Piperidine-substituted benzoic acid compounds, pharmaceutical compositions thereof and uses thereof

Abstract

The present invention discloses a piperidine-substituted benzoic acid compound, a pharmaceutical composition thereof, and its use. The piperidine-substituted benzoic acid compound of the present invention is a compound represented by Formula I, a stereoisomer thereof, a tautomer thereof, an isotope-labeled compound thereof, or a pharmaceutically acceptable salt of any of the foregoing. The compound has good inhibitory activity against complement factor B, good affinity for complement factor B, hemolytic activity in the alternative complement pathway, and inhibitory activity in the alternative complement pathway. TIFF2025541667000344.tif11998s

Description

[Technical Field]

[0001] This application claims priority from Chinese Patent Application No. 2022114146910, filed on November 11, 2022. This application incorporates the entire text of the above Chinese patent application by reference. The present invention relates to the pharmaceutical field, specifically to piperidine-substituted benzoic acid compounds, their pharmaceutical compositions and uses. [Background technology]

[0002] The complement system comprises a group of nonspecific globulins present in normal fresh serum of humans and vertebrates. They are involved in enzymatic activity. In the late 19th century, studies of immunolytic and immunohemolytic reactions revealed that these globulins were substances that aided in the lysis of cells by antibodies, and were named complement. Complement consists of nine components, named C1, C2, C3, ..., and C9. C1 has three subunits: C1q, C1r, and C1s. In addition to C1q, many of the other components exist in serum as enzyme precursors and can exert their biological activities after activation by antigen-antibody complexes or other factors. This is called the classic complement activation pathway. Over the past 20 years, the alternative activation pathway and several other activation pathways have been discovered, along with the discovery of numerous other serum factors involved in the activation of these pathways. Furthermore, numerous inactivated complement factors have been discovered. Therefore, factors involved in complement activation and its regulation are collectively referred to as the complement system. The organism regulates the activation process of the complement system through a complex series of factors to keep it moderate. For example, the C3b positive feedback pathway can amplify the biological effects of complement. However, excessive activation of the complement system not only wastes a large number of complement components, reducing the body's anti-infective capabilities, but also generates large amounts of activated substances during the activation process, which can trigger severe inflammatory responses and tissue damage, leading to pathological processes. Such excessive activation and its harmful consequences can be avoided through regulatory mechanisms. Although the three complement activation pathways have different activation mechanisms and activation sequences, they share a common terminal pathway. Activation of the bypass pathway is independent of antigen-antibody complexes. Typically, C3b deposited on cell surfaces binds to factor B, making it susceptible to degradation by factor D in serum. During this process, factor B is cleaved into Ba and Bb. The C3b-Bb complex then becomes the C3 transforming enzyme C3bBb in the bypass pathway. In this process, complement factor B plays an early and central role in activating the bypass pathway of the complement cascade.C3b is the product of C3 decomposition by C3 convertase, and the bypass pathway is a component of C3 convertase, forming a feedback amplification mechanism in which the classical pathway and the bypass pathway influence each other.Currently, research has revealed that various diseases, including hematological, autoimmune, inflammatory, and neurodegenerative, are associated with dysfunction of the complement system.

[0003] Paroxysmal nocturnal hemoglobinuria (PNH) is a non-malignant clonal disease caused by mutations in one or more acquired somatic PIG-A (phosphotidyl inpositol glycan complementation group A) genes in hematopoietic stem cells. PIG-A mutations cause abnormalities in glycosylphosphatidylinositol (GPI) synthesis, resulting in the loss of a group of membrane proteins with GPI anchors, including CD16, CD55, and CD59. While typical PNH manifests clinically as chronic intravascular hemolysis, hemopoietic dysfunction, and recurrent thrombosis, chronic intravascular hemolysis, hemoglobinuria, and iron-containing flavinuria, patients with PNH often present with atypical symptoms, including abrupt onset, prolonged course, and varying severity. The peak age of onset is between 20 and 40 years old, with cases occurring separately in children and the elderly, with a significantly higher male prevalence than females. Currently, this disease can only be treated with immunotherapy, using eculizumab monoclonal antibody to alleviate symptoms. However, eculizumab monoclonal antibody is expensive and requires patients to receive continuous blood transfusions via intravenous infusion. Therefore, the development of novel complement inhibitors that meet clinical needs is important for patients.

[0004] C3 nephropathy (C3G) is a disease characterized by abnormal deposition of complement C3 in the glomeruli due to genetic or acquired regulatory defects in the complement bypass pathway (AP). In 2015, the latest renal pathology typing proposed the independent classification of C3G as an immune-mediated nephropathy. The disease is characterized primarily by immunofluorescent or immunohistochemical glomerular C3 deposition, with minimal or no immunoglobulin deposition. Depending on the location of dense matter deposits on electron microscopy, the clinical manifestations of C3G differ primarily between dense matter deposition disease (DDD) and C3 glomerulonephritis (C3GN). C3G often presents with asymptomatic hematuria, proteinuria, or nephritic syndrome, nephrotic syndrome, and ultimately renal dysfunction. Research has demonstrated certain differences in the clinical manifestations of DDD and C3GN. Compared with DDD, the clinical manifestations of C3GN lack specificity, and while there is no obvious lipid metabolism disorder, some patients may develop monoclonal C-globulinopathy. C3GN has a better prognosis than DDD patients, with a lower risk of progression to ESRD. CFHR5 patients present with trace proteinuria and microscopic or macroscopic hematuria, similar to the clinical symptoms of IgA nephropathy. However, serum C3 levels are nearly normal, suggesting that C3 hyperactivation is limited to the glomerulus. CFHR5 patients are more likely to progress to ESRD in children, particularly males. A retrospective study found that treatment with chlorphenate (MMF) or rituximab failed to alter renal survival in C3G patients. Because hormonal therapy is effective only in a subset of C3GN patients and not in DDD patients, the development of novel AP pathway inhibitors to meet clinical needs is urgently needed.

[0005] Currently, there are no small molecule drugs that inhibit complement factor B in clinical use. The only known and currently under investigation drugs are oligonucleotide-based drugs developed by IONIS Pharmaceuticals Inc., which are complement factor B (CFB)-specific inhibitors and are used to treat, prevent, or alleviate diseases associated with complement bypass pathway disorders.

[0006] Small molecule complement factor B inhibitors developed by Novartis AG (W0201508939) treat diseases such as age-related macular degeneration (AMD) (W02013164802 W02013192345 W02014143638 W02015009616 W02015066241), and diseases such as C3G and IgAN (W02019043609 A1). Small molecule complement factor D inhibitors developed by Achillion Pharmaceuticals Inc. treat diseases such as age-related macular degeneration (AMD) (W0201805552). Small molecule complement factor B inhibitors developed by Shanghai Meiyue Biotechnology Development Co., Ltd. treat diseases such as age-related macular degeneration (AMD) (CN114057758A). CN114057692A), and a small molecule complement factor B inhibitor developed by Nanjing Mingde New Drug Research and Development Co., Ltd. treats diseases such as age-related macular degeneration (AMD) (WO2022143940 A1).

[0007] China ranks first in the world in the number of patients with chronic kidney disease (CKD), and there are no small molecule targeted drugs for complement factor B on the market. The immunotherapy monoclonal antibody eculizumab is currently the first-line treatment, but it is expensive, has poor healing, causes anemia in patients, and requires maintenance blood transfusions. Therefore, there is a strong clinical need for small molecule orally administered complement inhibitors. Summary of the Invention

[0008] The problem to be solved by the present invention is the limited number of small molecule inhibitors of complement factor B available, and the present invention provides a compound as an inhibitor of complement factor B, its pharmaceutical composition, and applications. The compound has good inhibitory activity against complement factor B and can be used to treat diseases such as paroxysmal nocturnal hemoglobinuria, C3 nephropathy, IgA nephropathy, and age-related macular degeneration (AMD).

[0009] The present invention provides a compound represented by formula I, a stereoisomer thereof, a tautomer thereof, an isotopically labeled compound thereof, or a pharmaceutically acceptable salt of any one of the foregoing (a compound represented by formula I, a stereoisomer thereof, a tautomer thereof, or an isotopically labeled compound thereof).

[0010] [ka]

[0011] however, p is 0, 1, or 2; L is a single bond, NR 0 , O or S; R 1 is hydrogen, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-6 Cycloalkyl groups, C 3-6 Cycloalkenyl group, C 3-6 Cycloalkynyl group, -C 1-3 Alkyl-C 3-6 a cycloalkyl group, "a 3- to 12-membered heterocycloalkyl group in which the heteroatom is one, two, or three selected from N, O, and S, and the number of heteroatoms is one, two, or three," -C 1-3 alkyl group - "a 3- to 12-membered heterocycloalkyl group in which the heteroatom is one, two, or three selected from N, O, and S, and the number of heteroatoms is one, two, or three" or one or more R a (e.g., 1, 2, 3, 4, or 5, R a If there are multiple, R a may be the same or different) and 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-6 Cycloalkyl groups, C 3-6 Cycloalkenyl group, C 3-6 Cycloalkynyl group, -C 1-3 Alkyl-C 3-6 a cycloalkyl group, "a 3- to 12-membered heterocycloalkyl group in which the heteroatom is one, two, or three selected from N, O, and S, and the number of heteroatoms is one, two, or three" or -C 1-3alkyl group - "a 3- to 12-membered heterocycloalkyl group in which the heteroatom is one, two, or three selected from N, O, and S, and the number of heteroatoms is one, two, or three"; m and n are each independently 0, 1, 2, 3, or 4; R 2 , R 3 , R 4 , R 5 , R 7 , R 8 and R 9 are each independently hydrogen, halogen, OH, CN, NO2, NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl, C 3-6 Cycloalkynyl, -C 1-3 Alkyl-C 3-6 cycloalkyl, or one or more R b (e.g., 2, 3, 4, or 5, R b If there are multiple, R b may be the same or different) and 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl, C 3-6 Cycloalkynyl or -C 1-3 Alkyl-C 3-6 is cycloalkyl, R 0 and R 6 are each independently hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl, C 3-6 Cycloalkynyl, -C 1-3 Alkyl-C 3-6 cycloalkyl, or one or more R c(e.g., 2, 3, 4, or 5, R c If there are multiple, R c may be the same or different) and 1-6 Alkyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl, C 3-6 Cycloalkynyl or -C 1-3 Alkyl-C 3-6 is cycloalkyl, X is -C(=O)-, -C(=NR 10 )-, -C(=S)-, -CFR 11 -, -NR 12 -, -CR 13 R 14 -CR 15 R 16 -, -S- or -S(=O)2-; R 11 , R 13 , R 14 , R 15 and R 16 are each independently hydrogen, halogen, OH, CN, NO2, NH2, C 1-6 Alkyl, C 3-6 cycloalkyl, or one or more R d (e.g., 2, 3, 4, or 5, R d If there are multiple, R d may be the same or different) and 1-6 Alkyl or C 3-6 is cycloalkyl, R 10 and R 12 are each independently hydrogen, C 1-6 alkyl or one or more R e (e.g., 2, 3, 4, or 5, R e If there are multiple, R e may be the same or different) 1-6 is alkyl, R a , R b , R c , R d and Re are each independently halogen, OH, CN, NO2, or NH2.

[0012] In some preferred embodiments of the present invention, some groups of the compound represented by the above formula I, its stereoisomer, its tautomer, its isotopically labeled product, or a pharmaceutically acceptable salt of any one of the above (the compound represented by the above formula I, its stereoisomer, its tautomer, or its isotopically labeled product) are defined as follows, and groups not mentioned are the same as those described in any one aspect of the present invention (abbreviated as "some aspects of the present invention").

[0013] In one embodiment of the present invention, R 0 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 and R 16 In the above, C 1-6 Alkyl and Substituted C 1-6 C in alkyl 1-6 Alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, or hexyl, for example, methyl or ethyl.

[0014] In one embodiment of the present invention, R 2 , R 3 , R 4 , R 5 , R 7 , R 8 and R 9 In the above, C 1-6 Alkoxy and Substituted C 1-6 C in alkyl 1-6Alkoxy is independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy, for example methoxy.

[0015] In one embodiment of the present invention, R 0 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 11 , R 13 , R 14 , R 15 and R 16 In the above, C 3-6 Cycloalkyl, -C 1-3 Alkyl-C 3-6 Cycloalkyl, substituted C 3-6 Cycloalkyl and substituted -C 1-3 Alkyl-C 3-6 C in cycloalkyl 3-6 Cycloalkyl is independently cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, for example cyclopropyl or cyclobutyl.

[0016] In one embodiment of the present invention, R 2 , R 3 , R 4 , R 5 , R 7 , R 8 , R 9 , R 11 , R 13 , R 14 , R 15 , R 16 , R a , R b , R c , R d and R e wherein the halogens are independently fluorine, chlorine, bromine or iodine, for example fluorine.

[0017] In one embodiment of the invention, L is a single bond, O or S, preferably a single bond or O.

[0018] In some embodiments of the invention, p is 1.

[0019] In one embodiment of the present invention, R 1 is C 1-6 Alkyl, C 3-6 Cycloalkyl, -C 1-3 Alkyl-C 3-6 cycloalkyl, or one or more R a the following groups substituted with: 1-6 Alkyl group, C 3-6 Cycloalkyl or -C 1-3 Alkyl-C 3-6 It is cycloalkyl.

[0020] In one embodiment of the present invention, R a are each independently a halogen, for example, fluorine.

[0021] In one embodiment of the present invention, R 2 , R 3 , R 4 , R 5 , R 6 and R 8 is hydrogen.

[0022] In one embodiment of the present invention, R 2 is hydrogen or OH. In some embodiments of the present invention, R 3 , R 4 , R 5 , R 6 and R 8 is hydrogen.

[0023] In one embodiment of the present invention, R 7 is C 1-6 It is alkyl, for example, methyl.

[0024] In some embodiments of the present invention, X is -C(=O)-, -CFR 11 -, -NR 12-, -S- or -S(=O)2-, preferably -C(=O)- or -NR 12 -or -S(=O)2-.

[0025] In one embodiment of the present invention, R 9 is C 1-6 An alkoxy group, for example, methoxy.

[0026] In one embodiment of the present invention, R 11 is H or a halogen.

[0027] In one embodiment of the present invention, R 12 is hydrogen or C 1-6 It is alkyl, preferably hydrogen.

[0028] In some embodiments of the invention, m is 0 or 1, for example 0.

[0029] In some embodiments of the invention, n is 0.

[0030] In one embodiment of the invention, L is a single bond,

[0031] [ka]

[0032] (for example,

[0033] [ka]

[0034] or

[0035] [ka]

[0036] (for example,

[0037] [ka]

[0038] where the a-terminus is R 1 is preferably a single bond or

[0039] [ka]

[0040] (for example,

[0041] [ka]

[0042] is.

[0043] In one embodiment of the present invention, R 1 teeth,

[0044] [ka]

[0045] (for example,

[0046] [ka]

[0047] or

[0048] [ka]

[0049] or

[0050] [ka]

[0051] and preferably

[0052] [ka]

[0053] (for example,

[0054] [ka]

[0055] is.

[0056] In one embodiment of the present invention, R 1 teeth,

[0057] [ka]

[0058] and preferably

[0059] [ka]

[0060] is.

[0061] In one embodiment of the invention, -L-R1 is

[0062] [ka]

[0063] (for example,

[0064] [ka]

[0065] (for example,

[0066] [ka]

[0067] (for example,

[0068] [ka]

[0069] (for example,

[0070] [ka]

[0071] (for example,

[0072] [ka]

[0073] (for example,

[0074] [ka]

[0075] (for example,

[0076] [ka]

[0077] (for example,

[0078] [ka]

[0079] (for example,

[0080] [ka]

[0081] (for example,

[0082] [ka]

[0083] (for example,

[0084] [ka]

[0085] (for example,

[0086] [ka]

[0087] and preferably

[0088] [ka]

[0089] (for example,

[0090] [ka]

[0091] (for example,

[0092] [ka]

[0093] (for example,

[0094] [ka]

[0095] (for example,

[0096] [ka]

[0097] (for example,

[0098] [ka]

[0099] (for example,

[0100] [ka]

[0101] (for example,

[0102] [ka]

[0103] (for example,

[0104] [ka]

[0105] is.

[0106] In one embodiment of the present invention, -LR 1 teeth,

[0107] [ka]

[0108] and preferably

[0109] [ka]

[0110] is.

[0111] In one embodiment of the invention, X is

[0112] [ka]

[0113] and preferably

[0114] [ka]

[0115] and more preferably

[0116] [ka]

[0117] is.

[0118] In one embodiment of the present invention,

[0119] [ka]

[0120] teeth

[0121] [ka]

[0122] is.

[0123] In one embodiment of the invention, L is a single bond, O or S, preferably a single bond or O, p is 1, R 1 is C 1-6 Alkyl group, C 3-6 Cycloalkyl groups, -C 1-3 Alkyl-C 3-6 a cycloalkyl group or one or more R a the following groups substituted with: C 1-6 Alkyl group, C 3-6 Cycloalkyl or -C 1-3 Alkyl-C 3-6 is cycloalkyl, R a are each independently a halogen, for example, fluorine; R 2 is an OH group, R 3 , R 4 , R 5 , R 6 and R 8 is hydrogen, R 7 is C 1-6 an alkyl group, such as methyl; X is -C(=O)-, -CFR 11 -, -NR 12 -, -S- or -S(=O)2-, preferably -C(=O)- or -NR 12 - or -S(=O)2-, R 9 is C 1-6 an alkoxy group, for example a methoxy group; R 11 is H or a halogen, R 12 is hydrogen or C 1-6 alkyl, preferably hydrogen; m is 0 or 1, preferably 0; n is 0.

[0124] In one embodiment of the present invention, the compound represented by formula (I) has a structure represented by formula (I)-1, formula (I)-2, formula (I)-3 or formula (I)-4.

[0125] [ka]

[0126] Preferably, the compound represented by formula I and formula (I) is represented by formula (I)-1 and formula (I)-2, and more preferably, the compound represented by formula (I) is represented by formula (I)-2.

[0127] In one embodiment of the present invention, the compound represented by formula (I) is selected from any one of the following compounds:

[0128] [ka]

[0129] [ka]

[0130] [ka]

[0131] [ka]

[0132] [ka]

[0133] The present invention further comprises: (1) A compound represented by any one of the above formula (I), a stereoisomer thereof, a tautomer thereof, an isotopically labeled compound thereof, or a pharmaceutically acceptable salt of any one of the above (referring to a compound represented by the above formula (I), a stereoisomer thereof, a tautomer thereof, or an isotopically labeled compound thereof); and (2) a pharmaceutically acceptable carrier.

[0134] The present invention further provides use of a compound represented by formula (I) described in any one of the above, a stereoisomer thereof, a tautomer thereof, an isotopically labeled compound thereof, or a pharmaceutically acceptable salt of any one of the above (referring to a compound represented by formula (I), a stereoisomer thereof, a tautomer thereof, or an isotopically labeled compound thereof), or a pharmaceutical composition described in any one of the above, in the manufacture of a medicament for treating and / or preventing a complement factor B-mediated disease.

[0135] The present invention further provides a method for treating and / or preventing a complement factor B-mediated disease, comprising administering a therapeutically effective amount of a substance X to a desired individual, wherein the substance X is a compound represented by formula (I) described in any one of the above, a stereoisomer thereof, a tautomer thereof, an isotopically labeled substance thereof, or a pharmaceutically acceptable salt of any one of the above (referring to the compound represented by formula (I), a stereoisomer thereof, a tautomer thereof, or an isotopically labeled substance thereof), or a pharmaceutical composition described in any one of the above.

[0136] Preferably, the complement factor B mediated disease is a blood disease, an autoimmune disease, an inflammatory disease and a neurological disease, or a disease associated with a dysfunction of the complement system.

[0137] Furthermore, the complement factor B mediated diseases include, but are not limited to, paroxysmal nocturnal hemoglobinuria, C3 nephropathy, macular degeneration, age-related macular degeneration, and the like.

[0138] The present invention further provides use of a compound represented by formula (I) described in any one of the above items, a stereoisomer thereof, a tautomer thereof, an isotopically labeled compound thereof, or a pharmaceutically acceptable salt of any one of the above (referring to a compound represented by formula (I) described above, a stereoisomer thereof, a tautomer thereof, or an isotopically labeled compound thereof), or a pharmaceutical composition described in any one of the above items, in the manufacture of a complement factor B inhibitor.

[0139] In the above-mentioned use, the complement factor B inhibitor may be used in vivo in a mammal or in vitro, mainly for experimental purposes, for example, as a standard or control sample for comparison, or to prepare a kit according to conventional methods in the art to provide rapid detection of the inhibitory effect of complement factor B.

[0140] The present invention further provides compounds represented by formula (II)-1, formula (II)-2 or formula (II)-3.

[0141] [ka]

[0142] where L and R 1 is as defined in any one of the preceding paragraphs.

[0143] In one embodiment of the present invention, the compound represented by formula (II)-1 is selected from any one of the following compounds:

[0144] [ka]

[0145] In one embodiment of the present invention, the compound represented by formula (II)-2 is selected from any one of the following compounds:

[0146] [ka]

[0147] In one embodiment of the present invention, the compound represented by formula (II)-3 is selected from any one of the following compounds:

[0148] [ka]

[0149] The present invention further provides a compound selected from any one of the following compounds:

[0150] [ka]

[0151] Unless otherwise defined, all technical and scientific terms used herein have the standard meaning required in the field to which the category being protected belongs. In the event that there are multiple definitions for a term, the definition in this document shall prevail.

[0152] As used herein, the singular forms "a," "an," and "an" should be understood to include plural references unless otherwise specified. Also, the term "comprises" is not a closed term but an open limitation, i.e., it includes the subject matter set forth in the present invention but does not exclude other aspects.

[0153] Unless otherwise stated, the present invention employs conventional methods of mass spectrometry and elemental analysis, and each step and condition can refer to conventional operation steps and conditions in this field.

[0154] Unless otherwise explained, this invention employs standard nomenclature and standard laboratory steps and techniques in analytical chemistry, synthetic organic chemistry, and optics. In some cases, standard techniques are used for dry chemical synthesis, chemical analysis, and performance detection of light-emitting devices.

[0155] Furthermore, as should be explained, unless otherwise clearly indicated, the description method "independently" used in the present invention should be understood in a broad sense, and each of the described individuals is independent of each other and may be the same or different specific groups. More specifically, the description method "independently" may refer to specific options expressed between the same symbols in different groups not affecting each other, or may indicate that specific options expressed between the same symbols in the same group not affecting each other.

[0156] The term "alkyl group" refers to a group having a given number of carbon atoms (e.g., C 1-6 Alkyl refers to a straight or branched, saturated monovalent hydrocarbon radical having the following structure: alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, and the like.

[0157] The term "cycloalkyl group" refers to a cyclic, saturated, monovalent hydrocarbon group having a specified number of carbon atoms (e.g., C3-6) and is monocyclic. A cycloalkyl group is:

[0158] [ka]

[0159] Including, but not limited to, the following:

[0160] At the end of the structural fragment

[0161] [ka]

[0162] means that the structural fragment is linked to the rest of the molecule through that site. For example,

[0163] [ka]

[0164] means cyclohexyl.

[0165] A "-" at the end of a group indicates that the group is connected to the rest of the molecule through that site. For example, CH3-C(=O)- denotes an acetyl group.

[0166] The term "stereoisomer" refers to cis-trans isomers or optical isomers, where cis-trans isomers are isomers resulting from the inability to freely rotate about double bonds or single bonds of ring-forming carbon atoms, and optical isomers are stereoisomers with different optically active properties resulting from the absence of antiaxial symmetry in the molecule.

[0167] The term "isotopically labeled compound" refers to a compound in which the isotopic abundance of one or more atoms differs from the natural abundance. For example, one or more atoms in the compound are replaced with atoms that naturally occupy a lower mass number, and one hydrogen atom in the compound is replaced with deuterium.

[0168] The term "pharmaceutically acceptable" refers to something that is relatively non-toxic, safe, and suitable for use by patients.

[0169] The term "pharmaceutically acceptable salt" refers to a salt obtained by reacting a compound with a pharmaceutically acceptable acid or base. When a compound contains a relatively acidic functional group, a base addition salt can be obtained by contacting the compound with a sufficient amount of a pharmaceutically acceptable base in a suitable inert solvent. When a compound contains a relatively basic functional group, an acid addition salt can be obtained by contacting the compound with a sufficient amount of a pharmaceutically acceptable acid in a suitable inert solvent. For details, see Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl, Camille G. Wermuth, 2011, 2nd Revised Edition).

[0170] The term "therapeutically effective amount" refers to an amount administered to a patient that is sufficient to effectively treat a disease. The therapeutically effective amount varies depending on the type of compound, the type of disease, the severity of the disease, the age of the patient, etc., but can be adjusted appropriately by those skilled in the art.

[0171] The term "treatment" refers to eliminating the cause or alleviating the symptoms.

[0172] The term "prevention" means reducing the risk of developing a disease.

[0173] Unless contrary to common knowledge in the art, the above-mentioned preferable conditions can be arbitrarily combined to obtain preferable embodiments of the present invention.

[0174] All of the reagents and raw materials used in the present invention are commercially available.

[0175] The positive effect of the present invention is that the compounds of the present invention have inhibitory activity against complement factor B, and have good affinity with complement factor B, hemolytic activity of the alternative complement pathway, and inhibitory activity against the alternative complement pathway (in the complement hemolytic activity test, the inhibitory activity against complement factor B IC 50 All values ​​were <5 μM, and most were IC 50 <1.5 μM, with some IC 50 <1 μM). DETAILED DESCRIPTION OF THE INVENTION

[0176] The present invention will be further described below by way of examples, but the present invention is not limited to the scope of the examples. In the following examples, experimental methods for which specific conditions are not specified are selected according to conventional methods and conditions or according to product instructions.

[0177] The technical solution of the present invention will be described in more detail below with reference to specific examples. The following examples are intended to exemplify and explain the present invention, and should not be construed as limiting the scope of protection of the present invention. Any technology realized based on the above content of the present invention is included in the scope of protection of the present invention.

[0178] Unless otherwise specified, all materials and reagents used in the following examples are commercially available or can be prepared by known methods.

[0179] The structures of compounds are determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) are given in units of 10 ppm. NMR measurements were performed using a Bruker ASCEND-400Hz or 600Hz nuclear magnetometer, with deuterated dimethyl sulfoxide (DMSO-d6), tritiated chloroform (CDCl3), and tritiated methanol (CD3OD) as solvents, and tetramethylsilane (TMS) as the internal standard.

[0180] For MS measurements, Waters2695, Waters2988, and WatersQDa liquid mass spectrometers were used.

[0181] For HPLC measurements, Waters 2695 and Waters 2988 (Sunfire TM ) was used.

[0182] Unless otherwise specified, all reactions are carried out under an argon or nitrogen gas atmosphere. An argon or nitrogen gas atmosphere refers to an argon or nitrogen gas balloon of approximately 1 liter volume attached to the reaction flask. A hydrogen gas atmosphere refers to an argon or nitrogen gas balloon of approximately 1 liter volume attached to the reaction flask.

[0183] Unless otherwise specified, the reaction temperature is room temperature, and the temperature range is 20-30°C.

[0184] Unless otherwise specified, hydrochloric acid water refers to an aqueous solution of HCl with a mass concentration of 1%.

[0185] The intermediates according to the present invention may be synthesized by the typical reaction methods shown in the following schemes 1 to 5, and the compounds represented by formula (I) may be synthesized by the typical reaction methods shown in the following schemes 6 to 11, in which the concentrations and ratios of the respective raw materials are those generally used in the relevant reactions in this field.

[0186] Scheme 1:

[0187] [ka]

[0188] Scheme 2:

[0189] [ka]

[0190] Scheme 3:

[0191] [ka]

[0192] Scheme 4:

[0193] [ka]

[0194] Scheme 5:

[0195] [ka]

[0196] Scheme 6:

[0197] [ka]

[0198] Scheme 7:

[0199] [ka]

[0200] Scheme 8:

[0201] [ka]

[0202] Scheme 9:

[0203] [ka]

[0204] Scheme 10:

[0205] [ka]

[0206] Scheme 11:

[0207] [ka]

[0208] In Schemes 6 to 11, Y is -OR 1 , -SR 1 , -NR 0 R 1 or

[0209] [ka]

[0210] and R 0 and R 1 are defined as described in this specification.

[0211] For RP-HPLC, the following preparation method was used: Stationary phase: Waters SunFire Prep C18 OBD5um30×100mm Mobile phase: Gradient, 1% HCl in water / acetonitrile

[0212] Column chromatography is carried out using the following method. Stationary phase: 300-400 mesh silica gel Mobile phase gradient, petroleum ether / ethyl acetate, dichloromethane / methanol

[0213] Example 1 Synthesis of Intermediate 1-1: Benzyl 4-carbonyl-3,4-dihydropyridine-1(2H)-carboxylate

[0214] [ka]

[0215] 4-Methoxypyridine was placed in a 1 L four-neck flask and dissolved in 500 mL of methanol. When the internal temperature dropped below -78 °C, benzyl chloroformate (1 eq) in anhydrous tetrahydrofuran (50 mL) was added dropwise. After 3 hours, solid sodium borohydride was added in several portions. The reaction was continued for 3 hours while maintaining the internal temperature below -78 °C. 200 g of water was then added, followed by 15.3 mL of concentrated hydrochloric acid and 50 mL of water, maintaining the internal temperature at 0-5 °C. The mixture was washed twice with dichloromethane and 2N hydrochloric acid, and then twice with 3 wt% sodium carbonate solution. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound as a white solid. MS m / z (ESI): 232.20 [M+1]. 1 HNMR(400 MHz, CDCl3) δ 7.75 (s, 1H), 7.32 - 7.26 (m, 5H), 5.24 (d,J = 6.2 Hz, 1H), 5.17 (s, 2H), 3.97 - 3.90 (m, 2H), 2.49 - 2.41 (m, 2H).

[0216] Example 2 Synthesis of Intermediate 1-2: Benzyl (S)-2-(4-(methyl ester group <methoxycarbonyl>)phenyl)-4-carbonylpiperidine-1-carboxylate

[0217] [ka]

[0218] Intermediate 1-1, 4-methoxycarbonylphenylboronic acid (1 eq), (S)xylBINAP, and Rh(Acac)(C2H5)2 were placed in a 1 L reaction flask, and 1,4-dioxane (500 mL) and water (200 mL) were added. A stream of nitrogen gas was continuously bubbled through the reaction mixture for 10 min. The reaction mixture was then refluxed for 24 h, then returned to room temperature and concentrated under reduced pressure. Ethyl acetate was added, the mixture was dissolved, and the mixture was filtered with suction. The filtrate was purified by column chromatography to give the title compound. MS m / z (ESI): 368.20 [M+1]. 1 HNMR(600 MHz, CDCl3) δ 7.92 (d,J = 8.3 Hz, 2H), 7.33 - 7.20 (m, 7H), 5.75 (s, 1H), 5.21 - 5.08 (m, 2H), 4.24 (s, 1H), 3.84 (s, 3H), 3.16 (s, 1H), 2.95 - 2.79 (m, 2H), 2.53 - 2.43 (m, 1H), 2.32 (d,J = 16.1 Hz, 1H).

[0219] Example 3 Synthesis of Intermediate 1-3: Benzyl (2S,4S)-4-hydroxy-2-(4-(methyl ester group <methoxycarbonyl>)phenyl)piperidine-1-carboxylate

[0220] [ka]

[0221] Intermediate 1-2 was placed in a 500 mL four-neck flask, and 50 mL of dichloromethane and 50 mL of carbon tetrachloride were added to the reaction flask. (R)-(+)-2-methyl-CBS-oxaborane was dissolved in 30 mL of toluene, and the mixture was purged with nitrogen gas and maintained at an internal temperature of 78 °C. BH3 / THF was added dropwise, and the internal temperature was maintained at 78 °C until the addition was complete. After 5 hours, the reaction was quenched by adding water, and the mixture was extracted three times with ethyl acetate. The combined organic phases were concentrated under reduced pressure to give the title compound as a white solid (9.5 g, yield: 95.4%). MS m / z (ESI): 380.20 [M+1]. 1HNMR(400 MHz, CDCl3) δ 7.93 (dd,J = 8.5, 1.9 Hz, 2H), 7.32 - 7.20 (m, 7H), 5.62 (s, 1H), 5.10 (d,J = 21.8 Hz, 2H), 4.15 (dd,J = 34.6, 16.9 Hz, 1H), 3.84 (d,J = 3.2 Hz, 3H), 3.73 - 3.63 (m, 1H), 2.77 (td,J = 13.7, 2.9 Hz, 1H), 2.57 (d,J = 13.3 Hz, 1H), 1.86 - 1.73 (m, 2H), 1.42 (dd,J = 11.8, 7.1 Hz, 1H).

[0222] Example 4 Synthesis of Intermediate 1-4: Benzyl (2S,4S)-4-ethoxy-2-(4-(methyl ester group <methoxycarbonyl>)phenyl)piperidine-1-carboxylate

[0223] [ka]

[0224] Sodium hydride was placed in a 50 mL three-neck flask, 10 mL of anhydrous N,N-dimethylformamide was added, and the mixture was left in an ice bath for 10 minutes. Intermediate 1-3 was then dissolved in 10 mL of anhydrous N,N-dimethylformamide and added dropwise to the reaction flask. After 30 minutes, ethyl iodide (1 eq) was added dropwise. 30 minutes after the addition, water and ethyl acetate were added, and the organic layer was concentrated under reduced pressure to give the title compound as a colorless oil. MS m / z (ESI): 398.20 [M+1].

[0225] Example 5 Synthesis of Intermediate 1-5: 4-((2S,4S)-4-ethoxypiperidin-2-yl)benzoate hydrochloride

[0226] [ka]

[0227] Intermediate 1-4 was placed in a single-neck reaction flask, 10 mL of methanol was added, followed by 2N hydrochloric acid. 10% palladium-carbon was added to the reaction flask, and the mixture was purged with hydrogen three times and allowed to react overnight. After completion of the reaction, the mixture was suction filtered and concentrated under reduced pressure to obtain a white solid. Methyl tert-butyl ether was added to form a slurry to remove impurities, and the mixture was filtered to obtain the title compound as a white solid powder. MS m / z (ESI): 264.20 [M+1]. 1 HNMR(600 MHz, CDCl3) δ 9.74 (s, 2H), 8.00 (d,J = 7.6 Hz, 2H), 7.69 (d,J = 7.8 Hz, 2H), 4.41 (s, 1H), 3.92 (s, 3H), 3.80 (s, 1H), 3.52 - 3.40 (m, 2H), 3.16 (s, 1H), 2.90 (s, 1H), 2.28 - 2.06 (m, 3H), 1.92 (d,J = 14.1 Hz, 1H), 1.21 (t,J = 6.9 Hz, 3H).

[0228] Example 6 Synthesis of Intermediate 1-6: Methyl 4-((2S,4S)-4-ethoxy-1-nitrosopiperidin-2-yl)benzoate

[0229] [ka]

[0230] Intermediate 1-5 was placed in a 25 mL two-neck flask, and 5 mL of DCM was added to dissolve it. The reaction flask was placed in an ice bath, and pyridine was added, and nitronium tetrafluoroborate was added. After the reaction was completed, water and ethyl acetate were added, and the organic layer was dried and concentrated under reduced pressure to give the title compound (14 mg, yield). MS m / z (ESI): 293.20 [M+1].

[0231] Example 7 Synthesis of Intermediate 1-7: Methyl 4-((2S,4S)-1-amino-4-ethoxypiperidin-2-yl)benzoate

[0232] [ka]

[0233] Intermediate 1-6 was placed in a reaction flask and dissolved in 5 mL of glacial acetic acid. Zinc powder (6.0 mg) was added, and the reaction was completed after 5 hours. The mixture was filtered, and the filtrate was concentrated to give the title compound. MS m / z (ESI): 279.20 [M+1].

[0234] Synthesis of intermediates 1-8

[0235] [ka]

[0236] The intermediate 1-7 was placed in a reaction flask, dissolved in dichloromethane, and iodomethane was added dropwise. After the reaction was completed, saturated brine and dichloromethane were added, and the organic layer was concentrated under reduced pressure and purified by column chromatography to obtain the title compound. MS m / z (ESI): 293.20 [M+1].

[0237] Example 8 Synthesis of Intermediate 2-1: Benzyl (2S,4R)-4-hydroxy-2-(4-(methyl ester group <methoxycarbonyl>)phenyl)piperidine-1-carboxylate

[0238] [ka]

[0239] Intermediate 1-2 was placed in a 500 mL four-neck flask, and 50 mL of dichloromethane and 50 mL of carbon tetrachloride were added to the reaction flask. (S)-3,3-Diphenyl-1-methylpyrrolidino[1,2-c]-1,3,2-oxazaborole was dissolved in 30 mL of toluene. The mixture was purged with nitrogen gas and the internal temperature was lowered to -78 °C. BH3 / THF was added dropwise while maintaining the internal temperature at 78 °C. After 5 hours, water was added to quench the reaction, and the mixture was extracted three times with ethyl acetate. The combined organic phases were concentrated under reduced pressure to give the title compound as a white solid. MS m / z (ESI): 380.20 [M+1]. 1 HNMR(400 MHz, CDCl3) δ 7.93 (dd,J = 8.5, 1.9 Hz, 2H), 7.32 - 7.20 (m, 7H), 5.62 (s, 1H), 5.10 (d,J = 21.8 Hz, 2H), 4.15 (dd,J = 34.6, 16.9 Hz, 1H), 3.84 (d,J = 3.2 Hz, 3H), 3.73 - 3.63 (m, 1H), 2.77 (td,J = 13.7, 2.9 Hz, 1H), 2.57 (d,J = 13.3 Hz, 1H), 1.86 - 1.73 (m, 2H), 1.42 (dd,J = 11.8, 7.1 Hz, 1H).

[0240] Example 9 Synthesis of Intermediate 2-2: Benzyl (2S,4R)-4-ethoxy-2-(4-(methyl ester group <methoxycarbonyl>)phenyl)piperidine-1-carboxylate

[0241] [ka]

[0242] Sodium hydride was placed in a 50 mL three-neck flask, 10 mL of anhydrous N,N-dimethylformamide was added, and the mixture was left in an ice bath for 10 minutes. Intermediate 2-1 was dissolved in 10 mL of anhydrous N,N-dimethylformamide and added dropwise to the reaction flask. Thirty minutes later, ethyl iodide was added dropwise. Water and ethyl acetate were added, and the organic layer was concentrated under reduced pressure to give the title compound as a colorless oil. MS m / z (ESI): 398.20 [M+1]. 1HNMR(400 MHz, CDCl3) δ 8.00 (d,J = 8.4 Hz, 2H), 7.32 (dt,J = 17.7, 7.9 Hz, 7H), 5.68 (s, 1H), 5.19 (s, 2H), 4.27 (d,J = 13.4 Hz, 1H), 3.92 (s, 3H), 3.56 - 3.42 (m, 2H), 3.40 - 3.28 (m, 1H), 2.84 (td,J = 13.6, 2.9 Hz, 1H), 2.65 (d,J = 13.4 Hz, 1H), 2.06 - 1.91 (m, 1H), 1.84 (ddd,J = 13.4, 11.4, 5.8 Hz, 1H), 1.54 - 1.40 (m, 1H), 1.18 (t,J = 7.0 Hz, 3H).

[0243] Example 10 Synthesis of Intermediate 2-3: Methyl 4-((2S,4R)-ethoxypiperidin-2-yl)benzoate Hydrochloride

[0244] [ka]

[0245] Intermediate 2-2 was placed in a single-neck reaction flask, and 10 mL of methanol was added. 2N hydrochloric acid was then added. 10% palladium on carbon was added to the reaction flask, and the mixture was purged with hydrogen three times and allowed to react overnight. After completion of the reaction, the mixture was suction filtered and concentrated under reduced pressure to obtain a white solid. Methyl tert-butyl ether was added to form a slurry to remove impurities, and the mixture was filtered to obtain the title compound as a white solid powder. MS m / z (ESI): 264.20 [M+1]. 1HNMR(600 MHz, CDCl3) δ 9.74 (s, 2H), 8.00 (d,J = 7.6 Hz, 2H), 7.69 (d,J = 7.8 Hz, 2H), 4.41 (s, 1H), 3.92 (s, 3H), 3.80 (s, 1H), 3.52 - 3.40 (m, 2H), 3.16 (s, 1H), 2.90 (s, 1H), 2.28 - 2.06 (m, 3H), 1.92 (d,J = 14.1 Hz, 1H), 1.21 (t,J = 6.9 Hz, 3H).

[0246] Example 11 Synthesis of Intermediate 2-4: Methyl 4-((2S,4R)-4-ethoxy-1-nitrosopiperidin-2-yl)benzoate

[0247] [ka]

[0248] Intermediate 2-3 was placed in a 25 mL two-neck flask and dissolved in 5 mL of DCM. The reaction flask was placed in an ice bath and pyridine was added. After the reaction was completed, water and ethyl acetate were added to dry the organic layer, which was then concentrated under reduced pressure to give the title compound. MS m / z (ESI): 293.20 [M+1]. 1 H NMR (400 MHz, CDCl3) δ 8.02 - 7.90 (m, 2H), 7.27 (d, J = 8.1 Hz, 1H), 7.04 (d, J = 7.9 Hz, 1H), 6.48 - 5.93 (m, 1H), 4.90 - 4.56 (m, 1H), 4.05 (q, J = 7.1 Hz, 1H), 3.85 (d, J = 4.6 Hz, 3H), 3.68 - 3.37 (m, 4H), 2.26 - 2.14 (m, 1H), 2.08 - 1.99 (m, 1H), 1.72 - 1.55 (m, 2H).

[0249] Example 12 Synthesis of Intermediate 2-5: Methyl 4-((2S,4R)-4-ethoxy-1-nitrosopiperidin-2-yl)benzoate

[0250] [ka]

[0251] Intermediate 2-4 was placed in a reaction flask and dissolved in 5 mL of glacial acetic acid. After adding zinc powder, the reaction was completed after 5 hours. The mixture was filtered and the filtrate was concentrated to give the title compound. MS m / z (ESI): 279.20 [M+1].

[0252] Synthesis of intermediate 2-6

[0253] [ka]

[0254] The intermediate 2-5 was placed in a reaction flask, dissolved in dichloromethane, and iodomethane was added dropwise. After the reaction was completed, saturated brine and dichloromethane were added, and the organic layer was concentrated under reduced pressure and purified by column chromatography to obtain the title compound. MS m / z (ESI): 293.20 [M+1].

[0255] Example 13 Synthesis of Intermediate 3-1

[0256] [ka]

[0257] Sodium hydride was placed in a 50 mL three-neck flask, 10 mL of anhydrous N,N-dimethylformamide was added, and the mixture was left in an ice bath for 10 minutes. Intermediate 1-3 was then dissolved in 10 mL of anhydrous N,N-dimethylformamide and added dropwise to the reaction flask. After 30 minutes, 2,2,2-trifluoroethyl trifluoromethanesulfonate was added dropwise. 30 minutes after the addition was complete, water and ethyl acetate were added, and the organic layer was concentrated under reduced pressure to give the title compound as a colorless oil. MS m / z (ESI): 452.20 [M+1].

[0258] Example 14 Synthesis of Intermediate 3-2

[0259] [ka]

[0260] Intermediate 3-1 was placed in a single-neck reaction flask, and 10 mL of methanol was added. 2N hydrochloric acid was then added. 10% palladium on carbon was added to the reaction flask, and the mixture was purged with hydrogen three times and allowed to react overnight. After completion of the reaction, the mixture was suction filtered and concentrated under reduced pressure to give a white solid. Methyl tert-butyl ether was added to form a slurry to remove impurities, and the solid was filtered to give the title compound as a white solid powder. (MS m / z (ESI): 318.12 [M+1])

[0261] Example 15 Synthesis of Intermediate 3-3

[0262] [ka]

[0263] Intermediate 3-2 was placed in a 25 mL two-neck flask and dissolved in 5 mL of DCM. The reaction flask was placed in an ice bath and pyridine was added, followed by nitronium tetrafluoroborate. After the reaction was complete, water and ethyl acetate were added. The organic layer was dried and concentrated under reduced pressure to give the title compound. MS m / z (ESI): 347.20 [M+1].

[0264] Example 16 Synthesis of Intermediate 3-4

[0265] [ka]

[0266] Intermediate 3-3 was placed in a reaction flask, and 5 mL of glacial acetic acid was added to dissolve the product. Zinc powder was added and the reaction mixture was left for 5 hours. After the reaction was completed, the mixture was filtered and the filtrate was concentrated to give the title compound. MS m / z (ESI): 333.20 [M+1].

[0267] Synthesis of intermediates 3-5

[0268] [ka]

[0269] The intermediate 3-4 was placed in a reaction flask, dissolved in dichloromethane, and iodomethane was added dropwise. After the reaction was completed, saturated brine and dichloromethane were added, and the organic layer was concentrated under reduced pressure and purified by column chromatography to obtain the title compound. MS m / z (ESI): 347.16 [M+1].

[0270] Example 17 Synthesis of Intermediate 4-1

[0271] [ka]

[0272] Sodium hydride was placed in a 50 mL three-neck flask, 10 mL of anhydrous N,N-dimethylformamide was added, and the mixture was left in an ice bath for 10 minutes. Intermediate 2-1 was then dissolved in 10 mL of anhydrous N,N-dimethylformamide and added dropwise to the reaction flask. After 30 minutes, 2,2,2-trifluoroethyl trifluoromethanesulfonate was added dropwise. After 30 minutes, water and ethyl acetate were added, and the organic layer was concentrated under reduced pressure to give the title compound as a colorless oil. MS m / z (ESI): 452.20 [M+1].

[0273] Example 18 Synthesis of Intermediate 4-2

[0274] [ka]

[0275] Intermediate 4-1 was placed in a single-neck reaction flask, 10 mL of methanol was added, and 2N hydrochloric acid was added. 10% palladium on carbon was added to the reaction flask, and the mixture was purged with hydrogen three times and allowed to react overnight. After completion of the reaction, the mixture was suction filtered and concentrated under reduced pressure to give a white solid. Methyl tert-butyl ether was added to form a slurry to remove impurities, and the mixture was filtered to give the title compound as a white solid powder. MS m / z (ESI): 318.12 [M+1].

[0276] Example 19 Synthesis of Intermediate 4-3

[0277] [ka]

[0278] Intermediate 4-2 was placed in a 25 mL two-neck flask and dissolved in 5 mL of DCM. The reaction flask was placed in an ice bath and pyridine was added, followed by nitronium tetrafluoroborate. After the reaction was complete, water and ethyl acetate were added. The organic layer was dried and concentrated under reduced pressure to give the title compound. MS m / z (ESI): 347.20 [M+1]

[0279] Example 20 Synthesis of Intermediate 4-4

[0280] [ka]

[0281] Intermediate 4-3 was placed in a reaction flask, and 5 mL of glacial acetic acid was added to dissolve the product. Zinc powder was added and the reaction mixture was left for 5 hours. After the reaction was completed, the mixture was filtered and the filtrate was concentrated to give the title compound. MS m / z (ESI): 333.20 [M+1].

[0282] Synthesis of intermediate 4-5

[0283] [ka]

[0284] The intermediate 4-4 was placed in a reaction flask, dissolved in dichloromethane, and iodomethane was added dropwise. After the reaction was completed, saturated brine and dichloromethane were added, and the organic layer was concentrated under reduced pressure and purified by column chromatography to obtain the title compound. MS m / z (ESI): 347.20 [M+1].

[0285] Example 21 Synthesis of Intermediate 5-1

[0286] [ka]

[0287] Sodium hydride was placed in a 50 mL three-neck flask, 10 mL of anhydrous N,N-dimethylformamide was added, and the mixture was left in an ice bath for 10 minutes. Intermediate 1-3 was then dissolved in 10 mL of anhydrous N,N-dimethylformamide and added dropwise to the reaction flask. 30 minutes later, 2,2-difluoroethyltrifluoromethanesulfonate was added dropwise. 30 minutes later, water and ethyl acetate were added, and the organic layer was concentrated under reduced pressure to give the title compound as a colorless oil. MS m / z (ESI): 434.20 [M+1].

[0288] Example 22 Synthesis of Intermediate 5-2

[0289] [ka]

[0290] Intermediate 5-1 was placed in a single-neck reaction flask, and 10 mL of methanol and 2N hydrochloric acid were added. Then, 10% palladium on carbon was added to the reaction flask, and the mixture was purged with hydrogen three times and allowed to react overnight. After completion of the reaction, the mixture was suction filtered and concentrated under reduced pressure to give a white solid. Methyl tert-butyl ether was added to form a slurry to remove impurities, and the mixture was filtered to give the title compound as a white solid powder. MS m / z (ESI): 300.12 [M+1].

[0291] Example 23 Synthesis of Intermediate 5-3

[0292] [ka]

[0293] Intermediate 5-2 was placed in a 25 mL two-neck flask and dissolved in 5 mL of DCM. The reaction flask was placed in an ice bath and pyridine was added, followed by nitronium tetrafluoroborate. After the reaction was completed, water and ethyl acetate were added. The organic layer was dried and concentrated under reduced pressure to give the title compound. MS m / z (ESI): 329.20 [M+1].

[0294] Example 24 Synthesis of Intermediate 5-4

[0295] [ka]

[0296] The intermediate 5-3 was placed in a reaction flask and dissolved in 5 mL of glacial acetic acid. After adding zinc powder, the reaction was completed after 5 hours. The mixture was filtered and the filtrate was concentrated to give the title compound. MS m / z (ESI): 315.20 [M+1].

[0297] Synthesis of intermediate 5-5

[0298] [ka]

[0299] The intermediate 5-4 was placed in a reaction flask, dissolved in dichloromethane, and iodomethane was added dropwise. After the reaction was completed, saturated brine and dichloromethane were added, and the organic layer was concentrated under reduced pressure and purified by column chromatography to obtain the title compound. MS m / z (ESI): 329.20 [M+1].

[0300] Example 25 Synthesis of Intermediate 6-1

[0301] [ka]

[0302] Sodium hydride was placed in a 50 mL three-neck flask, 10 mL of anhydrous N,N-dimethylformamide was added, and the mixture was left in an ice bath for 10 minutes. Intermediate 2-1 was dissolved in 10 mL of anhydrous N,N-dimethylformamide and added dropwise to the reaction flask. 30 minutes later, 2,2-difluoroethyltrifluoromethanesulfonate was added dropwise. 30 minutes later, water and ethyl acetate were added, and the organic layer was concentrated under reduced pressure to give the title compound as a colorless oil. MS m / z (ESI): 434.20 [M+1].

[0303] Example 26 Synthesis of Intermediate 6-2

[0304] [ka]

[0305] Intermediate 6-1 was placed in a single-neck reaction flask, and 10 mL of methanol was added. 2N hydrochloric acid was then added. 10% palladium-carbon was added to the reaction flask, and the mixture was purged with hydrogen three times and allowed to react overnight. After completion of the reaction, the mixture was suction filtered and concentrated under reduced pressure to give a white solid. Methyl tert-butyl ether was added to form a slurry to remove impurities, and the mixture was filtered to give the title compound as a white solid powder. MS m / z (ESI): 300.12 [M+1].

[0306] Example 27 Synthesis of Intermediate 6-3

[0307] [ka]

[0308] Intermediate 6-2 was placed in a 25 mL two-neck flask and dissolved in 5 mL of DCM. The reaction flask was placed in an ice bath and pyridine was added, followed by nitronium tetrafluoroborate. After the reaction was complete, water and ethyl acetate were added. The organic layer was dried and concentrated under reduced pressure to give the title compound. MS m / z (ESI): 329.20 [M+1].

[0309] Example 28 Intermediate 6-4

[0310] [ka]

[0311] Intermediate 6-3 was placed in a reaction flask and dissolved in 5 mL of glacial acetic acid. Zinc powder was added and the reaction was completed after 5 hours. The mixture was filtered and the filtrate was concentrated to give the title compound. MS m / z (ESI): 315.20 [M+1].

[0312] Synthesis of intermediate 6-5

[0313] [ka]

[0314] The intermediate 6-4 was placed in a reaction flask, dissolved in dichloromethane, and iodomethane was added dropwise. After the reaction was completed, saturated brine and dichloromethane were added, and the organic layer was concentrated under reduced pressure and purified by column chromatography to obtain the title compound. MS m / z (ESI): 329.20 [M+1].

[0315] Example 29 Synthesis of Intermediate 7-1

[0316] [ka]

[0317] Sodium hydride was placed in a 50 mL three-neck flask, 10 mL of anhydrous N,N-dimethylformamide was added, and the mixture was left in an ice bath for 10 minutes. Intermediate 1-3 was then dissolved in 10 mL of anhydrous N,N-dimethylformamide and added dropwise to the reaction flask. 30 minutes later, 2-fluoroethyltrifluoromethanesulfonate was added dropwise. 30 minutes later, water and ethyl acetate were added, and the organic layer was concentrated under reduced pressure to give the title compound as a colorless oil. MS m / z (ESI): 416.18 [M+1].

[0318] Example 30 Synthesis of Intermediate 7-2

[0319] [ka]

[0320] Intermediate 7-1 was placed in a single-neck reaction flask, and 10 mL of methanol was added, followed by 2N hydrochloric acid. 10% palladium-carbon was added to the reaction flask, and the mixture was purged with hydrogen three times and allowed to react overnight. After completion of the reaction, the mixture was suction filtered and concentrated under reduced pressure to give a white solid. Methyl tert-butyl ether was added to form a slurry to remove impurities, and the mixture was filtered to give the title compound as a white solid powder. MS m / z (ESI): 282.12 [M+1].

[0321] Example 31 Synthesis of Intermediate 7-3

[0322] [ka]

[0323] Intermediate 7-2 was placed in a 25 mL two-neck flask and dissolved in 5 mL of DCM. The reaction flask was placed in an ice bath and pyridine was added, followed by nitronium tetrafluoroborate. After the reaction was completed, water and ethyl acetate were added. The organic layer was dried and concentrated under reduced pressure to give the title compound. MS m / z (ESI): 311.20 [M+1].

[0324] Example 32 Synthesis of Intermediate 7-4

[0325] [ka]

[0326] The intermediate 7-3 was placed in a reaction flask and dissolved in 5 mL of glacial acetic acid. After adding zinc powder, the reaction was completed after 5 hours. The mixture was filtered and the filtrate was concentrated to give the title compound. MS m / z (ESI): 297.20 [M+1].

[0327] Synthesis of intermediate 7-5

[0328] [ka]

[0329] The intermediate 7-4 was placed in a reaction flask, dissolved in dichloromethane, and iodomethane was added dropwise. After the reaction was completed, saturated brine and dichloromethane were added, and the organic layer was concentrated under reduced pressure and purified by column chromatography to obtain the title compound. MS m / z (ESI): 310.20 [M+1].

[0330] Example 33 Synthesis of Intermediate 8-1

[0331] [ka]

[0332] Sodium hydride was placed in a 50 mL three-neck flask, 10 mL of anhydrous N,N-dimethylformamide was added, and the mixture was left in an ice bath for 10 minutes. Intermediate 2-1 was then dissolved in 10 mL of anhydrous N,N-dimethylformamide and added dropwise to the reaction flask. 30 minutes later, 2-fluoroethyltrifluoromethanesulfonate was added dropwise. 30 minutes later, water and ethyl acetate were added, and the organic layer was concentrated under reduced pressure to give the title compound as a colorless oil. MS m / z (ESI): 416.18 [M+1].

[0333] Example 34 Synthesis of Intermediate 8-2

[0334] [ka]

[0335] Intermediate 8-1 was placed in a single-neck reaction flask, and 10 mL of methanol was added. 2N hydrochloric acid was then added. 10% palladium-carbon was added to the reaction flask, and the mixture was purged with hydrogen three times and allowed to react overnight. After completion of the reaction, the mixture was suction filtered and concentrated under reduced pressure to give a white solid. Methyl tert-butyl ether was added to form a slurry to remove impurities, and the solid was filtered to give the title compound as a white solid powder. MS m / z (ESI): 282.12 [M+1].

[0336] Example 35 Synthesis of Intermediate 8-3

[0337] [ka]

[0338] Intermediate 8-2 was placed in a 25 mL two-neck flask and dissolved in 5 mL of DCM. The reaction flask was placed in an ice bath and pyridine was added, followed by nitronium tetrafluoroborate. After the reaction was completed, water and ethyl acetate were added. The organic layer was dried and concentrated under reduced pressure to give the title compound. MS m / z (ESI): 311.20 [M+1].

[0339] Example 36 Synthesis of Intermediate 8-4

[0340] [ka]

[0341] Intermediate 8-3 was placed in a reaction flask and dissolved in 5 mL of glacial acetic acid. After adding zinc powder, the reaction was completed after 5 hours. The mixture was filtered and the filtrate was concentrated to give the title compound. MS m / z (ESI): 297.20 [M+1].

[0342] Synthesis of intermediate 8-5

[0343] [ka]

[0344] The intermediate 8-4 was placed in a reaction flask, dissolved in dichloromethane, and iodomethane was added dropwise. After the reaction was completed, saturated brine and dichloromethane were added, and the organic layer was concentrated under reduced pressure and purified by column chromatography to obtain the title compound. MS m / z (ESI): 310.20 [M+1].

[0345] Example 37 Synthesis of Intermediate 9-1

[0346] [ka]

[0347] Sodium hydride was placed in a 50 mL three-neck flask, 10 mL of anhydrous N,N-dimethylformamide was added, and the mixture was left in an ice bath for 10 minutes. Intermediate 1-3 was then dissolved in 10 mL of anhydrous N,N-dimethylformamide and added dropwise to the reaction flask. After 30 minutes, cyclohexylmethyl bromide was added dropwise, followed by the addition of water and ethyl acetate. The organic layer was concentrated under reduced pressure to give the title compound as a colorless oil. MS m / z (ESI): 424.18 [M+1]. 1HNMR(400 MHz, CDCl3) δ 8.00 (d,J = 8.3 Hz, 2H), 7.44 - 7.27 (m, 7H), 5.19 (s, 2H), 3.92 (s, 3H), 3.36 (t,J = 11.1 Hz, 1H), 3.26 (d,J = 6.8 Hz, 2H), 2.83 (dd,J = 13.4, 10.9 Hz, 1H), 2.66 (d,J = 13.4 Hz, 1H), 2.06 - 1.80 (m, 2H), 1.25 (s, 2H), 1.01 (s, 1H), 0.87 (d,J = 10.3 Hz, 2H), 0.52 (d,J = 8.0 Hz, 2H), 0.17 (q,J = 4.9 Hz, 2H)

[0348] Example 38 Synthesis of Intermediate 9-2

[0349] [ka]

[0350] Intermediate 9-1 was placed in a single-neck reaction flask, and 10 mL of methanol was added, followed by 2N hydrochloric acid. 10% palladium-carbon was added to the reaction flask, and the mixture was purged with hydrogen three times and allowed to react overnight. After completion of the reaction, the mixture was suction filtered and concentrated under reduced pressure to give a white solid. Methyl tert-butyl ether was added to form a slurry to remove impurities, and the mixture was filtered to give the title compound as a white solid powder. MS m / z (ESI): 290.12 [M+1]. 1HNMR(400 MHz, MeOD) δ 8.12 (d,J = 8.4 Hz, 2H), 7.61 (d,J = 8.3 Hz, 2H), 4.71 - 4.56 (m, 1H), 3.98 (s, 1H), 3.92 (s, 3H), 3.49 (dd,J = 18.3, 7.8 Hz, 1H), 3.38 (dd,J = 17.1, 4.9 Hz, 3H), 2.35 - 2.11 (m, 3H), 2.04 - 1.91 (m, 1H), 1.19 - 1.06 (m, 1H), 0.61 - 0.51 (m, 2H), 0.33 - 0.21 (m, 2H).

[0351] Example 39 Synthesis of Intermediate 9-3

[0352] [ka]

[0353] Intermediate 9-2 was placed in a 25 mL two-neck flask and dissolved in 5 mL of DCM. The reaction flask was placed in an ice bath and pyridine was added, followed by nitronium tetrafluoroborate. After the reaction was completed, water and ethyl acetate were added. The organic layer was dried and concentrated under reduced pressure to give the title compound. MS m / z (ESI): 319.20 [M+1].

[0354] Example 40 Synthesis of Intermediate 9-4

[0355] [ka]

[0356] Intermediate 9-3 was placed in a reaction flask and dissolved in 5 mL of glacial acetic acid. After adding zinc powder, the reaction was completed after 5 hours. The mixture was filtered and the filtrate was concentrated to give the title compound. MS m / z (ESI): 305.20 [M+1].

[0357] Synthesis of intermediate 9-5

[0358] [ka]

[0359] The intermediate 9-4 was placed in a reaction flask, dissolved in dichloromethane, and iodomethane was added dropwise. After the reaction was completed, saturated brine and dichloromethane were added, and the organic layer was concentrated under reduced pressure and purified by column chromatography to obtain the title compound. MS m / z (ESI): 319.20 [M+1].

[0360] Example 41 Synthesis of Intermediate 10-1

[0361] [ka]

[0362] Sodium hydride was placed in a 50 mL three-neck flask, 10 mL of anhydrous N,N-dimethylformamide was added, and the mixture was left in an ice bath for 10 minutes. Intermediate 2-1 was dissolved in 10 mL of anhydrous N,N-dimethylformamide and added dropwise to the reaction flask. After 30 minutes, cyclohexylmethyl bromide was added dropwise, and 30 minutes later, water and ethyl acetate were added. The organic layer was concentrated under reduced pressure to give the title compound as a colorless oil. MS m / z (ESI): 424.18 [M+1].

[0363] Example 42 Synthesis of Intermediate 10-2

[0364] [ka]

[0365] Intermediate 10-1 was placed in a single-neck reaction flask, and 10 mL of methanol was added, followed by 2N hydrochloric acid. 10% palladium-carbon was added to the reaction flask, and the mixture was purged with hydrogen three times and allowed to react overnight. After completion of the reaction, the mixture was suction filtered and concentrated under reduced pressure to give a white solid. Methyl tert-butyl ether was added to form a slurry to remove impurities, and the mixture was filtered to give the title compound as a white solid powder. MS m / z (ESI): 290.12 [M+1].

[0366] Example 43 Synthesis of Intermediate 10-3

[0367] [ka]

[0368] Intermediate 10-2 was placed in a 25 mL two-neck flask and dissolved in 5 mL of DCM. The reaction flask was placed in an ice bath and pyridine was added, followed by nitronium tetrafluoroborate. After the reaction was completed, water and ethyl acetate were added. The organic layer was dried and concentrated under reduced pressure to give the title compound. MS m / z (ESI): 319.20 [M+1].

[0369] Example 44 Synthesis of Intermediate 10-4

[0370] [ka]

[0371] Intermediate 10-3 was placed in a reaction flask and dissolved in 5 mL of glacial acetic acid. After adding zinc powder, the reaction was completed after 5 hours. The mixture was filtered and the filtrate was concentrated to give the title compound. MS m / z (ESI): 305.20 [M+1].

[0372] Synthesis of intermediate 10-5

[0373] [ka]

[0374] The intermediate 10-4 was placed in a reaction flask, dissolved in dichloromethane, and iodomethane was added dropwise. After the reaction was completed, saturated brine and dichloromethane were added, and the organic layer was concentrated under reduced pressure and purified by column chromatography to obtain the title compound. MS m / z (ESI): 319.20 [M+1].

[0375] Example 45 Synthesis of Intermediate 11-1

[0376] [ka]

[0377] tert-Butyl-4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylate was added to a 50 mL three-neck flask, dissolved in DCM, and then 20% hydrogen peroxide was added in an ice bath and allowed to react overnight. The mixture was then separated, extracted, washed three times with saturated brine, concentrated under reduced pressure, and purified by column chromatography to obtain the title compound. MS m / z (ESI): 306.20 [M+1]. 1 HNMR(600 MHz, CDCl3) δ 7.64 (d,J = 3.7 Hz, 1H), 7.60 (d,J = 3.7 Hz, 1H), 6.82 (s, 1H), 4.11 (s, 3H), 2.68 (s, 3H), 1.63 (s, 9H).

[0378] Example 46 Synthesis of Intermediate 12-1

[0379] [ka]

[0380] 1-Bromo-2-methoxy-4-methyl-5-nitrobenzene was placed in a Schreck tube, purged with nitrogen gas three times, and then placed at -20 °C for reaction. A solution of vinylmagnesium bromide in tetrahydrofuran was added dropwise and allowed to react for 20 minutes. The reaction flask was then placed at room temperature and allowed to react overnight. Upon completion of the reaction, the reaction was quenched with saturated aqueous ammonium chloride solution, extracted with dichloromethane, and the organic phase was concentrated under reduced pressure. The title compound was obtained by column chromatography (). MS m / z (ESI): 240.20 [M+1]. H NMR (600 MHz, CDCl ) δ 7.54 (d, J = 3.7 Hz, 1H), 6.74 (s, 1H), 6.59 (d, J = 3.7 Hz, 1H), 3.93 (s, 3H), 2.61 (s, 3H).

[0381] Example 47 Synthesis of Intermediate 12-2

[0382] [ka]

[0383] Intermediate 12-1 was added to a reaction flask, followed by the addition of di-tert-butyl dicarbonate, 4-dimethylaminopyridine, and N,N-diisopropylethylamine. The mixture was allowed to react at room temperature for 2 hours. After the reaction was complete, saturated ammonium chloride solution was added, followed by extraction with dichloromethane. The organic layer was concentrated under reduced pressure to give a white solid powder, which was the title compound. MS m / z (ESI): 340.20 [M+1]. 1 HNMR(600 MHz, CDCl3) δ 7.54 (d,J = 3.7 Hz, 1H), 6.74 (s, 1H), 6.59 (d,J = 3.7 Hz, 1H), 3.93 (s, 3H), 2.61 (s, 3H), 1.63 (s, 9H).

[0384] Example 48 Synthesis of Intermediate 13-1: tert-butyl 4-(hydroxymethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate

[0385] [ka]

[0386] Solid tert-butyl 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylate was placed in a 100 mL three-neck flask, dissolved in methanol, and then solid sodium borohydride was added in several portions. After the reaction was completed, the reaction was quenched by adding 2N hydrochloric acid. The mixture was extracted with dichloromethane and concentrated under reduced pressure to give the title compound as a white solid powder. MS m / z (ESI): 292.20 [M+1]. 1 HNMR(400 MHz, CDCl3) δ 7.52 (d,J = 3.8 Hz, 1H), 6.74 (s, 1H), 6.61 (d,J = 3.8 Hz, 1H), 4.88 (s, 2H), 3.89 (s, 3H), 2.62 (s, 3H), 1.62 (s, 9H).

[0387] Example 49 Synthesis of intermediate 13-2: tert-butyl 4-(chloromethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate

[0388] [ka]

[0389] Intermediate 13-1 was placed in a 100 mL three-neck flask, dissolved in dichloromethane, and triethylamine was added. The reaction flask was placed in an ice bath, dichlorosulfoxide was added, and the mixture was allowed to react in the ice bath for 2 hours. After the reaction was completed, brine was added to quench the reaction. The organic phase was concentrated under reduced pressure and purified by column chromatography to obtain the title compound. MS m / z (ESI): 310.20 [M+1].

[0390] Example 50 Synthesis of intermediate 13-3: tert-butyl 4-(fluoromethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate

[0391] [ka]

[0392] Intermediate 13-1 was placed in a 100 mL three-neck flask and dissolved in dichloromethane. The reaction flask was placed in an ice bath, and N,N-diethylaminosulfur trifluoride was added. The reaction was allowed to proceed overnight in the ice bath. After completion of the reaction, saturated brine was added to quench the reaction. After separation, the organic phase was concentrated under reduced pressure to give the title compound. MS m / z (ESI): 294.10 [M+1].

[0393] Example 51 Synthesis of intermediate 13-4: tert-butyl 4-(bromofluoromethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate

[0394] [ka]

[0395] Intermediate 13-3 was placed in a 100 mL three-neck flask and dissolved in dichloromethane. The reaction flask was placed in an ice bath and solid N-bromosuccinimide was added. After 2 hours, the reaction was complete. Saturated brine was added to quench the reaction. The organic layer was concentrated under reduced pressure and purified by column chromatography to give the title compound. MS m / z (ESI): 372.10 [M+1].

[0396] Example 52 Synthesis of intermediate 14-1: tert-butyl 4-(difluoromethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate

[0397] [ka]

[0398] The solid tert-butyl 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylate was placed in a 100 mL three-neck flask and dissolved in dichloromethane. The reaction flask was placed in an ice bath and diethylaminosulfur trifluoride was added to complete the reaction. Saturated sodium bicarbonate solution was added to quench the reaction. The organic phase was concentrated under reduced pressure and purified by column chromatography to give the title compound. MS m / z (ESI): 312.30 [M+1].

[0399] Example 53 Synthesis of intermediate 14-2: tert-butyl 4-(bromodifluoromethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate

[0400] [ka]

[0401] Intermediate 14-1 was placed in a 100 mL three-neck flask and dissolved in dichloromethane. The reaction flask was placed in an ice bath and bromine water was added. After the reaction was completed, the mixture was washed three times with saturated sodium bicarbonate. The organic phase was concentrated under reduced pressure and purified by column chromatography to obtain the title compound. MS m / z (ESI): 390.00 [M+1].

[0402] Example 54 Synthesis of Compound 1-1: tert-butyl 4-((2S,4S)-4-ethoxy-2-(4-(methyl ester group <methoxycarbonyl> phenyl)piperidine-1-carbonyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate

[0403] [ka]

[0404] Intermediate 1-5 was added to a 10 mL three-neck flask, dissolved in dichloromethane, and N,N-diisopropylethylamine was added. The mixture was placed in an ice bath, followed by the addition of Intermediate 11-1. After stirring for 10 minutes, tert-butyl 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate was added. After the reaction was complete, dichloromethane and saturated brine were added, and the organic phase was concentrated under reduced pressure to give the title compound. MS m / z (ESI): 551.26 [M+1]. 1HNMR(600 MHz, CDCl3) δ 8.04 - 7.84 (m, 2H), 7.52 (ddd,J = 30.1, 29.6, 8.1 Hz, 2H), 7.37 (dd,J = 32.9, 27.2 Hz, 1H), 7.22 (d,J = 8.1 Hz, 1H), 6.73 (dd,J = 38.0, 16.8 Hz, 1H), 6.54 - 6.33 (m, 1H), 5.38 - 4.71 (m, 1H), 3.97 - 3.83 (m, 6H), 3.71 (dd,J = 31.7, 4.6 Hz, 1H), 3.43 - 3.12 (m, 4H), 2.72 - 2.54 (m, 4H), 1.63 (d,J = 6.5 Hz, 9H), 1.41 - 1.11 (m, 6H)..

[0405] Example 55 Synthesis of Compound 1: 4-((2S,4S)-4-ethoxy-1-(5-methoxy-7-methyl-1H-indole-4-carbonyl)piperidin-2-yl)benzoic acid

[0406] [ka]

[0407] Compound 1-1 was placed in a 10 mL three-neck flask, dissolved in tetrahydrofuran and methanol, and then heated to 45°C overnight with 1 M aqueous lithium hydroxide. After the reaction was complete, the mixture was concentrated under reduced pressure and subjected to reverse phase preparative separation (gradient elution with aqueous hydrochloric acid and acetonitrile) to obtain the title compound. MS m / z (ESI): 437.20 [M+1]. 1 HNMR(600 MHz, MeOD) δ 8.02 (ddd,J = 66.1, 32.9, 7.3 Hz, 2H), 7.72 - 7.45 (m, 2H), 7.38 - 7.21 (m, 1H), 6.77 (dd,J = 66.8, 34.7 Hz, 1H), 6.43 - 6.27 (m, 1H), 5.07 (d,J = 90.3 Hz, 1H), 3.97 - 3.61 (m, 3H), 3.60 - 3.41 (m, 4H), 2.95 (dddd,J = 63.1, 56.8, 46.2, 45.4 Hz, 2H), 2.67 - 2.46 (m, 3H), 2.17 - 1.30 (m, 3H), 1.21 - 1.13 (m, 3H).

[0408] Example 56 Synthesis of Compound 2-1: tert-butyl 4-((2S,4R)-4-ethoxy-2-(4-(methyl ester group <methoxycarbonyl>)phenyl)piperidine-1-carbonyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate

[0409] [ka]

[0410] Intermediate 2-3 was added to a 10 mL three-neck flask, dissolved in dichloromethane, and N,N-diisopropylethylamine was added. The mixture was placed in an ice bath, and then Intermediate 11-1 was added. After stirring for 10 minutes, tert-butyl 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate was added. After the reaction was completed, dichloromethane and saturated brine were added, and the organic phase was concentrated under reduced pressure to give the title compound. MS m / z (ESI): 551.26 [M+1]. 1HNMR(600 MHz, CDCl3) δ 8.04 - 7.84 (m, 2H), 7.52 (ddd,J = 30.1, 29.6, 8.1 Hz, 2H), 7.37 (dd,J = 32.9, 27.2 Hz, 1H), 7.22 (d,J = 8.1 Hz, 1H), 6.73 (dd,J = 38.0, 16.8 Hz, 1H), 6.54 - 6.33 (m, 1H), 5.38 - 4.71 (m, 1H), 3.97 - 3.83 (m, 6H), 3.71 (dd,J = 31.7, 4.6 Hz, 1H), 3.43 - 3.12 (m, 4H), 2.72 - 2.54 (m, 4H), 1.63 (d,J = 6.5 Hz, 9H), 1.41 - 1.11 (m, 6H).

[0411] Example 57 Synthesis of Compound 2: 4-((2S,4R)-4-ethoxy-1-(5-methoxy-7-methyl-1H-indole-4-carbonyl)piperidin-2-yl)benzoic acid

[0412] [ka]

[0413] Compound 2-1 was placed in a 10 mL three-neck flask, and tetrahydrofuran and methanol were added to dissolve the compound. 1 M aqueous lithium hydroxide solution was added, and the mixture was heated to 45°C and kept at this temperature overnight. After the reaction was completed, the mixture was concentrated under reduced pressure and subjected to reverse phase separation (gradient elution of aqueous hydrochloric acid:acetonitrile) to obtain the title compound. MS m / z(ESI):437.20[M+1],1HNMR(600 MHz, MeOD) δ 8.02 (ddd,J = 66.1, 32.9, 7.3 Hz, 2H), 7.72 - 7.45 (m, 2H), 7.38 - 7.21 (m, 1H), 6.77 (dd,J = 66.8, 34.7 Hz, 1H), 6.43 - 6.27 (m, 1H), 5.07 (d,J = 90.3 Hz, 1H), 3.97 - 3.61 (m, 3H), 3.60 - 3.41 (m, 4H), 2.95 (dddd,J = 63.1, 56.8, 46.2, 45.4 Hz, 2H), 2.67 - 2.46 (m, 3H), 2.17 - 1.30 (m, 3H), 1.21 - 1.13 (m, 3H).

[0414] Example 58 Synthesis of Compound 3-1: tert-butyl 5-methoxy-4-((2S,4S)-2-(4-(methyl ester group <methoxycarbonyl>)phenyl)-4-(2,2,2-trifluoroethoxy)piperidine-1-carbonyl)-7-methyl-1H-indole-1-carboxylate

[0415] [ka]

[0416] Intermediate 3-2 was added to a 10 mL three-neck flask, dissolved in dichloromethane, and N,N-diisopropylethylamine was added. The mixture was placed in an ice bath, and then Intermediate 11-1 was added. After stirring for 10 minutes, tert-butyl 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate was added. After the reaction was completed, dichloromethane and saturated brine were added, and the organic phase was concentrated under reduced pressure to give the title compound. MS m / z (ESI): 605.26 [M+1].

[0417] Example 59 Synthesis of Compound 3: 4-((2S,4S)-1-(5-methoxy-7-methyl-1H-indole-4-carbonyl)-4-(2,2,2-trifluoroethoxy)piperidin-2-yl)benzoic acid

[0418] [ka]

[0419] Compound 3-1 was placed in a 10 mL three-neck flask, dissolved in tetrahydrofuran and methanol, and then 1 M aqueous lithium hydroxide was added. The mixture was heated to 45°C and kept overnight. After the reaction was complete, the mixture was concentrated under reduced pressure and subjected to reverse phase preparative separation (hydrochloric acid:acetonitrile gradient elution) to obtain the title compound. MS m / z (ESI): 491.20 [M+1]

[0420] Example 60 Synthesis of Compound 4-1: tert-butyl 5-methoxy-4-((2S,4R)-2-(4-(methyl ester group <methoxycarbonyl>)phenyl)-4-(2,2,2-trifluoroethoxy)piperidine-1-carbonyl)-7-methyl-1H-indole-1-carboxylate

[0421] [ka]

[0422] Intermediate 4-2 was added to a 10 mL three-neck flask, dissolved in dichloromethane, and N,N-diisopropylethylamine was added. The mixture was placed in an ice bath, and then Intermediate 11-1 was added. After stirring for 10 minutes, tert-butyl 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate was added. After the reaction was completed, dichloromethane and saturated brine were added, and the organic phase was concentrated under reduced pressure to give the title compound. MS m / z (ESI): 605.26 [M+1].

[0423] Example 61 Synthesis of Compound 4: 4-((2S,4R)-1-(5-methoxy-7-methyl-1H-indole-4-carbonyl)-4-(2,2,2-trifluoroethoxy)piperidin-2-yl)benzoic acid

[0424] [ka]

[0425] Compound 4-1 was placed in a 10 mL three-neck flask, dissolved in tetrahydrofuran and methanol, and then 1 M aqueous lithium hydroxide was added. The mixture was heated to 45°C and kept overnight. After the reaction was complete, the mixture was concentrated under reduced pressure and subjected to reverse phase preparative separation (hydrochloric acid:acetonitrile gradient elution) to obtain the title compound. MS m / z (ESI): 491.20 [M+1]

[0426] Example 62 Synthesis of Compound 5-1: tert-butyl 4-((2S,4S)-4-(2,2-difluoroethoxy)-2-(4-(methyl ester group <methoxycarbonyl>)phenyl)piperidine-1-carbonyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate

[0427] [ka]

[0428] Intermediate 5-2 was added to a 10 mL three-neck flask, dissolved in dichloromethane, and N,N-diisopropylethylamine was added. The mixture was placed in an ice bath, and then Intermediate 11-1 was added. After stirring for 10 minutes, tert-butyl 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate was added. After the reaction was completed, dichloromethane and saturated brine were added, and the organic phase was concentrated under reduced pressure to give the title compound. MS m / z (ESI): 587.30 [M+1].

[0429] Example 63 Synthesis of Compound 5: 4-((2S,4S)-4-(2,2-difluoroethoxy)-1-(5-methoxy-7-methyl-1H-indole-4-carbonyl)piperidin-2-yl)benzoic acid

[0430] [ka]

[0431] Compound 5-1 was placed in a 10 mL three-neck flask, dissolved in tetrahydrofuran and methanol, and then 1 M aqueous lithium hydroxide was added. The mixture was heated to 45°C and kept overnight. After the reaction was complete, the mixture was concentrated under reduced pressure and subjected to reverse phase preparative separation (hydrochloric acid:acetonitrile gradient elution) to obtain the title compound. MS m / z (ESI): 473.20 [M+1]

[0432] Example 64 Synthesis of Compound 6-1: tert-butyl 4-((2S,4R)-4-(2,2-difluoroethoxy)-2-(4-(methyl ester group <methoxycarbonyl>)phenyl)piperidine-1-carbonyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate

[0433] [ka]

[0434] Intermediate 6-2 was added to a 10 mL three-neck flask, dissolved in dichloromethane, and N,N-diisopropylethylamine was added. The mixture was placed in an ice bath, and then Intermediate 11-1 was added. After stirring for 10 minutes, tert-butyl 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate was added. After the reaction was completed, dichloromethane and saturated brine were added, and the organic phase was concentrated under reduced pressure to give the title compound. MS m / z (ESI): 587.30 [M+1].

[0435] Example 65 Synthesis of Compound 6: 4-((2S,4R)-4-(2,2-difluoroethoxy)-1-(5-methoxy-7-methyl-1H-indole-4-carbonyl)piperidin-2-yl)benzoic acid

[0436] [ka]

[0437] Compound 6-1 was placed in a 10 mL three-neck flask, dissolved in tetrahydrofuran and methanol, and then 1 M aqueous lithium hydroxide was added. The mixture was heated to 45°C and kept overnight. After the reaction was complete, the mixture was concentrated under reduced pressure and subjected to reverse phase preparative separation (hydrochloric acid:acetonitrile gradient elution) to obtain the title compound. MS m / z (ESI): 473.20 [M+1]

[0438] Example 66 Synthesis of Compound 7-1: tert-butyl 4-((2S,4S)-4-(2-fluoroethoxy)-2-(4-(methyl ester group <methoxycarbonyl>)phenyl)piperidine-1-carbonyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate

[0439] [ka]

[0440] Intermediate 7-2 was added to a 10 mL three-neck flask, dissolved in dichloromethane, and N,N-diisopropylethylamine was added. The mixture was placed in an ice bath, and then Intermediate 11-1 was added. After stirring for 10 minutes, tert-butyl 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate was added. After the reaction was completed, dichloromethane and saturated brine were added, and the organic phase was concentrated under reduced pressure to give the title compound. MS m / z (ESI): 569.30 [M+1]. Example 67 Synthesis of Compound 7: 4-((2S,4S)-4-(2-fluoroethoxy)-1-(5-methoxy-7-methyl-1H-indole-4-carbonyl)piperidin-2-yl)benzoic acid

[0441] [ka]

[0442] Compound 7-1 was placed in a 10 mL three-neck flask, dissolved in tetrahydrofuran and methanol, and then 1 M aqueous lithium hydroxide was added. The mixture was heated to 45°C and kept overnight. After the reaction was complete, the mixture was concentrated under reduced pressure and subjected to reverse phase preparative separation (hydrochloric acid:acetonitrile gradient elution) to obtain the title compound. MS m / z (ESI): 455.20 [M+1]

[0443] Example 68 Synthesis of Compound 8-1: tert-butyl 4-((2S,4R)-4-(2-fluoroethoxy)-2-(4-(methyl ester group <methoxycarbonyl>)phenyl)piperidine-1-carbonyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate

[0444] [ka]

[0445] Intermediate 8-2 was added to a 10 mL three-neck flask, dissolved in dichloromethane, and N,N-diisopropylethylamine was added. The mixture was placed in an ice bath, and then Intermediate 11-1 was added. After stirring for 10 minutes, tert-butyl 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate was added. After the reaction was completed, dichloromethane and saturated brine were added, and the organic phase was concentrated under reduced pressure to give the title compound. MS m / z (ESI): 569.30 [M+1].

[0446] Example 69 Synthesis of Compound 8: 4-((2S,4R)-4-(2-fluoroethoxy)-1-(5-methoxy-7-methyl-1H-indole-4-carbonyl)piperidin-2-yl)benzoic acid

[0447] [ka]

[0448] Compound 8-1 was placed in a 10 mL three-neck flask, dissolved in tetrahydrofuran and methanol, and then 1 M aqueous lithium hydroxide was added. The mixture was heated to 45°C and kept overnight. After the reaction was complete, the mixture was concentrated under reduced pressure and subjected to reverse phase preparative separation (hydrochloric acid:acetonitrile gradient elution) to obtain the title compound. MS m / z (ESI): 455.20 [M+1]

[0449] Example 70 Synthesis of Compound 9-1: tert-butyl 4-((2S,4S)-4-(cyclopropylmethoxy)-2-(4-(methyl ester group <methoxycarbonyl>)phenyl)piperidine-1-carbonyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate

[0450] [ka]

[0451] Intermediate 9-2 was added to a 10 mL three-neck flask, dissolved in dichloromethane, and N,N-diisopropylethylamine was added. The mixture was placed in an ice bath, and then Intermediate 11-1 was added. After stirring for 10 minutes, tert-butyl 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate was added. After the reaction was completed, dichloromethane and saturated brine were added, and the organic phase was concentrated under reduced pressure to give the title compound. MS m / z (ESI): 577.30 [M+1].

[0452] Example 71 Synthesis of Compound 9: 4-((2S,4S)-4-(cyclopropylmethoxy)-1-(5-methoxy-7-methyl-1H-indole-4-carbonyl)piperidin-2-yl)benzoic acid

[0453] [ka]

[0454] Compound 9-1 was placed in a 10 mL three-neck flask, dissolved in tetrahydrofuran and methanol, and then 1 M aqueous lithium hydroxide was added. The mixture was heated to 45°C and kept overnight. After the reaction was complete, the mixture was concentrated under reduced pressure and purified by reverse phase preparative separation (hydrochloric acid:acetonitrile gradient elution) to obtain the title compound. MS m / z (ESI): 463.55 [M+1]. 1HNMR(600 MHz, MeOD) δ 8.13 - 7.88 (m, 2H), 7.76 - 7.45 (m, 2H), 7.32 (dt,J = 68.1, 33.3 Hz, 1H), 6.77 (dd,J = 67.1, 35.1 Hz, 1H), 6.35 (dd,J = 19.9, 3.0 Hz, 1H), 3.99 - 3.88 (m, 3H), 3.68 - 3.40 (m, 2H), 3.37 - 3.33 (m, 3H), 2.99 - 2.80 (m, 2H), 2.60 - 2.46 (m, 3H), 1.87 (ddd,J = 34.4, 30.0, 24.2 Hz, 2H), 1.76 - 1.20 (m, 2H).

[0455] Example 72 Synthesis of Compound 10-1: tert-butyl 4-((2S,4R)-4-(cyclopropylmethoxy)-2-(4-(methyl ester group <methoxycarbonyl>)phenyl)piperidine-1-carbonyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate

[0456] [ka]

[0457] Intermediate 10-2 was added to a 10 mL three-neck flask, dissolved in dichloromethane, and N,N-diisopropylethylamine was added. The mixture was placed in an ice bath, and then Intermediate 11-1 was added. After stirring for 10 minutes, tert-butyl 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate was added. After the reaction was completed, dichloromethane and saturated brine were added, and the organic phase was concentrated under reduced pressure to give the title compound. MS m / z (ESI): 577.30 [M+1].

[0458] Example 73 Synthesis of Compound 10: 4-((2S,4R)-4-(cyclopropylmethoxy)-1-(5-methoxy-7-methyl-1H-indole-4-carbonyl)piperidin-2-yl)benzoic acid

[0459] [ka]

[0460] Compound 10-1 was placed in a 10 mL three-neck flask, dissolved in tetrahydrofuran and methanol, and then 1 M aqueous lithium hydroxide was added. The mixture was heated to 45°C and kept overnight. After the reaction was complete, the mixture was concentrated under reduced pressure and purified by reverse phase preparative separation (hydrochloric acid:acetonitrile gradient elution) to obtain the title compound. MS m / z (ESI): 463.55 [M+1]. 1HNMR(600 MHz, MeOD) δ 8.13 - 7.88 (m, 2H), 7.76 - 7.45 (m, 2H), 7.32 (dt,J = 68.1, 33.3 Hz, 1H), 6.77 (dd,J = 67.1, 35.1 Hz, 1H), 6.35 (dd,J = 19.9, 3.0 Hz, 1H), 3.99 - 3.88 (m, 3H), 3.68 - 3.40 (m, 2H), 3.37 - 3.33 (m, 3H), 2.99 - 2.80 (m, 2H), 2.60 - 2.46 (m, 3H), 1.87 (ddd,J = 34.4, 30.0, 24.2 Hz, 2H), 1.76 - 1.20 (m, 2H).

[0461] Example 74 Synthesis of Compound 11-1: tert-butyl 4-((2S,4S)-4-ethoxy-2-(4-(methyl ester group <methoxycarbonyl>)phenyl)piperidin-1-yl)amino)-5-methoxy-7-methyl-1H-indole-1-carboxylate

[0462] [ka]

[0463] Intermediate 1-7 was placed in a 10 mL three-neck flask, and Intermediate 12-2 was added as a solid, followed by 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl and tris(dibenzylideneacetone)dipalladium. Finally, sodium tert-butoxide was added as a solid. Toluene was added, and the mixture was purged with nitrogen three times. The mixture was heated to 100°C and reacted overnight. After completion of the reaction, the reaction was quenched by heating saturated aqueous ammonium chloride solution. The organic phase was concentrated under reduced pressure, and the title compound was obtained by column chromatography. MS m / z (ESI): 538.30 [M+1]

[0464] Example 75 Synthesis of Compound 11: 4-((2S,4S)-4-ethoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)amino)piperidin-2-yl)benzoic acid

[0465] [ka]

[0466] Compound 11-1 was placed in a 10 mL three-neck flask, dissolved in tetrahydrofuran and methanol, and then 1 M aqueous lithium hydroxide was added. The mixture was heated to 45°C and kept overnight. After the reaction was complete, the mixture was concentrated under reduced pressure and subjected to reverse phase preparative separation (hydrochloric acid:acetonitrile gradient elution) to obtain the title compound. MS m / z (ESI): 463.55 [M+1]

[0467] Example 76 Synthesis of Compound 12-1: tert-butyl 4-((2S,4R)-4-ethoxy-2-(4-(methyl ester group <methoxycarbonyl>)phenyl)piperidin-1-yl)amino)-5-methoxy-7-methyl-1H-indole-1-carboxylate

[0468] [ka]

[0469] Intermediate 2-5 was placed in a 10 mL three-neck flask, and Intermediate 12-2 was added as a solid, followed by 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl and tris(dibenzylideneacetone)dipalladium. Finally, sodium tert-butoxide was added as a solid, toluene was added, the mixture was dissolved, and the atmosphere was purged with nitrogen three times. The mixture was heated to 100 °C and reacted overnight. After completion of the reaction, the reaction was quenched by heating saturated aqueous ammonium chloride. The organic phase was concentrated under reduced pressure, and the title compound was obtained by column chromatography. MS m / z (ESI): 538.30 [M+1].

[0470] Example 77 Synthesis of Compound 12: 4-((2S,4R)-4-ethoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)amino)piperidin-2-yl)benzoic acid

[0471] [ka]

[0472] Compound 12-1 was placed in a 10 mL three-neck flask, dissolved in tetrahydrofuran and methanol, and then 1 M aqueous lithium hydroxide was added. The mixture was heated to 45°C and kept overnight. After the reaction was complete, the mixture was concentrated under reduced pressure and subjected to reverse phase preparative separation (hydrochloric acid:acetonitrile gradient elution) to obtain the title compound. MS m / z (ESI): 463.55 [M+1]

[0473] Example 78 Synthesis of Compound 13-1: tert-butyl 5-methoxy-4-((2S,4S)-2-(4-(methyl ester group <methoxycarbonyl>)phenyl)-4-(2,2,2-trifluoroethoxy)piperidin-1-yl)amino)-7-methyl-1H-indole-1-carboxylate

[0474] [ka]

[0475] Intermediate 3-4 was placed in a 10 mL three-neck flask, and Intermediate 12-2 was added as a solid, followed by 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl and tris(dibenzylideneacetone)dipalladium. Finally, sodium tert-butoxide was added as a solid, toluene was added, the mixture was dissolved, and the atmosphere was purged with nitrogen three times. The mixture was heated to 100 °C and reacted overnight. After completion of the reaction, the reaction was quenched by heating saturated aqueous ammonium chloride solution. The organic phase was concentrated under reduced pressure and purified by column chromatography to obtain the title compound. MS m / z (ESI): 592.30 [M+1].

[0476] Example 79 Synthesis of Compound 13: 4-((2S,4S)-1-((5-methoxy-7-methyl-1H-indol-4-yl)amino)-4-(2,2,2-trifluoroethoxy)piperidin-2-yl)benzoic acid

[0477] [ka]

[0478] Compound 13-1 was placed in a 10 mL three-neck flask, dissolved in tetrahydrofuran and methanol, and then 1 M aqueous lithium hydroxide was added. The mixture was heated to 45°C and kept overnight. After the reaction was complete, the mixture was concentrated under reduced pressure and subjected to reverse phase preparative separation (hydrochloric acid:acetonitrile gradient elution) to obtain the title compound. MS m / z (ESI): 478.55 [M+1]

[0479] Example 80 Synthesis of Compound 14-1: tert-butyl 5-methoxy-4-((2S,4R)-2-(4-(methyl ester group <methoxycarbonyl>)phenyl)-4-(2,2,2-trifluoroethoxy)piperidin-1-yl)amino)-7-methyl-1H-indole-1-carboxylate

[0480] [ka]

[0481] Intermediate 4-4 was placed in a 10 mL three-neck flask, and Intermediate 12-2 was added as a solid, followed by 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl and tris(dibenzylideneacetone)dipalladium. Finally, sodium tert-butoxide was added as a solid, dissolved in toluene, and purged with nitrogen three times. The mixture was heated to 100 °C and reacted overnight. After completion of the reaction, the reaction was quenched by heating saturated aqueous ammonium chloride. The organic phase was concentrated under reduced pressure and purified by column chromatography to obtain the title compound. MS m / z (ESI): 592.30 [M+1].

[0482] Example 81 Synthesis of Compound 14: 4-((2S,4R)-1-((5-methoxy-7-methyl-1H-indol-4-yl)amino)-4-(2,2,2-trifluoroethoxy)piperidin-2-yl)benzoic acid

[0483] [ka]

[0484] Compound 14-1 was placed in a 10 mL three-neck flask, dissolved in tetrahydrofuran and methanol, and then 1 M aqueous lithium hydroxide was added. The mixture was heated to 45°C and kept overnight. After the reaction was complete, the mixture was concentrated under reduced pressure and subjected to reverse phase preparative separation (hydrochloric acid:acetonitrile gradient elution) to obtain the title compound. MS m / z (ESI): 478.55 [M+1]

[0485] Example 82 Synthesis of Compound 15-1: tert-butyl 4-((2S,4S)-4-(2,2-difluoroethoxy)-2-(4-(methyl ester group <methoxycarbonyl>)phenyl)piperidin-1-yl)amino)-5-methoxy-7-methyl-1H-indole-1-carboxylate

[0486] [ka]

[0487] Intermediate 5-4 was placed in a 10 mL three-neck flask, and Intermediate 12-2 was added as a solid, followed by 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl and tris(dibenzylideneacetone)dipalladium. Finally, sodium tert-butoxide was added as a solid, toluene was added, the mixture was dissolved, and the atmosphere was purged with nitrogen three times. The mixture was heated to 100 °C and reacted overnight. After completion of the reaction, the reaction was quenched by heating saturated aqueous ammonium chloride solution. The organic phase was concentrated under reduced pressure, and the title compound was obtained by column chromatography. MS m / z (ESI): 574.30 [M+1].

[0488] Example 83 Synthesis of Compound 15: 4-((2S,4S)-4-(2,2-difluoroethoxy)-1-((5-methoxy-7-methyl-1H-indol-4-yl)amino)piperidin-2-yl)benzoic acid

[0489] [ka]

[0490] Compound 15-1 was placed in a 10 mL three-neck flask, dissolved in tetrahydrofuran and methanol, and then 1 M aqueous lithium hydroxide was added. The mixture was heated to 45°C and kept overnight. After the reaction was complete, the mixture was concentrated under reduced pressure and subjected to reverse phase preparative separation (hydrochloric acid:acetonitrile gradient elution) to obtain the title compound. MS m / z (ESI): 460.55 [M+1]

[0491] Example 84 Synthesis of compound 16-1: tert-butyl 4-(((2S,4R)-4-(2,2-difluoroethoxy)-2-(4-(methyl ester group <methoxycarbonyl>)phenyl)piperidin-1-yl)amino)-5-methoxy-7-methyl-1H-indole-1-carboxylate

[0492] [ka]

[0493] Intermediate 6-4 was placed in a 10 mL three-neck flask, and Intermediate 12-2 was added as a solid, followed by 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl and tris(dibenzylideneacetone)dipalladium. Finally, sodium tert-butoxide was added as a solid, toluene was added, the mixture was dissolved, and the atmosphere was purged with nitrogen three times. The mixture was heated to 100 °C and reacted overnight. After completion of the reaction, the reaction was quenched by heating saturated aqueous ammonium chloride solution. The organic phase was concentrated under reduced pressure, and the title compound was obtained by column chromatography. MS m / z (ESI): 574.30 [M+1].

[0494] Example 85 Synthesis of Compound 16: 4-((2S,4R)-4-(2,2-difluoroethoxy)-1-((5-methoxy-7-methyl-1H-indol-4-yl)amino)piperidin-2-yl)benzoic acid

[0495] [ka]

[0496] Compound 16-1 was placed in a 10 mL three-neck flask, dissolved in tetrahydrofuran and methanol, and then 1 M aqueous lithium hydroxide was added. The mixture was heated to 45°C and kept overnight. After the reaction was complete, the mixture was concentrated under reduced pressure and subjected to reverse phase preparative separation (hydrochloric acid:acetonitrile gradient elution) to obtain the title compound. MS m / z (ESI): 460.55 [M+1]

[0497] Example 86 Synthesis of Compound 17-1: tert-butyl 4-(((2S,4S)-4-(2-fluoroethoxy)-2-(4-(methyl ester group <methoxycarbonyl>)phenyl)piperidin-1-yl)amino)-5-methoxy-7-methyl-1H-indole-1-carboxylate

[0498] [ka]

[0499] Intermediate 7-4 was placed in a 10 mL three-neck flask, and Intermediate 12-2 was added as a solid, followed by 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl and tris(dibenzylideneacetone)dipalladium. Finally, sodium tert-butoxide was added as a solid, toluene was added, the mixture was dissolved, and the atmosphere was purged with nitrogen three times. The mixture was heated to 100 °C and reacted overnight. After completion of the reaction, the reaction was quenched by heating saturated aqueous ammonium chloride. The organic phase was concentrated under reduced pressure, and the title compound was obtained by column chromatography. MS m / z (ESI): 556.30 [M+1].

[0500] Example 87 Synthesis of Compound 17: 4-((2S,4S)-4-(2-fluoroethoxy)-1-((5-methoxy-7-methyl-1H-indol-4-yl)amino)piperidin-2-yl)benzoic acid

[0501] [ka]

[0502] Compound 17-1 was placed in a 10 mL three-neck flask, dissolved in tetrahydrofuran and methanol, and then 1 M aqueous lithium hydroxide was added. The mixture was heated to 45°C and kept overnight. After the reaction was complete, the mixture was concentrated under reduced pressure and subjected to reverse phase preparative separation (hydrochloric acid:acetonitrile gradient elution) to obtain the title compound. MS m / z (ESI): 442.55 [M+1]

[0503] Example 88 Synthesis of Compound 18-1: tert-butyl 4-((2S,4R)-4-(2-fluoroethoxy)-2-(4-(methyl ester group <methoxycarbonyl>)phenyl)piperidin-1-yl)amino)-5-methoxy-7-methyl-1H-indole-1-carboxylate

[0504] [ka]

[0505] Intermediate 8-4 was placed in a 10 mL three-neck flask, and Intermediate 12-2 was added as a solid, followed by 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl and tris(dibenzylideneacetone)dipalladium. Finally, sodium tert-butoxide was added as a solid, dissolved in toluene, and purged with nitrogen three times. The mixture was heated to 100 °C and reacted overnight. After completion of the reaction, the reaction was quenched by heating saturated aqueous ammonium chloride. The organic phase was concentrated under reduced pressure and purified by column chromatography to obtain the title compound. MS m / z (ESI): 556.30 [M+1].

[0506] Example 89 Synthesis of Compound 18: 4-((2S,4R)-4-(2-fluoroethoxy)-1-((5-methoxy-7-methyl-1H-indol-4-yl)amino)piperidin-2-yl)benzoic acid

[0507] [ka]

[0508] Compound 18-1 was placed in a 10 mL three-neck flask, dissolved in tetrahydrofuran and methanol, and then 1 M aqueous lithium hydroxide was added. The mixture was heated to 45°C and kept overnight. After the reaction was complete, the mixture was concentrated under reduced pressure and subjected to reverse phase preparative separation (hydrochloric acid:acetonitrile gradient elution) to obtain the title compound. MS m / z (ESI): 442.55 [M+1]

[0509] Example 90 Synthesis of Compound 19-1: tert-butyl 4-((2S,4S)-4-(cyclopropylmethoxy)-2-(4-(methyl ester group <methoxycarbonyl>)phenyl)piperidin-1-yl)amino)-5-methoxy-7-methyl-1H-indole-1-carboxylate

[0510] [ka]

[0511] Intermediate 9-4 was placed in a 10 mL three-neck flask, and Intermediate 12-2 was added as a solid, followed by 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl and tris(dibenzylideneacetone)dipalladium. Finally, sodium tert-butoxide was added as a solid, dissolved in toluene, and purged with nitrogen three times. The mixture was heated to 100 °C and reacted overnight. After completion of the reaction, the reaction was quenched by heating saturated aqueous ammonium chloride. The organic phase was concentrated under reduced pressure and purified by column chromatography to obtain the title compound. MS m / z (ESI): 564.30 [M+1].

[0512] Example 91 Synthesis of Compound 19: 4-((2S,4S)-4-(cyclopropylmethoxy)-1-((5-methoxy-7-methyl-1H-indol-4-yl)amino)piperidin-2-yl)benzoic acid

[0513] [ka]

[0514] Compound 19 was placed in a 10 mL three-neck flask, dissolved in tetrahydrofuran and methanol, and then added with 1 M aqueous lithium hydroxide. The mixture was heated to 45°C and kept overnight. After the reaction was complete, the mixture was concentrated under reduced pressure and purified by reverse phase elution (hydrochloric acid:acetonitrile gradient elution) to give the title compound. MS m / z (ESI): 450.55 [M+1].

[0515] Example 92 Synthesis of compound 20-1: tert-butyl 4-(((2S,4R)4-(cyclopropylmethoxy)2-(4-(methyl ester group<methoxycarbonyl>)phenyl)piperidin-1-yl)amino)5-methoxy-7-methyl-1H-indole-1-carboxylate

[0516] [ka]

[0517] Intermediate 9-4 was placed in a 10 mL three-neck flask, and Intermediate 12-2 was added as a solid. Then, 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl and tris(dibenzylideneacetone)dipalladium were added. Finally, sodium tert-butoxide was added as a solid. Toluene was added to dissolve the mixture, and the mixture was purged with nitrogen gas three times. The mixture was heated to 100 °C and reacted overnight. After completion of the reaction, the reaction was quenched by heating saturated aqueous ammonium chloride solution. The organic phase was concentrated under reduced pressure and purified by column chromatography to obtain the title compound. MS m / z (ESI): 564.30 [M+1].

[0518] Example 93 Synthesis of Compound 20: 4-((2S,4R)-4-(cyclopropylmethoxy)-1-((5-methoxy-7-methyl-1H-indol-4-yl)amino)piperidin-2-yl)benzoic acid

[0519] [ka]

[0520] Compound 20-1 was placed in a 10 mL three-neck flask, dissolved in tetrahydrofuran and methanol, and then added with 1 M aqueous lithium hydroxide. The mixture was heated to 45°C and kept overnight. After the reaction was complete, the mixture was concentrated under reduced pressure and purified by reverse phase elution (hydrochloric acid:acetonitrile gradient elution) to give the title compound. MS m / z (ESI): 450.55 [M+1].

[0521] Example 94 Synthesis of compound 21-1: tert-butyl 4-(((2S,4S)-4-ethoxy-2-(4-(methyl ester group <methoxycarbonyl>)phenyl)piperidin-1-yl)fluoromethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate

[0522] [ka]

[0523] Intermediate 1-5 was added to a 10 mL three-neck flask, dissolved in dichloromethane, and triethylamine was added. Intermediate 13-4 was added and reacted overnight at room temperature. After completion of the reaction, saturated ammonium chloride solution was added to quench the reaction. The organic phase was concentrated under reduced pressure and purified by column chromatography to obtain the title compound. MS m / z (ESI): 555.30 [M+1].

[0524] Example 95 Synthesis of Compound 21: 4-((2S,4S)4-ethoxy-1-(fluoro(5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl)benzoic acid

[0525] [ka]

[0526] Compound 21-1 was placed in a 10 mL three-neck flask, dissolved in tetrahydrofuran and methanol, and then 1 M aqueous lithium hydroxide solution was added. The mixture was heated to 45°C and kept overnight. After the reaction was complete, the mixture was concentrated under reduced pressure and purified by reverse phase elution (hydrochloric acid:acetonitrile gradient elution) to give the title compound. MS m / z (ESI): 441.21 [M+1].

[0527] Example 96 Synthesis of compound 22-1: tert-butyl 4-(((2S,4R)4-ethoxy 2-(4-(methyl ester group <methoxycarbonyl>)phenyl)piperidin-1-yl)fluoromethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate

[0528] [ka]

[0529] Intermediate 2-3 was added to a 10 mL three-neck flask, dissolved in dichloromethane, and triethylamine was added. Intermediate 13-4 was added and reacted overnight at room temperature. After completion of the reaction, saturated ammonium chloride solution was added to quench the reaction. The organic phase was concentrated under reduced pressure and purified by column chromatography to obtain the title compound. MS m / z (ESI): 555.30 [M+1].

[0530] Example 97 Synthesis of Compound 22: 4-((2S,4R)-4-ethoxy-1-(fluoro(5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl)benzoic acid

[0531] [ka]

[0532] Compound 22-1 was placed in a 10 mL three-neck flask, dissolved in tetrahydrofuran and methanol, and then 1 M aqueous lithium hydroxide was added. The mixture was heated to 45°C and kept overnight. After the reaction was complete, the mixture was concentrated under reduced pressure and purified by reverse phase elution (hydrochloric acid:acetonitrile gradient elution) to give the title compound. MS m / z (ESI): 441.21 [M+1].

[0533] Example 98 Synthesis of compound 23-1: tert-butyl 4-(fluoro((2S,4S)-2-(4-(methyl ester group<methoxycarbonyl>)phenyl)4-(2,2,2-trifluoroethoxy)piperidin-1-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate

[0534] [ka]

[0535] Intermediate 3-2 was added to a 10 mL three-neck flask, dissolved in dichloromethane, and triethylamine was added. Intermediate 13-4 was added and reacted overnight at room temperature. After completion of the reaction, saturated ammonium chloride solution was added to quench the reaction. The organic phase was concentrated under reduced pressure and purified by column chromatography to obtain the title compound. MS m / z (ESI): 609.30 [M+1].

[0536] Example 99 Synthesis of Compound 23: 4-((2S,4S)-1-(fluoro(5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-(2,2,2-trifluoroethoxy)piperidin-2-yl)benzoic acid

[0537] [ka]

[0538] Compound 23-1 was placed in a 10 mL three-neck flask, dissolved in tetrahydrofuran and methanol, and then added with 1 M aqueous lithium hydroxide. The mixture was heated to 45°C and kept overnight. After the reaction was complete, the mixture was concentrated under reduced pressure and purified by reverse phase elution (hydrochloric acid:acetonitrile gradient elution) to give the title compound. MS m / z (ESI): 495.21 [M+1].

[0539] Example 100 Synthesis of Compound 24-1: tert-butyl 4-(fluoro((2S,4R)-2-(4-(methyl ester group<methoxycarbonyl>)phenyl)4-(2,2,2-trifluoroethoxy)piperidin-1-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate

[0540] [ka]

[0541] Intermediate 4-2 was added to a 10 mL three-neck flask, dissolved in dichloromethane, and triethylamine was added. Intermediate 13-4 was then added and reacted overnight at room temperature. After completion of the reaction, saturated ammonium chloride solution was added to quench the reaction. The organic phase was concentrated under reduced pressure and purified by column chromatography to obtain the title compound. MS m / z (ESI): 609.30 [M+1].

[0542] Example 101 Synthesis of Compound 24: 4-((2S,4R)-1-(fluoro(5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-(2,2,2-trifluoroethoxy)piperidin-2-yl)benzoic acid

[0543] [ka]

[0544] Compound 24-1 was placed in a 10 mL three-neck flask, dissolved in tetrahydrofuran and methanol, and then 1 M aqueous lithium hydroxide was added. The mixture was heated to 45°C and kept overnight. After the reaction was complete, the mixture was concentrated under reduced pressure and purified by reverse phase elution (hydrochloric acid:acetonitrile gradient elution) to give the title compound. MS m / z (ESI): 495.21 [M+1].

[0545] Example 102 Synthesis of Compound 25-1: tert-butyl 4-(((2S,4S)4-(2,2-difluoroethoxy)2-(4-(methyl ester group<methoxycarbonyl>)phenyl)piperidin-1-yl)fluoromethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate

[0546] [ka]

[0547] Intermediate 5-2 was added to a 10 mL three-neck flask, dissolved in dichloromethane, and triethylamine was added. Intermediate 13-4 was then added and reacted overnight at room temperature. After completion of the reaction, saturated ammonium chloride solution was added to quench the reaction. The organic phase was concentrated under reduced pressure and purified by column chromatography to obtain the title compound. MS m / z (ESI): 591.30 [M+1].

[0548] Example 103 Synthesis of Compound 25: 4-((2S,4S)4-(2,2-difluoroethoxy)-1-(fluoro(5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl)benzoic acid

[0549] [ka]

[0550] Compound 25-1 was placed in a 10 mL three-neck flask, dissolved in tetrahydrofuran and methanol, and then 1 M aqueous lithium hydroxide was added. The mixture was heated to 45°C and kept overnight. After the reaction was complete, the mixture was concentrated under reduced pressure and purified by reverse phase elution (hydrochloric acid:acetonitrile gradient elution) to give the title compound. MS m / z (ESI): 477.21 [M+1].

[0551] Example 104 Synthesis of compound 26-1: tert-butyl 4-(((2S,4R)-4-(2,2-difluoroethoxy)-2-(4-(methyl ester group<methoxycarbonyl>)phenyl)piperidin-1-yl)fluoromethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate

[0552] [ka]

[0553] Intermediate 6-2 was added to a 10 mL three-neck flask, dissolved in dichloromethane, and triethylamine was added. Intermediate 13-4 was added and reacted overnight at room temperature. After completion of the reaction, saturated ammonium chloride solution was added to quench the reaction. The organic phase was concentrated under reduced pressure and purified by column chromatography to obtain the title compound. MS m / z (ESI): 591.30 [M+1].

[0554] Example 105 Synthesis of Compound 26: 4-((2S,4S)4-(2,2-difluoroethoxy)-1-(fluoro(5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl)benzoic acid

[0555] [ka]

[0556] Compound 26-1 was placed in a 10 mL three-neck flask, dissolved in tetrahydrofuran and methanol, and then added with 1 M aqueous lithium hydroxide. The mixture was heated to 45°C and kept overnight. After the reaction was complete, the mixture was concentrated under reduced pressure and purified by reverse phase elution (hydrochloric acid:acetonitrile gradient elution) to give the title compound. MS m / z (ESI): 477.21 [M+1].

[0557] Example 106 Synthesis of Compound 27-1: tert-butyl 4-(fluoro((2S,4S)4-(2-fluoroethoxy)2-(4-(methyl ester group<methoxycarbonyl>)phenyl)piperidin-1-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate

[0558] [ka]

[0559] Intermediate 7-2 was added to a 10 mL three-neck flask, dissolved in dichloromethane, and triethylamine was added. Intermediate 13-4 was added and reacted overnight at room temperature. After completion of the reaction, saturated ammonium chloride solution was added to quench the reaction. The organic phase was concentrated under reduced pressure and purified by column chromatography to obtain the title compound. MS m / z (ESI): 573.30 [M+1].

[0560] Example 107 Synthesis of Compound 27: 4-((2S,4S)-1-(fluoro(5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-(2-fluoroethoxy)piperidin-2-yl)benzoic acid

[0561] [ka]

[0562] Compound 27-1 was placed in a 10 mL three-neck flask, dissolved in tetrahydrofuran and methanol, and then 1 M aqueous lithium hydroxide solution was added. The mixture was heated to 45°C and kept overnight. After the reaction was complete, the mixture was concentrated under reduced pressure and purified by reverse phase elution (hydrochloric acid:acetonitrile gradient elution) to give the title compound. MS m / z (ESI): 459.21 [M+1].

[0563] Example 108 Synthesis of Compound 28-1: tert-butyl 4-(fluoro((2S,4R)-4-(2-fluoroethoxy)-2-(4-(methyl ester group<methoxycarbonyl>)phenyl)piperidin-1-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate

[0564] [ka]

[0565] Intermediate 8-2 was added to a 10 mL three-neck flask, dissolved in dichloromethane, and triethylamine was added. Intermediate 13-4 was then added and reacted overnight at room temperature. After completion of the reaction, saturated ammonium chloride solution was added to quench the reaction. The organic phase was concentrated under reduced pressure and purified by column chromatography to obtain the title compound. MS m / z (ESI): 573.30 [M+1].

[0566] Example 109 Synthesis of Compound 28: 4-((2S,4R)-1-(fluoro(5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-(2-fluoroethoxy)piperidin-2-yl)benzoic acid

[0567] [ka]

[0568] Compound 28-1 was placed in a 10 mL three-neck flask, dissolved in tetrahydrofuran and methanol, and then added with 1 M aqueous lithium hydroxide. The mixture was heated to 45°C and kept overnight. After the reaction was complete, the mixture was concentrated under reduced pressure and purified by reverse phase elution (hydrochloric acid:acetonitrile gradient elution) to give the title compound. MS m / z (ESI): 459.21 [M+1].

[0569] Example 110 Synthesis of Compound 29-1: tert-butyl 4-(((2S,4S)4-(cyclopropylmethoxy)2-(4-(methyl ester group<methoxycarbonyl>)phenyl)piperidin-1-yl)fluoromethyl)5-methoxy-7-methyl-1H-indole-1-carboxylate

[0570] [ka]

[0571] Intermediate 9-2 was added to a 10 mL three-neck flask, dissolved in dichloromethane, and triethylamine was added. Intermediate 13-4 was then added and reacted overnight at room temperature. After completion of the reaction, saturated ammonium chloride solution was added to quench the reaction. The organic phase was concentrated under reduced pressure and purified by column chromatography to obtain the title compound. MS m / z (ESI): 581.30 [M+1].

[0572] Example 111 Synthesis of Compound 29: 4-((2S,4S)4-(cyclopropylmethoxy)1-(fluoro(5-methoxy7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl)benzoic acid

[0573] [ka]

[0574] Compound 29-1 was placed in a 10 mL three-neck flask, dissolved in tetrahydrofuran and methanol, and then added with 1 M aqueous lithium hydroxide. The mixture was heated to 45°C and kept overnight. After the reaction was complete, the mixture was concentrated under reduced pressure and purified by reverse phase elution (hydrochloric acid:acetonitrile gradient elution) to give the title compound. MS m / z (ESI): 467.21 [M+1].

[0575] Example 112 Synthesis of compound 30-1: tert-butyl 4-(((2S,4R)4-(cyclopropylmethoxy)2-(4-(methyl ester group<methoxycarbonyl>)phenyl)piperidin-1-yl)fluoromethyl)5-methoxy-7-methyl-1H-indole-1-carboxylate

[0576] [ka]

[0577] Intermediate 10-2 was placed in a 10 mL three-neck flask, dissolved in dichloromethane, and triethylamine was added. Intermediate 13-4 was added and reacted overnight at room temperature. After completion of the reaction, saturated ammonium chloride solution was added to quench the reaction. The organic phase was concentrated under reduced pressure and purified by column chromatography to obtain the title compound. MS m / z (ESI): 581.30 [M+1].

[0578] Example 113 Synthesis of Compound 30: 4-((2S,4R)-4-(cyclopropylmethoxy)-1-(fluoro(5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl)benzoic acid

[0579] [ka]

[0580] Compound 30-1 was placed in a 10 mL three-neck flask, dissolved in tetrahydrofuran and methanol, and then added with 1 M aqueous lithium hydroxide. The mixture was heated to 45 °C and kept overnight. After the reaction was complete, the mixture was concentrated under reduced pressure and purified by reverse phase elution (hydrochloric acid:acetonitrile gradient elution) to give the title compound. MS m / z (ESI): 467.21 [M+1].

[0581] Example 114 Synthesis of compound 31-1: tert-butyl 4-(((2S,4S)4-ethoxy 2-(4-(methyl ester group <methoxycarbonyl>)phenyl)piperidin-1-yl)difluoromethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate

[0582] [ka]

[0583] Intermediate 1-5 was added to a 10 mL three-neck flask, dissolved in dichloromethane, and triethylamine was added. Intermediate 14-2 was added and reacted overnight at room temperature. After the reaction was completed, saturated ammonium chloride solution was added to quench the reaction. The organic phase was concentrated under reduced pressure and purified by column chromatography to obtain the title compound. MS m / z (ESI): 573.30 [M+1].

[0584] Example 115 Synthesis of Compound 31: 4-((2S,4S)-1-(difluoro(5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-ethoxypiperidin-2-yl)benzoic acid

[0585] [ka]

[0586] Compound 31-1 was placed in a 10 mL three-neck flask, dissolved in tetrahydrofuran and methanol, and then added with 1 M aqueous lithium hydroxide. The mixture was heated to 45°C and kept overnight. After the reaction was complete, the mixture was concentrated under reduced pressure and purified by reverse phase elution (hydrochloric acid:acetonitrile gradient elution) to give the title compound. MS m / z (ESI): 459.21 [M+1].

[0587] Example 116 Synthesis of Compound 32-1: tert-butyl 4-(((2S,4R)-4-ethoxy-2-(4-(methyl ester group <methoxycarbonyl>)phenyl)piperidin-1-yl)difluoromethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate

[0588] [ka]

[0589] Intermediate 2-3 was added to a 10 mL three-neck flask, dissolved in dichloromethane, and triethylamine was added. Intermediate 14-2 was added and reacted overnight at room temperature. After completion of the reaction, saturated ammonium chloride solution was added to quench the reaction. The organic phase was concentrated under reduced pressure and purified by column chromatography to obtain the title compound. MS m / z (ESI): 573.30 [M+1].

[0590] Example 117 Synthesis of Compound 32: 4-((2S,4R)-1-(difluoro(5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-ethoxypiperidin-2-yl)benzoic acid

[0591] [ka]

[0592] Compound 32-1 was placed in a 10 mL three-neck flask, dissolved in tetrahydrofuran and methanol, and then 1 M aqueous lithium hydroxide was added. The mixture was heated to 45°C and kept overnight. After the reaction was complete, the mixture was concentrated under reduced pressure and purified by reverse phase elution (hydrochloric acid:acetonitrile gradient elution) to give the title compound. MS m / z (ESI): 459.21 [M+1].

[0593] Example 118 Synthesis of compound 33-1: tert-butyl 4-(difluoro((2S,4S)-2-(4-(methyl ester group<methoxycarbonyl>)phenyl)4-(2,2,2-trifluoroethoxy)piperidin-1-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate

[0594] [ka]

[0595] Intermediate 3-2 was added to a 10 mL three-neck flask, dissolved in dichloromethane, and triethylamine was added. Intermediate 14-2 was added and reacted overnight at room temperature. After completion of the reaction, saturated ammonium chloride solution was added to quench the reaction. The organic phase was concentrated under reduced pressure and purified by column chromatography to obtain the title compound. MS m / z (ESI): 627.30 [M+1].

[0596] Example 119 Synthesis of Compound 33: 4-((2S,4S)-1-(difluoro(5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-(2,2,2-trifluoroethoxy)piperidin-2-yl)benzoic acid

[0597] [ka]

[0598] Compound 33-1 was placed in a 10 mL three-neck flask, dissolved in tetrahydrofuran and methanol, and then added with 1 M aqueous lithium hydroxide. The mixture was heated to 45°C and kept overnight. After the reaction was complete, the mixture was concentrated under reduced pressure and purified by reverse phase elution (hydrochloric acid:acetonitrile gradient elution) to give the title compound. MS m / z (ESI): 513.21 [M+1].

[0599] Example 120 Synthesis of Compound 34-1: tert-butyl 4-(difluoro((2S,4R)-2-(4-(methyl ester group<methoxycarbonyl>)phenyl)4-(2,2,2-trifluoroethoxy)piperidin-1-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate

[0600] [ka]

[0601] Intermediate 4-2 was added to a 10 mL three-neck flask, dissolved in dichloromethane, and triethylamine was added. Intermediate 14-2 was added and reacted overnight at room temperature. After completion of the reaction, saturated ammonium chloride solution was added to quench the reaction. The organic phase was concentrated under reduced pressure and purified by column chromatography to obtain the title compound. MS m / z (ESI): 627.30 [M+1].

[0602] Example 121 Synthesis of Compound 34: 4-((2S,4R)-1-(difluoro(5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-(2,2,2-trifluoroethoxy)piperidin-2-yl)benzoic acid

[0603] [ka]

[0604] Compound 34-1 was placed in a 10 mL three-neck flask, dissolved in tetrahydrofuran and methanol, and then 1 M aqueous lithium hydroxide was added. The mixture was heated to 45°C and kept overnight. After the reaction was complete, the mixture was concentrated under reduced pressure and purified by reverse phase elution (hydrochloric acid:acetonitrile gradient elution) to give the title compound. MS m / z (ESI): 513.21 [M+1].

[0605] Example 122 Synthesis of Compound 35-1: tert-butyl 4-(((2S,4S)4-(2,2-difluoroethoxy)2-(4-(methyl ester group<methoxycarbonyl>)phenyl)piperidin-1-yl)difluoromethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate

[0606] [ka]

[0607] Intermediate 5-2 was added to a 10 mL three-neck flask, dissolved in dichloromethane, and triethylamine was added. Intermediate 14-2 was added and reacted overnight at room temperature. After the reaction was completed, saturated ammonium chloride solution was added to quench the reaction. The organic phase was concentrated under reduced pressure and purified by column chromatography to obtain the title compound. MS m / z (ESI): 609.30 [M+1].

[0608] Example 123 Synthesis of Compound 35: 4-((2S,4S)-1-(difluoro(5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-(2,2-difluoroethoxy)piperidin-2-yl)benzoic acid

[0609] [ka]

[0610] Compound 35-1 was placed in a 10 mL three-neck flask, dissolved in tetrahydrofuran and methanol, and then added with 1 M aqueous lithium hydroxide. The mixture was heated to 45°C and kept overnight. After the reaction was complete, the mixture was concentrated under reduced pressure and purified by reverse phase elution (hydrochloric acid:acetonitrile gradient elution) to give the title compound. MS m / z (ESI): 495.21 [M+1].

[0611] Example 124 Synthesis of compound 36-1: tert-butyl 4-(((2S,4R)-4-(2,2-difluoroethoxy)-2-(4-(methyl ester group <methoxycarbonyl>)phenyl)piperidin-1-yl)difluoromethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate

[0612] [ka]

[0613] Intermediate 6-2 was added to a 10 mL three-neck flask, dissolved in dichloromethane, and triethylamine was added. Intermediate 14-2 was added and reacted overnight at room temperature. After the reaction was completed, saturated ammonium chloride solution was added to quench the reaction. The organic phase was concentrated under reduced pressure and purified by column chromatography to obtain the title compound. MS m / z (ESI): 609.30 [M+1].

[0614] Example 125 Synthesis of Compound 36: 4-((2S,4R)-1-(difluoro(5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-(2,2-difluoroethoxy)piperidin-2-yl)benzoic acid

[0615] [ka]

[0616] Compound 36-1 was placed in a 10 mL three-neck flask, dissolved in tetrahydrofuran and methanol, and then 1 M aqueous lithium hydroxide was added. The mixture was heated to 45°C and kept overnight. After the reaction was complete, the mixture was concentrated under reduced pressure and purified by reverse phase elution (hydrochloric acid:acetonitrile gradient elution) to give the title compound. MS m / z (ESI): 495.21 [M+1].

[0617] Example 126 Synthesis of Compound 37-1: tert-butyl 4-(difluoro((2S,4S)4-(2-fluoroethoxy)2-(4-(methyl ester group<methoxycarbonyl>)phenyl)piperidin-1-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate

[0618] [ka]

[0619] Intermediate 7-2 was added to a 10 mL three-neck flask, dissolved in dichloromethane, and triethylamine was added. Intermediate 14-2 was added and reacted overnight at room temperature. After completion of the reaction, saturated ammonium chloride solution was added to quench the reaction. The organic phase was concentrated under reduced pressure and purified by column chromatography to obtain the title compound. MS m / z (ESI): 591.30 [M+1].

[0620] Example 127 Synthesis of Compound 37: 4-((2S,4S)-1-(difluoro(5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-(2-fluoroethoxy)piperidin-2-yl)benzoic acid

[0621] [ka]

[0622] Compound 37-1 was placed in a 10 mL three-neck flask, dissolved in tetrahydrofuran and methanol, and then 1 M aqueous lithium hydroxide was added. The mixture was heated to 45°C and kept overnight. After the reaction was complete, the mixture was concentrated under reduced pressure and purified by reverse phase elution (hydrochloric acid:acetonitrile gradient elution) to give the title compound. MS m / z (ESI): 477.21 [M+1].

[0623] Example 128 Synthesis of Compound 38-1: tert-butyl 4-(difluoro((2S,4R)-4-(2-fluoroethoxy)-2-(4-(methyl ester group<methoxycarbonyl>)phenyl)piperidin-1-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate

[0624] [ka]

[0625] Intermediate 8-2 was added to a 10 mL three-neck flask, dissolved in dichloromethane, and triethylamine was added. Intermediate 14-2 was then added and reacted overnight at room temperature. After completion of the reaction, saturated ammonium chloride solution was added to quench the reaction. The organic phase was concentrated under reduced pressure and purified by column chromatography to obtain the title compound. MS m / z (ESI): 591.30 [M+1].

[0626] Example 129 Synthesis of Compound 38: 4-((2S,4R)-1-(difluoro(5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-(2-fluoroethoxy)piperidin-2-yl)benzoic acid

[0627] [ka]

[0628] Compound 38-1 was placed in a 10 mL three-neck flask, dissolved in tetrahydrofuran and methanol, and then added with 1 M aqueous lithium hydroxide. The mixture was heated to 45°C and kept overnight. After the reaction was complete, the mixture was concentrated under reduced pressure and purified by reverse phase elution (hydrochloric acid:acetonitrile gradient elution) to give the title compound. MS m / z (ESI): 477.21 [M+1].

[0629] Example 130 Synthesis of compound 39-1: tert-butyl 4-(((2S,4S)4-(cyclopropylmethoxy)2-(4-(methyl ester group<methoxycarbonyl>)phenyl)piperidin-1-yl)difluoromethyl)5-methoxy7-methyl-1H-indole-1-carboxylate

[0630] [ka]

[0631] Intermediate 9-2 was added to a 10 mL three-neck flask, dissolved in dichloromethane, and triethylamine was added. Intermediate 14 was then added and reacted overnight at room temperature. After completion of the reaction, saturated ammonium chloride solution was added to quench the reaction. The organic phase was concentrated under reduced pressure and purified by column chromatography to obtain the title compound. MS m / z (ESI): 599.30 [M+1].

[0632] Example 131 Synthesis of Compound 39: 4-((2S,4S)4-(cyclopropylmethoxy)-1-(fluoro(5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl)benzoic acid

[0633] [ka]

[0634] Compound 39-1 was placed in a 10 mL three-neck flask, dissolved in tetrahydrofuran and methanol, and then added with 1 M aqueous lithium hydroxide. The mixture was heated to 45°C and kept overnight. After the reaction was complete, the mixture was concentrated under reduced pressure and purified by reverse phase elution (hydrochloric acid:acetonitrile gradient elution) to obtain the title compound. MS m / z (ESI): 485.21 [M +1 ].

[0635] Example 132 Synthesis of compound 40-1: tert-butyl 4-(((2R,4R)4-(cyclopropylmethoxy)2-(4-(methyl ester group<methoxycarbonyl>)phenyl)piperidin-1-yl)difluoromethyl)5-methoxy7-methyl-1H-indole-1-carboxylate

[0636] [ka]

[0637] Intermediate 10-2 was placed in a 10 mL three-neck flask, dissolved in dichloromethane, and triethylamine was added. Intermediate 14-2 was added and reacted overnight at room temperature. After completion of the reaction, saturated ammonium chloride solution was added to quench the reaction. The organic phase was concentrated under reduced pressure and purified by column chromatography to obtain the title compound. MS m / z (ESI): 599.30 [M+1].

[0638] Example 133 Synthesis of Compound 40: 4-((2S,4R)-4-(cyclopropylmethoxy)-1-(fluoro(5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl)benzoic acid

[0639] [ka]

[0640] Compound 40-1 was placed in a 10 mL three-neck flask, dissolved in tetrahydrofuran and methanol, and then 1 M aqueous lithium hydroxide was added. The mixture was heated to 45°C and kept overnight. After the reaction was complete, the mixture was concentrated under reduced pressure and purified by reverse phase elution (hydrochloric acid:acetonitrile gradient elution) to give the title compound. MS m / z (ESI): 485.21 [M+1].

[0641] Example 134 Synthesis of intermediate 15-1:

[0642] [ka]

[0643] tert-Butyl 5-methoxy-7-methyl-1H-indole-1-carboxylate was placed in a 100 mL three-neck flask, the internal temperature was lowered to 0 °C, dichloromethane was added to dissolve, and sulfonyl chloride was added dropwise. After the reaction was completed, saturated brine was added to quench the reaction. The mixture was extracted with dichloromethane and washed three times with brine. The organic phase was concentrated under reduced pressure and purified by column chromatography to obtain the title compound. MS m / z (ESI): 360.10 [M+1].

[0644] Synthesis of intermediate 15-2

[0645] [ka]

[0646] Intermediate 15-1 was placed in a 100 mL single-neck flask, dissolved in formic acid, and then 10% wet palladium on carbon and triphenylphosphine were added. The mixture was allowed to react overnight. After the reaction was complete, the mixture was filtered, concentrated under reduced pressure, and purified by column chromatography to give the title compound. MS m / z (ESI): 295.10 [M+1].

[0647] Synthesis of compound 41-1: tert-butyl 4-(((2S,4S)-4-ethoxy-2-(4-(methyl ester group <methoxycarbonyl>)phenyl)piperidin-1-yl))(methyl)amino)-5-methoxy-7-methyl-1H-indole-1-carboxylate

[0648] [ka]

[0649] Intermediate 1-8 was placed in a 10 mL three-neck flask, and Intermediate 12-2 was added as a solid. Then, 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl and tris(dibenzylideneacetone)dipalladium were added. Finally, sodium tert-butoxide was added as a solid. Toluene was added to dissolve the mixture, and the mixture was purged with nitrogen gas three times. The mixture was heated to 100 °C and reacted overnight. After completion of the reaction, the reaction was quenched by heating saturated aqueous ammonium chloride solution. The organic phase was concentrated under reduced pressure and purified by column chromatography to obtain the title compound. MS m / z (ESI): 552.30 [M+1].

[0650] Synthesis of Compound 41: 4-((2S,4S)4-ethoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)(methyl)amino)piperidin-2-yl)benzoic acid

[0651] [ka]

[0652] Compound 41-1 was placed in a 10 mL three-neck flask, dissolved in tetrahydrofuran and methanol, and then 1 M aqueous lithium hydroxide was added. The mixture was heated to 45°C and kept overnight. After the reaction was complete, the mixture was concentrated under reduced pressure and purified by reverse phase elution (hydrochloric acid:acetonitrile gradient elution) to give the title compound. MS m / z (ESI): 438.21 [M+1].

[0653] Example 135 Synthesis of compound 42-1: tert-butyl 4-(((2S,4R)-4-ethoxy-2-(4-(methyl ester group <methoxycarbonyl>)phenyl)piperidin-1-yl))(methyl)amino)-5-methoxy-7-methyl-1H-indole-1-carboxylate

[0654] [ka]

[0655] Intermediate 2-6 was placed in a 10 mL three-neck flask, and Intermediate 12-2 was added as a solid. Subsequently, 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl and tris(dibenzylideneacetone)dipalladium were added. Finally, sodium tert-butoxide was added as a solid. Toluene was added to dissolve the mixture, and the mixture was purged with nitrogen gas three times. The mixture was heated to 100 °C and reacted overnight. After completion of the reaction, the reaction was quenched by heating saturated aqueous ammonium chloride solution. The organic phase was concentrated under reduced pressure and purified by column chromatography to obtain the title compound. MS m / z (ESI): 552.30 [M+1].

[0656] Synthesis of Compound 42: 4-((2S,4R)-4-ethoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)(methyl)amino)piperidin-2-yl)benzoic acid

[0657] [ka]

[0658] Compound 42-1 was placed in a 10 mL three-neck flask, dissolved in tetrahydrofuran and methanol, and then 1 M aqueous lithium hydroxide solution was added. The mixture was heated to 45°C and kept overnight. After the reaction was complete, the mixture was concentrated under reduced pressure and purified by reverse phase elution (hydrochloric acid:acetonitrile gradient elution) to give the title compound. MS m / z (ESI): 438.21 [M+1].

[0659] Example 136 Synthesis of compound 43-1: tert-butyl 5-methoxy-4-(((2S,4S)-2-(4-(methyl ester group <methoxycarbonyl>)phenyl)-4-(2,2,2-trifluoroethoxy)piperidin-1-yl)(methyl)amino)-7-methyl-1H-indole-1-carboxylate

[0660] [ka]

[0661] Intermediate 3-5 was placed in a 10 mL three-neck flask, and Intermediate 12-2 was added as a solid, followed by 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl and tris(dibenzylideneacetone)dipalladium. Finally, sodium tert-butoxide was added as a solid. Toluene was added to dissolve the mixture, and the mixture was purged with nitrogen gas three times. The mixture was heated to 100 °C and reacted overnight. After completion of the reaction, the reaction was quenched by heating saturated aqueous ammonium chloride solution. The organic phase was concentrated under reduced pressure and purified by column chromatography to obtain the title compound. MS m / z (ESI): 606.30 [M+1].

[0662] Synthesis of Compound 43: 4-((2S,4S)-1-((5-methoxy-7-methyl-1H-indol-4-yl)(methyl)amino)-4-(2,2,2-trifluoroethoxy)piperidin-2-yl)benzoic acid

[0663] [ka]

[0664] Compound 43-1 was placed in a 10 mL three-neck flask, dissolved in tetrahydrofuran and methanol, and then 1 M aqueous lithium hydroxide was added. The mixture was heated to 45°C and kept overnight. After the reaction was complete, the mixture was concentrated under reduced pressure and purified by reverse phase elution (hydrochloric acid:acetonitrile gradient elution) to give the title compound. MS m / z (ESI): 492.21 [M+1].

[0665] Example 137 Synthesis of compound 44-1: tert-butyl 5-methoxy-4-(((2S,4R)-2-(4-(methyl ester group <methoxycarbonyl>)phenyl)-4-(2,2,2-trifluoroethoxy)piperidin-1-yl)(methyl)amino)-7-methyl-1H-indole-1-carboxylate

[0666] [ka]

[0667] Intermediate 4-5 was placed in a 10 mL three-neck flask, and Intermediate 12-2 was added as a solid. Subsequently, 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl and tris(dibenzylideneacetone)dipalladium were added. Finally, sodium tert-butoxide was added as a solid. Toluene was added to dissolve the mixture, and the mixture was purged with nitrogen gas three times. The mixture was heated to 100 °C and reacted overnight. After completion of the reaction, the reaction was quenched by heating saturated aqueous ammonium chloride solution. The organic phase was concentrated under reduced pressure and purified by column chromatography to obtain the title compound. MS m / z (ESI): 606.30 [M+1].

[0668] Synthesis of compound 44: 4-((2S,4R)-1-((5-methoxy-7-methyl-1H-indol-4-yl)(methyl)amino)-4-(2,2,2-trifluoroethoxy)piperidin-2-yl)benzoic acid

[0669] [ka]

[0670] Compound 44-1 was placed in a 10 mL three-neck flask, dissolved in tetrahydrofuran and methanol, and then 1 M aqueous lithium hydroxide solution was added. The mixture was heated to 45°C and kept overnight. After the reaction was complete, the mixture was concentrated under reduced pressure and purified by reverse phase elution (hydrochloric acid:acetonitrile gradient elution) to give the title compound. MS m / z (ESI): 492.21 [M+1].

[0671] Example 138 Synthesis of compound 45-1: tert-butyl 4-(((2S,4S)-(4-(2,2-difluoroethoxy)2-(4-(methyl ester group <methoxycarbonyl>)phenyl)piperidin-1-yl)(methyl)amino)-5-methoxy-7-methyl-1H-indole-1-carboxylate

[0672] [ka]

[0673] Intermediate 5-5 was placed in a 10 mL three-neck flask, and Intermediate 12-2 was added as a solid. This was followed by 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl and tris(dibenzylideneacetone)dipalladium. Finally, sodium tert-butoxide was added as a solid. Toluene was added to dissolve the mixture, and the mixture was purged with nitrogen gas three times. The mixture was heated to 100 °C and reacted overnight. After completion of the reaction, the reaction was quenched by heating saturated aqueous ammonium chloride solution. The organic phase was concentrated under reduced pressure and purified by column chromatography to obtain the title compound. MS m / z (ESI): 588.30 [M+1].

[0674] Synthesis of Compound 45: 4-((2S,4S)-1-((5-methoxy-7-methyl-1H-indol-4-yl)(methyl)amino)-4-(2,2-difluoroethoxy)piperidin-2-yl)benzoic acid

[0675] [ka]

[0676] Compound 45-1 was placed in a 10 mL three-neck flask, dissolved in tetrahydrofuran and methanol, and then 1 M aqueous lithium hydroxide was added. The mixture was heated to 45°C and kept overnight. After the reaction was complete, the mixture was concentrated under reduced pressure and purified by reverse phase elution (hydrochloric acid:acetonitrile gradient elution) to give the title compound. MS m / z (ESI): 474.21 [M+1].

[0677] Example 139 Synthesis of compound 46-1: tert-butyl 4-(((2S,4R)-4-(2,2-difluoroethoxy)-2-(4-(methyl ester group <methoxycarbonyl>)phenyl)piperidin-1-yl)(methyl)amino)-5-methoxy-7-methyl-1H-indole-1-carboxylate

[0678] [ka]

[0679] Intermediate 6-5 was placed in a 10 mL three-neck flask, and Intermediate 12-2 was added as a solid. Subsequently, 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl and tris(dibenzylideneacetone)dipalladium were added. Finally, sodium tert-butoxide was added as a solid. Toluene was added to dissolve the mixture, and the mixture was purged with nitrogen gas three times. The mixture was heated to 100 °C and reacted overnight. After completion of the reaction, the reaction was quenched by heating saturated aqueous ammonium chloride solution. The organic phase was concentrated under reduced pressure and purified by column chromatography to obtain the title compound. MS m / z (ESI): 588.30 [M+1].

[0680] Synthesis of Compound 46: 4-((2S,4R)-1-((5-methoxy-7-methyl-1H-indol-4-yl)(methyl)amino)-4-(2,2-difluoroethoxy)piperidin-2-yl)benzoic acid

[0681] [ka]

[0682] Compound 46-1 was placed in a 10 mL three-neck flask, dissolved in tetrahydrofuran and methanol, and then 1 M aqueous lithium hydroxide was added. The mixture was heated to 45°C and kept overnight. After the reaction was complete, the mixture was concentrated under reduced pressure and purified by reverse phase elution (hydrochloric acid:acetonitrile gradient elution) to give the title compound. MS m / z (ESI): 474.21 [M+1].

[0683] Example 140 Synthesis of compound 47-1: tert-butyl 4-(((2S,4S)-4-(2-fluoroethoxy)-2-(4-(methyl ester group <methoxycarbonyl>)phenyl)piperidin-1-yl)(methyl)amino)-5-methoxy-7-methyl-1H-indole-1-carboxylate

[0684] [ka]

[0685] Intermediate 7-5 was placed in a 10 mL three-neck flask, and Intermediate 12-2 was added as a solid. Subsequently, 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl and tris(dibenzylideneacetone)dipalladium were added. Finally, sodium tert-butoxide was added as a solid. Toluene was added to dissolve the mixture, and the mixture was purged with nitrogen gas three times. The mixture was heated to 100 °C and reacted overnight. After completion of the reaction, the reaction was quenched by heating saturated aqueous ammonium chloride solution. The organic phase was concentrated under reduced pressure and purified by column chromatography to obtain the title compound. MS m / z (ESI): 570.30 [M+1].

[0686] Synthesis of compound 47: 4-((2S,4S)-1-((5-methoxy-7-methyl-1H-indol-4-yl)(methyl)amino)-4-(2-difluoroethoxy)piperidin-2-yl)benzoic acid

[0687] [ka]

[0688] Compound 47-1 was placed in a 10 mL three-neck flask, dissolved in tetrahydrofuran and methanol, and then 1 M aqueous lithium hydroxide was added. The mixture was heated to 45°C and kept overnight. After the reaction was complete, the mixture was concentrated under reduced pressure and purified by reverse phase elution (hydrochloric acid:acetonitrile gradient elution) to give the title compound. MS m / z (ESI): 456.21 [M+1].

[0689] Example 141 Synthesis of compound 48-1: tert-butyl 4-(((2S,4R)-4-(2-fluoroethoxy)-2-(4-(methyl ester group <methoxycarbonyl>)phenyl)piperidin-1-yl)(methyl)amino)-5-methoxy-7-methyl-1H-indole-1-carboxylate

[0690] [ka]

[0691] Intermediate 8-5 was placed in a 10 mL three-neck flask, and Intermediate 12-2 was added as a solid, followed by 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl and tris(dibenzylideneacetone)dipalladium. Finally, sodium tert-butoxide was added as a solid, and toluene was added to dissolve the mixture. The atmosphere was purged with nitrogen gas three times, and the mixture was heated to 100 °C overnight. After completion of the reaction, the reaction was quenched by heating saturated aqueous ammonium chloride solution. The organic phase was concentrated under reduced pressure, and the title compound was obtained by column chromatography. MS m / z (ESI): 570.30 [M+1].

[0692] Synthesis of Compound 48: Synthesis of 4-((2S,4R)-1-((5-methoxy-7-methyl-1H-indol-4-yl)(methyl)amino)-4-(2-difluoroethoxy)piperidin-2-yl)benzoic acid

[0693] [ka]

[0694] Compound 48-1 was placed in a 10 mL three-neck flask, dissolved in tetrahydrofuran and methanol, and then added with 1 M aqueous lithium hydroxide. The mixture was heated to 45°C and kept overnight. After the reaction was complete, the mixture was concentrated under reduced pressure and purified by reverse phase elution (hydrochloric acid:acetonitrile gradient elution) to give the title compound. MS m / z (ESI): 456.21 [M+1].

[0695] Example 142 Synthesis of compound 49-1: tert-butyl 4-(((2S,4S)4-(cyclopropylmethoxy)2-(4-(methyl ester group <methoxycarbonyl>)phenyl)piperidin-1-yl)(methyl)amino)5-methoxy-7-methyl-1H-indole-1-carboxylate

[0696] [ka]

[0697] Intermediate 9-5 was placed in a 10 mL three-neck flask, and Intermediate 12-2 was added as a solid, followed by 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl and tris(dibenzylideneacetone)dipalladium. Finally, sodium tert-butoxide was added as a solid, and toluene was added to dissolve the mixture. The atmosphere was purged with nitrogen gas three times, and the mixture was heated to 100 °C and reacted overnight. After completion of the reaction, the reaction was quenched by heating saturated aqueous ammonium chloride solution. The organic phase was concentrated under reduced pressure, and the title compound was obtained by column chromatography. MS m / z (ESI): 578.30 [M+1].

[0698] Synthesis of Compound 49: 4-((2S,4S)-4-(cyclopropylmethoxy)-1-((5-methoxy-7-methyl-1H-indol-4-yl)(methyl)amino)piperidin-2-yl)benzoic acid

[0699] [ka]

[0700] Compound 49-1 was placed in a 10 mL three-neck flask, dissolved in tetrahydrofuran and methanol, and then added with 1 M aqueous lithium hydroxide. The mixture was heated to 45°C and kept overnight. After the reaction was complete, the mixture was concentrated under reduced pressure and purified by reverse phase elution (hydrochloric acid:acetonitrile gradient elution) to give the title compound. MS m / z (ESI): 464.21 [M+1].

[0701] Example 143 Synthesis of compound 50-1: tert-butyl 4-(((2S,4R)-4-(cyclopropylmethoxy)-2-(4-(methyl ester group <methoxycarbonyl>)phenyl)piperidin-1-yl)(methyl)amino)-5-methoxy-7-methyl-1H-indole-1-carboxylate

[0702] [ka]

[0703] Intermediate 10-5 was placed in a 10 mL three-neck flask, and Intermediate 12-2 was added as a solid. Then, 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl and tris(dibenzylideneacetone)dipalladium were added. Finally, sodium tert-butoxide was added as a solid. Toluene was added to dissolve the mixture, and the mixture was purged with nitrogen gas three times. The mixture was heated to 100 °C and reacted overnight. After completion of the reaction, the reaction was quenched by heating saturated aqueous ammonium chloride solution. The organic phase was concentrated under reduced pressure and purified by column chromatography to obtain the title compound. MS m / z (ESI): 578.30 [M+1].

[0704] Synthesis of Compound 50: 4-((2S,4R)-4-(cyclopropylmethoxy)-1-((5-methoxy-7-methyl-1H-indol-4-yl)(methyl)amino)piperidin-2-yl)benzoic acid

[0705] [ka]

[0706] Compound 50-1 was placed in a 10 mL three-neck flask, dissolved in tetrahydrofuran and methanol, and then 1 M aqueous lithium hydroxide was added. The mixture was heated to 45°C and kept overnight. After the reaction was complete, the mixture was concentrated under reduced pressure and purified by reverse phase elution (hydrochloric acid:acetonitrile gradient elution) to give the title compound. MS m / z (ESI): 464.21 [M+1].

[0707] Example 144 Synthesis of compound 51-1: tert-butyl 4-(((2S,4S)-4-ethoxy-2-(4-(methyl ester group <methoxycarbonyl>)phenyl)piperidin-1-yl)sulfonyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate

[0708] [ka]

[0709] Intermediate 1-5 was added to a 10 mL three-neck flask, dissolved in dichloromethane, and triethylamine was added. Intermediate 15-1 was added and reacted overnight at room temperature. After completion of the reaction, saturated ammonium chloride solution was added to quench the reaction. The organic phase was concentrated under reduced pressure and purified by column chromatography to obtain the title compound. MS m / z (ESI): 555.30 [M+1].

[0710] Synthesis of Compound 51: 4-((2S,4S)-4-ethoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)sulfonyl)piperidin-2-yl)benzoic acid

[0711] [ka]

[0712] Compound 51-1 was placed in a 10 mL three-neck flask, dissolved in tetrahydrofuran and methanol, and then 1 M aqueous lithium hydroxide solution was added. The mixture was heated to 45°C and kept overnight. After the reaction was complete, the mixture was concentrated under reduced pressure and purified by reverse phase elution (hydrochloric acid:acetonitrile gradient elution) to give the title compound. MS m / z (ESI): 474.21 [M+1].

[0713] Example 145 Synthesis of compound 52-1: tert-butyl 4-(((2S,4R)-4-ethoxy-2-(4-(methyl ester group <methoxycarbonyl>)phenyl)piperidin-1-yl)sulfonyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate

[0714] [ka]

[0715] Intermediate 2-3 was added to a 10 mL three-neck flask, dissolved in dichloromethane, and triethylamine was added. Intermediate 15-1 was added and reacted overnight at room temperature. After completion of the reaction, saturated ammonium chloride solution was added to quench the reaction. The organic phase was concentrated under reduced pressure and purified by column chromatography to obtain the title compound. MS m / z (ESI): 555.30 [M+1].

[0716] Synthesis of Compound 52: 4-((2S,4R)-4-ethoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)sulfonyl)piperidin-2-yl)benzoic acid

[0717] [ka]

[0718] Compound 52-1 was placed in a 10 mL three-neck flask, dissolved in tetrahydrofuran and methanol, and then 1 M aqueous lithium hydroxide was added. The mixture was heated to 45°C and kept overnight. After the reaction was complete, the mixture was concentrated under reduced pressure and purified by reverse phase elution (hydrochloric acid:acetonitrile gradient elution) to give the title compound. MS m / z (ESI): 474.21 [M+1].

[0719] Example 146 Synthesis of compound 53-1: tert-butyl 5-methoxy-4-(((2S,4S)-2-(4-(methyl ester group <methoxycarbonyl>)phenyl)-4-(2,2-trifluoroethoxy)piperidin-1-yl)sulfonyl)-7-methyl-1H-indole-1-carboxylate

[0720] [ka]

[0721] Intermediate 3-2 was added to a 10 mL three-neck flask, dissolved in dichloromethane, and triethylamine was added. Intermediate 15-1 was added and reacted overnight at room temperature. After completion of the reaction, saturated ammonium chloride solution was added to quench the reaction. The organic phase was concentrated under reduced pressure and purified by column chromatography to obtain the title compound. MS m / z (ESI): 641.30 [M+1].

[0722] Synthesis of Compound 53: 4-((2S,4S)-4-ethoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)sulfonyl)piperidin-2-yl)benzoic acid

[0723] [ka]

[0724] Compound 53-1 was placed in a 10 mL three-neck flask, dissolved in tetrahydrofuran and methanol, and then 1 M aqueous lithium hydroxide solution was added. The mixture was heated to 45°C and kept overnight. After the reaction was complete, the mixture was concentrated under reduced pressure and purified by reverse phase elution (hydrochloric acid:acetonitrile gradient elution) to give the title compound. MS m / z (ESI): 527.21 [M+1].

[0725] Example 147 Synthesis of compound 54-1: tert-butyl 5-methoxy-4-(((2S,4R)-2-(4-(methyl ester group <methoxycarbonyl>)phenyl)-4-(2,2,2-trifluoroethoxy)piperidin-1-yl)sulfonyl)-7-methyl-1H-indole-1-carboxylate

[0726] [ka]

[0727] Intermediate 4-2 was added to a 10 mL three-neck flask, dissolved in dichloromethane, and triethylamine was added. Intermediate 15-1 was added and reacted overnight at room temperature. After completion of the reaction, saturated ammonium chloride solution was added to quench the reaction. The organic phase was concentrated under reduced pressure and purified by column chromatography to obtain the title compound. MS m / z (ESI): 641.30 [M+1].

[0728] Synthesis of Compound 54: 4-((2S,4R)-4-ethoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)sulfonyl)piperidin-2-yl)benzoic acid

[0729] [ka]

[0730] Compound 54-1 was placed in a 10 mL three-neck flask, dissolved in tetrahydrofuran and methanol, and then added with 1 M aqueous lithium hydroxide. The mixture was heated to 45°C and kept overnight. After the reaction was complete, the mixture was concentrated under reduced pressure and purified by reverse phase elution (hydrochloric acid:acetonitrile gradient elution) to give the title compound. MS m / z (ESI): 527.21 [M+1].

[0731] Example 148 Synthesis of compound 55-1: tert-butyl 5-methoxy-4-(((2S,4S)-2-(4-(methyl ester group <methoxycarbonyl>)phenyl)-4-(2,2-difluoroethoxy)piperidin-1-yl)sulfonyl)-7-methyl-1H-indole-1-carboxylate

[0732] [ka]

[0733] Intermediate 5-2 was added to a 10 mL three-neck flask, dissolved in dichloromethane, and triethylamine was added. Intermediate 15-1 was added and reacted overnight at room temperature. After the reaction was completed, saturated ammonium chloride solution was added to quench the reaction. The organic phase was concentrated under reduced pressure and purified by column chromatography to obtain the title compound. MS m / z (ESI): 623.30 [M+1].

[0734] Synthesis of Compound 55: tert-butyl 5-methoxy-4-(((2S,4S)-2-(4-(methyl ester group <methoxycarbonyl>)phenyl)-4-(2,2-difluoroethoxy)piperidin-1-yl)sulfonyl)-7-methyl-1H-indole-1-carboxylate

[0735] [ka]

[0736] Compound 55-1 was placed in a 10 mL three-neck flask, dissolved in tetrahydrofuran and methanol, and then 1 M aqueous lithium hydroxide was added. The mixture was heated to 45°C and kept overnight. After the reaction was complete, the mixture was concentrated under reduced pressure and purified by reverse phase elution (hydrochloric acid:acetonitrile gradient elution) to give the title compound. MS m / z (ESI): 509.21 [M+1].

[0737] Example 149 Synthesis of compound 56-1: tert-butyl 5-methoxy-4-(((2S,4R)-2-(4-(methyl ester group <methoxycarbonyl>)phenyl)-4-(2,2-difluoroethoxy)piperidin-1-yl)sulfonyl)-7-methyl-1H-indole-1-carboxylate

[0738] [ka]

[0739] Intermediate 6-2 was added to a 10 mL three-neck flask, dissolved in dichloromethane, and triethylamine was added. Intermediate 15-1 was added and reacted overnight at room temperature. After completion of the reaction, saturated ammonium chloride solution was added to quench the reaction. The organic phase was concentrated under reduced pressure and purified by column chromatography to obtain the title compound. MS m / z (ESI): 623.30 [M+1].

[0740] Synthesis of Compound 56: tert-butyl 5-methoxy-4-(((2S,4SR)-2-(4-(methyl ester group <methoxycarbonyl>)phenyl)-4-(2,2-difluoroethoxy)piperidin-1-yl)sulfonyl)-7-methyl-1H-indole-1-carboxylate

[0741] [ka]

[0742] Compound 56-1 was placed in a 10 mL three-neck flask, dissolved in tetrahydrofuran and methanol, and then 1 M aqueous lithium hydroxide solution was added. The mixture was heated to 45°C and kept overnight. After the reaction was complete, the mixture was concentrated under reduced pressure and purified by reverse phase elution (hydrochloric acid:acetonitrile gradient elution) to give the title compound. MS m / z (ESI): 509.21 [M+1].

[0743] Example 150 Synthesis of compound 57-1: tert-butyl 4-(((2S,4S)4-(2-fluoroethoxy)2-(4-(methyl ester group <methoxycarbonyl>)phenyl)piperidin-1-yl)sulfonyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate

[0744] [ka]

[0745] Intermediate 7-2 was added to a 10 mL three-neck flask, dissolved in dichloromethane, and triethylamine was added. Intermediate 15-1 was added and reacted overnight at room temperature. After completion of the reaction, saturated ammonium chloride solution was added to quench the reaction. The organic phase was concentrated under reduced pressure and purified by column chromatography to obtain the title compound. MS m / z (ESI): 605.30 [M+1].

[0746] Synthesis of Compound 57: 4-((2S,4S)-4-(2-fluoroethoxy)-1-((5-methoxy-7-methyl-1H-indol-4-yl)sulfonyl)piperidin-2-yl)benzoic acid

[0747] [ka]

[0748] Compound 57-1 was placed in a 10 mL three-neck flask, dissolved in tetrahydrofuran and methanol, and then 1 M aqueous lithium hydroxide was added. The mixture was heated to 45°C and kept overnight. After the reaction was complete, the mixture was concentrated under reduced pressure and purified by reverse phase elution (hydrochloric acid:acetonitrile gradient elution) to give the title compound. MS m / z (ESI): 491.21 [M+1].

[0749] Example 151 Synthesis of compound 58-1: tert-butyl 4-(((2S,4R)-4-(2-fluoroethoxy)-2-(4-(methyl ester group <methoxycarbonyl>)phenyl)piperidin-1-yl)sulfonyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate

[0750] [ka]

[0751] Intermediate 8-2 was added to a 10 mL three-neck flask, dissolved in dichloromethane, and triethylamine was added. Intermediate 15-1 was added and reacted overnight at room temperature. After the reaction was completed, saturated ammonium chloride solution was added to quench the reaction. The organic phase was concentrated under reduced pressure and purified by column chromatography to obtain the title compound. MS m / z (ESI): 605.30 [M+1].

[0752] Synthesis of Compound 58: 4-((2S,4R)-4-(2-fluoroethoxy)-1-((5-methoxy-7-methyl-1H-indol-4-yl)sulfonyl)piperidin-2-yl)benzoic acid

[0753] [ka]

[0754] Compound 58-1 was placed in a 10 mL three-neck flask, dissolved in tetrahydrofuran and methanol, and then 1 M aqueous lithium hydroxide was added. The mixture was heated to 45°C and kept overnight. After the reaction was complete, the mixture was concentrated under reduced pressure and purified by reverse phase elution (hydrochloric acid:acetonitrile gradient elution) to give the title compound. MS m / z (ESI): 491.21 [M+1].

[0755] Example 152 Synthesis of compound 59-1: tert-butyl 4-(((2S,4S)4-(cyclopropylmethoxy)2-(4-(methyl ester group <methoxycarbonyl>)phenyl)piperidin-1-yl)sulfonyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate

[0756] [ka]

[0757] Intermediate 9-2 was added to a 10 mL three-neck flask, dissolved in dichloromethane, and triethylamine was added. Intermediate 15-1 was added and reacted overnight at room temperature. After the reaction was completed, saturated ammonium chloride solution was added to quench the reaction. The organic phase was concentrated under reduced pressure and purified by column chromatography to obtain the title compound. MS m / z (ESI): 613.30 [M+1].

[0758] Synthesis of Compound 59: 4-((2S,4S)-4-(cyclopropylmethoxy)-1-((5-methoxy-7-methyl-1H-indol-4-yl)sulfonyl)piperidin-2-yl)benzoic acid

[0759] [ka]

[0760] Compound 59-1 was placed in a 10 mL three-neck flask, dissolved in tetrahydrofuran and methanol, and then added with 1 M aqueous lithium hydroxide. The mixture was heated to 45°C and kept overnight. After the reaction was complete, the mixture was concentrated under reduced pressure and purified by reverse phase elution (hydrochloric acid:acetonitrile gradient elution) to give the title compound. MS m / z (ESI): 499.21 [M+1].

[0761] Example 153 Synthesis of compound 60-1: tert-butyl 4-(((2S,4R)-4-(cyclopropylmethoxy)-2-(4-(methyl ester group <methoxycarbonyl>)phenyl)piperidin-1-yl)sulfonyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate

[0762] [ka]

[0763] Intermediate 10-2 was placed in a 10 mL three-neck flask, dissolved in dichloromethane, and triethylamine was added. Intermediate 15-1 was added and reacted overnight at room temperature. After completion of the reaction, saturated ammonium chloride solution was added to quench the reaction. The organic phase was concentrated under reduced pressure and purified by column chromatography to obtain the title compound. MS m / z (ESI): 613.30 [M+1].

[0764] Synthesis of Compound 60: 4-((2S,4R)-4-(cyclopropylmethoxy)-1-((5-methoxy-7-methyl-1H-indol-4-yl)sulfonyl)piperidin-2-yl)benzoic acid

[0765] [ka]

[0766] Compound 60-1 was placed in a 10 mL three-neck flask, dissolved in tetrahydrofuran and methanol, and then added with 1 M aqueous lithium hydroxide. The mixture was heated to 45°C and kept overnight. After the reaction was complete, the mixture was concentrated under reduced pressure and purified by reverse phase elution (hydrochloric acid:acetonitrile gradient elution) to give the title compound. MS m / z (ESI): 499.21 [M+1].

[0767] Example 154 1. Synthesis of Compound 61-1: Benzyl (2S)-4-cyclobutyl-4-hydroxy-2-(4-(methyl ester group <methoxycarbonyl>)phenyl)piperidine-1-carboxylate

[0768] [ka]

[0769] Intermediate 1-2 was placed in a 500 mL four-neck flask, 50 mL of tetrahydrofuran was added to the reaction flask, and the reaction mixture was purged with nitrogen gas. The internal temperature was lowered to 0°C and then to -78°C. Cyclobutylmagnesium bromide was added dropwise, maintaining the internal temperature at -0°C until the addition was complete. After 5 hours, the reaction was quenched by adding saturated ammonium chloride, and the mixture was extracted three times with ethyl acetate. The organic phases were combined and concentrated under reduced pressure to give the title compound (9.5 g, 95.4% yield) as a white solid. MS m / z (ESI): 424.20 [M+1].

[0770] 2. Synthesis of 61-2: Methyl 4-((2S)4-cyclobutyl 4-hydroxypiperidin-2-yl)benzoate

[0771] [ka]

[0772] The 61-1 intermediate prepared in Step 1 was placed in a single-neck reaction flask, and 10 mL of methanol was added. 2N hydrochloric acid was then added, and 10% palladium-carbon was added to the reaction flask. The mixture was then purged with hydrogen gas three times and allowed to react overnight. After completion of the reaction, the mixture was filtered under reduced pressure to give a white solid. Methyl tert-butyl ether was added to form a slurry to remove impurities, and the mixture was filtered to give the title compound as a white solid powder. MS m / z (ESI): 326.20 [M+1].

[0773] 3. Synthesis of Compound 61-3: tert-butyl 4-((2S)4-cyclobutyl-4-hydroxy-2-(4-(methyl ester group <methoxycarbonyl>)phenyl)piperidine-1-carbonyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate

[0774] [ka]

[0775] The 61-2 intermediate obtained in Step 2 was placed in a 10 mL three-neck flask and dissolved in dichloromethane. N,N-diisopropylethylamine was added and the flask was placed in an ice bath. Intermediate 11-1 was then added and stirred for 10 minutes. After that, tert-butyl 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate was added. After the reaction was complete, dichloromethane and saturated brine were added, and the organic phase was concentrated under reduced pressure to give the title compound. MS m / z (ESI): 577.26 [M+1].

[0776] 4. Synthesis of Compound 61: 4-((2S)4-cyclobutyl-4-hydroxy-1-(5-methoxy-7-methyl-1H-indole-4-carbonyl)piperidin-2-yl)benzoic acid

[0777] [ka]

[0778] The compound 61-3 obtained in step 3 was placed in a 10 mL three-neck flask, and tetrahydrofuran and methanol were added to dissolve it. 1 M aqueous lithium hydroxide solution was then added, and the mixture was heated to 45°C and kept overnight. After the reaction was completed, the mixture was concentrated under reduced pressure and purified by reverse phase elution (gradient elution with aqueous hydrochloric acid:acetonitrile) to obtain the final product, which was a racemic compound. MS m / z(ESI):463.20[M+1],1HNMR(400 MHz, MeOD) δ 8.07 - 7.78 (m, 2H), 7.69 - 7.25 (m, 3H), 7.13 - 6.56 (m, 1H), 6.02 (dd,J= 34.2, 4.7 Hz, 1H), 4.09 - 3.84 (m, 3H), 3.61 - 3.34 (m, 2H), 2.64 - 2.24 (m, 5H), 1.98 (dd,J = 14.5, 6.8Hz, 2H), 1.93 - 1.77 (m, 4H), 1.68 (ddd,J = 25.0, 16.4, 9.9Hz, 2H), 1.34 (ddd,J = 29.8, 17.9, 8.3 Hz,2H).

[0779] Example 155 1. Synthesis of Compound 62-1: Benzyl (2S)-4-cyclopropyl-4-hydroxy-2-(4-(methyl ester group <methoxycarbonyl>)phenyl)piperidine-1-carboxylate

[0780] [ka]

[0781] Intermediate 1-2 was placed in a 500 mL four-neck flask, 50 mL of tetrahydrofuran was added to the reaction flask, and the mixture was purged with nitrogen gas. The internal temperature was lowered to 0°C, then to -78°C. Cyclopropylmagnesium bromide was added dropwise, and the internal temperature was maintained at -0°C. After the addition was complete, the reaction was allowed to proceed. After 5 hours, the reaction was quenched by adding saturated ammonium chloride, and the mixture was extracted three times with ethyl acetate. The organic phases were combined and concentrated under reduced pressure to give the title compound as a white solid (9.5 g, yield: 95.4%). MS m / z (ESI): 410.20 [M+1].

[0782] 2. Synthesis of 62-2: Methyl 4-((2S)4-cyclopropyl 4-hydroxypiperidin-2-yl)benzoate

[0783] [ka]

[0784] The intermediate 62-1 obtained in Step 1 was placed in a single-neck reaction flask, and 10 mL of methanol was added. 2N hydrochloric acid was then added, and 10% palladium-carbon was added to the reaction flask. The atmosphere was purged with hydrogen gas three times and the reaction was allowed to proceed overnight. After completion of the reaction, the mixture was filtered under reduced pressure to give a white solid. Methyl tert-butyl ether was added to form a slurry to remove impurities, and the mixture was filtered to give the title compound as a white solid powder. MS m / z (ESI): 276.20 [M+1].

[0785] 3. Synthesis of Compound 62-3: tert-butyl 4-((2S)4-cyclopropyl 4-hydroxy-2-(4-(methyl ester group <methoxycarbonyl>)phenyl)piperidine-1-carbonyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate

[0786] [ka]

[0787] The 62-2 intermediate obtained in Step 2 was placed in a 10 mL three-neck flask, dissolved in dichloromethane, and N,N-diisopropylethylamine was added. The flask was placed in an ice bath. Intermediate 11-1 was then added and stirred for 10 minutes. After that, tert-butyl 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate was added. After the reaction was complete, dichloromethane and saturated brine were added. The organic phase was concentrated under reduced pressure to give the title compound. MS m / z (ESI): 563.26 [M+1].

[0788] 4. Synthesis of Compound 62: 4-((2S)4-cyclopropyl-4-hydroxy-1-(5-methoxy-7-methyl-1H-indole-4-carbonyl)piperidin-2-yl)benzoic acid

[0789] [ka]

[0790] The compound 62-3 obtained in step 3 was placed in a 10 mL three-neck flask, and tetrahydrofuran and methanol were added to dissolve it. 1 M aqueous lithium hydroxide solution was then added, and the mixture was heated to 45°C and kept overnight. After the reaction was completed, the mixture was concentrated under reduced pressure and purified by reverse phase elution (hydrochloric acid water:acetonitrile gradient elution) to obtain the final product. MS m / z(ESI):463.20[M+1],1HNMR(400 MHz, MeOD) δ 8.11 - 7.76 (m, 2H), 7.72 - 7.09 (m, 3H), 6.90 - 6.54 (m, 1H), 6.33 - 5.96(m, 1H), 4.06 - 3.39 (m, 5H), 2.67 (s, 1H), 2.58 - 2.33 (m, 4H), 2.29 - 1.21 (m, 3H), 1.04 - 0.79 (m, 1H),0.74 - 0.12 (m, 3H).

[0791] Example 156 1. Synthesis of Compound 63-1: Benzyl (2S,4S)-4-methoxy-2-(4-(methyl ester group <methoxycarbonyl>)phenyl)piperidine-1-carboxylate

[0792] [ka]

[0793] Sodium hydride was placed in a 50 mL three-neck flask, 10 mL of anhydrous N,N-dimethylformamide was added, and the flask was placed in an ice bath. After 10 minutes, intermediate 1-3 was dissolved in 10 mL of anhydrous N,N-dimethylformamide and added dropwise to the reaction flask. After 30 minutes, iodoethane was added dropwise. 30 minutes after the addition was complete, water and ethyl acetate were added, and the organic layer was concentrated under reduced pressure to give the title compound as a colorless oil. MS m / z (ESI): 384.20 [M+1].

[0794] 2. Synthesis of compound 63-2: methyl 4-((2S,4S)-4-methoxypiperidin-2-yl)phthalate

[0795] [ka]

[0796] The 63-1 intermediate prepared in step 1 was placed in a single-necked reaction flask, and 10 mL of methanol was added. 10% palladium carbon was then added to the reaction flask, and the mixture was purged with hydrogen gas three times and allowed to react overnight. After the reaction was complete, the mixture was filtered with suction and concentrated under reduced pressure to give a white solid. Methyl tert-butyl ether was added to form a slurry to remove impurities, and the solid was filtered to give the title compound as a white solid powder. MS m / z(ESI):250.20[M+1]. 1HNMR(400 MHz, CDCl3) δ 9.76 (s, 2H), 8.01 (d,J = 7.7 Hz, 2H), 7.69 (d,J = 7.9 Hz, 2H), 4.36 (s,1H), 3.92 (s, 3H), 3.70 (s, 1H), 3.33 (s, 3H), 3.00 (d,J = 75.9 Hz, 2H), 2.13 (ddd,J = 82.1, 47.9, 14.0 Hz,4H).

[0797] 3. Synthesis of compound 63-3: tert-butyl 5-methoxy-4-((2S,4S)-4-methoxy-2-(4-(methyl ester group <methoxycarbonyl>)phenyl)piperidine-1-carbonyl)-7-methyl-1H-indole-1-carboxylate

[0798] [ka]

[0799] The 63-2 intermediate prepared in Step 2 was placed in a 10 mL three-neck flask and dissolved in dichloromethane. N,N-diisopropylethylamine was added and the flask was placed in an ice bath. Intermediate 11-1 was then added and stirred for 10 minutes. After that, tert-butyl 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate was added. After the reaction was complete, dichloromethane and saturated brine were added, and the organic phase was concentrated under reduced pressure to give the title compound. MS m / z (ESI): 564.26 [M+1]. 1HNMR (400 MHz, CDCl3) δ8.11-7.92(m, 2H), 7.64-7.53(m, 2H), 7.49-7.42(m, 1H), 6.57(ddd, J=35.5, 15.3, 12.5 Hz, 2H), 4.00-3.61(m, 6H), 3.51(d, J=14.4 Hz, 1H), 3.38-3.24(m, 4H), 3.01-2.70(m, 2H), 2.63(d, J=31.7 Hz, 3H), 2.09-1.75(m, 2H), 1.64-1.58(m, 9H), 1.41-1.14(m, 2H).

[0800] 4. Synthesis of Compound 63: 4-((2S,4S)-4-Methoxy-1-(5-methoxy-7-methyl-1H-indole-4-carbonyl)piperidin-2-yl)benzoic acid

[0801] [ka]

[0802] The compound 63-3 obtained in Step 3 was placed in a 10 mL three-neck flask, and tetrahydrofuran and methanol were added to dissolve it. 1 M aqueous lithium hydroxide solution was then added, and the mixture was heated to 45°C and kept overnight. After the reaction was completed, the mixture was concentrated under reduced pressure and purified by reverse phase elution (hydrochloric acid water:acetonitrile gradient elution) to obtain the title compound. MS m / z(ESI):423.20[M+1],1HNMR(600 MHz, MeOD) δ 8.13 - 7.88 (m, 2H), 7.76 - 7.45 (m, 2H), 7.32 (dt,J = 68.1, 33.3 Hz, 1H), 6.77 (dd,J = 67.1, 35.1 Hz, 1H), 6.35 (dd,J = 19.9, 3.0 Hz, 1H), 3.99 - 3.88 (m, 3H), 3.68 - 3.40 (m, 2H), 3.37 - 3.33 (m, 3H), 2.99 - 2.80 (m, 2H), 2.60 - 2.46 (m, 3H), 1.87 (ddd,J = 34.4, 30.0, 24.2 Hz, 2H), 1.76 - 1.20 (m, 2H).

[0803] Example 157 1. Synthesis of Compound 64-1: Benzyl (2S,4S)-4-cyclobutoxy-2-(4-(methyl ester group <methoxycarbonyl>)phenyl)piperidine-1-carboxylate

[0804] [ka]

[0805] Sodium hydride was placed in a 50 mL three-neck flask, 10 mL of anhydrous N,N-dimethylformamide was added, and the mixture was placed in an ice bath. After 10 minutes, intermediate 1-3 was dissolved in 10 mL of anhydrous N,N-dimethylformamide and added dropwise to the reaction flask. After 30 minutes, cyclobutane iodide was added dropwise. 30 minutes after the addition was complete, water and ethyl acetate were added, and the organic layer was concentrated under reduced pressure to give the title compound as a colorless oil. MS m / z (ESI): 424.20 [M+1]. 1HNMR(400 MHz, CDCl3) δ 8.00 (d,J = 8.4 Hz, 2H), 7.38 - 7.26 (m, 7H), 5.19 (s, 2H), 4.24 (d,J =12.6 Hz, 1H), 4.02 - 3.94 (m, 1H), 3.92 (d,J = 5.1 Hz, 3H), 3.40 - 3.29 (m, 1H), 2.80 (td,J = 13.6, 2.9Hz, 1H), 2.61 (d,J = 13.3 Hz, 1H), 2.16 (ddt,J = 10.9, 9.0, 7.2 Hz, 2H), 2.00 - 1.78 (m, 4H), 1.66 - 1.58(m, 3H), 1.52 - 1.41 (m, 2H), 1.34 - 1.24 (m, 1H).

[0806] 2. Synthesis of compound 64-2: methyl 4-((2S,4S)4-cyclobutoxypiperidin-2-yl)benzoate

[0807] [ka]

[0808] The 64-1 intermediate obtained in Step 1 was placed in a single-neck reaction flask, and 10 mL of methanol was added. Then, 10% palladium-carbon was added to the reaction flask, and the mixture was purged with hydrogen gas three times and allowed to react overnight. After completion of the reaction, the mixture was suction filtered and concentrated under reduced pressure to give a white solid. Methyl tert-butyl ether was added to form a slurry to remove impurities, and the mixture was filtered to give the title compound as a white solid powder. MS m / z (ESI): 290.20 [M+1].

[0809] 3. Synthesis of Compound 64-3: tert-butyl 4-((2S,4S)4-cyclobutoxy 2-(4-(methyl ester group <methoxycarbonyl>)phenyl)piperidine-1-carbonyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate

[0810] [ka]

[0811] The 64-2 intermediate obtained in Step 2 was placed in a 10 mL three-neck flask and dissolved in dichloromethane. N,N-diisopropylethylamine was added and the mixture was placed in an ice bath. Intermediate 11-1 was then added and stirred for 10 minutes. After that, tert-butyl 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate was added. After the reaction was complete, dichloromethane and saturated brine were added, and the organic phase was concentrated under reduced pressure to give the title compound. MS m / z (ESI): 577.26 [M+1].

[0812] 4. Synthesis of Compound 64: 4-((2S,4S)-4-cyclobutoxy-1-(5-methoxy-7-methyl-1H-indole-4-carbonyl)piperidin-2-yl)benzoic acid

[0813] [ka]

[0814] The compound 64-3 obtained in Step 3 was placed in a 10 mL three-neck flask, and tetrahydrofuran and methanol were added to dissolve it. 1 M aqueous lithium hydroxide solution was then added, and the mixture was heated to 45°C and kept at that temperature overnight. After the reaction was completed, the mixture was concentrated under reduced pressure and purified by reverse phase elution (hydrochloric acid water:acetonitrile gradient elution) to obtain the title compound. MS m / z(ESI):463.20[M+1],1HNMR(400 MHz, MeOD) δ 8.15 - 7.87 (m, 2H), 7.70 - 7.22 (m, 3H), 7.05 - 6.63 (m, 1H), 6.34 (dt,J= 12.6, 6.7 Hz, 1H), 4.18 - 3.78 (m, 4H), 3.64 - 3.40 (m, 2H), 3.07 - 2.68 (m, 2H), 2.51 (d,J = 28.6 Hz,2H), 2.18 (d,J = 5.5 Hz, 2H), 1.90 (dt,J = 17.9, 10.2 Hz, 3H), 1.67 (dd,J = 21.0, 10.8 Hz, 2H), 1.58 -1.41 (m, 2H), 1.38 - 1.13 (m, 2H).

[0815] Example 158 1. Synthesis of Compound 65-1: Benzyl (2S)-4-hydroxy-2-(4-(methyl ester group <methoxycarbonyl>)phenyl)-4-propylpiperidine-1-carboxylate

[0816] [ka]

[0817] Intermediate 1-2 was placed in a 500 mL four-neck flask, 50 mL of tetrahydrofuran was added to the reaction flask, and the reaction mixture was purged with nitrogen gas. The internal temperature was lowered to 0°C and then to -78°C. Cyclopropylmagnesium bromide was added dropwise, maintaining the internal temperature at -0°C until the addition was complete. After 5 hours, the reaction was quenched by adding saturated ammonium chloride, and the mixture was extracted three times with ethyl acetate. The organic phases were combined and concentrated under reduced pressure to give the title compound (9.5 g, 95.4% yield) as a white solid. MS m / z (ESI): 412.20 [M+1].

[0818] 2. Synthesis of Compound 65-2: Benzyl (S)-2-(4-(methyl ester group <methoxycarbonyl>)phenyl)-4-propyl-3,6-dihydropyridine-1(2H)-carboxylate

[0819] [ka]

[0820] The 65-1 intermediate obtained in Step 1 was placed in a 500 mL four-neck flask, 50 mL of tetrahydrofuran was added to the reaction flask, and the flask was purged with nitrogen gas. The internal temperature was lowered to 0 °C. Burgis's reagent was added, and the internal temperature was maintained at -0 °C until the addition was complete. After 5 h, the reaction was quenched by adding saturated ammonium chloride, and the mixture was extracted three times with ethyl acetate. The organic phases were combined and concentrated under reduced pressure to give the title compound as a white solid. MS m / z (ESI): 394.20 [M+1].

[0821] 3. Synthesis of compound 65-3: methyl 4-((2S)4-propylpiperidin-2-yl)benzoate

[0822] [ka]

[0823] The 65-2 intermediate prepared in Step 2 was placed in a single-neck reaction flask and 10 mL of methanol was added. Then, 10% palladium on carbon was added to the reaction flask, and the mixture was purged with hydrogen gas three times and allowed to react overnight. After completion of the reaction, the mixture was filtered and concentrated under reduced pressure to give a white solid. Methyl tert-butyl ether was added to form a slurry to remove impurities, and the mixture was filtered to give the title compound as a white solid powder. MS m / z (ESI): 262.20 [M+1].

[0824] 4. Synthesis of Compound 65-4: tert-butyl 5-methoxy-4-((2S)-2-(4-(methyl ester group <methoxycarbonyl>)phenyl)-4-propylpiperidine-1-carbonyl)-7-methyl-1H-indole-1-carboxylate

[0825] [ka]

[0826] The 65-3 intermediate obtained in Step 3 was placed in a 10 mL three-neck flask and dissolved in dichloromethane. N,N-diisopropylethylamine was added and the flask was placed in an ice bath. Intermediate 11-1 was then added and stirred for 10 minutes. After that, tert-butyl 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate was added. After the reaction was complete, dichloromethane and saturated brine were added, and the organic phase was concentrated under reduced pressure to give the title compound. MS m / z (ESI): 549.26 [M+1].

[0827] 5. Synthesis of Compound 65: 4-((2S)-1-(5-methoxy-7-methyl-1H-indole-4-carbonyl)-4-propylpiperidin-2-yl)benzoic acid

[0828] [ka]

[0829] The 65-4 compound obtained in Step 4 was placed in a 10 mL three-neck flask, and dissolved by adding tetrahydrofuran and methanol. 1 M aqueous lithium hydroxide solution was then added, and the mixture was heated to 45°C and kept overnight. After the reaction was complete, the mixture was concentrated under reduced pressure and purified by reverse phase elution (hydrochloric acid:acetonitrile gradient elution) to obtain the final product, which was a racemic compound.

[0830] MS m / z(ESI):435.20[M+1],1HNMR(400 MHz, MeOD) δ 8.11 - 7.76 (m, 2H), 7.72 - 7.09 (m, 3H), 6.90 - 6.54 (m, 1H), 6.33 - 5.96(m, 1H), 4.06 - 3.39 (m, 5H), 2.67 (s, 1H), 2.58 - 2.33 (m, 4H), 2.29 - 1.21 (m, 3H), 1.04 - 0.79 (m, 1H),0.74 - 0.12 (m, 3H).

[0831] Example 159 1. Compound of Example 158 was obtained under the following chromatographic conditions:

[0832] [ka]

[0833] was separated. Column: CHIRALPAK® IB, 10 μm, 30 × 250 mm Mobile phase A: HEX+0.2%DEA Mobile phase B:ETOH+0.2%DEA Detection wavelength: 214nm / 254nm Flow rate: 25mL / min Column temperature: RT Isocratic elution procedure: Mobile phase A:Mobile phase B = 95:5 (V / V) Separation gave chiral isomers Compound 159-1A and Compound 159-1B, whose retention times were 6.063 min and 8.812 min, respectively.

[0834] [ka]

[0835] 2. Compounds 159A and 159B were obtained by the methods of Steps 4 and 5 of Example 158 using Compounds 159-1A and 159-1B obtained in Step 1 as starting materials, respectively.

[0836] Compound 159A: 1 H NMR(400 MHz, MeOD) δ 8.11 - 7.76 (m, 2H), 7.72 - 7.09 (m, 3H), 6.90 - 6.54 (m, 1H), 6.33 - 5.96(m, 1H), 4.06 - 3.39 (m, 5H), 2.67 (s, 1H), 2.58 - 2.33 (m, 4H), 2.29 - 1.21 (m, 3H), 1.04 - 0.79 (m, 1H),0.74 - 0.12 (m, 3H)

[0837] Compound 159B: 1 H NMR(400 MHz, MeOD) δ 8.11 - 7.76 (m, 2H), 7.72 - 7.09 (m, 3H), 6.90 - 6.54 (m, 1H), 6.33 - 5.96(m, 1H), 4.06 - 3.39 (m, 5H), 2.67 (s, 1H), 2.58 - 2.33 (m, 4H), 2.29 - 1.21 (m, 3H), 1.04 - 0.79 (m, 1H),0.74 - 0.12 (m, 3H)

[0838] [ka]

[0839] Effect Example 1 Optical Surface Plasmon Resonance (SPR) Binding Force Detection For SPR experiments, PBS buffer supplemented with 0.05% (v / v) P20 and 5% DMSO was used as the running buffer at 25°C. The analytical instrument used was a GE Healthcare Biacore 8K with 400 mM EDC and 100 mM NHS. A CM3 chip (GE Healthcare) was activated for 420 s at a flow rate of 30 μL / min. Complement factor B was diluted to 50 μg / mL in 10 mM sodium acetate (pH 40) and allowed to bind at a flow rate of 10 μL / min for 1,200 s to covalently bind complement factor B to the detection chip (protein hardening level: 25,000 RU). The detection chip was then sealed with 1 M ethanolamine hydrochloride at a flow rate of 10 μL / min for 300 s. The target compound concentration was 500 μM, with a binding time of 120 s and a dissociation time of 300 s. Data analysis was performed using a 1:1 binding model (Biacore Insight Evaluation Software Version 2.0.1512933).

[0840] The detection results show that all the compounds of the present invention have affinity activity with complement factor B, and KD 50 The values ​​are 0.1nM-500nM.

[0841] [Table 1]

[0842] [Table 2]

[0843] Effect Example 2 Complement hemolytic activity detection For hemolysis experiments to detect complement hemolytic activity, Xuan Yuan et al. (2017) 102:466-475 was used. The optimal concentration of normal human serum (NHS) required to achieve 100% lysis of rabbit red blood cells (RE) was determined by titration prior to the experiment. In this experiment, NHS was diluted with GVB0 buffer (0.1% gelatin, 5 mM Veronal, 145 mM NaCl, 0.025% NaN, pH 7.3) containing 10 mM Mg-EGTA and incubated with various concentrations of test compounds at 37°C for 15 minutes. Freshly suspended RE (collected from healthy Japanese large-eared white rabbits) in GVB0 buffer containing 10 mM Mg-EGTA was added to 1 × 10 8 The cells were added to a final concentration of 1000 cells / ml and incubated at 37°C for 30 minutes. The positive control (100% lysis) consisted of 10 mM Mg-EGTA in GVB0 buffer with NHS and RE but no test compound. The negative control (0% lysis) consisted of inactivated NHS (heated at 56°C for 30 minutes or 65°C for 5 minutes) and 10 mM Mg-EGTA in GVB0 buffer with RE but no test compound. The samples were centrifuged at 2000g for 5 minutes, and the supernatant was collected. The absorbance at 415 nm (A415) was detected using a microplate reader (Molecular Devices SpectraMaxi3X). IC 50 Values ​​were calculated from the percentage hemolysis as a function of test compound concentration by nonlinear regression using GraphPad Prism 7.0 software.

[0844] The results showed that all the compounds of the present invention have hemolytic activity via the alternative complement pathway, and their IC 50 The values ​​were shown to be between 0.1 nM and 500 nM.

[0845] Effect Example 3 Measurement of inhibition of the alternative pathway of PNH-like erythrocytes Rationale: One indication for PNH using complement inhibitors is typically demonstrated using the Ham test, which demonstrates that acidified serum can activate the alternative pathway and induce hemolysis of PNH red blood cells but not normal red blood cells. Literature has shown that the use of AET can disrupt complement regulatory proteins on the surface of normal human red blood cells, producing PNH-like red blood cells.

[0846] Reagents and equipment: PBS buffer, normal human serum (NHS), Alsever solution, microplate reader, MgCl2, EGTA, EDTA, HCl, normal human red blood cells, AET: anti-CD55 antibody (BRIC216; Sigma). PBS buffer solution: potassium dihydrogen phosphate (KH2PO4): 0.24 g / L, disodium hydrogen phosphate (Na2HPO4): 1.44 g / L, sodium chloride (NaCl): 8 g / L, potassium chloride (KCl): 0.2 g / L, pH 7.4 PBSE buffer: PBS, 10mM EDTA, pH7.4 PBSMg buffer: PBS, 1mM Mg++; pH6.4 10x Mg-EGTA stock solution: 25 mM MgCl2, 80 mM EGTA; pH 6.4 10x EDTA stock solution: 100 mM EDTA; pH 6.4

[0847] Methods: An in vitro model of PNH was used to evaluate inhibition of alternative pathway-mediated erythrocyte lysis. Normal human erythrocytes were sensitized with 2-aminoethylisothiuronium bromide (AET), which inactivates cell surface complement regulatory proteins and induces a PNH-like phenotype.

[0848] Two milliliters of normal human red blood cells were mixed with two milliliters of Alsever's solution and washed three times with PBS. The mixture was then centrifuged at 2500 × g to remove the top 10% of the red blood cell layer. After washing, 1 mL of the washed red blood cells was incubated with 4 mL of 8% w / v AET (pH 8.0) at 37°C for 10 minutes for sensitization, followed by three washes with PBS. The red blood cell concentration in PBS (red blood cell stock solution) was then adjusted with PBS so that when 10 μL of the red blood cell stock solution was diluted with 190 μL of water, the absorbance at 412 nm was 1.5-2.0 (indicating hemoglobin release).

[0849] 1.5 mL of such stock red blood cells was mixed with anti-CD55 antibody (BRIC216E; Sigma, final concentration 6.7 μg / mL) and incubated on ice for 30 minutes. After one wash with PBS, the treated red blood cells were resuspended in PBS-Mg to an initial volume of 1.5 mL. The following AP-mediated degradation assay was performed on such red blood cell preparations with an induced PNH phenotype.

[0850] Serum from a healthy donor was acidified to pH 6.4% with 0.2 M HCl and supplemented with MgCl2 and EGTA to final concentrations of 2.5 and 8 mM, respectively. 80 μL of this serum mixture was mixed with 10 μL of PBS-Mg (negative blank) or 10 μL of samples at different concentrations. Healthy donor serum was acidified to pH 6.4% with 0.2 M HCl and supplemented with EDTA to a final concentration of 10 mM. 80 μL of this serum mixture was mixed with 10 μL of PBS-Mg (negative blank) to serve as a blank positive control. The sample and serum were incubated on ice for 5 minutes, after which 10 μL of sensitized red blood cells were added. The final serum concentration in this reaction mixture was approximately 64% v / v. After 60 minutes of incubation at 37°C, the reaction was quenched by adding 50 μL of ice-cold PBS containing 10 mM EDTA. The remaining unlysed cells were centrifuged at 2500 × g for 10 minutes, and 100 μL of the supernatant was added to a 96-well plate. The amount of hemoglobin released during the erythrocyte lysis process was quantified by measuring the absorbance at 412 nm. A405 indicated the relative lysis of PNH-like erythrocytes (expressed as a percentage; PC samples were set to 0% and NC samples were set to 100%). Absorbance was detected using a microplate reader (Molecular Devices SpectraMaxi3X). IC 50 Values ​​were calculated as percentage hemolysis as a function of test compound concentration by nonlinear regression using GraphPad Prism 9.0 software.

[0851] result:

[0852] [Table 3]

[0853] [Table 4]

[0854] [Table 5]

[0855] Effect Example 4: Elisa measurement of human complement factor B 2 mg of the sample compound (approximately 0.0091 mmol) was dissolved in 455 μL of DMSO (molecular biology grade) to prepare a 20 mM sample compound stock solution A. 1. 100 μL of 2000 μM sample compound stock solution A was taken and 900 μL of dilution solution was added to form the first solution. 2. 100 μL of the 500 μM first solution was taken and 300 μL of the dilution solution was added to form the second solution. 3. 100 μL of the 125 μM second solution was taken and 300 μL of the dilution solution was added to form the third solution. 4. 100 μL of 31.25 μM third solution was taken and 300 μL of dilution solution was added to form the fourth solution. 5. 100 μL of 7.8125 μM fourth solution was taken and 300 μL of dilution solution was added to form the fifth solution. 6. 100 μL of 0.488281 μM solution No. 5 was taken and 300 μL of dilution solution was added to form solution No. 6. 7. 100 μL of 0.12207 μM solution 6 was taken and 300 μL of dilution solution was added to form solution 7. 8. 100 μL of 0.030518 μM solution 7 was taken and 300 μL of dilution solution was added to form solution 8. 9. 100 μL of 0.007629 μM solution 8 was taken and 300 μL of dilution solution was added to form solution 9. 100 μL of the above samples 1 to 9 was taken out and diluted 20 times with 1900 μL of dilution solution to obtain samples 1′ to 9′. After adding 8.8 μL of the dilution solution to a 96T plate well, 0.2 μL CVF-Bb (0.1 μmol / mL) was added to obtain sample compounds 1′–9′, and the mixture was incubated at room temperature for 1 h. Thereafter, 9 μL of the successfully incubated sample was taken and added to a 96T plate well, and 1 μL of complement C3 protein was added, followed by reaction at 37° C. for 2 hours. A negative control was prepared by mixing 9 μL of the above sample-free liquid with 1 μL of complement C3 protein. 10 μL of the successfully incubated sample was taken and the inhibitory concentration was measured by ELISA. The OD value at 450 nm was measured and a curve was plotted. The data obtained was applied to GraphPad Prism 7.0 software, and a Log concentration-inhibition rate curve was plotted using a nonlinear regression model to calculate the IC50 value. The detection results showed that all the compounds of the present invention had inhibitory activity IC50 values ​​of the alternative complement pathway of 0.1 nM to 500 nM.

[0856] [Table 6]

[0857] [Table 7]

[0858] Effect Example 5 Pharmacokinetic Activity Test Experimental Objective: In this experiment, the test substance was administered to mice by intravenous and intragastric administration at a single dose, and the concentration of the test substance in the mouse plasma was measured to evaluate the pharmacokinetic properties of the test substance in the mouse body. Experimental animals: C57 mice or conventional testable mice. Experimental Method: IV dose: 1 mg / kg; Vehicle: 0.5% DMSO or 0.5% MeOH-5% pharmaceutical grade polyethylene glycol-15 hydroxystearate-PBS Oral dose: 10 mg / kg; Vehicle: 0.5% DMSO or 0.5% MeOH-0.1% Tween 80-30% PEG 300-70% PBS Sample collection: At each time point, 0.03 mL blood samples were collected from the experimental animals via hidden venipuncture, and the actual blood collection time was recorded. All blood samples were placed in standard 1.5 mL commercial EDTA-K2 anticoagulant tubes (supplied by Jiangsu Kangjian Medical Products Co., Ltd.). Within 30 minutes of collection, the blood samples were centrifuged at 3000 g for 10 minutes at 4°C to aspirate the supernatant plasma. The samples were immediately placed on dry ice and stored in a -80°C freezer for LCMS / MS analysis. Blood collection points: 5 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 12 hours, 20 hours, 24 hours. Test compounds: positive compound LNP023, final product of Example 158, final products Compound 159A and Compound 159B of Example 159, Compound 11 of Example 75.

[0859] Experimental results: Compared with the positive compound LNP023, the clearance and half-life in the in vivo metabolic process of the final product of Example 158, the final products of Example 159, Compounds 159A and 159B, and Compound 11 of Example 75, were all equal to or greater than those of the positive compound LNP023.

[0860] Effect Example 6 In vivo efficacy test in mice in which complement activation was induced by LPS Purpose of the experiment: The inhibitory effect of the compound of the present invention on mouse complement activity induced by LPS stimulation was examined. Experimental animals: Female C57BL / 6J mice, 7-9 weeks old, weighing 17-23 g. Experimental Procedure: Complement activation was induced in mice by intraperitoneal injection of 100 μg of lipopolysaccharide (LPS) from Salmonella typhimurium (Sigma) dissolved in 100 μL of sterile PBS. Negative control animals received 100 μL of sterile PBS intraperitoneally and were administered by gavage (PO) alone. Positive control animals received LPS intraperitoneally and drug vehicle (0.5% (w / v) methylcellulose and 0.5% (v / v) Tween 80) PO. Sample collection: 0.3 mL blood samples were collected from the retro-orbital venous plexus. All blood samples were placed in standard 1.5 mL commercial EDTA-K2 anticoagulant tubes. Within 30 minutes of collection, blood samples were centrifuged at 3000 g for 10 minutes at 4°C, and the supernatant plasma was aspirated. The cells were immediately placed on dry ice and stored at -80°C for Western blot analysis of downstream C3d protein levels after complement activation. Sample analysis: Mouse plasma (5 μL) + lysis buffer (27.5 μL) + loading buffer (12.5 μL) + reducing buffer (5 μL) were mixed uniformly and incubated at 100°C for 15 minutes. The loading volume was 5 μL / well, i.e., the plasma loading volume per well was 0.5 μL. Test compounds: positive compound LNP023, final product of Example 158, final products Compound 159A and Compound 159B of Example 159, Compound 11 of Example 75.

[0861] Experimental results: The effects of the final product of Example 158, Compounds 159A and 159B, which are the final products of Example 159, and Compound 11 of Example 75 on alleviating bone swelling in mice in a mouse inflammation model were superior to or equivalent to the effects of the positive compound LNP023.

[0862] Efficacy Example 7 In vivo efficacy test in passive Heymann nephritis rats Experimental Objective: The ability of the compounds of the present invention to improve renal function in rats with Heymann nephritis induced by sheep anti-rat Fx1A serum was investigated, including evaluation of reduction in proteinuria levels and improvement in renal tissue damage. Experimental animals: Male SD rats, 7-10 weeks old, weighing 200-300g.

[0863] Testing Procedure: 1. Building the model: Urine samples were collected from rats within two days prior to administration. On Day 1, animals in the control group (Group 1) were administered 5 mL / kg of sheep non-immune serum via a single tail vein injection, while animals in the model and treatment groups (Groups 2–6) were administered 5 mL / kg of sheep anti-rat FxlA serum via a single tail vein injection. 2. Administration: The administration method was intragastric administration twice daily with an 8-h interval and a dose volume of 10 mL / kg. On Day 1, within 1 hour before model construction, animals in Groups 1 and 2 were administered a blank solvent (20% PEG400 / 10% Solutol / 70% water), animals in Group 3 were administered LNP023 (60 mpk), and animals in Groups 4 to 6 were administered different concentrations of the synthetic compound (5 mpk, 20 mpk, and 60 mpk). Each group was administered a second dose 8 hours later, with the same dose and volume as the first dose. On Days 2 to 14, animals in each group were administered a different compound or vehicle at the same dose, volume, mode, and frequency as Day 1 for 14 consecutive days (including Day 1). 3. Sample collection: Urine samples were collected from rats on day D-2 before administration, and on days D4, D6, D8, D11, and D14 after administration, 2 to 4 hours and 4 to 6 hours after the first administration, transferred to EP tubes, and stored in a refrigerator at -80°C to 60°C for use in detecting rat urinary protein and urinary creatinine. Kidney sample collection: All animals were euthanized by CO2 inhalation anesthesia on Day 15, and both kidneys were harvested. The left kidney was transected and the right kidney was cut longitudinally. The transected half (left) and the longitudinal half (right) were fixed in formalin (placed in the same EP tube). 4. Sample analysis: (1) The normal loading for rat urinary creatinine (uCRE) was 10 μL of sample after 10-fold dilution (Decrease mode) + 90 μL of saline (0.9% saline). If the upper limit of detection was exceeded, the normal loading was 5 μL of sample + 95 μL of saline (0.9% saline). For rat urinary total protein (uTP), if the upper limit of detection was exceeded in the original detection, the normal loading was 10 μL of sample + 90 μL of saline (0.9% saline). If the upper limit of detection was still exceeded after 10-fold dilution, the normal loading was 100-fold diluted (Increase mode) + 2 μL of sample + 198 μL of saline (0.9% saline). The data were read using the HITACHI LST008AS(P) analytical instrument. (2) Renal pathology score: The degree of drug damage to rat kidneys (paraffin sections) was analyzed using HE staining. The scoring criteria were: 0 = normal, 1 = few cellular infiltration into the mesangium, 2 = many cellular infiltration into the mesangium, 3 = multiple glomerular mesangial cell hyperplasia and multiple mesangial cell infiltration, and 4 = tubular casts, atrophy, glomerular crescent formation, and sclerosis. Test compounds: positive compound LNP023, final product of Example 158, final products Compound 159A and Compound 159B of Example 159, Compound 11 of Example 75.

[0864] Experimental results: The final product of Example 158, the final products of Example 159, Compounds 159A and 159B, and Compound 11 of Example 75 were all superior to the positive control LNP023 in urine and kidney pathological analysis in a kidney disease model.

Claims

1. A compound represented by formula I, a stereoisomer thereof, a tautomer thereof, an isotopically labeled compound thereof, or a pharmaceutically acceptable salt of any of the foregoing. 【Chemistry 1】 (however, p is 0, 1 or 2; L is a single bond, NR ０ , O or S; R １ is hydrogen, C １－６ Alkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－６ Cycloalkyl group, C ３－６ Cycloalkenyl group, C ３－６ cycloalkynyl group, —C １－３ Alkyl-C ３－６ a cycloalkyl group, "a 3- to 12-membered heterocycloalkyl group in which the heteroatom is one, two, or three selected from N, O, and S, and the number of heteroatoms is one, two, or three," -C １－３ alkyl group—“a 3- to 12-membered heterocycloalkyl group in which the heteroatom is one, two, or three selected from N, O, and S, and the number of heteroatoms is one, two, or three,” or one or more R ａ the following groups substituted with: １－６ Alkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－６ Cycloalkyl group, C ３－６ Cycloalkenyl group, C ３－６ cycloalkynyl group, —C １－３ Alkyl-C ３－６ a cycloalkyl group, "a 3- to 12-membered heterocycloalkyl group in which the heteroatom is one, two, or three selected from N, O, and S, and the number of heteroatoms is one, two, or three," or -C １－３ alkyl group - "a 3- to 12-membered heterocycloalkyl group in which the heteroatom is one, two, or three selected from N, O, and S, and the number of heteroatoms is one, two, or three"; m and n are each independently 0, 1, 2, 3, or 4; R ２ , R ３ , R ４ , R ５ , R ７ , R ８ and R ９ are each independently hydrogen, halogen, OH, CN, NO ２ , N.H. ２ , C １－６ Alkyl, C １－６ Alkoxy, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－６ Cycloalkyl, C ３－６ Cycloalkenyl, C ３－６ Cycloalkynyl, -C １－３ Alkyl-C ３－６ cycloalkyl, or one or more R ｂ the following groups substituted with: １－６ Alkyl, C １－６ Alkoxy, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－６ Cycloalkyl, C ３－６ Cycloalkenyl, C ３－６ Cycloalkynyl or -C １－３ Alkyl-C ３－６ is cycloalkyl, R ０ and R ６ are each independently hydrogen, C １－６ Alkyl, C ３－６ Cycloalkyl, C ３－６ Cycloalkenyl, C ３－６ Cycloalkynyl, -C １－３ Alkyl-C ３－６ cycloalkyl, or one or more R ｃ the following groups substituted with: １－６ Alkyl, C ３－６ Cycloalkyl, C ３－６ Cycloalkenyl, C ３－６ Cycloalkynyl or -C １－３ Alkyl-C ３－６ is cycloalkyl, X is -C(=O)-, -C(=NR １０ )-, -C(=S)-, -CFR １１ -, -NR １２ -, -CR １３ R １４ -CR １５ R １６ -, -S- or -S(=O) ２ - and R １１ , R １３ , R １４ , R １５ and R １６ are each independently hydrogen, halogen, OH, CN, NO ２ , N.H. ２ , C １－６ Alkyl, C ３－６ cycloalkyl or one or more R ｄ the following groups substituted with: １－６ Alkyl or C ３－６ is cycloalkyl, R １０ and R １２ are each independently hydrogen, C １－６ alkyl or one or more R ｅ C substituted with １－６ is alkyl, R ａ , R ｂ , R ｃ , R ｄ and R ｅ are each independently a halogen, OH, CN, or NO ２ or NH ２ It is.)

2. The compound represented by formula (I) is (1) R ０ , R １ , R ２ , R ３ , R ４ , R ５ , R ６ , R ７ , R ８ , R ９ , R １０ , R １１ , R １２ , R １３ , R １４ , R １５ and R １６ In the above, １－６ Alkyl groups and substituted C １－６ C in alkyl group １－６ the alkyl groups are independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, or hexyl, e.g., methyl or ethyl; (2) R ２ , R ３ , R ４ , R ５ , R ７ , R ８ and R ９ In the above, １－６ Alkoxy groups and substituted C １－６ C in alkyl group １－６ alkoxy groups are independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, or tert-butoxy, e.g., methoxy; (3) R ０ , R １ , R ２ , R ３ , R ４ , R ５ , R ６ , R ７ , R ８ , R ９ , R １１ , R １３ , R １４ , R １５ and R １６ In the above, ３－６ cycloalkyl group, -C １－３ Alkyl-C ３－６ Cycloalkyl group, substituted C ３－６ Cycloalkyl groups and substituted -C １－３ Alkyl-C ３－６ C in cycloalkyl group ３－６ cycloalkyl groups are independently cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl groups, e.g., cyclopropyl or cyclobutyl groups; (4) R ２ , R ３ , R ４ , R ５ , R ７ , R ８ , R ９ , R １１ , R １３ , R １４ , R １５ , R １６ , R ａ , R ｂ , R ｃ , R ｄ and R ｅ wherein the halogen is independently fluorine, chlorine, bromine or iodine, e.g., fluorine; 2. A compound represented by formula (I) according to claim 1, a stereoisomer thereof, a tautomer thereof, an isotopically labeled compound thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound satisfies one or more of the following conditions:

3. The compound represented by formula (I) is (1) L is a single bond, O, or S; (2) p is 1; (3) R １ is C １－６ Alkyl group, C ３－６ cycloalkyl group, -C １－３ Alkyl group -C ３－６ a cycloalkyl group, or one or more R ａ the following groups substituted with: １－６ Alkyl group, C ３－６ cycloalkyl group or -C １－３ Alkyl group -C ３－６ the condition that it is a cycloalkyl group; (4) R ａ are each independently a halogen, for example, fluorine; (5) R ２ , R ３ , R ４ , R ５ , R ６ and R ８ is the condition for hydrogen, (6) R ７ is C １－６ the condition that the alkyl group is, for example, a methyl group; (7) X is —C(═O)—, —CFR １１ -, -NR １２ -, -S- or -S(=O) ２ - the condition, (8) R ９ is C １－６ the condition that it is an alkoxy group, for example, a methoxy group; (9) R １１ is H or a halogen; (10) R １２ is hydrogen or C １－６ The condition that the group is an alkyl group, (11) m is 0; (12) n is 0; 2. The compound represented by formula (I) according to claim 1, a stereoisomer thereof, a tautomer thereof, an isotopically labeled compound thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound satisfies one or more of the following conditions:

4. The compound represented by formula (I) is (1) L is a single bond or O; (2) X is —C(═O)—, —NR １２ - or -S(=O) ２ - the condition, (3) R ２ is hydrogen or OH; (4) R ３ , R ４ , R ５ , R ６ and R ８ is the condition for hydrogen, (5) R １２ is the condition for hydrogen, (6) m is 0 or 1, for example, 0; 2. The compound represented by formula (I) according to claim 1, a stereoisomer thereof, a tautomer thereof, an isotopically labeled compound thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound satisfies one or more of the following conditions:

5. The compound represented by formula (I) is (1) L is a single bond, 【Chemistry 2】 is preferably a single bond or 【Transformation 3】 the condition that (2) R １ teeth, 【Chemistry 4】 and preferably 【Transformation 5】 the condition that (3) X is 【Transformation 6】 and preferably 【Transformation 7】 and more preferably 【Transformation 8】 the condition that 2. The compound represented by formula (I) according to claim 1, a stereoisomer thereof, a tautomer thereof, an isotopically labeled compound thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound satisfies one or more of the following conditions:

6. The compound represented by formula (I) is （１） 【Chemistry 9】 teeth 【Chemistry 10】 where the a-terminus is R １ Conditions linked to （２） 【Chemistry 11】 teeth 【Chemistry 12】 where the a-terminus is R １ Conditions linked to （３） 【Chemistry 13】 teeth 【Chemistry 14】 the condition that 6. A compound represented by formula (I) according to claim 5, a stereoisomer thereof, a tautomer thereof, an isotopically labeled compound thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound satisfies one or more of the following conditions:

7. R １ teeth 【Chemistry 15】 and preferably 【Chemistry 16】 2. The compound represented by formula (I) according to claim 1, a stereoisomer thereof, a tautomer thereof, an isotopically labeled compound thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein:

8. The compound represented by formula (I) is (1)-L-R １ teeth, 【Chemistry 17】 and preferably [Chemistry 18] the condition that （２） 【Chemistry 19】 teeth 【Chemistry 20】 the condition that 2. The compound represented by formula (I) according to claim 1, a stereoisomer thereof, a tautomer thereof, an isotopically labeled compound thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound satisfies one or more of the following conditions:

9. The compound represented by formula (I) is （１） 【Chemistry 21】 teeth 【Chemistry 22】 the condition that （２） 【Chemistry 23】 teeth 【Chemistry 24】 the condition that （３） 【Chemistry 25】 teeth 【Chemistry 26】 the condition that （４） 【Chemistry 27】 teeth 【Chemistry 28】 the condition that （５） 【Chemistry 29】 teeth 【Transformation 30】 the condition that （６） 【Chemistry 31】 teeth 【Chemistry 32】 the condition that （７） 【Transformation 33】 teeth 【Transformation 34】 the condition that （８） 【Chemistry 35】 teeth 【Transformation 36】 the condition that （９） 【Chemistry 37】 teeth 【Transformation 38】 the condition that （１０） 【Chemistry 39】 teeth 【Chemistry 40】 the condition that （１１） 【Chemistry 41】 teeth 【Chemistry 42】 the condition that （１２） 【Chemistry 43】 teeth 【Chemistry 44】 the condition that 9. The compound represented by formula (I) according to claim 8, a stereoisomer thereof, a tautomer thereof, an isotopically labeled compound thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound satisfies one or more of the following conditions:

10. -L-R １ teeth 【Chemistry 45】 and more preferably 【Chemistry 46】 2. The compound represented by formula (I) according to claim 1, a stereoisomer thereof, a tautomer thereof, an isotopically labeled compound thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein:

11. The compound represented by formula (I) according to any one of claims 1 to 10, a stereoisomer thereof, a tautomer thereof, an isotopically labeled compound thereof, or a pharmaceutically acceptable salt of any of the foregoing, characterized in that the compound represented by formula (I) is represented by formula (I)-1, formula (I)-2, formula (I)-3, or formula (I)-4, preferably the compound represented by formula (I)-1 or formula (I)-2, more preferably the compound represented by formula (I)-2. 【Chemistry 47】

12. The compound represented by formula (I) according to claim 1, characterized in that the compound represented by formula (I) is selected from any one of the following compounds: a compound represented by formula (I), a stereoisomer thereof, a tautomer thereof, an isotopically labeled compound thereof, or a pharmaceutically acceptable salt of any of the foregoing. 【Chemistry 48】 【Chemistry 49】 [Transformation 50] 【Chemistry 51】

13. (1) A compound represented by formula (I) according to any one of claims 1 to 10, a stereoisomer thereof, a tautomer thereof, an isotope-labeled compound thereof, or a pharmaceutically acceptable salt of any of the foregoing; and (2) a pharmaceutically acceptable carrier; A pharmaceutical composition comprising:

14. Use of a compound represented by formula (I) according to any one of claims 1 to 10, a stereoisomer thereof, a tautomer thereof, an isotopically labeled compound thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition according to claim 10, (1) Producing a medicament for treating and / or preventing a complement factor B-mediated disease; Preferably, the complement factor B-mediated disease is a blood disease, an autoimmune disease, an inflammatory disease, a neurological disease, or a disease associated with a dysfunction of the complement system; Furthermore, the complement factor B mediated disease is paroxysmal nocturnal hemoglobinuria, C3 nephropathy, macular degeneration, age-related macular degeneration; (2) conditions for producing a complement factor B inhibitor; The use characterized by satisfying one or more of the following:

15. A compound represented by formula (II)-1, formula (II)-2 or formula (II)-3. 【Chemistry 52】 (However, L and R １ The definition of is the same as that described in any one of claims 1 to 10. Preferably, the compound represented by formula (II)-1 is selected from any one of the following compounds: 【Chemistry 53】 Preferably, the intermediate compound represented by formula (II)-2 is selected from any one of the following compounds: 【Chemistry 54】 Preferably, the intermediate compound represented by formula (II)-3 is selected from any one of the following compounds: 【Transformation 55】

16. A compound selected from compounds of any one of the following formulae: 【Transformation 56】

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