Pyrazole derivatives modulators, methods of making and using the same

Abstract

The present application relates to pyrazole derivatives modulator, its preparation method and application. Particularly, the present application relates to the compound shown in general formula (I), its preparation method and pharmaceutical composition containing the compound, and its application as TAAR1 receptor agonist in the preparation of drugs for treating, preventing or controlling neurological disorders, wherein each substituent in general formula (II-A) is the same as defined in the specification.

Description

Technical Field

[0001] This invention belongs to the field of biomedical technology, specifically relating to a pyrazole derivative regulator, its preparation method, and its application. Background Technology

[0002] Schizophrenia is the most prevalent mental illness, characterized by a slow progression and a tendency to relapse, worsen, or deteriorate, placing a heavy burden on patients and their families. Patients with schizophrenia experience positive symptoms such as delusions, hallucinations, and disordered thought, speech, and behavior; negative symptoms such as apathy, lack of expression, impoverished speech, and lack of pleasure; and cognitive impairment. Although significant progress has been made in the research and clinical application of antipsychotic drugs over the past few decades, traditional first-generation antipsychotics (haloperidol, fluperidone, thioridazine, etc.) and atypical second-generation antipsychotics (clozapine, risperidone, olanzapine, aripiprazole, etc.) target D2 and 5-HT2A mechanisms, showing good efficacy in treating positive symptoms but less effective in improving negative symptoms and cognitive impairment, and often have side effects such as extrapyramidal symptoms and weight gain. Numerous studies have been conducted on antipsychotic drugs targeting non-D2 / 5-HT2A receptors, including GlyT1 D1, D4, D3, NMDA, mGluR2 / 3, AMPA 5-HT2C, nicotinic a7, muscarinic M1 / M4, H3, and NK-3. While these targets have shown promising efficacy in preclinical models, most novel drugs targeting non-D2 / 5-HT2A mechanisms have demonstrated limited efficacy or failure in clinical trials. Therefore, there is an urgent need to develop novel antipsychotic drugs targeting not only positive symptoms but also negative symptoms and cognitive impairment, without extrapyramidal side effects.

[0003] Trace amines (TAs) are a class of substances structurally similar to classic monoamine neurotransmitters (DA, 5-HT, and norepinephrine). Trace amines are present in very low concentrations in the mammalian brain, and their levels are altered in many mental illnesses (schizophrenia, depression, anxiety disorders, Parkinson's disease / attention deficit hyperactivity disorder). The TARR1 receptor is a subtype of the TA1 receptor, belonging to the G protein-coupled receptor family. It is primarily expressed in peripheral organs and cells (such as the stomach, small intestine, duodenum, and leukocytes) and in the presynaptic membranes of astrocytes in the central nervous system (CNS), as well as in the axonal terminals of monoamine neurons. It plays a role in regulating DA, 5-HT, and glutamatergic activity.

[0004] The 5-HT1A receptor is a member of the G protein-coupled receptor family and a subtype of the 5-HT receptor. It is distributed in both the central and peripheral nervous systems and is closely related to mental state, mood, learning, and memory. The density of 5-HT1A receptors is increased in the frontal and temporal cortex of patients with schizophrenia. Activation of 5-HT1A receptors can improve the negative symptoms of schizophrenia, and studies have also found that it is related to the improvement of positive symptoms.

[0005] The international patent application WO2011069063, for SEP-363856, a TARR1 receptor agonist and a partial 5-HT1A receptor agonist, has been published for the treatment of schizophrenia. Phase II clinical trial results were promising, demonstrating efficacy and good safety for both positive and negative symptoms. It has now entered Phase III clinical trials. Additionally, the international patent application WO2017157873, for RG-7906, a partial TARR1 receptor agonist, has entered Phase II clinical trials for the treatment of schizophrenia. Preclinical data shows good safety, and it could be developed for depression, anxiety disorders, bipolar disorder, ADHD, neurodegenerative diseases, and metabolic diseases. There is an urgent need to develop drugs with novel targets that are effective against both positive and negative symptoms and have good safety profiles for the treatment of schizophrenia to meet the huge market demand. Summary of the Invention

[0006] The object of this invention is to provide a compound of general formula (II-A), its stereoisomers, or pharmaceutically acceptable salts thereof:

[0007]

[0008] in:

[0009] R1 is selected from hydrogen, deuterium, or C. 1-6 Alkyl; more preferably hydrogen, deuterium or C 1-3 alkyl;

[0010] R2 is selected from hydrogen, deuterium, halogens, and C. 1-6 Alkyl, C 1-6 Halogenated alkyl or C 3-8 Cycloalkyl; more preferably hydrogen, deuterium, C 1-3 Alkyl, C 1-3 Halogenated alkyl or C 3-6 cycloalkyl;

[0011] R3 is selected from hydrogen, deuterium, halogens, and C. 1-6 Alkyl, C 1-6 Halogenated alkyl or C 3-8 Cycloalkyl; more preferably hydrogen, deuterium, halogen, C 1-3 Alkyl or C 3-6 cycloalkyl;

[0012] Alternatively, R2 and R3 can be linked to form C.3-8 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl, wherein the C 3-8 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl groups, optionally further converted by hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, oxo, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-8 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 One or more substitutions of aryl and 5-14 heteroaryl groups; preferably C 3-6 Cycloalkyl or 3-8 membered heterocyclic groups; more preferably five-membered cycloalkyl, six-membered cycloalkyl, and 5- or 6-membered heterocyclic groups containing 1-3 N, O, or S atoms, wherein the five- or six-membered cycloalkyl, six-membered cycloalkyl, and 5- or 6-membered heterocyclic groups containing 1-3 N, O, or S atoms are optionally further modified by hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, oxo, or C. 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 One or more substitutions of aryl and 5-14 heteroaryl groups;

[0013] R a Selected from hydrogen, deuterium, halogens, and C 1-6 Alkyl, C 1-6 Deuterated alkyl or C 1-6 Halogenated alkyl groups;

[0014] R aa Selected from hydrogen, deuterium, halogens, and C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy or C 3-8 cycloalkyl;

[0015] Or, R aa Linked with R3 to form C 3-8 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14Aryl or 5-14 heteroaryl, wherein the C 3-8 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl groups, optionally further converted by hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, oxo, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-8 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 The aryl group is substituted with one or more of 5-14-membered heteroaryl groups; preferably 3-8-membered heterocyclic groups; more preferably containing 1-3 5- or 6-membered heterocyclic groups selected from N, O, or S atoms, wherein the 5- or 6-membered heterocyclic groups containing 1-3 N, O, or S atoms are optionally further substituted with hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, oxo, or C. 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 One or more substitutions of aryl and 5-14 heteroaryl groups;

[0016] R b Selected from hydrogen, deuterium, halogens, and C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkyl group, -(CH2) n1 NR A1 R B1 or -CR A1 R B1 (CH2) n1 NR C1 R D1 ;

[0017] R c Selected from hydrogen, deuterium, halogens, and C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkyl group, -(CH2) n1 NR A1 R B1 or -CRA1 R B1 (CH2) n1 NR C1 R D1 ;

[0018] Or, R b With R c Link formation C 3-8 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl, wherein the C 3-8 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl groups, optionally further converted by hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, oxo, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-8 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 The aryl group is substituted with one or more of the following: aryl and 5-14-membered heteroaryl groups; preferably 3-8-membered heterocyclic groups; more preferably containing 1-3 six-, seven-, or eight-membered heterocyclic groups selected from N, O, or S atoms, wherein the six-, seven-, or eight-membered heterocyclic groups containing 1-3 N, O, or S atoms are optionally further substituted with hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, oxo, or C. 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 One or more substitutions of aryl and 5-14 heteroaryl groups;

[0019] x is an integer from 1 to 6; and

[0020] n1 is an integer from 0 to 3.

[0021] In a further preferred embodiment of the invention, the compound represented by formula (II-A) is further represented as shown in formula (III):

[0022]

[0023] R4 is selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, C1-6 alkyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, 3-12 heterocyclic, C6-14 aryl or 5-14 heteroaryl;

[0024] y is an integer from 0 to 5.

[0025] In some embodiments, in any of the above general formula compounds, R a Selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl, 5-14 heteroaryl, -(CH2) n1 NR A1 R B1 -CR A1 R B1 (CH2) n1 NR C1 R D1 -(CH2) n1 R A1 -CR A1 R B1 R C1 -(CH2) n1 OR A1 -(CH2) n1 SR A1 -(CH2) n1 C(O)R A1 -(CH2) n1 S(O) m1 R A1 -(CH2) n1 C(O)OR A1 -(CH2) n1 C(O)NR A1 R B1 -(CH2) n1 NR A1 C(O)R B1 -(CH2) n1 NR A1 C(O)OR B1-(CH2) n1 NR A1 C(O)NR B1 R C1 or -NR A1 (CH2) n1 R B1 Preferred elements include hydrogen, deuterium, halogens, and carbon. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, 3-8 heterocyclic, -(CH2) n1 NR A1 R B1 or -CR A1 R B1 (CH2) n1 NR C1 R D1 More preferably hydrogen, deuterium, halogens, and carbon. 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, containing 1-3 3-8 heterocyclic groups selected from N, O or S atoms, -(CH2) n1 NR A1 R B1 or -CR A1 R B1 (CH2) n1 NR C1 R D1 ;

[0026] Further preferred compounds include hydrogen, deuterium, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, trifluoromethyl, morpholino, -(CH2)2NHCH3, -CH(OCH3)CH2NHCH3, 1,2,5,6-tetrahydropyridin-3-yl, 1,4-oxacrylonitrile-2-yl, or 1,4-oxacrylonitrile-7-yl.

[0027] R A1 R B1 R C1 and R D1 Each group is independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, and C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 cycloalkyl, C 3-8 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl groups;

[0028] m1 is an integer from 0 to 2; and

[0029] n1 is an integer from 0 to 3.

[0030] In some embodiments, in any of the above general formula compounds, R1 is selected from hydrogen, deuterium, or C. 1-6 Alkyl; more preferably hydrogen, deuterium or C 1-3 alkyl;

[0031] In some embodiments, in any of the above general formula compounds, R2 is selected from hydrogen, deuterium, halogens, and C. 1-6 Alkyl, C 1-6 Halogenated alkyl or C 3-8 Cycloalkyl; more preferably hydrogen, deuterium, C 1-3 Alkyl, C 1-3 Halogenated alkyl or C 3-6 cycloalkyl;

[0032] In some embodiments, in any of the above general formula compounds, R3 is selected from hydrogen, deuterium, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl or C 3-8 Cycloalkyl; more preferably hydrogen, deuterium, halogen, C 1-3 Alkyl or C 3-6 cycloalkyl;

[0033] In some embodiments, in any of the above general formula compounds, R2 and R3 are linked to form C 3-8 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl, wherein the C 3-8 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl groups, optionally further converted by deuterium, halogen, amino, nitro, hydroxyl, cyano, oxo, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-8 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 One or more substitutions of aryl and 5-14 heteroaryl groups; preferably C 3-6 Cycloalkyl or 3-8 membered heterocyclic groups; more preferably five-membered cycloalkyl, six-membered cycloalkyl, and 5- or 6-membered heterocyclic groups containing 1-3 N, O, or S atoms, wherein the five- or six-membered cycloalkyl, six-membered cycloalkyl, and 5- or 6-membered heterocyclic groups containing 1-3 N, O, or S atoms are optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, oxo, or C.1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 One or more substitutions of aryl and 5-14 heteroaryl groups;

[0034] In some embodiments, in any of the above general formula compounds, R4 is selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, C1-6 alkyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, 3-12 membered heterocyclic, C6-14 aryl, or 5-14 membered heteroaryl;

[0035] In some embodiments, in any of the above general formula compounds, R a Selected from hydrogen, deuterium, halogens, and C 1-6 Alkyl, C 1-6 Deuterated alkyl or C 1-6 Halogenated alkyl groups;

[0036] In some embodiments, in any of the above general formula compounds, R aa Selected from hydrogen, deuterium, halogens, and C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy or C 3-8 cycloalkyl;

[0037] In some embodiments, in any of the above general formula compounds, R aa Linked with R3 to form C 3-8 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl, wherein the C 3-8 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl groups, optionally further converted by deuterium, halogen, amino, nitro, hydroxyl, cyano, oxo, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-8Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 The aryl group is substituted with one or more of the following: aryl and 5-14-membered heteroaryl groups; preferably 3-8-membered heterocyclic groups; more preferably containing 1-3 5- or 6-membered heterocyclic groups selected from N, O, or S atoms, wherein the 1-3 5- or 6-membered heterocyclic groups containing 1-3 N, O, or S atoms are optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, oxo, or C. 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 One or more substitutions of aryl and 5-14 heteroaryl groups;

[0038] In some embodiments, in any of the above general formula compounds, R b Selected from hydrogen, deuterium, halogens, and C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkyl group, -(CH2) n1 NR A1 R B1 or -CR A1 R B1 (CH2) n1 NR C1 R D1 ;

[0039] In some embodiments, in any of the above general formula compounds, R c Selected from hydrogen, deuterium, halogens, and C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkyl group, -(CH2) n1 NR A1 R B1 or -CR A1 R B1 (CH2) n1 NR C1 R D1 ;

[0040] In some embodiments, in any of the above general formula compounds, R b With R c Link formation C 3-8 Cycloalkyl, 3-12 membered heterocyclic groups, C6-14 Aryl or 5-14 heteroaryl, wherein the C 3-8 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl groups, optionally further converted by deuterium, halogen, amino, nitro, hydroxyl, cyano, oxo, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-8 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 The aryl group is substituted with one or more of the following: aryl and 5-14-membered heteroaryl groups; preferably 3-8-membered heterocyclic groups; more preferably containing 1-3 six-, seven-, or eight-membered heterocyclic groups selected from N, O, or S atoms, wherein the six-, seven-, or eight-membered heterocyclic groups containing 1-3 N, O, or S atoms are optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, oxo, or C. 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 One or more substitutions of aryl and 5-14 heteroaryl groups;

[0041] In some embodiments, in any of the above general formula compounds, R A1 R B1 R C1 and R D1 Each group is independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, and C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-12 membered heterocyclic C 6-14 aryl and 5-14 heteroaryl groups, optionally further converted by deuterium, halogen, amino, nitro, hydroxyl, cyano, oxo, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C1-6 Halogenated alkoxy groups, C 3-8 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 One or more substitutions of aryl and 5-14 heteroaryl groups;

[0042] In some embodiments, x is an integer from 1 to 6 in any of the above general formula compounds;

[0043] In some embodiments, in any of the above general formula compounds, y is an integer from 0 to 5;

[0044] In some embodiments, n1 is an integer from 0 to 3 in any of the above general formula compounds.

[0045] In some embodiments, in any of the above general formula compounds, R1 is hydrogen; when R3 is methyl, R2 is not ethyl or hydrogen.

[0046] In some embodiments, in any of the above general formula compounds, when for When R1 is H, R3 is H or methyl, R2 is not phenyl or a 6-membered nitrogen-containing heteroaryl group;

[0047] In some embodiments, in any of the above general formula compounds, when for When R1 is H and R2 is H, R3 is not a methyl group;

[0048] In some embodiments, in any of the above general formula compounds, when for When R2 is H and R3 is H, R1 is not ethyl, phenyl, or a 6-membered nitrogen-containing heteroaryl group;

[0049] In some embodiments, in any of the above general formula compounds, when for When R1 is ethyl and R3 is H, R2 is not phenyl.

[0050] In some embodiments, in any of the above general formula compounds, in a further preferred embodiment of the present invention, when for When R1 is H and R3 is methyl, R2 is not ethyl;

[0051] In some embodiments, in any of the above general formula compounds, when for When R1 is H, R3 is H or methyl, R2 is not H.

[0052] In some embodiments, in any of the above general formula compounds, when for When R1 is H and R2 is H, R3 is not a methyl group;

[0053] In some embodiments, in any of the above general formula compounds, when for When R2 is H and R3 is H, R1 is not an ethyl group.

[0054] In some embodiments, in any of the above general formula compounds, when for When R1 is ethyl and R3 is H, R2 is not...

[0055] In some embodiments, in any of the above general formula compounds, R b With R c Not formed

[0056] In some implementations, R1 and R aa Each is independently selected from hydrogen;

[0057] R2 and R3 are each independently selected from halogens, C 1-3 Alkyl or C 3-6 Cycloalkyl, preferably chloro, methyl, ethyl or cyclopropyl, provided that R2 is not ethyl when R3 is methyl;

[0058] x is 1;

[0059] y is 0.

[0060] In some implementations, R1 and R aa Each is independently selected from hydrogen;

[0061] R2 and R3 link together to form C 3-8 Cycloalkyl, preferably five-membered or six-membered cycloalkyl, and more preferably cyclohexyl;

[0062] x is 1;

[0063] y is 0.

[0064] The present invention also provides a method for preparing a compound of general formula (II-A), the method comprising the following steps:

[0065]

[0066] The reaction of general formula compound (M-1) with general formula compound (M-2) can optionally be deprotected to give general formula compound (II-A);

[0067] Among them, R1, R2, R3, R aa Ra R b R c The definitions of x and x are as described above.

[0068] The present invention also provides a pharmaceutical composition comprising a therapeutically effective dose of each general formula compound, its stereoisomer or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0069] The present invention also provides a preferred embodiment relating to the general formula compounds and their stereoisomers or pharmaceutically acceptable salts thereof, or the use of the pharmaceutical compositions thereof in the preparation of TAAR1 receptor agonist drugs.

[0070] The present invention also relates to the use of the compounds of the general formulas described herein, their stereoisomers or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof in the preparation of medicaments for the treatment, prevention or control of neurological disorders.

[0071] In some implementations, the neurological disorder is selected from schizophrenia, social dysfunction, or psychosis; the schizophrenia is selected from schizophrenia spectrum disorders, acute schizophrenia, chronic schizophrenia, NOS schizophrenia, paranoid schizophrenia, schizophrenia-like personality disorder, or schizotypal personality disorder; the psychosis is selected from delusional disorders, short-term psychotic disorders, shared psychotic disorders, psychotic disorders caused by physical illness, drug-induced psychosis, psychotic disorders, aggressiveness, mental confusion, Parkinson's psychosis, agitated psychosis, Tourette syndrome, organ or NOS psychosis, seizures, agitation, post-traumatic stress disorder, behavioral disorder, neurodegenerative diseases, Alzheimer's disease, Parkinson's disease, movement disorders, Huntington's disease. Huntington's disease, dementia, affective disorders, anxiety disorders, affective psychosis, depression, major depressive disorder, mood disorders, bipolar disorder, mania, seasonal affective disorder, attention deficit disorder, attention deficit hyperactivity disorder, obsessive-compulsive disorder, vertigo, epilepsy, pain, neuropathic pain, neuropathic pain predisposition, inflammatory pain, fibromyalgia, migraine, cognitive impairment, movement disorders, restless limb syndrome, multiple sclerosis, sleep disorders, sleep apnea, hypersomnia, excessive daytime sleepiness, jet lag, drowsiness as a side effect of medication, insomnia, substance abuse and dependence, addiction, eating disorders, sexual dysfunction, hypertension, vomiting, Lesche-Nyhane disease, Wilson's disease, autism, Huntington's disease, or premenstrual anxiety.

[0072] Detailed description of the invention

[0073] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0074] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight-chain or branched group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 8 carbon atoms, more preferably an alkyl group containing 1 to 6 carbon atoms, and most preferably an alkyl group containing 1 to 3 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-Dimethylpentyl, 2,4-Dimethylpentyl, 2,2-Dimethylpentyl, 3,3-Dimethylpentyl, 2-Ethylpentyl, 3-Ethylpentyl, n-Octyl, 2,3-Dimethylhexyl, 2,4-Dimethylhexyl, 2,5-Dimethylhexyl, 2,2-Dimethylhexyl, 3,3-Dimethylhexyl, 4,4-Dimethylhexyl, 2-Ethylhexyl, 3-Ethylhexyl, 4-Ethylhexyl, 2-Methyl-2-Ethylpentyl, 2-Methyl-3-Ethylpentyl, n-Nonyl, 2-Methyl-2-Ethylhexyl, 2-Methyl-3-Ethylhexyl, 2,2-Diethylpentyl, n-Decyl, 3,3-Diethylhexyl, 2,2-Diethylhexyl, and their various branched isomers, etc. More preferably, lower alkyl groups containing 1 to 6 carbon atoms are used. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, etc. Alkyl groups can be substituted or unsubstituted. When substituted, the substituent can be substituted at any usable connection point. The substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, or carboxylic acid ester groups. The present invention preferably uses methyl, ethyl, isopropyl, tert-butyl, haloalkyl, deuteralkyl, alkoxy-substituted alkyl, and hydroxy-substituted alkyl.

[0075] The term "alkylene" refers to an alkyl group in which one hydrogen atom is further substituted, for example: "methylene" refers to -CH2-, "ethylene" refers to -(CH2)2-, "propylene" refers to -(CH2)3-, "butylene" refers to -(CH2)4-, etc. The term "alkenyl" refers to an alkyl group as defined above, consisting of at least two carbon atoms and at least one carbon-carbon double bond, such as vinyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3-butenyl, etc. Alkenyl groups can be substituted or unsubstituted; when substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, and heterocycloalkylthio.

[0076] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, wherein the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 8 carbon atoms, and even more preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclohepttrienyl, cyclooctyl, etc.; polycyclic cycloalkyl groups include spirocyclic, fused-ring, and bridged-ring cycloalkyl groups, preferably cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, and cycloheptyl.

[0077] The cycloalkyl ring may be fused to an aryl, heteroaryl, or heterocycloalkyl ring, wherein the ring connected to the parent structure is a cycloalkyl group, and non-limiting examples include indanyl, tetrahydronaphthyl, benzocycloheptyl, etc. The cycloalkyl group may be optionally substituted or unsubstituted; when substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, or carboxylic acid ester group.

[0078] The term "heterocyclic group" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent containing 3 to 20 ring atoms, one or more of which are selected from nitrogen, oxygen, or S(O). m(where m is an integer from 0 to 2) heteroatoms, but excluding the ring portions of -OO-, -OS-, or -SS-, with the remaining ring atoms being carbon. Preferably, it contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; preferably, it contains 1 to 3 heterocyclic groups selected from N, O, or S atoms; more preferably, it contains 3 to 10 ring atoms; most preferably, it contains 3 to 8 ring atoms; and even more preferably, it contains 5 to 8 ring atoms. Non-limiting examples of monocyclic heterocyclic groups include oxobutyryl, azirhelyl, tetrahydropyranyl, azirheptanyl, tetrahydropyrrolidonyl, tetrahydropyrrolyl, tetrahydrofuranyl, tetrahydrothiophenyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolidonyl, tetrahydropyridyl, piperidinyl, piperidinoneyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, tetrahydropyridinyl or oxacheptyl, etc., preferably morpholinyl, tetrahydropyridinyl, tetrahydropyrrolidonyl, piperidinyl, piperidinoneyl, 1,2,5,6-tetrahydropyridin-3-yl, 1,4-oxacheptyl-2-yl or 1,4-oxacheptyl-7-yl. Polycyclic heterocyclic groups include spirocyclic, fused-ring, and bridged-ring heterocyclic groups; wherein the spirocyclic, fused-ring, and bridged-ring heterocyclic groups involved may optionally be connected to other groups by single bonds, or may be further cyclically linked to other cycloalkyl, heterocyclic, aryl, and heteroaryl groups by any two or more atoms on the ring.

[0079] The heterocyclic ring can be fused to an aryl, heteroaryl, or cycloalkyl ring, wherein the ring connected to the parent structure is a heterocyclic group.

[0080] The heterocyclic group can be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, or carboxylic acid ester group.

[0081] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (i.e., a ring sharing adjacent carbon atom pairs) group having a conjugated π-electron system, preferably 6- to 10-membered, more preferably 6- to 8-membered, such as thiophene, pyridyl, or furanyl groups. The aryl ring may be fused to a heteroaryl, heterocyclic, or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring.

[0082] The aryl group can be substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylic acid ester group.

[0083] The term "heteroaryl" refers to a heteroaryl system comprising 1 to 4 heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. The heteroaryl group is preferably 5 to 10-membered, more preferably 5 to 8-membered, such as imidazolyl, furanyl, thiophene, thiazolyl, pyrazolyl, oxazolyl, pyrroleyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, thiadiazole, pyrazinyl, oxadiazole, etc., preferably triazolyl, thiophene, imidazolyl, pyrazolyl or pyrimidinyl, thiazolyl; more preferably triazolyl, pyrroleyl, thiophene, thiazolyl, pyrimidinyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, thiadiazole, and oxadiazoleyl. The heteroaryl ring may be fused to an aryl, heterocyclic, or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring.

[0084] The heteroaryl group can be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylic acid ester group.

[0085] The term "alkoxy" refers to -O- (alkyl) and -O- (unsubstituted cycloalkyl), where alkyl is defined as described above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, and cyclohexoxy. Alkoxy groups can be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carboxylic acid ester group.

[0086] "Halogenated alkyl" refers to an alkyl group that has been substituted with one or more halogens, wherein the alkyl group is as defined above.

[0087] "Haloalkoxy" refers to an alkoxy group that has been substituted by one or more halogens, wherein the alkoxy group is as defined above.

[0088] "Hydroxyalkyl" refers to an alkyl group that has been replaced by a hydroxyl group, where the alkyl group is as defined above.

[0089] "Alkenyl" refers to an alkenyl group, also known as an olefinic group, which is a straight-chain or branched group containing 2 to 20 carbon atoms, preferably an alkenyl group containing 2 to 8 carbon atoms, more preferably an alkenyl group containing 2 to 6 carbon atoms, and most preferably an alkenyl group containing 2 to 4 carbon atoms. The alkenyl group can be further substituted with other related groups, such as: alkyl, alkenyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carboxylic acid ester group.

[0090] "Alynyl" refers to (CH≡C-), which is a straight-chain or branched group containing 2 to 20 carbon atoms, preferably an alkynyl group containing 2 to 8 carbon atoms, more preferably an alkynyl group containing 2 to 6 carbon atoms, and most preferably an alkynyl group containing 2 to 4 carbon atoms. The alkynyl group may be further substituted with other related groups, such as: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carboxylic acid ester group.

[0091] "Hydroxy" refers to the -OH group.

[0092] "Halogen" refers to fluorine, chlorine, bromine, or iodine.

[0093] "Amino" refers to -NH2.

[0094] “Cyano” refers to -CN.

[0095] "Nitro" refers to -NO2.

[0096] "Carboxyl group" refers to -C(O)OH.

[0097] "THF" refers to tetrahydrofuran.

[0098] “EtOAc” refers to ethyl acetate.

[0099] “MeOH” refers to methanol.

[0100] "DMF" refers to N,N-dimethylformamide.

[0101] "DIPEA" refers to diisopropylethylamine.

[0102] "TFA" refers to trifluoroacetic acid.

[0103] “MeCN” refers to Yi Qing.

[0104] “DMA” stands for N,N-dimethylacetamide.

[0105] “Et2O” refers to diethyl ether.

[0106] “DCE” refers to 1,2-dichloroethane.

[0107] "DIPEA" refers to N,N-diisopropylethylamine.

[0108] “NBS” refers to N-bromosuccinimide.

[0109] “NIS” refers to N-iodosuccinimide.

[0110] “Cbz-Cl” refers to benzyl chloroformate.

[0111] “Pd2(dba)3” refers to tris(dibenzylacetone)dipalladium.

[0112] “Dppf” refers to 1,1'-bis(diphenylphosphine)ferrocene.

[0113] “HATU” refers to 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethylurea hexafluorophosphate.

[0114] "KHMDS" refers to potassium hexamethyldisilamide.

[0115] "LiHMDS" refers to lithium bis(trimethylsilyl)amine.

[0116] “MeLi” refers to methyl lithium.

[0117] “n-BuLi” refers to n-butyllithium.

[0118] "NaBH(OAc)3" refers to sodium triacetoxyborohydride.

[0119] The different terms such as "X is selected from A, B, or C", "X is selected from A, B, and C", "X is A, B, or C", and "X is A, B, and C" all express the same meaning, that is, X can be any one or more of A, B, and C.

[0120] All hydrogen atoms described in this invention can be replaced by their isotope deuterium, and any hydrogen atom in the compounds of the embodiments of this invention can also be replaced by deuterium.

[0121] "Optional" or "optionally" means that the event or environment described below may but does not have to occur, and the description includes the possibility or absence of such event or environment. For example, "optionally alkyl-substituted heterocyclic group" means that the alkyl group may but does not have to be present, and the description includes cases where the heterocyclic group is substituted with an alkyl group and cases where the heterocyclic group is not substituted with an alkyl group.

[0122] "Substituted" refers to one or more hydrogen atoms in a group, preferably up to five, and more preferably one to three hydrogen atoms, which are independently substituted by the corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without much effort. For example, an amino or hydroxyl group with free hydrogen atoms may be unstable when bonded to a carbon atom with an unsaturated bond (such as an alkene).

[0123] "Pharmaceutical composition" means a mixture containing one or more of the compounds described herein or their physiologically / pharmacologically acceptable salts or prodrugs, along with other chemical components, such as physiologically / pharmacologically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to a living organism, thereby promoting the absorption of the active ingredient and the exertion of its biological activity.

[0124] "Medicinal salts" refers to salts of the compounds of this invention that are safe and effective when used in mammals and have the appropriate biological activity. Detailed Implementation

[0125] The present invention is further described below with reference to embodiments, but these embodiments do not limit the scope of protection of the present invention.

[0126] Example 1

[0127] 4-Chloro-5-ethyl-N-(4-(morpholin-2-yl)phenyl)-1H-pyrazole-3-carboxamide

[0128]

[0129] Method 1:

[0130]

[0131] Step 1: Preparation of 2-amino-1-(4-bromophenyl)ethane-1-ol:

[0132]

[0133] 2-Amino-4'-bromoacetophenone hydrochloride (2.51 g, 10 mmol) was dissolved in methanol (30 mL) at 0 °C, followed by the addition of sodium borohydride (0.95 g, 25 mmol). The reaction was carried out at 0 °C for 1 hour, and the reaction was indicated by LC-MS to be complete. The reaction was quenched with water, and the reaction solution was extracted with ethyl acetate (25 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to give the crude product 2-amino-1-(4-bromophenyl)ethane-1-ol (1.94 g, yield: 90%).

[0134] MS m / z (ESI): 215.9, 217.9 [M+H] + .

[0135] Step 2: Preparation of N-(2-(4-bromophenyl)-2-hydroxyethyl)-2-chloroacetamide:

[0136]

[0137] 2-Amino-1-(4-bromophenyl)ethane-1-ol (1.94 g, 9 mmol) was dissolved in dichloromethane (30 mL) at 0 °C, followed by the addition of triethylamine (1.82 g, 18 mmol), and then dropwise addition of chloroacetyl chloride (1.22 g, 10.8 mmol). The reaction was carried out at 0 °C for one hour. The reaction was indicated by LCMS to be complete. The reaction solution was diluted with dichloromethane (25 mL), and then washed successively with saturated sodium bicarbonate solution and saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to give the crude product N-(2-(4-bromophenyl)-2-hydroxyethyl)-2-chloroacetamide (2.37 g, yield: 90%).

[0138] MS m / z (ESI): 291.9, 293.9 [M] + .

[0139] Step 3: Preparation of 6-(4-bromophenyl)morpholin-3-one:

[0140]

[0141] N-(2-(4-bromophenyl)-2-hydroxyethyl)-2-chloroacetamide (2.37 g, 8.1 mmol) was dissolved in tetrahydrofuran (30 mL) at 0 °C, followed by the addition of potassium tert-butoxide (1.81 g, 16.2 mmol). The mixture was stirred at 0 °C for one hour, then heated to room temperature and reacted at room temperature for two hours. The reaction was considered complete by LC-MS. The reaction solution was diluted with ethyl acetate (25 mL), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to give the crude product 6-(4-bromophenyl)morpholin-3-one (1.37 g, yield: 70%).

[0142] MS m / z (ESI): 255.9, 257.9 [M] + .

[0143] Step 4: Preparation of 2-(4-bromophenyl)morpholine:

[0144]

[0145] 6-(4-bromophenyl)morpholin-3-one (1.37 g, 5.67 mmol) was dissolved in tetrahydrofuran (20 mL) at room temperature, and then lithium aluminum hydride (0.43 g, 11.34 mmol) was added. The mixture was heated under reflux for 2 hours, and the reaction was indicated to be complete by LCMS. After cooling to room temperature, the reaction solution was quenched with sodium sulfate decahydrate, filtered, and the filtrate was evaporated to dryness to give the crude product 2-(4-bromophenyl)morpholin (0.82 g, yield: 60%).

[0146] MS m / z(ESI): 242.0, 244.0 [M] + .

[0147] Step 5: Preparation of tert-butyl-2-(4-bromophenyl)morpholine-4-carboxylic acid ester:

[0148]

[0149] Under ice bath conditions, 2-(4-bromophenyl)morpholine (1.39 g, 5.74 mmol) and triethylamine (1.16 g, 11.5 mmol) were dissolved in tetrahydrofuran (15 mL), followed by the addition of di-tert-butyl dicarbonate (1.38 g, 6.31 mmol). The mixture was stirred under ice bath conditions for one hour, then stirred overnight at room temperature. The reaction solution was diluted with ethyl acetate (50 mL), washed with aqueous sodium hydroxide solution (1 M), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was separated by column chromatography to obtain tert-butyl 2-(4-bromophenyl)morpholine-4-carboxylic acid ester (1.81 g, yield: 95%).

[0150] MS m / z (ESI): 342.0, 344.0 [M] + .

[0151] Step 6: Preparation of tert-butyl 2-(4-((diphenylmethylene)amino)phenyl)morpholine-4-carboxylic acid ester:

[0152]

[0153] At room temperature, tert-butyl-2-(4-bromo-3-methylphenyl)morpholine-4-carboxylic acid ester (479 mg, 1.4 mmol), benzophenone imine (0.51 g, 2.8 mmol), sodium tert-butoxide (0.27 g, 2.8 mmol), tris(diphenylmethyleneacetone)dipalladium (0.013 g, 0.014 mmol), and di(diphenylphosphine)-1,1-binaphthyl were dissolved in toluene (5 mL), N2 was substituted, and the mixture was heated to 100 °C and reacted overnight. After cooling to room temperature, the reaction was indicated to be complete by LC-MS. The residue was evaporated to dryness, dissolved in ethyl acetate (25 mL), and then washed with saturated brine (15 mL × 2). The organic phase was dried over anhydrous sodium sulfate, filtered, evaporated to dryness, and the residue was separated by preparative thin-layer chromatography to give the product tert-butyl 2-(4-((diphenylmethylene)amino)-3-methylphenyl)morpholine-4-carboxylic acid ester (0.31 g, yield: 50%).

[0154] MS m / z (ESI): 443.2 [M] + .

[0155] Step 7: Preparation of tert-butyl-2-(4-amino-phenyl)morpholine-4-carboxylic acid ester:

[0156]

[0157] At room temperature, tert-butyl 2-(4-((diphenylmethylene)amino)-3-methylphenyl)morpholine-4-carboxylic acid ester (0.31 g, 0.7 mmol) was dissolved in methanol (6 mL), and formic acid ammonium (0.66 g, 10.5 mmol) was added. Nitrogen gas was then introduced, followed by the addition of 10% palladium on carbon (50 mg). The mixture was heated to 60 °C and reacted for 2 hours. After cooling to room temperature, the mixture was filtered through diatomaceous earth, washed with ethyl acetate, and evaporated to dryness. The residue was dissolved in ethyl acetate (50 mL), and the organic phase was washed successively with saturated sodium bicarbonate solution and saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was separated by column chromatography to obtain tert-butyl 2-(4-amino-3-methylphenyl)morpholine-4-carboxylic acid ester (0.14 g, yield: 70%).

[0158] MS m / z(ESI): 279.1 [M] + .

[0159] Step 8: Preparation of ethyl 5-ethyl-1H-pyrazole-3-carboxylic acid ester:

[0160]

[0161] Ethyl 2-diazotanoic acid ester (1 g, 8.76 mmol) was dissolved in dimethyl sulfoxide (15 mL), and butyraldehyde (1.26 g, 17.53 mmol) and diethylamine (128 mg, 1.75 mmol) were added. The mixture was reacted at room temperature for 16 hours. Water (45 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL × 2). The organic phases were combined, dried, and concentrated to obtain a crude product. The crude product was purified by rapid silica gel chromatography (eluting with petroleum ether:ethyl acetate = 10:1 to 4:1) to give the product ethyl 5-ethyl-1H-pyrazole-3-carboxylic acid ester (1 g, yield: 67.8%).

[0162] MS m / z(ESI): 169.0 [M+H] + .

[0163] Step 9: Preparation of ethyl 4-chloro-5-ethyl-1H-pyrazole-3-carboxylic acid ester

[0164]

[0165] Ethyl 5-ethyl-1H-pyrazole-3-carboxylic acid ester (1 g, 5.95 mmol) was dissolved in chloroform (10 mL), and sulfonyl chloride (1 g, 7.73 mmol) was added at 0 °C, and the reaction was carried out at 60 °C for 4 hours. The reaction was quenched with water (5 mL), the organic phase was separated, dried, concentrated to obtain the crude product, and purified by rapid silica gel chromatography (elution with petroleum ether:ethyl acetate = 10:1 to 4:1) to give the product ethyl 4-chloro-5-ethyl-1H-pyrazole-3-carboxylic acid ester (0.6 g, yield: 49.8%).

[0166] MS m / z(ESI): 203.2 [M+H] + .

[0167] Step 10: Preparation of 4-chloro-5-ethyl-1H-pyrazole-3-carboxylic acid

[0168]

[0169] Ethyl 4-chloro-5-ethyl-1H-pyrazole-3-carboxylic acid ester (0.6 g, 2.96 mmol) was dissolved in tetrahydrofuran (6 mL), and an aqueous solution of lithium hydroxide monohydrate (373 mg, 8.88 mmol) (2 mL) was added. The reaction was carried out at room temperature for 16 hours, the pH was adjusted to 4-5 with 1N hydrochloric acid aqueous solution, and the mixture was extracted with ethyl acetate (10 mL × 2). The combined organic phases were dried and concentrated under reduced pressure to give the product 4-chloro-5-ethyl-1H-pyrazole-3-carboxylic acid (0.35 g, yield: 67.7%).

[0170] MS m / z(ESI): 175.0 [M+H] + .

[0171] Step 11: Preparation of tert-butyl-2-(4-(4-chloro-5-ethyl-1H-pyrazole-3-carbonoxylazolylamino(oxiamino)phenyl)morpholine-4-carboxylic acid ester

[0172]

[0173] The compound product, 4-chloro-5-ethyl-1H-pyrazole-3-carboxylic acid (100 mg, 0.57 mmol), was dissolved in N,N-dimethylformamide (3 mL), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (262 mg, 0.369 mmol), N,N-diisopropylethylamine (90 mg, 0.69 mmol), and tert-butyl-2-(4-aminophenyl)morpholine-4-carboxylic acid ester (158 mg, 0.57 mmol) were added. The mixture was reacted at room temperature for 16 hours. Water (10 mL) was added, and the mixture was extracted with ethyl acetate (10 mL × 2). After the organic phases were combined and dried, the crude product was concentrated under reduced pressure and purified by prep-TLC to obtain the product 2-(4-(4-chloro-5-ethyl-1H-pyrazole-3-carbon oxaloylamino(oxadiamino))phenyl)morpholine-4-carboxylic acid ester (160 mg, yield: 64.8%).

[0174] MS m / z(ESI): 435.0 [M+H] + .

[0175] Step 12: Preparation of 4-chloro-5-ethyl-N-(4-(morpholin-2-yl)phenyl)-1H-pyrazole-3-carboxamide

[0176]

[0177] 5 mL of 4M dioxane hydrochloride solution was added to tert-butyl-2-(4-(4-chloro-5-ethyl-1H-pyrazole-3-carbonoxylate amino(oxidamido))phenyl)morpholine-4-carboxylic acid ester (100 mg, 0.23 mmol), and the reaction was carried out at room temperature for 1 hour. The product was concentrated under reduced pressure to give 4-chloro-5-ethyl-N-(4-(morpholin-2-yl)phenyl)-1H-pyrazole-3-carboxamide (70 mg, yield: 75%).

[0178] MS m / z(ESI): 335.0 [M+H] + .

[0179] Method 2:

[0180] Step 1: Preparation of 2-(4-nitrophenyl)oxalopropyl ring:

[0181]

[0182] 10 g (40.98 mmol) of 2-bromo-1-(4-nitrophenyl)ethane-1-one was dissolved in 150 mL of methanol. Sodium borohydride (1.71 g, 45.07 mmol) was added under ice-water bath cooling and nitrogen protection. The mixture was stirred at 0 °C for 2 hours. Then, potassium carbonate (5.66 g, 40.98 mmol) was added. The mixture was stirred at 20 °C for 16 hours. The reaction was quenched by adding saturated brine (250 mL). The mixture was extracted with ethyl acetate (50 mL × 3), the organic phases were combined, washed successively with saturated brine (50 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The target product, 2-(4-nitrophenyl)oxalopropylcyclohexane (6.77 g), was obtained and used directly in the next step.

[0183] Step 2: Preparation of 2-((2-hydroxyethyl)amino)-1-(4-nitrophenyl)ethane-1-ol:

[0184]

[0185] 2-(4-nitrophenyl)oxalanine (6.77 g, 40.99 mmol) was dissolved in tetrahydrofuran (150 mL), and 2-aminoethanol (25.04 g, 409.94 mmol) was added. The mixture was stirred at 20 °C for 24 hours. The reaction was quenched by adding saturated brine (250 mL). The mixture was extracted with ethyl acetate (50 mL × 3), the organic phases were combined, washed successively with saturated brine (50 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the target product 2-((2-hydroxyethyl)amino)-1-(4-nitrophenyl)ethane-1-ol (9.2 g), which was used directly in the next step.

[0186] MS m / z(ESI): 227.1 [M+H] + .

[0187] Step 3: Preparation of tert-butyl (2-hydroxy-2-(4-nitrophenyl)ethyl)(2-hydroxyethyl)carbamate:

[0188]

[0189] 2-((2-hydroxyethyl)amino)-1-(4-nitrophenyl)ethane-1-ol (12.5 g, 55.25 mmol) and triethylamine (13.98 g, 138.13 mmol, 19.25 mL) were dissolved in dichloromethane (150 mL). Under ice-water bath cooling and nitrogen protection, di-tert-butyl dicarbonate (14.47 g, 66.30 mmol) was added. The mixture was stirred at 20 °C for 16 hours. The mixture was washed with saturated brine (50 mL × 2), the organic phase was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography (elution with petroleum ether: ethyl acetate = 100:0 to 50:50) to give the target product, tert-butyl(2-hydroxy-2-(4-nitrophenyl)ethyl)(2-hydroxyethyl)carbamate (11 g, yield: 61.00%), as a white solid.

[0190] MS m / z (ESI): 327.1 [M+H] + .

[0191] Step 4: Preparation of tert-butyl-2-(4-nitrophenyl)morpholine-4-carboxylic acid ester:

[0192]

[0193] tert-Butyl(2-hydroxy-2-(4-nitrophenyl)ethyl)(2-hydroxyethyl)carbamate (9.5 g, 29.11 mmol) and triphenylphosphine (9.16 g, 34.93 mmol) were dissolved in a solution. Under ice-water bath cooling and nitrogen protection, diisopropyl azodicarbonate (7.06 g, 34.93 mmol, 6.88 mL) was added. The mixture was stirred at 20 °C for 16 hours. The mixture was concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography (elution with petroleum ether:ethyl acetate = 100:0 to 70:30) to give the target product, tert-butyl-2-(4-nitrophenyl)morpholine-4-carboxylic acid ester (4 g, yield: 44.57%), as a pale yellow solid.

[0194] 1 H NMR (400MHz, CDCl3) δ8.26–8.20(m,2H),7.59–7.53(m,2H),4.63–4.42(m,1H),4.28 –3.87(m,3H),3.79–3.54(m,1H),3.16–2.94(m,1H),2.88–2.59(m,1H),1.49(s,9H).

[0195] MS m / z(ESI): 309.1 [M+H] + .

[0196] Step 5: Preparation of tert-butyl-2-(4-amino-3-methylphenyl)morpholine-4-carboxylic acid ester:

[0197]

[0198] tert-Butyl-2-(4-nitrophenyl)morpholine-4-carboxylic acid ester (3 g, 9.73 mmol) was dissolved in methanol (80 mL), and 10% palladium on carbon (0.3 g, 50% water content (w / w)) was added under nitrogen protection. The mixture was stirred at 15 °C and hydrogen (1 atm) for 16 hours. The reaction solution was filtered to remove the solid catalyst, and the organic phase was evaporated to dryness to give the crude product (2.6 g, yield: 96%).

[0199] 1H NMR(400MHz, CDCl3)δ7.18(d,J=8.3Hz,2H),6.71(d,J=8.0Hz,2H),4.36–4.25(m,1H),4 .10–3.79(m,5H),3.71–3.56(m,1H),3.12–2.95(m,1H),2.95–2.72(m,1H),1.47(s,9H).

[0200] MS m / z(ESI): 279.1 [M+H] + .

[0201] Step 6: Preparation of tert-butyl(S)-2-(4-aminophenyl)morpholine-4-carboxylic acid ester and tert-butyl(R)-2-(4-aminophenyl)morpholine-4-carboxylic acid ester:

[0202]

[0203] The sample was separated by chiral high-performance liquid chromatography (column type: Chiralpak OD, 4.6 x 250 mm, 5 μM; buffer system: ethanol; flow rate F = 0.5 mL / min; temperature T = 35 °C) to obtain the product tert-butyl(S)-2-(4-aminophenyl)morpholine-4-carboxylic acid ester (1 g, 3.59 mmol, yield: 36.92%, ee value: 99.7%; retention time: 6.50 min) and tert-butyl(R)-2-(4-aminophenyl)morpholine-4-carboxylic acid ester (1 g, 3.59 mmol, yield: 36.92%, ee value: 99.7%; retention time: 12.55 min).

[0204] MS m / z(ESI): 279.1 [M+H] + .

[0205] Step 7: Preparation of ethyl 5-ethyl-1H-pyrazole-3-carboxylic acid ester:

[0206]

[0207] Ethyl 2-diazotanoic acid ester (5 g, 43.82 mmol) was dissolved in dimethyl sulfoxide (80 mL), and butyraldehyde (6.32 g, 87.64 mmol) and diethylamine (641 mg, 8.76 mmol) were added. The mixture was reacted at room temperature for 16 hours. Water (240 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL × 2). The organic phases were combined, dried, and concentrated to obtain a crude product. The crude product was purified by rapid silica gel chromatography (elution with petroleum ether: ethyl acetate = 10:1 to 2:3) to give the product ethyl 5-ethyl-1H-pyrazole-3-carboxylic acid ester (5 g, yield: 67.8%).

[0208] MS m / z(ESI): 169.0 [M+H] + .

[0209] Step 8: Preparation of ethyl 4-chloro-5-ethyl-1H-pyrazole-3-carboxylic acid ester

[0210]

[0211] Ethyl 5-ethyl-1H-pyrazole-3-carboxylic acid ester (1 g, 5.95 mmol) was dissolved in chloroform (15 mL), and sulfonyl chloride (1 g, 7.73 mmol) was added at 0 °C, and the reaction was carried out at 60 °C for 4 hours. The reaction was quenched with water (5 mL), the organic phase was separated, dried, concentrated to obtain a crude product, and purified by rapid silica gel chromatography (eluting with petroleum ether:ethyl acetate = 10:1 to 2:3) to give the product ethyl 4-chloro-5-ethyl-1H-pyrazole-3-carboxylic acid ester (1 g, yield: 83%).

[0212] MS m / z(ESI): 202.9 [M+H] + .

[0213] Step 9: Preparation of 4-chloro-5-ethyl-1H-pyrazole-3-carboxylic acid

[0214]

[0215] Ethyl 4-chloro-5-ethyl-1H-pyrazole-3-carboxylic acid ester (0.6 g, 2.96 mmol) was dissolved in tetrahydrofuran (6 mL), and an aqueous solution of lithium hydroxide monohydrate (373 mg, 8.88 mmol) (2 mL) was added. The reaction was carried out at room temperature for 16 hours, the pH was adjusted to 4-5 with 1N hydrochloric acid aqueous solution, and the mixture was extracted with ethyl acetate (10 mL × 2). The combined organic phases were dried and concentrated under reduced pressure to give the product 4-chloro-5-ethyl-1H-pyrazole-3-carboxylic acid (0.35 g, yield: 67.7%).

[0216] MS m / z (ESI): 174.9 [M+H] + .

[0217] Step 10: Preparation of tert-butyl-2-(4-(4-chloro-5-ethyl-1H-pyrazole-3-carbonoxylazolylamino(oxiamino)phenyl)morpholine-4-carboxylic acid ester

[0218]

[0219] The compound product, 4-chloro-5-ethyl-1H-pyrazole-3-carboxylic acid (100 mg, 0.57 mmol), was dissolved in N,N-dimethylformamide (3 mL), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (262 mg, 0.369 mmol), N,N-diisopropylethylamine (90 mg, 0.69 mmol), and tert-butyl-2-(4-aminophenyl)morpholine-4-carboxylic acid ester (158 mg, 0.57 mmol) were added. The mixture was reacted at room temperature for 16 hours. Water (10 mL) was added, and the mixture was extracted with ethyl acetate (10 mL × 2). After the organic phases were combined and dried, the crude product was concentrated under reduced pressure and purified by prep-TLC to obtain the product 2-(4-(4-chloro-5-ethyl-1H-pyrazole-3-carbon oxaloylamino(oxadiamino))phenyl)morpholine-4-carboxylic acid ester (60 mg, yield: 24%).

[0220] MS m / z (ESI): 435.2 [M+H] + .

[0221] Step 11: Preparation of 4-chloro-5-ethyl-N-(4-(morpholin-2-yl)phenyl)-1H-pyrazole-3-carboxamide

[0222]

[0223] 5 mL of 4 M dioxane hydrochloride solution was added to tert-butyl-2-(4-(4-chloro-5-ethyl-1H-pyrazole-3-carbonoxylate amino(oxidamido))phenyl)morpholine-4-carboxylic acid ester (100 mg, 0.23 mmol), and the reaction was carried out at room temperature for 1 hour. The product was concentrated under reduced pressure to give 4-chloro-5-ethyl-N-(4-(morpholin-2-yl)phenyl)-1H-pyrazole-3-carboxamide (47.3 mg, yield: 78.4%).

[0224] MS m / z(ESI): 335.0 [M+H] + .

[0225] 1H NMR (400MHz, DMSO-d6) δ10.15(s,1H),9.25–9.07(m,2H),7.81(d,J=8.4Hz,2H),7.34(d,J=8.4Hz,2H),4.69(d,J=11.2Hz,1H), 4.11(d,J=12.8Hz,1H),3.92–3.84(m,1H),3.41–3.23(m,2H),3.14–2.99(m,3H),2.66(q,J=8.0Hz,2H),1.21(t,J=8.0Hz,3H).

[0226] Example 1-S

[0227] (S)-4-chloro-5-ethyl-N-(4-(morpholin-2-yl)phenyl)-1H-pyrazole-3-carboxamide

[0228] Method 1:

[0229]

[0230] Step 1: Preparation of (S)-2-(4-bromophenyl)morpholine:

[0231]

[0232] 6-(4-bromophenyl)morpholin-3-one (1.37 g, 5.67 mmol) was dissolved in tetrahydrofuran (20 mL) at room temperature, followed by the addition of lithium aluminum hydride (0.43 g, 11.34 mmol). The mixture was heated under reflux for 2 hours, and the reaction was indicated to be complete by LC-MS. After cooling to room temperature, the reaction solution was quenched with sodium sulfate decahydrate, filtered, and the filtrate was evaporated to dryness to obtain the crude product. The crude product was separated by column chromatography to obtain (RS)-2-(4-bromophenyl)morpholin (0.82 g, yield: 60%).

[0233] (RS)-2-(4-bromophenyl)morpholine chiral high-performance liquid chromatography separation:

[0234] Column type: Chiralpak IA, 8 x 32 cm; Buffer system: n-heptane / ethanol (1:11) containing 0.1% diethylamine;

[0235] (S)-2-(4-bromophenyl)morpholine collection time increased from 7.6 min to 9.4 min. Yield: 42.6%, ee value: 97.5%.

[0236] MS m / z(ESI): 242.0, 244.0 [M] + .

[0237] Step 2: Preparation of (S)-4-chloro-5-ethyl-N-(4-(morpholin-2-yl)phenyl)-1H-pyrazole-3-carboxamide:

[0238]

[0239] Using (S)-2-(4-bromophenyl)morpholine as a raw material, (S)-4-chloro-5-ethyl-N-(4-(morpholin-2-yl)phenyl)-1H-pyrazole-3-carboxamide was obtained by referring to steps 5, 6, 7, 11 and 12 of Example 1.

[0240] MS m / z(ESI): 335.0 [M+H] + .

[0241] Method 2:

[0242] Step 1: Preparation of (S)-4-chloro-5-ethyl-N-(4-(morpholin-2-yl)phenyl)-1H-pyrazole-3-carboxamide:

[0243]

[0244] Using tert-butyl(S)-2-(4-aminophenyl)morpholine-4-carboxylic acid ester as raw material, (S)-4-chloro-5-ethyl-N-(4-(morpholin-2-yl)phenyl)-1H-pyrazole-3-carboxamide was obtained by referring to steps 10 and 11 of method 2 in Example 1.

[0245] MS m / z (ESI): 335.1 [M+H] + .

[0246] Example 1-R

[0247] (R)-4-chloro-5-ethyl-N-(4-(morpholin-2-yl)phenyl)-1H-pyrazole-3-carboxamide

[0248] Method 1:

[0249]

[0250] Step 1: Preparation of (R)-2-(4-bromophenyl)morpholine:

[0251]

[0252] 6-(4-bromophenyl)morpholin-3-one (1.37 g, 5.67 mmol) was dissolved in tetrahydrofuran (20 mL) at room temperature, followed by the addition of lithium aluminum hydride (0.43 g, 11.34 mmol). The mixture was heated under reflux for 2 hours, and the reaction was indicated to be complete by LC-MS. After cooling to room temperature, the reaction solution was quenched with sodium sulfate decahydrate, filtered, and the filtrate was evaporated to dryness to obtain the crude product. The crude product was separated by column chromatography to obtain (RS)-2-(4-bromophenyl)morpholin (0.82 g, yield: 60%).

[0253] (RS)-2-(4-bromophenyl)morpholine chiral high-performance liquid chromatography separation:

[0254] Column type: Chiralpak IA, 8 x 32 cm; Buffer system: n-heptane / ethanol (1:11) containing 0.1% diethylamine;

[0255] The collection time for (R)-2-(4-bromophenyl)morpholine increased from 9.8 min to 13.9 min. Yield: 43.7%, ee value: 97.5%.

[0256] MS m / z(ESI): 242.0, 244.0 [M] + .

[0257] Step 2: Preparation of (R)-4-chloro-5-ethyl-N-(4-(morpholin-2-yl)phenyl)-1H-pyrazole-3-carboxamide:

[0258]

[0259] Using (R)-2-(4-bromophenyl)morpholine as a raw material, (R)-4-chloro-5-ethyl-N-(4-(morpholin-2-yl)phenyl)-1H-pyrazole-3-carboxamide was obtained by referring to steps 5, 6, 7, 11 and 12 of Example 1.

[0260] MS m / z(ESI): 335.0 [M+H] + .

[0261] Method 2:

[0262] Step 1: Preparation of (R)-4-chloro-5-ethyl-N-(4-(morpholin-2-yl)phenyl)-1H-pyrazole-3-carboxamide:

[0263]

[0264] Using tert-butyl(R)-2-(4-aminophenyl)morpholine-4-carboxylic acid ester as a raw material, (R)-4-chloro-5-ethyl-N-(4-(morpholin-2-yl)phenyl)-1H-pyrazole-3-carboxamide was obtained by referring to steps 10 and 11 of method 2 in Example 1.

[0265] MS m / z (ESI): 335.1 [M+H] + .

[0266] Example 2

[0267] 5-Ethyl-4-fluoro-N-(4-(morpholin-2-yl)phenyl)-1H-pyrazole-3-carboxamide

[0268]

[0269] Step 1: Preparation of ethyl 4-fluoro-5-ethyl-1H-pyrazole-3-carboxylic acid ester

[0270]

[0271] Ethyl 5-ethyl-1H-pyrazole-3-carboxylic acid ester (300 mg, 5.95 mmol) was dissolved in acetonitrile (10 mL), and a selective fluorine reagent (122 mg, 2.14 mmol) was added. The mixture was reacted at 65 °C for 18 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure to obtain a crude product, which was purified by rapid silica gel chromatography (eluting with petroleum ether:ethyl acetate = 10:1 to 4:1) to give the product ethyl 4-fluoro-5-ethyl-1H-pyrazole-3-carboxylic acid ester (0.33 g, yield: 74.9%).

[0272] MS m / z(ESI): 187.0 [M+H] + .

[0273] Step 2: Preparation of 5-ethyl-4-fluoro-N-(4-(morpholin-2-yl)phenyl)-1H-pyrazole-3-carboxamide:

[0274]

[0275] The synthesis method is described in steps 10 to 12 of Example 1.

[0276] MS m / z (ESI): 319.2 [M+H] + .

[0277] 1H NMR (400MHz, DMSO-d6) δ10.09(s,1H),9.52–9.36(m,2H),7.80(d,J=8.4Hz,2H),7.34(d,J=8.4Hz,2H),4.72(d,J=10.8Hz,1H),4.10(dd,J= 12.6,3.6Hz,1H),3.95–3.87(m,1H),3.52–3.49(m,1H),3.27–3.22(m,1H),3.12–2.95(m,3H),2.65(q,J=7.6Hz,2H),1.22(t,J=7.6Hz,3H).

[0278] Example 3

[0279] 5-Cyclopropyl-4-methyl-N-(4-(morpholin-2-yl)phenyl)-1H-pyrazole-3-carboxamide

[0280]

[0281] Step 1: Preparation of ethyl 4-cyclopropyl-3-methyl-2,4-dicarbonylbutyrate

[0282]

[0283] 1-Cyclopropylpropane-1-one 1 (1 g, 20.38 mmol) was dissolved in tetrahydrofuran (10 mL), and 1M bis(trimethylsilylamino)lithium (11.2 mL) was added dropwise at -78 °C. After the addition was complete, the reaction was continued at -78 °C for 1 hour. Diethyl oxalate (1.8 g, 12.23 mmol) was added dropwise to the reaction solution, and the reaction was carried out at room temperature for 24 hours. The reaction was quenched by adding 1M hydrochloric acid aqueous solution (10 mL), and extracted with dichloromethane (10 mL × 2). The organic phases were combined, dried, and concentrated under reduced pressure to give the product ethyl 4-cyclopropyl-3-methyl-2,4-dicarbonylbutyrate (1.8 g, yield: 89.1%).

[0284] MS m / z (ESI): 199.2 [M+H] + .

[0285] Step 2: Preparation of ethyl 4-cyclopropyl-3-methyl-2,4-dicarbonylbutyrate

[0286]

[0287] Ethyl 4-cyclopropyl-3-methyl-2,4-dicarbonylbutyrate (1 g, 5.04 mmol) was dissolved in ethanol (10 mL), and 80% hydrazine hydrate (202 mg, 5.04 mmol) was added. The mixture was reacted at 70 °C for 1 hour. After filtration, the filtrate was concentrated under reduced pressure to obtain the crude product, which was dissolved in diethyl ether (10 mL) and 2 M diethyl ether hydrochloride solution (5 mL). After stirring at room temperature for 2 hours, the mixture was filtered and the solid was dried to give the product ethyl 4-cyclopropyl-3-methyl-2,4-dicarbonylbutyrate (550 mg, yield: 56.1%).

[0288] MS m / z (ESI): 195.1 [M+H] + .

[0289] Step 3: Preparation of 5-cyclopropyl-4-methyl-N-(4-(morpholin-2-yl)phenyl)-1H-pyrazole-3-carboxamide:

[0290]

[0291] The synthesis method is described in steps 10 to 12 of Example 1.

[0292] MS m / z (ESI): 327.1 [M+H] + .

[0293] Example 4

[0294] 4-Cyclopropyl-5-ethyl-N-(4-(morpholin-2-yl)phenyl)-1H-pyrazole-3-carboxamide

[0295]

[0296] Step 1: Preparation of ethyl 4-cyclopropyl-5-ethyl-1H-pyrazole-3-carboxylic acid ester

[0297]

[0298] Ethyl 2-diazotanoic acid ester (1 g, 8.76 mmol) was dissolved in dimethyl sulfoxide (10 mL), and cyclopropyl propyl ketone (1.18 g, 10.52 mmol) and pyrrolidine (125 mg, 1.75 mmol) were added. After reacting at room temperature for 16 hours, water (15 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL × 2). The combined organic phases were dried, concentrated to obtain a crude product, and purified by rapid silica gel chromatography (elution with petroleum ether:ethyl acetate = 10:1 to 4:1) to give the product ethyl 4-cyclopropyl-5-ethyl-1H-pyrazole-3-carboxylic acid ester (0.5 g, yield: 27.4%).

[0299] MS m / z(ESI): 209.2 [M+H] + .

[0300] Step 2: Preparation of 4-cyclopropyl-5-ethyl-N-(4-(morpholin-2-yl)phenyl)-1H-pyrazole-3-carboxamide

[0301]

[0302] The synthesis method is described in steps 10 to 12 of Example 1.

[0303] MS m / z (ESI): 341.2 [M+H] + .

[0304] 1 H NMR (400MHz, DMSO-d6) δ9.91 (s, 1H), 9.62–9.40 (m, 2H), 7.80 (d, J = 8.6Hz, 2H), 7.32 (d,J=8.6Hz,2H),4.73(d,J=10.8Hz,1H),4.10(dd,J=12.4,3.6Hz,1H),3.95–3.89( m,1H),3.40–3.34(m,1H),3.26–3.22(m,1H),3.12–2.96(m,3H),2.65(q,J=7.6Hz,2 H),1.88–1.79(m,1H),1.20(t,J=7.6Hz,3H),0.84–0.76(m,2H),0.58–0.50(m,2H).

[0305] Example 5

[0306] N-(4-(morpholino-2-yl)phenyl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxamide

[0307]

[0308] Method 1:

[0309] Step 1: Preparation of N-(4-(morpholin-2-yl)phenyl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxamide

[0310]

[0311] The synthesis steps are as described in steps 10 to 12 of Example 1.

[0312] MS m / z(ESI): 327.2 [M+H] + .

[0313] Method 2:

[0314]

[0315] The synthesis steps are as described in Example 1, Method 2, steps 10 to 11.

[0316] MS m / z (ESI): 327.1 [M+H] + .

[0317] 1 H NMR(400MHz, DMSO-d6)δ10.00(s,1H),9.72–9.49(m,2H),7.89(d,J=8.4Hz,2H),7.37(d,J=8.4Hz,2H),4.79(d,J=8.0Hz,1H)4.18–4.13(m, 1H),4.01–3.98(m,1H),3.45–3.40(m,1H),3.32–3.27(m,1H),3.19–3 .04(m,3H),2.77–2.73(m,2H),2.70–2.67(m,2H),1.85–1.70(m,4H).

[0318] Example (S)-5

[0319] (S)-N-(4-(morpholin-2-yl)phenyl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxamide

[0320]

[0321] The synthesis steps are as described in Example 5, Method 2:

[0322] MS m / z(ESI): 327.0 [M+H] + .

[0323] 1 H NMR (400MHz, DMSO-d6) δ9.94(s,1H),9.67–9.50(m,2H),7.83(d,J=8.4Hz,2H),7.31(d,J=8.4Hz,2H),4.73(d,J=11.0Hz,1H),4.12–4.07(m ,1H),3.97–3.90(m,1H),3.39–3.33(m,1H),3.27–3.21(m,1H),3.14– 2.95(m,3H),2.72–2.66(m,2H),2.65–2.59(m,2H),1.78–1.64(m,4H).

[0324] Example (R)-5

[0325] (R)-N-(4-(morpholin-2-yl)phenyl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxamide

[0326]

[0327] The synthesis steps are as described in Example 5, Method 2:

[0328] MS m / z(ESI): 327.0 [M+H] + .

[0329] 1H NMR (400MHz, DMSO-d6) δ9.94(s,1H),9.64–9.47(m,2H),7.83(d,J=8.4Hz,2H),7.31(d,J=8.4Hz,2H),4.73(d,J=10.4Hz,1H),4.12–4.08(m ,1H),3.96–3.90(m,1H),3.40–3.34(m,1H),3.26–3.20(m,1H),3.14– 2.94(m,3H),2.73–2.65(m,2H),2.65–2.58(m,2H),1.79–1.62(m,4H).

[0330] Example 6

[0331] 3-Ethyl-5-(4-(morpholin-2-yl)phenyl)-4,5-dihydropyrrolo[3,4-c]pyrazol-6(1H)-one

[0332]

[0333] Step 1: Preparation of methyl 4-bromo-5-ethyl-1H-pyrazole-3-carboxylic acid ester

[0334]

[0335] Methyl 5-ethyl-1H-pyrazole-3-carboxylic acid ester (5 g, 32.5 mmol) was dissolved in dichloromethane (50 mL), and N-bromosuccinimide (5.8 g, 32.5 mmol) was added. The reaction was stirred at room temperature for 16 hours, and water (50 mL) was added to the reaction mixture. The mixture was extracted with dichloromethane (50 mL × 2), and the organic phase was dried over anhydrous sodium sulfate. The mixture was filtered, concentrated, and the crude product was purified by column chromatography (petroleum ether: ethyl acetate = 10:1 to 2:1) to give methyl 4-bromo-5-ethyl-1H-pyrazole-3-carboxylic acid ester (5.5 g, yield: 73%).

[0336] MS m / z(ESI):233.2,235.2[M+H] + .

[0337] Step 2: Preparation of methyl 4-bromo-1-(2,4-dimethoxybenzyl)-3-ethyl-1H-pyrazole-5-carboxylic acid ester

[0338]

[0339] Methyl 4-bromo-5-ethyl-1H-pyrazole-3-carboxylic acid ester (5 g, 21.5 mmol) was dissolved in tetrahydrofuran (100 mL), and 2,4-dimethoxybenzaldehyde (3.9 g, 23.6 mmol) and tetraisopropyl titanate (20 mL) were added. The reaction was stirred at 70 °C for 16 hours. After cooling to 0 °C, sodium borohydride (0.98 g, 25.8 mmol) was added, and the reaction was stirred at room temperature for 1 hour. The reaction was quenched with water (100 mL), extracted with ethyl acetate (100 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by column chromatography (petroleum ether:ethyl acetate = 10:1 to 1:1) to give methyl 4-bromo-1-(2,4-dimethoxybenzyl)-3-ethyl-1H-pyrazole-5-carboxylic acid ester (4.0 g, yield: 61%).

[0340] MS m / z(ESI):383.2, 385.2[M+H] + .

[0341] Step 3: Preparation of methyl 4-cyano-1-(2,4-dimethoxybenzyl)-3-ethyl-1H-pyrazole-5-carboxylic acid ester

[0342]

[0343] Methyl 4-bromo-1-(2,4-dimethoxybenzyl)-3-ethyl-1H-pyrazole-5-carboxylic acid ester (1 g, 2.6 mmol) was dissolved in N,N-dimethylformamide (10 mL), and cuprous cyanide (2.3 g, 26 mmol) was added. The reaction was stirred at 100 °C for 16 hours. Water (30 mL) was added, and the mixture was extracted with ethyl acetate (30 mL × 2). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by column chromatography (petroleum ether:ethyl acetate = 10:1 to 1:1) to give methyl 4-cyano-1-(2,4-dimethoxybenzyl)-3-ethyl-1H-pyrazole-5-carboxylic acid ester (0.4 g, yield: 47%).

[0344] MS m / z (ESI): 330.2 [M+H] + .

[0345] Step 4: Preparation of methyl 4-(aminomethyl)-1-(2,4-dimethoxybenzyl)-3-ethyl-1H-pyrazole-5-carboxylic acid ester

[0346]

[0347] Methyl 4-cyano-1-(2,4-dimethoxybenzyl)-3-ethyl-1H-pyrazole-5-carboxylic acid ester (0.4 g, 1.2 mmol) was dissolved in methanol (10 mL), and Raney-Ni (0.4 g) was added to replace the hydrogen gas (×3). The reaction was stirred at 50 °C for 16 hours. The reaction solution was filtered and concentrated to give methyl 4-(aminomethyl)-1-(2,4-dimethoxybenzyl)-3-ethyl-1H-pyrazole-5-carboxylic acid ester (0.4 g, yield: 100%).

[0348] MS m / z(ESI): 334.2 [M+H] + .

[0349] Step 5: Preparation of 1-(2,4-dimethoxybenzyl)-3-ethyl-4,5-dihydropyrrolo[3,4-c]pyrazole-6(1H)-one

[0350]

[0351] Methyl 4-(aminomethyl)-1-(2,4-dimethoxybenzyl)-3-ethyl-1H-pyrazole-5-carboxylic acid ester (0.4 g, 1.2 mmol) was dissolved in ethylene glycol dimethyl ether (10 mL) and water (10 mL), and potassium carbonate (0.33 g, 2.4 mmol) was added, purging with nitrogen (×3). The reaction was stirred at room temperature for 48 hours. The reaction solution was filtered, and the crude product was purified by column chromatography (petroleum ether: ethyl acetate = 10:1 to 1:3) to give 1-(2,4-dimethoxybenzyl)-3-ethyl-4,5-dihydropyrrolo[3,4-c]pyrazole-6(1H)-one (0.15 g, yield: 42%).

[0352] MS m / z (ESI): 302.2 [M+H] + .

[0353] Step 6: Preparation of tert-butyl 2-(4-(1-(2,4-dimethoxybenzyl)-3-ethyl-6-carbonyl-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-yl)phenyl)morpholine-4-carboxylic acid ester

[0354]

[0355] 1-(2,4-Dimethoxybenzyl)-3-ethyl-4,5-dihydropyrrolo[3,4-c]pyrazole-6(1H)-one (0.1 g, 0.3 mmol), tert-butyl-2-(4-bromophenyl)morpholine-4-carboxylic acid ester (0.11 g, 0.33 mmol), cuprous iodide (12 mg, 0.06 mmol), cesium carbonate (0.29 g, 0.9 mmol), and N,N'-dimethylethylenediamine (16 mg, 0.18 mmol) were dissolved in N,N-dimethylformamide (10 mL), and nitrogen gas was purged (×3). The reaction was stirred at 140 °C for 18 hours. Water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 2). The organic phase was dried with anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by column chromatography (petroleum ether: ethyl acetate = 10:1 to 1:3) to obtain tert-butyl 2-(4-(1-(2,4-dimethoxybenzyl)-3-ethyl-6-carbonyl-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-yl)phenyl)morpholine-4-carboxylic acid ester (70 mg, yield: 48%).

[0356] MS m / z (ESI): 564.2 [M+H] + .

[0357] Step 7: Preparation of 3-ethyl-5-(4-(morpholin-2-yl)phenyl)-4,5-dihydropyrrolo[3,4-c]pyrazol-6(1H)-one

[0358]

[0359] 70 mg (0.12 mmol) of tert-butyl-2-(4-(1-(2,4-dimethoxybenzyl)-3-ethyl-6-carbonyl-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-yl)phenyl)morpholine-4-carboxylic acid ester was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (3 mL) was added. The reaction was stirred at room temperature for 2 hours. Water (10 mL) was added, and the pH was adjusted to approximately 14 with 4M sodium hydroxide solution. The mixture was extracted with ethyl acetate (20 mL × 2). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by high performance liquid chromatography to give 3-ethyl-5-(4-(morpholino-2-yl)phenyl)-4,5-dihydropyrrolo[3,4-c]pyrazol-6(1H)-one (15 mg, yield: 38%).

[0360] MS m / z (ESI): 313.2 [M+H] + .

[0361] Example 7

[0362] 3-Ethyl-6-(4-(morpholin-2-yl)phenyl)-2,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one

[0363]

[0364] Step 1: Preparation of methyl(E)-4-(2-((tert-butoxycarbonyl)amino)vinyl)-1-(2,4-dimethoxybenzyl)-3-ethyl-1H-pyrazole-5-carboxylic acid ester

[0365]

[0366] Methyl 4-bromo-1-(2,4-dimethoxybenzyl)-3-ethyl-1H-pyrazole-5-carboxylic acid ester (1 g, 2.6 mmol) was dissolved in N,N-dimethylformamide (10 mL), and tert-butylvinylcarbamate (0.37 g, 2.6 mmol), sodium acetate (0.64 g, 7.8 mmol), and bis(triphenylphosphine)palladium chloride (0.18 g, 0.26 mmol) were added. Nitrogen gas was purged (×3), and the reaction was stirred at 110 °C for 16 hours. Water (50 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (50 mL × 2). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by column chromatography (petroleum ether: ethyl acetate = 10:1 to 1:2) to give methyl(E)-4-(2-((tert-butoxycarbonyl)amino)vinyl)-1-(2,4-dimethoxybenzyl)-3-ethyl-1H-pyrazole-5-carboxylic acid ester (1 g, yield: 86%).

[0367] MS m / z (ESI): 446.2 [M+H] + .

[0368] Step 2: Preparation of methyl 4-(2-((tert-butoxycarbonyl)amino)ethyl)-1-(2,4-dimethoxybenzyl)-3-ethyl-1H-pyrazole-5-carboxylic acid ester

[0369]

[0370] Methyl(E)-4-(2-((tert-butoxycarbonyl)amino)vinyl)-1-(2,4-dimethoxybenzyl)-3-ethyl-1H-pyrazole-5-carboxylic acid ester (1 g, 2.2 mmol) was dissolved in methanol (10 mL), and 10% palladium on carbon (0.5 g) was added to replace the hydrogen gas (×3). The reaction was stirred at room temperature for 16 hours. The reaction solution was filtered through diatomaceous earth, and the filter cake was washed with ethyl acetate (20 mL × 2). The filtrate was concentrated to give methyl 4-(2-((tert-butoxycarbonyl)amino)ethyl)-1-(2,4-dimethoxybenzyl)-3-ethyl-1H-pyrazole-5-carboxylic acid ester (1 g, yield: 100%).

[0371] MS m / z (ESI): 448.2 [M+H] + .

[0372] Step 3: Preparation of methyl 4-(2-aminoethyl)-1-(2,4-dimethoxybenzyl)-3-ethyl-1H-pyrazole-5-carboxylic acid ester

[0373]

[0374] Methyl 4-(2-((tert-butoxycarbonyl)amino)ethyl)-1-(2,4-dimethoxybenzyl)-3-ethyl-1H-pyrazole-5-carboxylic acid ester (1 g, 2.2 mmol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (3 mL) was added. The reaction was stirred at room temperature for 2 hours. The solvent was evaporated to dryness, and water (10 mL) was added. The pH of the aqueous phase was adjusted to approximately 14 with 4 M NaOH solution. The aqueous phase was extracted with ethyl acetate (20 mL × 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give methyl 4-(2-aminoethyl)-1-(2,4-dimethoxybenzyl)-3-ethyl-1H-pyrazole-5-carboxylic acid ester (0.5 g, yield: 64%).

[0375] MS m / z (ESI): 348.2 [M+H] + .

[0376] Step 4: Preparation of 1-(2,4-dimethoxybenzyl)-3-ethyl-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one

[0377]

[0378] Referring to step 5 of Example 6, 1-(2,4-dimethoxybenzyl)-3-ethyl-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one was obtained.

[0379] MS m / z (ESI): 316.2 [M+H] + .

[0380] Step 5: Preparation of tert-butyl 2-(4-(1-(2,4-dimethoxybenzyl)-3-ethyl-7-carbonyl-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)phenyl)morpholine-4-carboxylic acid ester

[0381]

[0382] Referring to step 6 of Example 6, tert-butyl 2-(4-(1-(2,4-dimethoxybenzyl)-3-ethyl-7-carbonyl-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)phenyl)morpholine-4-carboxylic acid ester was obtained.

[0383] MS m / z (ESI): 577.2 [M+H] + .

[0384] Step 6: Preparation of 3-ethyl-6-(4-(morpholin-2-yl)phenyl)-2,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one

[0385]

[0386] Referring to step 7 of Example 6, 3-ethyl-6-(4-(morpholin-2-yl)phenyl)-2,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one was obtained.

[0387] MS m / z(ESI): 327.2 [M+H] + .

[0388] Example 8

[0389] 5-Ethyl-4-methyl-N-(4-(1,2,5,6-tetrahydropyridin-3-yl)phenyl)-1H-pyrazole-3-carboxamide

[0390] Step 1: Preparation of tert-butyl-5-(4-aminophenyl)-3,6-dihydropyridine-1(2H)-carboxylic acid ester

[0391]

[0392] 4-Bromoaniline (0.5 g, 2.91 mmol) was dissolved in 1,4-dioxane (10 mL) and water (1 mL), and 1-tert-butoxycarbonyl-3,6-dihydro-2H-pyridine-5-boronic acid pinacol ester (988 mg, 3.2 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloromethane dichloride complex (237 mg, 0.29 mmol) and cesium carbonate (2.84 g, 8.72 mmol) were added. After purging with nitrogen, the mixture was reacted at 100 °C for 3 hours. After the reaction was cooled to room temperature, the mixture was filtered and extracted with ethyl acetate (10 mL × 2). The organic phases were combined, dried, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid silica gel chromatography (elution with petroleum ether: ethyl acetate = 10:1 to 5:1) to give the product tert-butyl 5-(4-aminophenyl)-3,6-dihydropyridine-1(2H)-carboxylic acid ester (550 mg, yield: 69%).

[0393] MS m / z(ESI): 275.2 [M+H] + .

[0394] Step 2: Preparation of 5-ethyl-4-methyl-N-(4-(1,2,5,6-tetrahydropyridin-3-yl)phenyl)-1H-pyrazole-3-carboxamide

[0395]

[0396] The synthesis steps are as described in steps 11 to 12 of Example 1.

[0397] MS m / z(ESI): 311.2 [M+H] + .

[0398] Example 9

[0399] N-(4-(1,4-oxaprotenyl-2-yl)phenyl)-5-ethyl-4-methyl-1H-pyrazole-3-carboxamide

[0400]

[0401] Method 1:

[0402]

[0403] Step 1: Preparation of 2-(2-(4-nitrophenyl)-2-carbonylethyl)isodihydroindole-1,3-dione

[0404]

[0405] 2-Bromo-1-(4-nitrophenyl)ethane-1-one (1 g, 4.1 mmol) was dissolved in N,N-dimethylformamide (10 mL), and isodihydroindole-1,3-dione (0.6 g, 4.1 mmol) and potassium carbonate (1.7 g, 12.3 mmol) were added. The reaction mixture was stirred at 100 °C for 16 hours. Water (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL × 2). The organic phase was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by column chromatography (petroleum ether: ethyl acetate = 10:1 to 1:1) to give 2-(2-(4-nitrophenyl)-2-carbonylethyl)isodihydroindole-1,3-dione (0.8 g, yield: 63%).

[0406] MS m / z(ESI): 311.2 [M+H] +

[0407] Step 2: Preparation of 2-(2-hydroxy-2-(4-nitrophenyl)ethyl)isodihydroindole-1,3-dione

[0408]

[0409] 2-(2-(4-nitrophenyl)-2-carbonylethyl)isodihydroindole-1,3-dione (0.8 g, 2.6 mmol) was dissolved in methanol (10 mL), acetic acid (0.1 mL) was added, and sodium cyanoboride (0.5 g, 7.8 mmol) was added at 0 °C. The reaction mixture was stirred at room temperature for 16 hours. Water (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL × 2). The organic phase was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give 2-(2-hydroxy-2-(4-nitrophenyl)ethyl)isodihydroindole-1,3-dione (0.7 g, yield: 88%).

[0410] MS m / z (ESI): 313.2 [M+H] + .

[0411] Step 3: Preparation of 2-amino-1-(4-nitrophenyl)ethane-1-ol

[0412]

[0413] 2-(2-hydroxy-2-(4-nitrophenyl)ethyl)isodihydroindole-1,3-dione (0.7 g, 2.2 mmol) was dissolved in water (10 mL), and 85% hydrazine hydrate (0.16 g, 2.6 mmol) was added. The reaction was stirred at 60 °C for 3 hours. After cooling to room temperature, the mixture was extracted with dichloromethane (20 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give 2-amino-1-(4-nitrophenyl)ethane-1-ol (0.2 g, yield: 48%).

[0414] MS m / z (ESI): 183.1 [M+H] + .

[0415] Step 4: Preparation of 2-(4-nitrophenyl)-1,4-oxacloheptan-5-one

[0416]

[0417] 2-Amino-1-(4-nitrophenyl)ethane-1-ol (0.2 g, 1.1 mmol) was dissolved in dichloromethane (5 mL), cooled to 0 °C, and triethylamine (0.25 g, 2.5 mmol) and 3-chloropropionyl chloride (0.16 g, 1.3 mmol) were added. The reaction mixture was stirred at 0 °C for 1 hour. The reaction mixture was poured into 1M HCl aqueous solution (10 mL) and extracted with ethyl acetate (10 mL × 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was dissolved in isopropanol (10 mL), and potassium hydroxide (0.19 g, 3.3 mmol) was added at room temperature. The reaction mixture was stirred at room temperature for 18 hours. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL × 2). The mixture was dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by column chromatography (petroleum ether: ethyl acetate = 10:1 to 1:1) to give 2-(4-nitrophenyl)-1,4-oxaconitane-5-one (0.1 g, yield: 38%).

[0418] MS m / z(ESI): 237.1 [M+H] +

[0419] Step 5: Preparation of 2-(4-nitrophenyl)-1,4-oxacloheptan

[0420]

[0421] 2-(4-nitrophenyl)-1,4-oxachatane-5-one (0.1 g, 0.4 mmol) was dissolved in tetrahydrofuran (5 mL), purged with nitrogen (×3), cooled to 0 °C, and borane / tetrahydrofuran (2 mL, 2 mmol) was added. The reaction was stirred at room temperature for 2 hours. The reaction was quenched with methanol (2 mL), the solvent was evaporated to dryness, and the crude product was purified by column chromatography (petroleum ether: ethyl acetate = 10:1 to 1:1) to give 2-(4-nitrophenyl)-1,4-oxachatane (80 mg, yield: 85%).

[0422] MS m / z(ESI): 223.1 [M+H] +

[0423] Step 6: Preparation of tert-butyl-2-(4-nitrophenyl)-1,4-oxacloheptan-4-carboxylic acid ester

[0424]

[0425] 2-(4-nitrophenyl)-1,4-oxacrylonitrile (80 mg, 0.36 mmol) was dissolved in dichloromethane (5 mL), cooled to 0 °C, and triethylamine (182 mg, 1.8 mmol) and di-tert-butyl dicarbonate (118 mg, 0.54 mmol) were added. The reaction was stirred at room temperature for 2 hours. Water (10 mL) was added, and the mixture was extracted with dichloromethane (10 mL × 2). The extract was dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by column chromatography (petroleum ether: ethyl acetate = 10:1 to 1:1) to give tert-butyl 2-(4-nitrophenyl)-1,4-oxacrylonitrile-4-carboxylic acid ester (100 mg, yield: 86%).

[0426] Step 7: Preparation of tert-butyl-2-(4-aminophenyl)-1,4-oxacloheptan-4-carboxylic acid ester

[0427]

[0428] 100 mg (0.31 mmol) of tert-butyl-2-(4-nitrophenyl)-1,4-oxacrylephalothran-4-carboxylic acid ester was dissolved in tetrahydrofuran (5 mL), and palladium on carbon (100 mg) was added to replace the hydrogen gas (×3). The reaction mixture was stirred at room temperature for 18 hours. The reaction solution was filtered through diatomaceous earth, and the filter cake was washed with ethyl acetate (20 mL × 2). The filtrate was evaporated to dryness to give 90 mg (100%) of tert-butyl-2-(4-aminophenyl)-1,4-oxacrylephalothran-4-carboxylic acid ester.

[0429] MS m / z(ESI): 293.2 [M+H] + .

[0430] Step 8: Preparation of tert-butyl-2-(4-(5-ethyl-4-methyl-1H-pyrazole-3-carbonoxylazolylamino)phenyl)-1,4-oxacloheptan-4-carboxylic acid ester

[0431]

[0432] Referring to step 11 of Example 1, tert-butyl 2-(4-(5-ethyl-4-methyl-1H-pyrazole-3-carbon-oxoylamino)phenyl)-1,4-oxaconitane-4-carboxylic acid ester was obtained.

[0433] MS m / z(ESI): 429.2 [M+H] + .

[0434] Step 9: Preparation of N-(4-(1,4-oxacloheptan-2-yl)phenyl)-5-ethyl-4-methyl-1H-pyrazole-3-carboxamide

[0435]

[0436] Referring to step 12 of Example 1, N-(4-(1,4-oxapron-2-yl)phenyl)-5-ethyl-4-methyl-1H-pyrazole-3-carboxamide was obtained.

[0437] MS m / z(ESI): 329.2 [M+H] + .

[0438] Method 2:

[0439] Step 1: Preparation of 2-(4-nitrophenyl)oxalanine

[0440]

[0441] Using 2-bromo-1-(4-nitrophenyl)ethane-1-one as the raw material, the same as the first step of Example 1.

[0442] Step 2: Preparation of 3-((2-hydroxy-2-(4-nitrophenyl)ethyl)amino)propane-1-ol

[0443]

[0444] Referring to the second step of Example 1, 3-((2-hydroxy-2-(4-nitrophenyl)ethyl)amino)propane-1-ol was obtained.

[0445] MS m / z(ESI): 241.1 [M+H] + .

[0446] Step 3: Preparation of tert-butyl (2-hydroxy-2-(4-nitrophenyl)ethyl)(3-hydroxypropyl)carbamate

[0447]

[0448] Referring to step 3 of Example 1, tert-butyl(2-hydroxy-2-(4-nitrophenyl)ethyl)(3-hydroxypropyl)carbamate was obtained.

[0449] MS m / z(ESI): 341.1 [M+H] + .

[0450] Step 4: Preparation of tert-butyl-2-(4-nitrophenyl)-1,4-oxacloheptan-4-carboxylic acid ester

[0451]

[0452] Referring to step four of Example 1, tert-butyl 2-(4-nitrophenyl)-1,4-oxaconitane-4-carboxylic acid ester was obtained.

[0453] MS m / z(ESI): 323.1 [M+H] +

[0454] Step 5: Preparation of tert-butyl-2-(4-aminophenyl)-1,4-oxacloheptan-4-carboxylic acid ester

[0455]

[0456] Referring to step 5 of Example 1, tert-butyl 2-(4-aminophenyl)-1,4-oxacloheptan-4-carboxylic acid ester was obtained.

[0457] MS m / z(ESI): 293.2 [M+H] + .

[0458] Step 6: Preparation of tert-butyl-2-(4-(5-ethyl-4-methyl-1H-pyrazole-3-carbonoxylazolylamino)phenyl)-1,4-oxacloheptan-4-carboxylic acid ester

[0459]

[0460] Referring to step 10 of Example 1, tert-butyl 2-(4-(5-ethyl-4-methyl-1H-pyrazole-3-carbon oxaloylamino)phenyl)-1,4-oxapron-4-carboxylic acid ester was obtained.

[0461] MS m / z(ESI): 429.2 [M+H] + .

[0462] Step 7: Preparation of N-(4-(1,4-oxacloheptan-2-yl)phenyl)-5-ethyl-4-methyl-1H-pyrazole-3-carboxamide

[0463]

[0464] Referring to step 11 of Example 1, N-(4-(1,4-oxapron-2-yl)phenyl)-5-ethyl-4-methyl-1H-pyrazole-3-carboxamide was obtained.

[0465] MS m / z(ESI): 329.2 [M+H] + .

[0466] Example 10

[0467] N-(4-(1,4-oxaheptan-7-yl)phenyl)-5-ethyl-4-methyl-1H-pyrazole-3-carboxamide

[0468]

[0469]

[0470] Step 1: Preparation of 1-(4-bromophenyl)-3-chloropropane-1-ol

[0471]

[0472] Sodium borohydride (0.77 g, 20 mmol) was dissolved in tetrahydrofuran (30 mL), and nitrogen gas was introduced (×3). The mixture was cooled to 0 °C, and a tetrahydrofuran (20 mL) solution of 1-(4-bromophenyl)-3-chloropropane-1-one (5 g, 20 mmol) was added dropwise. The reaction was stirred at room temperature for 2 hours. Water (50 mL) was added, and the mixture was extracted with ethyl acetate (50 mL × 2). The extract was dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by column chromatography (petroleum ether: ethyl acetate = 10:1 to 2:1) to give 1-(4-bromophenyl)-3-chloropropane-1-ol (5 g, yield: 100%).

[0473] MS m / z(ESI): 249.0, 251.0 [M+H] + .

[0474] Step 2: Preparation of 1-(4-bromophenyl)-3-(((R)-1-phenylethyl)amino)propane-1-ol

[0475]

[0476] 1-(4-bromophenyl)-3-chloropropane-1-ol (5 g, 20 mmol) was dissolved in acetonitrile (50 mL), and 1-(4-bromophenyl)-3-chloropropane-1-one (4.84 g, 40 mmol), potassium iodide (6.6 g, 40 mmol), and potassium carbonate (5.5 g, 40 mmol) were added. The reaction mixture was stirred at 75 °C for 48 hours. After cooling to room temperature, the reaction mixture was filtered, water (50 mL) was added, and the mixture was extracted with ethyl acetate (50 mL × 2). The extract was dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by column chromatography (petroleum ether: ethyl acetate = 10:1 to 1:1) to give 1-(4-bromophenyl)-3-(((R)-1-phenylethyl)amino)propane-1-ol (6 g, yield: 90%).

[0477] MS m / z (ESI): 334.1, 336.1 [M+H] + .

[0478] Step 3: Preparation of 7-(4-bromophenyl)-4-((R)-1-phenylethyl)-1,4-oxaheptan-3-one

[0479]

[0480] 1-(4-bromophenyl)-3-(((R)-1-phenylethyl)amino)propane-1-ol (6 g, 18 mmol) was dissolved in dichloromethane (50 mL), cooled to 0 °C, and then triethylamine (4.5 g, 45 mmol) and 2-chloroacetyl chloride (2.4 g, 22 mmol) were added. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into 1 M HCl aqueous solution (100 mL) and extracted with ethyl acetate (100 mL × 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was dissolved in isopropanol (50 mL), and potassium hydroxide (2 g, 36 mmol) was added at room temperature. The reaction mixture was stirred at room temperature for 18 hours. Water (100 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL × 2). The mixture was dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by column chromatography (petroleum ether: ethyl acetate = 10:1 to 1:1) to obtain 7-(4-bromophenyl)-4-((R)-1-phenylethyl)-1,4-oxaconitane-3-one (2 g, yield: 30%).

[0481] MS m / z (ESI): 374.2, 376.2 [M+H] + .

[0482] Step 4: Preparation of tert-butyl(4-(3-carbonyl-4-((R)-1-phenylethyl)-1,4-oxacloheptan-7-yl)phenyl)carbamate

[0483]

[0484] 7-(4-bromophenyl)-4-((R)-1-phenylethyl)-1,4-oxacloheptan-3-one (1 g, 2.7 mmol) was dissolved in toluene (10 mL), and tert-butylcarbamate (0.38 g, 3.24 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene (0.31 g, 0.54 mmol), cesium carbonate (2.6 g, 8.1 mmol), and bis(diphenylmethyleneacetone)palladium (0.16 g, 0.27 mmol) were added. Nitrogen gas was purged (×3), and the reaction was stirred at 100 °C for 18 hours. The reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (50 mL × 2). The organic phase was dried with anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 10:1 to 1:1) to give tert-butyl(4-(3-carbonyl-4-((R)-1-phenylethyl)-1,4-oxacloheptan-7-yl)phenyl)carbamate (0.7 g, yield: 64%).

[0485] MS m / z(ESI): 411.2 [M+H] + .

[0486] Step 5: Preparation of 7-(4-aminophenyl)-4-((R)-1-phenylethyl)-1,4-oxacloheptan-3-one

[0487]

[0488] 0.7 g (1.7 mmol) of tert-butyl(4-(3-carbonyl-4-((R)-1-phenylethyl)-1,4-oxacrylephalo-7-yl)phenyl)carbamate was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (3 mL) was added. The reaction was stirred at room temperature for 2 hours. The solvent was evaporated to dryness, and water (10 mL) was added. The pH of the aqueous phase was adjusted to approximately 14 with 4 M NaOH solution. The aqueous phase was extracted with ethyl acetate (20 mL × 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give 0.5 g (94% yield) of 7-(4-aminophenyl)-4-((R)-1-phenylethyl)-1,4-oxacrylephalo-3-one.

[0489] MS m / z(ESI): 311.2 [M+H] + .

[0490] Step 6: Preparation of 5-ethyl-4-methyl-N-(4-(3-carbonyl-4-((R)-1-phenylethyl)-1,4-oxacloheptan-7-yl)phenyl)-1H-pyrazole-3-carboxamide

[0491]

[0492] Referring to step 11 of Example 1, 5-ethyl-4-methyl-N-(4-(3-carbonyl-4-((R)-1-phenylethyl)-1,4-oxacloheptan-7-yl)phenyl)-1H-pyrazole-3-carboxamide was obtained.

[0493] MS m / z(ESI): 447.2 [M+H]+

[0494] Step 7: Preparation of N-(4-(1,4-oxacloheptan-7-yl)phenyl)-5-ethyl-4-methyl-1H-pyrazole-3-carboxamide

[0495]

[0496] N-(4-(1,4-oxacroheptan-7-yl)phenyl)-5-ethyl-4-methyl-1H-pyrazole-3-carboxamide (0.2 g, 0.45 mmol) and ethyl chloroformate (0.19 g, 1.35 mmol) were dissolved in 1,2-dichloroethane (5 mL), and the reaction was refluxed and stirred for 4 hours. After cooling to room temperature, N,N-diisopropylethylamine (65 mg, 0.5 mmol) was added, and the reaction was refluxed and stirred for another 4 hours. The solvent was evaporated to dryness, and the crude product was separated by high-performance liquid chromatography to give N-(4-(1,4-oxacroheptan-7-yl)phenyl)-5-ethyl-4-methyl-1H-pyrazole-3-carboxamide (30 mg, yield: 20%).

[0497] MS m / z(ESI): 329.2 [M+H] + .

[0498] Example 11

[0499] 5-Ethyl-4-methyl-N-(4-(2-(methylamino)ethyl)phenyl)-1H-pyrazole-3-carboxamide

[0500]

[0501] Step 1: Preparation of ethyl 5-ethyl-4-methyl-1H-pyrazole-3-carboxylic acid ester

[0502]

[0503] Ethyl 2-diazotanoic acid ester (2 g, 17.5 mmol) was dissolved in dimethyl sulfoxide (35 mL), and pentane-2-one (3 g, 35.1 mmol) and pyrrolidine (125 mg, 1.75 mmol) were added. After reacting at room temperature for 16 hours, water (100 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL × 2). The combined organic phases were dried, concentrated to obtain a crude product, and purified by rapid silica gel chromatography (elution with petroleum ether:ethyl acetate = 10:1 to 4:1) to give the product ethyl 4-cyclopropyl-5-ethyl-1H-pyrazole-3-carboxylic acid ester (1 g, yield: 31.3%).

[0504] MS m / z(ESI): 183.0 [M+H] + .

[0505] Step 2: Preparation of 5-ethyl-4-methyl-1H-pyrazole-3-carboxylic acid

[0506]

[0507] Refer to step 10 of Example 1.

[0508] MS m / z(ESI): 155.0 [M+H] + .

[0509] Step 3: Preparation of tert-butylmethyl (4-nitrophenylethyl) carbamate

[0510]

[0511] N-methyl-2-(4-nitrophenyl)ethane-1-amine (500 mg, 2.77 mmol) was dissolved in dichloromethane (10 mL), and triethylamine (337 mg, 3.33 mmol) and di-tert-butyl dicarbonate (666 mg, 3.05 mmol) were added. The mixture was reacted at room temperature for 16 hours. After concentration under reduced pressure, the product was purified by rapid silica gel chromatography (eluting with petroleum ether:ethyl acetate = 10:1 to 5:1) to give tert-butylmethyl (4-nitrophenylethyl)carbamate (700 mg, yield: 90%).

[0512] Step 4: Preparation of tert-butylmethyl (4-aminophenylethyl) carbamate

[0513]

[0514] 700 mg (2.5 mmol) of tert-butylmethyl (4-nitrophenylethyl) carbamate was dissolved in methanol (5 mL), and 200 mg of 10% palladium on carbon was added. The mixture was reacted under hydrogen atmosphere for 3 hours. After filtration, the product tert-butylmethyl (4-aminophenylethyl) carbamate (550 mg, yield: 88%) was concentrated under reduced pressure.

[0515] MS m / z (ESI): 251.2 [M+H] + .

[0516] Step 5: Preparation of 5-ethyl-4-methyl-N-(4-(2-(methylamino)ethyl)phenyl)-1H-pyrazole-3-carboxamide

[0517]

[0518] The synthesis steps are as described in steps 11 to 12 of Example 1.

[0519] MS m / z(ESI): 287.2 [M+H] + .

[0520] Example 12

[0521] 5-Ethyl-4-methyl-N-(5-(2-(methylamino)ethyl)thiophen-2-yl)-1H-pyrazole-3-carboxamide

[0522]

[0523] Step 1: Preparation of 2-(thiophen-2-yl)ethyl methanesulfonate

[0524]

[0525] 2-(thien-2-yl)ethane-1-ol (1.28 g, 10 mmol) was dissolved in anhydrous dichloromethane (20 mL) at 0 °C, followed by the dropwise addition of triethylamine (2.02 g, 20 mmol) and then methanesulfonyl chloride (1.37 g, 12 mmol). The mixture was stirred at 0 °C for one hour, and the reaction was considered complete by TLC. The reaction solution was diluted with dichloromethane (50 mL), and then washed successively with saturated sodium bicarbonate aqueous solution and saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain crude 2-(thien-2-yl)ethyl methanesulfonate (1.96 g, yield: 95%).

[0526] Step 2: Preparation of N-methyl-2-(thiophen-2-yl)ethane-1-amine

[0527]

[0528] 2-(thiophen-2-yl)ethyl methanesulfonate (1.96 g, 9.5 mmol) was dissolved in ethanol (20 mL) at 0 °C, followed by the addition of methylamine hydrochloride (0.77 g, 11.4 mmol), and then N,N-diisopropylethylamine (2.45 g, 19 mmol). The mixture was heated to reflux for four hours. The reaction was completed by LCMS. After cooling to room temperature, the mixture was evaporated to dryness. The residue was dissolved in ethyl acetate (30 mL), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to give crude N-methyl-2-(thiophen-2-yl)ethane-1-amine (1.07 g, yield: 80%).

[0529] MS m / z (ESI): 142.1 [M+H] + .

[0530] Step 3: Preparation of 2,2,2-trifluoro-N-methyl-N-(2-(thiophen-2-yl)ethyl)acetamide

[0531]

[0532] At 0 °C, N-methyl-2-(thiophen-2-yl)ethane-1-amine (1.07 g, 7.6 mmol) was dissolved in dichloromethane (15 mL), followed by the addition of triethylamine (1.54 g, 15.2 mmol), and then the slow addition of trifluoromethanesulfonic anhydride (1.60 g, 7.6 mmol) while stirring for one hour. The reaction was indicated by LCMS to be complete. The reaction solution was diluted with dichloromethane (20 mL), and then washed successively with saturated sodium bicarbonate solution and saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to give 2,2,2-trifluoro-N-methyl-N-(2-(thiophen-2-yl)ethyl)acetamide (1.44 g, yield: 80%).

[0533] MS m / z(ESI): 238.0 [M+H] + .

[0534] Step 4: Preparation of 2,2,2-trifluoro-N-methyl-N-(2-(5-nitrothiophen-2-yl)ethyl)acetamide

[0535]

[0536] 2,2,2-trifluoro-N-methyl-N-(2-(5-nitrothiophen-2-yl)ethyl)acetamide (1.44 g, 6.08 mmol) was dissolved in acetic acid (10 mL) at -20 °C, and then 4 mL of acetic acid solution containing fuming nitric acid (0.6 mL) was added dropwise. The reaction was allowed to proceed for one hour, and the reaction was indicated to be complete by LCMS. The reaction solution was then poured into ice water, and the pH was adjusted to 6 with sodium hydroxide aqueous solution (10 M). The solution was then extracted with ethyl acetate, and the organic phases were combined. The organic phases were washed successively with saturated sodium bicarbonate aqueous solution and saturated brine. The organic phases were dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was separated by silica gel column chromatography to obtain 2,2,2-trifluoro-N-methyl-N-(2-(5-nitrothiophen-2-yl)ethyl)acetamide (1.03 g, yield: 60%).

[0537] MS m / z(ESI): 283.1 [M+H] + .

[0538] Step 5: Preparation of N-(2-(5-aminothiophene-2-yl)ethyl)-2,2,2-trifluoro-N-methylacetamide

[0539]

[0540] At room temperature, 1.03 g (3.65 mmol) of 2,2,2-trifluoro-N-methyl-N-(2-(5-nitrothiophen-2-yl)ethyl)acetamide was dissolved in 15 mL of ethanol, followed by 5 mL of saturated ammonium chloride aqueous solution, and then 2.04 g (36.5 mmol) of iron powder. The mixture was heated under reflux for 3 hours, and the reaction was stopped by LCMS. After cooling to room temperature, the ethanol was removed by rotary evaporation, and the residue was dissolved in 20 mL of ethyl acetate. The organic phase was washed successively with saturated sodium bicarbonate aqueous solution and saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to give crude N-(2-(5-aminothiophen-2-yl)ethyl)-2,2,2-trifluoro-N-methylacetamide (0.78 g, yield: 85%).

[0541] MS m / z (ESI): 253.1 [M+H] + .

[0542] Step 6: Preparation of 5-ethyl-4-methyl-N-(5-(2-(2,2,2-trifluoro-N-methylacetamido)ethyl)thiophene-2-yl)-1H-pyrazole-3-carboxamide

[0543]

[0544] At 0 °C, N-(2-(5-aminothiophene-2-yl)ethyl)-2,2,2-trifluoro-N-methylacetamide (0.78 g, 3.10 mol) was dissolved in dichloromethane (10 mL), followed by the addition of N,N-diisopropylethylamine (0.80 g, 6.20 mmol), 5-ethyl-4-methyl-1H-pyrazole-3-carboxylic acid (0.57 g, 3.72 mmol), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (1.41 g, 3.72 mmol). The reaction was allowed to proceed for 16 hours at room temperature. The reaction was considered complete by LCMS, and water (20 mL) was added. The reaction mixture was extracted with ethyl acetate (20 mL × 2). After the organic phases were combined and dried, the crude product was concentrated under reduced pressure. The crude product was separated by silica gel column chromatography to obtain 5-ethyl-4-methyl-N-(5-(2-(2,2,2-trifluoro-N-methylacetamido)ethyl)thiophene-2-yl)-1H-pyrazole-3-carboxamide (0.78 g, yield: 65%).

[0545] MS m / z (ESI): 389.1 [M+H] + .

[0546] Step 7: Preparation of 5-ethyl-4-methyl-N-(5-(2-(2,2,2-trifluoro-N-methylacetamido)ethyl)thiophene-2-yl)-1H-pyrazole-3-carboxamide

[0547]

[0548] At room temperature, 0.20 g (0.51 mmol) of 5-ethyl-4-methyl-N-(5-(2-(2,2,2-trifluoro-N-methylacetamido)ethyl)thiophene-2-yl)-1H-pyrazole-3-carboxamide was dissolved in acetonitrile (5 mL), followed by the addition of 2 mL of an aqueous solution of sodium hydroxide (0.082 g, 2.04 mmol). The mixture was heated to 50 °C and reacted overnight. The reaction was complete as indicated by LC-MS. After cooling to room temperature, the pH of the reaction solution was adjusted to 6-7 with dilute hydrochloric acid. The reaction solution was extracted with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The residue was separated by preparative high-performance liquid chromatography (HPLC). The final product (100 mg, yield: 66%) was obtained by lyophilization.

[0549] MS m / z(ESI): 293.1 [M+H] + .

[0550] Example 13

[0551] 5-Ethyl-N-(5-(1-methoxy-2-(methylamino)ethyl)thiophen-2-yl)-4-methyl-1H-pyrazole-3-carboxamide

[0552]

[0553] Step 1: Preparation of 2-(5-nitrothiophene-2-yl)oxalopropyl ring:

[0554]

[0555] Under nitrogen protection and at 0°C, sodium hydrogen sulfide (0.76 g, 19 mmol, 60% w / w) was dissolved in anhydrous tetrahydrofuran (15 mL) and dimethyl sulfoxide (15 mL), followed by the slow dropwise addition of a solution of trimethylsulfonium iodide (3.12 g, 15 mmol) in dimethyl sulfoxide (4 mL). The mixture was stirred for 5 minutes under nitrogen protection and at 0°C, followed by the addition of 5-nitrothiophene-2-carboxaldehyde (2 g, 12.7 mmol) in a single batch. The reaction mixture was slowly brought to room temperature and stirred overnight. The reaction mixture was cooled, quenched with ice water, extracted with dichloromethane (30 mL × 3), and the organic phases were combined, washed successively with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography (elution with petroleum ether: ethyl acetate = 100:0 to 80:20) to give the target product 2-(5-nitrothiophene-2-yl)oxalopropylcyclohexane (1.7 g, yield: 78%).

[0556] Step 2: Preparation of 2-(methylamino)-1-(5-nitrothiophene-2-yl)ethane-1-ol:

[0557]

[0558] 2-(5-nitrothiophen-2-yl)oxalopropylcyclohexane (1.7 g, 10 mmol) was added to a methanol solution of methylamine (3 M, 40 mL). The reaction solution was stirred at room temperature for 72 hours. The reaction solution was then evaporated to dryness to obtain crude 2-(methylamino)-1-(5-nitrothiophen-2-yl)ethane-1-ol (2 g), which was used directly in the next step.

[0559] MS m / z(ESI): 203.0 [M+H] + .

[0560] Step 3: Preparation of tert-butyl (2-hydroxy-2-(5-nitrothiophen-2-yl)ethyl)(methyl)carbamate:

[0561]

[0562] Under nitrogen protection and at 0°C, di-tert-butyl dicarbonate (2.6 g, 11.9 mmol) was slowly added dropwise to 2-(methylamino)-1-(5-nitrothiophen-2-yl)ethane-1-ol (2 g, 10 mmol) and triethylamine (2.5 g, 24.7 mmol) in dichloromethane (40 mL). The reaction mixture was stirred at 0°C for 1 hour. The reaction mixture was quenched with saturated brine (50 mL), the organic phase was separated, and the mixture was washed successively with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography (petroleum ether: ethyl acetate = 100:0 to 50:50 elution) to give the target product tert-butyl(2-hydroxy-2-(5-nitrothiophen-2-yl)ethyl)(methyl)carbamate (1.4 g, yield: 47%).

[0563] MS m / z(ESI): 303.0 [M+H] + .

[0564] Step 4: Preparation of tert-butyl (2-methoxy-2-(5-nitrothiophen-2-yl)ethyl)(methyl)carbamate:

[0565]

[0566] Iodomethane (1.3 g, 9.3 mmol) was added to a solution of tert-butyl(2-hydroxy-2-(5-nitrothiophen-2-yl)ethyl)(methyl)carbamate (1.4 g, 4.6 mmol) and potassium carbonate (1.9 g, 13.9 mmol) in acetonitrile (40 mL). The mixture was heated to 60 °C for 3 hours under nitrogen. The reaction solution was then evaporated to dryness. The crude product was dissolved in dichloromethane (90 mL), washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography (elution with petroleum ether:ethyl acetate = 100:0 to 80:20) to give the target product tert-butyl(2-methoxy-2-(5-nitrothiophen-2-yl)ethyl)(methyl)carbamate (1.2 g, yield: 82%).

[0567] MS m / z (ESI): 317.1 [M+H] + .

[0568] Step 5: Preparation of tert-butyl (2-(5-aminothiophen-2-yl)-2-methoxyethyl)(methyl)carbamate:

[0569]

[0570] 1.2 g (3.8 mmol) of tert-butyl(2-methoxy-2-(5-nitrothiophen-2-yl)ethyl)(methyl)carbamate was dissolved in methanol (30 mL). Under nitrogen protection, 1.5 g (10% palladium, 50% w / w water) of 10% palladium catalyst on carbon was added. The mixture was reacted under hydrogen (1 atm) for 4 hours. The catalyst was then removed by filtration, and the organic phase was evaporated to dryness to obtain crude tert-butyl(2-(5-aminothiophen-2-yl)-2-methoxyethyl)(methyl)carbamate (0.9 g), which was used directly in the next step.

[0571] MS m / z(ESI): 287.1 [M+H] + .

[0572] Step 6: Preparation of tert-butyl(2-(5-(5-ethyl-4-methyl-1H-pyrazole-3-amido)thiophen-2-yl)-2-methoxyethyl)(methyl)carbamate:

[0573]

[0574] 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (200 mg, 0.53 mmol) was added to a solution of tert-butyl(2-(5-aminothiophene-2-yl)-2-methoxyethyl)(methyl)carbamate (100 mg, 0.35 mmol), 5-ethyl-4-methyl-1H-pyrazole-3-carboxylic acid (54 mg, 0.35 mmol), and N,N-diisopropylethylamine (90 mg, 0.70 mmol) in N,N-dimethylformamide (3 mL). The reaction mixture was stirred overnight at room temperature. The reaction solution was quenched with saturated brine (15 ml), extracted with dichloromethane (20 mL × 3), and the organic phase was separated. The mixture was washed successively with saturated brine (15 mL × 6), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the residue tert-butyl(2-(5-(5-ethyl-4-methyl-1H-pyrazol-3-amido)thiophen-2-yl)-2-methoxyethyl)(methyl)carbamate (150 mg), which was used directly in the next step.

[0575] MS m / z(ESI): 423.2 [M+H] + .

[0576] Step 7: Preparation of 5-ethyl-N-(5-(1-methoxy-2-(methylamino)ethyl)thiophen-2-yl)-4-methyl-1H-pyrazole-3-carboxamide:

[0577]

[0578] 150 mg of tert-butyl(2-(5-(5-ethyl-4-methyl-1H-pyrazole-3-amido)thiophen-2-yl)-2-methoxyethyl)(methyl)carbamate was dissolved in 5 mL of dichloromethane, and 3 mL of trifluoroacetic acid was added. The mixture was stirred at 25 °C for 1 hour. The reaction solution was evaporated to dryness under reduced pressure, and the crude product was separated by preparative high performance liquid chromatography to obtain 38 mg of 5-ethyl-N-(5-(1-methoxy-2-(methylamino)ethyl)thiophen-2-yl)-4-methyl-1H-pyrazole-3-carboxamide.

[0579] MS m / z(ESI): 323.1 [M+H] + .

[0580] Example 14

[0581] 5-Ethyl-4-methyl-N-(5-(morpholin-2-yl)thiophen-2-yl)-1H-pyrazole-3-carboxamide

[0582]

[0583] Step 1: Preparation of 2-(5-nitrothiophene-2-yl)oxalopropyl ring:

[0584]

[0585] Sodium hydrogen hydride (0.48 g, 12 mmol, 60%) was added to dimethyl sulfoxide (50 mL) at room temperature under a nitrogen atmosphere and stirred for 15 minutes. Then, trimethylsulfonium iodide (2.64 g, 12 mmol) was added in portions to the reaction system, and the mixture was heated to 40 °C and reacted for three hours. After cooling to room temperature, 5-nitro-2-thiophenecarboxaldehyde (1.57 g, 10 mmol) was added, and the mixture was reacted for three hours at room temperature. The reaction was indicated to be complete by TLC. The reaction solution was quenched with saturated ammonium chloride solution (50 mL), then extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to give the crude product 2-(5-nitrothiophene-2-yl)oxalopropylcyclohexane (1.40 g, yield: 82%).

[0586] Step 2: Preparation of 2-((2-hydroxyethyl)amino)-1-(5-nitrothiophene-2-yl)ethane-1-ol:

[0587]

[0588] At room temperature, 1.40 g (8.2 mmol) of 2-(5-nitrothiophene-2-yl)oxalopropylcyclohexane was dissolved in 20 mL of tetrahydrofuran, followed by the addition of 0.55 g (9 mmol) of ethanolamine. The mixture was stirred overnight at room temperature. The reaction solution was diluted with 50 mL of ethyl acetate, washed with saturated brine, and the organic phase was dried over anhydrous sodium sulfate. The solution was filtered and evaporated to dryness. The crude product was separated by column chromatography to give 1.33 g (70% yield) of 2-((2-hydroxyethyl)amino)-1-(5-nitrothiophene-2-yl)ethane-1-ol.

[0589] MS m / z(ESI): 233.1 [M+H] + .

[0590] Step 3: Preparation of tert-butyl (2-hydroxy-2-(-5-nitrothiophen-2-yl)ethyl)(2-hydroxyethyl)carbamate:

[0591]

[0592] 2-((2-hydroxyethyl)amino)-1-(5-nitrothiophen-2-yl)ethane-1-ol (1.33 g, 5.74 mmol) was dissolved in tetrahydrofuran (15 mL) under ice bath conditions, followed by the addition of di-tert-butyl dicarbonate (1.38 g, 6.31 mmol). The mixture was stirred under ice bath conditions for one hour, and then stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate (50 mL), washed with aqueous sodium hydroxide solution (1 M), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to give the crude product tert-butyl(2-hydroxy-2-(-5-nitrothiophen-2-yl)ethyl)(2-hydroxyethyl)carbamate (1.81 g, yield: 95%).

[0593] MS m / z(ESI): 333.3 [M] + .

[0594] Step 4: Preparation of tert-butyl 2-(5-nitrothiophen-2-yl)morpholine-4-carboxylic acid ester:

[0595]

[0596] Under ice bath conditions, tert-butyl(2-hydroxy-2-(-5-nitrothiophen-2-yl)ethyl)(2-hydroxyethyl)carbamate (1.81 g, 5.45 mmol) was dissolved in anhydrous tetrahydrofuran (15 mL), purged with nitrogen, and then triphenylphosphine (1.71 g, 6.54 mmol) was added. The mixture was stirred under ice bath conditions for 10 minutes, followed by the addition of diisopropyl azodicarbonate (1.35 mL). The mixture was stirred under ice bath conditions for one hour, and then stirred overnight at room temperature. The reaction mixture was quenched with saturated ammonium chloride solution (15 mL), diluted with ethyl acetate (50 mL), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was separated by column chromatography to give tert-butyl-2-(5-nitrothiophen-2-yl)morpholine-4-carboxylic acid ester (1.28 g, yield: 75%).

[0597] MS m / z (ESI): 315.1 [M] + .

[0598] Step 5: Preparation of tert-butyl 2-(5-aminothiophen-2-yl)morpholine-4-carboxylic acid ester:

[0599]

[0600] Using tert-butyl 2-(5-nitrothiophen-2-yl)morpholine-4-carboxylic acid ester as the raw material, tert-butyl 2-(5-aminothiophen-2-yl)morpholine-4-carboxylic acid ester was obtained by referring to step 5 of Example 12.

[0601] MS m / z(ESI): 285.1 [M] + .

[0602] Step 6: Preparation of tert-butyl 2-(5-(5-ethyl-4-methyl-1H-pyrazole-3-carbon oxaloylamino(oxiamethoxy)thiophen-2-yl)morpholine-4-carboxylic acid ester:

[0603]

[0604] Using tert-butyl 2-(5-aminothiophen-2-yl)morpholine-4-carboxylic acid ester as the raw material, tert-butyl 2-(5-(5-ethyl-4-methyl-1H-pyrazole-3-carbon oxaloylamino(oxiamylamino)thiophen-2-yl)morpholine-4-carboxylic acid ester was obtained by referring to step 11 of Example 1.

[0605] MS m / z (ESI): 421.2 [M] + .

[0606] Step 7: Preparation of 5-ethyl-4-methyl-N-(5-(morpholin-2-yl)thiophen-2-yl)-1H-pyrazole-3-carboxamide:

[0607]

[0608] The synthesis was carried out according to step 11 of Example 1 to obtain 5-ethyl-4-methyl-N-(5-(morpholin-2-yl)thiophen-2-yl)-1H-pyrazole-3-carboxamide.

[0609] MS m / z (ESI): 321.2 [M] + .

[0610] Example 15

[0611] 5-Ethyl-4-methyl-N-(4-(morpholin-2-yl)thiophen-2-yl)-1H-pyrazole-3-carboxamide

[0612]

[0613] Step 1: Preparation of 5-ethyl-4-methyl-N-(4-(morpholin-2-yl)thiophen-2-yl)-1H-pyrazole-3-carboxamide

[0614]

[0615] Using 5-nitro-3-thiophenecarboxaldehyde as a raw material, 5-ethyl-4-methyl-N-(4-(morpholin-2-yl)thiophen-2-yl)-1H-pyrazole-3-carboxamide was obtained by referring to steps one through seven of Example 14.

[0616] MS m / z (ESI): 321.2 [M] + .

[0617] Example 16

[0618] 5-Ethyl-4-methyl-N-(2-methyl-4-(morpholin-2-yl)phenyl)-1H-pyrazole-3-carboxamide

[0619]

[0620] Step 1: Preparation of tert-butyl-2-(4-bromo-3-methylphenyl)morpholine-4-carboxylic acid ester:

[0621]

[0622] Using 3-methyl-4-bromobenzaldehyde as a raw material, tert-butyl 2-(4-bromo-3-methylphenyl)morpholine-4-carboxylic acid ester was obtained by referring to the first to fourth steps of Example 14.

[0623] MS m / z (ESI): 356.1, 358.1 [M] + .

[0624] Step 2: Preparation of tert-butyl 2-(4-((diphenylmethylene)amino)-3-methylphenyl)morpholine-4-carboxylic acid ester:

[0625]

[0626] At room temperature, tert-butyl 2-(4-bromo-3-methylphenyl)morpholine-4-carboxylic acid ester (0.50 g, 1.4 mmol), benzophenone imine (0.51 g, 2.8 mmol), sodium tert-butoxide (0.27 g, 2.8 mmol), tris(diphenylmethyleneacetone)dipalladium (0.013 g, 0.014 mmol), and di(diphenylphosphine)-1,1-binaphthyl were dissolved in toluene (5 mL), N2 was substituted, and the mixture was heated to 100 °C and reacted overnight. After cooling to room temperature, the reaction was indicated to be complete by LC-MS. The residue was evaporated to dryness, dissolved in ethyl acetate (25 mL), washed with saturated brine (15 mL × 2), dried over anhydrous sodium sulfate, filtered, evaporated to dryness, and the residue was separated by preparative thin-layer chromatography to give the product tert-butyl 2-(4-((diphenylmethylene)amino)-3-methylphenyl)morpholine-4-carboxylic acid ester (0.32 g, yield: 50%).

[0627] MS m / z (ESI): 457.2 [M] + .

[0628] Step 3: Preparation of tert-butyl 2-(4-amino-3-methylphenyl)morpholine-4-carboxylic acid ester:

[0629]

[0630] At room temperature, tert-butyl 2-(4-((diphenylmethylene)amino)-3-methylphenyl)morpholine-4-carboxylic acid ester (0.32 g, 0.7 mmol) was dissolved in methanol (6 mL), and formic acid ammonium (0.66 g, 10.5 mmol) was added. Nitrogen gas was then added, followed by palladium on carbon (50 mg). The mixture was heated to 60 °C and reacted for 2 hours. After cooling to room temperature, the mixture was filtered through diatomaceous earth, washed with ethyl acetate, and evaporated to dryness. The residue was dissolved in ethyl acetate (50 mL), and the organic phase was washed successively with saturated sodium bicarbonate solution and saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was separated by column chromatography to obtain tert-butyl 2-(4-amino-3-methylphenyl)morpholine-4-carboxylic acid ester (0.14 g, yield: 70%).

[0631] MS m / z(ESI): 293.1 [M] + .

[0632] Step 4: Preparation of tert-butyl-2-(4-(5-ethyl-4-methyl-1H-pyrazole-3-carbonoxylate-(oxiamethoxy)-3-methylphenyl)morpholine-4-carboxylic acid ester:

[0633]

[0634] Using tert-butyl 2-(4-amino-3-methylphenyl)morpholine-4-carboxylic acid ester as a raw material, tert-butyl 2-(4-(5-ethyl-4-methyl-1H-pyrazole-3-carbon oxaloylamino(oxiamylamino)-3-methylphenyl)morpholine-4-carboxylic acid ester was obtained by referring to step 11 of Example 1.

[0635] MS m / z (ESI): 429.2 [M] + .

[0636] Step 5: Preparation of 5-ethyl-4-methyl-N-(2-methyl-4-(morpholin-2-yl)phenyl)-1H-pyrazole-3-carboxamide:

[0637]

[0638] Using 2-(4-(5-ethyl-4-methyl-1H-pyrazole-3-carbon oxaloylamino(oxiamylamino)-3-methylphenyl)morpholine-4-carboxylic acid ester as a raw material, 5-ethyl-4-methyl-N-(2-methyl-4-(morpholin-2-yl)phenyl)-1H-pyrazole-3-carboxamide was obtained by referring to step 12 of Example 1.

[0639] MS m / z(ESI): 329.2 [M] + .

[0640] Example 17

[0641] 5-Ethyl-N-(2-fluoro-4-(morpholin-2-yl)phenyl)-4-methyl-1H-pyrazole-3-carboxamide

[0642]

[0643] Method 2:

[0644] Step 1: Preparation of 5-ethyl-N-(2-fluoro-4-(morpholin-2-yl)phenyl)-4-methyl-1H-pyrazole-3-carboxamide:

[0645]

[0646] Using 3-fluoro-4-bromobenzaldehyde as a raw material, and referring to the first to fourth steps of Example 14, the second to third steps of Example 16, and the eleventh to twelfth steps of Example 1, 5-ethyl-N-(2-fluoro-4-(morpholin-2-yl)phenyl)-4-methyl-1H-pyrazole-3-carboxamide was obtained.

[0647] MS m / z (ESI): 333.2 [M]+ .

[0648] Method 2:

[0649] Step 1: Preparation of 2-(4-bromo-3-fluorophenyl)oxalanine

[0650]

[0651] Under ice bath conditions, trimethyl sulfoxide (5.42 g, 24.63 mmol) was dissolved in acetonitrile (60 mL), followed by the addition of potassium hydroxide (2.07 g, 36.95 mmol). The mixture was stirred at room temperature for one hour, then a solution of 4-bromo-3-fluorobenzaldehyde (5.0 g, 24.63 mmol) in acetonitrile (30 mL) was added dropwise, followed by the addition of water (2 mL). The mixture was stirred overnight at room temperature. TLC indicated that the reaction was not yet complete. The mixture was then heated to 60 °C and reacted for 3 hours. After cooling to room temperature, TLC indicated that the reaction was complete. The solid was removed by filtration. The mother liquor was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product (5.35 g, colorless oil) was used directly in the next reaction.

[0652] Step 2: 1-(4-bromo-3-fluorophenyl)-2-((2-hydroxyethyl)amino)ethane-1-ol

[0653]

[0654] At room temperature, 2-(4-bromo-3-fluorophenyl)oxalan (5.35 g, 24.65 mmol) was dissolved in tetrahydrofuran (180 mL), followed by the addition of triethylamine (7.48 g, 73.95 mmol, 10.31 mL), and then ethanolamine (15.06 g, 0.25 mol). The mixture was stirred overnight at room temperature, and the reaction was stopped by LCMS. The reaction solution was diluted with ethyl acetate (100 mL), washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The residue (5.82 g, yellow oil) was used directly in the next reaction.

[0655] MS m / z(ESI): 278.0, 280.0 [M+H] + .

[0656] Step 3: Tert-butyl(2-(4-bromo-3-fluorophenyl)(2-hydroxyethyl)(2-hydroxyethyl)carbamate

[0657]

[0658] At room temperature, 1-(4-bromo-3-fluorophenyl)-2-((2-hydroxyethyl)amino)ethane-1-ol (5.82 g, 20.93 mmol) was dissolved in dichloromethane (50 mL), followed by the addition of triethylamine (5.29 g, 52.32 mmol, 7.30 mL) and di-tert-butyl dicarbonate (5.48 g, 25.11 mmol). The mixture was stirred overnight at room temperature. LC-MS indicated the end of the reaction. The reaction solution was washed with saturated brine (15 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The solution was filtered, evaporated to dryness, and the residue was purified by rapid silica gel chromatography (eluting with petroleum ether:ethyl acetate = 85:15 to 50:50) to obtain the target product, which was a yellow oil (0.80 g, overall yield of three steps: 10.1%).

[0659] MS m / z (ESI): 378.0, 380.0 [M+H] + .

[0660] Step 4: Tert-butyl-2-(4-bromo-3-fluorophenyl)morpholine-4-carboxylic acid ester

[0661]

[0662] Under ice bath conditions, tert-butyl(2-(4-bromo-3-fluorophenyl)(2-hydroxyethyl)(2-hydroxyethyl)carbamate (0.26 g, 0.69 mmol) and triphenylphosphine (0.22 g, 0.82 mmol) were dissolved in tetrahydrofuran (6 mL), purged with nitrogen, and then diisopropyl azodicarbonate (0.21 g, 1.03 mmol) was added dropwise. The mixture was stirred under ice bath conditions for one hour, then heated to room temperature and stirred overnight. The reaction was considered complete by LCMS. The reaction solution was diluted with ethyl acetate (20 mL), washed with saturated sodium bicarbonate solution (10 mL × 2), and then washed with saturated brine (10 mL × 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The residue was separated by preparative thin-layer chromatography (PE:EA = 2:1) to obtain the target product as a yellow oil (0.11 g, yield: 44%).

[0663] MS m / z (ESI): 360.2, 362.2 [M+H] + .

[0664] Step 5: Tert-butyl-2-(4-((diphenylmethylene)amino)-3-fluorophenyl)morpholine-4-carboxylic acid ester

[0665]

[0666] At room temperature, tert-butyl 2-(4-bromo-3-fluorophenyl)morpholine-4-carboxylic acid ester (0.11 g, 0.31 mmol), tris(diphenylmethyleneacetone)dipalladium (0.028 g, 0.03 mmol), di(diphenylphosphino)-1,1-binaphthyl (0.038 g, 0.06 mmol), sodium tert-butoxide (0.059 g, 0.61 mmol), and benzophenone imine (0.08 g, 0.46 mmol) were dissolved in toluene (6 mL), purged with nitrogen, heated to 90 °C, and reacted for 14 hours. After cooling to room temperature, the reaction was considered complete by LC-MS. The reaction solution was diluted with ethyl acetate (20 mL), then washed with saturated brine (10 mL × 2), the organic phase was dried with anhydrous sodium sulfate, filtered, evaporated to dryness, and the residue was separated by preparative thin-layer chromatography (PE:EA = 1:1) to obtain the target product as a yellow oil (0.06 g, yield: 43%).

[0667] MS m / z (ESI): 461.2 [M+H] + .

[0668] Step 6: Tert-butyl-2-(4-amino-3-fluorophenyl)morpholine-4-carboxylic acid ester

[0669]

[0670] At room temperature, tert-butyl 2-(4-((diphenylmethylene)amino)-3-fluorophenyl)morpholine-4-carboxylic acid ester (0.06 g, 0.13 mmol) was dissolved in methanol (6 mL), purged with nitrogen, and then 10% palladium on carbon (40 mg, 50% aqueous content w / w) was added, purging with hydrogen. The mixture was stirred at room temperature for 14 hours. The reaction was completed by LCMS. The catalyst was removed by filtration, the mother liquor was evaporated to dryness, and the crude product was used directly for the next step (0.03 g, yield: 77.7%).

[0671] MS m / z(ESI): 297.2 [M+H] + .

[0672] Step 7: Tert-butyl-2-(4-(5-ethyl-4-methyl-1H-pyrazole-3-carbamoylamino(oxiamino))-3-fluorophenyl)morpholine-4-carboxylic acid ester

[0673]

[0674] At room temperature, 5-ethyl-4-methyl-1H-pyrazole-3-carboxylic acid (0.017 g, 0.11 mmol) and tert-butyl-2-(4-amino-3-fluorophenyl)morpholine-4-carboxylic acid ester (0.03 g, 0.10 mmol) were dissolved in N,N-dimethylformamide (3 mL), followed by the addition of 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate ester (0.057 g, 0.15 mmol) and N-ethyl-N-isopropyl-propane-2-amine (0.039 g, 0.30 mol, 52.90 μL). The mixture was stirred overnight at room temperature. The reaction was indicated by LC-MS to be complete. The reaction solution was diluted with ethyl acetate (20 mL), washed with saturated brine (10 mL × 2), and the organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The residue was separated by preparative high-performance liquid chromatography. The target product was obtained by freeze drying. The product was a white solid (20 mg, yield: 45.7%).

[0675] MS m / z(ESI): 433.2 [M+H] + .

[0676] Step 8: 5-Ethyl-N-(2-fluoro-4-(morpholin-2-yl)phenyl)-4-methyl-1H-pyrazole-3-carboxamide

[0677]

[0678] 0.015 g (0.035 mmol) of tert-butyl-2-(4-(5-ethyl-4-methyl-1H-pyrazole-3-carbamoylamino(oxadiamino))-3-fluorophenyl)morpholine-4-carboxylic acid ester was dissolved in hydrochloric acid / dioxane (3 mL, 4 M) under ice bath conditions and stirred at room temperature for 3 hours. The reaction was stopped by LCMS. The solution was evaporated to dryness, and the residue was diluted with water and lyophilized to give the hydrochloride salt of the target compound. The product was a white solid (11.4 mg, yield: 86.4%).

[0679] MS m / z(ESI): 333.2 [M+H] + .

[0680] 1H NMR(400M,DMSO-d6)δ9.57-9.77(m,2H),9.43(s,1H),8.03(t,J=8.0Hz,1H ),7.33(d,J=8.0Hz,1H),7.22(d,J=8.0Hz,1H),4.80(d,J=10.0Hz,1H),4.1 0-4.13(m,1H),3.92-3.98(m,1H),3.39-3.45(m,2H),3.23-3.26(m,1H),2. 98-3.14(m,2H),2.60(q,J=7.6Hz,2H),2.19(s,3H),1.77(d,J=7.6Hz,3H).

[0681] Example 18

[0682] N-(2-chloro-4-(morpholin-2-yl)phenyl)-5-ethyl-4-methyl-1H-pyrazole-3-carboxamide

[0683]

[0684] Step 1: Preparation of N-(2-chloro-4-(morpholin-2-yl)phenyl)-5-ethyl-4-methyl-1H-pyrazole-3-carboxamide:

[0685]

[0686] Using 3-chloro-4-bromobenzaldehyde as a raw material, referring to the first to fourth steps of Example 14, the second to third steps of Example 16, and the eleventh to twelfth steps of Example 1, N-(2-chloro-4-(morpholin-2-yl)phenyl)-5-ethyl-4-methyl-1H-pyrazole-3-carboxamide was obtained.

[0687] MS m / z (ESI): 349.1 [M] + .

[0688] Example 19

[0689] N-(3-chloro-4-(morpholin-2-yl)phenyl)-5-ethyl-4-methyl-1H-pyrazole-3-carboxamide

[0690]

[0691] Method 1:

[0692] Step 1: Preparation of N-(3-chloro-4-(morpholin-2-yl)phenyl)-5-ethyl-4-methyl-1H-pyrazole-3-carboxamide:

[0693]

[0694] Using 2-chloro-4-bromobenzaldehyde as a raw material, referring to the first to fourth steps of Example 14 and the second to third steps of Example 16, and the eleventh to twelfth steps of Example 1, N-(3-chloro-4-(morpholin-2-yl)phenyl)-5-ethyl-4-methyl-1H-pyrazole-3-carboxamide was obtained.

[0695] MS m / z(ESI): 349.1 [M]+.

[0696] Method 2:

[0697] Step 1: Preparation of 2-(4-bromo-2-chlorophenyl)oxalanine

[0698]

[0699] Under ice-water bath cooling and nitrogen protection, sodium hydroxide (2.03 g, 50.87 mmol) was added to dimethyl sulfoxide (70 mL). The mixture was stirred at 0 °C for 10 minutes. Then, trimethyl sulfoxide (11.01 g, 50.03 mmol) was added in portions, and the mixture was stirred at 0 °C for 10 minutes, followed by stirring at 40 °C for 3 hours. The reaction mixture was cooled, and under ice-water bath cooling and nitrogen protection, a solution of 4-bromo-2-chlorobenzaldehyde (9.15 g, 41.69 mmol) in dimethyl sulfoxide (15 mL) was added to the reaction mixture. The mixture was then stirred at 20 °C for 1 hour. The reaction mixture was quenched with saturated ammonium chloride aqueous solution (100 mL), and the mixture was extracted with ethyl acetate (80 mL × 3). The organic phases were combined, washed successively with saturated brine (100 mL × 6), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product 2-(4-bromo-2-chlorophenyl)oxalan (9g) was used directly in the next step.

[0700] Step 2: Preparation of tert-butyl-2-(2-chloro-4-((diphenylmethylene)amino)phenyl)morpholine-4-carboxylic acid ester

[0701]

[0702] Using 2-(4-bromo-2-chlorophenyl)oxalanine as a starting material, referring to steps two to five of Example 17, tert-butyl 2-(2-chloro-4-((diphenylmethylene)amino)phenyl)morpholine-4-carboxylic acid ester was obtained.

[0703] MS m / z(ESI): 477.2[M+H]+.

[0704] Step 3: Preparation of tert-butyl-2-(4-amino-2-chlorophenyl)morpholine-4-carboxylic acid ester

[0705]

[0706] 48 mg (100.63 μmol) of tert-butyl-2-(2-chloro-4-((diphenylmethylene)amino)phenyl)morpholine-4-carboxylic acid ester was dissolved in methanol (5 mL), and hydroxylamine hydrochloride (20.98 mg, 301.89 μmol) and sodium acetate (33.02 mg, 402.52 μmol) were added. The mixture was stirred at room temperature for 16 hours. The reaction solution was evaporated to dryness, and saturated brine (15 mL) was added. The mixture was extracted with dichloromethane (20 mL), separated, and the organic phase was dried over anhydrous sodium sulfate. The solution was purified by rapid silica gel chromatography (petroleum ether: ethyl acetate = 5:1) to give the target product tert-butyl-2-(4-amino-2-chlorophenyl)morpholine-4-carboxylic acid ester (30 mg, yield: 95.31%).

[0707] MS m / z(ESI): 313.1[M+H]+.

[0708] Step 3: Preparation of N-(3-chloro-4-(morpholin-2-yl)phenyl)-5-ethyl-4-methyl-1H-pyrazole-3-carboxamide:

[0709]

[0710] Using tert-butyl-2-(4-amino-2-chlorophenyl)morpholine-4-carboxylic acid ester as a raw material, referring to steps 10 to 11 of method 2 in Example 1, N-(3-chloro-4-(morpholine-2-yl)phenyl)-5-ethyl-4-methyl-1H-pyrazole-3-carboxamide was obtained.

[0711] 1 H NMR(400MHz, CDCl3)δ8.03–7.93(m,1H),7.68–7.59(m,1H),7.59–7.47(m,1H),5.19–5.05(m,1H),4.36–4.20(m,1H) ,4.09–3.93(m,1H),3.81–3.43(m,4H),3.06–2.91(m,1H),2.73–2.55(m,2H),2.35–2.07(m,3H),1.31–1.19(m,3H).

[0712] MS m / z(ESI): 349.1 [M]+.

[0713] Example 20

[0714] N-(5-ethyl-4-methyl-1H-pyrazol-3-yl)-4-(morpholin-2-yl)benzamide

[0715]

[0716] Step 1: Preparation of ethyl 2-methyl-3-carbonylpentanoate:

[0717]

[0718] Potassium carbonate (2.4 g, 17 mmol) was added to an anhydrous acetone (75 mL) solution of ethyl propionyl acetate (5 g, 35 mmol). The mixture was stirred at room temperature for 10 minutes, followed by the addition of methyl iodoform (4.9 g, 35 mmol). The reaction mixture was heated under reflux for 12 hours. The reaction mixture was cooled and filtered, and the organic phase was evaporated to dryness. The crude product was separated by column chromatography (petroleum ether: ethyl acetate = 95:5) to give ethyl 2-methyl-3-carbonylpentanoate (5 g, yield: 91%).

[0719] Step 2: Preparation of 2-methyl-3-carbonylpentanamide:

[0720]

[0721] Ethyl 2-methyl-3-carbonylpentanoate (5 g, 31.6 mmol) was added to a 4 M ammonia-methanol (75) solution at 0 °C. The reaction solution was stirred at 0 °C for 2 hours and then evaporated to dryness to obtain 2-methyl-3-carbonylpentanoamide (4 g, yield: 91%). The product was used directly in the next step.

[0722] MS m / z (ESI): 130.1 [M] + .

[0723] Step 3: Preparation of 5-ethyl-4-methyl-1H-pyrazole-3-amine:

[0724]

[0725] 2-Methyl-3-carbonylpentanamide (4 g, 31 mmol) was dissolved in ethanol (24 mL), and 80% hydrazine hydrate (1.9 g, 31 mmol) was added. The mixture was reacted at 70 °C for 1 hour. After filtration, the filtrate was concentrated under reduced pressure to obtain the crude product, which was dissolved in diethyl ether (30 mL) and 2M diethyl ether hydrochloride solution (15 mL). After stirring at room temperature for 2 hours, the mixture was filtered and the solid was dried to give the product ethyl 4-cyclopropyl-3-methyl-2,4-dicarbonylbutyrate (3.1, yield: 80%).

[0726] MS m / z (ESI): 125.1 [M] + .

[0727] Step 4: Preparation of 4-(4-(tert-butoxycarbonyl)morpholin-2-yl)benzoic acid:

[0728]

[0729] At -78°C, tert-butyl 2-(4-bromophenyl)morpholine-4-carboxylic acid ester (1.0 g, 2.92 mmol) was dissolved in tetrahydrofuran (30 mL), and nitrogen gas was introduced to replace the nitrogen gas. Then, butyllithium (1.6 M, 2.74 mL, 4.38 mmol) was added, and the mixture was stirred at -78°C for 30 minutes. Then, carbon dioxide gas was introduced, and the mixture was stirred at -78°C for 30 minutes. The temperature was then slowly increased to -10°C, and the reaction was carried out for 1.5 hours. The reaction solution was quenched with saturated ammonium chloride aqueous solution, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate. The solution was filtered, evaporated to dryness, and the crude product was obtained. The crude product was separated by column chromatography to obtain 4-(4-(tert-butoxycarbonyl)morpholine-2-yl)benzoic acid (0.51 g, yield: 57%).

[0730] MS m / z (ESI): 308.1 [M] + .

[0731] Step 5: Preparation of tert-butyl 2-(4-((5-ethyl-4-methyl-1H-pyrazol-3-yl)carbamoyl)phenyl)morpholine-4-carboxylic acid ester:

[0732]

[0733] Using 4-(4-(tert-butoxycarbonyl)morpholin-2-yl)benzoic acid as a raw material, referring to step 11 of Example 1, tert-butyl 2-(4-((5-ethyl-4-methyl-1H-pyrazol-3-yl)carbamoyl)phenyl)morpholin-4-carboxylic acid ester was obtained.

[0734] MS m / z (ESI): 415.2 [M] + .

[0735] Step 6: Preparation of N-(5-ethyl-4-methyl-1H-pyrazol-3-yl)-4-(morpholin-2-yl)benzamide:

[0736]

[0737] Using tert-butyl 2-(4-((5-ethyl-4-methyl-1H-pyrazol-3-yl)carbamoyl)phenyl)morpholine-4-carboxylic acid ester as the raw material, N-(5-ethyl-4-methyl-1H-pyrazol-3-yl)-4-(morpholine-2-yl)benzamide was obtained by referring to step 12 of Example 1.

[0738] MS m / z (ESI): 315.2 [M] + .

[0739] Example 21

[0740] 5-Ethyl-4-methyl-N-(4-(morpholin-2-yl)-2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamide

[0741]

[0742] Step 1: Preparation of 5-ethyl-4-methyl-N-(4-(morpholin-2-yl)-2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamide:

[0743]

[0744] Using 3-trifluoromethyl-4-bromobenzaldehyde as a raw material, and referring to the first to fourth steps of Example 14 and the second to third steps of Example 16, and the eleventh to twelfth steps of Example 1, 5-ethyl-4-methyl-N-(4-(morpholin-2-yl)-2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamide was obtained.

[0745] MS m / z (ESI): 383.1 [M] + .

[0746] Example 22

[0747] 4-Methyl-N-(4-(morpholin-2-yl)phenyl)-5-(trifluoromethyl)-1H-pyrazole-3-carboxamide

[0748]

[0749] Step 1: Preparation of 4-methyl-N-(4-(morpholin-2-yl)phenyl)-5-(trifluoromethyl)-1H-pyrazole-3-carboxamide

[0750]

[0751] Using 4,4,4,-trifluorobutyl-2-one as a raw material, and referring to the first step of Example 11 and steps 10 to 12 of Example 1, 4-methyl-N-(4-(morpholin-2-yl)phenyl)-5-(trifluoromethyl)-1H-pyrazole-3-carboxamide was obtained.

[0752] MS m / z (ESI): 355.1 [M] + .

[0753] Example 23

[0754] 5-Ethyl-N-(4-(1-methoxy-2-(methylamino)ethyl)phenyl)-4-methyl-1H-pyrazole-3-carboxamide

[0755]

[0756] Step 1: Preparation of 2-(4-nitrophenyl)oxalopropyl ring:

[0757]

[0758] Using 4-nitrobenzaldehyde as a starting material, 2-(4-nitrophenyl)oxalan was obtained according to the first step of Example 1. The second step was the preparation of 2-(methylamino)-1-(4-nitrophenyl)ethane-1-ol.

[0759]

[0760] Using 2-(4-nitrophenyl)oxalanine as a starting material, 2-(methylamino)-1-(4-nitrophenyl)ethane-1-ol was obtained by referring to the second step of Example 1.

[0761] MS m / z (ESI): 197.1 [M+H] + .

[0762] Step 3: Preparation of tert-butyl (2-hydroxy-2-(4-nitrophenyl)ethyl)(methyl)carbamate:

[0763]

[0764] Using 2-(methylamino)-1-(4-nitrophenyl)ethane-1-ol as a raw material, tert-butyl(2-hydroxy-2-(4-nitrophenyl)ethyl)(methyl)carbamate was obtained by referring to the third step of Example 1.

[0765] MS m / z(ESI): 297.1 [M+H] + .

[0766] Step 4: Preparation of tert-butyl(2-methoxy-2-(4-nitrophenyl)ethyl)(methyl)carbamate:

[0767]

[0768] Using tert-butyl(2-hydroxy-2-(4-nitrophenyl)ethyl)(methyl)carbamate as a raw material, tert-butyl(2-methoxy-2-(4-nitrophenyl)ethyl)(methyl)carbamate was obtained in step 4 of Example 13.

[0769] MS m / z(ESI): 311.2 [M+H] + .

[0770] Step 5: Preparation of tert-butyl (2-(4-aminophenyl)-2-methoxyethyl)(methyl)carbamate:

[0771]

[0772] Using tert-butyl(2-methoxy-2-(4-nitrophenyl)ethyl)(methyl)carbamate as a raw material, tert-butyl(2-(4-aminophenyl)-2-methoxyethyl)(methyl)carbamate was obtained by referring to step 5 of Example 1.

[0773] MS m / z(ESI): 281.2[M+H]+.

[0774] Step 6: Preparation of tert-butyl(2-(4-(5-ethyl-4-methyl-1H-pyrazole-3-carbonoxylazolylamino(oxiamino)phenyl)-2-methoxyethyl)(methyl)carbamate:

[0775]

[0776] Using tert-butyl(2-(4-aminophenyl)-2-methoxyethyl)(methyl)carbamate as a raw material, tert-butyl(2-(4-(5-ethyl-4-methyl-1H-pyrazole-3-carbon oxaloylamino(oxiamino)phenyl)-2-methoxyethyl)(methyl)carbamate was obtained by referring to step 10 of Example 1.

[0777] MS m / z (ESI): 417.2 [M+H] + .

[0778] Step 7: Preparation of 5-ethyl-N-(4-(1-methoxy-2-(methylamino)ethyl)phenyl)-4-methyl-1H-pyrazole-3-carboxamide:

[0779]

[0780] Using tert-butyl(2-(4-(5-ethyl-4-methyl-1H-pyrazole-3-carbon oxaloylamino(oxadiamino)phenyl)-2-methoxyethyl)(methyl)carbamate as a raw material, 5-ethyl-N-(4-(1-methoxy-2-(methylamino)ethyl)phenyl)-4-methyl-1H-pyrazole-3-carboxamide was obtained by referring to step eleven of Example 1.

[0781] MS m / z (ESI): 317.2 [M+H] + .

[0782] Example 24

[0783] N-(4-(morpholin-2-yl)phenyl)-1,4,5,6-tetrahydrocyclopentadien[c]pyrazole-3-carboxamide

[0784]

[0785] Step 1: Preparation of N-(4-(morpholin-2-yl)phenyl)-1,4,5,6-tetrahydrocyclopentadien[c]pyrazole-3-carboxamide

[0786] Refer to steps 10 and 11 of Example 1

[0787] MS m / z(ESI): 313.1 [M+H] + .

[0788] 1 H NMR (400MHz, DMSO-d6) δ10.03(s,1H),9.73–9.56(m,2H),7.82(d,J=8.4Hz,2H),7.33(d,J=8.2Hz,2H),4.74(d,J=10.1Hz,1H),4.14–4.06(m ,1H),3.99–3.89(m,1H),3.74–3.43(m,1H),3.43–3.35(m,1H),3.25– 3.22(m,1H),3.14–2.95(m,2H),2.75–2.63(m,4H),2.49–2.44(m,2H).

[0789] Example 25

[0790] 4,4-Difluoro-N-(4-(morpholin-2-yl)phenyl)-1,4,5,6-tetrahydrocyclopentadien[c]pyrazole-3-carboxamide

[0791]

[0792] Step 1: Preparation of ethyl 4,4-difluoro-1,4,5,6-tetrahydrocyclopentadieno[c]pyrazole-3-carboxylic acid ester

[0793]

[0794] The compound ethyl 4-carbonyl-1,4,5,6-tetrahydrocyclopentadien[c]pyrazole-3-carboxylic acid ester (1 g, 5.15 mmol) was dissolved in dichloromethane (10 mL), and diethylamino-sulfur trifluoride (5.7 g, 25.8 mmol) was added under ice bath conditions. After the addition was complete, the reaction was carried out at room temperature for 16 hours. The reaction was quenched by adding sodium bicarbonate aqueous solution (5 mL), the organic phase was separated, dried, and then evaporated to dryness to obtain the crude product. The crude product was purified by column chromatography (PE:EA = 5:1-1:1) to give the product ethyl 4,4-difluoro-1,4,5,6-tetrahydrocyclopentadien[c]pyrazole-3-carboxylic acid ester (320 mg, yield: 28.7%).

[0795] MS m / z(ESI): 217.0 [M+H] + .

[0796] Step 2: Preparation of 4,4-difluoro-N-(4-(morpholin-2-yl)phenyl)-1,4,5,6-tetrahydrocyclopentadien[c]pyrazole-3-carboxamide

[0797]

[0798] Refer to steps 10 to 12 of Example 1.

[0799] MS m / z (ESI): 349.1 [M+H] + .

[0800] Example 26

[0801] 4,4-Difluoro-N-(4-(morpholin-2-yl)phenyl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxamide

[0802]

[0803] Step 1: Preparation of 4,4-difluoro-N-(4-(morpholin-2-yl)phenyl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxamide

[0804]

[0805] The synthesis steps are as described in Example 25.

[0806] MS m / z(ESI): 363.1 [M+H] + .

[0807] Example 27

[0808] 4-Chloro-5-cyclopropyl-N-(4-(morpholin-2-yl)phenyl)-1H-pyrazole-3-carboxamide

[0809]

[0810] Step 1: Preparation of ethyl 5-cyclopropyl-1H-pyrazole-3-carboxylic acid ester

[0811]

[0812] Using ethyl diazonyl acetate and cyclopropylacetaldehyde as raw materials, ethyl 5-cyclopropyl H-pyrazole-3-carboxylic acid ester was obtained by referring to step 7 of Example 1.

[0813] MS m / z(ESI): 181.1 [M+H] + .

[0814] Step 2: Preparation of ethyl 4-chloro-5-cyclopropyl-1H-pyrazole-3-carboxylic acid ester

[0815]

[0816] Referring to step 8 of Example 1, ethyl 4-chloro-5-cyclopropyl-1H-pyrazole-3-carboxylic acid ester was obtained.

[0817] MS m / z(ESI): 215.0 [M+H] + .

[0818] Step 3: Preparation of 4-chloro-5-cyclopropyl-1H-pyrazole-3-carboxylic acid

[0819]

[0820] Referring to step nine of Example 1, 4-chloro-5-cyclopropyl-1H-pyrazole-3-carboxylic acid was obtained.

[0821] MS m / z(ESI): 187.0 [M+H] + .

[0822] Step 4: Preparation of tert-butyl 2-(4-(4-chloro-5-cyclopropyl-1H-pyrazole-3-carbonoxylazolylamino(oxiamethoxylamino))phenyl)morpholine-4-carboxylic acid ester

[0823]

[0824] Referring to step 10 of Example 1, tert-butyl 2-(4-(4-chloro-5-cyclopropyl-1H-pyrazole-3-carbon oxaloylamino(oxadiamino))phenyl)morpholine-4-carboxylic acid ester was obtained.

[0825] MS m / z (ESI): 447.2 [M+H] + .

[0826] Step 5: Preparation of 4-chloro-5-cyclopropyl-N-(4-(morpholin-2-yl)phenyl)-1H-pyrazole-3-carboxamide

[0827]

[0828] Referring to step 11 of Example 1, 4-chloro-5-cyclopropyl-N-(4-(morpholin-2-yl)phenyl)-1H-pyrazole-3-carboxamide was obtained.

[0829] MS m / z (ESI): 347.1 [M+H] + .

[0830] Example 28

[0831] N-(4-(1,4-oxaheptan-2-yl)phenyl)-4-chloro-5-methyl-1H-pyrazole-3-carboxamide

[0832]

[0833] Step 1: Preparation of N-(4-(1,4-oxacloheptan-2-yl)phenyl)-4-chloro-5-methyl-1H-pyrazole-3-carboxamide

[0834]

[0835] Referring to steps eight to eleven of Example 1, N-(4-(1,4-oxapron-2-yl)phenyl)-4-chloro-5-methyl-1H-pyrazole-3-carboxamide was obtained.

[0836] MS m / z (ESI): 335.1 [M+H] + .

[0837] Example 29

[0838] 5-Cyclopropyl-N-(4-(morpholin-2-yl)phenyl)-1H-pyrazole-3-carboxamide

[0839]

[0840] Step 1: Preparation of 5-cyclopropyl-N-(4-(morpholin-2-yl)phenyl)-1H-pyrazole-3-carboxamide

[0841]

[0842] Using ethyl 5-cyclopropyl-1H-pyrazole-3-carboxylic acid ester as a raw material, 5-cyclopropyl-N-(4-(morpholin-2-yl)phenyl)-1H-pyrazole-3-carboxamide was obtained by referring to steps 10 to 12 of Example 1.

[0843] MS m / z (ESI): 313.2 [M+H] + .

[0844] Preparation of a single configuration in Examples 2-29

[0845]

[0846]

[0847]

[0848]

[0849]

[0850]

[0851]

[0852]

[0853] Biological testing evaluation

[0854] The present invention will be further described and explained below with reference to test examples, but these embodiments are not intended to limit the scope of the present invention.

[0855] Test Example 1: Determination of the effect of the compound of the present invention on cAMP levels in cells stably expressing the TAAR1 receptor.

[0856] 1. Experimental objective:

[0857] The activation effect of the compound on the TAAR1 receptor was measured.

[0858] 2. Experimental instruments and reagents:

[0859] 2.1 Instruments:

[0860] 384-well test plate (Perkin Elmer; 6007680)

[0861] 96-well conical btm PP Plt nature RNASE / Dnase-free plate (ThermoFisher; 249944)

[0862] EnVision (Perkin Elmer)

[0863] 2.2 Reagents:

[0864] Fetal Bovine Serum (Gibco, 10999141)

[0865] Ham's F-12K(Kaighn's)Medium(Hyclone; SH30526.01)

[0866] Penicillin-Streptomycin, Liquid (Gibco; 15140122)

[0867] Hygromycin B

[0868] BSA stabilizer (Perkin Elmer; CR84-100)

[0869] cAMP kit (Cisbio; 62AM4PEC)

[0870] IBMX (Sigma; I5879)

[0871] HEPES (Gibco; 15630080)

[0872] HBSS (Gibco; 14025076)

[0873] TrypLE(ThermoFisher;12604021)

[0874] DMEM

[0875] 3. Experimental methods:

[0876] 1) Preparation of experimental buffer: 1*HBSS + 20mM HEPES + 0.1% BSA + 500μM IBMX.

[0877] 2) Complete culture medium:

[0878] Ham's F12K+10%Fetal Bovine Serum+1*Penicillin-Streptomycin+200μg / mLHygromycin B for CHO

[0879] DMEM+10%Fetal Bovine Serum+1*Penicillin-Streptomycin+200μg / mLHygromycin B for HEK293

[0880] 3) The TAAR1 cell line was cultured in complete medium at 37°C and 5% CO2. After TrypLE digestion, the cells were resuspended in experimental buffer and seeded into 384 cell culture plates at a seeding density of 8000 cells / 15 μL / well.

[0881] 4) Dilute the compound with experimental buffer, add 5 μL of the compound to each well, and incubate at 37°C for 30 minutes.

[0882] 5) Freeze-thaw cAMP-d2 and Anti-cAMP-Eu 3+ Dilute it 20-fold with lysis buffer; add 10 μL of cAMP-d2 to the experimental wells, followed by 10 μL of Anti-cAMP-Eu. 3+ Transfer the solution to the experimental wells; centrifuge the reaction plate at 200g for 30s at room temperature, let it stand at 25℃ for 1h, and then collect data using Envision.

[0883] 4. Experimental data processing methods:

[0884] 1)Z'factor=1-3*(SDMax+SDMin) / (MeanMax-MeanMin);

[0885] 2)CVMax=(SDMax / MeanMax)*100%;

[0886] 3)CVMin=(SDMin / MeanMin)*100%;

[0887] 4) S / B = Single / Background;

[0888] 5) Calculate compound EC using GraphPad nonlinear fitting formula. 50 :

[0889] Y=Bottom+(Top-Bottom) / (1+10^((LogEC 50 -X)*HillSlope))

[0890] X: Log value of compound concentration; Y: Activation%

[0891] 5. Experimental Results:

[0892] Effects of the compound on cAMP in EC2 cells stably expressing the TAAR1 receptor 50 value

[0893] 1 4.9 1-S 4.1 2 7.1 2-S 4.0 5-S 11.0 14 8.8 27-S 3.0 29-S 3.3

[0894] 6. Experimental Conclusion:

[0895] The data above show that the compounds in the embodiments of this invention exhibit good agonistic activity in experiments on the effect of stable TAAR1 receptor expression on cAMP.

[0896] Test Example 2: Determination of the in vitro binding activity of the compound of the present invention to the 5HT1A receptor

[0897] 1. Experimental objective:

[0898] The in vitro binding effect of the compound on the 5HT1A receptor was measured.

[0899] 2. Experimental instruments and reagents:

[0900] 2.1 Instruments:

[0901] vortex mixer IKA MS3 basic Electric thermostatic incubator Shanghai Yiheng DHP-9032 Microplate vibrating screen VWR 12620-928 TopCount PerkinElmer NTX Universal Harvester Perkin Elmer UNIFILTER-96

[0902] 2.2 Reagents:

[0903]

[0904]

[0905] 3. Experimental methods:

[0906] 1) Preparation of buffer solution

[0907] Experimental buffer: 50mM Tris-HCl pH 7.4, 10mM MgSO4, 0.5mM EDTA, 0.1% ascorbicacid; Washing buffer: 50mM Tris-HCl pH 7.4, stored at 4℃; 0.5% PEI solution: 0.5mL PEI in 100mL ddH2O, stored at 4℃.

[0908] 2) Add 5 μL of the compound and 100 μL of experimental buffer to the 96-well deep plate.

[0909] 3) Add 1.5 μL of cell membrane and 298.5 μL of experimental buffer to each well.

[0910] 4) Add 0.5 Nm of [3H]-8-Hydroxy-DPAT to 100 M l of experimental buffer and incubate at 27 °C for 60 minutes.

[0911] 5) Pretreat the filter plate with 0.5% PEI for 1 hour. Wash the filter plate twice with 1 ml of washing solution per well, transfer the membrane mixture to the filter plate, and wash 4 times.

[0912] 6) Incubate at 55℃ for 10 minutes.

[0913] 7) Add 40ml of ULTIMA GOLD and read CDM using TopCount.

[0914] 4. Experimental data processing methods:

[0915] 1)Z'factor=1-3*(SDMax+SDMin) / (MeanMax-MeanMin);

[0916] 2)CVMax=(SDMax / MeanMax)*100%;

[0917] 3)CVMin=(SDMin / MeanMin)*100%;

[0918] 4) S / B = Single / Background;

[0919] 5) Calculate compound EC using a nonlinear fitting formula. 50 :

[0920] Y=Bottom+(Top-Bottom) / (1+10^((LogEC 50 -X)*HillSlope))

[0921] X: log value of compound concentration; Y: Activation%

[0922] 5. Experimental Results:

[0923] Through the above scheme, it is concluded that the compound presented in the present invention exhibits binding EC in cells stably expressing 5HT1A receptor 50 value is about 0.1 nM to 1000 nM.

[0924] In some embodiments, the EC for binding exhibited by the compound of the present invention in cells stably expressing 5HT1A receptor 50 value is less than about 1000 nM, preferably the compound is less than about 500 nM, more preferably less than about 100 nM, still more preferably less than about 50 nM, and most preferably less than 10 nM or even less than about 1 nM among the compounds listed in the present invention.

[0925] 6. Experimental Conclusion:

[0926] The above data show that the example compounds presented in the present invention exhibit good binding effect on 5HT1A receptor cells.

[0927] Test Example 3: Determination of Pharmacokinetics in Balb / C Mice

[0928] 1. Research Objective:

[0929] Using Balb / C mice as test animals, the pharmacokinetic behavior in plasma of the following example compounds after oral administration at a dose of 5 mg / kg in mice was studied.

[0930] 2. Test Protocol

[0931] 2.1 Test Drug:

[0932] The examples of the present invention, prepared in-house.

[0933] 2.2 Test Animal:

[0934] 21 Balb / C Mice per example, male, supplied by Shanghai Jiesijie Experimental Animal Co., Ltd., Animal Production License No. (SCXK (Hu) 2013-0006 No. 311620400001794).

[0935] 2.3 Drug Preparation:

[0936] 0.5% CMC-Na (1% Tween 80), dissolved by ultrasonication, prepared into a clear solution or homogeneous suspension.

[0937] 2.3 Administration:

[0938] Male Balb / C mice were fasted overnight and then orally administered at a dose of 5 mg / kg in a volume of 10 mL / kg.

[0939] 2.4 Sample Collection:

[0940] Before and after drug administration, 0.1 mL of blood was collected from the heart of mice at 0, 0.25, 0.5, 1, 2, 4, 8 and 24 hours. The blood was placed in EDTA-K2 tubes and centrifuged at 6000 rpm for 6 min at 4℃ to separate the plasma. After dissection, the brain tissue was weighed and stored at -80℃.

[0941] 2.5 Sample preparation:

[0942] 1) Add the tumor tissue to methanol and water at a ratio of 1:3, homogenize, centrifuge and collect the supernatant. Take 40 μL of the tumor homogenate supernatant and plasma sample, add 160 μL of acetonitrile to precipitate, mix and centrifuge at 3500×g for 5-20 minutes.

[0943] 2) Take 100 μL of the supernatant solution after treatment and analyze the concentration of the analyte by LC / MS / MS.

[0944] 2.6 Liquid Chromatography Analysis

[0945] • Liquid phase conditions: Shimadzu LC-20AD pump

[0946] Mass spectrometry conditions: AB Sciex API 4000 mass spectrometer

[0947] • Column: phenomenex Gemiu 5um C18 50×4.6mm

[0948] • Mobile phase: Solution A is a 0.1% formic acid aqueous solution, and solution B is acetonitrile.

[0949] • Flow rate: 0.8 mL / min

[0950] • Elution time: 0-4.0 minutes, eluent as follows:

[0951]

[0952]

[0953] 3. Experimental Results and Analysis

[0954] The main pharmacokinetic parameters were calculated using WinNonlin 8.2. The results of the mouse pharmacokinetic experiment are shown in the table below:

[0955]

[0956] 4. Experimental conclusions:

[0957] As can be seen from the results of the mouse pharmacokinetics experiment in the table, the compounds in the embodiments of the present invention exhibit good metabolic properties, and the AUC and maximum plasma concentration C in plasma and brain tissue are [data missing]. max They all performed well.

Claims

1. A compound or a pharmaceutically acceptable salt thereof, characterized in that, The specific structure of the compound is as follows: or .

2. A compound or a pharmaceutically acceptable salt thereof, characterized in that, The specific structure of the compound is as follows: or .

3. A pharmaceutical composition comprising a therapeutically effective dose of the compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

4. The use of the compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 3 in the preparation of a TAAR1 receptor agonist medicament.

5. The use of the compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 3 in the preparation of a medicament for the treatment, prevention or control of schizophrenia.

6. The use of the compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 3 in the preparation of a medicament for the treatment, prevention or control of acute schizophrenia, chronic schizophrenia, NOS schizophrenia, paranoid schizophrenia, schizophrenia-like personality disorder or schizotypal personality disorder.

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