etc.); and non-domesticated animals, such as wild animals, etc.

[0107] "Pharmaceutically acceptable carriers, diluents or excipients" include, but are not limited to, any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent or emulsifier that has been approved by, for example, the U.S. Food and Drug Administration (FDA) as acceptable for use in humans or farmed animals.

[0108] In the present application, the term "pharmaceutically acceptable salt" includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0109] "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, naphthalene disulfonate, and pamoate. These salts can be prepared by methods known in the art.

[0110] "Pharmaceutically acceptable base addition salts" refer to salts formed with inorganic or organic bases that retain the biological effectiveness of the free acid without other side effects. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts. Preferred inorganic salts are ammonium, sodium, potassium, calcium, and magnesium salts. The salt derived from organic base includes but is not limited to following salt: primary amines, secondary amines and tertiary amines, substituted amines, including natural substituted amines, cyclic amines and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, triethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resins etc. Preferred organic bases include isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine. These salts can be prepared by methods known in the art.

[0111] Examples of prodrugs of the compounds of the present invention may include simple esters of compounds containing carboxylic acids (e.g., esters obtained by condensation with C1-4 alcohols according to methods known in the art); esters of compounds containing hydroxy groups (e.g., esters obtained by condensation with C1-4 carboxylic acids, C3-6 diacids, or anhydrides thereof, such as succinic anhydride and fumaric anhydride, according to methods known in the art); imines of compounds containing amino groups (e.g., imines obtained by condensation with C1-4 aldehydes or ketones according to methods known in the art); carbamates of compounds containing amino groups, such as those described by Leu et al. (J. Med. Chem., 42:3623-3628 (1999)) and Greenwald et al. (J. Med. Chem., 42:3657-3667 (1999)); acetals or ketals of compounds containing alcohols (e.g., those obtained by condensation with chloromethyl methyl ether or chloromethyl ethyl ether according to methods known in the art).

[0112] As used herein, the term "solvate" refers to an aggregate comprising one or more molecules of a compound of the invention and one or more solvent molecules. The solvent may be water, in which case the solvate may be a hydrate. Alternatively, the solvent may be an organic solvent. Thus, the compounds of the invention may exist as hydrates, including monohydrates, dihydrates, hemihydrates, sesquihydrates, trihydrates, tetrahydrates, and the like, as well as the corresponding solvated forms. The compounds of the invention may be true solvates, while in other cases, the compounds of the invention may merely retain adventitious water or a mixture of water and some adventitious solvent.

[0113] "Pharmaceutical composition" refers to a preparation of a compound of the present invention and a medium generally recognized in the art for delivering biologically active compounds to mammals (eg, humans), including any pharmaceutically acceptable carriers, diluents, or excipients thereof.

[0114] "Effective amount" refers to a therapeutically effective amount or a prophylactic effective amount. "Therapeutically effective amount" refers to an amount that effectively achieves the desired therapeutic outcome (e.g., reduces pain, relieves itching) at the required dose and for the required period of time. The therapeutically effective amount of a compound may vary according to factors such as the subject's disease state, age, sex, and weight, and the ability of the compound to elicit the desired response in the subject. The dosing regimen may be adjusted to provide the optimal therapeutic response. "Prophylactic effective amount" refers to an amount that effectively achieves the desired prophylactic outcome at the required dose and for the required period of time. Typically, a prophylactic dose is used in a subject before or in the early stages of the disease so that the prophylactic effective amount may be less than the therapeutically effective amount.

[0115] As used herein, "treatment" encompasses the treatment of a disease or condition of interest in a mammal, preferably a human, suffering from the disease or condition of interest, and includes:

[0116] (i) preventing the occurrence of the disease or condition in a mammal, particularly where the mammal is susceptible to the condition but has not yet been diagnosed with the condition;

[0117] (ii) inhibiting the disease or condition, i.e., arresting its development;

[0118] (iii) alleviate the disease or condition, i.e., cause regression of the disease or condition; or

[0119] (iv) Alleviation of symptoms caused by the disease or condition, i.e., relief of pain without resolving the underlying disease or condition.

[0120] As used herein, the terms "administer," "administer," "dosing," and the like refer to methods capable of delivering a compound or composition to the desired site for biological action. Methods of administration known in the art can be used in the present invention. These methods include, but are not limited to, oral routes, intraduodenal routes, parenteral injection (including intrapulmonary, intranasal, intrathecal, intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion), topical administration, and rectal administration. Those skilled in the art are familiar with administration techniques that can be used for the compounds and methods described herein, such as those discussed in Goodman and Gilman, The Pharmacological Basis of Therapeutics, current ed.; Pergamon; and Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, Pa. In a preferred embodiment, the compounds of the present invention, their pharmaceutically acceptable salts, enantiomers, diastereomers, tautomers, solvates, isotopically substituted products, polymorphs, prodrugs or metabolites, or pharmaceutical compositions thereof, are administered orally.

[0121] As used herein, "stereoisomers" refer to compounds composed of the same atoms, bonded by the same bonding methods, but having different three-dimensional structures. The present invention is intended to encompass various stereoisomers and mixtures thereof, such as geometric isomers, enantiomers, diastereomers, and racemic mixtures.

[0122] When the compounds of the present invention contain double bonds, and unless specified otherwise, it is intended that the compounds of the present invention include both E- and Z- geometric isomers.

[0123] "Tautomers" refer to isomers formed when a proton is shifted from one atom of a molecule to another atom of the same molecule. All tautomeric forms of the compounds of the present invention are intended to be encompassed within the scope of the present invention.

[0124] The compounds of the present invention, or pharmaceutically acceptable salts thereof, may contain one or more chiral carbon atoms and may therefore give rise to enantiomers, diastereomers, and other stereoisomeric forms. Each chiral carbon atom may be defined as (R)- or (S)- based on stereochemistry. The present invention is intended to include all possible isomers, as well as racemates and optically pure forms thereof. The compounds of the present invention may be prepared using racemates, diastereomers, or enantiomers as starting materials or intermediates. Optically active isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, such as crystallization and chiral chromatography.

[0125] It should be understood by those skilled in the art that the solid line wedge key or dotted wedge key Used to indicate the absolute configuration of a chiral center, the thick solid bond or bold dashed key Indicates the relative configuration of the chiral center.

[0126] Conventional techniques for preparing / isolating individual isomers include chiral synthesis from appropriate optically pure precursors, or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high performance liquid chromatography, see, for example, Gerard Gübitz and Martin G. Schmid (Eds.), Chiral SepaRations, Methods and Protocols, Methods in Molecular Biology, Vol. 243, 2004; A.M. Stalcup, Chiral SepaRations, Annu. Rev. Anal. Chem. 3: 341-63, 2010; Fumiss et al. (eds.), VOGEL'S ENCYCLOPEDIA OF PRaCTICAL ORGANIC CHEMISTRY. sup. TH ED., Longman Scientific and Technical Ltd., Essex, 1991, 809-816; Heller, Acc. Chem. Res. 1990, 23, 128.

[0127] The present invention also includes all suitable isotopic variants of the compounds of the present invention or their pharmaceutically acceptable salts. Isotopic variants of the compounds of the present invention or their pharmaceutically acceptable salts are defined as those in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from the atomic mass normally found in nature. Isotopes that can be incorporated into the compounds of the present invention and their pharmaceutically acceptable salts include, but are not limited to, isotopes of H, C, N and O, for example 2 H. 3 H. 11 C. 13 C. 14 C. 15 N. 17 O. 18 O. 35 S. 18 F. 36 Cl and 125 I. Isotopic variations of the compounds of the present invention or pharmaceutically acceptable salts thereof can be prepared by conventional techniques using appropriate isotopic variations of suitable reagents.

[0128] II.Compounds

[0129] The present invention provides a compound of the following formula II, or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, isotope-substituted product, polymorph, prodrug or metabolite thereof:

[0130] Where,

[0131] X is -O- or -CH2-;

[0132] E is -O- or -CH2-;

[0133] A is -NR a - or -CH2-;

[0134] B is -NR a - or -CH2-;

[0135] R a Selected from H and C 1-6 alkyl;

[0136] D is -O- or -CH2-;

[0137] Y is selected from substituted or unsubstituted 6-14 membered aryl, substituted or unsubstituted 5-14 membered heteroaryl and substituted or unsubstituted C 1-6 Alkyl, Y is optionally substituted by 1, 2, 3, 4 or 5 R1, each R1 is independently selected from deuterium, cyano, C 1-3 alkyl, halogen, 5-14 membered heteroaryl optionally substituted by 1, 2, 3, 4 or 5 halogens, and 6-14 membered aryl optionally substituted by 1, 2, 3, 4 or 5 halogens, the 5-14 membered heteroaryl including 1, 2, 3 or 4 heteroatoms selected from N, O and S;

[0138] Z is selected from H, hydroxyl, C 1-6 Alkyl and C 1-6 alkoxy;

[0139] R2 is selected from deuterium, C 1-3 Alkyl or halogen;

[0140] R3 is selected from deuterium, C 1-3 Alkyl or halogen;

[0141] m is 0, 1, 2, or 3;

[0142] o is 0, 1, 2, or 3;

[0143] The chiral carbon atom at position 1 is in S configuration or R configuration;

[0144] The chiral carbon atom at position 2 is in S configuration or R configuration;

[0145] Provided that the compound of formula II is not the following compounds and their salts: (4aR,8aS)-4α-(2-thienyl)octahydro-2H-benzo[b][1,4]oxazine, (4aR,8aR)-4α-(2-chloro-3-thienyl)octahydro-2H-benzo[b][1,4]oxazine, (4aS,8aR)-4α-(2-thienyl)octahydro-2H-benzo[b][1,4]oxazine, (4aR,8aS)-4α-(3-methyl-2-thienyl)octahydro-2H-benzo[b][1,4]oxazine, (4aR,8aR)-4α-(4-methyl-3-thienyl)octahydro-2H-benzo[b][1,4]oxazine, (4aR,8aR)-4 α-(3-chlorophenyl)octahydro-2H-benzo[b][1,4]oxazine, (4aS,8aS)-4α-(3-chlorophenyl)octahydro-2H-benzo[b][1,4]oxazine, (4aR,8aR)-4α-(2-chlorophenyl)octahydro-2H-benzo[b][1,4]oxazine, (4aS,8aS)-4α-(2-chlorophenyl)octahydro-2H-benzo[b][1,4]oxazine, 4a-phenyloctahydro-2H-benzo[b][1,4]oxazine, 4a-(2-methoxyphenyl)octahydro-2H-benzo[b][1,4]oxazine, 4a-(3-fluorophenyl)octahydro-2H-benzo[b][1,4]oxazine, 4a-(4-fluorophenyl)octahydro-2 H-benzo[b][1,4]oxazine, 4a-(2,3-difluorophenyl)octahydro-2H-benzo[b][1,4]oxazine, 4a-(2-fluorophenyl)octahydro-2H-benzo[b][1,4]oxazine, 6-methyl-4a-phenyloctahydro-2H-benzo[b][1,4]oxazine, 6-ethyl-4a-phenyloctahydro-2H-benzo[b][1,4]oxazine, 4a-(3-chlorophenyl)octahydro-2H-benzo[b][1,4]oxazine, 4a-(3-methylphenyl)octahydro-2H-benzo[b][1,4]oxazine, 4a-(2-chlorophenyl)octahydro-2H-benzo[b][1,4]oxazine, 4a-(4-chlorophenyl)octahydro-2H-benzo[b][1,4]oxazine [1,4]oxazine, 4a-(4-methylphenyl)octahydro-2H-benzo[b][1,4]oxazine, 4a-(3-(trifluoromethyl)phenyl)octahydro-2H-benzo[b][1,4]oxazine, 8-methyl-4a-phenyloctahydro-2H-benzo[b][1,4]oxazine, 5-methyl-4a-phenyloctahydro-2H-benzo[b][1,4]oxazine, 7-methyl-4a-phenyloctahydro-2H-benzo[b][1,4]oxazine, 4-methyl-4a-phenyloctahydro-2H-benzo[b][1,4]oxazine, 3,3-dimethyl-5a-phenyldecahydrobenzo[b][1,4]olanzapine, 4a-(3-methoxyphenyl)octahydro-2H-benzo[b][1,4]oxazine, 4a-(3-(trifluoromethoxy)phenyl)octahydro-2H-benzo[b][1,4]oxazine, 4a-(4-(trifluoromethyl)phenyl)octahydro-2H-benzo[b][1,4]oxazine, 4a-(2,6-dimethylphenyl)octahydro-2H-benzo[b][1,4]oxazine, 4a-(4-(tert-butyl)phenyl)octahydro-2H-benzo[b][1,4]oxazine, 4a-(2,3-dichlorophenyl)octahydro-2H-benzo[b][1,4]oxazine, 4a-(2-isopropylphenyl)octahydro-2H-benzo[b][1,4]oxazine, 4a-(2,5-dimethylphenyl)octahydro-2H-benzo[b][1,4 ]oxazine, 4a-(2-chloro-3-fluorophenyl)octahydro-2H-benzo[b][1,4]oxazine, 4a-(3,4-difluorophenyl)octahydro-2H-benzo[b][1,4]oxazine, 6,6-dimethyl-4a-phenyloctahydro-2H-benzo[b][1,4]oxazine, 4a-(2-chloro-5-fluorophenyl)octahydro-2H-benzo[b][1,4]oxazine, 4α-(3-ethoxyphenyl)octahydro-2H-benzo[b][1,4]oxazine, 4α-(2-chloro-4-methoxyphenyl)octahydro-2H-benzo[b][1,4]oxazine, 4a-(2-chloro-6-fluorophenyl)octahydro-2H-benzo[b][1,4]oxazine.

[0146] In some embodiments of the compound of Formula II, one of X and E is -O- and the other is -CH2-; or both X and E are -CH2-.

[0147] In some embodiments of the compound of Formula II, one of A and B is -NR a -, and the other is -CH2-.

[0148] In some embodiments of the compound of Formula II, Z is selected from H and hydroxy. In some embodiments, Z is H. In some embodiments, Z is hydroxy.

[0149] In some embodiments of the compound of Formula II, Y is selected from substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted 5-7 membered heteroaryl, and substituted or unsubstituted C 1-3 Preferably, Y is selected from substituted or unsubstituted phenyl, substituted or unsubstituted 5-6 membered heteroaryl and substituted or unsubstituted methyl; Preferably, Y is selected from substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted 5-7 membered heteroaryl and substituted or unsubstituted C 1-3 Alkyl, the 6-10 membered aryl and 5-7 membered heteroaryl are each independently substituted by 1, 2, 3 or 4 groups selected from deuterium, cyano, C 1-3 Alkyl and halogen groups are substituted, the C 1-3The alkyl group is optionally substituted with 1 or 2 groups selected from the group consisting of 5-7 membered heteroaryl groups optionally substituted with 1, 2, 3 or 4 halogens and 6-10 membered aryl groups optionally substituted with 1, 2, 3 or 4 halogens. In some embodiments, Y is phenyl or thienyl groups optionally substituted with 1, 2, 3, 4 or 5 R1.

[0150] In some embodiments of the compound of Formula II, each R1 is independently selected from deuterium, cyano, C 1-3 alkyl, halogen, 5-7 membered heteroaryl optionally substituted by 1, 2, 3 or 4 halogens and 6-10 membered aryl optionally substituted by 1, 2, 3 or 4 halogens; preferably, each R1 is independently selected from deuterium, cyano, C 1-3 Alkyl, halogen and 6-10 membered aryl optionally substituted with 1, 2, 3 or 4 halogens; preferably, the halogen is selected from F and Cl.

[0151] In some embodiments of the compound of Formula II, D is -CH2-; or D is -O-, provided that X and E are both -CH2-.

[0152] In some embodiments, the present invention provides a compound of Formula A, or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, isotope-substituted compound, polymorph, prodrug, or metabolite thereof:

[0153] Where,

[0154] Y is a 6-14 membered aryl or 5-7 membered heteroaryl group optionally substituted with 1, 2, 3, 4 or 5 R1 substituents, wherein each

[0155] R1 is independently selected from deuterium, cyano, C 1-3 Alkyl and halogen;

[0156] R2 is selected from deuterium, C 1-3 Alkyl or halogen;

[0157] R3 is selected from deuterium, C 1-3 Alkyl or halogen;

[0158] m is 0, 1, 2, or 3;

[0159] o is 0, 1, 2, or 3;

[0160] X is -O- or -CH2-;

[0161] The chiral carbon atom at position 1 is in S configuration or R configuration;

[0162] The chiral carbon atom at position 2 is in S configuration or R configuration;

[0163] Provided that the compound of formula A is not the following compounds and their salts: (4aR,8aS)-4α-(2-thienyl)octahydro-2H-benzo[b][1,4]oxazine, (4aR,8aR)-4α-(2-chloro-3-thienyl)octahydro-2H-benzo[b][1,4]oxazine, (4aS,8aR)-4α-(2-thienyl)octahydro-2H-benzo[b][1,4]oxazine, (4aR,8aS)-4α-(3-methyl-2-thienyl)octahydro-2H-benzo[b][1,4]oxazine, (4aR,8aR)-4α-(4-methyl-3-thienyl)octahydro-2H-benzo[b][1,4]oxazine, (4aR,8aR)-4 α-(3-chlorophenyl)octahydro-2H-benzo[b][1,4]oxazine, (4aS,8aS)-4α-(3-chlorophenyl)octahydro-2H-benzo[b][1,4]oxazine, (4aR,8aR)-4α-(2-chlorophenyl)octahydro-2H-benzo[b][1,4]oxazine, (4aS,8aS)-4α-(2-chlorophenyl)octahydro-2H-benzo[b][1,4]oxazine, 4a-phenyloctahydro-2H-benzo[b][1,4]oxazine, 4a-(2-methoxyphenyl)octahydro-2H-benzo[b][1,4]oxazine, 4a-(3-fluorophenyl)octahydro-2H-benzo[b][1,4]oxazine, 4a-(4-fluorophenyl)octahydro-2 H-benzo[b][1,4]oxazine, 4a-(2,3-difluorophenyl)octahydro-2H-benzo[b][1,4]oxazine, 4a-(2-fluorophenyl)octahydro-2H-benzo[b][1,4]oxazine, 6-methyl-4a-phenyloctahydro-2H-benzo[b][1,4]oxazine, 6-ethyl-4a-phenyloctahydro-2H-benzo[b][1,4]oxazine, 4a-(3-chlorophenyl)octahydro-2H-benzo[b][1,4]oxazine, 4a-(3-methylphenyl)octahydro-2H-benzo[b][1,4]oxazine, 4a-(2-chlorophenyl)octahydro-2H-benzo[b][1,4]oxazine, 4a-(4-chlorophenyl)octahydro-2H-benzo[b][1,4]oxazine [1,4]oxazine, 4a-(4-methylphenyl)octahydro-2H-benzo[b][1,4]oxazine, 4a-(3-(trifluoromethyl)phenyl)octahydro-2H-benzo[b][1,4]oxazine, 8-methyl-4a-phenyloctahydro-2H-benzo[b][1,4]oxazine, 5-methyl-4a-phenyloctahydro-2H-benzo[b][1,4]oxazine, 7-methyl-4a-phenyloctahydro-2H-benzo[b][1,4]oxazine, 4-methyl-4a-phenyloctahydro-2H-benzo[b][1,4]oxazine, 3,3-dimethyl-5a-phenyldecahydrobenzo[b][1,4]olanzapine, 4a-(3-methoxyphenyl)octahydro-2H-benzo[b][1,4]oxazine, 4a-(3-(trifluoromethoxy)phenyl)octahydro-2H-benzo[b][1,4]oxazine, 4a-(4-(trifluoromethyl)phenyl)octahydro-2H-benzo[b][1,4]oxazine, 4a-(2,6-dimethylphenyl)octahydro-2H-benzo[b][1,4]oxazine, 4a-(4-(tert-butyl)phenyl)octahydro-2H-benzo[b][1,4]oxazine, 4a-(2,3-dichlorophenyl)octahydro-2H-benzo[b][1,4]oxazine, 4a-(2-isopropylphenyl)octahydro-2H-benzo[b][1,4]oxazine, 4a-(2,5-dimethylphenyl)octahydro-2H-benzo[b][1,4 ]oxazine, 4a-(2-chloro-3-fluorophenyl)octahydro-2H-benzo[b][1,4]oxazine, 4a-(3,4-difluorophenyl)octahydro-2H-benzo[b][1,4]oxazine, 6,6-dimethyl-4a-phenyloctahydro-2H-benzo[b][1,4]oxazine, 4a-(2-chloro-5-fluorophenyl)octahydro-2H-benzo[b][1,4]oxazine, 4α-(3-ethoxyphenyl)octahydro-2H-benzo[b][1,4]oxazine, 4α-(2-chloro-4-methoxyphenyl)octahydro-2H-benzo[b][1,4]oxazine, 4a-(2-chloro-6-fluorophenyl)octahydro-2H-benzo[b][1,4]oxazine.

[0164] In some embodiments of the compound of formula A, when Y is 1 chloro-substituted phenyl, X is -CH2-, and m and o are both 0, the chiral carbon atom at position 1 and the chiral carbon atom at position 2 are not simultaneously in S configuration or R configuration (for example, the chiral carbon atom at position 1 is in S configuration and the chiral carbon atom at position 2 is in R configuration; or the chiral carbon atom at position 1 is in R configuration and the chiral carbon atom at position 2 is in S configuration); when Y is unsubstituted 2-thienyl, X is -CH2-, and m and o are both 0, the chiral carbon atom at position 1 and the chiral carbon atom at position 2 are simultaneously in S configuration or simultaneously in R configuration (for example, the chiral carbon atoms at positions 1 and 2 are both in S configuration; or the carbon atoms at positions 1 and 2 are both in R configuration).

[0165] In some embodiments of the compound of formula A, Y is optionally substituted with 1, 2, 3, 4 or 5 groups selected from deuterium, cyano, C 1-3 Phenyl or thienyl substituted with an alkyl or halogen substituent. The thienyl may be 2-thienyl or 3-thienyl.

[0166] In some embodiments of the compound of Formula A, R2 is selected from deuterium or halogen.

[0167] In some embodiments of the compound of Formula A, R3 is selected from deuterium or halogen.

[0168] In some embodiments, the present invention provides a compound of Formula I, or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, isotopic substitution, polymorph, prodrug, or metabolite thereof:

[0169] Where:

[0170] R1 is selected from deuterium, C 1-3 Alkyl or halogen;

[0171] R2 is selected from deuterium, C 1-3 Alkyl or halogen;

[0172] R3 is selected from deuterium, C 1-3 Alkyl or halogen;

[0173] n is 0, 1, or 2;

[0174] m is 0, 1, 2, or 3;

[0175] o is 0, 1, 2, or 3;

[0176] X is -O- or -CH2-;

[0177] The chiral carbon atom at position 1 is in S configuration or R configuration;

[0178] The chiral carbon atom at position 2 is in S configuration or R configuration;

[0179] provided that the compound of formula I is not the following compounds and their salts: (4aR,8aR)-4α-(3-chlorophenyl)octahydro-2H-benzo[b][1,4]oxazine, (4aS,8aS)-4α-(3-chlorophenyl)octahydro-2H-benzo[b][1,4]oxazine, (4aR,8aR)-4α-(2-chlorophenyl)octahydro-2H-benzo[b][1,4]oxazine and (4aS,8aS)-4α-(2-chlorophenyl)octahydro-2H-benzo[b][1,4]oxazine.

[0180] In some embodiments of the compound of Formula I, when n is 1, R1 is chlorine, X is -CH2-, and m and o are both 0, the chiral carbon atom at position 1 and the chiral carbon atom at position 2 are not in the S configuration or the R configuration at the same time (e.g., the chiral carbon atom at position 1 is in the S configuration and the chiral carbon atom at position 2 is in the R configuration; or the chiral carbon atom at position 1 is in the R configuration and the chiral carbon atom at position 2 is in the S configuration).

[0181] In some embodiments of the compounds of formula A and I, R1 is halogen, more preferably Cl.

[0182] In some embodiments of compounds of formula A and I, n is 1; preferably, R1 is located at the meta or ortho position.

[0183] In some embodiments of the compound of formula A and I, m is 0.

[0184] In some embodiments of the compounds of formula A and I, R2 is deuterium, and preferably m is 1 or 2.

[0185] In some embodiments of the compounds of formula A and I, R2 is methyl, and preferably m is 1 or 2.

[0186] In some embodiments of compounds of formula A and I, R2 is F; preferably, then m is 1; preferably, then X is -CH2-.

[0187] In some embodiments of the compounds of formula A and I, o is 0.

[0188] In some embodiments of formulas A and I, R3 is deuterium, preferably o is 1 or 2.

[0189] In some embodiments of Formulas A and I, m is 0, o is 1 or 2, and R3 is deuterium.

[0190] In some embodiments of Formulas A and I, X is O, and at least one of m and o is not 0, and correspondingly at least one of R2 and R3 is deuterium.

[0191] In some embodiments of the compound of formula A, Y is unsubstituted thienyl (eg, 3-thienyl), m and o are 0, and X is -CH2-.

[0192] It should be understood that when X is -CH2-, and m is 1 or 2, X may also be substituted with 1 or 2 R2.

[0193] In some embodiments, the compound of formula I has the structure shown in the following formula I-1, I-2 or I-3:

[0194] wherein R1, R2, R3, m, o and X are as defined in any of the preceding embodiments.

[0195] In some embodiments of the compounds of Formula I-1 and Formula I-2, R1 is Cl.

[0196] In some embodiments of the compounds of formula I-1, formula I-2 and I-3, X is -CH2-, wherein the chiral carbon atom at position 1 is in the S configuration and the chiral carbon atom at position 2 is in the R configuration; or the chiral carbon atom at position 1 is in the R configuration and the chiral carbon atom at position 2 is in the S configuration.

[0197] In some embodiments of the compounds of formula I-1 and formula I-2, X is -CH2-; preferably, R1 is Cl; further preferably, the chiral carbon atom at position 1 is in S configuration and the chiral carbon atom at position 2 is in R configuration; or the chiral carbon atom at position 1 is in R configuration and the chiral carbon atom at position 2 is in S configuration.

[0198] In some embodiments of the compounds of formula I-1, formula I-2 and formula I-3, X is O, and m and o are both 0. Preferably, in this case, the chiral carbon atom at position 1 and the chiral carbon atom at position 2 are both in the same configuration, for example, the chiral carbon atom at position 1 and the chiral carbon atom at position 2 are both in the S configuration, or the chiral carbon atom at position 1 and the chiral carbon atom at position 2 are both in the R configuration.

[0199] In some embodiments of compounds of formula I-1, formula I-2, and I-3, X is O, m is 1 or 2, and R2 is deuterium. In some embodiments of compounds of formula I-1, formula I-2, and I-3, X is O, o is 1 or 2, and R3 is deuterium.

[0200] In some embodiments of the compounds of Formula I-1 and Formula I-2, X is O or -CH2-, R1 is Cl, o is 1 or 2, and R3 is deuterium.

[0201] In some embodiments of the compound of formula I-3, X is -CH2-; R2 is F and m is 1, or R2 is deuterium and m is 2; and o is 0.

[0202] In some embodiments, the compound of formula I has the structure shown in the following formula I-4 or I-5:

[0203] wherein R1, R2, R3, m, o and X are as defined in any of the preceding embodiments.

[0204] In some embodiments of compounds of Formula I-4 and Formula I-5, R1 is Cl.

[0205] In some embodiments of compounds of Formula 1-4 and Formula 1-5, R2 is deuterium.

[0206] In some embodiments of compounds of Formula 1-4 and Formula 1-5, o is 0.

[0207] In some embodiments, the compound of formula A is selected from the following compounds:

[0208] In some embodiments, the present invention also provides pharmaceutically acceptable salts of compounds of Formula A and I, including but not limited to one or more of formate, hydrochloride, sulfate, phosphate, oxalate, pamoate, citrate, succinate, D-tartrate, fumarate, maleate, p-toluenesulfonate, methanesulfonate and benzenesulfonate.

[0209] In some embodiments, the pharmaceutically acceptable salt of the compound of formula A is selected from:

[0210] Compound 2 hydrochloride, compound 2 phosphate, compound 2 methanesulfonate, compound 2 formate, compound 2 oxalate, compound 2 pamoate, compound 3 hydrochloride, compound 3 phosphate, compound 3 methanesulfonate, compound 3 formate, compound 3 oxalate, compound 3 pamoate, compound 13 hydrochloride, compound 17 hydrochloride, compound 33 hydrochloride, compound 36 hydrochloride, compound 34 hydrochloride, compound 35 hydrochloride, compound 39 hydrochloride, compound 40 hydrochloride, compound 45 hydrochloride, compound 46 hydrochloride, compound 74 hydrochloride, compound 80 hydrochloride, compound 96 hydrochloride, compound 98 hydrochloride, compound 144 hydrochloride, compound 145 hydrochloride, compound 158 hydrochloride, compound 55 hydrochloride, compound 56 hydrochloride, compound 57 hydrochloride, compound 58 hydrochloride, compound 84 hydrochloride, compound 92 hydrochloride, compound 98 hydrochloride, compound 139 hydrochloride, compound Compound 141 hydrochloride, compound 155 hydrochloride, compound 156 hydrochloride, compound 157 hydrochloride, compound 158 hydrochloride, compound 159 hydrochloride, compound 160 hydrochloride, compound 161 hydrochloride, compound 177 hydrochloride, compound 178 hydrochloride, compound 179 hydrochloride, compound 180 hydrochloride, compound 218 methanesulfonate, compound 219 methanesulfonate, compound 242 methanesulfonate, compound 243 methanesulfonate, compound 167a methanesulfonate, compound 167b methanesulfonate, compound 29 methanesulfonate, compound 32 methanesulfonate, compound 51 methanesulfonate, compound 54 methanesulfonate, compound 62 methanesulfonate, compound 68 methanesulfonate, compound 230 methanesulfonate, compound 231 methanesulfonate, compound 196 methanesulfonate, compound 199 methanesulfonate, compound 226 methanesulfonate, compound 14 methanesulfonate, compound 163 methanesulfonate, and compound 164 methanesulfonate.

[0211] In some embodiments, the present invention provides a compound of the following formula A', or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, isotope-substituted product, polymorph, prodrug, or metabolite thereof:

[0212] Where,

[0213] Y' is C optionally substituted by a 6-14 membered aryl group 1-6 Alkyl, the 6-14 membered aryl group is optionally substituted with 1, 2, 3, 4 or 5 halogens;

[0214] R2 is selected from deuterium, C 1-3 Alkyl or halogen;

[0215] R3 is selected from deuterium, C 1-3 Alkyl or halogen;

[0216] m is 0, 1, 2, or 3;

[0217] o is 0, 1, 2, or 3;

[0218] X is -O- or -CH2-;

[0219] The chiral carbon atom at position 1 is in S configuration or R configuration;

[0220] The chiral carbon atom at position 2 is in S configuration or R configuration;

[0221] Provided that the compound of formula A' is not the following compounds and their salts: (4aR,8aS)-4α-(2-thienyl)octahydro-2H-benzo[b][1,4]oxazine, (4aR,8aR)-4α-(2-chloro-3-thienyl)octahydro-2H-benzo[b][1,4]oxazine, (4aS,8aR)-4α-(2-thienyl)octahydro-2H-benzo[b][1,4]oxazine, (4aR,8aS)-4α-(3-methyl-2-thienyl)octahydro-2H-benzo[b][1,4]oxazine, (4aR,8aR)-4α-(4-methyl-3-thienyl)octahydro-2H-benzo[b][1,4]oxazine, (4aR,8aR)-4 α-(3-chlorophenyl)octahydro-2H-benzo[b][1,4]oxazine, (4aS,8aS)-4α-(3-chlorophenyl)octahydro-2H-benzo[b][1,4]oxazine, (4aR,8aR)-4α-(2-chlorophenyl)octahydro-2H-benzo[b][1,4]oxazine, (4aS,8aS)-4α-(2-chlorophenyl)octahydro-2H-benzo[b][1,4]oxazine, 4a-phenyloctahydro-2H-benzo[b][1,4]oxazine, 4a-(2-methoxyphenyl)octahydro-2H-benzo[b][1,4]oxazine, 4a-(3-fluorophenyl)octahydro-2H-benzo[b][1,4]oxazine, 4a-(4-fluorophenyl)octahydro-2 H-benzo[b][1,4]oxazine, 4a-(2,3-difluorophenyl)octahydro-2H-benzo[b][1,4]oxazine, 4a-(2-fluorophenyl)octahydro-2H-benzo[b][1,4]oxazine, 6-methyl-4a-phenyloctahydro-2H-benzo[b][1,4]oxazine, 6-ethyl-4a-phenyloctahydro-2H-benzo[b][1,4]oxazine, 4a-(3-chlorophenyl)octahydro-2H-benzo[b][1,4]oxazine, 4a-(3-methylphenyl)octahydro-2H-benzo[b][1,4]oxazine, 4a-(2-chlorophenyl)octahydro-2H-benzo[b][1,4]oxazine, 4a-(4-chlorophenyl)octahydro-2H-benzo[b][1,4]oxazine [1,4]oxazine, 4a-(4-methylphenyl)octahydro-2H-benzo[b][1,4]oxazine, 4a-(3-(trifluoromethyl)phenyl)octahydro-2H-benzo[b][1,4]oxazine, 8-methyl-4a-phenyloctahydro-2H-benzo[b][1,4]oxazine, 5-methyl-4a-phenyloctahydro-2H-benzo[b][1,4]oxazine, 7-methyl-4a-phenyloctahydro-2H-benzo[b][1,4]oxazine, 4-methyl-4a-phenyloctahydro-2H-benzo[b][1,4]oxazine, 3,3-dimethyl-5a-phenyldecahydrobenzo[b][1,4]olanzapine, 4a-(3-methoxyphenyl)octahydro-2H-benzo[b][1,4]oxazine, 4a-(3-(trifluoromethoxy)phenyl)octahydro-2H-benzo[b][1,4]oxazine, 4a-(4-(trifluoromethyl)phenyl)octahydro-2H-benzo[b][1,4]oxazine, 4a-(2,6-dimethylphenyl)octahydro-2H-benzo[b][1,4]oxazine, 4a-(4-(tert-butyl)phenyl)octahydro-2H-benzo[b][1,4]oxazine, 4a-(2,3-dichlorophenyl)octahydro-2H-benzo[b][1,4]oxazine, 4a-(2-isopropylphenyl)octahydro-2H-benzo[b][1,4]oxazine, 4a-(2,5-dimethylphenyl)octahydro-2H-benzo[b][1,4 ]oxazine, 4a-(2-chloro-3-fluorophenyl)octahydro-2H-benzo[b][1,4]oxazine, 4a-(3,4-difluorophenyl)octahydro-2H-benzo[b][1,4]oxazine, 6,6-dimethyl-4a-phenyloctahydro-2H-benzo[b][1,4]oxazine, 4a-(2-chloro-5-fluorophenyl)octahydro-2H-benzo[b][1,4]oxazine, 4α-(3-ethoxyphenyl)octahydro-2H-benzo[b][1,4]oxazine, 4α-(2-chloro-4-methoxyphenyl)octahydro-2H-benzo[b][1,4]oxazine, 4a-(2-chloro-6-fluorophenyl)octahydro-2H-benzo[b][1,4]oxazine.

[0222] In some embodiments of the compound of formula A', X is -CH2-.

[0223] In some embodiments of the compound of Formula A', m is 0.

[0224] In some embodiments of the compound of formula A', o is 0.

[0225] In some embodiments of the compound of formula A', Y' is C optionally substituted with 6-10 membered aryl. 1-3 alkyl, the 6-10 membered aryl is optionally substituted by 1, 2, 3, 4 or 5 halogens; preferably, Y' is methyl substituted by a 6-10 membered aryl, the 6-10 membered aryl is optionally substituted by 1, 2, 3, 4 or 5 halogens selected from Cl and F; preferably, Y' is methyl substituted by a phenyl, the phenyl is optionally substituted by 1, 2 or 3 Cl.

[0226] In some embodiments, the compound of formula A' is selected from the following compounds:

[0227] In some embodiments, the present invention provides a compound of the following formula II-1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, isotope-substituted product, polymorph, prodrug, or metabolite thereof:

[0228] Where,

[0229] X is -O- or -CH2-;

[0230] E is -O- or -CH2-;

[0231] A is -NR a - or -CH2-;

[0232] B is -NR a - or -CH2-;

[0233] R a Selected from H and C 1-6 alkyl;

[0234] Y is selected from substituted or unsubstituted 6-14 membered aryl and substituted or unsubstituted 5-14 membered heteroaryl, Y is optionally substituted by 1, 2, 3, 4 or 5 R1, each R1 is independently selected from deuterium, cyano, C 1-3 alkyl and halogen, the 5-14 membered heteroaryl group includes 1, 2, 3 or 4 heteroatoms selected from N, O and S;

[0235] Z is selected from H, hydroxyl, C 1-6 Alkyl and C 1-6 alkoxy;

[0236] R2 is selected from deuterium, C 1-3 Alkyl or halogen;

[0237] R3 is selected from deuterium, C 1-3 Alkyl or halogen;

[0238] m is 0, 1, 2, or 3;

[0239] o is 0, 1, 2, or 3;

[0240] The chiral carbon atom at position 1 is in S configuration or R configuration;

[0241] The chiral carbon atom at position 2 is in S configuration or R configuration.

[0242] In some embodiments of the compound of formula II-1, X and E are both -CH2-; or one of X and E is -O- and the other is -CH2-.

[0243] In some embodiments of the compound of Formula II-1, one of A and B is -NR a -, and the other is -CH2-.

[0244] In some embodiments of the compound of Formula II-1, Z is selected from H and hydroxy.

[0245] In some embodiments of the compound of formula II-1, Y is selected from substituted or unsubstituted 6-10 membered aryl and substituted or unsubstituted 5-7 membered heteroaryl; preferably, Y is optionally substituted with 1, 2, 3, 4 or 5 halogens; preferably, the halogens are selected from Cl and F.

[0246] In some embodiments of the compound of Formula II-1, m is 0.

[0247] In some embodiments of the compound of Formula II-1, o is 0.

[0248] In some embodiments, the present invention provides a compound of the following formula II-2, or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, isotope-substituted product, polymorph, prodrug, or metabolite thereof:

[0249] Where,

[0250] Y is selected from substituted or unsubstituted 6-14 membered aryl and substituted or unsubstituted 5-14 membered heteroaryl, Y is optionally substituted by 1, 2, 3, 4 or 5 R1, each R1 is independently selected from deuterium, cyano, C 1-3 alkyl and halogen, the 5-14 membered heteroaryl group includes 1, 2, 3 or 4 heteroatoms selected from N, O and S;

[0251] Z is selected from hydroxyl, C 1-6 Alkyl and C 1-6 alkoxy;

[0252] R2 is selected from deuterium, C 1-3 Alkyl or halogen;

[0253] R3 is selected from deuterium, C 1-3 Alkyl or halogen;

[0254] m is 0, 1, 2, or 3;

[0255] o is 0, 1, 2, or 3;

[0256] The chiral carbon atom at position 1 is in S configuration or R configuration;

[0257] The chiral carbon atom at position 2 is in S configuration or R configuration.

[0258] In some embodiments of the compound of Formula II-2, Z is hydroxy.

[0259] In some embodiments of the compound of formula II-2, Y is selected from substituted or unsubstituted 6-10 membered aryl and substituted or unsubstituted 5-7 membered heteroaryl; preferably, Y is optionally substituted with 1, 2, 3, 4 or 5 halogens; preferably, the halogens are selected from Cl and F.

[0260] In some embodiments of the compound of Formula II-2, m is 0.

[0261] In some embodiments of the compound of Formula II-2, o is 0.

[0262] In some embodiments, the compound of formula II-2 is selected from the following compounds:

[0263] In some embodiments, the present invention provides a compound of the following formula II-3, or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, isotope-substituted product, polymorph, prodrug, or metabolite thereof:

[0264] Where,

[0265] A is -NR a - or -CH2-;

[0266] B is -NR a - or -CH2-;

[0267] R a Selected from H and C 1-6 alkyl;

[0268] Y is selected from substituted or unsubstituted 6-14 membered aryl and substituted or unsubstituted 5-14 membered heteroaryl, Y is optionally substituted by 1, 2, 3, 4 or 5 R1, each R1 is independently selected from deuterium, cyano, C 1-3 alkyl and halogen, the 5-14 membered heteroaryl group includes 1, 2, 3 or 4 heteroatoms selected from N, O and S;

[0269] R2 is selected from deuterium, C 1-3 Alkyl or halogen;

[0270] R3 is selected from deuterium, C 1-3 Alkyl or halogen;

[0271] m is 0, 1, 2, or 3;

[0272] o is 0, 1, 2, or 3;

[0273] The chiral carbon atom at position 1 is in S configuration or R configuration;

[0274] The chiral carbon atom at position 2 is in S configuration or R configuration.

[0275] In some embodiments of the compound of Formula II-3, one of A and B is -NR a -, and the other is -CH2-.

[0276] In some embodiments of the compound of formula II-3, Y is selected from substituted or unsubstituted 6-10 membered aryl and substituted or unsubstituted 5-7 membered heteroaryl; preferably, Y is optionally substituted with 1, 2, 3, 4 or 5 halogens; preferably, the halogens are selected from Cl and F.

[0277] In some embodiments of the compound of Formula II-3, m is 0.

[0278] In some embodiments of the compound of Formula II-3, o is 0.

[0279] In some embodiments, the compound of formula II-3 is selected from the following compounds:

[0280] In some embodiments, the present invention provides a compound of the following formula II-4, or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, isotope-substituted product, polymorph, prodrug, or metabolite thereof:

[0281] R a Selected from H and C 1-6 alkyl;

[0282] Y is selected from substituted or unsubstituted 6-14 membered aryl and substituted or unsubstituted 5-14 membered heteroaryl, Y is optionally substituted by 1, 2, 3, 4 or 5 R1, each R1 is independently selected from deuterium, cyano, C 1-3 alkyl and halogen, the 5-14 membered heteroaryl group includes 1, 2, 3 or 4 heteroatoms selected from N, O and S;

[0283] R2 is selected from deuterium, C 1-3 Alkyl or halogen;

[0284] R3 is selected from deuterium, C 1-3 Alkyl or halogen;

[0285] m is 0, 1, 2, or 3;

[0286] o is 0, 1, 2, or 3;

[0287] The chiral carbon atom at position 1 is in S configuration or R configuration;

[0288] The chiral carbon atom at position 2 is in S configuration or R configuration.

[0289] In some embodiments of the compound of formula II-4, Y is selected from substituted or unsubstituted 6-10 membered aryl and substituted or unsubstituted 5-7 membered heteroaryl; preferably, Y is optionally substituted with 1, 2, 3, 4 or 5 halogens; preferably, the halogens are selected from Cl and F.

[0290] In some embodiments of the compound of Formula II-4, m is 0.

[0291] In some embodiments of the compound of Formula II-4, o is 0.

[0292] In some embodiments, the compound of formula II-4 is selected from the following compounds:

[0293] In some embodiments, the present invention also provides a compound of Formula III, or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, isotope-substituted product, polymorph, prodrug, or metabolite thereof:

[0294] Where,

[0295] L, M, P and Q are each independently selected from N and CH;

[0296] R4, R5, R6 and R7 are each independently selected from C 1-6 Alkyl, C 1-6 Alkoxy, -NR b R c , substituted or unsubstituted 6-14 membered aryl and substituted or unsubstituted 5-14 membered heteroaryl, wherein the 6-14 membered aryl and the 5-14 membered heteroaryl are optionally selected from halogen, deuterium, C 1-6 Alkyl and C 1-6 substituted with an alkoxy group, wherein the 5-14 membered heteroaryl group includes 1, 2, 3 or 4 heteroatoms selected from N, O and S; R4 is further selected from oxo, provided that R5 is absent; R6 is further selected from oxo, provided that R7 is absent;

[0297] R b and R c Each independently selected from H and C 1-6 alkyl;

[0298] The carbon atom at the 3-position or 4-position is a chiral carbon atom, and the chiral carbon atom is in S configuration or R configuration.

[0299] In some embodiments of the compound of formula III, R4 is oxo, R5 is absent, R6 and R7 are each independently selected from C 1-6 Alkyl, C 1-6 Alkoxy, -NR b R c , substituted or unsubstituted 6-14 membered aryl and substituted or unsubstituted 5-14 membered heteroaryl; or

[0300] R6 is oxo, R7 is absent, R4 and R5 are each independently selected from C 1-6 Alkyl, C 1-6 Alkoxy, -NR b Rc , substituted or unsubstituted 6-14 membered aryl and substituted or unsubstituted 5-14 membered heteroaryl.

[0301] In some embodiments of the compound of Formula III, P is CH.

[0302] In some embodiments of the compound of Formula III, Q is CH.

[0303] In some embodiments of the compound of Formula III, one of L and M is CH and the other is N.

[0304] In some embodiments of the compound of formula III, M is N; L is CH; P is CH; Q is CH; R6 is oxo, R7 is absent, and R4 and R5 are each independently selected from C 1-6 Alkyl, C 1-6 Alkoxy, -NR b R c , substituted or unsubstituted 6-14 membered aryl and substituted or unsubstituted 5-14 membered heteroaryl.

[0305] In some embodiments of the compound of formula III, M is N; L is CH; P is CH; Q is CH; R4 is oxo, R5 is absent, and R6 and R7 are each independently selected from C 1-6 Alkyl, C 1-6 Alkoxy, -NR b R c , substituted or unsubstituted 6-14 membered aryl and substituted or unsubstituted 5-14 membered heteroaryl.

[0306] In some embodiments of the compound of formula III, M is CH; L is N; P is CH; Q is CH; R4 is oxo, R5 is absent, and R6 and R7 are each independently selected from C 1-6 Alkyl, C 1-6 Alkoxy, -NR b R c , substituted or unsubstituted 6-14 membered aryl and substituted or unsubstituted 5-14 membered heteroaryl.

[0307] In some embodiments of the compound of formula III, M is CH; L is N; P is CH; Q is CH; R6 is oxo, R7 is absent, and R4 and R5 are each independently selected from C 1-6 Alkyl, C 1-6 Alkoxy, -NR b R c , substituted or unsubstituted 6-14 membered aryl and substituted or unsubstituted 5-14 membered heteroaryl.

[0308] In some embodiments of the compound of Formula III, R4, R5, R6 and R7 are each independently selected from C 1-6Alkoxy, -NR b R c , substituted or unsubstituted 6-14 membered aryl and substituted or unsubstituted 5-14 membered heteroaryl; R4 is also selected from oxo, provided that R5 is absent; R6 is also selected from oxo, provided that R7 is absent. In some embodiments, R4, R5, R6 and R7 are each independently selected from -NR b R c and substituted or unsubstituted 6-14 membered aryl; R4 is further selected from oxo, provided that R5 is absent; R6 is further selected from oxo, provided that R7 is absent. In some embodiments, R4, R5, R6 and R7 are each independently selected from -NR b R c and optionally 1, 2, 3 or 4 selected from halogen, C 1-6 alkyl and deuterium substituted 6-10 membered aryl; R4 is further selected from oxo, provided that R5 is absent; R6 is further selected from oxo, provided that R7 is absent.

[0309] In some embodiments of the compound of Formula III, R4 and R5 are each independently selected from -NR b R c and optionally 1, 2, 3 or 4 selected from halogen, C 1-6 6-10 membered aryl substituted with alkyl and deuterium substituents, R6 is oxo, and R7 is absent; or

[0310] R6 and R7 are each independently selected from -NR b R c and optionally 1, 2, 3 or 4 selected from halogen, C 1-6 6-10 membered aryl substituted with alkyl and deuterium substituents, R4 is oxo, and R5 is absent.

[0311] In some embodiments of the compound of Formula III, R b and R c Each independently selected from H and C 1-3 Alkyl; preferably, R b and R c One is H and the other is C 1-3 alkyl.

[0312] In some embodiments, the compound of formula III is selected from the following compounds:

[0313] III. Preparation of Compounds

[0314] The compounds of the present invention can be prepared by reaction processes similar to those described in Examples 1 to 25 of the present application.

[0315] IV. Salt Form Data of Compounds

[0316] The present invention provides Compound 2 hydrochloride Form A, which has an X-ray powder diffraction pattern with characteristic peaks at at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12 or all 13 of the following 2θ angles: 6.79°±0.20°, 11.44°±0.20°, 13.15°±0.20°, 14.44°±0.20°, 15.00°±0.20°, 16.36°±0.20°, 17.16°±0.20°, 20.59°±0.20°, 23.38°±0.20°, 24.11°±0.20°, 24.30°±0.20°, 25.74°±0.20° and 26.72°±0.20°.

[0317] In some embodiments, the crystalline Form A has characteristic peaks at least at the following 2θ angles: 14.44°±0.20°, 17.16°±0.20°, 20.59°±0.20° and 23.38°±0.20°, and optionally at at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8 or all 9 of the following 2θ angles: 6.79°±0.20°, 11.44°±0.20°, 13.15°±0.20°, 15.00°±0.20°, 16.36°±0.20°, 24.11°±0.20°, 24.30°±0.20°, 25.74°±0.20° and 26.72°±0.20°.

[0318] In some embodiments, the crystalline Form A has characteristic peaks at least at the following 2θ angles: 14.44°±0.20°, 17.16°±0.20°, 20.59°±0.20° and 23.38°±0.20°, and has characteristic peaks at at least 1, at least 2, at least 3, at least 4, at least 5 or all 6 of the following 2θ angles: 11.44°±0.20°, 15.00°±0.20°, 16.36°±0.20°, 24.11°±0.20°, 24.30°±0.20° and 26.72°±0.20°, and optionally has characteristic peaks at at least 1, at least 2 or all 3 of the following 2θ angles: 6.79°±0.20°, 13.15°±0.20° and 25.74°±0.20°.

[0319] The XRPD pattern of the hydrochloride form A of the above-mentioned Compound 2 is shown in FIG1 .

[0320] The XRPD pattern analysis data of the above-mentioned Compound 2 hydrochloride Form A are shown in Table 1.

[0321] Table 1: XRPD pattern analysis data of Compound 2 Hydrochloride Form A

[0322] No absorption peak was detected in the differential scanning calorimetry curve of the above-mentioned Compound 2 hydrochloride form A.

[0323] The thermogravimetric analysis curve of the above Compound 2 hydrochloride Form A shows an initial weight loss temperature of approximately 205.5°C.

[0324] The DSC and TGA overlays of the above-mentioned Compound 2 hydrochloride Form A are shown in FIG2 .

[0325] The present invention provides a phosphate B crystal form of Compound 2, whose X-ray powder diffraction pattern has characteristic peaks at at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11 or all 12 of the following 2θ angles: 5.48°±0.20°, 10.96°±0.20°, 12.32°±0.20°, 13.49°±0.20°, 14.83°±0.20°, 15.44°±0.20°, 16.50°±0.20°, 18.48°±0.20°, 20.63°±0.20°, 22.49°±0.20°, 22.92°±0.20° and 27.64°±0.20°.

[0326] In some embodiments, the crystalline Form B has characteristic peaks at least at the following 2θ angles: 5.48°±0.20°, 18.48°±0.20°, 22.49°±0.20° and 22.92°±0.20°, and optionally has characteristic peaks at at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7 or all 8 of the following 2θ angles: 10.96°±0.20°, 12.32°±0.20°, 13.49°±0.20°, 14.83°±0.20°, 15.44°±0.20°, 16.50°±0.20°, 20.63°±0.20° and 27.64°±0.20°.

[0327] In some embodiments, the crystalline Form B has characteristic peaks at least at the following 2θ angles: 5.48°±0.20°, 18.48°±0.20°, 22.49°±0.20° and 22.92°±0.20°, and characteristic peaks at at least 1, at least 2, at least 3, at least 4 or all 5 of the following 2θ angles: 13.49°±0.20°, 15.44°±0.20°, 16.50°±0.20°, 20.63°±0.20° and 27.64°±0.20°, and optionally at at least 1, at least 2 or all 3 of the following 2θ angles: 10.96°±0.20°, 12.32°±0.20° and 14.83°±0.20°.

[0328] The XRPD pattern of the above-mentioned Compound 2 Phosphate B crystal form is shown in FIG3 .

[0329] The XRPD pattern analysis data of the above-mentioned Compound 2 Phosphate B Crystalline Form are shown in Table 2.

[0330] Table 2: XRPD pattern analysis data of Compound 2 Phosphate B Form

[0331] The differential scanning calorimetry curve of the above-mentioned Compound 2 Phosphate B crystal form has an endothermic peak starting point at 119.4±3.0°C and another endothermic peak starting point at 181.1±3.0°C.

[0332] The thermogravimetric analysis curve of the above-mentioned Compound 2 Phosphate B crystal form showed a weight loss of 2.87% at 150.0±3.0°C.

[0333] The DSC and TGA overlays of the above-mentioned Compound 2 Phosphate B Crystalline Form are shown in FIG4 .

[0334] The present invention provides a crystalline form C of the mesylate salt of Compound 2, whose X-ray powder diffraction pattern has characteristic peaks at at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9 or all 10 of the following 2θ angles: 8.05°±0.20°, 9.71°±0.20°, 12.00°±0.20°, 13.91°±0.20°, 14.37°±0.20°, 15.03°±0.20°, 16.18°±0.20°, 18.49°±0.20°, 22.65°±0.20° and 24.42°±0.20°.

[0335] In some embodiments, the crystalline Form C has characteristic peaks at least at the following 2θ angles: 8.05°±0.20°, 14.37±0.20°, 16.18°±0.20°, 18.49°±0.20° and 22.65°±0.20°, and optionally has characteristic peaks at at least 1, at least 2, at least 3, at least 4 or all 5 of the following 2θ angles: 9.71°±0.20°, 12.00°±0.20°, 13.91°±0.20°, 15.03°±0.20° and 24.42°±0.20°.

[0336] In some embodiments, the crystalline Form C has characteristic peaks at least at the following 2θ angles: 8.05°±0.20°, 14.37°±0.20°, 16.18°±0.20°, 18.49°±0.20° and 22.65°±0.20°, and has characteristic peaks at at least 1, at least 2 or all 3 of the following 2θ angles: 13.91°±0.20°, 15.03°±0.20° and 24.42°±0.20°, and optionally has characteristic peaks at any 1 or all 2 of the following 2θ angles: 9.71°±0.20° and 12.00°±0.20°.

[0337] In some embodiments, the crystalline Form C has characteristic peaks at least at the following 2θ angles: 8.05°±0.20°, 14.37±0.20°, 16.18°±0.20° and 18.49°±0.20°, and characteristic peaks at at least 1, at least 2, at least 3 or all 4 of the following 2θ angles: 13.91°±0.20°, 15.03°±0.20°, 22.65°±0.20° and 24.42°±0.20°, and optionally at any 1 or all 2 of the following 2θ angles: 9.71°±0.20° and 12.00°±0.20°.

[0338] The XRPD pattern of the above-mentioned Compound 2 mesylate salt Form C is shown in FIG5 .

[0339] The XRPD pattern analysis data of the above-mentioned Compound 2 mesylate C crystal form are shown in Table 3.

[0340] Table 3: XRPD pattern analysis data of Compound 2 mesylate salt Form C

[0341] The differential scanning calorimetry curve of the above-mentioned Compound 2 mesylate salt form C has an endothermic peak starting point at 186.9±3.0°C.

[0342] The thermogravimetric analysis curve of the above-mentioned Compound 2 mesylate salt Form C shows an initial weight loss temperature of approximately 259.9°C.

[0343] The DSC and TGA overlay of the above-mentioned Compound 2 mesylate salt Form C is shown in FIG6 .

[0344] The present invention provides a mesylate salt of Compound 2 in Form D, which has an X-ray powder diffraction pattern with characteristic peaks at at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, or all 11 of the following 2θ angles: 6.28°±0.20°, 11.33°±0.20°, 12.13°±0.20°, 12.53°±0. .20°, 14.80°±0.20°, 17.14°±0.20°, 18.08°±0.20°, 20.54°±0.20°, 21.46°±0.20°, 22.70°±0.20°, 23.37°±0.20°, 23.93°±0.20°, 24.66°±0.20° and 26.09°±0.20°.

[0345] In some embodiments, the crystalline form D has characteristic peaks at least at the following 2θ angles: 12.13°±0.20°, 14.80°±0.20°, 20.54°±0.20°, 23.37°±0.20° and 26.09°±0.20°, and optionally at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, to 7. There are at least 7, at least 8 or all 9 characteristic peaks: 6.28°±0.20°, 11.33°±0.20°, 12.53°±0.20°, 17.14°±0.20°, 18.08°±0.20°, 21.46°±0.20°, 22.70°±0.20°, 23.93°±0.20°, and 24.66°±0.20°.

[0346] In some embodiments, the crystalline form D has characteristic peaks at least at the following 2θ angles: 12.13°±0.20°, 14.80°±0.20°, 20.54°±0.20°, 23.37°±0.20° and 26.09°±0.20°, and has characteristic peaks at at least 1, at least 2, at least 3 or all 4 of the following 2θ angles: 17.14°±0.20°, 1 8.08°±0.20°, 22.70°±0.20°, 24.66°±0.20°, optionally with characteristic peaks at at least 1, at least 2, at least 3, at least 4 or all 5 of the following 2θ angles: 6.28°±0.20°, 11.33°±0.20°, 12.53°±0.20°, 21.46°±0.20° and 23.93°±0.20°.

[0347] The XRPD pattern of the above-mentioned Compound 2 mesylate salt Form D is shown in FIG7 .

[0348] The XRPD pattern analysis data of the above-mentioned Compound 2 mesylate D crystal form are shown in Table 4.

[0349] Table 4: XRPD pattern analysis data of Compound 2 mesylate salt D crystal form

[0350] The differential scanning calorimetry curve of the above-mentioned Compound 2 mesylate salt form D has an endothermic peak starting point at 136.4±3.0°C and another endothermic peak starting point at 185.6±3.0°C.

[0351] The thermogravimetric analysis curve of the above-mentioned Compound 2 mesylate salt form D showed a weight loss of 7.76% at 155.0±3.0°C.

[0352] The DSC of the above-mentioned Compound 2 mesylate salt form D is shown in FIG8 , and the TGA is shown in FIG9 .

[0353] The present invention provides a crystalline form E of the mesylate salt of Compound 2, whose X-ray powder diffraction pattern has characteristic peaks at at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13 or all 14 of the following 2θ angles: 6.24°±0.20°, 8.16°±0.20°, 12.13°±0.20°, 12.47°±0.20°, 14.48°±0.20°, 14.81°±0.20°, 16.30°±0.20°, 17.15°±0.20°, 18.60°±0.20°, 20.53°±0.20°, 21.45°±0.20°, 21.62°±0.20°, 22.75°±0.20° and 26.08°±0.20°.

[0354] In some embodiments, the crystalline form E has characteristic peaks at least at the following 2θ angles: 14.81°±0.20°, 16.30°±0.20°, 18.60°±0.20° and 22.75°±0.20°, and optionally at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9 or all of the following 2θ angles. There are characteristic peaks at part 10: 6.24°±0.20°, 8.16°±0.20°, 12.13°±0.20°, 12.47°±0.20°, 14.48°±0.20°, 17.15°±0.20°, 20.53°±0.20°, 21.45°±0.20°, 21.62°±0.20° and 26.08°±0.20°.

[0355] In some embodiments, the crystalline form E has characteristic peaks at least at the following 2θ angles: 14.81°±0.20°, 16.30°±0.20°, 18.60°±0.20° and 22.75°±0.20°, and at least 1, at least 2, at least 3, at least 4, at least 5 or all 6 of the following 2θ angles: 12.13°±0.20°, 14.48° ± 0.20°, 17.15° ± 0.20°, 20.53° ± 0.20°, 21.45° ± 0.20° and 21.62° ± 0.20°, optionally with characteristic peaks present at at least 1, at least 2, at least 3 or all 4 of the following 2θ angles: 6.24° ± 0.20°, 8.16° ± 0.20°, 12.47° ± 0.20° and 26.08° ± 0.20°.

[0356] The XRPD pattern of the above-mentioned Compound 2 mesylate salt Form E is shown in FIG10 .

[0357] The XRPD pattern analysis data of the above-mentioned Compound 2 mesylate E crystal form are shown in Table 5.

[0358] Table 5: XRPD pattern analysis data of Compound 2 Methanesulfonate Form E

[0359] The differential scanning calorimetry curve of the above-mentioned Compound 2 mesylate salt E crystal form has an endothermic peak starting point at 86.3±3.0°C and another endothermic peak starting point at 187.7±3.0°C.

[0360] The thermogravimetric analysis curve of the above-mentioned Compound 2 mesylate salt E crystal showed a weight loss of 2.53% at 105.0±3.0°C.

[0361] The DSC of the above-mentioned Compound 2 mesylate salt Form E is shown in FIG11 , and the TGA is shown in FIG12 .

[0362] The present invention provides Compound 2 formate F crystalline form, whose X-ray powder diffraction pattern has characteristic peaks at at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9 or all 10 of the following 2θ angles: 5.85°±0.20°, 11.35°±0.20°, 11.79°±0.20°, 12.99°±0.20°, 13.53°±0.20°, 15.89°±0.20°, 17.34°±0.20°, 22.37°±0.20°, 22.87°±0.20° and 23.76°±0.20°.

[0363] In some embodiments, the crystalline Form F has characteristic peaks at least at the following 2θ angles: 11.35°±0.20°, 13.53°±0.20°, and 23.76°±0.20°, and optionally at at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, or all 7 of the following 2θ angles: 5.85°±0.20°, 11.79°±0.20°, 12.99°±0.20°, 15.89°±0.20°, 17.34°±0.20°, 22.37°±0.20°, and 22.87°±0.20°.

[0364] In some embodiments, the crystalline Form F has characteristic peaks at least at the following 2θ angles: 11.35°±0.20°, 13.53°±0.20° and 23.76°±0.20°, and characteristic peaks at at least 1, at least 2, at least 3, at least 4 or all 5 of the following 2θ angles: 11.79°±0.20°, 12.99°±0.20°, 15.89°±0.20°, 17.34°±0.20° and 22.87°±0.20°, and optionally at any one or all two of the following 2θ angles: 5.85°±0.20°, 22.37°±0.20°.

[0365] The XRPD pattern of the formate salt F form of the above-mentioned Compound 2 is shown in FIG13 .

[0366] The XRPD pattern analysis data of the above-mentioned Compound 2 Formate F crystalline form are shown in Table 6:

[0367] Table 6: XRPD pattern analysis data of Compound 2 Formate F

[0368] The differential scanning calorimetry curve of the formate salt F crystalline form of the above-mentioned Compound 2 has an endothermic peak starting point at 116.8±3.0°C.

[0369] The thermogravimetric analysis curve of the formate salt F of the above-mentioned Compound 2 shows an initial weight loss temperature of approximately 107.0°C.

[0370] The DSC and TGA overlay of the formate F crystalline form of the above-mentioned Compound 2 is shown in FIG14 .

[0371] The present invention provides Compound 2 oxalate L crystalline form, whose X-ray powder diffraction pattern has characteristic peaks at at least 3, at least 4, at least 5, at least 6, at least 7, at least 8 or all 9 of the following 2θ angles: 9.43°±0.20°, 11.11°±0.20°, 15.61°±0.20°, 18.98°±0.20°, 19.42°±0.20°, 23.17°±0.20°, 26.30°±0.20°, 29.92°±0.20° and 31.69°±0.20°.

[0372] In some embodiments, the crystalline form L has characteristic peaks at least at the following 2θ angles: 9.43°±0.20°, 15.61°±0.20° and 26.30°±0.20°, and optionally has characteristic peaks at at least 1, at least 2, at least 3, at least 4, at least 5 or all 6 of the following 2θ angles: 11.11°±0.20°, 18.98°±0.20°, 19.42°±0.20°, 23.17°±0.20°, 29.92°±0.20° and 31.69°±0.20°.

[0373] In some embodiments, the crystalline form L has characteristic peaks at least at the following 2θ angles: 9.43°±0.20°, 15.61°±0.20° and 26.30°±0.20°, and has characteristic peaks at at least 1, at least 2, at least 3 or all 4 of the following 2θ angles: 18.98°±0.20°, 19.42°±0.20°, 23.17°±0.20°, 29.92°±0.20°, and optionally at any one or all two of the following 2θ angles: 11.11°±0.20°, 31.69°±0.20°.

[0374] The XRPD pattern of the above-mentioned Compound 2 oxalate L crystal form is shown in Figure 15.

[0375] The XRPD pattern analysis data of the above-mentioned Compound 2 oxalate L crystal form are shown in Table 7:

[0376] Table 7: XRPD pattern analysis data of Compound 2 oxalate L crystal form

[0377] The present invention provides Compound 2 Pamoate M crystalline form, whose X-ray powder diffraction pattern has characteristic peaks at at least 3, at least 4, at least 5 or all 6 of the following 2θ angles: 5.35°±0.20°, 6.49°±0.20°, 10.00°±0.20°, 10.75°±0.20°, 12.51°±0.20° and 21.01°±0.20°.

[0378] The XRPD pattern of the above-mentioned Compound 2 Pamoate M crystal form is shown in Figure 16.

[0379] The XRPD pattern analysis data of the above-mentioned Compound 2 Pamoate M crystal form are shown in Table 8:

[0380] Table 8: XRPD pattern analysis data of Compound 2 Pamoate M crystal form

[0381] The present invention provides a crystalline form of compound 3 hydrochloride G, which has an X-ray powder diffraction pattern with characteristic peaks at at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15 or all 16 of the following 2θ angles: 6.18°±0.20°, 8.52°±0.20°, 10.42°±0.20°, 10.96°± 0.20°, 11.42°±0.20°, 12.45°±0.20°, 13.57°±0.20°, 14.15°±0.20°, 17.14°±0.20°, 19.42°±0.20°, 20.02°±0.20°, 20.46°±0.20°, 23.41°±0.20°, 24.50°±0.20°, 24.88°±0.20° and 26.74°±0.20°.

[0382] In some embodiments, the crystalline form G has characteristic peaks at least at the following 2θ angles: 6.18°±0.20°, 11.42°±0.20°, 12.45°±0.20°, 20.02°±0.20° and 23.41°±0.20°, and optionally at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10 of the following 2θ angles. Or there are characteristic peaks at all 11 positions: 8.52°±0.20°, 10.42°±0.20°, 10.96°±0.20°, 13.57°±0.20°, 14.15°±0.20°, 17.14°±0.20°, 19.42°±0.20°, 20.46°±0.20°, 24.50°±0.20°, 24.88°±0.20° and 26.74°±0.20°.

[0383] In some embodiments, the crystalline form G has characteristic peaks at least at the following 2θ angles: 6.18°±0.20°, 11.42°±0.20°, 12.45°±0.20°, 20.02°±0.20° and 23.41°±0.20°, and has characteristic peaks at at least 1, at least 2, at least 3, at least 4, at least 5, at least 6 or all 7 of the following 2θ angles: 10.42°±0.20°, 13.57 ° ± 0.20°, 14.15° ± 0.20°, 17.14° ± 0.20°, 19.42° ± 0.20°, 24.50° ± 0.20° and 24.88° ± 0.20°, and optionally with characteristic peaks at at least 1, at least 2, at least 3 or all 4 of the following 2θ angles: 8.52° ± 0.20°, 10.96° ± 0.20°, 20.46° ± 0.20°, and 26.74° ± 0.20°.

[0384] The XRPD pattern of the above-mentioned Compound 3 hydrochloride Form G is shown in FIG17 .

[0385] The XRPD pattern analysis data of the above-mentioned Compound 3 hydrochloride G crystal form are shown in Table 9:

[0386] Table 9: XRPD pattern analysis data of Compound 3 Hydrochloride Form G

[0387] The differential scanning calorimetry curve of the above-mentioned Compound 3 hydrochloride G crystal form has an endothermic peak starting point at 121.3±3.0°C.

[0388] The thermogravimetric analysis curve of the above-mentioned Compound 3 hydrochloride Form G showed a weight loss of 4.49% at 135.0±3.0°C.

[0389] The DSC and TGA overlay of the above-mentioned Compound 3 hydrochloride Form G is shown in FIG18 .

[0390] The present invention provides a hydrochloride H form of compound 3, whose X-ray powder diffraction pattern has characteristic peaks at at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15 or all 16 of the following 2θ angles: 6.64°±0.20°, 12.64°±0.20°, 13.12°±0.20°, 13.31°± 0.20°, 14.16°±0.20°, 14.43°±0.20°, 16.99°±0.20°, 18.37°±0.20°, 21.48°±0.20°, 21.83°±0.20°, 23.06°±0.20°, 23.71°±0.20°, 26.17°±0.20°, 26.61°±0.20°, 29.21°±0.20° and 33.70°±0.20°.

[0391] In some embodiments, the crystalline form H has characteristic peaks at least at the following 2θ angles: 6.64°±0.20°, 13.12°±0.20°, 13.31°±0.20°, 21.83°±0.20° and 23.06°±0.20°, and optionally at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10 of the following 2θ angles. Or there are characteristic peaks at all 11 positions: 12.64°±0.20°, 14.16°±0.20°, 14.43°±0.20°, 16.99°±0.20°, 18.37°±0.20°, 21.48°±0.20°, 23.71°±0.20°, 26.17°±0.20°, 26.61°±0.20°, 29.21°±0.20° and 33.70°±0.20°.

[0392] In some embodiments, the crystalline form H has characteristic peaks at least at the following 2θ angles: 6.64°±0.20°, 13.12°±0.20°, 13.31°±0.20°, 21.83°±0.20° and 23.06°±0.20°, and has characteristic peaks at at least 1, at least 2, at least 3, at least 4, at least 5, at least 6 or all 7 of the following 2θ angles: 14.16°±0.20°, 18.37 ° ± 0.20°, 21.48° ± 0.20°, 23.71° ± 0.20°, 26.17° ± 0.20°, 29.21° ± 0.20° and 33.70° ± 0.20°, and optionally there are characteristic peaks at at least 1, at least 2, at least 3 or all 4 of the following 2θ angles: 12.64° ± 0.20°, 14.43° ± 0.20°, 16.99° ± 0.20° and 26.61° ± 0.20°.

[0393] The XRPD pattern of the above-mentioned Compound 3 hydrochloride Form H is shown in FIG19 .

[0394] The XRPD pattern analysis data of the above-mentioned compound 3 hydrochloride H crystal form are shown in Table 10

[0395] Table 10: XRPD pattern analysis data of Compound 3 Hydrochloride Form H

[0396] The differential scanning calorimetry curve of the above-mentioned Compound 3 hydrochloride H crystal form has an endothermic peak starting point at 73.6±3.0°C.

[0397] The thermogravimetric analysis curve of the above-mentioned Compound 3 hydrochloride Form H shows an initial weight loss temperature of approximately 142.8°C.

[0398] The DSC and TGA overlays of the above-mentioned Compound 3 hydrochloride Form H are shown in FIG20 .

[0399] The present invention provides a phosphate salt of compound 3 in crystalline form I, whose X-ray powder diffraction pattern has characteristic peaks at at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9 or all 10 of the following 2θ angles: 5.94°±0.20°, 12.29°±0.20°, 13.34°±0.20°, 14.94°±0.20°, 17.99°±0.20°, 19.20°±0.20°, 21.54°±0.20°, 23.80°±0.20°, 24.12°±0.20° and 24.54°±0.20°.

[0400] In some embodiments, the crystalline Form I has characteristic peaks at least at the following 2θ angles: 5.94°±0.20°, 12.29°±0.20°, 13.34°±0.20° and 17.99°±0.20°, and optionally has characteristic peaks at at least 1, at least 2, at least 3, at least 4, at least 5 or all 6 of the following 2θ angles: 14.94°±0.20°, 19.20°±0.20°, 21.54°±0.20°, 23.80°±0.20°, 24.12°±0.20° and 24.54°±0.20°.

[0401] In some embodiments, the crystalline Form I has characteristic peaks at least at the following 2θ angles: 5.94°±0.20°, 12.29°±0.20°, 13.34°±0.20° and 17.99°±0.20°, and characteristic peaks at at least 1, at least 2, at least 3, at least 4, at least 5 or all 6 of the following 2θ angles: 14.94°±0.20°, 19.20°±0.20°, 21.54°±0.20°, 23.80°±0.20°, 24.12°±0.20° and 24.54°±0.20°, and optionally a characteristic peak at a 2θ angle of 7.21°±0.20°.

[0402] The XRPD pattern of the above-mentioned Compound 3 Phosphate I Crystalline Form is shown in FIG21 .

[0403] The XRPD pattern analysis data of the above-mentioned Compound 3 Phosphate I Crystalline Form are shown in Table 11.

[0404] Table 11: XRPD pattern analysis data of Compound 3 Phosphate I crystal form

[0405] The differential scanning calorimetry curve of the above-mentioned Compound 3 phosphate I crystal form has an endothermic peak starting point at 73.3±3.0°C and another endothermic peak starting point at 90.4±3.0°C.

[0406] The thermogravimetric analysis curve of the above-mentioned Compound 3 phosphate form I showed a weight loss of 3.18% at 115.0±3.0°C.

[0407] The DSC and TGA overlays of the above-mentioned Compound 3 Phosphate Form I are shown in FIG22 .

[0408] The present invention provides a mesylate salt of Compound 3 in Form J, which has an X-ray powder diffraction pattern with characteristic peaks at at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, or all 14 of the following 2θ angles: 7.87°±0.20°, 11.94°±0.20°, 12.32°±0.20° , 14.75°±0.20°, 15.27°±0.20°, 15.81°±0.20°, 16.75°±0.20°, 18.21°±0.20°, 18.96°±0.20°, 21.89°±0.20°, 23.51°±0.20°, 24.44°±0.20°, 27.96°±0.20° and 30.06°±0.20°.

[0409] In some embodiments, the crystalline Form J has characteristic peaks at least at the following 2θ angles: 14.75°±0.20°, 15.81°±0.20°, and 21.89°±0.20°, and optionally at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, or all 11 of the following 2θ angles: 7.87°±0.20°, 11.94°±0.20°, 12.32°±0.20°, 15.27°±0.20°, 16.75°±0.20°, 18.21°±0.20°, 18.96°±0.20°, 23.51°±0.20°, 24.44°±0.20°, 27.96°±0.20° and 30.06°±0.20°.

[0410] In some embodiments, the crystalline form J has characteristic peaks at least at the following 2θ angles: 14.75°±0.20°, 15.81°±0.20° and 21.89°±0.20°, and has characteristic peaks at at least 1, at least 2, at least 3, at least 4 or all 5 of the following 2θ angles: 15.27°±0.20°, 16.75°±0.20°, 18.96°±0.20°, 2 3.51°±0.20°, 24.44°±0.20°, and optionally characteristic peaks at at least 1, at least 2, at least 3, at least 4, at least 5 or all 6 of the following 2θ angles: 7.87°±0.20°, 11.94°±0.20°, 12.32°±0.20°, 18.21°±0.20°, 27.96°±0.20° and 30.06°±0.20°.

[0411] The XRPD pattern of the above-mentioned Compound 3 mesylate salt Form J is shown in FIG23 .

[0412] The XRPD pattern analysis data of the above-mentioned compound 3 mesylate J crystal form are shown in Table 12

[0413] Table 12: XRPD pattern analysis data of Compound 3 Methanesulfonate Form J

[0414] The differential scanning calorimetry curve of the above-mentioned Compound 3 mesylate salt form J has an endothermic peak starting point at 247.2±3.0°C.

[0415] The thermogravimetric analysis curve of the above-mentioned Compound 3 mesylate salt Form J shows an initial weight loss temperature of approximately 247.4°C.

[0416] The DSC and TGA overlay of the above-mentioned Compound 3 mesylate Form J is shown in FIG24 .

[0417] The present invention provides Compound 3 formate K crystalline form, whose X-ray powder diffraction pattern has characteristic peaks at at least 3, at least 4, at least 5, at least 6, at least 7, at least 8 or all 9 of the following 2θ angles: 10.76°±0.20°, 11.92°±0.20°, 13.91°±0.20°, 14.38°±0.20°, 15.15°±0.20°, 18.41°±0.20°, 24.04°±0.20°, 24.90°±0.20° and 30.61°±0.20°.

[0418] In some embodiments, the crystalline form K has characteristic peaks at least at the following 2θ angles: 11.92°±0.20°, 15.15°±0.20° and 24.04°±0.20°, and optionally has characteristic peaks at at least 1, at least 2, at least 3, at least 4, at least 5 or all 6 of the following 2θ angles: 10.76°±0.20°, 13.91°±0.20°, 14.38°±0.20°, 18.41°±0.20°, 24.90°±0.20° and 30.61°±0.20°.

[0419] In some embodiments, the crystalline form K has characteristic peaks at least at the following 2θ angles: 11.92°±0.20°, 15.15°±0.20° and 24.04°±0.20°, and characteristic peaks at at least 1, at least 2, at least 3 or all 4 of the following 2θ angles: 13.91°±0.20°, 14.38°±0.20°, 18.41°±0.20° and 30.61°±0.20°, and optionally at any 1 or all 2 of the following 2θ angles: 10.76°±0.20° and 24.90°±0.20°.

[0420] The XRPD pattern of the formate K form of the above-mentioned compound 3 is shown in FIG25 .

[0421] The XRPD pattern analysis data of the formate salt K form of the above-mentioned compound 3 are shown in Table 13:

[0422] Table 13: XRPD pattern analysis data of compound 3 formate salt K form

[0423] The differential scanning calorimetry curve of the formate K crystal form of the above-mentioned compound 3 has an endothermic peak starting point at 195.4±3.0°C.

[0424] The thermogravimetric analysis curve of the formate K crystal form of the above-mentioned compound 3 shows an initial weight loss temperature of approximately 200.5°C.

[0425] The DSC and TGA overlay of the formate K crystal form of the above-mentioned compound 3 is shown in Figure 26.

[0426] The present invention provides Compound 3 oxalate salt N crystal form, which has an X-ray powder diffraction pattern with characteristic peaks at at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12 or all 13 of the following 2θ angles: 6.20°±0.20°, 7.49°±0.20°, 10.45°±0.20°, 11.45°±0.20°, 12.25°±0.20°, 12.47°±0.20°, 14.00°±0.20°, 15.06°±0.20°, 16.36°±0.20°, 23.43°±0.20°, 23.78°±0.20°, 24.07°±0.20° and 24.95°±0.20°.

[0427] In some embodiments, the crystalline Form N has characteristic peaks at least at the following 2θ angles: 6.20°±0.20°, 12.47°±0.20°, and 16.36°±0.20°, and optionally has characteristic peaks at at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, or all 9 of the following 2θ angles: 7.49°±0.20°, 11.45°±0.20°, 12.25°±0.20°, 14.00°±0.20°, 15.06°±0.20°, 23.43°±0.20°, 23.78°±0.20°, 24.07°±0.20°, and 24.95°±0.20°.

[0428] In some embodiments, the crystalline Form N has characteristic peaks at least at the following 2θ angles: 6.20°±0.20°, 12.47°±0.20° and 16.36°±0.20°, and characteristic peaks at at least 1, at least 2, at least 3, at least 4, at least 5, at least 6 or all 7 of the following 2θ angles: 7.49°±0.20°, 11.45°±0.20°, 12.25°±0.20°, 14.00°±0.20°, 15.06°±0.20°, 23.43°±0.20°, 23.78°±0.20°, and optionally at any 1 or all 2 of the following 2θ angles: 24.07°±0.20° and 24.95°±0.20°.

[0429] The XRPD pattern of the above-mentioned Compound 3 oxalate salt N crystal form is shown in Figure 27.

[0430] The XRPD pattern analysis data of the above-mentioned Compound 3 oxalate L crystal form are shown in Table 14:

[0431] Table 14: XRPD pattern analysis data of Compound 3 Oxalate Form N

[0432] The present invention provides Compound 3 Pamoate O Crystalline Form, which has an X-ray powder diffraction pattern with characteristic peaks at at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, or all 14 of the following 2θ angles: 6.18°±0.20°, 9.41°±0.20°, 10.40°±0.20°, 11.15°±0.20°, 12.46°±0.20°, 15.59°±0.20°, 18.96°±0.20°, 19.34°±0.20°, 23.12°±0.20°, 23.43°±0.20°, 25.00°±0.20°, 26.25°±0.20°, 29.90°±0.20° and 31.65°±0.20°.

[0433] In some embodiments, the crystalline form O has characteristic peaks at least at the following 2θ angles: 9.41°±0.20°, 11.10°±0.20°, 15.59°±0.20° and 26.25°±0.20°, and optionally at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9 or all of the following 2θ angles. There are 10 characteristic peaks: 6.18°±0.20°, 10.40°±0.20°, 12.46°±0.20°, 18.96°±0.20°, 19.34°±0.20°, 23.12°±0.20°, 23.43°±0.20°, 25.00°±0.20°, 29.90°±0.20° and 31.46°±0.20°.

[0434] In some embodiments, the crystalline form O has characteristic peaks at least at the following 2θ angles: 9.41°±0.20°, 11.10°±0.20°, 15.59°±0.20° and 26.25°±0.20°, and optionally at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7 or all 8 of the following 2θ angles: 10.40°±0. 2θ angles: 20°, 12.46°±0.20°, 18.96°±0.20°, 19.34°±0.20°, 23.12°±0.20°, 23.43°±0.20°, 29.90°±0.20° and 31.46°±0.20°, and optionally there are characteristic peaks at any one or all two of the following 2θ angles: 6.18°±0.20° and 25.00°±0.20°.

[0435] The XRPD pattern of the above-mentioned compound 3 pamoate salt O crystal form is shown in Figure 28.

[0436] The XRPD pattern analysis data of the above-mentioned compound 3 pamoate salt O crystal form are shown in Table 15:

[0437] Table 15: XRPD pattern analysis data of compound 3 pamoate salt O crystal form

[0438] The X-ray powder diffractometer (XRPD) method of the present invention is shown in Table A:

[0439] Table A

[0440] The differential scanning calorimeter (DSC) and thermal gravimetric analysis (TGA) methods of the present invention are shown in Table B:

[0441] Table B

[0442] V. Uses, Methods of Treatment, and Pharmaceutical Compositions

[0443] The compounds of the present invention are NMDA receptor antagonists. Therefore, the compounds of the present invention, their pharmaceutically acceptable salts, enantiomers, diastereomers, tautomers, solvates, isotope-substituted products, polymorphs, prodrugs or metabolites can be used to modulate the activity of NMDA receptors.

[0444] The present invention also provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of the present invention, a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, isotopic substitution, polymorph, prodrug or metabolite thereof, and a pharmaceutically acceptable carrier or excipient. The pharmaceutical composition of the present invention can be used to modulate NMDA receptor activity, thereby being useful for treating and / or preventing NMDA receptor-mediated diseases. The pharmaceutically acceptable salts of the compounds of the present invention are as described in any embodiment herein. Herein, modulating NMDA receptor activity can be used to treat and / or prevent NMDA receptor-mediated diseases. Therefore, in some embodiments, the present invention provides a compound of the present invention, a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, isotopic substitution, polymorph, prodrug or metabolite thereof, or the use of a pharmaceutical composition of the present invention in the preparation of a medicament for treating or preventing NMDA receptor-mediated diseases. The pharmaceutically acceptable salts of the compounds of the present invention are as described in any embodiment herein. In other embodiments, the present invention provides a compound of the present invention, a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, isotopic substitution, polymorph, prodrug or metabolite thereof for use in treating or preventing NMDA receptor-mediated diseases.

[0445] In some embodiments, the present invention provides a method for treating or preventing a disease mediated by an NMDA receptor in a subject, the method comprising administering to the subject a therapeutically effective amount or a prophylactic effective amount of a compound of the present invention, a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, isotopic substitution, polymorph, prodrug or metabolite thereof, or a pharmaceutical composition comprising a therapeutically effective amount or a prophylactic effective amount of a compound of the present invention, a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, isotopic substitution, polymorph, prodrug or metabolite thereof. The drug can be administered orally, intraduodenally, by parenteral injection (including intrapulmonary, intranasal, intrathecal, intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion), topically, and rectally. Those skilled in the art are familiar with administration techniques that can be used for the compounds and methods described herein, such as those discussed in Goodman and Gilman, The Pharmacological Basis of Therapeutics, current ed.; Pergamon; and Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, Pa. In a preferred embodiment, the compounds of the present invention, their pharmaceutically acceptable salts, enantiomers, diastereomers, tautomers, solvates, isotopically substituted, polymorphs, prodrugs or metabolites, or pharmaceutical compositions thereof, are administered orally.

[0446] Suitable pharmaceutical compositions can be formulated by methods known in the art and by their mode of administration and dosage determined by a skilled practitioner. With regard to parenteral administration, the compound can be dissolved in sterile water or physiological saline or in a pharmaceutically acceptable vehicle (such as those for vitamin K) for administering a water-insoluble compound. With regard to enteral administration, the compound can be administered in tablet or capsule form or dissolved in a liquid form. Tablets or capsules can be enteric-coated or in the form of a formulation for sustained release. A variety of suitable formulations are known, including polymers or protein microparticles, ointments, pastes, gels, hydrogels or solutions encapsulating the compound to be released, which can be used for compounds surface or topically. Sustained release patches or implants can be used to provide release over an extended period. Preparations for parenteral administration can, for example, contain excipient polyalkylene glycols (such as polyethylene glycol), oils of plant origin or hydrogenated naphthalene. Biocompatible, biodegradable lactide polymers, lactide / glycolide copolymers or polyoxyethylene-polyoxypropylene copolymers can be used to control the release of the compound. Other potentially useful parenteral delivery systems for modulating compounds include ethylene-vinyl acetate copolymer particles, osmotic pumps, implantable infusion systems, and liposomes. Formulations for inhalation may contain excipients such as lactose, or may be aqueous solutions containing, for example, polyoxyethylene-9-lauryl ether, glycocholate, and deoxycholate, or may be oily solutions for administration as nasal drops, or in the form of a gel.

[0447] It should be noted that dosage values ​​may vary with the precise imaging protocol. With respect to any particular subject, the specific dosage regimen may be adjusted over time according to individual needs and the professional judgment of the person administering or supervising the administration of the composition. The dosage ranges described herein are exemplary only and do not limit the dosage ranges that a medical practitioner may select. The amount of active compound in the composition may vary according to factors such as the subject's disease state, age, sex, and weight. The dosage regimen may be adjusted to provide optimal imaging results. For example, a single bolus may be administered, several divided doses may be administered over time, or the dosage may be proportionally reduced or increased as indicated by the imaging results. It may be advantageous to formulate parenteral compositions in a unit dosage form that is easy to administer and achieves dosage uniformity.

[0448] Herein, diseases associated with NMDA receptor activity include, but are not limited to, cerebral ischemia, traumatic brain injury, infarction, stroke, Alzheimer's disease, Parkinson's disease, Huntington's chorea, depression, anxiety, bipolar disorder, schizophrenia, autism, epilepsy, anti-NMDA receptor encephalitis, neuropathic pain, and other nervous system events or neurodegeneration caused by NMDA receptor activation. In some embodiments, the neuropathic pain includes peripheral diabetic neuropathy, postherpetic neuralgia, complex regional pain syndrome, peripheral neuropathy, chemotherapy-induced neuropathic pain, cancer neuropathic pain, neuropathic low back pain, HIV neuropathic pain, trigeminal neuralgia, and central post-stroke pain. In particular, the diseases associated with NMDA receptor activity described herein or NMDA receptor-mediated diseases are depression, schizophrenia, or epilepsy. The present invention also found that regulating NMDAR activity has the effect of increasing appetite, and NMDAR targets are also expected to be used to treat anorexia caused by various reasons. The present invention also found that regulating NMDAR activity is expected to be used to treat sleep disorder-related diseases such as insomnia, sleep apnea syndrome, atypical sleep cycle rhythm disorder, Down syndrome; and is also expected to be used to treat diseases such as itching.

[0449] In some embodiments, the compounds provided herein, their pharmaceutically acceptable salts, enantiomers, diastereomers, tautomers, solvates, isotopic substitutions, polymorphs, prodrugs or metabolites, or pharmaceutical compositions thereof, may also be used for anesthesia and analgesia of a subject. Therefore, in some embodiments, provided herein is an anesthetic or analgesic containing a compound as described herein, its pharmaceutically acceptable salts, enantiomers, diastereomers, tautomers, solvates, isotopic substitutions, polymorphs, prodrugs or metabolites as active ingredients that have an anesthetic or analgesic effect, and a carrier or excipient that is suitable for administration to a human or animal body and is safe. In other embodiments, also provided herein is the use of a compound as described herein, its pharmaceutically acceptable salts, enantiomers, diastereomers, tautomers, solvates, isotopic substitutions, polymorphs, prodrugs or metabolites in the preparation of an anesthetic or analgesic. In other embodiments, the present invention also provides a method of anesthesia or analgesia, comprising administering to an individual or subject in need thereof an effective amount of a compound described herein, its pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, isotopic substitution, polymorph, prodrug or metabolite, or a pharmaceutical composition thereof.

[0450] The present invention adopts the following abbreviations: Pd2(dba)3: trisdibenzylideneacetone dipalladium, SFC: supercritical fluid chromatography, prep-HPLC: preparative separation by high performance liquid chromatography, Pd(dppf)Cl2: (1,1'-bis(diphenylphosphino)ferrocene)palladium dichloride, Xantphos: 4,5-bisdiphenylphosphino-9,9-dimethylxanthene, (DHQ)2PHAL: hydroquinine 1,4-(2,3-naphthyridine) diether, (DHQD)2PHAL: hydroquinidine 1,4-(2,3-naphthyridine) diether, PCC: pyridinium chlorochromate, NH4Cl: ammonium chloride, THF: tetrahydrofuran, K2CO3: potassium carbonate, TfOH: trifluoromethanesulfonic acid, EA: ethyl acetate, PE: petroleum ether, DCM: dichloromethane, Na2SO4: sodium sulfate.

[0451] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are intended to illustrate the present invention only and are not intended to limit the scope of the invention. The experimental methods in the following examples, for which specific conditions are not specified, are generally based on conventional conditions or the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight.

[0452] Example 1: Preparation of Compound 1

[0453] Step 1: Synthesis of compound 1-2

[0454] Cyclohexanone (40.0 g, 418 mmol), 3-bromo-1-chlorobenzene (40.0 g, 209 mmol, 1-1) and cesium carbonate (149.8 g, 459.6 mmol) were dissolved in dioxane (400 mL) at 25 ° C. Pd2(dba)3 (1.9 g, 2.1 mmol) and Xantphos (2.4 g, 4.2 mmol) were added to the above reaction solution. Nitrogen was replaced, the reaction solution was heated to 100 ° C, and the reaction was continued for 20 hours. The temperature was lowered and filtered, and the filtrate was concentrated to dryness. Compound 1-2 was separated and purified by silica gel column chromatography. LCMS: 209.0 (M+H) + .

[0455] Step 2: Synthesis of Compound 1-3

[0456] Compound 1-2 (20.0 g, 95.4 mmol), copper acetate (9.6 g, 48 mmol), and cerium ammonium nitrate (131.4 g, 239.6 mmol) were added to 1,2-dichloroethane (400 mL) at 25°C. The atmosphere was replaced with nitrogen, and the reaction mixture was reacted at 80°C for 16 hours. The filtrate was filtered, concentrated, and purified by silica gel column chromatography to obtain compound 1-3. LCMS: 207.0 (M-NO2) + .

[0457] Step 3: Synthesis of Compound 1-4

[0458] At 0°C, compound 1-3 (9.0 g, 35 mmol) was added to acetic acid (100 mL), and then zinc powder (11.6 g, 177 mmol) was added to the mixture in batches. The reaction solution was heated to 80°C and stirred for 16 hours. The reaction solution was concentrated, H2O (100 mL) was added, and the pH was adjusted to 12 with aqueous sodium hydroxide solution (2 M). It was extracted with EA (100 mL x 2), the organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to dryness. It was separated and purified by silica gel column chromatography to obtain compound 1-4. LCMS: 224.2 (M+H) + .

[0459] Step 4: Synthesis of Compound 1-5A and Compound 1-5B

[0460] Compound 1-4 (4 g, 17.88 mmol) was separated by SFC to obtain compound 1-5B (1.70 g, retention time Rt = 2.190 min). LCMS: m / z = 224.2 (M+H) + and compound 1-5A (1.75 g, retention time Rt = 4.340 min). LCMS: m / z = 224.2 (M+H) + (SFC conditions: column: ChiralPak IE, 250×40 mm ID, 10 μm; mobile phase: A CO2 and B 50% ethanol (0.1% ammonia) + 50% acetonitrile (0.1% NH3·H3O); gradient: B 40%; flow rate: 120 mL / min).

[0461] Step 5: Synthesis of Compound 1-6

[0462] At 0°C, compound 1-5B (1.0 g, 4.5 mmol) and triethylamine (0.90 g, 8.9 mmol) were dissolved in DCM (20 mL), and chloroacetyl chloride (0.50 g, 4.4 mmol) was slowly added dropwise to the above solution. The reaction was allowed to react at 0°C for 2 hours. Water (10 mL) was added to quench the reaction, and the mixture was extracted with EA (50 mL x 2). The organic phases were combined, washed with saturated brine (10 mL x 1), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to dryness. The mixture was separated and purified by silica gel column chromatography to obtain compound 1-6. LCMS: 300.2 (M+H) + .

[0463] Step 6: Synthesis of Compound 1-7

[0464] At zero degrees Celsius, compound 1-6 (1.2 g, 4.0 mmol) was dissolved in methanol (25 mL), and sodium borohydride (0.3 g, 8.0 mmol) was slowly added in portions. The mixture was reacted at 25°C for 3 hours. The reaction solution was concentrated and purified by silica gel column chromatography to obtain compound 1-7. LCMS: 304.2 (M+H) + .

[0465] Step 7: Synthesis of Compound 1-8

[0466] At zero degrees, compound 1-7 (400 mg, 1.32 mmol) was dissolved in THF (15 mL), and sodium hydroxide (106 mg, 2.65 mmol, 60%) was slowly added in batches. The reaction solution was reacted at room temperature for 2 hours. The reaction solution was quenched with saturated NH4Cl (10 mL) and extracted with EA (50 mL x 2). The organic phases were combined, washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated to obtain compound 1-8, which was separated and purified by silica gel column chromatography. LCMS: 266.2 (M+H) + .

[0467] Step 8: Synthesis of Compound 1

[0468] At 0°C, 1-8 (300 mg, 1.13 mmol) was dissolved in THF (10 mL) and borane dimethyl sulfide (565 μL, 5.65 mmol) was slowly added dropwise. The reaction mixture was heated to 70°C and allowed to react for 4 hours. The reaction was quenched with methanol (5 mL) at 0°C and stirred at room temperature for 1 hour. The mixture was concentrated and purified by prep-HPLC to obtain compound 1.

[0469] MS:252.0(M+H) + . 1 H NMR (400MHz, DMSO) δ7.77(s,1H),7.69(d,J=7.2Hz,1H),7.38-7.34(m,1H),7.28-7.25(m,1H),3.82(dd,J=10.8Hz,10.8Hz 1H),3.64-3.58(m,1H),3.54-3.50(m,1H),2.52-2.50(m,3H),2.38-2.37(m,1H),1.70-1.69(m,3H),1.40-1.37(m,3H),0.85-0.75(m,1H).

[0470] Example 2: Preparation of Compound 2

[0471] Preparation method 1 (chemical resolution intermediate method):

[0472] Step 1: Synthesis of compound 2-1

[0473] At zero degrees, compound 1-5A (1.0 g, 4.47 mmol) and triethylamine (1.2 mL, 8.6 mmol) were dissolved in DCM (20 mL). Chloroacetyl chloride (0.5 g, 4.5 mmol) was slowly added dropwise to the above solution. The reaction solution was reacted at zero degrees for 3 hours. The reaction solution was diluted with ice water (10 mL) and extracted three times with DCM (30 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous Na2SO4, filtered, concentrated, and separated and purified by silica gel column chromatography to obtain compound 2-1. LCMS: 322.2 (M+Na) + .

[0474] Step 2: Synthesis of compound 2-2

[0475] Compound 2-1 (1.1 g, 3.7 mmol) was dissolved in methanol (20 mL) at zero temperature, and sodium borohydride (0.37 g, 9.78 mmol) was added. The reaction mixture was allowed to react at 25°C for 16 hours. The reaction solution was quenched with saturated NH4Cl (20 mL), extracted three times with EA (30 mL), and the combined organic phases were washed with saturated brine, dried over anhydrous Na2SO4, and concentrated to obtain compound 2-2. The mixture was separated and purified by silica gel column chromatography to obtain compound 2-2.

[0476] Step 3: Synthesis of compound 2-3

[0477] At zero degrees Celsius, compound 2-2 (300 mg, 0.993 mmol) was dissolved in THF (5 mL), and sodium hydroxide (80 mg, 2.0 mmol, 60%) was added in portions. The reaction solution was reacted at room temperature for 3 hours. The reaction solution was quenched with saturated NH4Cl solution and extracted twice with EA (30 mL). The combined organic phases were washed with saturated brine, dried over anhydrous Na2SO4, and concentrated to obtain compound 2-3. LCMS: m / z = 266.1 (M+H) + .

[0478] Step 4: Synthesis of compound 2

[0479] At zero degrees Celsius, compound 2-3 (240 mg, 0.903 mmol) was dissolved in THF (20 mL) and borane dimethyl sulfide (1.0 mL, 10 M, 10 mmol) was slowly added dropwise. The reaction solution was heated to 60°C and reacted for 16 hours. The reaction solution was quenched with methanol (20 mL) and stirred at room temperature for 1 hour. The solution was concentrated and purified by prep-HPLC to obtain compound 2. LCMS: 252.2 (M+H) + .

[0480] 1H NMR (400MHz, DMSO) δ7.82-7.76(m,1H),7.73-7.66(m,1H),7.38(t,J=8.0Hz,1H),7.32-7.25(m,1H),3.90-3.77(m,1H),3.67-3 .58(m,1H),3.56-3.49(m,1H),2.47-2.35(m,2H),2.24-2.14(m,1H),1.77-1.59(m,3H),1.49-1.33(m,3H),0.92-0.74(m,1H).

[0481] Method 2 (chiral synthesis route):

[0482] Step 1: Synthesis of compound 2-B

[0483] At room temperature, 2-A (50.0 g, 261 mmol), cyclohexene-1-boronic acid pinacol ester (32.9 g, 261 mmol), and sodium carbonate (83.04 g, 783.5 mmol) were dissolved in a mixture of dioxane (500 mL) and water (50 mL). Pd(dppf)Cl2 (3.8 g, 5.2 mmol) was added, and after nitrogen displacement, the temperature was raised to 90°C and refluxed for 16 hours. The reaction mixture was concentrated to obtain compound 2-B. The mixture was then purified by silica gel column chromatography.

[0484] 1 H NMR (400MHz, DMSO) δ7.42-7.40(m,1H),7.38-7.31(m,2H),7.29-7.25(m,1H),6.24-6. 20(m,1H),2.36-2.31(m,2H),2.21-2.15(m,2H),1.75-1.68(m,2H),1.62-1.56(m,2H).

[0485] Step 2: Synthesis of compound 2-C

[0486] At room temperature, K2CO3 (86.0 g, 622.8 mmol), potassium ferricyanide (205.0 g, 622.8 mmol), methanesulfonamide (23.7 g, 249.1 mmol), potassium osmate dihydrate (3.8 g, 10.4 mmol) and (DHQ)2PHAL (32.3 g, 41.5 mmol) were dissolved in water (400 mL). 2-B (40.0 g, 208 mmol) was dissolved in tert-butanol (250 mL) and added to the above reaction solution. The reaction was allowed to react at room temperature for 16 hours. EA (500 mL) was added to the reaction solution, and the mixture was washed three times with 15% aqueous sodium hydroxide solution (200 mL x 3). The organic phase was dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated to obtain compound 2-C. LCMS: 209.4 (M-18) + .

[0487] Step 3: Synthesis of compound 2-E

[0488] At -40 ° C, TfOH (32.2 mL, 364 mmol) was added dropwise to acetonitrile (550 mL) of 2-C (37.5 g, 165 mmol). After the addition was completed, the dry ice bath was removed, the reaction solution was naturally warmed to room temperature, and the reaction was continued for 1 hour. Water (370 mL) was added to the reaction solution and stirred for 10 minutes. The acetonitrile was removed by concentration under reduced pressure. The remaining aqueous solution was heated to 100 ° C and refluxed for 16 hours. The reaction solution was adjusted to pH 10 with aqueous sodium hydroxide solution. EA (800 mL) was added for extraction. The organic phase was washed with water (300 mL x 3) and saturated brine (300 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated to obtain. PE:EA (300 mL, v / v = 5 / 1) was added to the mixture and stirred for 10 minutes. Filter, collect the filter cake, and dry under reduced pressure to obtain compound 2-E. LCMS: 226.4 (M+H) + .

[0489] Step 4: Synthesis of compound 2-F

[0490] 2-E (54.0 g, 239 mmol) and triethylamine (83.0 mL, 597 mmol) were added to methyltetrahydrofuran (1 L) at 0°C. Chloroacetyl chloride (22.8 mL, 286.5 mmol) was slowly added dropwise. The mixture was reacted at 0°C for 1 hour. The reaction solution was diluted with water (500 mL) and extracted three times with EA (300 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated. Compound 2-E was separated and purified by silica gel column chromatography. LCMS: 302.4 (M+H) + .

[0491] Step 5: Synthesis of compound 2-1

[0492] At room temperature, 2-E (40.0 g, 132 mmol) was dissolved in DCM (700 mL) and PCC (71.3 g, 331 mmol) was added. The temperature was raised to 30°C and the reaction was allowed to proceed for 16 hours. The reaction solution was directly concentrated. Compound 2-1 was obtained by separation and purification via silica gel column chromatography. LCMS: 300.0 (M+H) + .

[0493] Step 6: Synthesis of compound 2-2

[0494] Compound 2-1 (1.1 g, 3.7 mmol) was dissolved in methanol (20 mL) at zero temperature, and sodium borohydride (0.37 g, 9.78 mmol) was added. The reaction mixture was allowed to react at 25°C for 16 hours. The reaction solution was quenched with saturated NH4Cl (20 mL), extracted three times with EA (30 mL), and the combined organic phases were washed with saturated brine, dried over anhydrous Na2SO4, and concentrated to obtain compound 2-2. The mixture was separated and purified by silica gel column chromatography to obtain compound 2-2.

[0495] Step 7: Synthesis of compound 2-3

[0496] At zero degrees Celsius, compound 2-2 (300 mg, 0.993 mmol) was dissolved in THF (5 mL), and sodium hydride (80 mg, 2.0 mmol, 60%) was added in portions. The reaction solution was reacted at room temperature for 3 hours. The reaction solution was quenched with saturated NH4Cl solution and extracted twice with EA (30 mL). The combined organic phases were washed with saturated brine, dried over anhydrous Na2SO4, and concentrated to obtain compound 2-3. LCMS: m / z = 266.1 (M+H) + .

[0497] Step 8: Synthesis of Compound 2

[0498] At zero degrees Celsius, compound 2-3 (240 mg, 0.903 mmol) was dissolved in THF (20 mL), and borane dimethyl sulfide (1.0 mL, 10 M in DMS, 10 mmol) was slowly added dropwise. The reaction solution was heated to 60°C and reacted for 16 hours. The reaction solution was quenched with methanol (20 mL) and stirred at room temperature for 1 hour. The crude product was concentrated to obtain a crude product, which was purified by prep-HPLC to obtain compound 2. LCMS: 252.2 (M+H) + .

[0499] 1H NMR (400MHz, DMSO) δ7.82-7.76(m,1H),7.73-7.66(m,1H),7.38(t,J=8.0Hz,1H),7.32-7.25(m,1H),3.90-3.77(m,1H),3.67-3 .58(m,1H),3.56-3.49(m,1H),2.47-2.35(m,2H),2.24-2.14(m,1H),1.77-1.59(m,3H),1.49-1.33(m,3H),0.92-0.74(m,1H).

[0500] Example 3: Preparation of Compound 3 Hydrochloride

[0501] Step 1: Synthesis of compound 3-2

[0502] Dissolve cyclohexanone (25.6 g, 261 mmol), 1-bromo-2-chlorobenzene (25.0 g, 131 mmol, 3-1) and cesium carbonate (93.6 g, 287 mmol) in dioxane (250 mL) at 25°C, and add Pd2(dba)3 (1.2 g, 1.3 mmol) and Xantphos (1.5 g, 2.6 mmol). Replace nitrogen, raise the temperature to 100°C, and react for 20 hours. Cool to room temperature, filter, and concentrate the filtrate to obtain a crude product. Separate and purify by silica gel column chromatography to obtain compound 3-2. LCMS: 209.0 (M+H) + .

[0503] Step 2: Synthesis of compound 3-3

[0504] Compound 3-2 (24.0 g, 115 mmol), copper acetate (11.5 g, 57.5 mmol), and cerium ammonium nitrate (157.6 g, 287.5 mmol) were added to 1,2-dichloroethane (350 mL) at 25°C, the atmosphere was replaced with nitrogen, and the mixture was reacted at 80°C for 16 hours. The crude product was filtered and concentrated, and purified by silica gel column chromatography to obtain compound 3-3. LCMS: 276.1 (M+Na) + .

[0505] Step 3: Synthesis of compound 3-4

[0506] At 0°C, compound 3-3 (16.0 g, 63.0 mmol) was added to acetic acid (200 mL), and then zinc powder (20.6 g, 315.3 mmol) was added in batches. The reaction solution was heated to 80°C and stirred for 16 hours. The reaction solution was concentrated to obtain a crude product, H2O (200 mL) was added, and the pH was adjusted to 12 with aqueous sodium hydroxide solution (2M). EA (200 mL x 2) was used for extraction, and the organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to obtain a crude product, which was separated and purified by silica gel column chromatography to obtain compound 3-4. LCMS: 224.2 (M+H) + .

[0507] Step 4: Synthesis of compound 3-4A

[0508] Compound 3-4 (6.0 g, 26.8 mmol) was added to anhydrous ethanol (25 mL) at 25 ° C. The solution was stirred at 65 ° C until clear. L-pyroglutamic acid (1.9 g, 14.7 mmol) was dissolved in a mixed solution of ethanol (12 mL) and H2O (3 mL). The mixed solution was slowly added dropwise to the above reaction solution. The temperature was raised to 75 ° C and the reaction was carried out for 1 hour. After standing overnight, a white solid precipitated. Filter and wash the filter cake twice with ethanol (10 ml). Add H2O (30 mL) to dissolve the filter cake and adjust the pH to 10 with 2M sodium hydroxide aqueous solution. Extract twice with EA (100 mL) and combine the organic phases. Dry with anhydrous Na2SO4, filter, and concentrate the filtrate under reduced pressure to obtain the crude product of compound 3-4A. Compound 3-4A was dissolved in anhydrous ethanol and the above process was repeated to obtain compound 3-4A. LCMS: m / z = 224.2 (M+H) + .

[0509] Step 5: Synthesis of compound 3-5

[0510] At 0°C, 3-4A (26.0 g, 116 mmol) was dissolved in methanol (500 mL). Sodium borohydride (13.2 g, 349 mmol) was slowly added in portions and allowed to react at 25°C for 2 hours. The reaction solution was concentrated to obtain a crude product, which was separated and purified by silica gel column chromatography to obtain compound 3-5. LCMS: 226.2 (M+H) + .

[0511] Step 6: Synthesis of Compound 3-6

[0512] At 0°C, compound 3-5 (23.0 g, 102 mmol) and triethylamine (22.0 g, 217.1 mmol) were dissolved in DCM (500 mL), and chloroacetyl chloride (14.7 g, 130.3 mmol) was slowly added dropwise to the above solution. The reaction was carried out at 0°C for 2 hours. Water (100 mL) was added to quench the mixture, and the mixture was extracted twice with EA (200 mL). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous Na2SO4, and filtered. The crude product of the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain compound 3-6. LCMS: 302.2 (M+H) + .

[0513] Step 7: Synthesis of Compound 3-7

[0514] Compound 3-6 (1.5 g, 5.0 mmol) was dissolved in THF (30 mL) at 0°C, and sodium hydroxide (0.5 g, 12.4 mmol, 60%) was slowly added in portions. The reaction was allowed to react at room temperature for 2 hours. The reaction was quenched with saturated NH4Cl (20 mL) and extracted twice with EA (50 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated to obtain a crude product, which was separated and purified by silica gel column chromatography to obtain compound 3-7. LCMS: 266.2 (M+H) + .

[0515] Step 8: Synthesis of compound 3

[0516] At 0°C, compound 3-7 (1.4 g, 5.27 mmol) was dissolved in THF (50 mL) and borane dimethyl sulfide (2.1 mL, 21.07 mmol) was slowly added dropwise. The temperature was raised to 70°C and the reaction was allowed to react for 4 hours. The temperature was lowered to 0°C and the reaction was slowly quenched with methanol (10 mL). The reaction was stirred at room temperature for 1 hour. The crude product was concentrated under reduced pressure and purified by prep-HPLC to obtain compound 3 hydrochloride.

[0517] LCMS: 252.0 (M+H) + . 1 H NMR (400MHz, DMSO)8.28-8.26(m,1H),7.63-7.59(m,1H),7.51-7.48(m,2H),4.25-4.21(m,1H),4.19-4.13(m,1H),4.05-4.01(m,1H),3. 42-3.36(m,1H),3.08(d,J=12.8Hz,1H),2.72-2.69(m,1H),2.11-1.96(m,3H),1.71-1.55(m,2H),1.47-1.38(m,1H),0.80-0.69(m,1H).

[0518] Example 4: Preparation of Compounds 13 and 17 Hydrochlorides

[0519] Step 1: Synthesis of compound 13-2

[0520] At room temperature, 3-chloro-1-(cyclohex-1-enyl)benzene (15.0 g, 77.8 mmol, 13-1), NMO (18.5 g, 158 mmol) and potassium osmate dihydrate (1.4 g, 3.8 mmol) were added to a mixed solvent of tert-butanol (100 mL) and H2O (150 mL). Nitrogen was replaced three times and the mixture was stirred at room temperature for 12 hours. EA (500 mL) was added to the reaction solution and washed three times with 15% aqueous sodium hydroxide solution (100 mL x 3). The organic phase was dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. Compound 13-2 was separated and purified by silica gel column chromatography. LCMS: 209.0 (M-18) + .

[0521] Step 2: Synthesis of compound 13-4

[0522] At -40 ° C, TfOH (13.0 mL, 147 mmol) was added dropwise to a solution of 13-2 (14.0 g, 61.8 mmol) in acetonitrile (250 mL) at -40 ° C. After the addition was completed, the dry ice bath was removed and the reaction solution was naturally warmed to room temperature and stirred for 1 hour. Water (150 mL) was added to the reaction solution and stirred for 30 minutes. The acetonitrile was removed by concentration under reduced pressure. The remaining aqueous solution was heated to 100 ° C and refluxed for 16 hours. The pH of the reaction solution was adjusted to 10 with 1N sodium hydroxide aqueous solution, and EA (300 mL) was added to the above mixed solution for extraction. The organic phase was washed with water (100 mL x 3) and saturated brine (100 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure, and PE:EA (200 mL, v / v=5 / 1) was added to the mixture and stirred for 10 minutes. Filter, collect the filter cake, and dry under reduced pressure to obtain compound 13-4. LCMS: 226.0 (M+H) + .

[0523] Step 3: Synthesis of compound 13-5

[0524] 13-4 (8.50 g, 37.7 mmol) and triethylamine (13.0 mL, 93.5 mmol) were dissolved in methyltetrahydrofuran (100 mL) at 0°C. Chloroacetyl chloride (3.60 mL, 45.2 mmol) was slowly added dropwise. After the addition, stirring was continued at 0°C for 2 hours. The reaction solution was diluted with water (200 mL) and extracted three times with EA (100 mL x 3). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated to give a crude product. Compound 13-5 was separated and purified by silica gel column chromatography. LCMS: 302.0 (M+H) + .

[0525] Step 4: Synthesis of compound 13-6

[0526] At room temperature, 13-5 (8.5 g, 28 mmol) was dissolved in DCM (100 mL), and PCC (15 g, 69.6 mmol) was added. The mixture was heated to 30°C and stirred for 12 hours. The reaction solution was directly concentrated. Compound 13-6 was obtained by separation and purification via silica gel column chromatography. LCMS: 300.0 (M+H) + .

[0527] Step 5: Synthesis of compound 13-7

[0528] Dissolve 13-6 (6.0 g, 20 mmol) in methanol (80 mL) at 0°C, and slowly add sodium borohydride (1.5 g, 39.7 mmol) in batches. React at 0°C for 2 hours. Concentrate the reaction mixture directly. Separate and purify by silica gel column chromatography to obtain compound 13-7. LCMS: 302.0 (M+H) + .

[0529] Step 6: Synthesis of compound 13-8

[0530] Dissolve 13-7 (4.7 g, 15.5 mmol) in isopropanol (60 mL) at 0°C, and add potassium tert-butoxide (5.20 g, 46.3 mmol) in portions. After reacting at 0°C for 30 minutes, remove the ice bath and allow the mixture to warm to room temperature for 2 hours. Concentrate the reaction mixture to obtain the product. Add water (50 mL), stir for 10 minutes, and filter. Collect the filter cake and dry it in vacuo to obtain compound 13-7. LCMS: 266.0 (M+H) + .

[0531] Step 7: Synthesis of compound 13-9

[0532] At 0°C, 13-8 (100.0 mg, 0.376 mmol) was dissolved in THF (3 mL), and boron trifluoride etherate (252.0 uL, 0.941 mmol) was slowly added dropwise. The reaction was allowed to react at 0°C for 20 minutes. NaBD4 (220.0 mg, 1.128 mmol) was then added to the reaction solution in batches, and the temperature was raised to 65°C for 2 hours. The reaction solution was cooled to room temperature and quenched with methanol (5 mL). The reaction solution was concentrated and purified by silica gel column chromatography to obtain compound 13-9. LCMS: 254.4 (M+H) + .

[0533] Step 8: Synthesis of Compounds 13 Hydrochloride and 17 Hydrochloride

[0534] Compound 13-9 (40 mg, 0.138 mmol) was separated by SFC, and the first fraction (Rt = 1.027 min) was collected and dried to obtain a colorless oil. Pure water (10 mL) and 1M dilute hydrochloric acid (200 uL) were added to the compound. The first fraction P1 (Rt = 1.027 min) was collected and lyophilized to obtain compound 13 hydrochloride. LCMS: 254.1 (M+H) + .

[0535] 1 H NMR (400MHz, DMSO) δ10.33(s,1H),9.37(s,1H),7.96(s,1H),7.92-7.91(m,1H),7.58-7.50(m,2H),4.12-3.97(m,3H),2.59-2.55(m,1H),1.9 8(td,J=13.2,3.2Hz,1H),1.92-1.85(m,1H),1.81-1.71(m,1H),1.70- 1.62(m,1H),1.57-1.53(m,1H),1.47-1.35(m,1H),0.87-0.76(m,1H).

[0536] The second fraction (Rt = 1.235 min) was collected and dried to give a colorless oily compound. Pure water (10 mL) and 1M dilute hydrochloric acid (200 uL) were added to the compound. Freeze-dried to give compound 17 hydrochloride. LCMS: 254.1 (M+H) + .

[0537] 1H NMR (400MHz, DMSO) δ10.32(s,1H),9.36(s,1H),7.96(s,1H),7.92-7.90(m,1H),7.57-7.51(m,2H),4.11-3.97(m,3H),2.59-2.55(m,1H),1.9 8(td,J=13.6,3.2Hz,1H),1.92-1.85(m,1H),1.82-1.71(m,1H),1.68- 1.64(m,1H),1.59-1.51(m,1H),1.47-1.34(m,1H),0.87-0.76(m,1H).

[0538] (SFC conditions: column: ChiralPAK-IG_100x3.0mm_3μm; mobile phase: A for CO2 and B for IPA (0.1% DEA); gradient: 10% in 3min flow rate: 2.0mL / min).

[0539] Example 5: Preparation of Compounds 30 and 31

[0540] Step 1: Synthesis of compound 30-2

[0541] At 25°C, 1,4-dioxane (50 mL) and H₂O (10 mL) were added to bromobenzene (5.0 g, 32 mmol, 30-1), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (6.7 g, 32 mmol), and Na₂CO₃ (6.75 g, 63.7 mmol). The atmosphere was replaced with nitrogen three times. Pd(dppf)Cl₂.CH₂Cl₂ (1.30 g, 1.59 mmol) was added, and the atmosphere was replaced with nitrogen three times. The temperature was raised to 100°C and the reaction was allowed to react for 16 hours. The mixture was then cooled to 25°C. The reaction was quenched by the addition of H₂O (100 mL), and the mixture was extracted with EA three times (100 mL x 3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated to obtain the crude product. Compound 30-2 was obtained by separation and purification via silica gel column chromatography. LCMS: 161.2 (M+H) + .

[0542] Step 2: Synthesis of compound 30-3

[0543] At 25°C, tert-butanol (50 mL) and H₂O (25 mL) were added to 30-2 (4.00 g, 19.5 mmol) and potassium osmate dihydrate (300 mg, 0.976 mmol). N-methylmorpholine oxide (4.60 g, 39.3 mmol) was then slowly added to the reaction mixture. The atmosphere was replaced with N₂ three times and the reaction was allowed to proceed at 25°C for 16 hours. The mixture was diluted with EA (30 mL) and filtered. The filtrate was extracted with EA (50 mL x 3). The organic layer was washed with saturated brine (30 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated to obtain the crude product. Compound 30-3 was purified by silica gel column chromatography.

[0544] Step 3: Synthesis of compound 30-5

[0545] 30-3 (500 mg, 2.49 mmol) was dissolved in acetonitrile (10 mL), replaced with N2 three times, cooled to -40°C, and TfOH (0.55 mL, 6.2 mmol) was slowly added dropwise. After the addition was complete, the cooling bath was removed and the mixture was stirred at room temperature for 2 hours. H2O (20 mL) was added and stirred for 10 minutes. The reaction solution was concentrated to remove the acetonitrile, and the remaining mother liquor was heated to 100°C and refluxed for 12 hours. The reaction solution was cooled to room temperature, adjusted to pH 10 with 1N NaOH solution, and extracted twice with EA (50 mL × 2). The organic layer was washed with saturated brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated to obtain the crude product. The mixture was slurried with 50 mL of a mixed solvent (PE / EA = 5 / 1), filtered, and concentrated under reduced pressure to obtain 30-5. LCMS: 194.2 (M+H) + .

[0546] Step 4: Synthesis of compound 30-6

[0547] Under nitrogen, 30-5 (250 mg, 0.996 mmol) was dissolved in DCM (10 mL), cooled to 0°C, and triethylamine (0.35 mL, 2.518 mmol) was slowly added dropwise. The mixture was stirred for 30 min. Chloroacetyl chloride (0.10 mL, 1.3 mmol) was added dropwise, and the mixture was warmed to room temperature and maintained for 2.5 hours. The reaction mixture was concentrated under reduced pressure to obtain the crude product, which was separated and purified by silica gel column chromatography to obtain compound 30-6. LCMS: 270.0 (M+H) + .

[0548] Step 5: Synthesis of compound 30-7

[0549] At 25°C, 30-6 (250 mg, 0.927 mmol) was dissolved in isopropanol (10 mL), potassium tert-butoxide (310 mg, 2.76 mmol) was added, the atmosphere was replaced with N2 three times, and the mixture was stirred for 5 hours. The reaction mixture was directly concentrated to obtain the crude product. Water (20 mL) was added, stirred for 10 minutes, and filtered. The filter cake was collected and dried under vacuum to obtain 30-7. LCMS: 234.2 (M+H) + .

[0550] Step 6: Synthesis of compound 30-8

[0551] At 0°C, 30-7 (150 mg, 0.643 mmol) was dissolved in THF (10 mL). Borane dimethyl sulfide (0.35 mL, 3.500 mmol) was slowly added dropwise. The temperature was raised to 70°C and the reaction was allowed to react for 16 hours. The temperature was lowered to 0°C and methanol (1 mL) was added to quench the reaction. Stir at room temperature for 1 hour. Sodium borohydride (50 mg, 1.322 mmol) was slowly added portionwise. The temperature was raised to 50°C and the reaction was continued for 16 hours. The reaction solution was concentrated to obtain the crude product, which was separated and purified by silica gel column chromatography to obtain compound 30-8.

[0552] Step 7: Synthesis of compounds 30 and 31

[0553] 30-8 (100 mg, 0.456 mmol) was separated by SFC. The second fraction (Rt = 4.4 min) was collected and dried to give a colorless oily compound, which was lyophilized with purified water to give compound 30. LCMS: 220.2 (M+H) + .

[0554] 1 H NMR (400MHz, CDCl3) δ7.55-7.48(m,2H),7.43-7.34(m,2H),7.32-7.27(m,1H),4.12-4.07(m,1H),4.05-3. 91(m,3H),3.72-3.63(m,1H),3.62-3.51(m,2H),3.27-3.15(m,1H),2.78-2.59(m,2H),1.92-1.83(m,1H).

[0555] The first fraction (Rt = 3 min) was collected and dried to obtain a colorless oily compound, which was lyophilized with purified water to obtain compound 31. LCMS: 220.2 (M+H) + .

[0556] 1H NMR (400MHz, CDCl3) δ7.55-7.49(m,2H),7.42-7.36(m,2H),7.32-7.27(m,1H),4.10-4.06(m,1H),4.05-3. 91(m,3H),3.71-3.63(m,1H),3.61-3.52(m,2H),3.24-3.14(m,1H),2.78-2.59(m,2H),1.94-1.82(m,1H).

[0557] (SFC conditions: column: ChiralPak IH, 40 mm ID×250 mm, 10 μm; mobile phase: A for Supercritical CO2 and B for 0.1% NH3.H2O MeOH; gradient: 30% B; flow rate: 120 mL / min).

[0558] Example 6: Preparation of Compounds 33 and 36 Hydrochloride

[0559] Step 1: Synthesis of compound 33-2

[0560] 2-Phenylcyclohexanone (5 g, 28.70 mmol, 33-1) was dissolved in 1,2-dichloroethane (100 mL), and cerium ammonium nitrate (47.2 g, 86.10 mmol) and copper acetate (5.21 g, 28.70 mmol) were added. After nitrogen was replaced, the temperature was raised to 85°C and refluxed for 12 h. After the reaction solution cooled to room temperature, it was filtered with celite, the filter cake was washed with DCM, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was separated and purified by silica gel column chromatography to obtain compound 33-2. LCMS: 173.0 (M-NO2) + .

[0561] Step 2: Synthesis of compound 33-3

[0562] 33-2 (2.89 g, 13.18 mmol) was dissolved in a mixture of methanol and acetic acid (30 mL:20 mL). After nitrogen was replaced, zinc powder (4.28 g, 65.91 mmol) was slowly added. The temperature was raised to 70°C and refluxed for 12 h. After the reaction solution cooled to room temperature, the pH was adjusted to alkaline with 2M NaOH solution. The solution was extracted twice with EA (100 mL). The organic phase was dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain a crude product, which was separated and purified by silica gel column chromatography to obtain compound 33-3. LCMS: 190.0 (M+H) + .

[0563] Step 3: Synthesis of compound 33-4

[0564] Dissolve 33-3 (1.89 g, 10.01 mmol) in DCM (40 mL). After replacing the nitrogen atmosphere, add triethylamine (1.22 g, 12.01 mmol). Cool to 0°C and add chloroacetyl chloride (1.24 g, 11.01 mmol) dropwise. After completion of the addition, warm to room temperature and stir for 1 h. Add water and EA (50 mL) and extract. The organic phase is dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain a crude product, which is separated and purified by silica gel column chromatography to obtain compound 33-4. LCMS: 266.0 (M+H) + .

[0565] Step 4: Synthesis of compound 33-6

[0566] 33-4 (2.04 g, 7.68 mmol) was dissolved in methanol (30 mL), cooled to 0°C, and sodium borohydride (291 mg, 7.68 mmol) was added in batches. The mixture was heated to room temperature and stirred for 1 h. The mixture was dried under reduced pressure to give compound 33-5. 33-5 was dissolved in THF (30 mL), cooled to 0°C, and NaH (369 mg, 9.22 mmol, 60% in mineral oil) was added. The mixture was heated to room temperature and stirred for 12 h. The mixture was quenched by adding saturated NH4Cl solution and extracted three times with DCM (40 mL). The organic phase was dried over anhydrous Na2SO4 and concentrated under reduced pressure to give a crude product, which was separated and purified by silica gel column chromatography to give compound 33-6. LCMS: 232.0 (M+H) + .

[0567] Step 5: Synthesis of compound 33-7

[0568] 33-6 (1.0 g, 4.32 mmol) was dissolved in THF (16 mL), and after nitrogen was purged, borane dimethyl sulfide (10.8 mL, 21.62 mmol) was added dropwise. After the addition was completed, the temperature was raised to 70 ° C and refluxed for 12 h. After the reaction solution was cooled to room temperature, methanol was added dropwise to quench. 1N HCl (8 mL) was added and stirred for 1 h, the pH was adjusted to alkaline with saturated sodium bicarbonate solution, and extracted twice with EA (50 mL). The organic phase was dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain a crude product, which was separated and purified by silica gel column chromatography to obtain compound 33-7. LCMS: 218.0 (M+H) + .

[0569] Step 6: Synthesis of compounds 33 and 36

[0570] 33-7 (100 mg, 0.46 mmol) was separated by SFC, and the first fraction (Rt = 3.785 min) was collected. Pure water (10 mL) and 1M dilute hydrochloric acid (200 uL) were added to the compound. Freeze-dried to obtain compound 33 as a hydrochloride salt. LCMS: 218.2 (M+H) + .

[0571] 1 H NMR(400MHz,MeOD)δ7.87(d,J=7.6Hz,2H),7.48-7.32(m,3H),4.16-4.07(m,1H),3.98-3.89(m,1H),3.87-3.81(m,1H) ),2.98-2.86(m,2H),2.69-2.55(m,1H),1.95-1.85(m,2H),1.80–1.63(m,2H),1.59-1.43(m,2H),1.03-0.90(m,1H).

[0572] The second fraction (Rt = 4.525 min) was collected. Pure water (10 mL) and 1M dilute hydrochloric acid (200 uL) were added to the compound. Freeze-dried to obtain compound 36 as a hydrochloride salt. LCMS: 218.2 (M+H) + .

[0573] 1 H NMR(400MHz,MeOD)δ7.94-7.79(m,2H),7.48-7.33(m,3H),4.15–4.05(m,1H),3.97–3.88(m,1H),3.86-3.78(m,1H) ,2.97–2.86(m,2H),2.66-2.56(m,1H),1.95–1.85(m,2H),1.80–1.62(m,2H),1.59-1.38(m,2H),1.04-0.87(m,1H).

[0574] (SFC conditions: column: ChiralPak IG, 250×40 mm ID, 10 μm; mobile phase: A for Supercritical CO 2 and B for 0.1 NH 3 .H 2 O EtOH; gradient: 10% B; flow rate: 80 mL / min).

[0575] Example 7: Preparation of Compound 34 Hydrochloride

[0576] Step 1: Synthesis of compound 34-2

[0577] At room temperature, bromobenzene (10.0 g, 63.7 mmol, 34-1), cyclohexene-1-boronic acid pinacol ester (13.2 g, 63.7 mmol), and sodium carbonate (13.5 g, 127.0 mmol) were added to a mixture of dioxane (100 mL) and water (20 mL). Pd(dppf)Cl2 (2.33 g, 3.18 mmol) was added to the reaction mixture. The atmosphere was replaced with nitrogen three times, and the reaction mixture was heated to 90°C and allowed to react for 16 hours. The reaction mixture was concentrated to obtain the crude product. This was then purified by silica gel column chromatography to obtain compound 34-2.

[0578] 1 H NMR (400MHz, DMSO) δ7.40-7.37(m,2H),7.33-7.27(m,2H),7.24-7.19(m,1H),6.17-6. 11(m,1H),2.38-2.33(m,2H),2.21-2.14(m,2H),1.77-1.69(m,2H),1.64-1.56(m,2H).

[0579] Step 2: Synthesis of compound 34-3

[0580] At room temperature, 34-2 (3.0 g, 18 mmol) was dissolved in water (25 mL) and tert-butanol (25 mL). KCO (7.86 g, 56.9 mmol), potassium ferricyanide (18.73 g, 56.88 mmol), methanesulfonamide (1.98 g, 20.9 mmol), potassium osmate dihydrate (0.35 g, 0.95 mmol), and (DHQ)PHAL (3.69 g, 4.74 mmol) were added portionwise. The mixture was allowed to react at room temperature for 16 hours. 15% aqueous sodium hydroxide solution (50 mL) was added to the reaction solution, and the mixture was extracted three times with EA (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous NaSO, filtered, and concentrated to obtain the crude product. Compound 34-3 was isolated and purified by silica gel column chromatography.

[0581] 1 H NMR (400MHz, DMSO) δ7.51-7.44(m,2H),7.32-7.24(m,2H),7.19-7.12(m,1H),4.32(s ,1H),4.10(d,J=6.8Hz,1H),3.78-3.68(m,1H),1.71-1.54(m,6H),1.42-1.29(m,2H).

[0582] Step 3: Synthesis of compound 34-5

[0583] To a solution of 34-3 (3.00 g, 15.6 mmol) in acetonitrile (40 mL) was added TfOH (3.42 mL, 39.0 mmol) dropwise at -40 ° C. After the addition was complete, the dry ice bath was removed, and the reaction solution was naturally warmed to room temperature and reacted for 1 hour. Water (40 mL) was added to the reaction solution and stirred for 10 minutes. The acetonitrile was removed by concentration under reduced pressure. The remaining aqueous phase was warmed to 100 ° C and refluxed for 16 hours. A 15% NaOH (50 mL) solution was added to the reaction solution, and EA (50 mL x 3) was added and extracted three times. The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated to obtain a crude product. PE:EA=10:1 (20 mL) was added to the reaction solution, and the mixture was slurried and filtered to obtain compound 34-5. LCMS: 192.4 (M+H) + .

[0584] Step 4: Synthesis of compound 34-6

[0585] 34-5 (2.5 g, 13 mmol) was dissolved in THF (25 mL). Triethylamine (3.6 mL, 26 mmol) was added at 0°C, and then chloroacetyl chloride (1.14 mL, 14.4 mmol) was slowly added to the mixed solution. The mixture was reacted at 0°C for 1 hour. The reaction solution was diluted with water (25 mL) and extracted three times with EA (25 mL x 3). The combined organic layers were washed with brine (25 mL), dried over anhydrous Na2SO4, filtered, and concentrated to obtain the crude product. Compound 34-6 was isolated and purified by silica gel column chromatography.

[0586] 1 H NMR(400MHz,DMSO)δ7.60(s,1H),7.36-7.25(m,4H),7.22-7.15(m,1H),4.32(s, 2H),3.71-3.61(m,1H),2.81-2.70(m,1H),1.79-1.56(m,4H),1.47-1.24(m,3H).

[0587] Step 5: Synthesis of compound 34-7

[0588] Dissolve 34-6 (2.00 g, 7.47 mmol) in isopropanol (20 mL) at 0°C. Add potassium tert-butoxide (1.68 g, 14.9 mmol) portionwise to the reaction mixture. Allow to react on ice for 1 hour. The reaction mixture is then spin-dried to obtain the crude product. Add H2O (20 mL) to precipitate a solid, which is filtered and washed with H2O (20 mL) and PE (20 mL). The filter cake is collected and dried under vacuum to yield compound 34-7.

[0589] 1H NMR (400MHz, DMSO) δ8.47(s,1H),7.49-7.41(m,2H),7.40-7.31(m,2H),7.28-7.21(m,1H),4.17(dd,J=1 4.4, 4.3Hz, 1H), 3.90 (dd, J=68.8, 17.1Hz, 2H), 1.93-1.70 (m, 4H), 1.66-1.55 (m, 1H), 1.54-1.40 (m, 3H).

[0590] Step 6: Synthesis of compound 34

[0591] 34-7 (200 mg, 0.865 mmol) was dissolved in THF (5 mL) at 0 ° C. Borane dimethyl sulfide (865 uL, 8.65 mmol) was slowly added dropwise to the above reaction solution. After the dropwise addition, the reaction solution was heated to 70 ° C and refluxed for 16 hours. The reaction solution was cooled to 0 ° C and quenched with methanol (5 mL). Stir for 1 hour after quenching. After cooling to zero degrees, sodium borohydride (163 mg, 4.32 mmol) was slowly added to the above reaction solution in batches. The reaction solution was heated to 50 ° C. The reaction was continued for 16 hours. The reaction solution was concentrated to obtain a crude product. Purified by silica gel column chromatography, pure water (10 mL) and 1N dilute hydrochloric acid (100 uL) were added to the colorless oily compound, and lyophilized to obtain the hydrochloride salt of compound 34. LCMS: 218.2 (M+H) + .

[0592] 1 H NMR(400MHz,DMSO)δ9.96(s,1H),9.33(s,1H),7.83-7.67(m,2H),7.57-7.3 9(m,3H),4.50(s,1H),4.09(dd,J=15.6,3.3Hz,1H),3.87(td,J=26.4,2.4Hz ,1H),3.50-3.37(m,1H),2.99-2.83(m,1H),2.50-2.26(m,2H),1.78(s,1H), 1.71-1.61(m,1H),1.57-1.40(m,2H),1.36-1.25(m,1H),1.19-1.01(m,1H).

[0593] Example 8: Preparation of Compound 35 Hydrochloride

[0594] Step 1: Synthesis of compound 35-2

[0595] Bromobenzene (10.0 g, 63.7 mmol, 35-1), cyclohexene-1-boronic acid pinacol ester (13.25 g, 63.69 mmol), and sodium carbonate (13.50 g, 127.4 mmol) were added to a mixture of dioxane (100 mL) and water (20 mL) at room temperature. Pd(dppf)Cl2 (2.33 g, 3.18 mmol) was added, the atmosphere was purged with nitrogen three times, and the temperature was raised to 90°C and refluxed for 16 hours. The reaction mixture was filtered, and the filtrate was concentrated to obtain the crude product, which was purified by silica gel column chromatography to obtain compound 35-2.

[0596] 1 H NMR (400MHz, DMSO) δ7.40-7.37(m,2H),7.33-7.27(m,2H),7.24-7.19(m,1H),6.17-6. 11(m,1H),2.38-2.33(m,2H),2.21-2.14(m,2H),1.77-1.69(m,2H),1.64-1.56(m,2H).

[0597] Step 2: Synthesis of compound 35-3

[0598] To water (40 mL) was added K2CO3 (10.5 g, 76.0 mmol), potassium ferricyanide (25.0 g, 75.9 mmol), methanesulfonamide (2.60 g, 27.3 mmol), potassium osmate dihydrate (470 mg, 1.26 mmol), and (DHQD)2PHAL (4.0 g, 5.1 mmol) at room temperature. 35-2 (4.0 g, 25 mmol) was dissolved in tert-butyl alcohol (25 mL) and added to the reaction mixture. The reaction was allowed to react at room temperature for 16 hours. EA (200 mL) was added to the reaction mixture, and the mixture was washed three times with 15% aqueous sodium hydroxide solution (50 mL). The organic phase was dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product, which was then purified by silica gel column chromatography to obtain compound 35-3.

[0599] 1 H NMR (400MHz, DMSO) δ7.49-7.46(m,2H),7.30-7.25(m,2H),7.19-7.14(m,1H),4.33(s ,1H),4.11(d,J=6.8Hz,1H),3.77-3.69(m,1H),1.70-1.56(m,6H),1.42-1.29(m,2H).

[0600] Step 3: Synthesis of compound 35-5

[0601] To a solution of 35-3 (3.50 g, 18.2 mmol) in acetonitrile (70 mL) was added dropwise TfOH (3.50 mL, 39.6 mmol) at -40 ° C. After the addition was completed, the dry ice bath was removed, the temperature was naturally raised to room temperature, and the reaction was continued for 1 hour. Water (35 mL) was added to the reaction solution, stirred for 10 minutes, and concentrated under reduced pressure to remove acetonitrile. The remaining aqueous phase was heated to 100 ° C and the reaction was continued for 16 hours. The pH of the reaction solution was adjusted to 10 with 1N sodium hydroxide aqueous solution. The above mixed solution was extracted twice with EA (50 mL x 2), the organic phases were combined, washed with saturated brine, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. PE:EA=3:1 (30 mL) was added to the reaction mixture, stirred for 10 minutes, filtered, the filter cake was collected, and dried under vacuum to obtain compound 35-5. LCMS: 192.4 (M+H) + .

[0602] Step 4: Synthesis of compound 35-6

[0603] 35-5 (1.3 g, 6.8 mmol) and triethylamine (2.40 mL, 17.3 mmol) were added to methyltetrahydrofuran (25 mL) at 0°C. Chloroacetyl chloride (0.60 mL, 7.5 mmol) was slowly added dropwise to the above solution. The reaction was allowed to proceed at zero degrees for 1 hour. The reaction solution was diluted with water (50 mL) and extracted twice with EA (25 mL x 2). The organic phases were combined, washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated to obtain a crude product. Compound 35-6 was separated and purified by silica gel column chromatography. LCMS: 268.4 (M+H) + .

[0604] Step 5: Synthesis of compound 35-7

[0605] 35-6 (900 mg, 3.36 mmol) was dissolved in isopropanol (20 mL) at 0°C. Potassium tert-butoxide (754 mg, 6.72 mmol) was added to the reaction mixture in batches. After reacting for 10 minutes under an ice bath, the ice bath was removed and the mixture was naturally warmed to room temperature and reacted for 2 hours. The reaction mixture was concentrated to obtain a crude product. Water (20 mL) was added to the mixture, stirred for 10 minutes, and filtered. The filter cake was collected and dried under vacuum to obtain compound 35-7. LCMS: 232.4 (M+H) + .

[0606] Step 6: Synthesis of compound 35

[0607] 35-7 (150 mg, 0.649 mmol) was dissolved in THF (10 mL) at 0 ° C. Borane dimethyl sulfide (325 uL, 3.25 mmol) was slowly added dropwise to the above reaction solution. After the addition was complete, the reaction solution was heated to 70 ° C and reacted for 16 hours. The reaction solution was cooled to 0 ° C and quenched with methanol (5 mL). After quenching, stirring was continued for 1 hour. The temperature was lowered to zero degrees and sodium borohydride (50 mg, 1.3 mmol) was slowly added to the above reaction solution in batches. The reaction solution was heated to 50 ° C. The reaction was continued for 16 hours. The reaction solution was concentrated to obtain a crude product. It was separated and purified by silica gel column chromatography. Pure water (10 mL) and 1N dilute hydrochloric acid (400 uL) were added to the colorless oily compound and lyophilized to obtain compound 35 as a hydrochloride salt. LCMS: 218.4 (M+H) + .

[0608] 1 H NMR(400MHz,DMSO)δ9.71(s,1H),9.20(s,1H),7.76-7.70(m,2H),7.54-7.49(m,2H ),7.48-7.43(m,1H),4.52-4.48(m,1H),4.12-4.07(m,1H),3.90-3.79(m,1H),3.47 -3.37(m,1H),2.96-2.89(m,1H),2.49-2.46(m,1H),2.35-2.26(m,1H),1.85-1.72( m,1H),1.70-1.62(m,1H),1.56-1.43(m,2H),1.35-1.28(m,1H),1.19-1.07(m,1H).

[0609] Example 9: Preparation of Compound 39 Hydrochloride

[0610] Step 1: Synthesis of compound 39

[0611] 35-7 (80 mg, 0.35 mmol) was dissolved in THF (5 mL) at 0°C. Boron trifluoride etherate (232 uL, 0.865 mmol) was slowly added dropwise and the reaction was allowed to proceed for 1 hour. Sodium borodeuteride (73.0 mg, 1.74 mmol) was slowly added in batches. The reaction solution was heated to 65°C and reacted for 2 hours. The temperature was lowered to 0°C, quenched with methanol (5 mL), and concentrated to obtain a crude product, which was purified by prep-HPLC. Pure water (10 mL) and 1N dilute hydrochloric acid (400 uL) were added and the product was lyophilized again to obtain compound 39 as a hydrochloride salt. LCMS: 220.4 (M+H) + .

[0612] (Prep-HPLC conditions: column: Xtimate C18, 21.2*250 mm, 5 um; mobile phase: A (0.05% NH3.H2O), B (ACN); gradient: 30%-60% B; flow rate: 20 mL / min).

[0613] 1 H NMR(400MHz,DMSO)δ9.85(s,1H),9.23(s,1H),7.89-7.65(m,2H),7.63-7.38( s,3H),4.50(s,1H),4.10-3.83(m,2H),2.47-2.25(s,2H),1.78-1.05(m,6H).

[0614] Example 10: Preparation of Compound 40 Hydrochloride

[0615] Step 1: Synthesis of Compound 40 Hydrochloride

[0616] 34-7 (200 mg, 0.865 mmol) was dissolved in THF (5 mL) at 0 ° C. Boron trifluoride etherate (534 uL, 4.33 mmol) was slowly added dropwise. Sodium borodeuteride (181 mg, 4.32 mmol) was slowly added in batches. The temperature was raised to 65 ° C and the reaction was reacted for 2 hours. The reaction solution was cooled to 0 ° C, quenched with methanol (5 mL), concentrated to remove the solvent, and water (10 ml) and EA (10 mL x 3) were added to the residue for extraction. The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated to obtain a crude product. Compound 40 free base was separated and purified by silica gel column chromatography. Pure water (10 mL) and 1N dilute hydrochloric acid (100 uL) were added to the colorless oily compound and lyophilized to obtain compound 40 hydrochloride. LCMS: 220.2 (M+H) + .

[0617] 1 H NMR (400MHz, DMSO) δ9.38(s,1H),8.97(s,1H),7.74-7.67(m,2H),7.58-7.44(m,3H),4.57-4.46(m,1H),4.10(d,J=12.8Hz,1H),3.86 -3.78(m,1H),2.57-2.51(m,1H),2.28(d,J=13.2Hz,1H),1.83-1.61(m,2H),1.58-1.43(m,2H),1.35-1.26(m,1H),1.18-1.05(m,1H).

[0618] Example 11: Preparation of Compound 45 Hydrochloride and Compound 46 Hydrochloride

[0619] Step 1: Synthesis of compound 45-2

[0620] Dissolve cyclohexanone oxime (45-1) (10.0 g, 88.4 mmol) in a mixture of DCM and n-hexane (1:15, 320 mL) at 0°C. Replace the nitrogen atmosphere and slowly add pyridine (7.1 mL, 88 mmol) dropwise. Stir the mixture at 0°C for 30 min, then slowly add benzoyl chloride (10.3 mL, 88.4 mmol) dropwise. Warm the mixture to room temperature and stir for 2 h. Add water (100 mL x 3) and separate the layers for extraction. Concentrate the organic layer to obtain compound 45-2.

[0621] Step 2: Synthesis of compound 45-3

[0622] Dissolve 45-2 (19 g, crude) in DCM (120 mL) at 0°C, replace the nitrogen atmosphere, and slowly add trifluoroacetic anhydride (65.0 mL, 468 mmol) dropwise. Slowly warm the mixture to room temperature and stir for 12 hours. Filter, and concentrate the filtrate under reduced pressure to obtain the crude product, which is then purified by silica gel column chromatography to afford compound 45-3.

[0623] 1 H NMR(400MHz, CDCl3)δ8.08(d,J=7.6Hz,2H),7.75-7.60(m,1H),7.58-7.44(m,2 H),6.43-6.12(m,1H),2.48-2.13(m,4H),1.81-1.71(m,2H),1.69-1.56(m,2H).

[0624] Step 3: Synthesis of compound 45-5

[0625] 45-3 (6.5 g, 20.7 mmol) was dissolved in THF (60 ml) and then slowly added dropwise to the solution of 45-4 at 0°C. The temperature was raised to reflux and stirred for 3 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was separated and purified by silica gel column chromatography to obtain compound 45-5.

[0626] 1H NMR (400MHz, CDCl3) δ7.99-7.89(m,2H),7.63-7.56(m,1H),7.53-7.41(m,2H),7.18-7.13(m,1H),7.04-6.95(m,2H),6.90 -6.86(m,1H),5.33-5.24(m,1H),3.35-3.25(m,1H),2.23-2.04(m,2H),1.90(m,1H),1.94-1.85(m,2H),1.59-1.41(m,2H).

[0627] Step 4: Synthesis of compound 45-6

[0628] 45-5 (4.0 g, 14.5 mmol) was dissolved in methanol (40 mL), and 10% aqueous sodium hydroxide solution (26 mL, 72.4 mmol) was slowly added dropwise at 0°C. The mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure to obtain a crude product, which was separated and purified by silica gel column chromatography to obtain compound 45-6.

[0629] 1 H NMR (400MHz, CDCl3) δ7.23-7.18(m,1H),7.05-6.95(m,2H),3.87(dd,J=9.6,3.8Hz,1H), 2.19(s,3H),1.98-1.90(m,1H),1.89-1.73(m,3H),1.72-1.49(m,3H),1.44-1.32(m,1H).

[0630] Step 5: Synthesis of compound 45-7

[0631] Compound 45-6 (600 mg, 3.0 mmol) was dissolved in acetone (15 mL) at room temperature, and Jones reagent (3 mL, 6.1 mmol) was slowly added dropwise. The reaction was allowed to proceed for 16 h. Water (10 mL) was added, and the pH was adjusted to 10 with 15% sodium hydroxide. The mixture was extracted with EA (20 mL x 2). The combined organic phases were washed with saturated brine, dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product, which was then purified by silica gel column chromatography to afford compound 45-7. LCMS: 196.3 (M+H) + .

[0632] Step 6: Synthesis of compound 45-8

[0633] Compound 45-7 (100 mg, 0.51 mmol) and triethylamine (104 mg, 1.02 mmol) were dissolved in DCM (5 mL) at 0°C, and chloroacetyl chloride (64 mg, 0.56 mmol) was slowly added dropwise. The mixture was allowed to react for 2 hours. Water (5 mL) was added, and the mixture was extracted with DCM (10 mL x 2). The organic phases were combined, washed with saturated brine, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. Compound 45-8 was then separated and purified by silica gel column chromatography. LCMS: 294.0 (M+H) + .

[0634] Step 7: Synthesis of compound 45-9

[0635] 45-8 (130 mg, 0.48 mmol) was dissolved in methanol (4 mL) at 0°C. Sodium borohydride (54 mg, 1.44 mmol) was slowly added in portions. The temperature was raised to 25°C and the mixture was reacted for 1 hour. The reaction solution was concentrated to obtain a crude product. Compound 45-9 was isolated and purified by silica gel column chromatography.

[0636] 1 H NMR (400MHz, CDCl3) δ7.21-7.20(m,2H),6.93(dd,J=4.0,4.8Hz,1H),6.79(s,1H),4.12(dd,J=3.6,8.0Hz,1H),3.91(s,2H),3 .47(s,1H),2.48-2.42(m,1H),2.15-2.08(m,1H),1.84-1.77(m,1H),1.72-1.63(m,1H),1.57-1.46(m,2H),1.41-1.32(m,1H).

[0637] Step 8: Synthesis of compound 45-10

[0638] 45-9 (130 mg, 0.48 mmol) was dissolved in THF (5 mL) at 0°C, and sodium hydride (57 mg, 1.43 mmol, 60%) was slowly added in portions. The mixture was warmed to room temperature and reacted for 2 hours. Saturated aqueous NH4Cl solution (5 mL) was added, and the mixture was extracted with EA (10 mL x 2). The organic phases were combined, washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated to obtain a crude product. Compound 45-10 was separated and purified by silica gel column chromatography. LCMS: 238.2 (M+H) + .

[0639] Step 9: Synthesis of compound 45-11

[0640] At 0°C, 45-10 (100 mg, 0.42 mmol) was dissolved in THF (5 mL), and borane dimethyl sulfide (210 uL, 2.10 mmol) was slowly added dropwise. The temperature was raised to 70°C and the reaction was allowed to react for 16 hours. The temperature was lowered to 0°C, the reaction was quenched with methanol (5 mL), and stirred at room temperature for 1 hour. The crude product was concentrated. Compound 45-11 was separated and purified by silica gel column chromatography. LCMS: 224.2 (M+H) + .

[0641] Step 10: Synthesis of compounds 45 and 46

[0642] 45-11 (60 mg, 0.27 mmol) was separated by SFC, and the first fraction (Rt = 3.69 min) was collected. After concentration under reduced pressure, pure water (10 mL) and 1M dilute hydrochloric acid (50 uL) were added. Freeze-dried to obtain compound 45 as a hydrochloride salt. LCMS: 224.2 (M+H) + .

[0643] 1 H NMR (400MHz, DMSO) δ10.56(s,1H),9.39(d,J=10.0Hz,1H),7.74(d,J=4.8Hz,1H),7.52(d,J=3.2Hz,1H),7.17(dd,J=3.6,5.2Hz,1H),4.10-3.9 5(m,3H),3.09-3.01(m,2H),2.54-2.50(m,1H),2.18-2.11(m,1H),1.79 -1.75(m,1H),1.65-1.57(m,3H),1.41-1.31(m,1H),1.17-1.07(m,1H).

[0644] The second fraction (Rt = 5.74 min) was collected. After concentration under reduced pressure, pure water (10 mL) and 1M dilute hydrochloric acid (50 uL) were added. Freeze-dried to obtain compound 46 as a hydrochloride salt. LCMS: 224.2 (M+H) + .

[0645] 1H NMR (400MHz, DMSO) δ10.62(s,1H),9.41(d,J=9.6Hz,1H),7.73(d,J=4.8Hz,1H),7.52(d,J=3.2Hz,1H),7.17(dd,J=3.6,5.2Hz,1H),4.09-3.95 (m,3H),3.09-3.01(m,2H),2.53-2.50(m,1H),2.19-2.12(m,1H),1.78 -1.76(m,1H),1.63-1.57(m,3H),1.41-1.31(m,1H),1.12-1.07(m,1H).

[0646] (SFC conditions: column: ChiralPak IG, 250×40 mm ID, 10 μm; mobile phase: A for CO2 and B for 50% MeOH (0.1% NH3·H2O) + 50% ACN (0.1% NH3·H2O); gradient: 50% B; flow rate: 120 mL / min).

[0647] Example 12: Preparation of Compounds 52 and 53

[0648] Step 1: Synthesis of compound 52-2

[0649] 52-1 (5.00 g, 28.6 mmol), 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester (6.00 g, 28.6 mmol), and sodium carbonate (9.08 g, 85.7 mmol) were added to a mixed solvent of dioxane (50 mL) and water (5 mL) at room temperature. Pd(dppf)Cl was added. 2. The nitrogen atmosphere was replaced three times with CH2Cl2 (0.47 g, 0.57 mmol), and the reaction solution was heated to 90°C and reacted for 16 hours. The reaction solution was concentrated to obtain a crude product, which was separated and purified by a flash silica gel column to obtain compound 52-2.

[0650] 1 H NMR (400MHz, MeOD) δ7.46-7.39(m,2H),7.08-7.01(m,2H),6.13-6.11(m,1H),4.28(q,J=2.8Hz,2H),3.91(t,J=5.6Hz,2H),2.52-2.46(m,2H).

[0651] Step 2: Synthesis of compound 52-3

[0652] At room temperature, 52-2 (3.00 g, 16.8 mmol) was dissolved in a mixed solvent of water (30 mL) and tert-butanol (45 mL). Potassium osmate dihydrate (310 mg, 0.842 mmol) and N-methylmorpholine oxide (3.94 g, 33.7 mmol) were added. The reaction was allowed to proceed for 16 hours. Water (50 mL) was added, and the mixture was extracted with EA (100 mL x 2). The organic phases were combined, washed with saturated brine, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product, which was then separated and purified by silica gel column chromatography to obtain compound 52-3.

[0653] 1 H NMR (400MHz, DMSO) δ7.57-7.51(m,2H),7.15-7.08(m,2H),4.82(d,J=1.6Hz,1H),4.61(d,J=6.8Hz,1H ),3.80-3.74(m,1H),3.69-3.58(m,3H),3.42(t,J=10.4Hz,1H),1.98-1.89(m,1H),1.58-1.53(m,1H).

[0654] Step 3: Synthesis of compound 52-5

[0655] To a solution of 52-3 (2.0 g, 9.4 mmol) in acetonitrile (30 mL) was added dropwise TfOH (2.08 mL, 23.6 mmol) at -40 °C. The dry ice bath was removed, and the reaction solution was naturally warmed to room temperature and reacted for 1 h. Water (20 mL) was added and stirred for 10 minutes. The acetonitrile was removed by concentration under reduced pressure. The remaining aqueous phase was warmed to 100 °C and the reaction was continued for 16 hours. The pH was adjusted to 10 with aqueous sodium hydroxide solution. EA (50 mL x 2) was used for extraction, the organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain the product. PE / EA (20 mL, v / v = 5 / 1) was added, stirred for 10 minutes, filtered, the filter cake was collected, and dried under vacuum to obtain compound 52-5. LCMS: 212.4 (M+H) + .

[0656] Step 4: Synthesis of compound 52-6

[0657] Compound 52-5 (800 mg, 3.79 mmol) and triethylamine (1.3 mL, 9.5 mmol) were added to methyltetrahydrofuran (20 mL) at 0°C, and chloroacetyl chloride (362 μL, 4.55 mmol) was added dropwise. The reaction was allowed to react for 1 hour. The reaction solution was concentrated under reduced pressure to obtain the crude product, which was then separated and purified by flash silica gel column chromatography to obtain compound 52-6.

[0658] 1H NMR (400MHz, CDCl3) δ7.41 (s, 1H), 7.39-7.34 (m, 2H), 7.11-7.05 (m, 2H), 4.10 (d, J = 0.8Hz, 2H), 3.96-3.91 (m, 1H), 3.89-3.81 (m ,2H),3.60(td,J=11.6,2.4Hz,1H),3.51(dd,J=11.6,9.6Hz,1H),2.83(dt,J=14.4,2.4Hz,1H),2.62(s,1H),2.33-2.24(m,1H).

[0659] Step 5: Synthesis of compound 52-7

[0660] To a solution of 52-6 (250 mg, 0.869 mmol) in isopropanol (10 mL) was added potassium tert-butoxide (292 mg, 2.61 mmol) at room temperature. The mixture was allowed to react for 2 hours. The reaction solution was directly concentrated to obtain a crude product, which was then purified by silica gel column chromatography to obtain compound 52-7. LCMS: 252.0 (M+H) + .

[0661] Step 6: Synthesis of compound 52-8

[0662] To a THF (10 mL) solution of 52-7 (150 mg, 0.597 mmol) was slowly added dropwise borane dimethyl sulfide (300 uL, 3.00 mmol) at 0°C. After the addition was complete, the reaction solution was heated to 70°C and reacted for 16 hours. The temperature was lowered to 0°C, methanol (1 mL) was added dropwise to quench the reaction, and the mixture was stirred for 1 hour. Sodium borohydride (45 mg, 1.2 mmol) was slowly added in batches at 0°C. The temperature was raised to 50°C and the reaction was continued for 16 hours. The reaction solution was concentrated to obtain a crude product, which was separated and purified by silica gel column chromatography to obtain compound 52-8. LCMS: 238.4 (M+H) + .

[0663] Step 7: Synthesis of compounds 52 and 53

[0664] 52-8 (100 mg, 0.421 mmol) was separated by SFC. The second fraction (Rt = 9.2 min) was collected. After concentration under reduced pressure, pure water (10 mL) was added and lyophilized to obtain compound 52. LCMS: 238.4 (M+H) + .

[0665] 1H NMR (400MHz, DMSO) δ7.63-7.56(m,2H),7.20-7.11(m,2H),4.10-4.07(m,1H),4.05-3.96(m,1H),3.78-3.71(m,2H),3.50- 3.45(m,1H),3.45-3.36(m,2H),2.79-2.70(m,1H),2.64(s,1H),2.56-2.50(m,1H),2.17-1.96(m,1H),1.66-1.59(m,1H).

[0666] The first fraction (Rt = 6.8 min) was collected and concentrated under reduced pressure, and then purified water (10 mL) was added and lyophilized to obtain compound 53. LCMS: 238.4 (M+H) + .

[0667] 1 H NMR (400MHz, DMSO) δ7.63-7.56(m,2H),7.20-7.12(m,2H),4.10-4.07(m,1H),4.06-3.96(m,1H),3.78-3.72(m,2H),3.50- 3.46(m,1H),3.45-3.36(m,2H),2.79-2.69(m,1H),2.65(s,1H),2.55-2.51(m,,1H),2.13-2.03(m,1H),1.68-1.58(m,1H).

[0668] (SFC conditions: column: ChiralPak IG, 250×40 mm ID, 10 μm; mobile phase: A for CO 2 and B for 30% MeOH (0.1% NH 3 ·H 2 O); gradient: 30% B; flow rate: 120 mL / min).

[0669] Example 13: Preparation of Compound 74 Hydrochloride

[0670] Step 1: Synthesis of compound 74-2

[0671] At room temperature, 74-1 (5.00 g, 25.3 mmol), cyclohexene-1-boronic acid pinacol ester (5.50 g, 26.4 mmol), and sodium carbonate (5.37 g, 50.6 mmol) were added to a mixture of dioxane (50 mL) and water (10 mL). Pd(dppf)Cl2·CH2Cl2 (0.41 g, 0.51 mmol) was added, and the atmosphere was purged with nitrogen three times. The temperature was raised to 90°C and stirred for 16 hours. The reaction mixture was cooled to room temperature and concentrated to obtain the crude product. Compound 74-2 was purified by silica gel column chromatography.

[0672] 1 H NMR (400MHz, DMSO) δ7.39 (d, J=5.6Hz, 1H), 7.00 (d, J=5.6Hz, 1H), 6.01-5.98 (m, 1H),2.32-2.26(m,2H),2.19-2.12(m,2H),1.71-1.65(m,2H),1.63-1.56(m,2H).

[0673] Step 2: Synthesis of compound 74-3

[0674] Potassium osmate dihydrate (0.42 g, 1.1 mmol), methanesulfonamide (2.37 g, 24.9 mmol), potassium ferricyanide (22.4 g, 67.9 mmol), (DHQ)2PHAL (3.5 g, 4.5 mmol), and K2CO3 (9.39 g, 67.9 mmol) were added to H2O (50 mL) at room temperature. Compound 74-2 (4.50 g, 22.6 mmol) was dissolved in tert-butanol (50 mL) and added to the reaction mixture. The reaction was allowed to react for 16 hours. EA (200 mL) was added and the mixture was washed with 15% sodium hydroxide (50 mL x 3). The organic phase was dried over anhydrous Na2SO4 and concentrated to obtain the crude product. Compound 74-3 was purified by silica gel column chromatography.

[0675] 1 H NMR (400MHz, DMSO) δ7.27(d,J=6.0Hz,1H),7.10(d,J=6.0Hz,1H),4.65(d,J=1.6Hz,1H),4.40 (d,J=6.8Hz,1H),4.03-3.96(m,1H),1.93-1.85(m,1H),1.72-1.51(m,5H),1.40-1.24(m,2H).

[0676] Step 3: Synthesis of compound 74-5

[0677] To a solution of 74-3 (2.90 g, 12.5 mmol) in acetonitrile (30 mL) was added dropwise TfOH (2.74 mL, 31.2 mmol) at -40 °C. The dry ice bath was removed, the temperature was naturally raised to room temperature, and the reaction was allowed to proceed for 1 hour. Water (30 mL) was added to the reaction solution and stirred for 10 minutes. The acetonitrile was removed by concentration under reduced pressure. The temperature was raised to 100 °C and refluxed for 16 hours. The temperature was lowered to room temperature and the pH was adjusted to 10 with 15% aqueous sodium hydroxide solution. Extracted with EA (100 mL). The organic phase was washed with water (50 mL x 3) and saturated brine (50 mL), and dried over anhydrous Na2SO4. Filtered, the filtrate was concentrated under reduced pressure to obtain a crude product, PE:EA (30 mL, v / v=5 / 1) was added, and stirred for 10 minutes. Filtered, the filter cake was collected, and dried under vacuum to obtain compound 74-5. LCMS: 232.4 (M+H) + .

[0678] Step 4: Synthesis of compound 74-6

[0679] At 0°C, 74-5 (2.40 g, 10.4 mmol) and triethylamine (2.90 mL, 20.9 mmol) were added to THF (30 mL). Chloroacetyl chloride (1.00 mL, 12.6 mmol) was slowly added dropwise. The reaction was allowed to proceed for 1 hour. Water (30 mL) was added, and the mixture was extracted with EA (30 mL x 3). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated to obtain the crude product. Compound 74-6 was purified by silica gel column chromatography.

[0680] 1 H NMR (400MHz, DMSO) δ7.72(s,1H),7.30(d,J=6.0Hz,1H),6.93(d,J=6.0Hz,1H),5.23(d,J=5.2Hz,1H),4.33- 4.24(m,2H),3.91-3.81(m,1H),2.80-2.71(m,1H),2.04-1.95(m,1H),1.73-1.56(m,3H),1.45–1.23(m,3H).

[0681] Step 5: Synthesis of compound 74-7

[0682] Dissolve 74-6 (1.0 g, 3.2 mmol) in DCM (20 mL) at room temperature and add PCC (1.8 g, 8.4 mmol). Heat to 40°C and react for 16 hours. Concentrate the reaction mixture to obtain a crude product, which is purified by silica gel column chromatography to obtain compound 74-7. LCMS: 306.0 (M+H) + .

[0683] Step 6: Synthesis of compound 74-8

[0684] Dissolve 74-7 (700 mg, 2.29 mmol) in methanol (20 mL) at 0°C, and slowly add sodium borohydride (173 mg, 4.57 mmol) in portions. Allow to react for 1 hour. Concentrate the reaction mixture to obtain a crude product, which is then purified by silica gel column chromatography to obtain compound 74-8. LCMS: 308.2 (M+H) + .

[0685] Step 7: Synthesis of compound 74-9

[0686] To a solution of 74-8 (600 mg, 1.95 mmol) in isopropanol (10 mL) was added potassium tert-butoxide (546 mg, 4.87 mmol) in portions at 0°C. The mixture was allowed to react for 10 minutes, then naturally warmed to room temperature and reacted for 2 hours. The reaction solution was concentrated to obtain the crude product. Water (10 mL) was added, stirred for 10 minutes, and filtered. The filter cake was collected and dried under vacuum to obtain compound 74-9. LCMS: 272.2 (M+H) + .

[0687] Step 8: Synthesis of Compound 74 Hydrochloride

[0688] To a THF (10 mL) solution of 74-9 (150 mg, 0.552 mmol) was slowly added dropwise borane dimethyl sulfide (276 uL, 2.76 mmol) at 0°C. The mixture was heated to 70°C and refluxed for 16 hours. The mixture was cooled to 0°C and quenched by adding methanol (2 mL). After quenching, the mixture was stirred for 1 hour. Sodium borohydride (21 mg, 0.55 mmol) was slowly added in batches at 0°C. The mixture was heated to 50°C. The reaction was continued for 16 hours. The reaction solution was concentrated to obtain a crude product. Compound 74 hydrochloride was obtained by purification by prep-HPLC. LCMS: 258.4 (M+H) + .

[0689] 1 H NMR (400MHz, DMSO) δ11.06-11.01(m,1H),8.95-8.80(m,1H),7.71(d,J=6. 0Hz,1H),7.60(d,J=6.0Hz,1H),4.14-4.02(m,2H),4.00-3.95(m,1H),3.2 9-3.19(m,1H),3.02-2.95(m,1H),2.82-2.71(m,1H),2.03-1.95(m,1H),1 .86-1.80(m,1H),1.67-1.58(m,3H),1.46-1.35(m,1H),1.03-0.91(m,1H).

[0690] Example 14: Preparation of Compound 80 Hydrochloride

[0691] Step 1: Synthesis of Compound 80 Hydrochloride

[0692] (4aS, 8aR)-4a-(thiophen-2-yl)hexahydro-2H-benzo[b][1,4]oxazine-3(4H)-one (100 mg, 0.421 mmol, 80-1) (synthesis see WO2022237849, compound 35) was dissolved in THF (5 mL) at 0 ° C. Boron trifluoride etherate (0.2 mL, 1.62 mmol) was slowly added dropwise, reacted for 1 hour, and sodium borodeuteride (53 mg, 1.26 mmol) was slowly added. The temperature was raised to 65 ° C and the reaction was continued for 5 hours. The temperature was lowered to 0 ° C and methanol (3 mL) was added to quench the reaction. The reaction solution was directly concentrated to obtain a crude product, which was purified by prep-HPLC to obtain compound 80 hydrochloride. LCMS: 226.2 (M+H) + .

[0693] 1 H NMR (400MHz, DMSO) δ9.68 (s, 1H), 9.15 (s, 1H), 7.75 (d, J = 5.2Hz, 1H), 7.55-7.67 (m, 1H), 7.27-7.07 (m, 1H), 4.30 (s, 1H), 4.12- 4.04(m,1H),3.85-3.76(m,1H),2.60-2.52(m,1H),2.18-2.10(m,1H),1.83-1.68(m,2H),1.65-1.43(m,2H),1.38-1.26(m,2H).

[0694] Example 15: Preparation of Compound 96 Hydrochloride

[0695] Step 1: Synthesis of compound 96-1

[0696] 34-7 (150 mg, 0.649 mmol) was dissolved in deuterated methanol (2 mL), and Cs2CO3 (1.05 g, 3.24 mmol) was added. The mixture was reacted at 80°C for 2 hours. The reaction solution was concentrated, and DCM (10 mL) was added to the residue for dissolution. The mixture was filtered, and the filter cake was washed with DCM (10 mL). The filtrate was dried over anhydrous Na2SO4 and concentrated to obtain compound 96-1. LCMS: 234.2 (M+H) + .

[0697] Step 2: Synthesis of Compound 96 Hydrochloride

[0698] 96-1 (150 mg, 0.643 mmol) was dissolved in THF (5 mL) at 0 ° C, and borane dimethyl sulfide (0.321 mL, 3.21 mmol) was slowly added dropwise. The temperature was raised to 70 ° C and the reaction was allowed to react for 16 hours. The temperature was lowered to 0 ° C, MeOH (5 mL) was added to quench the reaction, and then NaBH4 (122 mg, 3.22 mmol) was added and the temperature was raised to 50 ° C and the reaction was allowed to react for 16 hours. The reaction solution was concentrated to remove the solvent, water (5 ml) was added, and EA (5 mL x 3) was added. The combined organic layers were washed with saturated brine (5 mL), dried over anhydrous Na2SO4, and concentrated to obtain a crude product. The product was separated and purified by silica gel column chromatography, concentrated, added with 1N HCl (0.05 mL), and lyophilized to obtain compound 96 hydrochloride. LCMS: 220.2 (M+H) + .

[0699] 1 H NMR (400MHz, DMSO) δ7.67-7.58(m,2H),7.45-7.36(m,2H),7.31(t,J=14.4Hz,1H),4.28(s,1H),3.15-2.94(m,1 H),2.76-2.64(m,1H),2.23(s,1H),2.04-1.76(m,2H),1.66-1.51(m,2H),1.48-1.40(m,1H),1.32-1.18(m,2H).

[0700] Example 16: Preparation of Compound 98 Hydrochloride

[0701] Step 1: Synthesis of compound 98-1

[0702] Dissolve 35-7 (200 mg, 0.865 mmol) in deuterated methanol (2 mL) at room temperature. Add cesium carbonate (1.1 g, 3.5 mmol). Heat to 80°C and react for 1 hour. The reaction mixture is directly spin-dried to obtain the crude product. Add DCM (10 mL), filter, and concentrate the filtrate under reduced pressure to obtain compound 98-1. LCMS: 234.4 (M+H) + .

[0703] Step 2: Synthesis of compound 98

[0704] Dissolve 98-1 (180 mg, 0.772 mmol) in THF (10 mL) at 0°C. Slowly add dimethyl borane sulfide (380 uL, 3.80 mmol) dropwise. Warm to 70°C and react for 16 hours. Cool to 0°C and add methanol (5 mL) to quench. Continue stirring for 1 hour. Sodium borohydride (59 mg, 1.6 mmol) is added to the reaction mixture in batches at 0°C. Warm to 50°C and continue stirring for 16 hours. The reaction mixture is concentrated to obtain the crude product. Compound 98 hydrochloride is purified by prep-HPLC. LCMS: 220.4 (M+H) + .

[0705] 1 H NMR (400MHz, DMSO) δ10.2-9.99(m,1H),9.40-9.20(m,1H),7.77-7.72(m,2H),7.53-7.48(m,2H),7.47-7.42(m,1H),4.52-4.48(m,1H),3.47-3. 35(m,1H),2.94-2.87(m,1H),2.50-2.43(m,1H),2.36-2.32(m,1H),1.8 4-1.61(m,2H),1.58-1.43(m,2H),1.35-1.28(m,1H),1.19-1.06(m,1H).

[0706] Example 17: Preparation of Compound 144 Hydrochloride

[0707] Step 1: Synthesis of compound 144-2

[0708] Under nitrogen protection, Pd2(dba)3 (283 mg, 0.31 mmol), Xantphos (359 mg, 0.62 mmol) and cesium carbonate (22.1 g, 67.87 mmol) were dissolved in dioxane (35 ml), and deuterated bromobenzene (5 g, 30.85 mmol, 144-1) and cyclohexanone (6.05 g, 61.70 mmol) were added. The temperature was raised to 85°C and refluxed for 20 hours. After cooling to room temperature, the mixture was filtered through celite, extracted with EA (20 mL x 2), dried over anhydrous Na2SO4, and concentrated to obtain a crude product. It was separated and purified by silica gel column chromatography to obtain compound 144-2. LCMS: 180.0 (M+H) + .

[0709] Step 2: Synthesis of compound 144-3

[0710] Under nitrogen protection, ammonium cerium nitrate (36.5 g, 66.60 mmol), copper acetate (4.03 g, 22.20 mmol) and 144-2 (3.98 g, 22.20 mmol) were dissolved in 1,2-dichloroethane (60 ml). The temperature was raised to 80°C and refluxed for 12 hours. After cooling to room temperature, DCM was added to dilute the reaction solution, filtered through celite, the filter cake was washed with DCM, and concentrated to obtain the crude product. Compound 144-3 was separated and purified by silica gel column chromatography. LCMS: 178.0 (M-NO2) + .

[0711] Step 3: Synthesis of compound 144-4

[0712] Under nitrogen, 144-3 (1.64 g, 7.31 mmol) was dissolved in methanol (20 mL), glacial acetic acid (20 mL) was added, and zinc powder (2.37 g) was slowly added. The temperature was raised to 80°C and refluxed for 12 hours. The temperature was lowered to room temperature, the pH was adjusted to 10 with NaOH (2 M), and the mixture was extracted with EA (20 mL x 2). The organic phases were combined, dried over anhydrous Na2SO4, and concentrated to obtain the crude product. Compound 144-4 was separated and purified by silica gel column chromatography. LCMS: 195.0 (M+H) + .

[0713] Step 4: Synthesis of compound 144-5

[0714] Under nitrogen, triethylamine (850 mg, 8.4 mmol) was added to a solution of 144-4 (1.36 g, 7.0 mmol) in DCM (30 mL). The temperature was lowered to 0°C, and chloroacetyl chloride (790 mg, 7.0 mmol) was added dropwise. The mixture was warmed to room temperature and stirred for 1 hour. The mixture was extracted with EA, and the organic phases were combined, dried over anhydrous Na2SO4, and concentrated to obtain the crude product. Compound 144-5 was separated and purified by silica gel column chromatography. LCMS: 271.0 (M+H) + .

[0715] Step 5: Synthesis of compound 144-7

[0716] Under nitrogen protection, 144-5 (1.22 g, 4.51 mmol) was dissolved in methanol (20 mL), cooled to 0 ° C, and sodium borohydride (171 mg, 4.51 mmol) was added. The temperature was raised to room temperature and stirring was continued for 1 hour. The solvent was concentrated under reduced pressure to obtain 144-6, which was dissolved in THF (20 mL). The temperature was lowered to 0 ° C, and sodium hydride (216 mg, 5.41 mmol) was added. The temperature was raised to room temperature and stirring was continued for 12 hours. 1N HCl was added to quench the reaction, extracted with DCM, and the organic phases were combined, dried over anhydrous Na2SO4, and concentrated to obtain a crude product. Compound 144-7 was separated and purified by silica gel column chromatography. LCMS: 237.0 (M+H) + .

[0717] Step 6: Synthesis of Compound 144 Hydrochloride

[0718] Under nitrogen protection, 144-7 (876 mg, 3.70 mmol) was dissolved in THF (10 mL) and BH3 / Me2S (9.2 mL, 18.53 mmol) was added dropwise. The temperature was raised to 70°C and refluxed for 12 hours. After cooling to room temperature, MeOH was added dropwise and 1N HCl was added and stirred for 1 hour. The pH was adjusted to 8-9 with saturated NaHCO3 solution and extracted with EA. The organic phases were combined, dried over anhydrous Na2SO4, and concentrated to obtain the crude product, which was purified by prep-HPLC. After removing most of the water, 1M HCl was added and lyophilized to obtain compound 144 hydrochloride. LCMS: 223.2 (M+H) + .

[0719] 1 H NMR (400MHz, CDCl3) δ10.4(s,1H),9.7(s,1H),4.4(t,J=11.4Hz,1H),4.2(dd,J=12.0,4.6Hz,1H),4.0(dd,J=12 .5,3.7Hz,1H),2.9(m,2H),2.8(d,J=13.0Hz,1H),2.3(td,J=13.3,3.1Hz,1H),2.1–1.9(m,2H),1.8–1.5(m,4H).

[0720] Example 18: Preparation of Compound 145 Hydrochloride

[0721] Step 1: Synthesis of compound 145-2

[0722] At room temperature, 145-1 (3.50 g, 21.6 mmol), 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester (5.00 g, 23.8 mmol), and KCO (8.97 g, 64.92 mmol) were added to a mixture of dioxane (40 mL) and water (10 mL). Pd(dppf)Cl (0.88 g, 1.08 mmol) was added, and the atmosphere was purged with nitrogen three times. The temperature was raised to 80°C and the reaction was allowed to proceed for 12 hours. The reaction solution was concentrated to obtain the crude product, which was then purified by silica gel column chromatography to obtain compound 145-2.

[0723] Step 2: Synthesis of compound 145-3

[0724] At room temperature, 145-2 (3.42 g, 20.72 mmol) was added to a mixed solvent of water (27 mL) and tert-butanol (18 mL). Potassium osmate dihydrate (378 mg, 1.03 mmol), K2CO3 (8.59 g, 62.16 mmol) and potassium ferricyanide (20.46 g, 62.16 mmol) were added. The reaction was allowed to proceed for 16 hours. Water (50 mL) was added and the mixture was extracted with EA (100 mL x 2). The organic phases were combined, washed with saturated brine, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was separated and purified by silica gel column chromatography to obtain compound 145-3. LCMS: 182.0 (M-18) + .

[0725] Step 3: Synthesis of compound 145-5

[0726] To a solution of 145-3 (3.36 g, 16.86 mmol) in acetonitrile (50 mL) was added TfOH (2.98 mL, 33.72 mmol) dropwise at -40°C. After the addition was complete, the dry ice bath was removed, the temperature was naturally raised to room temperature, and the reaction was continued for 1 hour. Water (50 mL) was added to the reaction solution and stirred for 10 minutes. The acetonitrile was removed by concentration under reduced pressure. The remaining aqueous phase was heated to 100°C and the reaction was continued for 16 hours. The temperature was lowered to room temperature and the pH was adjusted to 10 with aqueous sodium hydroxide solution. Extracted with EA (50 mL x 2), the organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. PE / EA (20 mL, v / v = 5 / 1) was added to the mixture, stirred for 10 minutes, filtered, the filter cake was collected, and dried under vacuum to obtain compound 145-5. LCMS: 199.0 (M+H) + .

[0727] Step 4: Synthesis of compound 145-6

[0728] Under nitrogen, 145-5 (1.80 g, 9.12 mmol) was dissolved in DCM (36 mL) and triethylamine (1.11 g, 10.94 mmol) was added. The temperature was lowered to 0°C, and chloroacetyl chloride (1.13 g, 10.03 mmol) was added dropwise. The temperature was raised to room temperature and stirred for 1 hour. The mixture was extracted with EA, and the organic phase was dried over anhydrous Na2SO4 and concentrated to obtain the crude product, which was separated and purified by silica gel column chromatography to obtain compound 145-6. LCMS: 273.0 (MH) - .

[0729] Step 5: Synthesis of compound 145-7

[0730] 145-6 (795 mg, 2.90 mmol) was dissolved in THF (20 mL) at 0°C, and sodium hydroxide (139 mg, 3.48 mmol, 60%) was slowly added in portions. The mixture was allowed to react at room temperature for 2 hours. The mixture was quenched with saturated aqueous NH4Cl (5 mL), extracted with EA (10 mL x 2), and the organic phases were combined, washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated to obtain the crude product, which was separated and purified by silica gel column chromatography to obtain compound 145-7. LCMS: 239.0 (M+H) + .

[0731] Step 6: Synthesis of Compound 145 Hydrochloride

[0732] Under nitrogen, 145-7 (576 mg, 2.42 mmol) was dissolved in THF (12 mL) and BH3 / Me2S (6.1 mL, 12.10 mmol) was added dropwise. The temperature was raised to 70°C and refluxed for 12 hours. After cooling to room temperature, methanol was added dropwise to quench the reaction. 1N HCl was added and stirred for 1 hour. The pH was adjusted to 8-9 with saturated NaHCO3 solution. The reaction was extracted with EA, and the organic phases were combined, dried over anhydrous Na2SO4, and concentrated to obtain the crude product. The crude product was purified by prep-HPLC, concentrated to remove most of the water, and then lyophilized with 1M HCl to obtain compound 145 hydrochloride. LCMS: 225.0 (M+H) + .

[0733] 1 H NMR (400MHz, DMSO) δ10.27(s,1H),9.43(s,1H),4.44(d,J=1.9Hz,1H),4.11(dd,J=12.5,3.8Hz,1H),3.99–3.67(m,3H),3.41(d, J=12.8Hz,1H),3.15(td,J=11.9,1.8Hz,1H),2.97(d,J=13.0Hz,1H),2.80(td,J=12.9,12.4,4.4Hz,1H),2.35(d,J=12.7Hz,1H).

[0734] Example 19: Preparation of Compound 158 Hydrochloride

[0735] Step 1: Synthesis of compound 158-2

[0736] 158-1 (1.0 g, 4.1 mmol) was dissolved in acetic acid (10 mL), and N-chlorosuccinimide (0.61 g, 4.5 mmol) was added. The mixture was heated to 120°C and refluxed for 2 hours. After cooling to room temperature, water (10 mL) was added, and the mixture was extracted with EA (10 mL x 3). The combined organic layers were washed with saturated brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated to obtain the crude product, which was separated and purified by silica gel column chromatography to obtain compound 158-2.

[0737] 1 H NMR (400MHz, CDCl3) δ6.78 (s, 1H).

[0738] Step 2: Synthesis of compound 158-3

[0739] 158-2 (1.0 g, 3.6 mmol) was dissolved in acetic acid (10 mL), and zinc powder (2.37 g, 36.2 mmol) was slowly added. The temperature was raised to 100°C and stirred for 16 hours. The mixture was cooled to room temperature, and water (10 mL) was added. The mixture was extracted with DCM (10 mL x 3). The combined organic phases were washed with saturated Na2CO3 (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated to obtain compound 158-3.

[0740] Step 3: Synthesis of compound 158-4

[0741] Compound 158-3 (600 mg, 1.82 mmol, 60% purity) and 2-(cyclohex-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (417 mg, 2.00 mmol) were dissolved in a mixture of 1,4-dioxane (10 mL) and H₂O (2 mL). Sodium carbonate (386 mg, 3.64 mmol) was added, the atmosphere was replaced with nitrogen, and Pd(dppf)Cl₂ (66.7 mg, 0.091 mmol) was added. The mixture was heated to 90°C and refluxed for 16 hours. The reaction mixture was filtered and concentrated to obtain the crude product, which was then purified by silica gel column chromatography to obtain compound 158-4.

[0742] 1 H NMR (400MHz, DMSO) δ7.35(d,J=1.6Hz,1H),7.20(d,J=1.6Hz,1H),6.22-6.19(m,1H),1.73-1.62(m,4H),1.61-1.54(m,4H).

[0743] Step 4: Synthesis of compound 158-5

[0744] At room temperature, 158-4 (500 mg, 1.25 mmol, 50% purity) was dissolved in a mixture of water (5 mL) and tert-butanol (5 mL). Potassium osmate dihydrate (23 mg, 0.063 mmol), methanesulfonamide (143 mg, 1.51 mmol), potassium ferricyanide (1.24 g, 3.77 mmol), (DHQD)2PHAL (245 mg, 0.315 mmol), and K2CO3 (522 mg, 3.77 mmol) were added and reacted for 16 hours. 15% aqueous sodium hydroxide solution (10 mL) was added, and the mixture was extracted with EA (10 mL x 3). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated to obtain the crude product, which was then purified by silica gel column chromatography to obtain compound 158-5.

[0745] 1 H NMR (400MHz, DMSO) δ7.14(d,J=1.6Hz,1H),7.11(d,J=2.0Hz,1H),4.54(s,1H), 4.28(d,J=6.4Hz,1H),3.58-3.49(m,1H),1.65-1.54(m,6H),1.37-1.26(m,2H).

[0746] Step 5: Synthesis of compound 158-7

[0747] To a solution of 158-5 (300 mg, 1.16 mmol) in acetonitrile (5 mL) was added dropwise TfOH (0.28 mL, 3.2 mmol) at -40 ° C. The dry ice bath was removed, the temperature was naturally raised to room temperature, and the reaction was continued for 1 hour. Water (5 mL) was added and stirred for 10 minutes. The acetonitrile was removed by concentration under reduced pressure. The remaining aqueous phase was heated to 100 ° C and refluxed for 16 hours. The pH was adjusted to 10 with 1N sodium hydroxide aqueous solution. EA (10 mL x 3) was extracted, the organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated to obtain the crude product, and PE:EA = 10:1 (5 mL) was added thereto. Stir for 10 minutes, filter, collect the filter cake, and dry in vacuo to obtain compound 158-7. LCMS: 256.0 (M+H) + .

[0748] Step 6: Synthesis of compound 158-8

[0749] 158-7 (200 mg, 0.863 mmol) and triethylamine (0.24 mL, 1.7 mmol) were added to methyltetrahydrofuran (5 mL) at 0°C, and chloroacetyl chloride (0.082 mL, 1.0 mmol) was slowly added dropwise. After reacting for 1 hour, water (5 mL) was added, and the mixture was extracted with EA (5 mL x 3). The organic phases were combined, washed with saturated brine (5 mL), dried over anhydrous Na2SO4, filtered, and concentrated to obtain the crude product, which was separated and purified by silica gel column chromatography to obtain compound 158-8.

[0750] 1 H NMR (400MHz, DMSO) δ7.58(s,1H),7.10(d,J=1.6Hz,1H),7.05(d,J=1.6Hz,1H),5.17(d,J=5.2Hz,1H),4.28- 4.24(m,2H),3.59-3.48(m,1H),2.84-2.73(m,1H),1.70-1.53(m,4H),1.43-1.32(m,2H),1.26-1.19(m,1H).

[0751] Step 7: Synthesis of compound 158-9

[0752] 158-8 (150 mg, 0.487 mmol) was dissolved in isopropanol (5 mL) at 0°C, and potassium tert-butoxide (109 mg, 0.973 mmol) was added. After reacting for 1 hour, the solvent was removed by concentration to obtain a crude product. Water (5 mL) was added, stirred for 10 minutes, and filtered. The filter cake was collected and dried under vacuum to obtain compound 158-9.

[0753] 1 H NMR (400MHz, DMSO) δ8.40(s,1H),7.25(s,2H),4.09-4.04(m,1H),4.01-3.95(m,2H),1.93-1.73(m,3H),1.69-1.52(m,2H),1.46-1.37(m,3H).

[0754] Step 8: Synthesis of Compound 158 Hydrochloride

[0755] 158-9 (100 mg, 0.368 mmol) was dissolved in THF (2 mL) at 0 ° C. Borane dimethyl sulfide (368 uL, 3.68 mmol) was slowly added dropwise. The temperature was raised to 70 ° C and refluxed for 16 hours. The temperature was lowered to 0 ° C and quenched with methanol (2 mL). After stirring for 1 hour, the temperature was lowered to 0 ° C and sodium borohydride (69 mg, 1.8 mmol) was slowly added in batches. The temperature was raised to 50 ° C and the reaction was continued for 16 hours. The reaction solution was concentrated to obtain a crude product, which was separated and purified by silica gel column chromatography to obtain compound 158. Pure water (10 mL) and 1N dilute hydrochloric acid (100 uL) were added and lyophilized to obtain compound 158 hydrochloride. LCMS: 258.0 (M+H) + .

[0756] 1 H NMR (400MHz, DMSO) δ7.68(s,1H),7.41(d,J=1.6Hz,1H),4.19(s,1H),4.03-3.94(m,1H),3.75-3.66(m,1H),3.43-3.35(m,1H),2.83( d,J=12.8Hz,1H),2.40-2.26(m,1H),2.05-1.95(m,1H),1.87-1.70(m,1H),1.69-1.60(m,1H),1.54-1.46(m,2H),1.33-1.16(m,2H).

[0757] Example 20: The following compounds were prepared by referring to the above-mentioned analogous preparation methods, see Table 16.

[0758] Table 16: Preparation and characterization data of compounds

[0759] Example 21: Preparation of Compounds 177 and 178

[0760] Step 1: Synthesis of compound 177-2

[0761] At 0°C under nitrogen, (3-chlorophenyl)magnesium bromide (29.0 mL, 0.5 M, 14.5 mmol) was added dropwise to a solution of compound 177-1 (1.0 g, 7.3 mmol) in diethyl ether (30 mL). The temperature was slowly raised to 35°C and maintained for 6 hours. A saturated aqueous solution of NH4Cl (50 mL) was added, and the mixture was extracted with diethyl ether (50 mL x 3). The organic phases were combined, washed with saturated brine (50 mL), dried over Na2SO4, filtered, and concentrated to obtain the crude product. The crude product was purified by Pre-HPLC (column: Xtimate C18, 21.2 x 250 mm, 5 μm; mobile phase: (0.1% formic acid) water: acetonitrile; acetonitrile: 5%-35%) and lyophilized to obtain the formate salt of compound 177-2. The pH was adjusted to 8-9 with aqueous sodium hydroxide solution (2N), extracted with diethyl ether (20 mL x 3), and the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 177-2. LCMS: 266.4 (M+H) + .

[0762] Step 2: Synthesis of compounds 177 and 178

[0763] Compound 177-2 (100 mg, 0.376 mmol) was separated by SFC, and fraction P1 (Rt=6.48 min) and fraction P2 (Rt=7.12 min) were lyophilized, HCl (1N, 50 uL) and pure water (10 mL) were added, respectively, and lyophilized to give Compound 177 and Compound 178.

[0764] (SFC conditions: column: ChiralPak IGS, 250×40 mm ID, 10 μm; mobile phase: A supercritical CO 2 and B for MeOH; gradient: 25% B; flow rate: 130 mL / min).

[0765] Compound 177 (RT: 6.48)

[0766] LCMS: 266.4 (M+H) + . 1 H NMR:N230984-385-P1(400MHz,DMSO)δ8.95(br.s,1H),8.74(br.s,1H),8.34(s,1H),8.06(s,1H),7.51-7.42(m,2H),5.51(s,1H),3 .30-3.12(m,1H),3.05-2.89(m,1H),2.46-2.35(m,1H),2.21-2.05(m,2H),1.99-1.85(m,1H),1.76–1.34(m,7H),1.14-0.93(m,1H).

[0767] Compound 178 (RT: 7.12)

[0768] LCMS: 266.2 (M+H) + . 1 H NMR: N230984-385-P1(400MHz,DMSO)δ8.95(br.s,1H),8.74(br.s,1H),8.34(s,1H),8.06(s,1H),7.49-7.43(m,2H),5.51(s,1H),3 .29-3.15(m,1H),3.04-2.88(m,1H),2.46-2.37(m,1H),2.21-2.05(m,2H),1.98-1.86(m,1H),1.75-1.37(m,7H),1.15-0.94(s,1H).

[0769] Example 22: Preparation of Compound 244 Hydrochloride

[0770] Step 1: Synthesis of compound 244-1

[0771] At 0°C, compound 242 (530 mg, 2.29 mmol) was dissolved in dichloromethane (15 mL) and sulfuric acid (610 uL, 11.4 mmol) was slowly added dropwise. After the addition was complete, the reaction was allowed to react at room temperature for 16 hours. The temperature was lowered to 0°C and the pH was adjusted to 10 with 1N aqueous sodium hydroxide solution. The mixture was extracted twice with dichloromethane (20 mL), and the combined organic phases were washed with saturated brine (20 mL) and dried over anhydrous sodium sulfate. The crude product was filtered and concentrated to obtain the crude product, which was then separated and purified by flash silica gel column chromatography to obtain compound 244-1. LCMS: 214.6 (M+H) + .

[0772] Step 2: Synthesis of compound 244-2

[0773] To a solution of 244-1 (430 mg, 2.02 mmol) in tetrahydrofuran (10 mL) was added n-butyl lithium (926 uL, 4.03 mmol) at -78 ° C. Stir at -78 ° C for 0.5 hours, and di-tert-butyl dicarbonate (1.21 mL, 3.02 mmol) was added dropwise to the above reaction solution. After the addition was complete, the reaction solution was warmed to room temperature and continued to stir for 16 hours. The reaction was quenched with saturated aqueous ammonium chloride solution (30 mL) and extracted twice with ethyl acetate (30 mL). The combined organic phases were dried over anhydrous sodium sulfate. Filtered and concentrated to obtain a crude product. The crude product was separated and purified by rapid silica gel column chromatography to obtain compound 244-2. LCMS: 336.5 (M+Na) + .

[0774] Step 3: Synthesis of compound 244-3

[0775] At 0 ° C, m-chloroperbenzoic acid (550 mg, 2.71 mmol) was added to a solution of 244-2 (430 mg, 1.37 mmol) in dichloromethane (10 mL). After the addition, the reaction solution was warmed to room temperature and stirred for 4 hours. Dichloromethane (50 mL) was added to dilute and the reaction was quenched with saturated aqueous sodium sulfite solution (20 mL). The organic phase was washed with saturated aqueous sodium bicarbonate solution (20 mL) and dried over anhydrous sodium sulfate. Filtered and concentrated to obtain a crude product. The crude product was separated and purified by flash silica gel column chromatography to obtain compound 244-3. LCMS: 352.4 (M+Na) + .

[0776] Step 4: Synthesis of compound 244-4

[0777] To a solution of 244-3 (430 mg, 1.30 mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (2.00 mL, 25.9 mmol) at room temperature. After the addition was complete, the mixture was stirred at room temperature for 2 hours. The pH of the reaction solution was adjusted to 10 with 1N aqueous sodium hydroxide solution and extracted twice with dichloromethane (30 mL). The combined organic phases were washed with saturated brine (20 mL) and dried over anhydrous sodium sulfate. Filtered and concentrated to give compound 244-4. LCMS: 230.4 (M+H) + .

[0778] Step 5: Synthesis of racemic hydrochlorides of compounds 244 and 245

[0779] To a mixture of lithium aluminum tetrahydride (66.2 mg, 1.74 mmol) in tetrahydrofuran (2 mL) was added a solution of 244-4 (100 mg, 0.436 mmol) in tetrahydrofuran (2 mL) at 0°C. After the addition was complete, the reaction mixture was heated to 60°C and stirred for 16 hours. The reaction was quenched by adding sodium sulfate decahydrate, filtered, and concentrated to obtain the crude product. The crude product was separated and purified by flash silica gel column chromatography, then purified by pre-HPLC, concentrated to remove most of the water, and then lyophilized with 1 M HCl to obtain compound 244 hydrochloride. LCMS: 232.4 (M+H) + .

[0780] 1H NMR (400MHz, DMSO) δ9.02-8.73(m,1H),8.60-8.40(m,1H),7.88-7.77(m,2H),7.51-7.35(m,3H),5.52( s,1H),2.92-2.82(m,1H),2.35-2.14(m,5H),1.90-1.67(m,3H),1.63-1.41(m,4H),0.83-0.68(m,1H).

[0781] Example 23: The following compounds were prepared by referring to the above-mentioned analogous preparation methods, see Table 17.

[0782] Table 17: Preparation and characterization data of compounds

[0783] Example 24 Preparation of Compounds 62 Hydrochloride and 68 Hydrochloride

[0784] Step 1: Synthesis of compounds 62-2A and 62-2B

[0785] At room temperature, 62-1 (20.0 g, 109 mmol), vinylboronic acid pinacol ester (92.5 mL, 546 mmol), and potassium phosphate (69.6 g, 328 mmol) were added to a mixture of dioxane (200 mL) and water (4 mL). Palladium acetate (1.23 g, 5.46 mmol) and Sphos (4.49 g, 10.9 mmol) were added to the reaction mixture. After nitrogen displacement, the temperature was raised to 50°C and the reaction was allowed to proceed for 2 hours. The reaction mixture was then heated to 120°C and the reaction continued for 16 hours. The mixture was filtered, and the filtrate was concentrated to obtain a crude mixture of 62-2A and 62-2B.

[0786] Step 2: Synthesis of compounds 62-3A and 62-3B

[0787] At zero degrees Celsius, sodium hydroxide solution (112 mL, 224 mmol) was added to a solution of a mixture of 62-2A and 62-2B (32.0 g) in tetrahydrofuran (500 mL), and 30% hydrogen peroxide (95.7 g, 844 mmol) was slowly added dropwise. After the addition was complete, stirring was continued at 0°C for 2 hours. The reaction solution was diluted with ethyl acetate (300 mL) and quenched with saturated sodium thiosulfate solution. Ethyl acetate (100 mL) was added for extraction. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel chromatography to obtain a light yellow solid. The light yellow solid was slurried with petroleum ether (30 mL). Filtered, the filter cake was collected and dried to obtain 63-3B. The filtrate was concentrated to obtain a 1:1 mixture of 62-2A and 62-2B.

[0788] 63-3B: 1 HNMR(400MHz, CDCl3)δ7.40-7.37(m,2H),7.34-7.28(m,2H),7.25-7.21(m,1H),6.02-5.98(m,1H ),4.11-4.02(m,1H),2.66-2.48(m,3H),2.27-2.17(m,1H),2.05-1.99(m,1H),1.88-1.77(m,1H).

[0789] Step 3: Synthesis of compounds 62-4A and 62-4B

[0790] At room temperature, a mixture of 62-2A and 62-2B (2.0 g) was dissolved in dichloromethane (40 mL). The temperature was lowered to 0°C, and BAST (4.20 mL, 22.8 mmol) was slowly added dropwise to the reaction mixture. After the addition was complete, stirring was continued at 0°C for 2 hours. The pH of the reaction mixture was adjusted to 8 with saturated sodium bicarbonate aqueous solution and extracted with ethyl acetate (50 mL). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by column chromatography to obtain a mixture of 62-4A and 62-4B.

[0791] 1 HNMR(400MHz, CDCl3)δ7.40-7.36(m,2H),7.34-7.30(m,2H),7.26-7.22(m,1H),6.15-6.10(m,1H ),5.98-5.93(m,1H),5.14-4.88(m,1H),2.87-2.59(m,2H),2.53-2.25(m,2H),2.15-1.92(m,2H).

[0792] Step 4: Synthesis of compounds 62-5A and 62-5B

[0793] At room temperature, potassium carbonate (1.65 g, 11.9 mmol), potassium ferricyanide (3.92 g, 11.9 mmol), methanesulfonamide (415 mg, 4.36 mmol), potassium osmate dihydrate (73 mg, 0.20 mmol) and (DHQ)2PHAL (619 mg, 0.795 mmol) were added to water (10 mL). The mixture of 62-4A and 62-4B (700 mg) was dissolved in tert-butanol (6 mL) and added to the above reaction solution, and stirred at room temperature for 16 hours. Ethyl acetate (50 mL) was added to dilute the mixture and washed with water (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by column chromatography to obtain a mixture of 62-5A and 62-5B (730 mg).

[0794] 1 HNMR(400MHz, CDCl3)δ7.54-7.44(m,4H),7.43-7.35(m,4H),7.32-7.26(m,2H),5.13-5 .09(m,1H),5.06-4.97(m,1H),4.95-4.84(m,1H),4.77-4.56(m,1H),4.41-4.34(m,1H), 4.10-4.03(m,1H),4.03-3.94(m,1H),3.11(d,J=13.2Hz,1H),2.69-2.68(m,1H),2.67-2 .66(m,1H),2.41-2.21(m,3H),2.12-1.79(m,8H),1.71-1.60(m,2H),1.55-1.54(m,1H).

[0795] Step 5: Synthesis of compounds 62-7A and 62-7B

[0796] To a solution of 62-5A and 62-5B mixture (730 mg) in acetonitrile (20 mL) was added TfOH (670 μL, 7.63 mmol) dropwise at -40 ° C. The dry ice bath was removed, the temperature was naturally raised to room temperature, and the reaction was carried out for 1 hour. Water (20 mL) was added to the reaction solution and stirred for 10 minutes. The acetonitrile was removed by concentration under reduced pressure. The temperature was raised to 100 ° C and refluxed for 16 hours. The temperature was lowered to room temperature and the pH was adjusted to 10 with 15% aqueous sodium hydroxide solution. EA (50 mL) was extracted. The organic phase was washed with water (50 mL x 3) and saturated brine (50 mL) and dried over anhydrous sodium sulfate. Filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by column chromatography to obtain a mixture of 62-7A and 62-7B. LCMS: 210.4 (M+H) + .

[0797] Step 6: Synthesis of compounds 62-8A and 62-8B

[0798] At 0°C, a mixture of 62-7A and 62-7B (300 mg) and triethylamine (400 μL L, 2.88 mmol) was added to tetrahydrofuran (10 mL). Chloroacetyl chloride (100 μL, 1.25 mmol) was slowly added dropwise, and stirring was continued at 0°C for 1 hour after the addition was complete. Water (10 mL) and EA (30 mL x 3) were added for extraction. The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was separated and purified by column chromatography to obtain a mixture of 62-8A and 62-8B. LCMS: 308.2 (M+Na) + .

[0799] Step 7: Synthesis of compounds 62-9A and 62-9B

[0800] To a solution of a mixture of 62-8A and 62-8B (190 mg) in isopropanol (3 mL) was added potassium tert-butoxide (149 mg, 1.33 mmol) in portions at 0°C. The reaction mixture was naturally warmed to room temperature and stirred for 2 hours. The reaction mixture was concentrated to obtain a crude product. Water (10 mL) was added to dilute the mixture and extracted with ethyl acetate (20 mL). The combined organic phases were dried over anhydrous sodium sulfate and concentrated to obtain a mixture of 62-9A and 62-9B. LCMS: 250.2 (M+H) + .

[0801] Step 8: Synthesis of Compound 62 Hydrochloride and Compound 68 Hydrochloride

[0802] At 0°C, a mixture of 62-9A and 62-9B (150 mg) was dissolved in THF (10 mL), and borane dimethyl sulfide (600 uL, 6.00 mmol) was slowly added dropwise. The temperature was raised to 70°C and refluxed for 16 hours. The temperature was lowered to 0°C and methanol (5 mL) was added to quench the mixture. Sodium borohydride (45 mg, 1.2 mmol) was slowly added in batches at 0°C. The temperature was raised to 50°C. Stirring was continued for 16 hours. The reaction solution was concentrated to obtain a crude product. The crude product was purified by SFC. The first fraction (Rt = 12.0 min) was collected. After concentration under reduced pressure, pure water was added and lyophilized to obtain compound 62. LCMS: 236.3 (M+H) + .

[0803] 1H NMR(400MHz,MeOD)δ7.73-7.68(m,2H),7.59-7.49(m,3H),4.71-4.57(m,2H),4.23-4.16(m,1H),3.83(td,J=12.4,2.4Hz ,1H),3.65-3.55(m,1H),3.09-2.97(m,2H),2.37-2.24(m,2H),2.16-2.06(m,1H),2.04-1.86(m,1H),1.63-1.44(m,1H).

[0804] The second fraction (Rt = 14.0 min) was collected, concentrated under reduced pressure, and lyophilized with purified water to obtain compound 68. LCMS: 236.3 (M+H) + .

[0805] 1 H NMR (400MHz, MeOD) δ7.71-7.66(m,2H),7.52-7.42(m,3H),5.10-4.95(m,1H),4.68-4.64(m,1H),4.23-4.16(m,1H),3.94-3. 86(m,1H),3.62-3.54(m,1H),3.10-3.03(m,1H),2.94-2.86(m,1H),2.85-2.70(m,1H),2.11-1.88(m,3H),1.77-1.69(m,1H).

[0806] (SFC conditions: column: ChiralPak OD-H, 250×4.6 mm ID, 5 μm; mobile phase: A for n-hexane and B for ethanol; gradient: 80% B; flow rate: 1.0 mL / min).

[0807] Example 25 Preparation of Compounds 230 Hydrochloride and 231 Hydrochloride

[0808] Step 1: Synthesis of compound 230-2

[0809] At room temperature, 230-1 (11.5 g, 86.3 mmol) was dissolved in THF (300 mL), and potassium tert-butoxide (19.4 g, 174 mmol) was added to the reaction mixture. Stirring was carried out at room temperature for 12 hours. Tert-butyl nitrite (30.8 mL, 259 mmol) was then added to the reaction mixture. The reaction was continued at room temperature for 12 hours. Water (200 mL) was added to the reaction mixture to quench the mixture, and the mixture was extracted with ethyl acetate (200 mL x 2). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was slurried with ethanol (50 mL) and water (50 mL) to obtain 230-2.

[0810] 1 H NMR (400MHz, DMSO) δ11.62(s,1H),8.43(s,1H),8.36(d,J=5.2Hz,1H),7.68( d,J=5.2Hz,1H),2.75-2.69(m,2H),2.66(t,J=6.6Hz,2H),1.86-1.71(m,2H).

[0811] Step 2: Synthesis of compound 230-3

[0812] 230-2 (8 g, 49.325 mmol) was dissolved in a mixture of acetone (100 mL) and HCl (2 M, 60 mL), heated to 100°C, and refluxed for 12 hours. The crude product was concentrated under reduced pressure and slurried with ethanol. The resulting solid was dissolved in saturated sodium bicarbonate solution (100 mL) and extracted with ethyl acetate (100 mL x 2). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography to afford 230-3.

[0813] 1 H NMR (400MHz, CDCl3) δ8.65(d,J=0.4Hz,1H),8.61(d,J=5.2Hz,1H),7.74(d,J=5.2Hz,1H),2.96(t,J=6.0Hz,2H),2.74-2.58(m,2H),2.26-2.08(m,2H).

[0814] Step 3: Synthesis of compound 230-4

[0815] To a solution of 230-3 (4.00 g, 27.8 mmol) in THF (50 mL) at -78°C was added LDA (19.5 mL, 39.0 mmol) and 1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (12.9 g, 36.2 mmol). After addition, the temperature was slowly raised to 25°C and stirring was continued for 2 hours. The mixture was quenched by the addition of saturated ammonium chloride solution (200 mL) and extracted with ethyl acetate (200 mL x 2). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to yield the crude product. The crude product was purified by column chromatography to afford 230-4.

[0816] 1 H NMR (400MHz, CDCl3) δ8.55(d,J=5.2Hz,1H),8.44(d,J=0.8Hz,1H),7.20(d,J =5.2Hz,1H),6.26(t,J=4.8Hz,1H),2.89(t,J=8.4Hz,2H),2.64-2.57(m,2H).

[0817] Step 4: Synthesis of compound 230-5

[0818] To a mixed solution of 230-4 (4.30 g, 15.7 mmol) and (2-chlorophenyl)boronic acid (3.70 g, 23.6 mmol) in 1,4-dioxane (50 mL) and water (5 mL) were added NaCO (5.01 g, 47.2 mmol) and Pd(dppf)Cl (0.35 g, 0.473 mmol) at room temperature. The mixture was heated to 95°C and refluxed for 18 hours. Sodium chloride solution (200 mL) was added to quench the mixture, and the mixture was extracted with ethyl acetate (200 mL x 2). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography to afford 230-5.

[0819] 1 H NMR (400MHz, CDCl3) δ8.41 (s, 1H), 8.31 (d, J = 5.2Hz, 1H), 7.49-7.42 (m, 1H), 7.37-7.31 (m, 2H), 7.3 0-7.24(m,1H),6.53(d,J=5.2Hz,1H),6.26(t,J=4.4Hz,1H),2.92-2.87(m,2H),2.72-2.42(m,2H).

[0820] Step 5: Synthesis of compound 230-6

[0821] At room temperature, 230-5 (200 mg, 0.827 mmol) was dissolved in a mixture of tert-butanol (3 mL) and water (3 mL). NMO (387 mg, 1.65 mmol) and potassium osmate dihydrate (25.7 mg, 0.083 mmol) were added. The mixture was heated to 100°C and refluxed for 16 hours. 1N NaOH solution (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL x 2). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography to afford 230-6.

[0822] 1 H NMR (400MHz, DMSO) δ8.38 (s, 1H), 8.21 (d, J = 5.2Hz, 1H), 8.07-7.91 (m, 1H), 7.45-7.38 (m, 1H), 7.36-7.24 (m, 2H), 6 .58(d,J=5.2Hz,1H),5.53(s,1H),4.86(d,J=7.2Hz,1H),4.45-4.26(m,1H),2.98-2.80(m,2H),2.09-1.82(m,2H).

[0823] Step 6: Synthesis of compound 230-8

[0824] At -40°C, 230-6 (70.0 mg, 0.254 mmol) was dissolved in acetonitrile (10 mL), and TfOH (95.2 mg, 0.635 mmol) was added. The temperature was slowly raised to 80°C and refluxed for 16 hours. After the reaction mixture cooled to room temperature, water (10 mL) was added and the mixture was concentrated under reduced pressure to obtain crude intermediate 230-7. The crude product was dissolved in 1M aqueous HCl (10 mL) and refluxed at 100°C under N2 protection for 3 hours. After the reaction mixture cooled to room temperature, sodium chloride solution (30 mL) and ethyl acetate (20 mL x 2) were added, and the aqueous phase was retained. The aqueous phase was adjusted to pH 10 with saturated potassium carbonate solution and extracted with ethyl acetate (20 mL x 2). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography to obtain 230-8.

[0825] 1H NMR (400MHz, DMSO) δ8.32(s,1H),8.15(d,J=5.2Hz,1H),8.04(d,J=7.6Hz,1H),7.47-7.34(m,1H),7.32-7.22(m,2H),6.55(d,J=5 .2Hz,1H),4.97(d,J=5.6Hz,1H),4.41–4.27(m,1H),2.97-2.83(m,2H),2.26-2.18(m,2H),2.15-1.97(m,1H),1.92-1.78(m,1H).

[0826] Step 7: Synthesis of compound 230-9

[0827] To a solution of 230-8 (50 mg, 0.182 mmol) in MeOH (5 mL) was added paraformaldehyde (6.56 mg, 0.218 mmol), AcOH (0.010 mL, 0.182 mmol), and NaBH3CN (114 mg, 1.82 mmol) at room temperature. The mixture was stirred at 25°C under N2 protection for 16 hours. The reaction mixture was filtered and purified by Prep-HPLC to afford 230-9. LCMS: 289.1 (M+H) + .

[0828] Step 8: Synthesis of compound 230-10

[0829] To a solution of 230-9 (100 mg, 0.346 mmol) in acetone (20 mL) was added Jones reagent (5 mL) under ice bath. The mixture was stirred at 25 ° C for 16 hours under N2 protection. Water (20 mL) was added to quench the reaction, the pH was adjusted to 8 with saturated sodium bicarbonate solution, and the mixture was extracted with ethyl acetate (20 mL x 2). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product. The crude product was purified by Prep-HPLC to give 230-10. LCMS: 287.0 (M+H) + .

[0830] Step 9: Synthesis of Compounds 230 Hydrochloride and 231 Hydrochloride

[0831] 230-10 (20.0 mg, 69.0 μmol) was purified by SFC. The first fraction (Rt = 9.87 min) was collected. After concentration under reduced pressure, 1N HCl and pure water were added and lyophilized to obtain compound 230 hydrochloride. LCMS: 287.0 (M+H) + .

[0832] 1H NMR(400MHz,MeOD)δ8.95(s,1H),8.89(d,J=6.2Hz,1H),8.08(d,J=6.0Hz,1H),7.59-7.49(m,3H ),7.45(d,J=8.2Hz,1H),3.52-3.38(m,1H),3.25-3.13(m,1H),3.09-2.92(m,2H),2.66(s,3H).

[0833] The second fraction (Rt = 13.26 min) was collected. After concentration under reduced pressure, 1N HCl and pure water were added and lyophilized to obtain compound 231 hydrochloride. LCMS: 287.0 (M+H) + .

[0834] 1 H NMR(400MHz,MeOD)δ8.94(s,1H),8.89(d,J=6.0Hz,1H),8.07(d,J=6.2Hz,1H),7.59-7.48(m, 3H),7.48-7.42(m,1H),3.50-3.40(m,1H),3.23-3.13(m,1H),3.10-2.92(m,2H),2.65(s,3H).

[0835] (SFC conditions: column: ChiralPak IG, 250×50 mm ID, 10 μm; mobile phase: A for CO 2 and B for MeOH; gradient: 35% B; flow rate: 140 mL / min).

[0836] Example 26 Preparation of Compounds 196 Hydrochloride and 199 Hydrochloride

[0837] Step 1: Synthesis of compound 196-2

[0838] 196-1 (4.0 g, 20.0 mmol) was dissolved in THF (40 mL) at room temperature, and m-chlorobromobenzene (7.7 g, 40.0 mmol), tri-tert-butylphosphine (263 mg, 1.3 mmol), palladium acetate (224 mg, 1.0 mmol) and sodium tert-butoxide (2.9 g, 30.0 mmol) were added in sequence. The temperature was raised to 65 ° C and refluxed for 24 hours. After the reaction solution was cooled to room temperature, saturated sodium bicarbonate solution (40 mL) was added and extracted with EA (100 mL * 2). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The crude product was purified by column chromatography to obtain 196-2. LCMS: 310.0 (M+H) + .

[0839] Step 2: Synthesis of compound 196-3

[0840] Dissolve 196-2 (1.0 g, 3.23 mmol) in THF (9 mL), cool to 0°C, and slowly add a solution of NaH (155 mg, 3.87 mmol) in THF (6 mL) dropwise. After the addition is complete, warm to room temperature and stir for 4 hours. Then, add 1-chloro-3-iodopropane (2.64 g, 12.92 mmol) dropwise and continue stirring at room temperature overnight. The reaction mixture is quenched with water and extracted with EA (50 mL x 2). The combined organic phases are washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to yield the crude product. The crude product is purified by column chromatography to yield 196-3.

[0841] 1 H NMR (400MHz, CDCl3) δ7.5–7.0 (m, 4H), 4.9 (dd, J=75.8, 14.3Hz, 1H), 4.2 (dd, J=81.6, 12.0Hz, 1H), 3.4(t,J=6.3Hz,2H),3.1(m,2H),2.5(m,1H),2.3(m,1H),2.0(m,1H),1.7(m,1H),1.7–1.4(m,11H).

[0842] Step 3: Synthesis of compound 196-4

[0843] 196-3 (551 mg, 1.43 mmol) was dissolved in methanol (8 mL), cooled to 0°C, and sodium borohydride (60 mg, 1.57 mmol) was added in batches. The mixture was naturally warmed to room temperature and stirred for 1 hour. After concentration under reduced pressure, the residue was dissolved in THF (10 mL). The mixture was cooled to 0°C, and NaH (69 mg, 1.72 mmol) was added in batches. The mixture was naturally warmed to room temperature and stirred for 12 hours. 1N HCl was added dropwise to the reaction solution to quench the mixture, and the mixture was extracted with DCM (30 mL*2). The combined organic phases were dried over anhydrous sodium sulfate and concentrated to give a crude product. The crude product was purified by column chromatography to give 196-4. LCMS: 252.0 (M-Boc+H) + .

[0844] Step 4: Synthesis of compound 196-5

[0845] 196-4 (206 mg, 0.59 mmol) was dissolved in DCM (5 mL), and a hydrogen chloride-dioxane solution (4 M, 2 mL) was added, and the mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure to give 196-5. LCMS: 252.0 (M+H) + .

[0846] Step 5: Synthesis of Compounds 196 Hydrochloride and 199 Hydrochloride

[0847] 196-5 (47 mg, 0.19 mmol) was separated and purified by SFC. The first fraction (Rt = 7.2 min) was collected and concentrated under reduced pressure, followed by addition of 1N HCl and purified water and freeze-drying to obtain compound 199 hydrochloride or 196 hydrochloride.

[0848] LCMS: 252.2 (M+H) + . 1 H NMR(400MHz,MeOD)δ7.85-7.74(m,1H),7.71-7.59(m,1H),7.33(t,J=8.0Hz, 1H),7.26-7.21(m,1H),4.06-3.99(m,1H),3.92-3.83(m,1H),3.70-365(m,1H ),3.63-3.55(m,1H),3.21-3.16(m,1H),3.15-3.07(m,1H),3.00-2.93(m,1H) ,2.31-2.17(m,1H),2.00-1.92(m,1H),1.77-1.62(m,2H),1.47-1.27(m,2H).

[0849] The second fraction (Rt = 11.4 min) was collected and concentrated under reduced pressure, followed by addition of 1N HCl and pure water and freeze-drying to obtain compound 196 hydrochloride or 199 hydrochloride. LCMS: 252.2 (M+H) + .

[0850] 1 H NMR(400MHz,MeOD)δ7.89-7.73(m,1H),7.71-7.59(m,1H),7.33(t,J=8.0Hz,1 H),7.28-7.20(m,1H),4.08-3.98(m,1H),3.90-3.83(m,1H),3.72-3.65(m,1H ),3.63-3.55(m,1H),3.21-3.17(m,1H),3.16-3.07(m,1H),3.00-2.91(m,1H) ,2.31-2.16(m,1H),1.99-1.91(m,1H),1.77-1.61(m,2H),1.46-1.28(m,2H).

[0851] (SFC conditions: column: ChiralPak IE, 250×40 mm ID, 10 μm; mobile phase: A for n-hexane and B for ethanol; gradient: 30% B; flow rate: 80 mL / min).

[0852] Example 27 Preparation of Compound 226 Hydrochloride

[0853] Step 1: Synthesis of compound 226-2

[0854] To a solution of 1-(bromomethyl)-3-chlorobenzene (1.00 g, 4.86 mmol) in 1,4-dioxane (15 mL) and water (3 mL) at room temperature were added cyclohex-1-en-1-ylboronic acid (740 mg, 5.84 mmol), K2CO3 (2.02 g, 14.6 mmol), and Pd(dppf)Cl2 (110 mg, 0.146 mmol). Under nitrogen, the reaction mixture was stirred at 100°C for 18 hours and then cooled to room temperature. Saturated sodium chloride solution (30 mL) was added, and the mixture was extracted twice with ethyl acetate (50 mL x 2). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. Compound 226-2 was purified by column chromatography (petroleum ether:ethyl acetate = 50:1) to afford compound 226-2.

[0855] 1 H NMR: (400MHz, CDCl3) δ7.24-7.13(m,3H),7.07-7.02(m,1H),5.56-5.43(m, 1H),3.21(s,2H),2.08-1.97(m,2H),1.90-1.75(m,2H),1.62-1.47(m,4H).

[0856] Step 2: Synthesis of compound 226-3

[0857] To water (14 mL) at room temperature were added KCO (940 mg, 6.79 mmol), KFe(CN) (2.24 g, 6.79 mmol), MeSONH (240 mg, 2.49 mmol), KOsO.2HO (40.0 mg, 0.113 mmol), and (DHQD)PHAL (350 mg, 0.453 mmol). Compound 226-2 (500 mg, 2.26 mmol) in tert-butanol (8.4 mL) was then added. The reaction was allowed to proceed for 16 hours. Ethyl acetate (100 mL) was added, and the mixture was washed three times with 15% aqueous sodium hydroxide solution (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to yield the crude product. Compound 226-3 was purified by column chromatography (petroleum ether:ethyl acetate = 0-25%).

[0858] 1H NMR: (400MHz, DMSO) δ7.32-7.28(m,1H),7.28-7.21(m,2H),7.20-7.16(m,1H),4.49(d,J=6.0Hz,1H),3.92(d,J=1.2Hz,1H),3.15 (dd,J=13.6,6.4Hz,1H),2.82(d,J=13.2Hz,1H),2.71(d,J=13.2Hz,1H),1.59-1.46(m,3H),1.43-1.17(m,3H),1.15-0.95(m,2H).

[0859] Step 3: Synthesis of compound 226-5

[0860] At -40°C, trifluoromethanesulfonic acid (367uL, 4.15mmol) was added dropwise to a solution of compound 226-3 (400mg, 1.66mmol) in acetonitrile (10mL). The mixture was heated to room temperature and reacted for 1 hour. Water (10mL) was added and stirred for 10 minutes. The acetonitrile was removed by concentration under reduced pressure. The mixture was heated to 100°C and the reaction was continued for 16 hours. The mixture was cooled to room temperature and the pH was adjusted to 10 with aqueous sodium hydroxide solution (1N). The mixture was extracted with ethyl acetate (10mL x 3), the organic phases were combined, washed with saturated brine (10mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. Petroleum ether:ethyl acetate = 10:1 (10mL) was added to the crude product. The mixture was stirred (10min), filtered, the filter cake was collected, and dried under vacuum to obtain compound 226-5. LCMS: 240.0 (M+H) + .

[0861] Step 4: Synthesis of compound 226-6

[0862] To compound 226-5 (100 mg, 0.0830 mmol) and triethylamine (23 uL, 0.17 mmol) in tetrahydrofuran (2 mL) at 0°C was added chloroacetyl chloride (7 uL, 0.09 mmol) dropwise. The mixture was allowed to react for 1 hour. Water (5 mL) was added and the mixture was extracted with ethyl acetate (5 mL x 3). The organic phases were combined, washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. Compound 226-6 was purified by column chromatography (ethyl acetate:petroleum ether = 0-24%).

[0863] LCMS: 316.4 (M+H) + .

[0864] Step 5: Synthesis of compound 226-7

[0865] Compound 226-6 (110 mg, 0.348 mmol) and PCC (225 mg, 1.04 mmol) were added to dichloromethane (5 mL) at room temperature and reacted at 40°C for 16 hours. The reaction solution was concentrated to obtain a crude product, which was then purified by column chromatography (ethyl acetate:petroleum ether = 0-18%) to obtain compound 226-7.

[0866] LCMS: 314.0 (M+H) + .

[0867] Step 6: Synthesis of compound 226-8

[0868] Compound 226-8 (80 mg, 0.25 mmol) in methanol (2 mL) was added to 19 mg (0.51 mmol) at zero temperature. The mixture was allowed to react at room temperature for 1 hour. The crude product was concentrated and purified by column chromatography (ethyl acetate:petroleum ether = 0-28%) to afford compound 226-8 (50 mg, 0.16 mmol, 62% yield).

[0869] LCMS: 316.2 (M+H) + .

[0870] Step 7: Synthesis of compound 226-9

[0871] To a solution of compound 226-9 (50 mg, 0.16 mmol) in isopropanol (2 mL) at zero temperature was added potassium tert-butoxide (35 mg, 0.32 mmol) and allowed to react for 1 hour. The reaction solution was concentrated to remove most of the solvent to obtain the crude product. Water (2 mL) was added to the crude product, stirred for 10 minutes, and filtered. The filter cake was collected and dried under vacuum to obtain compound 226-9.

[0872] LCMS: 280.1 (M+H) + .

[0873] Step 6: Synthesis of Compound 226

[0874] Borane dimethyl sulfide (63 μL, 0.63 mmol) was added dropwise to a solution of compound 226-9 (35 mg, 0.13 mmol) in tetrahydrofuran (5 mL) at zero temperature. The mixture was heated to 70°C and reacted for 16 hours. The mixture was cooled to 0°C and quenched with methanol (2 mL). Sodium borohydride (14 mg, 0.38 mmol) was slowly added in batches and the temperature was raised to 50°C. The mixture was reacted for 32 hours, and the reaction solution was concentrated to obtain a crude product, which was then separated and lyophilized by prep-HPLC to obtain compound 226. LCMS: 266.4 (M+H) + .

[0875] (Prep-HPLC conditions: column: Xtimate C18, 21.2*250 mm, 5 um; mobile phase: A (0.1% HCl) + B (ACN); gradient: 16% B; flow rate: 20 mL / min).

[0876] 1 H NMR: (400MHz, DMSO) δ9.59(s,1H),7.97-7.75(m,1H),7.44-7.39(m,3H),7.31-7.27(m,1H),4.08-4.00 (m,1H),3.91-3.75(m,2H),3.71-3.64(m,1H),3.30-3.21(m,2H),3.06-3.01(m,1H),1.83-1.40(m,8H).

[0877] Example 28

[0878] Preparation of Compound 2 Hydrochloride Form A

[0879] Weigh compound 2 (2.0 g, 7.94 mmol) into a 100 mL glass bottle, add 20 mL of isopropanol, and stir to dissolve. Add 3.66 mL of hydrochloric acid in isopropanol (0.8 mL of concentrated hydrochloric acid diluted 5-fold with isopropanol, 1.1 eq), stir at room temperature for 24 hours, and filter. Dry the filter cake under vacuum at 25°C for 48 hours to obtain Compound 2 hydrochloride Form A. The salt ratio is 1:1. 1 H-NMR(400MHz,DMSO)δ10.41(s,1H),9.42(s,1H),7.98-7.93(m,2H),7.58-7.53(m,2H),4.14–4.01(m,3H),3.0 1(d,J=12,1H),2.79-2.73(m,1H),2.57-2.51(m,1H),2.01-1.77(m,4H),1.67-1.55(m,2H),0.89-0.79(m,1H).

[0880] Preparation of Compound 2 Phosphate B Crystalline Form

[0881] Compound 2 (2.0 g, 7.94 mmol) was weighed into a 100 mL glass bottle. 26 mL of acetone was added and stirred to dissolve. 2.93 mL of acetone phosphate solution (0.8 mL of phosphoric acid diluted 5-fold with acetone, 1.1 eq) was added. Stir at room temperature for 24 hours and then filter. The filter cake was vacuum-dried at 25°C for 48 hours. This yielded Compound 2 Phosphate Form B. The salt ratio was 1:1. 1H-NMR(400MHz,DMSO)δ7.84-7.75(m,2H),7.45-7.35(m,2H),0.94–3.90(m,1H),3.80–3.64(m,2H) ),2.61-2.49(m,2H),2.33-2.30(m,1H),1.71-1.60(m,4H),1.47-1.39(m,2H),0.82-0.78(m,1H).

[0882] Preparation of Compound 2 Methanesulfonate Crystal Form C

[0883] Method 1: Weigh compound 2 (3.0 g, 11.91 mmol) into a 100 mL glass bottle and add 54 mL of a 7:2 mixture of methyl tert-butyl ether and acetone. Stir and dissolve. Add 5.36 mL of a methyl tert-butyl ether solution of methanesulfonic acid (1.2 mL of methanesulfonic acid diluted 5-fold with methyl tert-butyl ether). Stir at room temperature for 24 hours and filter. Dry the filter cake under vacuum at 25°C for 48 hours. This yields Compound 2 mesylate salt Form C. The salt ratio is 1:1. 1 H-NMR(400MHz,DMSO)δ9.49(s,1H),9.13(s,1H),7.95-7.93(m,2H),7.60-7.57(m,2H),4.17-4.13(m,1H),3 .95-3.88(m,2H),3.09-3.06(m,1H),2.79-2.52(m,2H),2.36(s,3H),1.90-1.56(m,6H),0.90-0.83(m,1H).

[0884] Method 2: Take 200 mg of Compound 2 mesylate salt Form D, add EA (2 mL) to form a suspension, and stir for 24 hours. The filter cake is vacuum dried at 25°C for 48 hours to obtain Compound 2 mesylate salt Form C.

[0885] Method 3: Take 200 mg of Compound 2 mesylate salt Form D, add ethanol (2 mL) to form a suspension, stir for 24 hours, and dry the filter cake in vacuo at 25°C for 48 hours to obtain Compound 2 mesylate salt Form C.

[0886] Preparation of Compound 2 Methanesulfonate Form D

[0887] Method 1: Weigh Compound 2 mesylate salt Form C (50 mg, 0.20 mmol) into a 2 mL glass vial, add 0.1 mL of methanol, and stir to dissolve until clear. Evaporate the solvent in a semi-closed state at room temperature to obtain Compound 2 mesylate salt Form D.

[0888] Method 2: Take 200 mg of Compound 2 mesylate salt Form C and add ethanol:water (volume ratio: 1:1) (2 mL) to form a suspension. Stir for 24 hours. Dry the filter cake in vacuo at 25°C for 48 hours to obtain Compound 2 mesylate salt Form D.

[0889] Preparation of Compound 2 Methanesulfonate Form E

[0890] Compound 2 mesylate salt Form C (50 mg, 0.20 mmol) was weighed into a 2 mL glass vial, 0.1 mL of a 3:1 ethanol / water mixture was added, and the mixture was stirred until clear. The solvent was evaporated in a semi-closed state at room temperature to obtain Compound 2 mesylate salt Form E.

[0891] Preparation of Compound 2 Formate F Crystalline Form

[0892] Compound 2 (50 mg, 0.20 mmol) was weighed and placed in a 5 mL glass vial. 0.1 mL of methyl tert-butyl ether was added and stirred to dissolve. Formic acid (1.1 eq) was added and stirred at room temperature for 24 hours. 0.02 mL of n-heptane was added and the mixture was stirred at 40°C for 12 hours before filtering. The filter cake was vacuum dried at 25°C for 24 hours. This yielded Compound 2 formate salt Form F. The salt ratio was 1:1. 1 H-NMR(400MHz,DMSO)δ8.18(s,1H),7.79-7.71(m,2H),7.41-7.29(m,2H),3.87-3.84(m,1H),3 .67-3.54(m,2H),2.53-2.43(m,3H),1.75-1.66(m,3H),1.44-1.41(m,3H),0.87-0.80(m,1H).

[0893] Preparation of Compound 2 Oxalate L Crystal Form

[0894] Compound 2 (500 mg, 1.97 mmol) was weighed into a 10 mL glass vial. 5 mL of methyl tert-butyl ether and 2 mL of acetone were added and stirred to dissolve. Oxalic acid (0.5 eq) was added and stirred at room temperature for 24 hours. The solvent was evaporated in a semi-closed state at room temperature to obtain Compound 2 oxalate salt L-form. 1 H-NMR (400MHz, DMSO) δ7.85 (s, 2H), 7.80 (d, J = 7.6Hz, 2H), 7.49-7.36 (m, 4H), 4.00-3.94 (m, 2H), 3.80-3.68 (m, 4H), 2.7 1(d,J=10.8Hz,2H),2.65-2.55(m,2H),2.39(d,J=13.2Hz,2H),1.82-1.60(m,7H),1.51-1.40(m,3H),0.89-0.75(m,2H).

[0895] Preparation of Compound 2 Pamoate M Crystalline Form

[0896] Compound 2 (500 mg, 1.97 mmol) was weighed into a 10 mL glass vial. 5 mL of methyl tert-butyl ether and 2 mL of acetone were added and stirred to dissolve. Pamoic acid (0.5 eq) was added and stirred at room temperature for 24 hours. The solvent was evaporated in a semi-closed state at room temperature to obtain Compound 2 Pamoic acid salt Form M. 1 H-NMR (400MHz, DMSO) δ8.30 (s, 2H), 8.17 (d, J = 8.4Hz, 2H), 7.98-7.88 (m, 3H), 7.74 (d, J = 7 .6Hz,2H),7.54-7.51(m,2H),7.26-7.18(m,2H),7.09(t,J=14.8Hz,2H),4.73(s,2H),4.21 -4.06(m,1H),4.03-3.86(m,3H),3.09-3.01(m,4H),2.82-2.71(m,1H),2.65-2.57(m,1H) ,1.93-1.76(m,4H),1.71-1.53(m,3H),1.49-1.36(m,1H),1.11(s,8H),0.90-0.76(m,1H).

[0897] Preparation of Compound 3 Hydrochloride Form G

[0898] Weigh compound 3 (400 mg, 1.59 mmol) into a 10 mL glass bottle, add 2 mL of acetone, and stir to dissolve. Add 1.49 mL of hydrochloric acid acetone solution (1.49 mL of concentrated hydrochloric acid diluted 10 times with acetone), stir at room temperature for 20 hours, and then filter. The filter cake is vacuum-dried at 25°C for 16 hours. Compound 3 hydrochloride G crystal form is obtained. The salt ratio is 1:1 1 H NMR(400MHz,DMSO)δ11.07(m,1H),8.30-8.27(m,1),8.06(br.s,1H),7.65-7.61(m,1H),7.53-7.50(m,2H),4.23-4.03(m,3H),3.4 1-3.35(m,1H),3.12-3.08(m,1H),2.71-2.69(m,1H),2.71-2.69(m,1H),2.07-1.96(m,3H),1.73-1.46(m,3H),0.81-0.71(m,1H).

[0899] Preparation of Compound 3 Hydrochloride Form H

[0900] Weigh compound 3 (400 mg, 1.59 mmol) into a 10 mL glass vial, add 1 mL of EA, and stir to dissolve. Add 0.44 mL of a 4 M hydrogen chloride / EA solution, stir at room temperature for 6 hours, and filter. Dry the filter cake under vacuum at 25°C for 16 hours to obtain Compound 3 hydrochloride Form H.

[0901] Preparation of Compound 3 Phosphate I Crystalline Form

[0902] Compound 3 (400 mg, 1.59 mmol) was weighed into a 10 mL glass vial. 2 mL of acetone was added and stirred to dissolve. 0.118 mL of 85% w / w aqueous phosphoric acid was added, stirred at room temperature for 6 hours, and then filtered. The filter cake was vacuum-dried at 25°C for 16 hours. This yielded Compound 3 phosphate salt Form I. The salt ratio was 1.0:1.19. 1 H NMR (400MHz, DMSO) δ8.13-8.11(m,1),7.48-7.46(m,1H),7.37-7.28(m,2H),3.85-3.82(m,1H),3.75-3.63(m,2H), 3.10-3.06(m,2H),2.55-2.50(m,2H),2.03-1.99(m,1H),1.84-1.68(m,2H),1.46-1.35(m,3H),0.77-0.72(m,1H).

[0903] Preparation of Compound 3 Methanesulfonate Form J

[0904] Compound 3 (400 mg, 1.59 mmol) was weighed into a 10 mL glass vial, and 1 mL of DCM was added and stirred to dissolve. 170.4 mg of methanesulfonic acid was added, and the mixture was stirred at room temperature for 6 hours before filtering. The filter cake was vacuum-dried at 25°C for 16 hours to obtain Compound 3 mesylate Form J. 1 H NMR(400MHz,DMSO)δ10.00(m,1H),8.29-8.27(m,1),8.08(br.s,1H),7.66-7.63(m,1H),7.55-7.50(m,2H),4.11-4.07(m,1H),4.02-3.9 6(m,2H),3.42-3.35(m,1H),3.15-3.12(m,1H),2.76-2.70(m,1H),2.34(s,3H),2.08-2.01(m,2H),1.75-1.47(m,4H),0.82-0.75(m,1H).

[0905] Preparation of Compound 3 Formate K Crystal

[0906] Compound 3 (100 mg, 0.40 mmol) was weighed into a 10 mL glass vial, and 1 mL of EA was added and stirred to dissolve. 0.336 mL of formic acid solution in EA (0.1 mL of formic acid was diluted 10-fold with EA) was added, and the mixture was stirred at 70°C for 5 hours. Then, 0.8 mL of n-heptane was added, and the mixture was stirred at 60°C for 10 hours before filtration. The filter cake was vacuum-dried at 25°C for 24 hours. This yielded Compound 3 formate salt Form K. 1 H NMR (400MHz, DMSO) δ8.59(s,1),8.23-8.20(m,1H),7.49-7.47(m,1H),7.43-7.36(m,2H),4.13-3.91(m,2H),3. 70-3.54(m,2H),3.39-3.34(m,1H),2.32-2.12(m,2H),1.95-1.91(m,2H),1.75-1.40(m,3H),0.77-0.72(m,1H).

[0907] Preparation of Compound 3 Oxalate Form N

[0908] Compound 3 (250 mg, 1.0 mmol) was weighed into a 10 mL glass vial. 3.3 mL of methyl tert-butyl ether and 1.2 mL of acetone were added and stirred to dissolve. Oxalic acid (0.5 eq) was added and the mixture was stirred at room temperature for 24 hours before filtering. The filter cake was vacuum dried at 25°C for 48 hours. This yielded Compound 3 oxalate salt Form N. 1 H NMR (400MHz, DMSO) δ8.25-8.04(m,1H),7.60-7.51(m,1H),7.47-7.35(m,2H),3.96-3.89(m,3H),3.27-3.21(m,1H),2.92-2. 84(m,1H),2.67-2.55(m,1H),2.09-1.98(m,1H),1.96-1.85(m,1H),1.72-1.57(m,2H),1.53-1.36(m,2H),0.84-0.65(m,1H).

[0909] Preparation of Compound 3 Pamoate O Crystal

[0910] Compound 3 (250 mg, 1.0 mmol) was weighed into a 10 mL glass vial. 3.3 mL of methyl tert-butyl ether and 1.2 mL of acetone were added and stirred to dissolve. Pamoic acid (0.5 eq) was added and stirred at room temperature for 24 hours before filtering. The filter cake was vacuum dried at 25°C for 48 hours. This yielded Compound 3 (Pamoic acid salt, Form O). 1H NMR (400MHz, DMSO) δ8.43(s,2H),8.28-8.23(m,1H),8.14(d,J=8.8HZ,2H),7.85(d,J=8.0H z,2H),7.65-7.57(m,1H),7.52-7.44(m,3H),7.37-7.31(m,2H),7.23-7.16(m,2H),4.78(s, 2H),4.09-4.00(m,4H),3.08(s,1H),2.78-2.63(m,2H),2.12-1.91(m,3H),1.86-1.76(m,1H ),1.73-1.65(m,1H),1.60-1.53(m,1H),1.49-1.38(m,1H),1.11(s,4H),0.82-0.66(m,1H).

[0911] Example 29 Solubility Experiment

[0912] To test the solubility of different compound forms in media with varying pH values, weigh the compound sample into a glass vial and add 1 mL or 2 mL of pH 6.0 phosphate buffer, pure water, pH 8.0 phosphate buffer, and / or 0.9% saline. Stir magnetically at 20°C for 24 hours. Samples were then collected for solubility testing, and the 24-hour solution was tested for purity.

[0913] Table 18: Solubility test results of different salt forms of compound 2 at different pH

[0914] Table 19: Solubility test results of different salt forms of compound 3 at different pH

[0915] The results of the solubility experiment showed that the hydrochloride A crystal form, phosphate B crystal form, methanesulfonate C crystal form of compound 2, and the hydrochloride G crystal form, phosphate I crystal form and methanesulfonate J crystal form of compound 3 all exhibited excellent solubility in different pH media and had good solution stability.

[0916] Example 30: Solid Stability Experiment

[0917] Compound 2 hydrochloride form A, phosphate form B, mesylate form C and compound 3 hydrochloride form G, phosphate form I, mesylate form J were investigated and packaged and placed under accelerated conditions of 40°C / 75% RH, conventional conditions of 25°C / 60% RH, and high temperature conditions of 60°C, respectively. The purity, crystal form, and appearance of the compounds were evaluated at different time points.

[0918] Table 20 Solid stability test results of Compound 2 Hydrochloride A

[0919] Table 21 Solid stability test results of Compound 2 Phosphate B crystal form

[0920] Table 22 Solid stability test results of Compound 2 Methanesulfonate C

[0921] Table 23 Solid stability test results of Compound 3 Hydrochloride G crystal form

[0922] Table 24 Solid stability test results of compound 3 phosphate I crystal form

[0923] Table 25 Solid stability test results of Compound 3 Methanesulfonate Form J

[0924] The results of the stability study showed that the various salt forms of compounds 2 and 3 of the present invention were excellently stable under high temperature and accelerated conditions, and the purity of the compounds did not change significantly; except for the phosphate I form of compound 3, which underwent crystal transformation, the other forms remained stable.

[0925] Biological and chemical performance evaluation

[0926] The effects of the present invention are further evaluated and described below in conjunction with test examples, but these embodiments are not intended to limit the scope of the present invention.

[0927] Test Example 1: Detection of NMDA receptor-mediated current in HEK293 cells

[0928] 1. Expression of human NMDA receptor GluN1 and GluN2A subunits in HEK293 cells

[0929] One day before transfection, HEK293 cells were seeded in a 24-well plate on a 10 mm glass slide. The slide had been pre-coated with poly-lysine to enhance cell attachment. DMEM supplemented with 10% FBS was added and cultured in a 37°C, 5% CO2 incubator. After 18-24 hours, when the cells reached 60%-70% confluency, HEK293 cells were transfected using lipofectamine with plasmid cDNAs containing human GluN1 and GluN2A, TRE-GluN1-GluN2A, tTA, and pCAG-EGFP (0.2 μg:0.2 μg:0.02 μg:0.02 μg, respectively). Before transfection, replace the DMEM medium with fresh one and add 1 μg / mL Dox (doxycycline) to induce stable expression. Add 100 μM D-APV and 10 mM MgCl2 to prevent excitotoxicity caused by NMDAR overexpression. Approximately 24 hours after transfection, select cells that exhibit green fluorescence for electrophysiological recording.

[0930] 2. Whole-cell Patch Clamp Recording of HEK293 Cells

[0931] A glass slide seeded with HEK293 cells was placed in a recording chamber, and extracellular solution (NaCl 140 mM, KCl 2.8 mM, HEPES 10 mM, CaCl2 1 mM, glycine 0.1 mM, pH 7.2) was perfused at a rate of 4 mL / min. 3The channels of an eight-channel pressure perfusion system were filled with extracellular solution for washing, extracellular solution containing glutamate (100 μM), and extracellular solution containing glutamate and the test compound, at a drip rate of approximately 1 drop / second, 10 μL / drop. HEK293 cells with moderate green fluorescence intensity and good adhesion were selected for recording under a fluorescence microscope. The drug delivery micropipette of the perfusion system was placed approximately ten cells away from the cell to be recorded. Drugs were sprayed onto the cell surface under air pressure (0.02 MPa). Glass electrodes were drawn using a microelectrode puller with a resistance of 4-6 MΩ and filled with an electrode solution (125 mM CsCl, 10 mM HEPES, 11 mM EGTA). Using a microelectrode manipulator, the glass electrode was slowly advanced toward the cell. After the electrode adhered to the cell membrane, negative pressure was applied to create a high-resistance seal exceeding 1 GΩ between the electrode tip and the cell membrane. Then, negative pressure was applied to rupture the cell membrane, establishing whole-cell recording mode. After establishing whole-cell recording mode, the cell membrane potential was clamped at -70 mV. Extracellular solution containing 100 μM glutamate, 100 μM glutamate and the test compound, and then extracellular solution were sequentially injected onto the cell membrane through the perfusion system for 10 s, 20 s, and 10 s, respectively. NMDA receptor-mediated currents were recorded to assess the inhibitory effects of the test compounds on GluN2A-containing NMDARs. The experimental process was controlled by pCLAMP 10.6, and stimulation signals were generated and feedback signals were acquired using a Digidata 1440A digital-to-analog converter.

[0932] The inhibitory effect (%) of NMDAR-mediated currents was evaluated after compound administration at a concentration of 10 μM, or the inhibitory effect of the compound at concentrations of 10, 3, 1, 0.3, 0.1, and 0.03 μM was calculated as the fitted IC. 50 value.

[0933] The percentage inhibition of the NMDAR-mediated current by the compound herein (inhibition rate) = (1-NMDAR-mediated current after administration / NMDAR-mediated current before administration) * 100%. The inhibition rates of the compound at concentrations of 10, 3, 1, 0.3, 0.1, and 0.03 μM were imported into Graphpad Prism software for nonlinear regression analysis, and the IC was automatically calculated by curve fitting. 50 .

[0934] The in vitro activity test results of the compounds of the present invention are shown in Table 26.

[0935] Table 26: Inhibition results of each compound on NMDAR-mediated current

[0936] NA: Not tested

[0937] The results showed that the compounds of the present invention have excellent NMDAR-mediated current inhibitory effects.

[0938] Test Example 2: Mouse Behavior Test

[0939] Experimental animals: 10-12-week-old C57BL / 6J male mice were purchased from Spefox (Suzhou) Biotechnology Co., Ltd. They arrived at the testing center and acclimated to the housing room for at least 7 days before the experiment. Five mice were housed in a cage at a temperature of 23-24°C, with a 12 / 12-hour light / dark cycle. Animals were brought to the behavioral testing room 1 hour before behavioral testing to allow them to acclimate.

[0940] The forced swim test is a standard behavioral test for assessing depressive-like behavior in rodents. It places experimental animals in a confined environment, where they desperately struggle to escape but are unable to do so. This creates an inescapable, oppressive environment. Over time, the animals exhibit a characteristic "immobility," reflecting a state known as "behavioral despair." This behavioral despair is generally believed to mimic symptoms of depression in humans. The purpose of this study was to investigate the efficacy of the compounds of this invention on antidepressant behavior in C57 mice.

[0941] In the FST experiment, the number of animals per group (N) was 15. The drug was administered by intraperitoneal injection (ip) or oral gavage (po) at a dose of 5, 10, or 20 mg / kg (depending on the experimental requirements) in a volume of 10 mL / kg. The solvent was 0.9% saline solution.

[0942] Experimental procedure: 1. The experiment was conducted in a quiet environment. Animals were weighed and allowed to adapt to the experimental room for at least 30 minutes before the experiment.

[0943] 2. Dissolve the test compound in 0.9% saline and administer the corresponding volume of compound to the experimental group (i.p.) or the control group (po) by intraperitoneal injection (i.p.) or oral gavage (p.o.) according to the body weight of the mice, so that the dose reaches the target dose. The administration process is double-blind.

[0944] 3. One hour after administration, the mice were placed in a transparent organic glass water tank with a diameter of 15 cm and a height of 30 cm. The tank was filled with water to a height of about 15 cm and the water temperature was 23-25°C. The total recording time was 6 minutes.

[0945] 4. Analyze the immobility time of the mice within 4 minutes after the test to reflect the degree of helplessness and despair of the mice.

[0946] 5. The immobility time of mice in the treatment group was compared with that in the control group to analyze the antidepressant activity of the test compound (1-hour inhibition rate). The difference was analyzed by unpaired t-test to determine statistical significance. P < 0.05 was considered significant. *P < 0.05, **P < 0.01, ***P < 0.001.

[0947] Inhibition rate 1h (100%) = [immobility time (对照组,1h) - Immobility time (给药组,1h) ] / Immobility time (对照组,1h) 100%

[0948] Results: As shown in Figures 29-32 and Table 27, Compound 2 Hydrochloride Form A exhibited significant antidepressant effects at a 5 mg / kg ip dose; Compound 2 Methanesulfonate Form C exhibited significant antidepressant effects at 10 mg / kg and 20 mg / kg ip doses. Compound 3 Hydrochloride Form G exhibited significant antidepressant effects at 10 mg / kg ip, and the effects were significantly superior to those of its three isomers, 3-SS hydrochloride, 3-RR hydrochloride, and 3-RS hydrochloride. Compounds 60 hydrochloride, 73 hydrochloride, 80 hydrochloride, and 95 hydrochloride exhibited significant antidepressant effects at 10 mg / kg ip. Compounds 34 hydrochloride, 177 hydrochloride, 178 hydrochloride, 179 hydrochloride, and 180 hydrochloride exhibited significant antidepressant effects at 10 mg / kg po.

[0949] Table 27: Antidepressant activity results of the compounds of the present invention after intraperitoneal / oral administration

[0950] ip: intraperitoneal injection; po: oral administration;

[0951] The results showed that the compound of the present invention has excellent antidepressant efficacy in vivo.

[0952] Test Example 3: Evaluation of the analgesic effect of compounds

[0953] The intraperitoneal acetic acid writhing test is a method for inducing acute inflammatory pain through chemical stimulation. Acetic acid is injected into the peritoneal cavity of experimental animals to induce pain, and the writhing reaction is observed to determine whether pain is present. This is primarily used to evaluate the efficacy of analgesic drugs. Animal information is the same as in Test Example 2.

[0954] In the acetic acid writhing test, the number of animals in each group (N) was 10. The drug was administered by intraperitoneal injection (ip) or oral gavage (po), and the solvent was 0.9% saline solution.

[0955] Experimental procedure: 1. The experiment was conducted in a quiet environment. Animals were weighed and allowed to adapt to the experimental room for at least 30 minutes before the experiment.

[0956] 2. The test compound is administered by intraperitoneal injection (left side of the abdominal cavity) or oral gavage; the administration process is double-blind.

[0957] 3. 30 minutes after administration, administer 0.6% acetic acid (freshly prepared) to the other side of the abdominal cavity (right side of the abdominal cavity, administration volume 10 ml / kg), and then place the mouse in an observation box and record for 30 minutes;

[0958] 4. Count the number of writhing events in mice within 30 minutes after administration of 0.6% acetic acid. Compare the number of writhing events in the treated and control groups to analyze the analgesic activity (analgesia rate) of the test compound. Statistical significance was determined using an unpaired t-test. P < 0.05 was considered significant. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.

[0959] Analgesia rate (100%) = [number of writhings (control group) - number of writhings (drug treatment group)] / number of writhings (control group) × 100%

[0960] The results showed that the compound of the invention exhibited significant analgesic effects at a dose of 2 mg / kg to 5 mg / kg via intraperitoneal or oral administration, with an analgesic rate (%) of 50 to 74%, P < 0.05.

[0961] The compounds of the present invention have excellent analgesic effects in vivo.

[0962] Test Example 4: Compound Toxicity Test

[0963] Exploratory testing of a compound's non-toxic dose is an important indicator for evaluating compound safety. A higher safety profile leads to a wider therapeutic window. Animal information is the same as in Test Example 2.

[0964] Test process:

[0965] 1. The experiment was conducted in a quiet environment. Animals were weighed and allowed to acclimate to the experimental room for at least 30 minutes before the experiment.

[0966] 2. Dissolve the test compound in 0.9% saline. Intraperitoneally (ip) inject the compound in a volume corresponding to the target dose, based on the mouse's body weight. Each group consists of 2 or 3 animals.

[0967] 3. Place the mice after drug administration in a transparent observation chamber. Videotape and record behavioral changes for approximately one hour. (Note: During the observation period, if the mouse is lying motionless, manually turn it over to check for loss of its righting reflex (RR). If so, it is anesthetized, and the duration of anesthesia should be recorded.)

[0968] 4. After the one-hour observation period, return the mice to their cages and wipe the observation box with 75% alcohol to prevent residual information from the previous round of animals (such as odors of feces and urine) from affecting the next test results. Replace the next round of animals and continue the experiment.

[0969] Epileptic status was scored according to the rodent epileptic status scoring table shown in Table 24 below.

[0970] Table C Rodent Epileptiform Behavior Scale Scores

[0971] The test results are summarized in Table 28.

[0972] Table 28: Safety summary after administration to mice

[0973] *NOAEL: No Observed Adverse Event Level (STD10): The level at which 10% of the animals experience severe adverse events.

[0974] Conclusion: The compounds of this invention exhibit excellent in vivo safety. Compound 2 hydrochloride Form A and mesylate Form C exhibited higher no-observed-adverse-effect levels (NOAELs) than 2-SS mesylate. The lowest toxicity level (score 1) for Compound 2 mesylate Form C was significantly higher than that for the two comparative compounds, 2-SS and 2-RR. The STD10 doses for the compounds of this invention were significantly higher than those for PDHQ (SS or RR) and PDHQ (RR or SS).

[0975] Test Example 5: Mouse Open Field Test

[0976] The open field test is a standard behavioral method for evaluating the autonomous motor behavior and exploratory behavior of rodents. It is widely used in the study of neurological and psychiatric diseases such as depression, anxiety, Parkinson's disease, and central nervous system drug screening.

[0977] Due to the limited availability of experimental methods for evaluating the hallucinogenic effects of NMDAR antagonists, the open field test was used in this study not only to assess whether compounds affect the spontaneous activity of mice but also to indirectly assess whether compounds have hallucinogenic effects. Furthermore, increased spontaneous activity in mice is considered a positive symptom of schizophrenia, so the open field test can also be used to assess whether compounds have psychotomimetic behavioral side effects.

[0978] Animal information was the same as in Test Example 2. The number of animals in each group (N) was 10, and the drug was administered by intraperitoneal injection or oral gavage at a dose of 5 or 10 mg / kg in a volume of 10 mL / kg.

[0979] Experimental Procedure: The open-field test chamber was a soundproof, opaque plexiglass chamber with an inner diameter of 40 x 40 x 40 cm. Analysis software was purchased from Noldus (Ethovision XT 11.5). Experiments were conducted in a quiet environment. Animals were weighed and allowed to acclimate to the experimental room for at least 30 minutes before the experiment. EthoVision XT 11.5 software was configured before the experiment. Wild-type mice were placed in the center of the chamber floor, and their activity was recorded for 30 or 20 minutes as a baseline. After 30 minutes, the mice were removed and administered the vehicle (control group) or the test compound at the appropriate dose based on body weight. Immediately after administration, the mice were placed in the same observation chamber as the baseline phase, and their activity was recorded for 40 minutes after administration. After each experiment, the instrument was wiped with 75% alcohol to prevent residual information from the previous round of animals (such as odors of feces and urine) from influencing the results of the next test. The animals were replaced and the experiment continued. After the experiment, data were collected for statistical analysis. The statistical significance of the differences was detected by unpaired t-test, and P < 0.05 was considered to be a significant difference. # P < 0.05, *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001. After the experiment, the distance traveled (cm) per 5-minute period by the control and test compound groups was statistically analyzed. Representative results of the open field test evaluation of the compounds of the present invention are shown in Figures 33 to 36.

[0980] Conclusion: Analysis of open field test results showed that compared with the saline group, 10 mg / kg of S-ketamine significantly increased the distance traveled by mice within 5-20 minutes after administration. However, intraperitoneal administration of 10 mg / kg of Compound 2 hydrochloride Form A and Methanesulfonate Form C, Compound 3 hydrochloride Form G, and Compound 34 hydrochloride, and oral administration of 10 mg / kg of Compound 177 hydrochloride and Compound 178 hydrochloride, and 5 mg / kg of Compound 179 hydrochloride showed no significant difference in the distance traveled by mice compared with the vehicle group.

[0981] The compounds of the present invention do not have hallucinogenic side effects.

[0982] Test Example 6: Prepulse Suppression Experiment

[0983] Prepulse inhibition (PPI) is an important parameter for assessing sensorimotor gating function and an indicator of schizophrenia-like behavior. This phenomenon occurs when a weak stimulus precedes a stronger stimulus, reducing the animal's startle response to the stronger stimulus. The present invention utilizes PPI testing to assess whether compounds induce psychotomimetic behavior in mice.

[0984] Animal information was the same as in Test Example 2. The number of animals per group (N) was 10. Dosage was by intraperitoneal injection or oral gavage at a dose of 20 mg / kg for S-ketamine and 45 mg / kg for the other compounds, in a 10 mL / kg dosing volume. The oral gavage dose was 10 mg / kg.

[0985] Experimental process: The experiment was carried out in a quiet environment. Before the experiment, the mice were weighed and placed in the experimental room to acclimate for at least 30 minutes. The PPI experiment is divided into four stages: adaptation period, Block 1, Block 2, and Block 3. At the beginning of the experiment, the mice were given the corresponding dose of solvent (control) or test compound according to their body weight. Then, the mice were placed in the shock box and allowed to adapt for 5 minutes without stimulation. Then, in Blocks 1-3, the mice were given shock stimuli of different decibels. Block 1 and Block 3 were set to 10 trials. There was no prepulse stimulation in each trial. The shock stimulus was set to white noise 120dB. The time interval between each trial varied randomly between 10-15s. Block 2 consisted of 56 trials with three stimulus types: ① 8 trials with only a 120 dB startle stimulus; ② 32 trials with a 67, 70, 73, or 76 dB prepulse followed by a 120 dB startle stimulus; and 8 trials with only a prepulse stimulus (two trials with each of four prepulses); and ③ 8 trials with no stimulus, each lasting 200 ms. The prepulse stimulus lasted 20 ms, with a fixed interval of 100 ms. The startle stimulus lasted 40 ms in all blocks, and the background noise level was 62 dB. After each trial, the apparatus was wiped with 75% alcohol to prevent residual information from the previous round (such as odors of feces or urine) from influencing the subsequent test results. Statistical significance was tested using an unpaired t-test, with P < 0.05 considered significant. #P<0.05, *P<0.05, **P<0.01, ***P<0.001. Representative results of the PPI test of the compounds of the present invention are shown in Figure 37. The results show that at an ip dose of 45 mg / kg, the mesylate C form of the present invention compound 2 did not affect the PPI of native C57 mice, which was better than S-ketamine and significantly better than its two comparative molecular isomers 2SS and 2RR. Compound 2SS mesylate tended to cause a loss of PPI under 67 dB and 70 dB prepulses; compound 2RR mesylate caused a loss of PPI under 76 dB prepulses. In addition, compounds 177 hydrochloride, 178 hydrochloride, and 179 hydrochloride did not affect the PPI of mice at a po dose of 10 mg / kg, nor did they induce psychotomimetic behavior in mice.

[0986] Test conclusion: The compound of the present invention does not induce psychotic-like behavior.

[0987] Test Example 7: Evaluation of the Anti-itching Effect of Compounds

[0988] This study used a pruritus model established in male C57BL / 6 mice to evaluate the anti-pruritus effect of the inventive compounds.

[0989] Experimental Procedure: Male mice aged 6 to 8 weeks were used and housed for 7 days after purchase, with free access to food. Three days prior to the experiment, 2 cm by 3 cm of hair was removed from the nape of the animals' necks and backs, and they were acclimated to human touch to mitigate stress responses. A single dose of the compound of the invention was administered, and a histamine-induced pruritus model was established 30 minutes after administration.

[0990] Histamine-induced itch model: Before establishing the model, the animals were placed in a transparent test box (30 cm × 30 cm × 15 cm) for 15 minutes to acclimate to the environment. Histamine solution (100 μg histamine dissolved in 50 μL saline) was injected intradermally into the back of the neck of the mice using a syringe.

[0991] Behavioral testing: The mice were placed back into the test box and their itch behavior was observed for 30 minutes, and the number and duration of scratching were recorded. One scratch was defined as one or more times when the mouse raised its hind paw to scratch the injection site on the back of the neck and then put the hind paw into its mouth or put it back on the ground.

[0992] Data analysis: The scratching time and frequency of the mice were recorded. After the experiment, the animals were euthanized.

[0993] The test results showed that the total number of scratching times and scratching time within 30 minutes of the compound of the present invention were significantly reduced compared with the model group, showing significant anti-itching efficacy.

[0994] Test Example 8: Pharmacokinetics test in mice

[0995] This study investigated the pharmacokinetic characteristics of the inventive compound in C57BL / 6J male mice after oral administration (oral gavage) and intravenous injection.

[0996] Male C57BL / 6J mice aged 10-12 weeks were selected and administered with compound solutions by intravenous (iv) and oral (po) injection, respectively. The dosage is shown in the table below. The intravenous solvent was 0.9% normal saline injection, and the administration volume was 5 mL / kg. The animals ate and drank water normally before administration. The oral solvent was 0.9% normal saline injection, and the administration volume was 10 mL / kg. The animals fasted and deprived of water for about 16 hours before administration. About 70 μL of blood was collected from the facial vein of the two groups of animals at 0.0333, 0.1667, 0.3330, 1, 2, 4, 6, 8, and 24 hours after administration, respectively. The blood was placed in an anticoagulant tube with EDTA-K2 added and placed on wet ice. The plasma was separated by centrifugation at 4 degrees within 1 hour (4500g, 15 min). The drug concentration was analyzed by LC-MS / MS method, and the relevant pharmacokinetic parameters were calculated by non-compartmental linear logarithmic trapezoidal method using PKSolver2.0 kinetic software.

[0997] The test results are shown in Table 29.

[0998] Table 29: Pharmacokinetic data

[0999] Experimental conclusion: The compound of the present invention has good in vivo metabolic stability, excellent oral absorption drug exposure and good oral absorption bioavailability.

Claims

1. A compound of the following formula II, or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, isotope-substituted product, polymorph, prodrug or metabolite thereof: In the formula, X is -O- or -CH2-; E is -O- or -CH2-; A is -NR a - or -CH2-; B is -NR a - or -CH2-; R a Selected from H and C 1-6 alkyl; D is -O- or -CH2-; Y is selected from substituted or unsubstituted 6-14 membered aryl, substituted or unsubstituted 5-14 membered heteroaryl and substituted or unsubstituted C 1-6 alkyl, Y is optionally substituted by 1, 2, 3, 4 or 5 R1, each R1 being independently selected from deuterium, cyano, C 1-3 alkyl, halogen, 5-14 membered heteroaryl optionally substituted by 1, 2, 3, 4 or 5 halogens, and 6-14 membered aryl optionally substituted by 1, 2, 3, 4 or 5 halogens, the 5-14 membered heteroaryl comprising 1, 2, 3 or 4 heteroatoms selected from N, O and S; Z is selected from H, hydroxyl, C 1-6 Alkyl and C 1-6 Alkoxy; R2 is selected from deuterium, C 1-3 Alkyl or halogen; R3 is selected from deuterium, C 1-3 Alkyl or halogen; m is 0, 1, 2 or 3; o is 0, 1, 2, or 3; The chiral carbon atom at position 1 is in S configuration or R configuration; The chiral carbon atom at position 2 is in S configuration or R configuration; Provided that the compound of formula II is not the following compounds and their salts: (4aR,8aS)-4α-(2-thienyl)octahydro-2H-benzo[b][1,4]oxazine, (4aR,8aR)-4α-(2-chloro-3-thienyl)octahydro-2H-benzo[b][1,4]oxazine, (4aS,8aR)-4α-(2-thienyl)octahydro-2H-benzo[b][1,4]oxazine, (4aR,8aS)-4α-(3-methyl-2-thienyl)octahydro-2H-benzo[b][1,4]oxazine, (4aR,8aR)-4α-(4-methyl-3-thienyl)octahydro-2H-benzo[b][1,4]oxazine, (4aR,8aR)-4 α-(3-chlorophenyl)octahydro-2H-benzo[b][1,4]oxazine, (4aS,8aS)-4α-(3-chlorophenyl)octahydro-2H-benzo[b][1,4]oxazine, (4aR,8aR)-4α-(2-chlorophenyl)octahydro-2H-benzo[b][1,4]oxazine, (4aS,8aS)-4α-(2-chlorophenyl)octahydro-2H-benzo[b][1,4]oxazine, 4a-phenyloctahydro-2H-benzo[b][1,4]oxazine, 4a-(2-methoxyphenyl)octahydro-2H-benzo[b][1,4]oxazine, 4a-(3-fluorophenyl)octahydro-2H-benzo[b][1,4]oxazine, 4a-(4-fluorophenyl)octahydro-2 H-benzo[b][1,4]oxazine, 4a-(2,3-difluorophenyl)octahydro-2H-benzo[b][1,4]oxazine, 4a-(2-fluorophenyl)octahydro-2H-benzo[b][1,4]oxazine, 6-methyl-4a-phenyloctahydro-2H-benzo[b][1,4]oxazine, 6-ethyl-4a-phenyloctahydro-2H-benzo[b][1,4]oxazine, 4a-(3-chlorophenyl)octahydro-2H-benzo[b][1,4]oxazine, 4a-(3-methylphenyl)octahydro-2H-benzo[b][1,4]oxazine, 4a-(2-chlorophenyl)octahydro-2H-benzo[b][1,4]oxazine, 4a-(4-chlorophenyl)octahydro-2H-benzo[b][1,4]oxazine [1,4]oxazine, 4a-(4-methylphenyl)octahydro-2H-benzo[b][1,4]oxazine, 4a-(3-(trifluoromethyl)phenyl)octahydro-2H-benzo[b][1,4]oxazine, 8-methyl-4a-phenyloctahydro-2H-benzo[b][1,4]oxazine, 5-methyl-4a-phenyloctahydro-2H-benzo[b][1,4]oxazine, 7-methyl-4a-phenyloctahydro-2H-benzo[b][1,4]oxazine, 4-methyl-4a-phenyloctahydro-2H-benzo[b][1,4]oxazine, 3,3-dimethyl-5a-phenyldecahydrobenzo[b][1,4]olanzapine, 4a-(3-methoxyphenyl)octahydro-2H-benzo[b][1,oxazine, 4a-(3-(trifluoromethoxy)phenyl)octahydro-2H-benzo[b][1,4]oxazine, 4a-(4-(trifluoromethyl)phenyl)octahydro-2H-benzo[b][1,4]oxazine, 4a-(2,6-dimethylphenyl)octahydro-2H-benzo[b][1,4]oxazine, 4a-(4-(tert-butyl)phenyl)octahydro-2H-benzo[b][1,4]oxazine, 4a-(2,3-dichlorophenyl)octahydro-2H-benzo[b][1,4]oxazine, 4a-(2-isopropylphenyl)octahydro-2H-benzo[b][1,4]oxazine, 4a-(2,5-dimethylphenyl)octahydro-2H-benzo[b][1,4 ]oxazine, 4a-(2-chloro-3-fluorophenyl)octahydro-2H-benzo[b][1,4]oxazine, 4a-(3,4-difluorophenyl)octahydro-2H-benzo[b][1,4]oxazine, 6,6-dimethyl-4a-phenyloctahydro-2H-benzo[b][1,4]oxazine, 4a-(2-chloro-5-fluorophenyl)octahydro-2H-benzo[b][1,4]oxazine, 4α-(3-ethoxyphenyl)octahydro-2H-benzo[b][1,4]oxazine, 4α-(2-chloro-4-methoxyphenyl)octahydro-2H-benzo[b][1,4]oxazine, 4a-(2-chloro-6-fluorophenyl)octahydro-2H-benzo[b][1,4]oxazine. , 2. The compound according to claim 1, its pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, isotope-substituted product, polymorph, prodrug or metabolite, characterized in that: It has the structure shown in the following formula A': In the formula, Y' is C optionally substituted by 6-14 membered aryl 1-6 The 6-14 membered aryl group is optionally substituted by 1, 2, 3, 4 or 5 halogens.

3. The compound of claim 1, its pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, isotope-substituted product, polymorph, prodrug or metabolite, characterized in that: It has the structure shown in the following formula II-1: In the formula, Y is selected from substituted or unsubstituted 6-14 membered aryl and substituted or unsubstituted 5-14 membered heteroaryl, Y is optionally substituted by 1, 2, 3, 4 or 5 R1, each R1 is independently selected from deuterium, cyano, C 1-3 The 5- to 14-membered heteroaryl group includes 1, 2, 3 or 4 heteroatoms selected from N, O and S.

4. The compound of claim 1, its pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, isotope-substituted product, polymorph, prodrug or metabolite, characterized in that: It has the structure shown in the following formula A: Where: Y is a 6-14 membered aryl or 5-7 membered heteroaryl group optionally substituted by 1, 2, 3, 4 or 5 R1 substituents, wherein each R1 is independently selected from deuterium, cyano, C 1-3 Alkyl and halogen.

5. The compound of claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, isotope-substituted product, polymorph, prodrug or metabolite thereof, characterized in that: The pharmaceutically acceptable salt is selected from formate, hydrochloride, sulfate, phosphate, citrate, succinate, D-tartrate, fumarate, maleate, p-toluenesulfonate, methanesulfonate or benzenesulfonate, oxalate, pamoate, preferably selected from formate, hydrochloride, phosphate or methanesulfonate.

6. The compound of claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, isotope-substituted product, polymorph, prodrug or metabolite thereof, characterized in that: The compound of formula II is selected from the following compounds:

7. The compound of claim 1, its pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, isotope-substituted product, polymorph, prodrug or metabolite, characterized in that: The compound of formula II is selected from the following compounds: Optionally, the pharmaceutically acceptable salt of the compound of formula II is selected from compound 2 hydrochloride, compound 2 phosphate, compound 2 methanesulfonate, compound 2 formate, compound 2 oxalate, compound 2 pamoate, compound 3 hydrochloride, compound 3 phosphate, compound 3 methanesulfonate, compound 3 formate, compound 3 oxalate, compound 3 pamoate, compound 13 hydrochloride, compound 17 hydrochloride, compound 33 hydrochloride, compound 36 hydrochloride, compound 34 hydrochloride, compound 35 hydrochloride, compound 39 hydrochloride, compound 40 hydrochloride, compound 45 hydrochloride, compound 46 hydrochloride, compound 74 hydrochloride, compound 80 hydrochloride, compound 96 hydrochloride, compound 98 hydrochloride, compound 144 hydrochloride, compound 145 hydrochloride, compound 158 hydrochloride, compound 55 hydrochloride, compound 56 hydrochloride, compound 57 hydrochloride, compound 58 hydrochloride, compound 84 hydrochloride, compound 92 hydrochloride, compound 98 hydrochloride, compound 1 Compound 139 hydrochloride, compound 141 hydrochloride, compound 155 hydrochloride, compound 156 hydrochloride, compound 157 hydrochloride, compound 158 hydrochloride, compound 159 hydrochloride, compound 160 hydrochloride, compound 161 hydrochloride, compound 177 hydrochloride, compound 178 hydrochloride, compound 179 hydrochloride, compound 180 hydrochloride, compound 218 methanesulfonate, compound 219 methanesulfonate, compound 242 methanesulfonate, compound 243 methanesulfonate , compound 167a methanesulfonate, compound 167b methanesulfonate, compound 29 methanesulfonate, compound 32 methanesulfonate, compound 51 methanesulfonate, compound 54 methanesulfonate, compound 62 methanesulfonate, compound 68 methanesulfonate, compound 230 methanesulfonate, compound 231 methanesulfonate, compound 196 methanesulfonate, compound 199 methanesulfonate, compound 226 methanesulfonate, compound 14 methanesulfonate, compound 163 methanesulfonate and compound 164 methanesulfonate.

8. A compound of the following formula III, or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, isotope-substituted product, polymorph, prodrug or metabolite thereof: In the formula, L, M, P and Q are each independently selected from N and CH; R4, R5, R6 and R7 are each independently selected from C 1-6 Alkyl, C 1-6 Alkoxy, -NR b R c , substituted or unsubstituted 6-14 membered aryl and substituted or unsubstituted 5-14 membered heteroaryl, wherein the 6-14 membered aryl and the 5-14 membered heteroaryl are optionally selected from halogen, deuterium, C 1-6 Alkyl and C 1-6 The 5-14 membered heteroaryl group is substituted with an alkoxy group, wherein the 5-14 membered heteroaryl group includes 1, 2, 3 or 4 heteroatoms selected from N, O and S; R4 is also selected from oxo, provided that R5 is absent; R6 is also selected from oxo, provided that R7 is absent; R b and R c Each independently selected from H and C 1-6 alkyl; The carbon atom at the 3-position or 4-position is a chiral carbon atom, and the chiral carbon atom is in S configuration or R configuration.

9. The compound of claim 8, or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, isotope-substituted product, polymorph, prodrug or metabolite thereof, characterized in that: The compound of formula III is selected from the following compounds:

10. A salt crystal form of compound 2, selected from the following salt crystal forms A, B, C, D, E, F, L and M, characterized in that: The X-ray powder diffraction pattern of hydrochloride form A has characteristic peaks at the following 2θ angles: 14.44°±0.20°, 17.16°±0.20°, 20.59°±0.20° and 23.38°±0.20°; The X-ray powder diffraction pattern of the phosphate crystal form B has characteristic peaks at the following 2θ angles: 5.48°±0.20°, 18.48°±0.20°, 22.49°±0.20° and 22.92°±0.20°; The X-ray powder diffraction pattern of the mesylate salt form C has characteristic peaks at the following 2θ angles: 8.05°±0.20°, 14.37±0.20°, 16.18°±0.20°, 18.49°±0.20°, 22.65±0.20°; The X-ray powder diffraction pattern of the mesylate salt form D has characteristic peaks at the following 2θ angles: 12.13°±0.20°, 14.80°±0.20°, 20.54°±0.20°, 23.37°±0.20° and 26.09°±0.20°; The X-ray powder diffraction pattern of the mesylate salt form E has characteristic peaks at the following 2θ angles: 14.81°±0.20°, 16.30°±0.20°, 18.60°±0.20° and 22.75°±0.20°; The X-ray powder diffraction pattern of the formate salt form F has characteristic peaks at the following 2θ angles: 11.35°±0.20°, 13.53°±0.20° and 23.76°±0.20°; The X-ray powder diffraction pattern of the oxalate salt form L has characteristic peaks at the following 2θ angles: 9.44°±0.20°, 11.11°±0.20°, 15.61°±0.20°, 19.42°±0.20° and 26.30°±0.20°; The X-ray powder diffraction pattern of the pamoate salt form M has characteristic peaks at the following 2θ angles: 5.44°±0.20°, 6.49°±0.20°, 10.75°±0.20° and 21.01°±0.20°.

11. The salt crystal form according to claim 10, characterized in that The X-ray powder diffraction pattern of the hydrochloride salt form A also has characteristic peaks at one or more of the following 2θ angles: 11.44°±0.20°, 15.00°±0.20°, 16.36°±0.20°, 24.11°±0.20°, 24.30°±0.20° and 26.72°±0.20°; preferably, the X-ray powder diffraction pattern of the hydrochloride salt form A also has characteristic peaks at one or more of the following 2θ angles: 6.79°±0.20°, 13.15°±0.20° and 25.74°±0.20°; The X-ray powder diffraction pattern of the phosphate crystal form B also has characteristic peaks at one or more of the following 2θ angles: 13.49°±0.20°, 15.44°±0.20°, 16.50°±0.20°, 20.63°±0.20° and 27.64°±0.20°; preferably, the X-ray powder diffraction pattern of the phosphate crystal form B also has characteristic peaks at one or more of the following 2θ angles: 10.96°±0.20°, 12.32°±0.20° and 14.83°±0.20°; The X-ray powder diffraction pattern of the mesylate salt form C also has characteristic peaks at one or more of the following 2θ angles: 13.91°±0.20°, 15.03°±0.20° and 24.42°±0.20°; preferably, the X-ray powder diffraction pattern of the mesylate salt form C also has characteristic peaks at one or two of the following 2θ angles: 9.71°±0.20° and 12.00°±0.20°; The X-ray powder diffraction pattern of the mesylate salt form D also has characteristic peaks at one or more of the following 2θ angles: 17.14°±0.20°, 18.08°±0.20°, 22.70°±0.20°, 24.66°±0.20°; preferably, the X-ray powder diffraction pattern of the mesylate salt form D also has characteristic peaks at one or more of the following 2θ angles: 6.28°±0.20°, 11.33°±0.20°, 12.53°±0.20°, 21.46°±0.20° and 23.93°±0.20°; The X-ray powder diffraction pattern of the mesylate salt form E also has characteristic peaks at one or more of the following 2θ angles: 12.13°±0.20°, 14.48°±0.20°, 17.15°±0.20°, 20.53°±0.20°, 21.45°±0.20° and 21.62°±0.20°; preferably, the X-ray powder diffraction pattern of the mesylate salt form E also has characteristic peaks at one or more of the following 2θ angles: 6.24°±0.20°, 8.16°±0.20°, 12.47°±0.20° and 26.08°±0.20°; The X-ray powder diffraction pattern of the formate salt form F also has characteristic peaks at one or more of the following 2θ angles: 11.79°±0.20°, 12.99°±0.20°, 15.89°±0.20°, 17.34°±0.20° and 22.87°±0.20°; preferably, the X-ray powder diffraction pattern of the formate salt form F also has characteristic peaks at one or two of the following 2θ angles: 5.85°±0.20°, 22.37°±0.20°; The X-ray powder diffraction pattern of the oxalate crystal form L also has characteristic peaks at one or more of the following 2θ angles: 18.98°±0.20°, 23.17°±0.20° and 29.92°±0.20°; preferably, the X-ray powder diffraction pattern of the oxalate crystal form L also has characteristic peaks at the following 2θ angles: 31.69°±0.20°; The X-ray powder diffraction pattern of the pamoate salt form M also has characteristic peaks at one or more of the following 2θ angles: 5.35°±0.20°, 10.00°±0.20° and 12.51°±0.20°.

12. The salt crystal form according to claim 10, characterized in that The hydrochloride salt form A has an X-ray powder diffraction (XPRD) pattern substantially as shown in Figure 1, and / or a differential scanning calorimetry (DSC) pattern substantially as shown in Figure 2, and / or a thermogravimetric analysis (TGA) pattern substantially as shown in Figure 2; The phosphate crystal form B has an X-ray powder diffraction (XPRD) pattern substantially as shown in FIG3 , and / or a differential scanning calorimetry (DSC) pattern substantially as shown in FIG4 , and / or a thermogravimetric analysis (TGA) overlay pattern substantially as shown in FIG4 ; The mesylate salt Form C has an X-ray powder diffraction (XPRD) pattern substantially as shown in Figure 5, and / or a differential scanning calorimetry (DSC) pattern substantially as shown in Figure 6, and / or a thermogravimetric analysis (TGA) overlay pattern substantially as shown in Figure 6; The mesylate salt form D has an X-ray powder diffraction (XPRD) pattern substantially as shown in Figure 7, and / or a differential scanning calorimetry (DSC) pattern substantially as shown in Figure 8, and / or a thermogravimetric analysis (TGA) pattern substantially as shown in Figure 9; The mesylate salt Form E has an X-ray powder diffraction (XPRD) pattern substantially as shown in Figure 10, and / or a differential scanning calorimetry (DSC) pattern substantially as shown in Figure 11, and / or a thermogravimetric analysis (TGA) pattern substantially as shown in Figure 12; The formate salt Form F has an X-ray powder diffraction (XPRD) pattern substantially as shown in Figure 13, and / or a differential scanning calorimetry (DSC) pattern substantially as shown in Figure 14, and / or a thermogravimetric analysis (TGA) overlay pattern substantially as shown in Figure 14; Oxalate Form L has an X-ray powder diffraction (XPRD) pattern substantially as shown in Figure 15; Pamoate salt Form M has an X-ray powder diffraction (XPRD) pattern substantially as shown in FIG. 16 .

13. A salt crystal form of compound 3, selected from the following salt crystal forms G, H, I, J, K, N and O, characterized in that: The X-ray powder diffraction pattern of the hydrochloride form G has characteristic peaks at the following 2θ angles: 6.18°±0.20°, 11.42°±0.20°, 12.45°±0.20°, 20.02°±0.20° and 23.41°±0.20°; The X-ray powder diffraction pattern of the hydrochloride salt form H has characteristic peaks at the following 2θ angles: 6.64°±0.20°, 13.12°±0.20°, 13.31°±0.20°, 21.83°±0.20° and 23.06°±0.20°; The X-ray powder diffraction pattern of the phosphate crystal form I has characteristic peaks at the following 2θ angles: 5.94°±0.20°, 12.29°±0.20°, 13.34°±0.20° and 17.99°±0.20°; The X-ray powder diffraction pattern of the mesylate salt form J has characteristic peaks at the following 2θ angles: 14.75°±0.20°, 15.81°±0.20° and 21.89°±0.20°; The X-ray powder diffraction pattern of the formate salt form K has characteristic peaks at the following 2θ angles: 11.92°±0.20°, 15.15°±0.20° and 24.04°±0.20°; The X-ray powder diffraction pattern of the oxalate salt form N has characteristic peaks at the following 2θ angles: 6.20°±0.20°, 7.49°±0.20°, 12.25°±0.20°, 12.47°±0.20°, 16.36°±0.20° and 23.43°±0.20°; The X-ray powder diffraction pattern of the pamoate salt form O has characteristic peaks at the following 2θ angles: 6.18°±0.20°, 9.41°±0.20°, 11.10°±0.20°, 15.59°±0.20° and 26.25°±0.20°.

14. The salt crystal form according to claim 13, characterized in that The X-ray powder diffraction pattern of the hydrochloride form G also has characteristic peaks at one or more of the following 2θ angles: 10.42°±0.20°, 13.57°±0.20°, 14.15°±0.20°, 17.14°±0.20°, 19.42°±0.20°, 24.50°±0.20° and 24.88°±0.20°; preferably, the X-ray powder diffraction pattern of the hydrochloride form G also has characteristic peaks at one or more of the following 2θ angles: 8.52°±0.20°, 10.96°±0.20°, 20.46°±0.20°, and 26.74°±0.20°; The X-ray powder diffraction pattern of the hydrochloride salt form H also has characteristic peaks at one or more of the following 2θ angles: 14.16°±0.20°, 18.37°±0.20°, 21.48°±0.20°, 23.71°±0.20°, 26.17°±0.20°, 29.21°±0.20° and 33.70°±0.20°; preferably, the X-ray powder diffraction pattern of the hydrochloride salt form H also has characteristic peaks at one or more of the following 2θ angles: 12.64°±0.20°, 14.43°±0.20°, 16.99°±0.20° and 26.61°±0.20°; The X-ray powder diffraction pattern of the phosphate crystal form I also has characteristic peaks at one or more of the following 2θ angles: 14.94°±0.20°, 19.20°±0.20°, 21.54°±0.20°, 23.80°±0.20°, 24.12°±0.20° and 24.54°±0.20°; preferably, the X-ray powder diffraction pattern of the phosphate crystal form I also has a characteristic peak at 7.21°±0.20°; The X-ray powder diffraction pattern of the mesylate salt form J also has characteristic peaks at one or more of the following 2θ angles: 15.27°±0.20°, 16.75°±0.20°, 18.96°±0.20°, 23.51°±0.20°, 24.44°±0.20°; preferably, the X-ray powder diffraction pattern of the mesylate salt form J also has characteristic peaks at one or more of the following 2θ angles: 7.87°±0.20°, 11.94°±0.20°, 12.32°±0.20°, 18.21°±0.20°, 27.96°±0.20° and 30.06°±0.20°; The X-ray powder diffraction pattern of the formate salt form K also has characteristic peaks at one or more of the following 2θ angles: 13.91°±0.20°, 14.38°±0.20°, 18.41°±0.20° and 30.61°±0.20°; preferably, the X-ray powder diffraction pattern of the formate salt form K also has characteristic peaks at one or two of the following 2θ angles: 10.76°±0.20° and 24.90°±0.20°; The X-ray powder diffraction pattern of the oxalate crystal form N also has characteristic peaks at one or more of the following 2θ angles: 11.45°±0.20°, 14.00°±0.20°, 15.06°±0.20° and 23.78°±0.20°; preferably, the X-ray powder diffraction pattern of the oxalate crystal form N also has characteristic peaks at one or two of the following 2θ angles: 24.07°±0.20° and 24.95°±0.20°; The X-ray powder diffraction pattern of the pamoate salt form O also has characteristic peaks at one or more of the following 2θ angles: 10.40°±0.20°, 12.46°±0.20°, 18.96°±0.20°, 19.34°±0.20°, 23.12°±0.20°, 23.43°±0.20°, 29.90°±0.20° and 31.46°±0.20°; preferably, the X-ray powder diffraction pattern of the pamoate salt form O also has a characteristic peak at 25.00°±0.20°; 15. The salt crystal form according to claim 13, characterized in that The hydrochloride salt form G has an X-ray powder diffraction (XPRD) pattern substantially as shown in Figure 17, and / or a differential scanning calorimetry (DSC) pattern substantially as shown in Figure 18, and / or a thermogravimetric analysis (TGA) overlay pattern substantially as shown in Figure 18; The hydrochloride salt form H has an X-ray powder diffraction (XPRD) pattern substantially as shown in Figure 19, and / or a differential scanning calorimetry (DSC) pattern substantially as shown in Figure 20, and / or a thermogravimetric analysis (TGA) overlay pattern substantially as shown in Figure 20; The phosphate salt form I has an X-ray powder diffraction (XPRD) pattern substantially as shown in Figure 21, and / or has a differential scanning calorimetry (DSC) pattern substantially as shown in Figure 22, and / or a thermogravimetric analysis (TGA) overlay pattern substantially as shown in Figure 22; The mesylate salt Form J has an X-ray powder diffraction (XPRD) pattern substantially as shown in Figure 23, and / or a differential scanning calorimetry (DSC) pattern substantially as shown in Figure 24, and / or a thermogravimetric analysis (TGA) overlay pattern substantially as shown in Figure 24; The formate salt Form K has an X-ray powder diffraction (XPRD) pattern substantially as shown in Figure 25, and / or a differential scanning calorimetry (DSC) pattern substantially as shown in Figure 26, and / or a thermogravimetric analysis (TGA) overlay pattern substantially as shown in Figure 26; Oxalate Form N has an X-ray powder diffraction (XPRD) pattern substantially as shown in Figure 27; Pamoate salt Form O has an X-ray powder diffraction (XPRD) pattern substantially as shown in FIG. 28 .

16. A pharmaceutical composition, characterized in that The pharmaceutical composition contains a pharmaceutically acceptable carrier and: (i) a compound according to any one of claims 1 to 9, a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, isotope-substituted product, polymorph, prodrug or metabolite thereof, and a pharmaceutically acceptable carrier; or (ii) a crystalline salt of Compound 2 according to any one of claims 10 to 12; or (iii) The salt crystalline form of Compound 3 according to any one of claims 13 to 15.

17. The compound of any one of claims 1-9, its pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, isotope substitution, polymorph, prodrug or metabolite, the salt crystal form of compound 2 according to any one of claims 10-12, the salt crystal form of compound 3 according to any one of claims 13-15, or the pharmaceutical composition according to claim 16 in the preparation of a medicament for treating or preventing a disease mediated by an NMDA receptor, or in the preparation of an anesthetic or analgesic, a tranquilizer (for human or veterinary use); preferably, the NMDA receptor mediated The disease mediated by NMDA receptors is selected from the group consisting of cerebral ischemia, traumatic brain injury, infarction, stroke, Alzheimer's disease, Parkinson's disease, Huntington's disease, depression, anxiety, bipolar disorder, schizophrenia, autism, epilepsy, anti-NMDA receptor encephalitis, neuropathic pain, anorexia, sleep disorders or itch-related diseases, and other nervous system events or neurodegeneration caused by NMDA receptor activation; preferably, the NMDA receptor-mediated disease is depression, schizophrenia or epilepsy; preferably, the sleep disorder-related disease is insomnia, sleep apnea syndrome, atypical sleep cycle rhythm disorder or Down syndrome.

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