Indole-group-containing compound and use thereof

Abstract

The present invention relates to an indole-group-containing compound and a use thereof. The indole-group-containing compound of the present invention has a structure as represented by formula (I) or is a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug of a structure as represented by formula (I). The present invention further provides a pharmaceutical composition comprising the indole-group-containing compound. The indole-group-containing compound or pharmaceutical composition provided by the present invention can be used for preparing a drug for preventing, treating, alleviating, or regulating a disease related to complement factor B or a disease mediated by the complement factor B.

Description

A compound containing an indole group and uses thereof TECHNICAL FIELD

[0001] The present application relates to a compound containing an indole group and uses thereof, in particular, in the preparation of a medicament for preventing, treating, alleviating or regulating diseases related to complement factor B. BACKGROUND

[0002] Complement factor B (FB), also known as C3 activator precursor, is mainly synthesized by the liver and macrophages, is an important component in the complement alternative activation pathway, and is involved in the body defense, and plays an important role in the process of tissue and cell damage and inflammation. The complement system is involved in the occurrence and development of various diseases such as blood, autoimmune, inflammatory and neurodegenerative diseases, such as nervous system diseases Alzheimer's disease (AD), neuromyelitis optica (NMO), myasthenia gravis (gMG), eye diseases such as age-related macular degeneration (AMD), uveitis, glaucoma, kidney diseases such as atypical hemolytic uremic syndrome (aHUS), C3 glomerulopathy (C3G) and IgA nephropathy, and blood diseases such as cold agglutinin disease, paroxysmal nocturnal hemoglobinuria (PNH), thrombotic microangiopathy (TMAs) and the like.

[0003] In view of the role of FB in the complement system and the rise of complement drug research and development, FB has become a potential target for drug research and development of various diseases. There are many drugs targeting FB in clinical research stage worldwide. At present, there is no small molecule FB inhibitor on the market. Among them, Iptacopan is the most advanced drug among the FB targeting drugs under research. It is a first-in-class, oral, potent and selective FB inhibitor developed by Novartis, which is developed for the treatment of PNH, IgA nephropathy, C3 glomerular disease (C3G), atypical hemolytic uremic syndrome (aHUS), membranous nephropathy (MN), age-related macular degeneration (AMD) and the like. Among them, the indications for PNH and C3G were granted breakthrough therapy designations by FDA, EMA and CDE.

[0004] However, the treatment drugs for FB-mediated diseases still cannot meet the needs of the clinic, so it is necessary to develop new complement system FB small molecule inhibitors for the treatment of autoimmune, blood, neurodegenerative and other diseases caused by abnormal complement system, and to continuously meet the needs of the clinic. SUMMARY

[0005] In a first aspect, the present application provides a compound containing an indole group, which has a structure as shown in formula (I), or a stereoisomer, tautomer, nitroxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug of the structure shown in formula (I),

[0006] wherein, R1 H, alkyl, haloalkyl, heteroalkyl, or cycloalkyl;

[0007] R 2 , R 3 , R 4 , R 5 , R 6 , R 8 , R 9 , R 10 , R 12 , and R 13 are each independently hydrogen, deuterium, halogen, hydroxyl, amino, cyano, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkylalkyl, alkoxy, alkoxyalkyl, hydroxyalkyl, or cycloalkyl;

[0008] R 7 is hydrogen, deuterium, halogen, hydroxyl, amino, cyano, alkyl, haloalkyl, heteroalkyl, cycloalkylalkyl, alkoxyalkyl, hydroxyalkyl, cycloalkyl, -N(R a R b ), or -OR 16 ; R 16 is alkyl, haloalkyl, heteroalkyl, cycloalkylalkyl, alkoxy, alkoxyalkyl, hydroxyalkyl, or cycloalkyl; R a and R b are each independently selected from hydrogen, alkyl, haloalkyl, hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl, haloalkylalkyl, alkenylalkyl, alkynylalkyl;

[0009] optionally, R 3 , R 8 and the carbon atom to which they are attached together form a 5-7 membered carbocyclic ring or a 5-7 membered heterocyclic ring;

[0010] optionally, R 8 , R 13 and the carbon atom to which they are attached together form a 3-7 membered nitrogen-containing heterocyclic ring;

[0011] R 14 and R 15 are each independently hydrogen, deuterium, alkyl, or halogen; or R 14 , R 15 and the carbon atom to which they are attached together form C(=0);

[0012] A is -(CH2) m -S-R 11 , heterocyclyl, cycloalkyl, aryl, heteroaryl, or -SF5;

[0013] R 11It can be hydrogen, deuterium, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkylalkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, heterocyclic alkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl;

[0014] m can be 0, 1, 2, 3, 4, or 5;

[0015] n is 0, 1, 2, or 3;

[0016] 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 R 16 R a and R b The alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, hydroxyalkyl, alkoxy, alkoxyalkyl, cycloalkylalkyl, cycloalkyl, heterocyclic, heterocyclic alkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl groups are optionally substituted independently by 1, 2, 3 or 4 substituents selected from deuterium, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl or cycloalkyl.

[0017] In some embodiments, R in the compound 1 For H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Heteroalkyl or C 3-8 cycloalkyl; R 7 It can be hydrogen, deuterium, halogen, hydroxyl, amino, cyano, or C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Heteroalkyl, C 3-8 cycloalkyl C 1-6 Alkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 3-8 cycloalkyl, -N(R) a R b ) or -OR 16 ;R a and R b Each is independently selected from hydrogen and C. 1-6 Alkyl, C1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 3-8 cycloalkyl C 1-6 Alkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Halogenated alkyl C 1-6 Alkyl, C 2-6 alkenyl C 1-6 Alkyl, C 2-6 alkynyl C 1-6 Alkyl; R 16 C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Heteroalkyl, C 3-8 cycloalkyl C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Hydroxyalkyl or C 3-8 cycloalkyl; R 4 R 5 R 9 and R 12 Each of these can be independently represented by hydrogen, deuterium, halogen, hydroxyl, amino, cyano, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Heteroalkyl, C 3-8 cycloalkyl C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Hydroxyalkyl or C 3-8 cycloalkyl; R 1 R 4 R 5 R 7 R 9 R 12 R 16 R a and R b The C mentioned in 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Heteroalkyl, C 3-8 cycloalkyl C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkyl, C1-6 Hydroxyalkyl or C 3-8 The cycloalkyl group is independently and optionally surrounded by 1, 2, 3 or 4 groups selected from deuterium, F, Cl, Br, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 Cycloalkyl substituted.

[0018] In other embodiments, in the compound, R 1 H, methyl, ethyl, n-propyl, isopropyl, tert-butyl; R 7 For hydrogen, deuterium, -N(R) a R b ) or -OR 16 ;R a and R b Each is independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl; R 16 It is methyl, ethyl, n-propyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; R 4 R 5 R 9 and R 12 Each of the following C groups is independently substituted with hydrogen, deuterium, F, Cl, Br, I, hydroxyl, amino, cyano, methyl, ethyl, n-propyl, isopropyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, or cyclopropyl. 1-3 Alkyl, methoxy, ethoxy, n-propoxy, isopropoxy, methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, methoxyn-propyl, methoxyisopropyl, ethoxypropyl, ethoxyisopropyl, isopropoxymethyl, isopropoxyethyl, n-propoxymethyl, propoxyethyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; R 1 R 4 R 5 R 9 R 12 R 16 R a and R b The C-substituted compounds described herein are methyl, ethyl, n-propyl, isopropyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, and cyclopropyl. 1-3alkyl, methoxy, ethoxy, n-propoxy, isopropoxy, methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, methoxy-n-propyl, methoxyisopropyl, ethoxypropyl, ethoxyisopropyl, isopropoxymethyl, isopropoxyethyl, n-propoxymethyl, propoxyethyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl is independently optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of deuterium, F, Cl, Br, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl are substituted with 1, 2, 3, or 4 substituents selected from the group consisting of deuterium, F, Cl, Br, amino, hydroxyl, cyano, nitro, C

[0019] In some embodiments, the compound has the structure of Formula (II), (II’), or a stereoisomer, tautomer, N-oxide, solvate, metabolite, pharmaceutically acceptable salt, or prodrug of a compound of Formula (II), (II’),

[0020] R 2 , R 3 , R 6 , R 8 , R 10 , R 13 , R 14 , R 15 , R a , R b , A, n are as defined above in Formula (I);

[0021] R 16 is C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 heteroalkyl, C 3-8 cycloalkyl C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxy C 1-6 alkyl, C 1-6 hydroxyalkyl, or C 3-8 cycloalkyl, R 16 is C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 heteroalkyl, C 3-8 cycloalkyl C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxy C 1-6 alkyl, C 1-6 hydroxyalkyl, or C 3-8 cycloalkyl is optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of deuterium, F, Cl, Br, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, or C3-6 Substituents of cycloalkyl groups.

[0022] In some embodiments, R in the compound 2 R 3 R 6 R 8 R 10 and R 13 Each of these can be independently represented by hydrogen, deuterium, halogen, hydroxyl, amino, cyano, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Heteroalkyl, C 3-6 cycloalkyl C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Hydroxyalkyl or C 3-6 cycloalkyl; the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Heteroalkyl, C 3-6 cycloalkyl C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Hydroxyalkyl or C 3-6 The cycloalkyl group is independently and optionally surrounded by 1, 2, 3 or 4 groups selected from deuterium, F, Cl, Br, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 Cycloalkyl substituted.

[0023] In other embodiments, in the compound, R 2 R 3 R 6 R 8 R 10 and R 13 Each of the following C groups is independently substituted with hydrogen, deuterium, F, Cl, Br, I, hydroxyl, amino, cyano, methyl, ethyl, n-propyl, isopropyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, or cyclopropyl. 1-3alkyl, methoxy, ethoxy, n-propoxy, i-propoxy, methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, methoxy-n-propyl, methoxy-i-propyl, ethoxypropyl, ethoxy-i-propyl, i-propoxymethyl, i-propoxyethyl, n-propoxymethyl, propoxyethyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; said methyl, ethyl, n-propyl, i-propyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, cyclopropyl substituted C 1-3 alkyl, methoxy, ethoxy, n-propoxy, i-propoxy, methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, methoxy-n-propyl, methoxy-i-propyl, ethoxypropyl, ethoxy-i-propyl, i-propoxymethyl, i-propoxyethyl, n-propoxymethyl, propoxyethyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl independently optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of deuterium, F, Cl, Br, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, methoxy, ethoxy, n-propoxy, i-propoxy, methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, methoxy-n-propyl, methoxy-i-propyl, ethoxypropyl, ethoxy-i-propyl, i-propoxymethyl, i-propoxyethyl, n-propoxymethyl, propoxyethyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl independently optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of deuterium, F, Cl, Br, amino, hydroxyl, cyano, nitro, C

[0024] In some embodiments, R 3 , R 8 and the carbon atom to which they are attached together form a 5-, 6-, or 7- membered carbocyclic ring. 3 , R 8 and the carbon atom to which they are attached together form a 5-, 6-, or 7- membered heterocyclic ring.

[0025] In some embodiments, R 8 , R 13 and the carbon atom to which they are attached together form a 5-, 6-, or 7- membered nitrogen heterocyclic ring.

[0026] In some embodiments, R 14 and R 15 are each independently hydrogen, deuterium, C 1-6 alkyl, or halogen. In some embodiments, R 14 and R 15 are each independently hydrogen, deuterium, C 1-3 alkyl, F, Cl, or Br. In some embodiments, R 14 , R 15 and the carbon atom to which they are attached together form C(=O);

[0027] In some embodiments, the compound, A is -(CH2) m -S-R 11 , C 1-9 heterocyclyl, C 3-6 cycloalkyl, C 6-10 aryl, C 1-9haloalkyl, C 11 is hydrogen, deuterium, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxyC 1-6 alkyl, C 3-6 cycloalkylC 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 1-9 heterocyclyl, C 1-9 heterocyclylC 1-6 alkyl, C 6-10 aryl, C 6-10 arylC 1-6 alkyl, C 1-9 heteroaryl or C 1-9 heteroarylC 1-6 alkyl; said C 1-6 alkyl, C 3-6 cycloalkylC 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 1-9 heterocyclyl, C 1-9 heterocyclylC 1-6 alkyl, C 6-10 aryl, C 6-10 arylC 1-6 alkyl, C 1-9 heteroaryl or C 1-9 heteroarylC 1-6 alkyl is independently optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of deuterium, F, CI, Br, amino, hydroxyl, cyano, C 1-3 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl.

[0028] In other embodiments, the compounds, A is -(CH2) m -S-R 11 , C 1-9 heterocyclyl, C 3-6 cycloalkyl, C 6-10 aryl, C 1-9 heteroaryl or -S(F)5; R 11 is hydrogen, deuterium, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxyC 1-3 alkyl, C3-6 cycloalkyl C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 cycloalkyl, C 1-4 Heterocyclic group, C 2-6 Heterocyclic C 1-3 Alkyl, phenyl, phenyl C 1-3 Alkyl, C 3-6 heteroaryl or C 3-6 heteroaryl C 1-3 Alkyl; the C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 cycloalkyl, C 1-4 Heterocyclic group, C 2-6 Heterocyclic C 1-3 Alkyl, phenyl, phenyl C 1-3 Alkyl, C 3-6 heteroaryl or C 3-6 heteroaryl C 1-3 Alkyl groups are independently and optionally surrounded by 1, 2, 3, or 4 groups selected from deuterium, F, Cl, Br, amino, hydroxyl, cyano, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 Substituents of cycloalkyl groups.

[0029] In some embodiments, the compound has a structure as shown in formulas (III), (III'), (IV), (IV'), (V), (V'), (VI), or a stereoisomer, tautomer, nitride, solvate, metabolite, pharmaceutically acceptable salt, or prodrug of the structure shown in formulas (III), (III'), (IV), (IV'), (V), (V'), (VI).

[0030] In equations (III), (III'), (IV), (IV'), (V), (V'), and (VI), R 2 R 3 R 6 R 8 R 10 R 11 R 14 R 15 R 16 R a and R b The definition is the same as that in equations (I), (II), and (II');

[0031] In formulae (V) and (V’), X is a bond, O, NR 17 or CR 18 R 19 ; R 17 is H, C 1-6 alkyl, C 1-6 deuteroalkyl, or C 1-6 haloalkyl; R 18 and R 19 are each independently hydrogen, deuterium, halogen, C 1-6 alkyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, 3-6 membered cycloalkyl, or 3-7 membered heterocyclyl;

[0032] n is 0, 1, 2, or 3.

[0033] In some embodiments, in formulae (III), (III’), (IV), (IV’), (V), (V’), and (VI), R 2 , R 3 , R 6 , R 8 , and R 10 are each independently hydrogen, deuterium, halogen, hydroxyl, amino, cyano, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 heteroalkyl, C 3-6 cycloalkyl C 1-6 alkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, or C 3-6 cycloalkyl; said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 heteroalkyl, C 3-6 cycloalkyl C 1-6 alkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, or C 3-6 cycloalkyl is independently optionally substituted with 1, 2, 3, or 4 substituents selected from deuterium, F, Cl, Br, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 3-6 cycloalkyl.

[0034] In some embodiments, in formulae (III), (III’), (IV), (IV’), (V), (V’), and (VI), each R 11 is independently hydrogen, deuterium, C 1-6alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-9 heterocyclyl, C 1-9 heterocyclyl, C 1-6 alkyl, C 6-10 aryl, C 6-10 aryl, C 1-6 alkyl, C 1-9 heteroaryl, or C 1-9 heteroaryl, C 1-6 alkyl; the C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-9 heterocyclyl, C 1-9 heterocyclyl, C 1-6 alkyl, C 6-10 aryl, C 6-10 aryl, C 1-6 alkyl, C 1-9 heteroaryl, or C 1-9 heteroaryl, C 1-6 alkyl is independently optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of deuterium, F, Cl, Br, amino, hydroxyl, cyano, C 1-3 alkyl, C 3-6 cycloalkyl.

[0035] In some embodiments, in formula (III), (III'), (IV), (IV'), (V), (V'), and (VI), R 14 and R 15 are each independently hydrogen, deuterium, C 1-6 alkyl, F, Cl, or Br; or R 14 , R 15 and the carbon atom to which they are attached together form C(=O).

[0036] In some embodiments, in formula (III), (III'), (IV), (IV'), (V), (V'), and (VI), R 16 is C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 heteroalkyl, C 3-8 cycloalkyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxy, C 1-6 alkyl, C1-6 hydroxyalkyl or C 3-8 cycloalkyl; said C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 heteroalkyl, C 3-8 cycloalkyl C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxy C 1-6 alkyl, C 1-6 hydroxyalkyl or C 3-8 cycloalkyl is independently optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of deuterium, F, Cl, Br, amino, hydroxyl, cyano, nitro, C 1-3 alkyl or C 3-6 cycloalkyl.

[0037] In some embodiments, in formula (V) and (V’), X is a bond, O, NR 17 or CR 18 R 19 ; R 17 is H, C 1-3 alkyl, C 1-3 deuteroalkyl, C 1-3 haloalkyl; R 18 and R 19 are each independently hydrogen, deuterium, F, Cl, Br, C 1-3 alkyl, C 1-3 deuteroalkyl, C 1-3 haloalkyl, 3-6 membered cycloalkyl, or 3-7 membered heterocyclyl. In some embodiments, R 17 is H, methyl, ethyl, propyl, C 1-3 alkyl substituted with 1, 2, or 3 deuterium, C 1-3 alkyl substituted with 1, 2, or 3 fluorine.

[0038] In some embodiments, in formula (V) and (V’), X is a bond or CR 18 R 19 ; R 18 and R 19 are each independently H, methyl, ethyl, propyl, C 1-3 alkyl substituted with 1, 2, or 3 deuterium, C 1-3 alkyl substituted with 1, 2, or 3 fluorine.

[0039] In other embodiments, in the compounds described, R 2 , R 3 , R 6 , R 8 and R 10each independently hydrogen, deuterium, halogen, hydroxyl, amino, cyano, methyl, ethyl, n-propyl, i-propyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, cyclopropyl substituted C 1-3 alkyl, methoxy, ethoxy, n-propoxy, i-propoxy, hydroxymethyl, hydroxyethyl, hydroxypropyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; said methyl, ethyl, n-propyl, i-propyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, cyclopropyl substituted C 1-3 alkyl, methoxy, ethoxy, n-propoxy, i-propoxy, hydroxymethyl, hydroxyethyl, hydroxypropyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl are independently optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of deuterium, F, Cl, Br, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0040] In other embodiments, the compounds described herein, R 11 is hydrogen, deuterium, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy C 1-3 alkyl, C 3-6 cycloalkyl C 1-3 alkyl, C 3-6 cycloalkyl, C 1-4 heterocyclyl, C 1-4 heterocyclyl C 1-3 alkyl, phenyl, phenyl C 1-3 alkyl, C 1-6 heteroaryl or C 1-6 heteroaryl C 1-6 alkyl, preferably C 1-3 alkyl; said C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy C 1-3 alkyl, C 3-6 cycloalkyl C 1-3 alkyl, C 3-6 cycloalkyl, C 1-4 heterocyclyl, C 1-4 heterocyclyl C 1-3 alkyl, phenyl, phenyl C 1-3 alkyl, C 1-6 heteroaryl or C 1-6 heteroaryl C 1-6 alkyl, C 1-3 haloalkyl, C 3-6Substituents of cycloalkyl groups.

[0041] In some embodiments, R in the compound 14 and R 15 Each is independently hydrogen, deuterium, and C. 1-3 Alkyl, F, Cl or Br; or R 14 R 15 Together with the carbon atom it is attached to, it forms C (=O).

[0042] In some embodiments, in the compound, each R 16 Independently for C 1-6 Alkyl groups or C atoms substituted with 1, 2, 3 or 4 deuterium atoms. 1-6 alkyl.

[0043] In some embodiments, the compound has a structure as shown in formulas (I-1), (I-2), (I-3), (I-4), (I-5), (I-6), (I-7), (I-8), (I-9), (I-10), (I-11), (I-12), (I-13), (I-14), or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt, or prodrug of formulas (I-1), (I-2), (I-3), (I-4), (I-5), (I-6), (I-7), (I-8), (I-9), (I-10), (I-11), (I-12), (I-13), (I-14).

[0044] Among them, R 2 R 3 R 8 R 10 R 11 R 14 R 15 R 16 R a and R b The definition is the same as the definition mentioned above in this article.

[0045] In some embodiments, R in the compound 1 It is hydrogen.

[0046] In some embodiments, R in the compound 2 and R 3 Each is independently hydrogen, deuterium, and C. 1-3 Alkyl or deuterated C 1-3 Alkyl groups, such as hydrogen, deuterium, methyl, or deuterated methyl.

[0047] In some embodiments, R in the compound 4 and R 5 Each is either hydrogen or deuterium.

[0048] In some embodiments, in the compound, each R 6 Independently for C 1-3 Alkyl or deuterated C 1-3 Alkyl groups, such as methyl or deuterated methyl groups.

[0049] In some embodiments, R in the compound 9 R 12 and R 13 Both are hydrogen.

[0050] In some embodiments, in the compound, each R 8 Independent of hydrogen, deuterium, and C 1-3 Alkyl or deuterated C 1-3 Alkyl groups, such as H, methyl, or deuterated methyl.

[0051] In some embodiments, in the compound, each R 10 Independent of hydrogen, deuterium, and C 1-3 Alkyl or deuterated C 1-3 Alkyl groups, such as hydrogen or deuterium.

[0052] In some embodiments, in the compound, each R 11 Independently for C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 cycloalkyl, C 1-4 Heterocyclic groups or deuterated C 1-3 Alkyl groups, such as methyl, trifluoromethyl, deuterated methyl, cyclopropyl, cyclobutyl, ethylene oxide, or propylene oxide.

[0053] In some embodiments, R in the compound 14 and R 15 Each is independently hydrogen or deuterium; or R 14 R 15 Together with the carbon atom it is attached to, it forms C (=O).

[0054] In some implementation schemes, R a and R b Each is independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl.

[0055] In some embodiments, in the compound, each R 16 Independently for C 1-3 Alkyl, deuterated C 1-3 Alkyl, fluorinated C1-3 alkyl, for example, methyl, deuterated methyl, or fluorinated methyl.

[0056] In the present application, examples of deuterated methyl include -CH2D, -CHD2, -CD3, and the like; examples of fluorinated methyl include -CH2F, -CHF2, -CF3, and the like.

[0057] In some embodiments, the compound has the following structure or a stereoisomer, tautomer, nitroso, solvate, metabolite, pharmaceutically acceptable salt, or prodrug thereof,

[0058] In a second aspect, the present application also provides a pharmaceutical composition comprising the above-mentioned compound containing an indole group, and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle, or a combination thereof.

[0059] In a third aspect, the present application provides use of the compound containing an indole group or the pharmaceutical composition of the present application in the preparation of a medicament for preventing, treating, alleviating, or modulating a disease associated with or mediated by complement factor B (Factor B).

[0060] In some embodiments, the disease is selected from the group consisting of glomerulopathy, hemolytic uremic syndrome, atypical hemolytic uremic syndrome, paroxysmal nocturnal hemoglobinuria, age-related macular degeneration, geographic atrophy, diabetic retinopathy, uveitis, retinitis pigmentosa, macular edema, uveitis caused by Behcet's syndrome, multifocal choroiditis, Vogt-Koyanagi-Harada syndrome, birdshot retinochoroidopathy, sympathetic ophthalmia, ocular cicatricial pemphigoid, ocular pemphigoid, non-arteritic ischemic optic neuropathy, post-surgical inflammation, retinal vein occlusion, neurological disorders, multiple sclerosis, stroke, Guillain-Barre syndrome, traumatic brain injury, Parkinson's disease, inappropriate or undesirable complement activation disorders, hemodialysis complications, hyperacute allograft rejection, xenograft rejection, interleukin-2-induced toxicity during IL-2 therapy, Crohn's disease, adult respiratory distress syndrome, myocardial inflammation, post-ischemic reperfusion disorders, myocardial infarction, post-pump syndrome in balloon angioplasty, cardiopulmonary bypass surgery or renal bypass surgery, atherosclerosis, hemodialysis, renal ischemia, aortic reconstruction, mesenteric arterial reperfusion following infectious disease or sepsis, systemic lupus erythematosus, systemic lupus erythematosus nephritis, proliferative nephritis, liver fibrosis, hemolytic anemia, myasthenia gravis, tissue regeneration, nerve regeneration, dyspnea, hemoptysis, acute respiratory distress syndrome, asthma, chronic obstructive pulmonary disease, emphysema, pulmonary embolism and infarction, pneumonia, fibrotic dust diseases, pulmonary fibrosis, asthma, allergy, bronchoconstriction, parasitic diseases, Goodpasture's syndrome, pulmonary vasculitis, pauci-immune vasculitis, immune complex-related inflammation, anti-phospholipid syndrome, and obesity.

[0061] In some embodiments, the disease is selected from the group consisting of age-related macular degeneration, geographic atrophy, diabetic retinopathy, uveitis, retinitis pigmentosa, macular edema, uveitis caused by Behcet's syndrome, multifocal choroiditis, birdshot retinochoroidopathy, sympathetic ophthalmia, ocular cicatricial pemphigoid, ocular pemphigoid, non-arteritic ischemic optic neuropathy, post-surgical inflammation, retinal vein occlusion, C3 glomerulopathy, immunoglobulin A nephropathy, membranous glomerulonephritis, atypical hemolytic uremic syndrome (aHUS), and paroxysmal nocturnal hemoglobinuria (PNH).

[0062] In a fourth aspect, the present application provides a method of inhibiting or modulating the activity of complement Factor B in a cell, the method comprising contacting the cell with an effective amount of a compound of the present application described above containing an indole group or a pharmaceutical composition of the present application described above.

[0063] In some embodiments, the cell is a mammalian cell.

[0064] In a fifth aspect, the present application provides a method of inhibiting or modulating the activity of complement Factor B in a subject, comprising administering to the subject an effective amount of a compound of the present application described above containing an indole group or a pharmaceutical composition of the present application described above.

[0065] In some embodiments, the subject is a mammal, preferably a human.

[0066] In a sixth aspect, the present application provides a method of preventing, treating, ameliorating or modulating a disease associated with or mediated by complement Factor B, comprising administering to a patient an effective amount of a compound of the present application described above containing an indole group or a pharmaceutical composition of the present application described above.

[0067] In some embodiments, the method is for non-disease diagnostic purposes. In some embodiments, the method is for disease diagnostic purposes.

[0068] In some embodiments, the disease is selected from glomerulopathy, hemolytic uremic syndrome, atypical hemolytic uremic syndrome, paroxysmal nocturnal hemoglobinuria, age-related macular degeneration, geographic atrophy, diabetic retinopathy, uveitis, retinitis pigmentosa, macular edema, uveitis caused by Behcet's syndrome, multifocal choroiditis, Vogt-Koyanagi-Harada syndrome, birdshot retinochoroiditis, sympathetic ophthalmia, ocular cicatricial pemphigoid, ocular pemphigus, non-arteritic ischemic optic neuropathy, post-surgical inflammation, retinal vein occlusion, neurological disorders, multiple sclerosis, stroke, Guillain-Barre syndrome, traumatic brain injury, Parkinson's disease, inappropriate or undesirable complement activation disorders, hemodialysis complications, hyperacute allograft rejection, xenograft rejection, interleukin-2 induced toxicity during IL-2 therapy, Crohn's disease, adult respiratory distress syndrome, myocarditis, post-ischemic reperfusion disorders, myocardial infarction, post-pump syndrome in balloon angioplasty, cardiopulmonary bypass or renal bypass surgery, atherosclerosis, hemodialysis, renal ischemia, aortic reconstruction, mesenteric arterial reperfusion following infectious disease or sepsis, systemic lupus erythematosus, systemic lupus erythematosus nephritis, proliferative nephritis, liver fibrosis, hemolytic anemia, myasthenia gravis, tissue regeneration, nerve regeneration, dyspnea, hemoptysis, acute respiratory distress syndrome, asthma, chronic obstructive pulmonary disease, pulmonary emphysema, pulmonary embolism and infarction, pneumonia, fibrosis-causing dust diseases, pulmonary fibrosis, asthma, allergy, bronchoconstriction, parasitic diseases, Goodpasture's syndrome, pulmonary vasculitis, pauci-immune vasculitis, immune complex-related inflammation, anti-phospholipid syndrome, and obesity.

[0069] In some embodiments, the disease is selected from the group consisting of age-related macular degeneration, geographic atrophy, diabetic retinopathy, uveitis, retinitis pigmentosa, macular edema, uveitis caused by Behcet’s syndrome, multifocal choroiditis, birdshot retinochoroiditis, sympathetic ophthalmia, ocular cicatricial pemphigoid, ocular pemphigus, non-arteritic ischemic optic neuropathy, post-surgical inflammation, retinal vein occlusion, C3 glomerulopathy, immunoglobulin A nephropathy, membranous glomerulonephritis, atypical hemolytic uremic syndrome (aHUS), and paroxysmal nocturnal hemoglobinuria (PNH).

[0070] The foregoing outline merely provides an overview of some aspects of the application, and is not intended to exclude other aspects of the application. A more complete understanding of which can be obtained by referring to the following detailed description and the attached drawings. DETAILED DESCRIPTION

[0071] Definitions and General Terminology

[0072] Unless otherwise defined, all terms used in connection with the application herein, including technical and scientific terms, have the same meaning as is commonly understood by one of ordinary skill in the art to which this application belongs. It will be further understood that terms, such as those defined in commonly used dictionaries, should be interpreted as having a meaning that is consistent with their meaning in the context of the relevant art and the present disclosure, and will not be interpreted in an overly literal or overly formal sense.

[0073] Certain embodiments of the application will now be described in detail by way of examples, which are intended to be illustrative only, as illustrated by the chemical structures and formulas. The application is intended to cover all alternatives, modifications, and equivalents of the methods and materials disclosed herein, which include all those resulting from a program of research in which the present application is applied. Numerous methods and materials similar or equivalent to those described herein can be used in the practice of the application. The application is in no way limited to the methods and materials described herein. In the event that one or more of the incorporated literature, patents, and similar materials differs from or contradicts this application, including but not limited to defined terms, term application, described techniques, and the like, this application controls.

[0074] It should be further recognized that certain of the features of the application, described in detail herein, are described in the context of a number of separate embodiments, but can also be provided in combination in a single embodiment. Conversely, various features of the application, described in the context of a single embodiment, can also be provided separately or in any appropriate subcombination.

[0075] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. The application can employ, unless otherwise indicated, techniques of molecular biology, microbiology, cell biology, biochemistry, and immunology, which are within the skill of the art. All patents and publications referred to in this application are incorporated by reference.

[0076] The following definitions shall apply unless otherwise indicated. For the purposes of the present application, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, and the "Handbook of Chemistry and Physics" 75thEd. 1994. Additionally, general principles of organic chemistry are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry", by Michael B. Smith and Jerry March, John Wiley & Sons, New York: 2007, the entire contents of which are incorporated herein by reference.

[0077] The articles "a" and "an" are used herein to refer to one or to more than one (i.e., to "at least one") of the enumerated items, unless otherwise indicated by the context of the use of the terms. The term "the" is used herein to refer to one specific instance of something unless otherwise indicated by the context of the use of the term. The terms "comprising," "including," "containing," etc. shall be construed as open and inclusive, and do not preclude additional, unrecited elements or limitations.

[0078] The term "patient" as used herein refers to a human (including adults and children) or other animal. In some embodiments, "patient" refers to a human.

[0079] The term "subject" as used herein refers to a mammal or other animal. In some embodiments, "subject" refers to a mammal. In some embodiments, "subject" refers to a human (including adults and children).

[0080] The term "comprising" is used herein to mean including whatever follows the word, but not to the exclusion of anything not mentioned, which is also meant to be included.

[0081] The term "stereoisomers" refers to compounds which have the same chemical constitution, but differ in the arrangement of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotamers), geometric isomers (cis / trans), atropisomers, and the like. "Diastereomers" refers to stereoisomers which have two or more chiral centers and which are not mirror images of one another. Diastereomers have different physical properties, even if they have the same chemical composition and molecular formula. Mixtures of diastereomers can be separated by high resolution analytical techniques, such as electrophoresis and chromatography, e.g., HPLC.

[0082] The stereochemical definitions and rules recited herein generally follow S. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. In describing an optically active compound, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule about its chiral center(s). The prefixes d and 1 or (+) and (-) are employed to designate the sign of the rotation of plane-polarized light by the compound, i.e., (-) or 1 meaning that the compound is levorotatory. A compound, which is ( + ) or d is dextrorotatory. A specific stereoisomer is an enantiomer; a mixture of such isomers is called an enantiomeric mixture. A 50:50 mixture of enantiomers is referred to as a racemic mixture or racemate.

[0083] Any asymmetric atom (e.g., carbon) of a compound disclosed herein can exist in the form of a racemic or enantiomeric enrichment, e.g., in the (R)-, (S)-, or (R,S)-configurational form. In certain embodiments, each asymmetric atom is at least 50% enantiomeric excess in the (R)- or (S)- configuration, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess.

[0084] Depending on the choice of starting materials and methods, the compounds of the application can be synthesized as one of the possible isomers or a mixture of them, such as, for example, in the form of racemates and diastereomeric mixtures, depending on the number of asymmetric carbon atoms (see, for example, the examples). The optically active (R)- or (S)-isomers can be obtained by optical resolution of the racemates using conventional techniques, or by synthesis using chiral synthons or chiral reagents. If the compounds contain a double bond, the substituents can be in the E or Z configuration; if the compounds contain a disubstituted cycloalkyl, the substituents on the cycloalkyl can have a cis- or trans-configuration.

[0085] Any mixture of stereoisomers can be separated into the individual isomers by conventional techniques, such as HPLC or fractional crystallization, or any mixture of enantiomers can be converted to the individual isomers by methods known to those skilled in the art.

[0086] Unless otherwise indicated, the structural formulae described herein include all tautomeric forms (e.g., enantiomeric, diastereomeric, and geometric (or conformational) isomers: for example, R, S configurations about asymmetric centers; (Z), (E) isomers about double bonds; and (Z), (E) conformational isomers. Thus, individual stereochemical isomers and mixtures of their enantiomers, diastereomers, or geometric (or conformational) isomers, where possible, are within the scope of the application.

[0087] The term "prodrug" as used herein refers to a compound that is converted in vivo into a compound of Formula (I), (II), (III), (IV), (V), (VI), (IV-1), (V-1), (I-1), (I-2), (I-3), (I-4), (I-5), (I-6), or (I-7). Such conversion is effected by hydrolysis in blood or enzymatic conversion in blood or tissue to the parent structure. The prodrug class of compounds of the present application can be esters, and in the present application esters can be benzoic esters, aliphatic (C1-24) esters, acyloxymethyl esters, carbonates, carbamates, and amino acid esters. For example, a compound of the present application containing a hydroxyl group can be acylated to provide a prodrug form of the compound. Other prodrug forms include phosphates, such as those compounds which are phosphorylated on a hydroxyl group of the parent. A thorough discussion of prodrugs is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, J. Rautio et al, Prodrugs: Design and Clinical Applications, Nature Review Drug Discovery, 2008, 7, 255-270, and S. J. Hecker et al, Prodrugs of Phosphates and Phosphonates, Journal of Medicinal Chemistry, 2008, 51, 2328-2345.

[0088] Any resulting racemate of an end product or intermediate can be resolved into the individual optical antipodes by known methods, e.g., by separation of the diastereomeric salts thereof, which are obtained by treatment with the customary resolving agents. The racemates can also be separated by chiral chromatography, e.g., high performance liquid chromatography (HPLC) using chiral adsorbents. In particular, the enantiomers can be prepared by asymmetric synthesis, e.g., see Jacques, et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Principles of Asymmetric Synthesis (2nd Ed. Robert E. Gawley, Jeffrey Aubé, Elsevier, Oxford, UK, 2012); Eliel, E. L. Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, S. H. Tables of Resolving Agents and Optical Resolutions p. 268 (E. L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972); Chiral Separation Techniques: A Practical Approach (Subramanian, G. Ed., Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, Germany, 2007).

[0089] The term "tautomer" or "tautomerism" refers to structural isomers that have different energies and can interconvert by a low energy barrier. If tautomerism is possible (as in solution), a chemical equilibrium of the tautomers can be reached. For example, protontautomer (also known as prototropic tautomer) includes interconversions by proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomer includes interconversions by reorganization of some bonding electrons. A specific example of keto-enol tautomerism is the interconversion of pentane-2,4-dione and 4-hydroxypent-3-en-2-one tautomers. Another example of tautomerism is phenol-keto tautomerism. A specific example of phenol-keto tautomerism is the interconversion of pyridin-4-ol and pyridin-4(lH)-one tautomers. Unless otherwise indicated, all tautomeric forms of the compounds of the application are within the scope of the application.

[0090] The salts referred to herein are pharmaceutically acceptable salts, wherein "pharmaceutically acceptable salts" are those that are known in the art, as described in Berge et al., J. Pharmacol Sci, 1997, 66, 1-19. Non-limiting examples of pharmaceutically acceptable salts include inorganic acid salts formed with acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, metaphosphoric acid, sulfuric acid, sulfurous acid, nitric acid, perchloric acid, and organic acids such as carboxylic acids, sulfonic acids, sulfinic acids, sulfamic acids, and the like, specifically, but not limited to, methanesulfonic acid, ethanesulfonic acid, formic acid, acetic acid, succinic acid, benzoic acid, succinic acid, pamoic acid, salicylic acid, galactaric acid, glucoheptanoic acid, mandelic acid, 1,2-ethanedisulfonic acid, 2-naphthalenesulfonic acid, carbonic acid, trifluoroacetic acid, glycolic acid, glycollyl sulfonic acid, oxalic acid, maleic acid, tartaric acid, citric acid, malonic acid, benzenesulfonic acid, p-toluenesulfonic acid, malic acid, fumaric acid, lactic acid, lactobionic acid, or oxalic acid, or by other methods such as ion exchange procedures, as described in the literature. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, besylate, brofenacinate, borate, butyrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, laurate, lauryl sulfate, nicotinate, nitrate, oleate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, stearate, thiocyanate, undecanoate, valerate, and the like. In addition, pharmaceutically acceptable salts can include salts of acidic groups that are formed by appropriate bases, such as alkali metal, alkaline earth metal, ammonium and N+(C 1-4 alkyl)4 salts. The present application also contemplates the quaternary ammonium salts of any group containing N. Water or oil-soluble or dispersible products can be obtained by quaternization. Alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Pharmaceutically acceptable salts further include appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed by the addition of inorganic or organic acids to a basic group, such as halogen, carboxy, sulfate, phosphate, nitrate, C 1-8 sulfonate, and aromatic sulfonate.

[0091] Pharmaceutically acceptable salts can be formed with inorganic acids and organic acids, e.g., acetate, aspartate, benzoate, besylate, bromide / hydrobromide, bicarbonate / carbonate, bisulfate / sulfate, camsylate, chloride / hydrochloride, chlorobenzoate, citrate, edisylate, fumarate, gluceptate, gluconate, glucuronate, hippurate, hydroiodide / iodide, isethionate, lactate, lactobionate, laurylsulfate, malate, maleate, malonate, mandelate, mesylate, methylsulfate, naphthoate, napsylate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate, polygalacturonate, propionate, stearate, succinate, subsalicylate, tartrate, tosylate, and trifluoroacetate.

[0092] Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.

[0093] Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, subsalicylic acid, and the like.

[0094] The term "nitroso compound" as used herein refers to the oxidation of one or more than one nitrogen atom when the compound contains several amine functions. Particular examples of N-oxides are N-oxides of tertiary amines or N-oxides of nitrogen heterocycle ring nitrogen atoms. N-oxides can be formed by treatment of the corresponding amines with an oxidizing agent such as hydrogen peroxide or a peracid (e.g. peroxycarboxylic acid) (see Advanced Organic Chemistry, Wiley Interscience, 4thEdition, Jerry March, pages 622-623). In particular, N-oxides can be prepared by the method of L. W. Deady (Syn. Comm. 1977, 7, 509-514) wherein the amine compound is reacted with meta-chloroperoxybenzoic acid (MCPBA) for example in an inert solvent such as dichloromethane.

[0095] "Solvate" forms of the present application are intended to encompass any form of the application wherein one or more solvent molecules are associated with one or more compounds of the present application. Solvents include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, aminoethanol. The term "hydrate" refers to the solvate formed when the solvent is water.

[0096] The term "metabolite" as used herein refers to a product produced through metabolism in the body of a specified compound or salt thereof. Metabolites of a compound can be identified using techniques known in the art and can be active or inactive. Such products can result for example from the oxidation, reduction, hydrolysis, am idation, deam idation, esterification, deesterification, enzymatic cleavage, and the like of a administered compound. Accordingly, the present application includes metabolites of a compound, including those produced upon administration of the compound to a mammal for a period of time sufficient to yield a metabolic product.

[0097] The term "protecting group" or "PG" refers to a substituent that is commonly employed to block or protect the functionality of a particular group while reacting other functional groups on the molecule. For example, an "amino-protecting group" refers to a substituent attached to an amino group that blocks or protects the functionality of the amino group while other functional groups are reacted. Suitable amino-protecting groups include acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBZ) and 9-fluorenylmethyloxycarbonyl (Fmoc). Similarly, a "hydroxy-protecting group" refers to a substituent of a hydroxy group that blocks or protects the functionality of the hydroxy group while other functional groups are reacted. Suitable protecting groups for hydroxyl include acetyl and silyl. A "carboxy-protecting group" refers to a substituent of the carboxy group that blocks or protects the functionality of the carboxy group while other functional groups are reacted. Typical carboxy-protecting groups include -CH2CH2SO2Ph, cyanoethyl, 2-(trimethylsilyl)ethyl, 2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 2-(p-nitrophenylsulfonyl)ethyl, 2-(diphenylphosphino)ethyl, nitroethyl, and the like. For a general description of protecting groups, see T. W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991; and P. J. Kocienski, Protecting Groups, Thieme, Stuttgart, 2005.

[0098] "Pharmaceutical composition" means a mixture of one or more of the salts of the compounds described herein or physiologically / pharmaceutically acceptable salts or prodrugs thereof with other chemical components, such as physiologically / pharmaceutically acceptable carriers or excipients. The purpose of a pharmaceutical composition is to facilitate administration of the compound to an organism.

[0099] The term "treatment" of any disease or disorder, as used herein, means, in some embodiments, improvement of the disease or disorder (i.e., slowing or arresting or reducing the development of the disease or at least one of the clinical symptoms thereof). In other embodiments, "treatment" means alleviating or ameliorating at least one physical parameter including those not discernible by the patient. In other embodiments, "treatment" means modulating the disease or disorder, either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter), or both. In other embodiments, "treatment" means preventing or delaying the onset or development of a disease or disorder.

[0100] Any formula given herein is also intended to represent corresponding structural moieties having unisotopically enriched atoms. Isotopically enriched compounds have the structure depicted by the general formula given herein, except that one or more atoms are replaced by an atom having the selected atomic mass or mass number. Exemplary isotopes that can be found in compounds of the present application include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulphur, fluorine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 17 O, 18 O, 18 F, 31 P, 32 P, 35 S, 36 Cl, and 125 I.

[0101] In another aspect, the compounds of the present application include isotopically enriched compounds as defined herein, for example, where a radioisotope is present, such as 3 H, 14 C, and 18 F, or where a non-radioactive isotope is present, such as 2 H, and 13 C. Such isotopically enriched compounds are useful in metabolic studies (with 14 C), reaction kinetic studies (with, for example 2 H, or 3 H), detection or imaging techniques, such as positron emission tomography (PET) or single photon emission computed tomography (SPECT), or for patient therapy, such as therapeutic radiation. 18F Enriched compounds are particularly desirable for PET or SPECT studies. Isotopically enriched compounds of the present application can be prepared by conventional techniques familiar to those skilled in the art or by the use of appropriate isotopically-labeled reagents in the examples and procedures described in the present application, replacing non-labeled reagents that are otherwise employed.

[0102] In addition, substitution with heavier isotopes, particularly deuterium (i.e., 2H, D or 2 H or D) can afford certain therapeutic advantages resuiting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements or improved therapeutic index. It is understood that deuterium in the present application is taken to mean a substituent group of a compound of the present application. The concentration of such heavier isotopes, particularly deuterium, can be defined in terms of an isotopic enrichment factor. The term "isotopic enrichment factor" as used herein means the ratio of the isotopic abundance of the designated isotope to the natural abundance of the isotope. If a substituent group of a compound of the present application is designated as deuterium, the compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation) at each designated deuterium atom. Pharmaceutically acceptable solvates of the present application include those wherein the solvent of crystallization can be isotopically substituted, for example, D2O, acetone-d6, DMSO-d6.

[0103] As described herein, the compounds of the present application can optionally be substituted with one or more substituents, such as described herein for the compounds of the general formulae above, or as described in particular examples, subgroups, and classes of compounds encompassed by the present application. It will be appreciated that the term "optionally substituted" is used interchangeably with the term "substituted or unsubstituted." In general, the term "optionally" whether applied to a term used in the singular or plural can be taken to mean that the term is selected from the group consisting of substituted or unsubstituted. In general, the term "optionally" whether applied to a term used in the singular or plural, means that the given structure can optionally have one or more substituents at a variety of ring positions. Where more than one position in the given structure can be substituted with one or more substituents selected from a specified group, the substituents can be the same or different at each occurrence. The substituents described herein can be, but are not limited to, deuterium, hydroxyl, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkylthio, alkyl, alkenyl, alkynyl, heterocyclyl, thiol, nitro, aryloxy, heteroaryloxy, oxo (=0), carboxyl, hydroxyl substituted alkoxy, hydroxyl substituted alkyl-C(=0), alkyl-C(=0), alkyl-S(=0), alkyl-S(=0)2-, hydroxyl substituted alkyl-S(=0), hydroxyl substituted alkyl-S(=0)2, carboxyl alkoxy, and the like.

[0104] As used herein, the term "alkyl" means a saturated straight chain or branched chain monovalent hydrocarbon radical of one to twenty carbon atoms, or one to ten carbon atoms, or one to eight carbon atoms, or one to six carbon atoms, or one to four carbon atoms, or one to three carbon atoms, wherein the alkyl group can be independently and optionally substituted with one or more substituents as described herein. Examples of alkyl groups include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), n-propyl (n-Pr, -CH2CH2CH3), isopropyl (i-Pr, -CH(CH3)2), n-butyl (n-Bu, -CH2CH2CH2CH3), isobutyl (i-Bu, -CH2CH(CH3)2), sec-butyl (s-Bu, -CH(CH3)CH2CH3), t-butyl (t-Bu, -C(CH3)3), n-pentyl (-CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-l-butyl (-CH2CH2CH(CH3)2), 2-methyl-l-butyl (-CH2CH(CH3)CH2CH3), n-hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3), n-heptyl, n-octyl, and the like. The terms "alkyl" and its prefix "alk" as used herein encompass both straight chain and branched chain saturated carbon chains. The term "alkylene" as used herein means a saturated divalent hydrocarbon radical derived from a straight chain or branched chain saturated hydrocarbon by the removal of two hydrogen atoms, examples of which include, but are not limited to, methylene, ethylene, isopropylene, and the like.

[0105] The term "alkoxy" as used herein refers to an alkyl group, as defined herein, attached to the parent chain through an oxygen atom. Examples of such include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, and the like. The alkoxy group can be substituted or unsubstituted, wherein the substituents can be, but are not limited to, hydroxyl, amino, halogen, cyano, alkoxy, alkyl, alkenyl, alkynyl, thiol, nitro, and the like.

[0106] The term "alkenyl" refers to a straight or branched chain monovalent hydrocarbon radical of 2 to 12 carbon atoms, or 2 to 8 carbon atoms, or 2 to 6 carbon atoms, or 2 to 4 carbon atoms, wherein at least one position is unsaturated, i.e., one C-C is an sp2 double bond, wherein the alkenyl group can be independently and optionally substituted with one or more substituents described herein, including the positioning of the "trans", "cis", or "E", "Z" groups, wherein specific examples of alkenyl include, but are not limited to, ethenyl (-CH=CH2), allyl (-CH2CH=CH2), and the like.

[0107] The term "alkynyl" refers to a straight or branched chain monovalent hydrocarbon radical of 2 to 12 carbon atoms, or 2 to 8 carbon atoms, or 2 to 6 carbon atoms, or 2 to 4 carbon atoms, wherein at least one position is unsaturated, i.e., one C-C is an sp triple bond, wherein the alkynyl group can be independently and optionally substituted with one or more substituents described herein, wherein specific examples of alkynyl include, but are not limited to, ethynyl (-C≡CH), propargyl (-CH2C≡CH), and the like.

[0108] The term "cycloalkyl" or "carbocyclic" refers to a monovalent or multivalent, non-aromatic, saturated or partially unsaturated ring, and does not contain heteroatoms, including a monocyclic ring of 3 to 12 carbon atoms or a bicyclic ring of 7 to 12 carbon atoms. Bicyclic carbocyclic rings having 7 to 12 atoms can be bicyclo[4,5], [5,5], [5,6] or [6,6] systems, while bicyclic carbocyclic rings having 9 or 10 atoms can be bicyclo[5,6] or [6,6] systems. Suitable cyclic aliphatic groups include, but are not limited to, cycloalkyl, cycloalkenyl and cycloalkynyl groups. Examples of cyclic aliphatic groups include, but are in no way limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1- enyl, 1-cyclopentyl-2-enyl, 1-cyclopentyl-3-enyl, cyclohexyl, 1-cyclohexyl-1-enyl, 1- cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl and the like. Also, the "cyclic aliphatic" or "carbocyclic", "carbocyclyl", "cycloalkyl" groups can be substituted or unsubstituted, wherein the substituents can be, but are not limited to, hydroxy, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocyclyl, thiol, nitro, aryloxy, hydroxy-substituted alkoxy, hydroxy-substituted alkyl-C(=O), alkyl-C(=O), alkyl-S(=O), alkyl-S(=O)2-, hydroxy-substituted alkyl-S(=O), hydroxy-substituted alkyl-S(=O)2, carboxyalkoxy and the like.

[0109] The terms "heterocycle", "heterocyclyl", "heteroaliphatic" or "heterocyclic" are used interchangeably herein and refer to a monocyclic, bicyclic, or tricyclic ring system in which one or more carbon atoms in the ring is independently and optionally replaced by a heteroatom having the meaning as described herein, the ring can be fully saturated or contain one or more degrees of unsaturation, but is not aromatic. One or more ring hydrogen atoms are independently and optionally replaced by one or more substituents as described herein. In some embodiments, the "heterocycle", "heterocyclyl", "heteroaliphatic" or "heterocyclic" group is a 3-7 membered monocyclic ring (1-6 carbon atoms and 1-3 heteroatoms selected from N, O, P, S, wherein S or P is optionally replaced by one or more oxygen atoms to give groups such as SO, SO2, PO, PO2, when the ring is a three membered ring, and wherein only one heteroatom is present), or a 7-10 membered bicyclic ring (4-9 carbon atoms and 1-3 heteroatoms selected from N, O, P, S, wherein S or P is optionally replaced by one or more oxygen atoms to give groups such as SO, SO2, PO, PO2).

[0110] Heterocyclic groups can be carbonyl or heteroatomyl. "Heterocyclic group" also includes groups formed by the fusion of a heterocyclic group with a saturated or partially unsaturated ring or heterocycle. Examples of heterocycles include, but are not limited to, pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiophenyl, piperidinyl, morpholinyl, thiomorpholinyl, thiazolyl, thiazolyl, oxazolyl, piperazine, homopiperazine, aziridine, oxacyclobutyl, thiohexacyclobutyl, piperidinyl, homopiperidinyl, glycidyl, aziridineheptyl, oxacycloheptyl, thiohexacycloheptyl, 4-methoxy-piperidin-1-yl, 1,2,3,6-tetrahydropyridin-1-yl, oxacyclobutyl... 2-diaza Base, sulfur nitrogen 1-pyrrololin-1-yl, 2-pyrrololin-3-pyrrololin-1-yl, dihydroindolyl, 2H-pyranyl, 4H-pyranyl, dioxacyclohexyl, 1,3-dioxopentyl, pyrazolinyl, dithiaalkyl, dithiamonyl, dihydrothiophenyl, pyrazolinyl imidazolinyl, imidazolinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,6-thiadiazinane 1,1-dioxo-2-yl, 4-hydroxy-1,4-azaphosphane 4-oxide-1-yl, 2-hydroxy-1-(piperazin-1-yl)acetone-4-yl, 2-hydroxy-1-(5,6-dihydro-1,2,4-triazin-1(4H)-yl)acetone-4-yl, 5,6-dihydro-4 H-1,2,4-oxadiazine-4-yl, 2-hydroxy-1-(5,6-dihydropyridin-1(2H)-yl) acetone-4-yl, 3-azabicyclo[3.1.0]hexyl, 3-azabicyclo[4.1.0]heptyl, azabicyclo[2.2.2]hexyl, 2-methyl-5,6,7,8-tetrahydro-[1,2,4]triazol[1,5-c]pyrimidin-6-yl, 4,5,6,7-tetrahydroisoxazol[4,3-c]pyridin-5-yl, 3H-indolyl-2-oxo-5-azabicyclo[2.2.1]heptane-5-yl, 2-oxo-5-azabicyclo[2.2.2]octane-5-yl, quinazinyl and N-pyridinyl urea. Examples of heterocyclic groups also include 1,1-dioxothiomorpholino, and those in which two carbon atoms on the ring are replaced by oxygen atoms, such as pyrimidinide groups. Furthermore, the heterocyclic group can be substituted or unsubstituted, wherein the substituent can be, but is not limited to, oxo(=O), hydroxyl, amino, halogen, cyano, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocyclic, mercapto, nitro, aryloxy, hydroxy-substituted alkoxy, hydroxy-substituted alkyl-C(=O), alkyl-C(=O), alkyl-S(=O), alkyl-S(=O)2-, hydroxy-substituted alkyl-S(=O), hydroxy-substituted alkyl-S(=O)2, carboxyalkoxy, etc.

[0111] The term "aryl" or "aromatic ring" can be used alone or as part of "aralkyl", "aralkyloxy" or "aryloxyalkyl" to denote monocyclic, bicyclic, and tricyclic carbocyclic ring systems containing in combination 6 to 14 ring members, wherein at least one ring system is aromatic, wherein each ring system contains 3 to 7 ring members, and only one attachment point to the rest of the molecule. The term "aryl" can be used interchangeably with the term "aromatic ring" such that an aromatic ring can include phenyl, naphthyl, and anthryl groups. Also, the aryl group can be substituted or unsubstituted, wherein the substituents can be, but are not limited to, hydroxy, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocyclyl, thiol, nitro, aryloxy, hydroxy-substituted alkoxy, hydroxy-substituted alkyl-C(=O)-, alkyl-C(=O)-, alkyl-S(=O)-, alkyl-S(=O)2-, hydroxy-substituted alkyl-S(=O)-, hydroxy-substituted alkyl-S(=O)2-, carboxyalkoxy, and the like.

[0112] The term "heteroaryl" or "heteroaromatic ring" denotes monocyclic, bicyclic, and tricyclic ring systems containing in combination 5 to 14 ring members, wherein at least one ring system is aromatic, and at least one ring system contains one or more heteroatoms, wherein the heteroatoms have the meaning given in the present application, wherein each ring system contains 3 to 7 ring members, and only one attachment point to the rest of the molecule. The term "heteroaryl" can be used interchangeably with the term "heteroaromatic" or "heteroaromatic compound". Also, the heteroaryl group can be substituted or unsubstituted, wherein the substituents can be, but are not limited to, hydroxy, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocyclyl, thiol, nitro, aryloxy, hydroxy-substituted alkoxy, hydroxy-substituted alkyl-C(=O)-, alkyl-C(=O)-, alkyl-S(=O)-, alkyl-S(=O)2-, hydroxy-substituted alkyl-S(=O)-, hydroxy-substituted alkyl-S(=O)2-, carboxyalkoxy, and the like.

[0113] In other embodiments, heteroaryl groups include, but are not limited to, the following monocyclic rings: 2-furanyl, 3-furanyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 4-methylisoxazol-5-yl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, pyrimidin-5-yl, pyridazinyl (e.g., 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (e.g., 5-tetrazolyl), triazolyl (e.g., 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl, pyrazolyl (e.g., 2-pyrazolyl), isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazol-2-yl, pyrazinyl, pyrazin-2-yl, 1,3,5-triazinyl; and the following bicyclic rings, but are not limited to these bicyclic rings: benzimidazolyl, benzofuranyl, benzothiophenyl, indolyl (e.g., 2-indolyl), purinyl, quinolinyl (e.g., 2-quinolinyl, 3-quinolinyl, 4-quinolinyl), and isoquinolinyl (e.g., 1-isoquinolinyl, 3-isoquinolinyl, or 4-isoquinolinyl), benzo[d]thiazol-2-yl, imidazo[l,5-a]pyridin-6-yl.

[0114] The term "heteroatom" means one or more O, S, N, P and Si atoms, including forms of N, S and P in any oxidation state; forms of primary, secondary, tertiary amines and quaternary ammonium salts; or forms in which the hydrogen on a nitrogen atom in a heterocycle is replaced by substitution, e.g., N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR (as in N-substituted pyrrolidinyl).

[0115] The term "halogen" means F, Cl, Br or I.

[0116] The term "halo" as used herein means one or more halogen atoms.

[0117] The term "hydroxy" as used herein means one or more hydroxyl groups.

[0118] The term "substituted" when used between two groups means that the group preceding the substituent is substituted with the group following the substituent, e.g., "aryl substituted alkyl" means that the alkyl group is substituted with an aryl group, "alkoxycarbonyl substituted alkyl" means that the alkyl group is substituted with an alkoxycarbonyl group.

[0119] When multiple groups of the present application are used in conjunction, the substituent relationships proceed from left to right, e.g., "arylalkyl" indicates an aryl group substituted on the alkyl group, "alkoxyalkyl" indicates an alkoxy group substituted on the alkyl group.

[0120] The term "unsaturated" as used herein refers to a moiety containing one or more degrees of unsaturation.

[0121] Description of the compounds of the present application

[0122] In a first aspect, the present application provides a compound having a structure according to Formula (I), or a stereoisomer, tautomer, N-oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug of the structure of Formula (I),

[0123] wherein R 1 is H, alkyl, haloalkyl, heteroalkyl or cycloalkyl;

[0124] R 2 , R 3 , R 4 , R 5 , R 6 , R 8 , R 9 , R 10 , R 12 and R 13 are each independently hydrogen, deuterium, halogen, hydroxyl, amino, cyano, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkylalkyl, alkoxy, alkoxyalkyl, hydroxyalkyl or cycloalkyl;

[0125] R 7 is hydrogen, deuterium, halogen, hydroxyl, amino, cyano, alkyl, haloalkyl, heteroalkyl, cycloalkylalkyl, alkoxyalkyl, hydroxyalkyl, cycloalkyl, -N(R a R b ) or -OR 16 ; R 16 is alkyl, haloalkyl, heteroalkyl, cycloalkylalkyl, alkoxy, alkoxyalkyl, hydroxyalkyl or cycloalkyl; R a and R b are each independently selected from hydrogen, alkyl, haloalkyl, hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl, haloalkylalkyl, alkenylalkyl, alkynylalkyl;

[0126] Optionally, R 3 , R 8 and the carbon atom to which they are attached together form a 5-7 membered carbocyclic ring or a 5-7 membered heterocyclic ring;

[0127] Optionally, R 8 , R 13together with the carbon atom to which they are attached form a 3-7 membered nitrogen-containing heterocycloalkyl ring;

[0128] R 14 and R 15 are each independently hydrogen, deuterium, alkyl, or halogen; or R 14 , R 15 together with the carbon atom to which they are attached form C(=0);

[0129] A is -(CH2) m -S-R 11 , heterocycloalkyl, cycloalkyl, aryl, heteroaryl, or -S(F)5;

[0130] R 11 is hydrogen, deuterium, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkylalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl;

[0131] m is 0, 1, 2, 3, 4, or 5;

[0132] n is 0, 1, 2, or 3;

[0133] 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 , R 16 , R a , and R b the alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, hydroxyalkyl, alkoxy, alkoxyalkyl, cycloalkylalkyl, cycloalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl in R

[0134] In some embodiments, the compound is wherein R 1 is H, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 heteroalkyl, or C 3-8 cycloalkyl. In some embodiments, the compound is wherein R 1 is H or C1-6 alkyl.

[0135] In some embodiments, the compound is of Formula (I), wherein R 4 , R 5 , R 9 and R 12 are each independently hydrogen, deuterium, halogen, hydroxyl, amino, cyano, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 heteroalkyl, C 3-8 cycloalkyl C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxy C 1-6 alkyl, C 1-6 hydroxyalkyl, or C 3-8 cycloalkyl. In some embodiments, the compound is of Formula (I), wherein R 4 , R 5 , R 9 and R 12 are each independently hydrogen, deuterium, halogen, hydroxyl, amino, cyano, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 alkoxy C 1-4 alkyl, C 1-4 hydroxyalkyl, or C 3-6 cycloalkyl.

[0136] In some embodiments, the compound is of Formula (I), wherein R 7 is hydrogen, deuterium, halogen, hydroxyl, amino, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 heteroalkyl, C 3-8 cycloalkyl C 1-6 alkyl, C 1-6 alkoxy C 1-6 alkyl, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, -N(R a R b ), or -OR 16 ; R a and R b are each independently selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl C 1-6 alkyl, C 1-6 alkoxy C1-6 alkyl, C 1-6 haloalkyl C 1-6 alkyl, C 2-6 alkenyl C 1-6 alkyl, C 2-6 alkynyl C 1-6 alkyl; R 16 is C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 heteroalkyl, C 3-8 cycloalkyl C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxy C 1-6 alkyl, C 1-6 hydroxyalkyl or C 3-8 cycloalkyl. In some embodiments, R 16 is C 1-6 alkyl, C 3-8 cycloalkyl C 1-6 alkyl or C 3-8 cycloalkyl.

[0137] In some embodiments, the compounds described herein, R 1 , R 4 , R 5 , R 7 , R 9 , R 12 , R 16 , R a , and R b , the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 heteroalkyl, C 3-8 cycloalkyl C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxy C 1-6 alkyl, C 1-6 hydroxyalkyl or C 3-8 cycloalkyl are independently optionally substituted with 1, 2, 3, or 4 substituents selected from deuterium, F, Cl, Br, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl.

[0138] In some embodiments, the compounds described herein, R 1 is H, methyl, ethyl, n-propyl, i-propyl, t-butyl. In some embodiments, R1 H.

[0139] In some embodiments, the compound is of Formula (I), wherein R 7 is hydrogen, deuterium, -N(R a ) or -OR b ; R 16 ; R a and R b are each independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or t-butyl; R 16 is methyl, ethyl, n-propyl, isopropyl, t-butyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some specific embodiments, R 16 is methyl, ethyl, n-propyl, isopropyl, or t-butyl. In some embodiments, R 16 is methyl.

[0140] In some embodiments, the compound is of Formula (I), wherein R 4 , R 5 , R 9 and R 12 are each independently hydrogen, deuterium, F, Cl, Br, I, hydroxyl, amino, cyano, methyl, ethyl, n-propyl, isopropyl, ethenyl, propenyl, allyl, ethynyl, propynyl, propargyl, cyclopropyl-substituted C 1-3 alkyl, methoxy, ethoxy, n-propoxy, isopropoxy, methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, methoxy-n-propyl, methoxy-i-propyl, ethoxypropyl, ethoxy-i-propyl, i-propoxy-methyl, i-propoxy-ethyl, n-propoxy-methyl, propoxy-ethyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In other embodiments, the compound is of Formula (I), wherein R 4 , R 5 , R 9 and R 12 are each independently hydrogen, deuterium, methyl, ethyl, propyl, or isopropyl. In other embodiments, the compound is of Formula (I), wherein R 4 , R 5 , R 9 and R 12 are each independently hydrogen or deuterium. In some embodiments, R 4 , R 5 , R 9 and R 12 are each hydrogen.

[0141] In some embodiments, the compound is of Formula (I), wherein R 1 , R 4 , R 5 , R 9 , R 12, R 16 , R a , and R b in methyl, ethyl, n-propyl, isopropyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, cyclopropyl 1-3 , methoxy, ethoxy, n-propoxy, isopropoxy, methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, methoxy-n-propyl, methoxyisopropyl, ethoxypropyl, ethoxyisopropyl, isopropoxymethyl, isopropoxyethyl, n-propoxymethyl, propoxyethyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl is independently optionally substituted with 1, 2, 3, or 4 substituents selected from deuterium, F, Cl, Br, amino, hydroxyl, cyano, nitro, C 1-3 , alkyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0142] In some embodiments, the compound has the structure of Formula (II), or is a stereoisomer, tautomer, N-oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug of a compound of Formula (II),

[0143] R 2 , R 3 , R 6 , R 8 , R 10 , R 13 , R 14 , R 15 , R 16 , R a , R b , A, n are defined as in Formula (I).

[0144] In some embodiments, the compound has the structure of Formula (II), or is a stereoisomer, tautomer, N-oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug of a compound of Formula (II), 16 is C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 heteroalkyl, C 3-8 cycloalkyl C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxy C 1-6 alkyl, C 1-6 hydroxyalkyl, or C 3-8 cycloalkyl, R 16 is C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 heteroalkyl, C 3-8 cycloalkyl C 1-6 alkyl, C 1-6 alkoxy, C1-6 alkoxy C 1-6 alkyl, C 1-6 hydroxyalkyl or C 3-8 cycloalkyl is optionally substituted with 1, 2, 3, or 4 substituents selected from deuterium, F, Cl, Br, amino, hydroxyl, cyano, nitro, C 1-3 alkyl or C 3-6 cycloalkyl.

[0145] In some embodiments, the compound is of Formula (I), wherein R 16 is C 1-6 alkyl, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl C 1-6 alkyl or C 3-6 cycloalkyl. In some embodiments, the compound is of Formula (I), wherein R 16 is C 1-6 alkyl, C 1-6 alkyl. In some embodiments, the compound is of Formula (I), wherein R 16 is C 1-3 alkyl, C 1-3 alkyl. In some embodiments, the compound is of Formula (I), wherein R 16 is methyl, ethyl, n-propyl, isopropyl, methyl substituted with 1, 2, or 3 deuterium, ethyl substituted with 1, 2, 3, or 4 deuterium, propyl substituted with 1, 2, 3, or 4 deuterium, isopropyl substituted with 1, 2, 3, or 4 deuterium. In some embodiments, R 16 is methyl, methyl substituted with 1, 2, or 3 deuterium.

[0146] In some embodiments, the compound is of Formula (I), wherein R 2 , R 3 , R 6 , R 8 , R 10 , and R 13 are each independently hydrogen, deuterium, halogen, hydroxyl, amino, cyano, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 heteroalkyl, C 3-6 cycloalkyl C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxy C 1-6 alkyl, C 1-6 hydroxyalkyl or C 3-6Cycloalkyl. In some embodiments, R in the compound. 2 R 3 R 6 R 8 R 10 and R 13 Each is independently hydrogen, deuterium, and C. 1-6 Alkyl, C 3-6 cycloalkyl C 1-6 Alkyl or C 3-6 Cycloalkyl.

[0147] In some embodiments, R in the compound 14 and R 15 Each is independently hydrogen, deuterium, and C. 1-6 Alkyl or halogen; or R 14 R 15 Together with the carbon atom it is attached to, it forms C (=O).

[0148] In some embodiments, R in the compound 14 and R 15 Each is independently hydrogen or deuterium; or R 14 R 15 Together with the carbon atom it is attached to, it forms C (=O).

[0149] In some embodiments, R in the compound 2 R 3 R 6 R 8 R 10 R 13 R 14 and R 15 The C mentioned in 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Heteroalkyl, C 3-6 cycloalkyl C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Hydroxyalkyl or C 3-6 The cycloalkyl group is independently and optionally surrounded by 1, 2, 3 or 4 groups selected from deuterium, F, Cl, Br, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 Substituents of cycloalkyl groups.

[0150] In some embodiments, R in the compound 3 R 8 Together with the carbon atom attached thereto, it forms a 5, 6, or 7-membered carbon ring. In some embodiments, in the compound, R 3 R 8 Together with the carbon atom attached to it, they form 5, 6, or 7-membered heterocycles.

[0151] In some embodiments, R in the compound 8 R 13 Together with the carbon atom attached to it, they form 5, 6, or 7-membered nitrogen heterocycles.

[0152] In some embodiments, R in the compound 2 R 3 R 6 R 8 R 10 and R 13 Each of the following C groups is independently substituted with hydrogen, deuterium, F, Cl, Br, I, hydroxyl, amino, cyano, methyl, ethyl, n-propyl, isopropyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, or cyclopropyl. 1-3 Alkyl, methoxy, ethoxy, n-propoxy, isopropoxy, methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, methoxyn-propyl, methoxyisopropyl, ethoxypropyl, ethoxyisopropyl, isopropoxymethyl, isopropoxyethyl, n-propoxymethyl, propoxyethyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0153] In some embodiments, R in the compound 14 and R 15 Each is independently hydrogen, deuterium, and C. 1-3 Alkyl (e.g., methyl, ethyl, n-propyl, isopropyl), F, Cl, or Br; or R 14 R 15 Together with the carbon atom it is attached to, it forms C (=O).

[0154] In some embodiments, R in the compound 2 R 3 R 6 R 8 R 10 R 13 R 14 and R 15 The C-substituted compounds described herein are methyl, ethyl, n-propyl, isopropyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, and cyclopropyl. 1-3Alkyl, methoxy, ethoxy, n-propoxy, isopropoxy, methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, methoxyn-propyl, methoxyisopropyl, ethoxypropyl, ethoxyisopropyl, isopropoxymethyl, isopropoxyethyl, n-propoxymethyl, propoxyethyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl are independently and optionally separated by 1, 2, 3, or 4 elements selected from deuterium, F, Cl, Br, amino, hydroxyl, cyano, nitro, C 1-3 It is substituted by alkyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl substituents.

[0155] In some embodiments, A in the compound is -(CH2). m -SR 11 C 1-9 Heterocyclic group, C 3-6 cycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl or -S(F)5; m is 0, 1, 2, 3, 4 or 5; R 11 For hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 3-6 cycloalkyl C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 1-9 Heterocyclic group, C 1-9 Heterocyclic C 1-6 Alkyl, C 6-10 Aryl, C 6-10 Aryl C 1-6 Alkyl, C 1-9 heteroaryl or C 1-9 heteroaryl C 1-6 Alkyl; the C 1-6 Alkyl, C 3-6 cycloalkyl C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 1-9 Heterocyclic C 1-6 Alkyl, C 6-10 Aryl, C 6-10 Aryl C 1-6 Alkyl, C 1-9 heteroaryl or C 1-9 heteroaryl C 1-6alkyl is independently optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of deuterium, F, CI, Br, amino, hydroxyl, cyano, C 1-3 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C m alkyl, C 11 alkenyl, C m alkynyl, C 11 In some embodiments, m is 0, 1, 2, 3, or 4. In some embodiments, m is 0, 1, 2, or 3. In some embodiments, m is 0, 1, or 2. In some embodiments, m is 0 or 1. In some embodiments, m is 0.

[0156] In some embodiments, the compound is 11 hydrogen, deuterium, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy C 1-3 alkyl, C 3-6 cycloalkyl C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, C 1-4 heterocyclyl, C 2-6 heterocyclyl C 1-3 alkyl, phenyl, phenyl C 1-3 alkyl, C 3-6 heteroaryl, or C 3-6 heteroaryl C 1-3 alkyl; said C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, C 1-4 heterocyclyl, C 2-6 heterocyclyl C 1-3 alkyl, phenyl, phenyl C 1-3 alkyl, C 3-6 heteroaryl, or C 3-6 heteroaryl C 1-3 alkyl is independently optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of deuterium, F, CI, Br, amino, hydroxyl, cyano, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, C

[0157] In some embodiments, the compound has a structure according to Formula (III), (III'), (IV), (IV'), (V), (V'), or (VI), or is a stereoisomer, tautomer, nitroso, solvate, metabolite, pharmaceutically acceptable salt, or prodrug of a structure according to Formula (III), (III'), (IV), (IV'), (V), (V'), or (VI),

[0158] wherein R 2 , R 3 , R 6 , R 8 , R 10 , R 11 , R 14 , R 15 , R 16 , R a , R b are defined as in Formula (I), Formula (II), Formula (II'), and X is a bond, O, NR 17 , or CR 18 R 19 ; R 17 is H, C 1-6 alkyl, C 1-6 deuteroalkyl, or C 1-6 haloalkyl; R 18 and R 19 are each independently hydrogen, deuterium, halogen, C 1-6 alkyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, 3-6 membered cycloalkyl, or 3-7 membered heterocyclyl; and n is 0, 1, 2, or 3.

[0159] In some embodiments, in Formula (III), (III'), (IV), (IV'), (V), (V'), and (VI), R 2 , R 3 , R 6 , R 8 , and R 10 are each independently hydrogen, deuterium, halogen, hydroxyl, amino, cyano, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 heteroalkyl, C 3-6 cycloalkyl C 1-6 alkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, or C 3-6 haloalkyl.cycloalkyl. In some embodiments, the compound is one wherein R 2 , R 3 , R 6 , R 8 , and R 10 are each independently hydrogen, deuterium, or C 1-6 alkyl.

[0160] In some embodiments, R 2 , R 3 , R 6 , R 8 , and R 10 are each independently hydrogen, deuterium, or C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 heteroalkyl, C 3-6 cycloalkyl C 1-6 alkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, or C 3-6 cycloalkyl is independently optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of deuterium, F, Cl, Br, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 3-6 cycloalkyl.

[0161] In some embodiments, R 11 is hydrogen, deuterium, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy C 1-6 alkyl, C 3-6 cycloalkyl C 1-6 alkyl, C 3-6 cycloalkyl, C 1-9 heterocyclyl, C 1-9 heterocyclyl C 1-6 alkyl, C 6-10 aryl, C 6-10 aryl C 1-6 alkyl, C 1-9 heteroaryl, or C 1-9 heteroaryl C 1-6 alkyl. In some embodiments, the compound is one wherein R 11 is hydrogen, deuterium, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 3-6 cycloalkyl C 1-6alkyl or C 3-6 cycloalkyl. In some embodiments, in the compounds described herein, R 11 is hydrogen, deuterium, C 1-6 alkyl, C 1-6 haloalkyl.

[0162] In some embodiments, in formula (III), (III'), (IV), (IV'), (V), (V'), and (VI), R 11 is C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 alkyl, C 3-6 cycloalkyl C 1-6 alkyl, C 3-6 cycloalkyl, C 1-9 heterocyclyl, C 1-9 heterocyclyl C 1-6 alkyl, C 6-10 aryl, C 6-10 aryl C 1-6 alkyl, C 1-9 heteroaryl or C 1-9 heteroaryl C 1-6 alkyl is independently optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of deuterium, F, Cl, Br, amino, hydroxyl, cyano, C 1-3 alkyl, C 3-6 cycloalkyl.

[0163] In some embodiments, in formula (III), (III'), (IV), (IV'), (V), (V'), and (VI), R 14 and R 15 are each independently hydrogen, deuterium, C 1-6 alkyl, F, Cl, or Br; or R 14 , R 15 and the carbon atom to which they are attached together form C(=0).

[0164] In some embodiments, in formula (III), (III'), (IV), (IV'), (V), (V'), and (VI), R 16 is C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 heteroalkyl, C 3-8 cycloalkyl C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxy C 1-6 alkyl, C 1-6 hydroxyalkyl or C3-8 cycloalkyl. In some embodiments, in formula (III), (III'), (IV), (IV'), (V), (V'), and (VI), R 16 is C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl C 1-6 alkyl or C 3-6 cycloalkyl. In some embodiments, in formula (III), (III'), (IV), (IV'), (V), (V'), and (VI), R 16 is optionally substituted with 1, 2, 3, or 4 substituents selected from deuterium, F, Cl, Br, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, or C 3-6 cycloalkyl.

[0165] In some embodiments, in formula (V) or (V'), X is a bond, O, NR 17 or CR 18 R 19 ; R 17 is H, C 1-3 alkyl, C 1-3 deuteroalkyl, C 1-3 haloalkyl; R 18 and R 19 are each independently hydrogen, deuterium, F, Cl, Br, C 1-3 alkyl, C 1-3 deuteroalkyl, C 1-3 haloalkyl, 3-6 membered cycloalkyl, or 3-7 membered heterocyclyl.

[0166] In some embodiments, in formula (III), (III'), (IV), (IV'), (V), (V'), and (VI), n is 1.

[0167] In some embodiments, in formula (III), (III'), (IV), (IV'), (V), (V'), and (VI), R 2 , R 3 , R 6 , R 8 and R 10 are each independently hydrogen, deuterium, halogen, hydroxyl, amino, cyano, methyl, ethyl, n-propyl, i-propyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, C 1-3 alkyl substituted with cyclopropyl, methoxy, ethoxy, n-propoxy, i-propoxy, hydroxymethyl, hydroxyethyl, hydroxypropyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; said methyl, ethyl, n-propyl, i-propyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, C1-3 alkyl, methoxy, ethoxy, n-propoxy, isopropoxy, hydroxymethyl, hydroxyethyl, hydroxypropyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl is independently optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of deuterium, F, CI, Br, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl are substituted with 1, 2, 3, or 4 substituents selected from the group consisting of deuterium, F, CI, Br, amino, hydroxyl, cyano, nitro, C

[0168] In some embodiments, in formula (III), (III'), (IV), (IV'), (V), (V'), and (VI), R 11 is hydrogen, deuterium, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxyC 1-3 alkyl, C 3-6 cycloalkylC 1-3 alkyl, C 3-6 cycloalkyl, C 1-4 heterocyclyl, C 1-4 heterocyclylC 1-3 alkyl, phenyl, phenylC 1-3 alkyl, C 1-6 heteroaryl, or C 1-6 heteroarylC 1-6 alkyl. In other embodiments, in formula (III), (III'), (IV), (IV'), (V), (V'), and (VI), R 11 is C 1-3 alkyl. In other embodiments, R 11 is described above for C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxyC 1-3 alkyl, C 3-6 cycloalkylC 1-3 alkyl, C 3-6 cycloalkyl, C 1-4 heterocyclyl, C 1-4 heterocyclylC 1-3 alkyl, phenyl, phenylC 1-3 alkyl, C 1-6 heteroaryl, or C 1-6 heteroarylC 1-6 alkyl is independently optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of deuterium, F, CI, Br, amino, hydroxyl, cyano, C 1-3 alkyl, C 3-6 cycloalkyl.

[0169] In some embodiments, in formula (III), (III'), (IV), (IV'), (V), (V'), and (VI), each R 14 and R 15 is independently hydrogen, deuterium, C 1-3 alkyl, F, CI, or Br; or R 14 , R 15 and the carbon atom to which they are attached form C(=0).

[0170] In some embodiments, in formula (III), (III'), (IV), (IV'), (V), (V'), and (VI), each R 16 is independently C 1-6 alkyl or C 1-6 alkyl substituted with 1, 2, 3, or 4 deuterium. In other embodiments, in formula (III), (III'), (IV), (IV'), (V), (V'), and (VI), each R 16 is independently C 1-6 alkyl or C 1-3 alkyl substituted with 1, 2, 3, or 4 deuterium.

[0171] In some embodiments, in formula (III), (III'), (IV), (IV'), (V), (V'), and (VI), X is a bond or CR 18 R 19 ; R 18 and R 19 are each independently H, methyl, ethyl, propyl, C 1-3 alkyl substituted with 1, 2, or 3 deuterium, C 1-3 alkyl substituted with 1, 2, or 3 fluorine.

[0172] In some embodiments, the compound has a structure according to formula (I-1), (I-2), (I-3), (I-4), (I-5), (I-6), (I-7), (I-8), (I-9), (I-10), (I-11), (I-12), (I-13), (I-14), or a stereoisomer, tautomer, nitroso, solvate, metabolite, pharmaceutically acceptable salt, or prodrug of a structure according to formula (I-1), (I-2), (I-3), (I-4), (I-5), (I-6), (I-7), (I-8), (I-9), (I-10), (I-11), (I-12), (I-13), (I-14),

[0173] R 2 R 3 R 8 R 10 R 11 R 14 R 15 R 16 R a R b The definition is the same as that in the aforementioned equations (I), (II), (II'), (III), (III'), (IV), (IV'), (V), (V') and (VI).

[0174] In some embodiments, R in the compound 1 It is hydrogen.

[0175] In some embodiments, R in the compound 2 and R 3 Each is independently hydrogen, deuterium, and C. 1-3 Alkyl or deuterated C 1-3 Alkyl groups, such as hydrogen, deuterium, methyl, or deuterated methyl.

[0176] In some embodiments, R in the compound 4 and R 5 Each is independently either hydrogen or deuterium. In some embodiments, R 4 and R 5 Both are hydrogen.

[0177] In some embodiments, in the compound, each R 6 Independently for C 1-3 Alkyl or deuterated C 1-3 Alkyl groups, such as methyl or deuterated methyl groups.

[0178] In some embodiments, R in the compound 9 R 12 and R 13 Both are hydrogen.

[0179] In some embodiments, in the compound, each R 8 Independent of hydrogen, deuterium, and C 1-3 Alkyl or deuterated C 1-3 Alkyl groups, such as H, methyl, or deuterated methyl.

[0180] In some embodiments, in the compound, each R 10 Independent of hydrogen, deuterium, and C1-3 alkyl or deuterated C 1-3 alkyl, for example hydrogen or deuterium.

[0181] In some embodiments, the compound has the structure: 11 independently C 1-3 alkyl, C 1-3 haloalkyl, C 3-6 cycloalkyl, C 1-4 heterocyclyl, or deuterated C 1-3 alkyl, for example methyl, trifluoromethyl, deuterated methyl, cyclopropyl, cyclobutyl, oxiranyl, or oxetanyl.

[0182] In some embodiments, the compound has the structure: 14 and R 15 each independently hydrogen or deuterium; or R 14 , R 15 and the carbon atom to which they are attached together form C(=0).

[0183] In some embodiments, the compound has the structure: 16 independently C 1-3 alkyl, deuterated C 1-3 alkyl, fluoroC 1-3 alkyl, for example methyl, deuterated methyl, or fluoroC

[0184] In some embodiments, R a and R b each independently is selected from hydrogen, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, or t-butyl.

[0185] In some embodiments, the compound has the structure:

[0186] Compositions, formulations, and administration of compounds of the present invention

[0187] The pharmaceutical composition comprises any one of the compounds of the present invention. The pharmaceutical composition can further comprise a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle, or a combination thereof.

[0188] Substances which can serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylate, waxes, polyethylene-polyoxypropylene- block polymers, wool fat, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols such as propylene glycol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol, phosphate buffer solutions and other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, coloring agents, releasing agents, coating agents, sweetening agents, flavoring agents, and perfuming agents, preservatives and antioxidants.

[0189] When used in therapy, therapeutically effective amounts of the compounds of the present application can be administered as the neat chemical, or as the active ingredient in a pharmaceutical composition. Accordingly, the present application also provides pharmaceutical compositions which include a therapeutically effective amount of a compound of the present application, and one or more pharmaceutically acceptable carriers, diluents or excipients. The term "therapeutically effective amount" as used herein means the total amount of each active component that is sufficient to yield a meaningful patient benefit, e.g., reduction in viral load. When applied to an individual active ingredient, the term refers to that ingredient alone. When applied to a combination, the term refers to combined amounts of the active ingredients that result in the therapeutic effect, whether administered individually or together. The carrier(s), diluent(s) or excipient(s) must be acceptable in the sense of being compatible with the other ingredients of the formulation and not injurious to the subject. In accordance with another aspect of the present application, there is also provided a method for preparing a pharmaceutical formulation, which method comprises bringing into association a compound of the present application and one or more pharmaceutically acceptable carriers, diluents or excipients. The term "pharmaceutically acceptable" as used herein refers to compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of patients without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit / risk ratio, and effective for their intended use.

[0190] It will be appreciated that, in addition to ingredients particularly mentioned herein, formulations can include other agents conventional in the art for use in formulating pharmaceutical compositions, for example, those suitable for oral administration can include flavoring agents.

[0191] Use of the compounds and compositions of the present invention

[0192] The present invention provides use of a compound or pharmaceutical composition described herein in the manufacture of a medicament for preventing, treating, ameliorating or modulating a disease associated with or mediated by complement Factor B.

[0193] The diseases described herein include, but are not limited to, one or more of the following: glomerulopathy, hemolytic uremic syndrome, atypical hemolytic uremic syndrome, paroxysmal nocturnal hemoglobinuria, age-related macular degeneration, geographic atrophy, diabetic retinopathy, uveitis, retinitis pigmentosa, macular edema, uveitis caused by Behcet’s syndrome, multifocal choroiditis, Vogt-Koyanagi-Harada syndrome, birdshot retinochoroiditis, sympathetic ophthalmia, ocular cicatricial pemphigoid, ocular pemphigus, non-arteritic ischemic optic neuropathy, post-surgical inflammation, retinal vein occlusion, neurological disorders, multiple sclerosis, stroke, Guillain-Barre syndrome, traumatic brain injury, Parkinson’s disease, inappropriate or undesirable complement activation disorders, hemodialysis complications, hyperacute allograft rejection, xenograft rejection, interleukin-2 induced toxicity during IL-2 therapy, Crohn’s disease, adult respiratory distress syndrome, myocardial inflammation, post-ischemic reperfusion disorders, myocardial infarction, post-pump syndrome in balloon angioplasty, cardiopulmonary bypass surgery or renal bypass surgery, atherosclerosis, hemodialysis, renal ischemia, aortic reconstruction, mesenteric arterial reperfusion following infectious disease or sepsis, systemic lupus erythematosus, systemic lupus erythematosus nephritis, proliferative nephritis, liver fibrosis, hemolytic anemia, myasthenia gravis, tissue regeneration, nerve regeneration, dyspnea, hemoptysis, acute respiratory distress syndrome, asthma, chronic obstructive pulmonary disease, emphysema, pulmonary embolism and infarction, pneumonia, fibrosis-causing dust diseases, pulmonary fibrosis, asthma, allergy, bronchoconstriction, parasitic diseases, Goodpasture’s syndrome, pulmonary vasculitis, pauci-immune vasculitis, immune complex-related inflammation, anti-phospholipid syndrome, and obesity; more preferably in the manufacture of a medicament for treating and / or preventing age-related macular degeneration, geographic atrophy, diabetic retinopathy, uveitis, retinitis pigmentosa, macular edema, uveitis caused by Behcet’s syndrome, multifocal choroiditis, birdshot retinochoroiditis, sympathetic ophthalmia, ocular cicatricial pemphigoid, ocular pemphigus, non-arteritic ischemic optic neuropathy, post-surgical inflammation, retinal vein occlusion, C3 glomerulopathy, immunoglobulin A nephropathy, membranous glomerulonephritis, atypical hemolytic uremic syndrome (aHUS), and paroxysmal nocturnal hemoglobinuria (PNH).

[0194] An "effective amount" or "effective dose" of a compound or pharmaceutically acceptable composition of the present application means an amount effective at treating or lessening the severity of one or more of the disorders contemplated by the present application. Compounds and compositions thereof according to the present application can be used in any amount and by any route of administration effective to treat or lessen the severity of the disease. The exact amount required will vary depending on the subject's condition, age, general condition, severity of infection, special factors, mode of administration, and the like. Compounds or compositions of the present application can be administered in combination with one or more other therapeutic agents, as discussed herein.

[0195] In order to better understand the technical solutions of the present application, some non- limiting examples are further disclosed below to further illustrate the present application in detail.

[0196] General synthetic procedures

[0197] In general, compounds of the present application can be prepared by the methods described herein. The following reaction schemes and examples are intended to further illustrate the present application.

[0198] One skilled in the art will recognize that the chemical reactions described herein can be used to prepare many of the other compounds of the present application and that the other methods for preparation can be applicable to the synthesis of the compounds of the present application. For example, the synthesis of those non-exemplified compounds according to the present application can be successfully performed by modifications apparent to those skilled in the art, by analogy with the procedures described herein or with other known reactions. Also, other reactions disclosed herein or known in the art will be recognized as being applicable to the synthesis of other compounds of the present application.

[0199] Unless otherwise indicated, all temperatures are set forth in degrees Celsius. Reagents were purchased from commercial suppliers such as Aldrich, Acros, Maybridge, Biotrend, Aladdin, Acros, Aldrich Chemical Company, Inc., Arco Chemical Company and Alfa Chemical Company, and used without further purification, unless otherwise indicated. General reagents were purchased from Shantou Xilong Chemical Factory, Guangdong Guanghua Reagent Company, Guangzhou Reagent Factory, Tianjin Haoguoyu Chemicals Co. Ltd., Qingdao Tenglong Chemical Reagent Co. Ltd., and Qingdao Haoyan Chemical Factory.

[0200] Anhydrous tetrahydrofuran, dioxane, toluene, diethyl ether were dried over sodium metal. Anhydrous dichloromethane and chloroform were dried over calcium hydride. Ethyl acetate, petroleum ether, n-hexane, N,N-dimethylacetamide and N,N-dimethylformamide were used as received.

[0201] The following reactions were generally performed under an atmosphere of nitrogen or argon at positive pressure or under anhydrous conditions in a dry box (unless otherwise stated), reaction vessels were fitted with a suitable rubber septum and substrates were introduced via syringe. Glassware was oven- or flame-dried.

[0202] Chromatography columns were run using silica gel. Silica gel (300-400 mesh) was purchased from Qingdao Marine Chemical Plant. NMR spectra were recorded in CDC13, d6-DMSO, CD3OD or d6-acetone as solvent (reported in ppm) with TMS (0 ppm) or chloroform (7.25 ppm) as reference standard. When multiplets were present, the following abbreviations were used: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broadened), dd (doublet of doublets), dt (doublet of triplets). Coupling constants are expressed in Hertz (Hz).

[0203] Low resolution mass spectrometry (MS) data were determined by LC-MS spectrometer of Shimadzu LCMS-2020 series or LCMS-2050 series equipped with LC-20ADXR quaternary pump and CTO-20A (column temperature was kept at 40 °C), SIL-20ACXR autosampler and SPD-M40 PDA detector were applied for analysis, ESI source was applied for LC-MS spectrometer.

[0204] The following abbreviations are used throughout the application:

[0205] AcOH: acetic acid; Boc20, BOC anhydride: di-tert-butyl dicarbonate; Boc: tert- butyloxycarbonyl; Bu4NHS04: tetra-n-butylammonium hydrogen sulfate; CH3CN: acetonitrile; DCM: dichloromethane; DIPEA: N,N-diisopropylethylamine; EA: ethyl acetate; HC1: hydrogen chloride; HC1 / EA: ethyl acetate solution of hydrogen chloride; H20: water; NaOH: sodium hydroxide; Nal: sodium iodide; K2C03: potassium carbonate; rt, r.t.: room temperature; PE: petroleum ether; THF: tetrahydrofuran; EDCI: l-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride; DMAP: 4-dimethylaminopyridine; TBAI: tetrabutylammonium iodide; DMF: dimethylformamide; p-TsOH: p-toluenesulfonic acid; TAF: trifluoroacetic acid; TBAF: tetrabutylammonium fluoride;

[0206] Example

[0207] Preparation of intermediate 1a: (S)-6-(4-(methoxycarbonyl)phenyl)-2-oxo-7- azaspiro[3.5]non-7-carboxylic acid benzyl ester (intermediate 1a)

[0208] First step: Preparation of (S)-benzyl 2-(4-(methoxycarbonyl)phenyl)-4- oxopiperidine-1-carboxylate (1a-c)

[0209] tert-Amyl alcohol (400 mL), water (40 mL) were added into a 1 L three-necked flask at room temperature 25 °C, compound 1a-a (25.0 g, 108.1 mmol), compound 1a-b (48.6 g, 270.3 mmol), triethylamine (45 mL, 324.3 mmol), (S)-2,2'-bis[di(3,5-dimethylphenyl)phosphino]-1,1'- binaphthyl (1.6 g, 2.2 mmol), acetylacetonato bis(ethyl ene) rhodium (I) (0.6 g, 2.2 mmol) were added successively, replaced with nitrogen for three times, reacted at 100 °C for 18 h. After the reaction was completed, it was cooled to room temperature, filtered, the filtrate was concentrated under reduced pressure, purified by silica gel column (ethyl acetate: petroleum ether = 1:5) to obtain compound 1a-c (28.4 g, brown oil). LC-MS m / z (ESI) = 368.2 [M+H] + .

[0210] Second step: Preparation of (S)-benzyl 2-(4-(methoxycarbonyl)phenyl)-4- methyleneazapiperidine-1-carboxylate (1a-d)

[0211] Methyltriphenylphosphonium bromide (14.5 g, 40.8 mmol) was added to a 250 mL two-necked flask, 100 mL THF was added, and the flask was protected by nitrogen replacement. The mixture was stirred in an ice bath for 10 min, and then potassium bis(trimethylsilyl)amide (9.8 g, 48.9 mmol) was slowly added dropwise. The mixture was stirred for another half hour, and then a solution of compound 1a-c (10.0 g, 27.2 mmol) in super dry THF (20 mL) was slowly added dropwise. The mixture was stirred at room temperature for 10 min, and then quenched by the addition of saturated ammonium chloride (50 mL). The mixture was diluted with ethyl acetate (200 mL), and then washed with saturated sodium chloride (200 mL) three times. The organic phase was concentrated under reduced pressure. Purification was performed by silica gel column chromatography (ethyl acetate: petroleum ether = 2:5) to give compound 1a-d (5.5 g, yellow oil). LC-MS m / z (ESI) = 366.4 [M+H] + .

[0212] Step 3: Preparation of (6S)-1,1-dichloro-6-(4-(methoxycarbonyl)phenyl)-2-oxo-7- azaspiro[3.5]nonane-7-carboxylic acid benzyl ester (1a-e)

[0213] Compound 1a-d (5.5 g, 15.0 mmol) and zinc-copper reagent (19.4 g, 150.5 mmol) were added to a 250 mL two-necked flask, and 90 mL super dry 1,4-dioxane was added. The mixture was protected by nitrogen replacement, and then trichloroacetyl chloride (27.4 g, 150.5 mmol) was slowly added dropwise. The mixture was stirred at room temperature for half an hour. The mixture was diluted with ethyl acetate (100 mL), and then the pH was adjusted to 7 by the addition of saturated sodium carbonate. The mixture was filtered, and the filtrate was washed with saturated sodium chloride (200 mL) three times. The mixture was concentrated under reduced pressure to give compound 1a-e (brown oil), which was directly used in the next step. LC-MS m / z (ESI) = 476.5 [M+H] + .

[0214] Step 4: Preparation of (S)-6-(4-(methoxycarbonyl)phenyl)-2-oxo-7-azaspiro[3.5]nonane-7- carboxylic acid benzyl ester (intermediate 1a)

[0215] The crude product compound 1a-e from the previous step was added to a 250 mL single-necked flask, and 100 mL methanol was added. Ammonium chloride (8.0 g, 149.0 mmol) and zinc powder (9.7 g, 149.0 mmol) were added in sequence with stirring at room temperature. The mixture was stirred for 1 h, and then filtered. The filtrate was concentrated under reduced pressure, and then purified by silica gel column chromatography (ethyl acetate: petroleum ether = 3:10) to give intermediate 1a (4.7 g, yellow oil). LC-MS m / z (ESI) = 408.3 [M+H] + ; 1H NMR (500 MHz, CDC13) δ 8.05 - 7.97 (m, 2H), 7.41 - 7.27 (m, 7H), 5.65 (d, 1H), 5.22 - 5.14 (m, 2H), 4.46 - 4.36 (m, 1H), 3.96 - 3.89 (m, 3H), 3.16 (m, 1H), 2.95 - 2.75 (m, 2H), 2.53 - 2.43 (m, 1H), 2.41 - 2.31 (m, 2H), 2.28 - 2.20 (m, 1H), 1.90 (m, 1H), 1.73 - 1.65 (m, 1H) ppm.

[0216] Preparation of intermediate 1f: tert-butyl 4-formyl-5-methoxy-7-methyl-1H- indole-1-carboxylate (intermediate 1f)

[0217] First step: preparation of tert-butyl 5-methoxy-7-methyl-1H-indole-1- carboxylate (1f-b)

[0218] The starting material 1f-a (10 g, 62.04 mmol) was dissolved in dichloromethane (200 mL), and triethylamine (11.21 mL, 80.65 mmol), di-tert-butyl dicarbonate (17.6 g, 80.65 mmol), 4-dimethylaminopyridine (760 mg, 6.203 mmol) were added successively with stirring at room temperature, and stirring was continued for 2 h. The filtrate was concentrated under reduced pressure, and purification was performed on a silica gel column (ethyl acetate: petroleum ether = 1:10) to obtain compound 1f-b (15 g, yellow oil). LC-MS m / z (ESI) = 262.1 [M+H] + .

[0219] Second step: preparation of tert-butyl 4-formyl-5-methoxy-7-methyl-1H-indole-1- carboxylate (intermediate 1f)

[0220] Compound 1f-c (17.8 g, 132.02 mmol) was dissolved in dichloromethane (150 mL) and oxalyl chloride (16.76 g, 132.02 mmol) was added dropwise under nitrogen protection at room temperature. The reaction was allowed to react at room temperature for 18 h. The above reaction solution was slowly added dropwise to a mixture of dichloromethane (150 mL) and compound 1f-b (15 g, 57.4 mmol) at -15 °C, and the dropwise addition was continued at -15 °C for 1 h. 100 mL of water was slowly added to the system at -15 °C to quench the reaction, and the reaction was extracted twice with dichloromethane (300 mL). The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Purification on a silica gel column (ethyl acetate: petroleum ether = 1:10) gave intermediate 1f (11 g, white solid). LC-MS m / z (ESI) = 290.1 [M+H] + ; 1 H NMR (500 MHz, DMSO) δ 10.52 (s, 1H), 7.80 (d, J = 3.6 Hz, 1H), 7.31 (d, J = 3.6 Hz, 1H), 7.03 (s, 1H), 3.96 (s, 3H), 2.62 (s, 3H), 1.59 (s, 9H) ppm.

[0221] Preparation of intermediate 2: tert-butyl 4-(bromomethyl)-5-methoxy-7-methyl-1H- indole-1-carboxylate (intermediate 2)

[0222] First step: preparation of tert-butyl 4-(hydroxymethyl)-5-methoxy-7-methyl-1H- indole-1-carboxylate (2-b)

[0223] Methanol (100 mL) was added to a 500 mL single-necked flask at room temperature 25 °C, and compound 1f (5.0 g, 17.3 mmol) was added. Sodium borohydride (1.0 g, 26.0 mmol) was added portionwise under stirring at room temperature, and the reaction was continued for 10 min. After the reaction was completed, 50 mL of saturated ammonium chloride was added to quench the reaction, and the reaction was concentrated under reduced pressure. Purification on a silica gel column (ethyl acetate: petroleum ether = 1:5) gave compound 2-b (5.0 g, white solid). LC-MS m / z (ESI) = 292.2 [M+H] + Second step: preparation of tert-butyl 4-(bromomethyl)-5-methoxy-7-methyl-1H- indole-1-carboxylate (intermediate 2)

[0224] Into a 25 mL single necked flask, dry dichloromethane (2 mL) was added at room temperature 25 °C, compound 2-b (110 mg, 0.4 mmol) was added, triphenylphosphine (198 mg, 0.8 mmol), carbon tetrabromide (250 mg, 0.8 mmol) were added successively under stirring at room temperature, the reaction was continued for 2 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to get the crude intermediate 2 which was used directly for the next step.

[0225] Preparation of intermediate 3: tert-butyl 4-bromomethyl-5-(methoxy-d3)-7-methyl-1H- indole-1-carboxylate (intermediate 3)

[0226] First step: preparation of tert-butyl 4-formyl-5-(methoxy-d3)-7-methyl-1H-indole-1- carboxylate (3-b)

[0227] Into a 25 mL single necked flask, dry dichloromethane (2 mL) was added at room temperature 25 °C, compound 2-b (110 mg, 0.4 mmol) was added, triphenylphosphine (198 mg, 0.8 mmol), carbon tetrabromide (250 mg, 0.8 mmol) were added successively under stirring at room temperature, the reaction was continued for 2 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to get the crude intermediate 2 which was used directly for the next step. + ; 1 H NMR (500 MHz, CDCl3) δ 10.63 (s, 1H), 7.62 (d, 1H), 7.47 (d, 1H), 6.73 (s, 1H), 2.68 (s, 3H), 1.63 (s, 9H) ppm.

[0228] Second step: preparation of tert-butyl 4-hydroxymethyl-5-(methoxy-d3)-7-methyl-1H- indole-1-carboxylate (3-c)

[0229] Into a 25 mL single necked flask, dry dichloromethane (2 mL) was added at room temperature 25 °C, compound 2-b (110 mg, 0.4 mmol) was added, triphenylphosphine (198 mg, 0.8 mmol), carbon tetrabromide (250 mg, 0.8 mmol) were added successively under stirring at room temperature, the reaction was continued for 2 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to get the crude intermediate 2 which was used directly for the next step. + ;1 H NMR (500 MHz, CDC13) δ 7.53 (d, 1H), 6.74 (s, 1H), 6.61 (d, 1H), 4.89 (d, 2H), 2.63 (s, 3H), 1.62 (s, 9H) ppm.

[0230] Third Step: Preparation of 4-(Bromomethyl-d2)-5-methoxy-7-methyl-1H- indole-1-carboxylic acid tert-butyl ester (Intermediate 3)

[0231] Compound 3-c (120 mg, 0.407 mmol) was dissolved in 5 mL dry dichloromethane, cooled to 0 °C under nitrogen protection, triphenylphosphine (160 mg, 0.611 mmol), carbon tetrabromide (203 mg, 0.611 mmol) were added, stirring was continued at 0 °C for 40 minutes. The reaction solution was concentrated under reduced pressure to get the crude product of intermediate 3, which was used directly for the next step.

[0232] Intermediate 4: Preparation of 4-(Bromomethyl-d2)-5-methoxy-7-methyl-1H- indole-1-carboxylic acid tert-butyl ester (Intermediate 4)

[0233] First Step: Preparation of 1-(tert-Butoxycarbonyl)-5-methoxy-7-methyl-1H- indole-4-carboxylic acid (4-a)

[0234] Intermediate 1f (200 mg, 0.691 mmol) was dissolved in 5 mL tert-butyl alcohol and 5 mL tetrahydrofuran mixed solvent, 2-methyl-2-butene (967 mg, 13.8 mmol), sodium dihydrogen phosphate aqueous solution (663 mg, 5.52 mmol), sodium chlorite aqueous solution (125 mg, 1.38 mmol) were added in turn, and stirred at room temperature for 3 hours. 10 mL of water, 50 mL of ethyl acetate were added, and the organic layer was washed with 20 mL of saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel column (ethyl acetate: petroleum ether = 1:5) to obtain compound 4-a (170 mg, white solid). LC-MS m / z (ESI) = 306.0 [M+H] + ; 1 H NMR (500 MHz, CDC13) δ 7.53 (d, 1H), 6.74 (s, 1H), 6.61 (d, 1H), 4.89 (d, 2H), 2.63 (s, 3H), 1.62 (s, 9H) ppm.

[0235] Second Step: Preparation of 4-(Hydroxymethyl-d2)-5-methoxy-7-methyl-1H- indole-1-carboxylic acid tert-butyl ester (4-b)

[0236] Intermediate 4-a (170 mg, 0.557 mmol) was dissolved in 2 mL of dry tetrahydrofuran, CDI (100 mg, 0.612 mmol) was added, and the mixture was stirred at room temperature for 2 hours. Sodium borodeuteride (70 mg, 1.67 mmol) was dissolved in 5 mL of dry tetrahydrofuran and 1 mL of heavy water, and the resulting solution was slowly added to the above solution. After the addition was completed, the reaction was continued at room temperature for 20 minutes. Saturated ammonium chloride solution (10 mL) and ethyl acetate (30 mL) were added, and the mixture was separated. The organic layer was washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography (ethyl acetate: petroleum ether = 1:6) to obtain compound 4-b (120 mg, white solid). LC-MS m / z (ESI) = 292.2 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 7.58 (d, 1H), 6.82 (s, 1H), 6.77 (d, 1H), 4.70 (s, 1H), 3.80 (s, 3H), 2.52 (s, 3H), 1.58 (s, 9H) ppm.

[0237] Third step: Preparation of 4-(bromomethyl-d2)-5-methoxy-7-methyl-1H-indole-1- carboxylic acid tert-butyl ester (Intermediate 4)

[0238] Intermediate 3-b (120 mg, 0.409 mmol) was dissolved in 5 mL of dry dichloromethane, and the mixture was cooled to 0°C under nitrogen protection. Triphenylphosphine (161 mg, 0.614 mmol) and carbon tetrabromide (204 mg, 0.614 mmol) were added, and the mixture was stirred at 0°C for 40 minutes. The reaction mixture was concentrated under reduced pressure to obtain crude compound intermediate 4, which was used directly in the next step. LC-MS m / z (ESI) = 355.9, 357.9 [M+H] + .

[0239] Intermediate 5: Preparation of 4-(bromomethyl-d2)-5-methoxy-7-methyl-1H-indole-1- carboxylic acid tert-butyl ester (Intermediate 5)

[0240] First step: Preparation of 4-formyl-5-(methoxy-d3)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (5-a)

[0241] The starting material 3-a (9.5 g, 34.51 mmol) was dissolved in 100 mL of DMF, potassium carbonate (9.54 g, 69.01 mmol), deuterated methyl iodide (10.0 g, 69.01 mmol) were added, and stirred at room temperature for 2 hours. 100 mL of water was added and stirred, filtered, the filter cake was dissolved in ethyl acetate (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 5-a (9.8 g, white solid). LC-MS m / z (ESI) = 293.0 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 10.53 (s, 1H), 7.80 (d, 1H), 7.32 (d, 1H), 7.03 (s, 1H), 2.62 (s, 3H), 1.61 (s, 9H) ppm.

[0242] Second Step: Preparation of 1-(tert-butoxycarbonyl)-5-(methoxy-d3)-7-methyl-1H- indole-4-carboxylic acid (5-b)

[0243] Compound 5-a (9.8 g, 33.52 mmol) was dissolved in a mixed solvent of 90 mL of tert-butyl alcohol and 50 mL of tetrahydrofuran, 2-methyl-2-butene (47 g, 670.43 mmol), sodium phosphate monobasic aqueous solution (32.2 g, 268.17 mmol), sodium chlorite aqueous solution (6.06 g, 67.04 mmol) were added in sequence, and stirred at room temperature for 3 hours. 200 mL of water, 100 mL of ethyl acetate were added, and the mixture was separated, the organic layer was washed with 200 mL of saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel column (ethyl acetate: petroleum ether = 1:5) to obtain compound 5-b (10 g, white solid). LC-MS m / z (ESI) = 309.0 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 12.60 (s, 1H), 7.67 (d, 1H), 6.94 (s, 1H), 6.80 (d, 1H), 2.57 (s, 3H), 1.59 (s, 9H) ppm.

[0244] Third Step: Preparation of 4-(1H-imidazole-1-carbonyl)-5-(methoxy-d3)-7-methyl-1H- indole-1-carboxylic acid tert-butyl ester (5-c)

[0245] The starting material 5-b (10 g, 32.75 mmol) was dissolved in 100 mL of dry tetrahydrofuran, and CDI (6.37 g, 39.3 mmol) was added, and stirred at room temperature for 2 hours. After concentration under reduced pressure, the crude product was purified by silica gel column (ethyl acetate: petroleum ether = 1:6) to obtain compound 5-c (11.3 g, white solid). LC-MS m / z (ESI) = 359.0 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 8.04 (s, 1H), 7.74 (d, 1H), 7.59 (s, 1H), 7.09 (s, 2H), 6.44 (d, 1H), 2.65 (s, 3H), 1.60 (s, 9H) ppm.

[0246] Fourth step: Preparation of tert-butyl 4-(hydroxymethyl-d2)-5-(methoxy-d3)-7-methyl-1H- indole-1-carboxylate (5-d)

[0247] The starting material 5-c (11.3 g, 31.53 mmol) was dissolved in a mixed solvent of 100 mL of dry tetrahydrofuran and 10 mL of heavy water, and cooled to 0°C, and sodium borodeuteride (3.96 g, 94.58 mmol) was added. After addition, the reaction was continued at 0°C for 20 minutes. Quenching was performed by adding 20 mL of saturated ammonium chloride, 50 mL of ethyl acetate, and 100 mL of saturated sodium chloride, and the liquid was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column (ethyl acetate: petroleum ether = 1:5) to obtain compound 5-d (8.5 g, white solid). LC-MS m / z (ESI) = 295.3 [M-H] - ; 1 H NMR (400 MHz, DMSO) δ 7.61 (d, 1H), 6.84 (s, 1H), 6.80 (d, 1H), 4.75 (d, 1H), 2.55 (s, 3H), 1.61 (s, 9H) ppm.

[0248] Fifth step: Preparation of tert-butyl 4-(bromomethyl-d2)-5-(methoxy-d3)-7-methyl-1H-indole-1- carboxylate (intermediate 5)

[0249] The starting material 5-d (1.3 g, 4.39 mmol) was dissolved in 15 mL of dry dichloromethane, and cooled to 0°C under nitrogen protection, and triphenylphosphine (1.73 g, 6.58 mmol) and carbon tetrabromide (2.18 g, 6.58 mmol) were added, and stirring was continued at 0°C for 40 minutes. The reaction solution was concentrated under reduced pressure to obtain the crude product of compound intermediate 5, which was directly used in the next step. LC-MS m / z (ESI) = 359.0, 361.0 [M+H] + .

[0250] Preparation of Intermediate 6: tert-butyl 4-(bromomethyl)-5-(difluoromethoxy)-7-methyl-1H- indole-1-carboxylate (Intermediate 6)

[0251] First Step: Preparation of tert-butyl 5-(difluoromethoxy)-4-formyl-7-methyl-1H-indole-1- carboxylate (6-a)

[0252] Intermediate 3-a (560 mg, 2.03 mmol) was dissolved in 6 mL of acetonitrile and 6 mL of pure water, potassium hydroxide (1369 mg, 24.41 mmol) was added, and difluoromethyl triflate (1220 mg, 6.1 mmol) was slowly added at room temperature and stirred for 10 minutes. 10 mL of water was added, and extracted with ethyl acetate (10 mL), the organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and purified by silica gel column (ethyl acetate: petroleum ether = 1:10) to give compound 6-a (220 mg, yield 33.25%, colorless oil). LC-MS m / z (ESI) = 326.0 [M+H] + ; 1 H NMR (500 MHz, CDC13) δ 10.55 (s, 1H), 7.70 (d, 1H), 7.51 (d, 1H), 6.95 (s, 1H), 6.62 (t, 1H), 2.69 (s, 3H), 1.64 (s, 9H) ppm.

[0253] Second Step: Preparation of tert-butyl 5-(difluoromethoxy)-4-(hydroxymethyl)-7-methyl-1H- indole-1-carboxylate (6-b)

[0254] Compound 6-a (220 mg, 0.68 mmol) was dissolved in 5 mL of anhydrous methanol, and sodium borohydride (30.7 mg, 0.81 mmol) was added at room temperature under nitrogen protection, and stirred at room temperature for 1 hour. 10 mL of saturated ammonium chloride and 10 mL of ethyl acetate were added, and the mixture was separated, and the organic layer was washed with 10 mL of saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel column (ethyl acetate: petroleum ether = 1:6) to give compound 6-b (200 mg, yield 90.35%, white solid). LC-MS m / z (ESI) = 253.9 [M+H] + ;

[0255] Third Step: Preparation of tert-butyl 4-(bromomethyl)-5-(difluoromethoxy)-7-methyl-1H- indole-1-carboxylate (Intermediate 6)

[0256] Compound 6-b (100 mg, 0.31 mmol) was dissolved in 3 mL of dry dichloromethane, under nitrogen protection, triphenylphosphine (120 mg, 0.46 mmol), carbon tetrabromide (152 mg, 0.46 mmol) were added at room temperature, stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to obtain the crude intermediate 6, which was directly used in the next step.

[0257] Preparation of intermediate 7: (S)-benzyl 6-(4-(methoxycarbonyl)-2- methylphenyl)-2-oxo-7-azaspiro[3.5]nonane-7-carboxylate (intermediate 7)

[0258] First step: preparation of (S)-benzyl 2-(4-(methoxycarbonyl)-2- methylphenyl)-4-oxopiperidine-1-carboxylate (7-b)

[0259] Into a 500 mL three-necked flask, tert-amyl alcohol (130 mL), water (13 mL) were added at room temperature 25 °C, then compound 1a-a (20.0 g, 86.5 mmol), compound 7-a (59.7 g, 216.2 mmol), triethylamine (18 mL, 129.7 mmol), (S)-2,2'-bis[di(3,5-dimethylphenyl)phosphino]-1,1'- binaphthyl (3.2 g, 4.3 mmol), acetylacetonato bis(ethylene) rhodium (I) (1.2 g, 4.4 mmol) were added successively, replaced with nitrogen for three times, reacted at 100 °C for 18 h. After the reaction was completed, it was cooled to room temperature, filtered, the filtrate was concentrated under reduced pressure, purified by silica gel column (ethyl acetate: petroleum ether = 1:5) to obtain compound 7-b (10.0 g, brown oil). LC-MS m / z (ESI) = 382.1 [M+H] + .

[0260] Second step: preparation of (S)-benzyl 2-(4-(methoxycarbonyl)-2- methylphenyl)-4-methyleneazapiperidine-1-carboxylate (7-c)

[0261] Methyltriphenylphosphonium bromide (2.8 g, 7.9 mmol) was added to a 250 mL two-necked flask, 30 mL THF was added, and the flask was protected by nitrogen replacement. The mixture was stirred in an ice bath for 10 min, and then potassium tert-butoxide in THF (0.9 g, 7.9 mmol) was slowly added dropwise. The stirring was continued for half an hour, and then a solution of compound 7-b (2.0 g, 5.2 mmol) in super dry THF (10 mL) was slowly added dropwise. The reaction was continued at room temperature for 10 min, and then saturated ammonium chloride (50 mL) was added to quench the reaction. The mixture was diluted with ethyl acetate (200 mL), and then washed with saturated sodium chloride (200 mL) three times. The organic phase was concentrated under reduced pressure. Purification was performed by silica gel column chromatography (ethyl acetate: petroleum ether = 2:5) to obtain compound 7-c (1.4 g, light yellow oil). LC-MS m / z (ESI) = 380.0 [M+H] + .

[0262] Step 3: Preparation of (6S)-1,1-dichloro-6-(4-(methoxycarbonyl)-2-methylphenyl)-2- oxo-7-azaspiro[3.5]nonane-7-carboxylic acid benzyl ester (7-d)

[0263] Compound 7-c (1.4 g, 3.7 mmol) and zinc-copper reagent (2.7 g, 20.9 mmol) were added to a 250 mL two-necked flask, and 14 mL super dry dimethyl glycol was added. The mixture was protected by nitrogen replacement, and then trichloroacetyl chloride (2.7 g, 14.8 mmol) was slowly added dropwise. The reaction was continued at room temperature for half an hour. The mixture was diluted with ethyl acetate (100 mL), and then the pH was adjusted to 7 by adding saturated sodium carbonate. The mixture was filtered, and then the filtrate was washed with saturated sodium chloride (200 mL) three times. The mixture was concentrated under reduced pressure to obtain compound 7-d (brown oil), which was directly used in the next step. LC-MS m / z (ESI) = 490.2 [M+H] + .

[0264] Step 4: Preparation of (S)-6-(4-(methoxycarbonyl)-2-methylphenyl)-2-oxo-7-azaspiro[3.5]nonane-7-carboxylic acid benzyl ester (intermediate 7)

[0265] The crude product compound 7-d from the previous step was added to a 250 mL single-necked flask, and 50 mL methanol was added. Ammonium chloride (2.0 g, 37.4 mmol) and zinc powder (1.2 g, 18.5 mmol) were sequentially added with stirring at room temperature. The stirring was continued for 1 h, and then the mixture was filtered. The filtrate was concentrated under reduced pressure, and then purification was performed by silica gel column chromatography (ethyl acetate: petroleum ether = 3:10) to obtain intermediate 7 (0.9 g, yellow oil). LC-MS m / z (ESI) = 422.3 [M+H] + ; 1H NMR (500 MHz, CDC13) δ 7.85 (br s, 1H), 7.81 (d, 1H), 7.35 - 7.25 (m, 3H), 7.23 (d, 1H), 7.10 (m, 1H), 5.51 (t, 1H), 5.06 (dd, 2H), 4.36 (dt, 1H), 3.95 (s, 3H), 3.65 (m, 1H), 2.92 (br s, 2H), 2.74 (m, 1H), 2.45 - 2.35 (m, 4H), 2.24 (dd, 1H), 2.16-1.90 (m, 3H) ppm.

[0266] Example 1: Preparation of (S)-4-(7-((5-methoxy-7-methyl-lH-indol-4-yl)methyl)-2- (methylthio)-7-azaspiro[3.5]nonan-6-yl)benzoic acid (Compound 1)

[0267] First Step: Preparation of (S)-benzyl 2-hydroxy-6-(4-(methoxy carbonyl)phenyl)-7- azaspiro[3.5]nonane-7-carboxylate (1b)

[0268] The starting material 1a (200 mg, 0.49 mmol) was dissolved in 5 mL of methanol, cooled to 0 °C under nitrogen protection, and sodium borohydride (36 mg, 0.98 mmol) was added. After the addition was completed, the reaction was continued to stir at 0 °C for 20 minutes. 5 mL of saturated ammonium chloride was added, and 20 mL of ethyl acetate was used for extraction. The organic layer was washed with 10 mL of saturated sodium chloride again, dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. Purification on a silica gel column (ethyl acetate: petroleum ether = 1:4) gave compound 1b (170 mg, white solid). LC-MS m / z (ESI) = 409.6 [M+H] + .

[0269] Second Step: Preparation of (S)-benzyl 6-(4-(methoxy carbonyl)phenyl)-2-((methylsulfonyl)oxy)-7-azaspiro[3.5]nonane-7-carboxylate (1c) Compound 1b (170 mg, 0.42 mmol) was dissolved in 5 mL of dichloromethane, cooled to 0 °C under nitrogen protection, and triethylamine (126 mg, 1.25 mmol) and methanesulfonyl chloride (95 mg, 0.83 mmol) were added in turn. After the addition was completed, the reaction was continued to stir at room temperature for 2 hours. 5 mL of water and 20 mL of dichloromethane were added, and the liquid was separated. The organic layer was washed with 10 mL of saturated sodium chloride again, dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. Purification on a silica gel column (ethyl acetate: petroleum ether = 1:4) gave compound 1c (200 mg, white solid). LC-MS m / z (ESI) = 487.5 [M+H] + .

[0270] Step 3: Preparation of (S)-6-(4-(methoxycarbonyl)phenyl)-2-(methylthio)-7- azaspiro[3.5]nonane-7-carboxylic acid benzyl ester (1d)

[0271] Compound 1c (200 mg, 0.41 mmol) was dissolved in 2 mL of DMF, sodium thiomethoxide aqueous solution (20%, 2 ml) was added, and the reaction was carried out at 80°C for 4 hours under nitrogen protection. After cooling to room temperature, 5 mL of water was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was adjusted to about pH 5 with 1N dilute hydrochloric acid, and trimethylsilyldiazomethane (1.0 mL, 2.0 mmol) was added. The mixture was stirred at room temperature for 30 minutes. 10 mL of water and 20 mL of ethyl acetate were added, and the mixture was separated. The organic layer was washed with 10 mL of saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Purification on a silica gel column (ethyl acetate: petroleum ether = 1:9) gave compound 1d (124 mg, white solid). LC-MS m / z (ESI) = 440.1 [M+H] + .

[0272] Step 4: Preparation of methyl (S)-4-(2-(methylthio)-7-azaspiro[3.5]non-6-yl)benzoate (1e)

[0273] Compound 1d (124 mg, 0.28 mmol) was dissolved in 3 mL of methanol, and 10% palladium-carbon (150 mg) was added. The mixture was replaced with hydrogen three times, and then stirred at room temperature for 3 hours. After the reaction was completed, the mixture was filtered, and the filtrate was concentrated under reduced pressure. Purification on a silica gel column (dichloromethane:methanol = 20:1) gave compound 1e (53 mg, light yellow solid). LC-MS m / z (ESI) = 406.0 [M+H] + ; 1 H NMR (500 MHz, CDCl3) δ 8.03-7.98 (m, 2H), 7.48-7.42 (m, 2H), 3.92 (d, 3H), 3.71-3.61 (m, 1H), 3.46-3.37 (m, 1H), 3.15-3.03 (m, 1H), 2.87-2.75 (m, 1H), 2.50-2.40 (m, 1H), 2.23-2.12 (m, 1H), 2.08 (d, 3H), 1.93-1.76 (m, 4H), 1.67-1.48 (m, 2H) ppm.

[0274] Step 5: Preparation of tert-butyl (S)-5-methoxy-4-((6-(4-(methoxycarbonyl)phenyl)-2- (methylthio)-7-azaspiro[3.5]nonan-7-yl)methyl)-7-methyl-1H-indole-1-carboxylate (1g)

[0275] Compound 1e (53 mg, 0.17 mmol) was dissolved in 2 mL of DMAc, compound 1f (75 mg, 0.26 mmol) was added, stirred at room temperature for 2 h, then sodium triacetoxyborohydride (73 mg, 0.34 mmol) was added, stirred at room temperature overnight. 10 mL of saturated aqueous sodium bicarbonate solution was added, extracted with ethyl acetate (30 mL), the organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, purified on a silica gel column (ethyl acetate: petroleum ether = 1:19) to obtain compound 1g (30 mg, white solid). LC-MS m / z (ESI) = 579.2 [M+H] + .

[0276] Sixth step: Preparation of (S)-4-(7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-2- (methylthio)-7-azaspiro[3.5]nonan-6-yl)benzoic acid (Compound 1)

[0277] Compound 1g (28 mg, 0.048 mmol) was dissolved in a mixed solvent of methanol (1 mL) and THF (1 mL), water (0.5 mL) was added, lithium hydroxide monohydrate (20 mg, 0.48 mmol) was added, and the reaction was carried out at 70°C for 3 h under nitrogen protection. After the reaction was completed, it was allowed to stand at room temperature, the pH was adjusted to neutral with 1N dilute hydrochloric acid, concentrated under reduced pressure, and purified on a C18 column (acetonitrile: water = 90:10) to obtain compound 1 (13 mg, white solid). LC-MS m / z (ESI) = 465.0 [M+H] + ; 1 H NMR (400 MHz, CD3OD) δ 8.20 - 8.11 (m, 2H), 7.64 (t, 2H), 7.33 (d, 1H), 6.78 (s, 1H), 6.34 (s, 1H), 4.65 (s, 1H), 4.45 - 4.25 (m, 2H), 4.05 (d, 1H), 3.78 (s, 3H), 3.54 - 3.37 (m, 2H), 3.30 - 3.13 (m, 1H), 2.75 - 2.56 (m, 1H), 2.53 (s, 3H), 2.32 - 2.10 (m, 3H), 2.10 - 1.97 (m, 4H), 1.96 - 1.84 (m, 2H) ppm.

[0278] 40 mg of compound 1 was resolved by SFC, and the conditions are shown in Table 1 below.

[0279] Table 1

[0280] Compound 1A (15 mg, retention time 1.38 min) was obtained, 1H NMR (500 MHz, CD3OD) δ 8.14 (d, 2H), 7.62 (d, 2H), 7.32 (d, 1H), 6.76 (s, 1H), 6.32 (s, 1H), 4.33 (s, 2H), 4.06 (d, 1H), 3.76 (s, 3H), 3.49 - 3.39 (m, 2H), 3.28 - 3.18 (m, 1H), 2.59 (t, 1H), 2.52 (s, 3H), 2.28 - 1.96 (m, 8H), 1.95 - 1.83 (m, 2H) ppm.

[0281] Compound 1B (15 mg, retention time 1.52 min), 1 H NMR (500 MHz, CD3OD) δ 8.12 (s, 2H), 7.62 (d, 2H), 7.29 (d, 1H), 6.73 (s, 1H), 6.29 (s, 1H), 4.56 (s, 1H), 4.27 (d, 2H), 3.98 (d, 1H), 3.74 (s, 3H), 3.47 - 3.38 (m, 1H), 3.12 - 3.02 (m, 1H), 2.64 (t, 1H), 2.49 (s, 3H), 2.27 - 2.05 (m, 3H), 2.04 (s, 3H), 1.98 - 1.94 (m, 1H), 1.91 - 1.81 (m, 3H) ppm. Example 2: Preparation of (S)-4-(7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-2-((methyl-d3)thio)-7- azaspiro[3.5]nonan-6-yl)benzoic acid (Compound 2)

[0282] First Step: Preparation of (S)-benzyl 2-(acetylthio)-6-(4- (methoxycarbonyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (2a)

[0283] Compound 1c (620 mg, 1.27 mmol) was dissolved in 10 mL of DMF, potassium thioacetate (436 mg, 3.81 mmol) was added, and the reaction was carried out at 80 °C for 8 hours under nitrogen protection. Cooled to room temperature, added 20 mL of water, extracted with ethyl acetate, the ethyl acetate layer was washed with 20 mL of saturated sodium chloride, dried over anhydrous sodium sulfate, the filtrate was concentrated under reduced pressure, and purified on a silica gel column (ethyl acetate: petroleum ether = 1:5) to obtain compound 2a (460 mg, light yellow oil). LC-MS m / z (ESI) = 468.1 [M+H] + .

[0284] Second Step: Preparation of (S)-benzyl 6-(4-(methoxycarbonyl)phenyl)-2-((methyl-d3)thio)-7- azaspiro[3.5]nonane-7-carboxylate (2b)

[0285] Compound 2a (460 mg, 0.98 mmol) was dissolved in 10 mL of methanol, deuterated methyl iodide (285 mg, 1.97 mmol), lithium hydroxide monohydrate (62 mg, 1.47 mmol) were added successively, and stirred at room temperature for 20 minutes after completion of the addition. 20 mL of water was added, extracted with 30 mL of ethyl acetate once, and the organic layer was washed with 20 mL of saturated sodium chloride, dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. Purification on a silica gel column (ethyl acetate: petroleum ether = 1:9) gave compound 2b (299 mg, white solid).

[0286] LC-MS m / z (ESI) = 443.1 [M+H] + .

[0287] Third step: Preparation of methyl (S)-4-(2-((methyl-d3)thio)-7-azaspiro[3.5]nonan-6-yl)benzoate (2c)

[0288] Compound 2b (299 mg, 0.676 mmol) was dissolved in 5 mL of acetonitrile, cooled to 0°C under nitrogen protection, and trimethylsilyl iodide (405 mg, 2.02 mmol) was added. After completion of the addition, it was continuously stirred at 0°C for 1 hour. Saturated aqueous sodium bicarbonate solution was added dropwise to adjust the pH to basic, and then extracted with 30 mL of ethyl acetate. The organic layer was washed with 20 mL of saturated sodium chloride, dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. Purification on a silica gel column (methanol: dichloromethane = 1:10) gave compound 2c (173 mg, light yellow solid). LC-MS m / z (ESI) = 309.2 [M+H] + ; 1 H NMR (500 MHz, CDCl3) δ 8.01 (dd, 2H), 7.45 (dd, 2H), 3.93 (d, 3H), 3.72-3.60 (m, 1H), 3.45-3.37 (m, 1H), 3.15-3.02 (m, 1H), 2.87-2.72 (m, 1H), 2.50-2.38 (m, 1H), 2.24-2.12 (m, 1H), 1.94-1.73 (m, 5H), 1.69-1.48 (m, 2H) ppm.

[0289] Fourth step: Preparation of (S)-5-methoxy-4-((6-(4-(methoxy carbonyl)phenyl)-2-((methyl-d3)thio)-7-azaspiro[3.5]nonan-7-yl)methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (2d)

[0290] Compound 2c (80 mg, 0.259 mmol) was dissolved in 5 mL of DMF, and intermediate 2 (92 mg, 0.259 mmol), cesium carbonate (254 mg, 0.778 mmol) were added. After addition, the reaction was carried out at 80 °C for 1 h. After cooling to room temperature, 10 mL of water and 20 mL of ethyl acetate were added, and the organic layer was washed with 10 mL of saturated sodium chloride, dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure to give compound 2d (120 mg, white solid). LC-MS m / z (ESI) = 582.1 [M+H] + .

[0291] Fifth step: Preparation of (S)-4-(7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-2- ((methyl-d3)thio)-7-azaspiro[3.5]nonan-6-yl)benzoic acid (Compound 2)

[0292] Compound 2d (120 mg, 0.206 mmol) was dissolved in a mixed solvent of methanol (2 mL) and THF (2 mL), and water (1 mL) was added. Lithium hydroxide monohydrate (87 mg, 2.06 mmol) was added, and the reaction was carried out at 70 °C for 3 h under nitrogen protection. After the reaction was completed, the reaction was allowed to stand at room temperature, and the pH was adjusted to neutral with 1N dilute hydrochloric acid. After concentration under reduced pressure, preparative liquid chromatography was performed (instrument: Shimadzu LC-20AP; column: Agilent InfinityLab Poroshell 120HPH-C18, 21.2 x 150 mm x 4 μm; mobile phase A: 0.1% NH3·H2O in water, mobile phase B: ACN; flow rate: 15 mL / min, wavelength: 254 nm) to give compound 2 (70 mg, white solid). LC-MS m / z (ESI) = 468.0 [M+H] + ; 1 HNMR (500 MHz, CD3OD) δ 8.13-8.03 (m, 2H), 7.64-7.51 (m, 2H), 7.26 (d, 1H), 6.73 (s, 1H), 6.36 (s, 1H), 4.58 (s, 1H), 4.07 (s, 1H), 3.76 (s, 3H), 3.70-3.55 (m, 1H), 3.48-3.37 (m, 1H), 3.22-3.10 (m, 1H), 2.85-2.65 (m, 1H), 2.65-2.50 (m, 1H), 2.49 (s, 3H), 2.23-2.13 (m, 1H), 2.09-1.70 (m, 6H) ppm.

[0293] 68 mg of compound 2 was resolved by SFC, and the conditions are shown in Table 2 below.

[0294] Table 2

[0295] Compound 2A (38.7 mg, retention time 1.35 min), LC-MS m / z (ESI) = 468.4 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 10.82 (s, 1H), 7.96 (d, 2H), 7.65 (d, 2H), 7.25 (t, 1H), 6.65 (s, 1H), 6.50 - 6.43 (m, 1H), 3.70 (s, 3H), 3.52 (d, 1H), 3.40 - 3.32 (m, 1H), 3.15 (d, 2H), 2.67 - 2.61 (m, 1H), 2.42 (s, 3H), 2.35 - 2.27 (m, 1H), 2.05 - 1.97 (m, 2H), 1.87 - 1.80 (m, 1H), 1.74 - 1.50 (m, 4H), 1.40 - 1.32 (m, 1H) ppm.

[0296] Compound 2B (25.0 mg, retention time 1.53 min), LC-MS m / z (ESI) = 468.4 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 10.82 (s, 1H), 7.96 (d, 2H), 7.62 (d, 2H), 7.24 (t, 1H), 6.64 (s, 1H), 6.45 (s, 1H), 3.70 (s, 3H), 3.52 (d, 1H), 3.42 - 3.34 (m, 1H), 3.20 (d, 1H), 3.14 (d, 1H), 2.58 (d, 1H), 2.47 - 2.35 (m, 4H), 2.05 - 1.90 (m, 2H), 1.84 (d, 1H), 1.76 - 1.64 (m, 2H), 1.58 - 1.46 (m, 2H), 1.45 - 1.34 (m, 1H) ppm.

[0297] Example 3: Preparation of (S)-4-(7-((5-(methoxy-d3)-7-methyl-lH-indol-4-yl)methyl)-2- ((methyl-d3)thio)-7-azaspiro[3.5]nonan-6-yl)benzoic acid (Compound 3)

[0298] First Step: Preparation of (S)-5-(methoxy-d3)-4-((6-(4-(methoxy-carbonyl)phenyl)-2- ((methyl-d3)thio)-7-azaspiro[3.5]nonan-7-yl)methyl)-7-methyl-lH-indole-l-carboxylic acid tert-butyl ester (3a)

[0299] Compound 2c (80 mg, 0.259 mmol) was dissolved in 5 mL of DMF, and intermediate 3 (93 mg, 0.259 mmol), cesium carbonate (254 mg, 0.778 mmol) were added. After addition, the reaction was carried out at 80 °C for 1 h. After cooling to room temperature, 10 mL of water and 20 mL of ethyl acetate were added, and the organic layer was washed with 10 mL of saturated sodium chloride, dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure to give compound 3a (90 mg, white solid). LC-MS m / z (ESI) = 585.2 [M+H] + .

[0300] Second Step: Preparation of (S)-4-(7-((5-(methoxy-d3)-7-methyl-1H-indol-4-yl)methyl)-2- ((methyl-d3)thio)-7-azaspiro[3.5]nonan-6-yl)benzoic acid (Compound 3)

[0301] Compound 3a (90 mg, 0.154 mmol) was dissolved in a mixed solvent of methanol (2 mL) and THF (2 mL), and water (1 mL) was added. Lithium hydroxide monohydrate (65 mg, 1.54 mmol) was added, and the reaction was carried out at 70 °C for 3 h under nitrogen protection. After the reaction was completed, the reaction was allowed to stand at room temperature, and the pH was adjusted to neutral with 1N dilute hydrochloric acid. After concentration under reduced pressure, preparative liquid chromatography was performed (instrument: Shimadzu LC-20AP; column: Agilent InfinityLab Poroshell 120HPH-C18, 21.2 x 150 mm x 4 μm; mobile phase A: 0.1% NH3·H2O in water, mobile phase B: ACN; flow rate: 15 mL / min, wavelength: 254 nm) to give compound 3 (41 mg, white solid). LC-MS m / z (ESI) = 471.1 [M+H] + ; 1 HNMR (500 MHz, CD3OD) δ 8.10-7.99 (m, 2H), 7.62-7.51 (m, 2H), 7.22 (d, 1H), 6.69 (s, 1H), 6.35 (s, 1H), 3.99 (s, 1H), 3.75-3.45 (m, 2H), 3.42-3.35 (m, 1H), 3.14-3.00 (m, 1H), 2.71-2.49 (m, 2H), 2.47 (s, 3H), 2.17-2.10 (m, 1H), 2.05-1.84 (m, 3H), 1.82-1.67 (m, 3H) ppm.

[0302] 41 mg of compound 3 was resolved by SFC, and the conditions are shown in Table 3 below.

[0303] Table 3

[0304] Compound 3A (23 mg, retention time 1.36 min), LC-MS m / z (ESI) = 471.4 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 10.81 (s, 1H), 7.96 (d, 2H), 7.64 (d, 2H), 7.25 (t, 1H), 6.64 (s, 1H), 6.46 (s, 1H), 3.52 (d, 1H), 3.40 - 3.31 (m, 1H), 3.15 (d, 2H), 2.68 - 2.62 (m, 1H), 2.42 (s, 3H), 2.31 (t, 1H), 2.06 - 1.96 (m, 2H), 1.87 - 1.79 (m, 1H), 1.74 - 1.54 (m, 4H), 1.36 (t, 1H) ppm.

[0305] Compound 3B (18 mg, retention time 1.54 min), LC-MS m / z (ESI) = 471.4 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 10.87 (s, 1H), 7.92 (d, 2H), 7.45 (d, 2H), 7.23 (t, 1H), 6.63 (s, 1H), 6.48 - 6.43 (m, 1H), 3.54 (d, 1H), 3.45 - 3.41 (m, 1H), 3.13 (d, 2H), 2.59 - 2.54 (m, 1H), 2.46 - 2.38 (m, 4H), 2.00 (t, 1H), 1.91 (t, 1H), 1.82 (d, 1H), 1.75 - 1.64 (m, 2H), 1.57 (t, 1H), 1.49 (d, 1H), 1.44 - 1.35 (m, 1H) ppm.

[0306] Example 4: Preparation of (S)-4-(7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-2-((methyl-d3)thio)-7-azaspiro[3.5]nonan-6-yl-2-d)benzoic acid (Compound 4)

[0307] First Step: Preparation of (S)-2-hydroxy-6-(4-(methoxy carbonyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate-2-d benzyl ester (4a)

[0308] Compound 1a (500 mg, 1.22 mmol) was dissolved in 10 mL deuterated methanol, cooled to 0 °C under nitrogen protection, and sodium borodeuteride (103 mg, 2.45 mmol) was added. After the addition was completed, the reaction was continued to stir at 0 °C for 20 min. 5 mL saturated ammonium chloride was added, and 20 mL ethyl acetate was used for extraction. The organic layer was washed with 10 mL saturated sodium chloride again, dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. Compound 4a (400 mg, white solid) was obtained by silica gel column purification (ethyl acetate: petroleum ether = 1:4). LC-MS m / z (ESI) = 411.1 [M+H] + ; 1 H NMR (500 MHz, CDC13) δ 8.04 - 7.95 (m, 2H), 7.37 - 7.20 (m, 7H), 5.49 - 5.45 (m, 1H), 5.17 - 5.11 (m, 2H), 4.27 - 4.18 (m, 1H), 3.93 (s, 3H), 3.17 - 3.10 (m, 1H), 2.37 - 2.26 (m, 1H), 2.24 - 2.14 (m, 1H), 2.08 - 1.97 (m, 1H), 1.82 - 1.54 (m, 5H), 1.39 - 1.19 (m, 1H) ppm.

[0309] Second Step: Preparation of benzyl (S)-6-(4-(methoxycarbonyl)phenyl)-2- ((methylsulfonyl)oxy)-7-azaspiro[3.5]nonane-7-carboxylate-2-d (4b)

[0310] Compound 4a (400 mg, 0.974 mmol) was dissolved in 10 mL dichloromethane, cooled to 0 °C under nitrogen protection, and triethylamine (296 mg, 2.92 mmol) and methanesulfonyl chloride (223 mg, 1.95 mmol) were added successively. After the addition was completed, the reaction was continued to stir at room temperature for 2 h. 5 mL water and 20 mL dichloromethane were added, and the organic layer was washed with 10 mL saturated sodium chloride again, dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. Compound 4b (450 mg, white solid) was obtained by silica gel column purification (ethyl acetate: petroleum ether = 1:4).

[0311] Third Step: Preparation of benzyl (S)-2-(acetylsulfanyl)-6-(4- (methoxycarbonyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate-2-d (4c)

[0312] Compound 4b (450 mg, 0.921 mmol) was dissolved in 10 mL of DMF, potassium thioacetate (316 mg, 2.76 mmol) was added, and the reaction was carried out at 80 °C for 8 hours under nitrogen protection. After cooling to room temperature, 20 mL of water was added, and the mixture was extracted with 20 mL of ethyl acetate. The ethyl acetate layer was washed with 20 mL of saturated sodium chloride, dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. Purification on a silica gel column (ethyl acetate: petroleum ether = 1:5) gave compound 4c (260 mg, light yellow oil). LC-MS m / z (ESI) = 469.1 [M+H] + .

[0313] Fourth step: Preparation of (S)-6-(4-(methoxycarbonyl)phenyl)-2-((methyl-d3)thio)-7- azaspiro[3.5]nonane-7-carboxylate-2-d benzyl (4d)

[0314] Compound 4c (260 mg, 0.555 mmol) was dissolved in 5 mL of methanol, and deuterated methyl iodide (161 mg, 1.11 mmol) and lithium hydroxide monohydrate (20 mg, 0.477 mmol) were added in sequence. After the addition was complete, the mixture was stirred at room temperature for 20 minutes. Then 20 mL of water was added, and the mixture was extracted with 30 mL of ethyl acetate once. The organic layer was washed with 20 mL of saturated sodium chloride, dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. Purification on a silica gel column (ethyl acetate: petroleum ether = 1:9) gave compound 4d (216 mg, white solid). LC-MS m / z (ESI) = 444.1 [M+H] + .

[0315] Fifth step: Preparation of (S)-methyl 4-(2-((methyl-d3)thio)-7-azaspiro[3.5]non-6-yl-2-d) benzoate (4e)

[0316] Compound 4d (216 mg, 0.487 mmol) was dissolved in 5 mL of acetonitrile, and trimethylsilyl iodide (293 mg, 1.46 mmol) was added under nitrogen protection while cooling to 0 °C. After the addition was complete, the mixture was stirred at 0 °C for 1 hour. Then saturated aqueous sodium bicarbonate solution was added dropwise to adjust the pH to basic, and the mixture was extracted with 30 mL of ethyl acetate. The organic layer was washed with 20 mL of saturated sodium chloride, dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. Purification on a silica gel column (methanol:dichloromethane = 1:10) gave compound 4e (124 mg, light yellow solid). LC-MS m / z (ESI) = 310.4 [M+H] + ; 1H NMR (400 MHz, CDC13) δ 8.01 - 7.95 (m, 2H), 7.42 (t, 2H), 3.90 (s, 3H), 3.64 (dd, 1H), 3.14 - 3.00 (m, 1H), 2.88 - 2.71 (m, 1H), 2.41 (t, 1H), 2.20 - 2.08 (m, 1H), 1.92 - 1.70 (m, 4H), 1.67 - 1.45 (m, 2H), 1.26 (d, 1H) ppm.

[0317] Step 6: Preparation of (S)-5-methoxy-4-((6-(4-(methoxy carbonyl)phenyl)-2-((methyl- d3)thio)-7-azaspiro[3.5]nonan-7-yl-2-d)methyl)-7-methyl-lH-indole-l-carboxylic acid tert-butyl ester (4f)

[0318] Compound 4e (80 mg, 0.259 mmol) was dissolved in 5 mL DMF, and intermediate 2 (92 mg, 0.259 mmol), cesium carbonate (254 mg, 0.778 mmol) were added. After addition, the reaction was stirred at 80 °C for 1 h. After cooling to room temperature, 10 mL water and 20 mL ethyl acetate were added, and the organic layer was washed with 10 mL saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. Purification on a silica gel column (ethyl acetate: petroleum ether = 1:9) gave compound 4f (87 mg, white solid). LC-MS m / z (ESI) = 583.3 [M+H] + .

[0319] Step 7: Preparation of (S)-4-(7-((5-methoxy-7-methyl-lH-indol-4-yl)methyl)-2-((methyl- d3)thio)-7-azaspiro[3.5]nonan-6-yl-2-d)benzoic acid (compound 4)

[0320] Compound 4f (87 mg, 0.149 mmol) was dissolved in a mixed solvent of methanol (2 mL) and THF (2 mL), and water (1 mL) was added. Lithium hydroxide monohydrate (63 mg, 1.49 mmol) was added, and the reaction was stirred at 70 °C for 3 h under nitrogen protection. After the reaction was completed, the reaction was allowed to stand at room temperature, and the pH was adjusted to neutral with 1 N dilute hydrochloric acid. After concentration under reduced pressure, preparative liquid chromatography purification (instrument: Shimadzu LC-20AP; column: Agilent InfinityLab Poroshell 120HPH-C18, 21.2 x 150 mm x 4 pm; mobile phase A: 0.1% NH3-H2O in water, mobile phase B: ACN; flow rate: 15 mL / min, wavelength: 254 nm) gave compound 4 (52 mg, white solid). LC-MS m / z (ESI) = 469.2 [M+H] + ;1 H NMR (500 MHz, MeOD) δ 8.07 - 8.02 (m, 2H), 7.60 - 7.52 (m, 2H), 7.22 (d, 1H), 6.69 (s, 1H), 6.35 (s, 1H), 3.97 (s, 1H), 3.75 (d, 3H), 3.70 - 3.42 (m, 2H), 3.12 - 3.00 (m, 1H), 2.65 - 2.48 (m, 2H), 2.46 (s, 3H), 2.12 (d, 1H), 2.00 - 1.82 (m, 3H), 1.82 - 1.64 (m, 3H) ppm.

[0321] Take 48 mg of compound 4 to be resolved by SFC, the conditions are shown in Table 4 below.

[0322] Table 4

[0323] Compound 4A (20 mg, retention time 1.36 min) was obtained, LC-MS m / z (ESI) = 469.4 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 10.81 (s, 1H), 7.96 (d, 2H), 7.64 (d, 2H), 7.25 (t, 1H), 6.65 (s, 1H), 6.48 - 6.43 (m, 1H), 3.70 (s, 3H), 3.56 - 3.50 (m, 1H), 3.14 (d, 2H), 2.67 - 2.62 (m, 1H), 2.42 (s, 3H), 2.33 - 2.27 (m, 1H), 2.05 - 1.95 (m, 2H), 1.82 (d, 1H), 1.73 - 1.54 (m, 4H), 1.40 - 1.30 (m, 1H) ppm.

[0324] Compound 4B (13 mg, retention time 1.54 min), LC-MS m / z (ESI) = 469.4 [M+H] + ; 1H NMR (500 MHz, DMSO-d6) δ 10.85 (s, 1H), 7.90 (d, 2H), 7.44 (d, 2H), 7.23 (t, 1H), 6.63 (s, 1H), 6.45 (s, 1H), 3.70 (s, 3H), 3.54 (d, 1H), 3.16 - 3.07 (m, 2H), 2.59 - 2.54 (m, 1H), 2.44 - 2.38 (m, 4H), 2.01 - 1.94 (m, 1H), 1.91 (t, 1H), 1.82 (d, 1H), 1.74 - 1.64 (m, 2H), 1.57 (t, 1H), 1.49 (d, 1H), 1.43 - 1.35 (m, 1H) ppm.

[0325] Example 5: Preparation of (S)-4-(7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl-d2)-2- ((methyl-d3)thio)-7-azaspiro[3.5]nonan-6-yl-2-d)benzoic acid (Compound 5)

[0326] First Step: Preparation of (S)-5-methoxy-4-((6-(4-(methoxy carbonyl)phenyl)-2- ((methyl-d3)thio)-7-azaspiro[3.5]nonan-7-yl-2-d)methyl-d2)-7-methyl-1H-indole-1- carboxylate tert-butyl ester (5a)

[0327] Compound 4e (40 mg, 0.130 mmol) was dissolved in 3 mL of DMF, and intermediate 4 (46 mg, 0.130 mmol), cesium carbonate (126 mg, 0.389 mmol) were added. After addition, the reaction was carried out at 80 °C for 1 hour. After cooling to room temperature, 10 mL of water and 20 mL of ethyl acetate were added, and the organic layer was washed with 10 mL of saturated sodium chloride, dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. Purification on a silica gel column (ethyl acetate: petroleum ether = 1:9) gave compound 5a (45 mg, white solid). LC-MS m / z (ESI) = 585.2 [M+H] + .

[0328] Second Step: Preparation of (S)-4-(7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl-d2)-2- ((methyl-d3)thio)-7-azaspiro[3.5]nonan-6-yl-2-d)benzoic acid (Compound 5)

[0329] Compound 5a (45 mg, 0.077 mmol) was dissolved in a mixed solvent of methanol (2 mL) and THF (2 mL), water (1 mL) was added, lithium hydroxide monohydrate (32 mg, 0.77 mmol) was added, and the reaction was carried out at 70°C for 3 h under nitrogen protection. After the reaction was completed, it was allowed to stand at room temperature, 1N dilute hydrochloric acid was used to adjust the pH to neutral, concentrated under reduced pressure, and purified by preparative liquid chromatography (instrument: Shimadzu LC-20AP; column: Agilent InfinityLab Poroshell 120HPH-C18, 21.2 x 150 mm x 4 μm; mobile phase A: 0.1% NH3·H2O in water, mobile phase B: ACN; flow rate: 15 mL / min, wavelength: 254 nm) (acetonitrile: water = 90:10) to give compound 5 (33 mg, white solid). LC-MS m / z (ESI) = 471.0 [M+H] + ; 1 H NMR (500 MHz, CD3OD) δ 8.10-8.03 (m, 2H), 7.62-7.52 (m, 2H), 7.24 (d, 1H), 6.71 (s, 1H), 6.37 (s, 1H), 3.76 (s, 3H), 3.70-3.55 (m, 1H), 3.15-3.00 (m, 1H), 2.70-2.50 (m, 2H), 2.49 (s, 3H), 2.17-2.10 (m, 1H), 2.07-1.85 (m, 3H), 1.85-1.66 (m, 3H) ppm.

[0330] 31 mg of compound 5 was resolved by SFC, and the conditions are shown in Table 5 below.

[0331] Table 5

[0332] Compound 5A (12.8 mg, retention time 1.36 min) was obtained, LC-MS m / z (ESI) = 471.4 [M+H] + ; 1 H NMR (500 MHz, CD3OD) δ 8.12 (d, 2H), 7.60 (d, 2H), 7.30 (d, 1H), 6.75 (s, 1H), 6.34 (s, 1H), 3.76 (s, 3H), 3.37 (s, 1H), 3.14-3.00 (m, 1H), 2.56 (d, 1H), 2.51 (s, 3H), 2.20 (d, 1H), 2.14-1.89 (m, 4H), 1.86 (d, 2H), 1.31 (t, 1H) ppm.

[0333] Compound 5B (7.2 mg, retention time 1.53 min), LC-MS m / z (ESI) = 471.4 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 10.81 (s, 1H), 7.95 (d, 2H), 7.62 (d, 2H), 7.24 (t, 1H), 6.64 (s, 1H), 6.44 (s, 1H), 3.70 (s, 3H), 3.19 (dd, 1H), 2.57 (d, 1H), 2.43 (d, 4H), 2.02 - 1.88 (m, 2H), 1.83 (d, 1H), 1.73 - 1.63 (m, 2H), 1.56 - 1.45 (m, 2H), 1.44 - 1.35 (m, 1H) ppm.

[0334] Example 6: Preparation of (S)-4-(7-(5-(methoxy-d3)-7-methyl-1H-indol-4-yl)methyl-d2- (methylthio)-7-azaspiro[3.5]non-6-yl)benzoic acid (Compound 6)

[0335] First Step: Preparation of (S)-5-(methoxy-d3)-4-(6-(4-(methoxy-d3)phenyl)-2-(methylthio)- 7-azaspiro[3.5]non-7-yl)methyl-d2)-7-methyl-1H-indole-1-carboxylate tert-butyl ester (6-a)

[0336] Compound 1e (700 mg, 2.29 mmol), intermediate 5 (1.3 g, 3.62 mmol) were added into a 100 mL single-neck flask, 10 mL DMF was added, cesium carbonate (2.4 g, 7.37 mmol) was added, 80 °C stirring for 3 hours. 50 mL ethyl acetate was added, washed with 100 mL saturated sodium chloride three times, the organic phase was concentrated under reduced pressure, silica gel column purification (ethyl acetate: petroleum ether = 1:10) to obtain compound 6-a (700 mg, light yellow solid). LC-MS m / z (ESI) = 584.1 [M+H] + .

[0337] Second Step: Preparation of (S)-4-(7-(5-(methoxy-d3)-7-methyl-1H-indol-4-yl)methyl-d2- (methylthio)-7-azaspiro[3.5]non-6-yl)benzoic acid (Compound 6)

[0338] The compound 6-a obtained in the previous step was added to a 50 mL single-neck flask, 3 mL of THF, 2 mL of methanol, 1 mL of pure water were added, lithium hydroxide (503 mg, 12.0 mmol) was added, and stirring was carried out at 80°C for 3 hours. Filtration was carried out, the filtrate was adjusted to pH 7 with dilute hydrochloric acid, and then purified by preparative liquid phase (instrument: Shimadzu LC-20AP; column: Agilent InfinityLab Poroshell 120HPH-C18, 21.2 x 150 mm x 4 μm; gradient conditions: ACN / H2O: 10%-90%, 20 mL / min, retention time 5.8 min) to obtain compound 6 (320 mg, white solid).

[0339] 320 mg of compound 6 was resolved by SFC, and the conditions are shown in Table 6.

[0340] Table 6

[0341] Compound 6A (176.4 mg, retention time 4.19 min) was obtained, LC-MS m / z (ESI) = 470.1 [M+H] + .

[0342] 1 H NMR (400 MHz, DMSO-d6) δ 10.82 (s, 1H), 7.97 (d, 2H), 7.66 (d, 2H), 7.26 (t, 1H), 6.65 (s, 1H), 6.48-6.43 (m, 1H), 3.16 (d, 1H), 2.70-2.59 (m, 1H), 2.43 (s, 3H), 2.36-2.30 (m, 1H), 2.07-1.96 (m, 6H), 1.88-1.80 (m, 1H), 1.74-1.54 (m, 4H), 1.42-1.32 (m, 1H) ppm.

[0343] Compound 6B (139.9 mg, retention time 6.64 min), LC-MS m / z (ESI) = 470.1 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 10.81 (s, 1H), 7.92 (d, 2H), 7.53 (d, 2H), 7.25 (t, 1H), 6.65 (s, 1H), 6.47 - 6.43 (m, 1H), 3.16 (d, 1H), 2.61 - 2.55 (m, 1H), 2.48 - 2.40 (m, 4H), 2.05 - 1.97 (m, 5H), 1.97 - 1.88 (m, 1H), 1.87 - 1.80 (m, 1H), 1.77 - 1.65 (m, 2H), 1.60 - 1.46 (m, 2H), 1.46 - 1.35 (m, 1H) ppm.

[0344] Example 7: Preparation of (S)-4-(7-(5-methoxy-7-methyl-1H-indol-4-yl)methyl-d2)-2- ((methyl-d3)thio)-7-azaspiro[3.5]non-6-yl)benzoic acid (Compound 7)

[0345] First Step: Preparation of (S)-5-methoxy-4-(6-(4-(methoxycarbonyl)phenyl)-2- ((methyl-d3)thio)-7-azaspiro[3.5]non-7-yl)methyl-d2)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (7-a)

[0346] Compound 2c (590 mg, 1.91 mmol), intermediate 4 (1.02 g, 2.87 mmol) were added into a 100 mL single-neck flask, 10 mL DMF was added, cesium carbonate (1.87 mg, 5.74 mmol) was added, and stirring was performed at 80 °C under nitrogen protection for 3 hours. 50 mL ethyl acetate was added, and the organic phase was concentrated under reduced pressure after being washed with 100 mL saturated sodium chloride three times. Purification was performed on a silica gel column (ethyl acetate: petroleum ether = 1:10) to obtain compound 7-a (390 mg, light yellow solid). LC-MS m / z (ESI) = 584.2 [M+H] + .

[0347] Second Step: Preparation of (S)-4-(7-(5-methoxy-7-methyl-1H-indol-4-yl)methyl-d2)-2- ((methyl-d3)thio)-7-azaspiro[3.5]non-6-yl)benzoic acid (Compound 7)

[0348] The compound 7-a obtained in the previous step was added to a 50 mL single-neck flask, 3 mL THF, 2 mL methanol, 1 mL pure water were added, lithium hydroxide (280 mg, 6.68 mmol) was added, and stirring was carried out at 80 °C for 3 hours. Filtration was carried out, the filtrate was adjusted to pH 7 with dilute hydrochloric acid, and purified by preparative liquid phase (instrument: Shimadzu LC-20AP; column: Agilent InfinityLab Poroshell 120HPH-C18, 21.2 x 150 mm x 4 pm; gradient conditions: ACN / 0.10% NH3.H2O in H2O: 20%-80%, 20 mL / min, retention time 5.2 min) to obtain compound 7 (150 mg, white solid).

[0349] 380 mg of compound 7 was resolved by SFC, and the conditions are shown in Table 7.

[0350] Table 7

[0351] Compound 7A (146.5 mg, retention time 4.18 min) was obtained, LC-MS m / z (ESI) = 470.0 [M+H] + . 1 H NMR (500 MHz, DMSO-d6) δ 10.81 (s, 1H), 7.95 (d, 2H), 7.63 (d, 2H), 7.24 (t, 1H), 6.64 (s, 1H), 6.45-6.42 (m, 1H), 3.69 (s, 3H), 3.37-3.32 (m, 1H), 3.14 (d, 1H), 2.63 (d, 1H), 2.41 (s, 3H), 2.34-2.27 (t, 1H), 2.04-1.96 (m, 2H), 1.85-1.79 (m, 1H), 1.73-1.54 (m, 4H), 1.39-1.31 (m, 1H) ppm.

[0352] Compound 7B (145.2 mg, retention time 6.87 min), LC-MS m / z (ESI) = 470.0 [M+H] + . 1H NMR (500 MHz, DMSO-d6) δ 10.82 (s, 1H), 7.89 (d, 2H), 7.45 (d, 2H), 7.22 (t, 1H), 6.63 (s, 1H), 6.46 - 6.41 (m, 1H), 3.69 (s, 3H), 3.40 - 3.30 (m, 1H), 3.11 (dd, 1H), 2.58 - 2.52 (m, 1H), 2.45 - 2.36 (m, 4H), 1.99 (t, 1H), 1.91 (t, 1H), 1.81 (d, 1H), 1.74 - 1.64 (m, 2H), 1.55 (t, 1H), 1.48 (d, 1H), 1.42 - 1.34 (m, 1H) ppm.

[0353] Example 8: Preparation of (S)-4-(7-(5-methoxy-7-methyl-1H-indol-4-yl)methyl-d2)-2- ((methyl-d3)thio)-7-azaspiro[3.5]non-6-yl)benzoic acid (Compound 8)

[0354] First Step: Preparation of (S)-5-(methoxy-d3)-4-(6-(4-(methoxy carbonyl)phenyl)-2- ((methyl-d3)thio)-7-azaspiro[3.5]nonen-7-yl)methyl-d2)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (8-a)

[0355] Compound 2c (770 mg, 2.50 mmol), intermediate 5 (1.35 g, 3.74 mmol) were added into a 100 mL single-neck flask, 10 mL DMF was added, cesium carbonate (2.44 g, 7.49 mmol) was added, and stirring was performed at 80 °C under nitrogen protection for 3 hours. 50 mL ethyl acetate was added, and the organic phase was concentrated under reduced pressure after washing with 100 mL saturated sodium chloride three times. Purification was performed on a silica gel column (ethyl acetate: petroleum ether = 1:10) to obtain compound 8-a (940 mg, light yellow solid). LC-MS m / z (ESI) = 587.3 [M+H] + .

[0356] Second Step: Preparation of (S)-4-(7-(5-(methoxy-d3)-7-methyl-1H-indol-4-yl)methyl-d2- ((methyl-d3)thio)-7-azaspiro[3.5]non-6-yl)benzoic acid (Compound 8)

[0357] The compound 8-a obtained in the previous step was added to a 50 mL single-neck flask, 3 mL THF, 2 mL methanol, 1 mL pure water, lithium hydroxide (673 mg, 16.01 mmol) was added, and stirring was carried out at 80 °C for 3 hours. Filtration was carried out, the filtrate was adjusted to pH 7 with dilute hydrochloric acid, and purified by preparative liquid phase (instrument: Shimadzu LC-20AP; column: Agilent InfinityLab Poroshell 120HPH-C18, 21.2 x 150 mm x 4 pm; gradient condition ACN / 0.10% NH3.H2O in H2O: 20%-95%, 20 mL / min, retention time 4.7 min) to obtain compound 8 (510 mg, white solid).

[0358] Take 485 mg of compound 8 to be resolved by SFC, and the conditions are shown in Table 8.

[0359] Table 8

[0360] Compound 8A (258.4 mg, retention time 4.73 min) was obtained, LC-MS m / z (ESI) = 473.1 [M+H] + . 1 H NMR (500 MHz, DMSO-d6) δ 10.80 (s, 1H), 7.95 (d, 2H), 7.63 (d, 2H), 7.24 (t, 1H), 6.64 (s, 1H), 6.45 (s, 1H), 3.38-3.31 (m, 1H), 3.14 (d, 1H), 2.63 (d, 1H), 2.41 (s, 3H), 2.31 (t, 1H), 2.05-1.95 (m, 2H), 1.85-1.79 (m, 1H), 1.72-1.54 (m, 4H), 1.39-1.31 (m, 1H) ppm.

[0361] Compound 8B (191.3 mg, retention time 7.59 min), LC-MS m / z (ESI) = 473.1 [M+H] + . 1 H NMR (500 MHz, DMSO-d6) δ 10.84 (s, 1H), 7.90 (d, 2H), 7.44 (d, 2H), 7.22 (t, 1H), 6.62 (s, 1H), 6.46-6.41 (m, 1H), 3.11 (dd, 1H), 2.55 (d, 1H), 2.45-2.35 (d, 4H), 2.02-1.95 (m, 1H), 1.91 (t, 1H), 1.81 (d, 1H), 1.74-1.62 (m, 2H), 1.56 (t, 1H), 1.48 (d, 1H), 1.43-1.34 (m, 1H) ppm.

[0362] Example 9: Preparation of (S)-4-(7-(5-methoxy-7-methyl-1H-indol-4-yl)methyl-d2)-2- (methylthio)-7-azaspiro[3.5]non-6-yl)benzoic acid (Compound 9)

[0363] First Step: Preparation of tert-butyl (S)-5-methoxy-4-(6-(4-(methoxy carbonyl)phenyl)- 2-(methylthio)-7-azaspiro[3.5]non-7-yl)methyl-d2)-7-methyl-1H-indole-1-carboxylate (9-a)

[0364] Compound 1e (800 mg, 2.62 mmol), intermediate 4 (1.4 g, 3.93 mmol) were added into a 100 mL single-neck flask, 10 mL DMF was added, cesium carbonate (2.56 g, 7.86 mmol) was added, and stirring was performed at 80 °C for 3 hours. 50 mL ethyl acetate was added, and the mixture was washed with 100 mL saturated sodium chloride three times. The organic phase was concentrated under reduced pressure, and silica gel column purification (ethyl acetate: petroleum ether = 1:10) gave the title compound Compound 9-a (620 mg, light yellow solid). LC-MS m / z (ESI) = 581.3 [M+H] + .

[0365] Second Step: Preparation of (S)-4-(7-(5-methoxy-7-methyl-1H-indol-4-yl)methyl-d2)-2- (methylthio)-7-azaspiro[3.5]non-6-yl)benzoic acid (Compound 9)

[0366] The compound 9-a obtained in the previous step was added into a 50 mL single-neck flask, 3 mL THF, 2 mL methanol, 1 mL pure water were added, lithium hydroxide (450 mg, 10.67 mmol) was added, and stirring was performed at 80 °C for 3 hours. Filtration was performed, the filtrate was adjusted to pH 7 with dilute hydrochloric acid, and preparative liquid phase purification (instrument: Shimadzu LC-20AP; column: Agilent InfinityLab Poroshell 120HPH-C18, 21.2 x 150 mm x 4 μm; gradient condition: ACN / H2O: 10%-90%, 20 mL / min, retention time 5.8 min) gave Compound 9 (210 mg, white solid).

[0367] Take 210 mg of Compound 9 and separate by SFC, the conditions are shown in Table 9.

[0368] Table 9

[0369] Compound 9A (112.3 mg, retention time 3.85 min), LC-MS m / z (ESI) = 467.1 [M+H] + .

[0370] 1 H NMR (500 MHz, DMSO-d6) δ 10.83 (s, 1H), 7.97 (d, 2H), 7.65 (d, 2H), 7.26 (t, 1H), 6.66 (s, 1H), 6.48 - 6.44 (m, 1H), 3.71 (s, 3H), 3.16 (d, 1H), 2.68 - 2.61 (m, 1H), 2.43 (s, 3H), 2.37 - 2.29 (m, 1H), 2.06 - 1.97 (m, 6H), 1.88 - 1.79 (m, 1H), 1.75 - 1.55 (m, 4H), 1.41 - 1.32 (m, 1H) ppm.

[0371] Compound 9B (63.2 mg, retention time 6.51 min), LC-MS m / z (ESI) = 467.2 [M+H] + . 1 H NMR (500 MHz, DMSO-d6) δ 10.80 (s, 1H), 7.88 (d, 2H), 7.46 (d, 2H), 7.24 (t, 1H), 6.64 (s, 1H), 6.46 - 6.42 (m, 1H), 3.70 (s, 3H), 3.13 (d, 1H), 2.60 - 2.53 (m, 1H), 2.47 - 2.39 (m, 4H), 2.05 - 1.96 (m, 5H), 1.92 (t, 1H), 1.86 - 1.79 (m, 1H), 1.76 - 1.64 (m, 2H), 1.56 (t, 1H), 1.52 - 1.45 (m, 1H), 1.44 - 1.35 (m, 1H) ppm.

[0372] Example 10: Preparation of (S)-4-(7-((5-methoxy-7-methyl-lH-indol-4-yl)methyl)-2- (methyl-d3)thio)-7-azaspiro[3.5]nonan-6-yl)-3-methylbenzoic acid (Compound 10)

[0373] First step: Preparation of (S)-2-hydroxy-6-(4-(methoxycarbonyl)-2-methylphenyl)-7- azaspiro[3.5]nonane-7-carboxylic acid benzyl ester (10a)

[0374] Intermediate 7 (1 g, 2.37 mmol) was dissolved in 10 mL of methanol, cooled to 0 °C under nitrogen protection, and sodium borohydride (180 mg, 4.71 mmol) was added. After the addition was completed, the reaction was continued to stir at 0 °C for 20 min. 5 mL of saturated ammonium chloride was added, and 20 mL of ethyl acetate was used for extraction. The organic layer was washed with 10 mL of saturated sodium chloride again, dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. Compound 10a (1 g, white solid) was obtained by silica gel column purification (ethyl acetate: petroleum ether = 1:4). LC-MS m / z (ESI) = 424.1 [M+H] + .

[0375] Second step: Preparation of (S)-benzyl 6-(4-(methoxycarbonyl)-2-methylphenyl)-2- ((methylsulfonyl)oxy)-7-azaspiro[3.5]nonane-7-carboxylate (10b)

[0376] Compound 10a (1 g, 2.36 mmol) was dissolved in 10 mL of dichloromethane, cooled to 0 °C under nitrogen protection, and triethylamine (480 mg, 4.7 mmol) and methanesulfonyl chloride (320 mg, 2.79 mmol) were added successively. After the addition was completed, the reaction was continued to stir at room temperature for 2 h. 5 mL of water and 20 mL of dichloromethane were added, and the mixture was separated. The organic layer was washed with 10 mL of saturated sodium chloride again, dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. Compound 10b (962 mg, white solid) was obtained by silica gel column purification (ethyl acetate: petroleum ether = 1:4). LC-MS m / z (ESI) = 502.1 [M+H] + .

[0377] Third step: Preparation of (S)-benzyl 6-(4-(methoxycarbonyl)-2-methylphenyl)-2- (methylthio)-7-azaspiro[3.5]nonane-7-carboxylate (10c)

[0378] Compound 10b (962 mg, 1.92 mmol) was dissolved in 5 mL of DMF, and sodium thiomethoxide aqueous solution (20%, 4 mL) was added. The reaction was carried out at 80 °C for 4 h under nitrogen protection. After cooling to room temperature, 5 mL of water was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was adjusted to pH 5 or so with 1N dilute hydrochloric acid, and 10 mL of water and 20 mL of ethyl acetate were added. The mixture was separated, and the organic layer was washed with 10 mL of saturated sodium chloride again, dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. Compound 10c (554 mg, white solid) was obtained by silica gel column purification (ethyl acetate: petroleum ether = 1:9). LC-MS m / z (ESI) = 482.1 [M+H] + .

[0379] Step 4: Preparation of (S)-6-(4-(methoxycarbonyl)-2-methylphenyl)-2-((methyl- d3)thio)-7-azaspiro[3.5]nonane-7-carboxylic acid benzyl ester (10d)

[0380] Compound 10c (554 mg, 1.2 mmol) was dissolved in 10 mL of methanol, deuterated methyl iodide (333 mg, 2.3 mmol), lithium hydroxide (41 mg, 1.7 mmol) were added successively, and the mixture was stirred at room temperature for 20 minutes after the addition was completed. 20 mL of water was added, and the mixture was extracted with 30 mL of ethyl acetate once. The organic layer was washed with 20 mL of saturated sodium chloride, dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. Purification on a silica gel column (ethyl acetate: petroleum ether = 1:9) gave compound 10d (406 mg, white solid). LC-MS m / z (ESI) = 457.1 [M+H] + .

[0381] Step 5: Preparation of (S)-methyl 3-methyl-4-(2-(methyl-d3)thio)-7- azaspiro[3.5]nonan-6-yl)benzoate (10e)

[0382] Compound 10d (406 mg, 0.89 mmol) was dissolved in 5 mL of acetonitrile, and the mixture was cooled to 0°C under nitrogen protection. Trimethylsilyl iodide (533 mg, 2.662 mmol) was added, and the mixture was stirred at 0°C for 1 hour after the addition was completed. Saturated aqueous sodium bicarbonate solution was added dropwise to adjust the pH to basic, and the mixture was extracted with 30 mL of ethyl acetate. The organic layer was washed with 20 mL of saturated sodium chloride, dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. Purification on a silica gel column (methanol:dichloromethane = 1:10) gave compound 10e (185 mg, light yellow solid). LC-MS m / z (ESI) = 323.0 [M+H] + ;

[0383] Step 6: Preparation of (S)-tert-butyl 5-methoxy-4-((6-(4-(methoxycarbonyl)-2-((methyl- d3)thio)-7-azaspiro[3.5]non-7-yl)methyl)-7-methyl-1H-indole-1-carboxylate (10f)

[0384] Compound 10e (185 mg, 0.57 mmol), intermediate 2 (329.5 mg, 0.93 mmol) were added to a 100 mL single-neck flask, 10 mL of DMF was added, and cesium carbonate (505.2 mg, 1.55 mmol) was added. The mixture was stirred at 80°C for 3 hours. 50 mL of ethyl acetate was added, and the mixture was washed with 100 mL of saturated sodium chloride three times. The organic phase was concentrated under reduced pressure, and purification on a silica gel column (ethyl acetate: petroleum ether = 1:10) gave compound 10f (119 mg, light yellow solid). LC-MS m / z (ESI) = 596.2 [M+H]+ .

[0385] Step 7: Preparation of (S)-4-(7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-2-((methyl-d3)thio)-7-azaspiro[3.5]non-6-yl)-3-methylbenzoic acid (compound 10)

[0386] Compound 10f (119 mg, 0.2 mmol) was dissolved in a mixed solvent of methanol (2 mL) and THF (2 mL), water (1 mL) was added, and lithium hydroxide (95.6 mg, 4.0 mmol) was added. The reaction was carried out at 70 °C for 3 h under nitrogen protection. After the reaction was completed, the mixture was allowed to stand at room temperature, the pH was adjusted to neutral with 1 N dilute hydrochloric acid, concentrated under reduced pressure, and purified by C18 column chromatography (acetonitrile:water = 90:10) to give compound 10 (49 mg, white solid). LC-MS m / z (ESI) = 482.0 [M+H] + ;

[0387] 49 mg of compound 10 was separated by SFC under the conditions shown in Table 10 below.

[0388] Table 10

[0389] Compound 10A (18 mg, retention time 3.58 min) was obtained. 1 H NMR(400MHz,DMSO-d6)δ10.80(d,1H),7.85(d,2H),7.76(d,1H),7.30–7.22(m,1H),6.64(d,1H),6.46(d,1H),3.71(s,3H),3.58(d,1H),3.40(s ,2H),3.12(d,1H),2.68(d,1H),2.46(s,3H),2.43(s,3H),2.36(d,1H), 2.03(t,2H),1.81(dd,1H),1.67(dd,3H),1.49(s,1H),1.38(t,1H)ppm.

[0390] Compound 10B (12 mg, retention time 4.97 min), 1H NMR (400 MHz, DMSO-d6) δ 10.80 (d, 1H), 7.84 (d, 2H), 7.76 (d, 1H), 7.28 - 7.23 (m, 1H), 6.65 (d, 1H), 6.45 (d, 1H), 3.71 (s, 3H), 3.57 (d, 1H), 3.44 (d, 2H), 3.13 (d, 1H), 2.62 (d, 1H), 2.48 (s, 3H), 2.43 (s, 3H), 2.37 (d, 1H), 1.99 (t, 2H), 1.74 (ddd, 3H), 1.53 (d, 1H), 1.46 - 1.36 (m, 2H) ppm. Example 11: Preparation of (S)-4-(7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-2-((trifluoromethyl)thio)-7- azaspiro[3.5]non-6-yl)benzoic acid (Compound 11)

[0391] First Step: Preparation of (S)-6-(4-(methoxycarbonyl)phenyl)-2-((trifluoromethyl)thio)-7- azaspiro[3.5]nonane-7-carboxylic acid benzyl ester (11a)

[0392] 100 mL single neck flask was charged with 1b (860 mg, 2.1 mmol), toluene (20 mL), tetrabutylammonium iodide (9.3 g, 25.2 mmol), potassium iodide (2.8 g, 16.8 mmol) and silver trifluoromethanethiolate (1.76 g, 8.4 mmol) under nitrogen protection, the reaction was stirred at 120 °C for 16 h. After the reaction was completed, water was added for quenching, ethyl acetate was used for extraction, the organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and purified by silica gel column (ethyl acetate: petroleum ether = 1:5) to give compound 11a (600 mg, yellow oil). LC-MS m / z (ESI) = 494.1 [M+H] + .

[0393] Second Step: Preparation of (S)-4-(2-((trifluoromethyl)thio)-7-azaspiro[3.5]nonan-6-yl)benzoic acid methyl ester (11b)

[0394] Compound 11a (600 mg, 1.2 mmol) was dissolved in 5 mL of acetonitrile, cooled to 0 °C under nitrogen protection, and trimethylsilyl iodide (729 mg, 3.6 mmol) was added. After the addition was completed, it was continuously stirred at 0 °C for 1 h. Saturated aqueous sodium bicarbonate solution was added dropwise to adjust the pH to basic, and then extracted with 30 mL of ethyl acetate. The organic layer was washed with 20 mL of saturated sodium chloride, dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. Purification on a silica gel column (methanol: dichloromethane = 1:10) gave compound 11b (428 mg, light yellow solid). LC-MS m / z (ESI) = 360.1 [M+H] + .

[0395] Step 3: Preparation of (S)-5-methoxy-4-((6-(4-(methoxycarbonyl)phenyl)-2-((trifluoromethyl)thio)-7-azaspiro[3.5]non-7-yl)methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (11c)

[0396] Compound 11b (120 mg, 0.33 mmol) and intermediate 2 (141.9 mg, 0.40 mmol) were added to a 100 mL single-neck flask, 10 mL of DMF was added, and cesium carbonate (326.3 mg, 1.0 mmol) was added. It was stirred at 80 °C for 3 h. 50 mL of ethyl acetate was added, and it was washed with 100 mL of saturated sodium chloride three times. The organic phase was concentrated under reduced pressure, and purification on a silica gel column (ethyl acetate: petroleum ether = 1:10) gave compound 11c (106 mg, light yellow solid). LC-MS m / z (ESI) = 633.2 [M+H] + .

[0397] Step 4: Preparation of (S)-4-(7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-2-((trifluoromethyl)thio)-7-azaspiro[3.5]non-6-yl)benzoic acid (compound 11)

[0398] Compound 11c (106 mg, 0.17 mmol) was dissolved in a mixed solvent of methanol (2 mL) and THF (2 mL), water (1 mL) was added, and lithium hydroxide (80.2 mg, 3.3 mmol) was added. It was reacted at 70 °C under nitrogen protection for 3 h. After the reaction was completed, it was allowed to stand at room temperature, the pH was adjusted to neutral with 1N dilute hydrochloric acid, concentrated under reduced pressure, and purified on a C18 column (acetonitrile: water = 90:10) to give compound 11 (47 mg, white solid). LC-MS m / z (ESI) = 519.0 [M+H] + ;

[0399] 47 mg of compound 11 was resolved by SFC under the conditions shown in Table 11.

[0400] Table 11

[0401] Compound 11A (20 mg, retention time 1.79 min) was obtained, 1 H NMR (500 MHz, DMSO-d6) δ 11.16 (d, 1H), 8.90 (d, 1H), 8.13 (s, 2H), 7.80 (s, 1H), 7.42 (s, 1H), 6.74 (d, 1H), 6.37 (d, 1H), 4.51 (s, 1H), 4.19 (s, 1H), 4.06 (d, 2H), 3.69 (s, 3H), 3.21 (s, 2H), 2.48 (s, 3H), 2.27 (s, 2H), 2.13 (t, 1H), 2.04 (s, 4H), 1.87 (s, 1H) ppm.

[0402] Compound 11B (10 mg, retention time 2.37 min), 1 H NMR (500 MHz, DMSO-d6) δ 10.79 (d, 1H), 7.92 (d, 2H), 7.60 (d, 2H), 7.26 - 7.20 (m, 1H), 6.63 (d, 1H), 6.43 (d, 1H), 4.08 - 4.00 (m, 1H), 3.69 (s, 3H), 3.53 (s, 1H), 3.21 (d, 2H), 3.14 (d, 2H), 2.41 (s, 3H), 2.21 (t, 1H), 1.97 - 1.85 (m, 4H), 1.56 - 1.49 (m, 2H), 1.44 (dd, 1H) ppm.

[0403] Example 12: Preparation of (S)-4-(7-(5-(difluoromethoxy)-7-methyl-1H-indol-4-yl)methyl)-2- ((methyl-d3)thio)-7-azaspiro[3.5]non-6-yl)benzoic acid (Compound 12)

[0404] First Step: Preparation of (S)-5-(difluoromethoxy)-4-(6-(4- (methoxycarbonyl)phenyl)-2-((methyl-d3)thio)-7-azaspiro[3.5]non-7-yl)methyl)-7- methyl-1H-indole-1-carboxylic acid tert-butyl ester (12-a)

[0405] Compound 2c (550 mg, 1.78 mmol), intermediate 6 (1.04 g, 2.67 mmol) were added into a 100 mL single-neck flask, 10 mL DMF was added, cesium carbonate (1.74 g, 5.35 mmol) was added, and stirring was performed at 80 °C for 3 h. 50 mL ethyl acetate was added, and the mixture was washed with 100 mL saturated sodium chloride three times. The organic phase was concentrated under reduced pressure, and purification was performed on a silica gel column (ethyl acetate: petroleum ether = 1:10) to obtain the title compound compound 12-a (820 mg, yellow solid). LC-MS m / z (ESI) = 618.1 [M+H] + .

[0406] Second step: Preparation of (S)-4-(7-(5-(difluoromethoxy)-7-methyl-1H-indol-4-yl)methyl)-2-((methyl-d3)thio)-7-azaspiro[3.5]non-6-yl)benzoic acid (compound 12)

[0407] The compound 12-a obtained in the previous step was added into a 50 mL single-neck flask, 3 mL THF, 2 mL methanol, 1 mL pure water were added, lithium hydroxide (557 mg, 13.27 mmol) was added, and stirring was performed at 80 °C for 3 h. Filtration was performed, the filtrate was adjusted to pH 7 with dilute hydrochloric acid, and purification was performed on an Agilent InfinityLab Poroshell 120 HPH-C18, 21.2 x 150 mm x 4 μm column (acetonitrile / 0.1% NH3-H2O in H2O: 10%-90%, 20 mL / min, retention time 6.6 min) to obtain compound 12 (520 mg, white solid).

[0408] 490 mg of compound 12 was resolved by SFC, and the conditions are shown in Table 12.

[0409] Table 12

[0410] Compound 12-A (256.1 mg, retention time 2.76 min) was obtained, LC-MS m / z (ESI) = 504.2 [M+H] + .

[0411] 1H NMR (500 MHz, DMSO-d6) δ 11.16 (s, 1H), 7.95 (d, 2H), 7.64 (d, 2H), 7.37 (s, 1H), 7.13 - 6.75 (t, 1H), 6.72 (s, 1H), 6.63 (s, 1H), 3.59 (d, 1H), 3.39 - 3.31 (m, 1H), 3.16 (d, 2H), 2.55 (d, 1H), 2.44 (s, 3H), 2.31 (t, 1H), 2.05 - 1.95 (m, 2H), 1.87 - 1.80 (m, 1H), 1.75 - 1.59 (m, 4H), 1.38 (t, 1H) ppm. 19 F NMR (471 MHz, DMSO-d6) δ -78.49, -78.85, -79.35, -79.70 ppm.

[0412] Compound 12-B (187.7 mg, retention time 5.11 min), LC-MS m / z (ESI) = 504.1 [M+H] + . 1 H NMR (500 MHz, DMSO-d6) δ 11.21 (s, 1H), 7.88 (d, 2H), 7.43 (d, 2H), 7.35 (s, 1H), 6.91 (t, 1H), 6.70 (s, 1H), 6.62 (s, 1H), 3.61 (d, 1H), 3.39 - 3.31 (m, 1H), 3.12 (d, 2H), 2.49 - 2.40 (m, 5H), 2.01 (t, 1H), 1.94 - 1.80 (m, 2H), 1.75 - 1.57 (m, 3H), 1.50 (d, 1H), 1.45 - 1.37 (m, 1H) ppm. 19 F NMR (471 MHz, DMSO-d6) δ -78.39, -78.74, -79.23, -79.58 ppm.

[0413] Example 13: Preparation of (S)-4-(7-(5-methoxy-7-methyl-lH-indol-4-yl)methyl)-2- (cyclobutyloxymercapto)-7-azaspiro[3.5]non-6-yl)benzoic acid (Compound 13)

[0414] First Step: Preparation of 4-(2-oxo-7-azaspiro[3.5]non-6-yl)-benzoic acid methyl ester (Compound 13-a)

[0415] Compound 1a (1.2 g, 3.20 mmol) was dissolved in 15 mL of ethyl acetate, 1.2 g of 10% palladium carbon was added, the system was replaced with hydrogen for 3 times, and stirred at room temperature for 2 hours; the reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain compound 13-a (800 mg, white solid). LC-MS m / z (ESI) = 274.2 [M+H] + .

[0416] Second step: preparation of (S)-5-methoxy-4-(6-(4-(methoxycarbonyl)phenyl)-2-oxo-7- azaspiro[3.5]non-7-ylmethyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (compound 13-b)

[0417] Compound 13-a (800 mg, 2.93 mmol) was dissolved in 10 mL of DMF, 1e.q. of a DMF solution of intermediate 2 was added, and the reaction was carried out at room temperature for 12 h under nitrogen protection. After the reaction was completed, the system was diluted with water, 50 mL of ethyl acetate was added, washed with 100 mL of saturated sodium chloride for three times, the organic phase was concentrated under reduced pressure, and purified by silica gel column (ethyl acetate: petroleum ether = 1:10) to obtain compound 13-b (890 mg, colorless oil). LC-MS m / z (ESI) = 547.3 [M+H] + .

[0418] Third step: preparation of (S)-5-methoxy-4-(6-(4-(methoxycarbonyl)phenyl)-2-hydroxy-7- azaspiro[3.5]non-7-ylmethyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (compound 13-c)

[0419] Compound 13-b (890 mg, 1.63 mmol) was dissolved in a mixture of 4 mL of methanol and 4 mL of tetrahydrofuran, (95 mg, 2.5 mmol) of sodium borohydride was added in batches, and the reaction was carried out at room temperature for 1 h. After the reaction was completed, the system was diluted with water, extracted with 20 mL of ethyl acetate for three times, the organic phase was concentrated under reduced pressure, and purified by silica gel column (ethyl acetate: petroleum ether = 2:8) to obtain compound 13-c (820 mg, colorless oil). LC-MS m / z (ESI) = 549.2 [M+H] + .

[0420] Fourth step: preparation of (S)-5-methoxy-4-(6-(4-(methoxycarbonyl)phenyl)-2-hydroxy-7- azaspiro[3.5]non-7-ylmethyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (compound 13-d)

[0421] Compound 13-c (820 mg, 1.49 mmol) was dissolved in 9 mL of dichloromethane, (205 mg, 1.80 mmol) of methanesulfonyl chloride, (303 mg, 3.00 mmol) of triethylamine and (36.5 mg, 0.30 mmol) of DMAP were added successively, and the reaction was allowed to proceed at room temperature for 2 h. After the reaction was completed, the system was diluted with water, extracted with 20 mL of ethyl acetate three times, the organic phase was concentrated under reduced pressure, and purified by silica gel column (ethyl acetate: petroleum ether = 1:9) to obtain compound 13-d (930 mg, colorless oil). LC-MS m / z (ESI) = 627.1 [M+H] + .

[0422] Step 5: Preparation of tert-butyl (S)-5-methoxy-4-(6-(4- (methoxycarbonyl)phenyl)-2-(oxetanylsulfanyl)-7-azaspiro[3.5]non-7-ylmethyl)-7- methyl-1H-indole-1-carboxylate (Compound 13-e)

[0423] Compound 13-d (105 mg, 0.17 mmol) was dissolved in 3 mL of DMF, (23 mg, 0.26 mmol) of 3-mercaptooxetane and (164 mg, 0.50 mmol) of cesium carbonate were added successively, and the reaction was allowed to proceed at 60°C for 12 h. After the reaction was completed, the system was diluted with water, extracted with 20 mL of ethyl acetate three times, and the organic phase was concentrated under reduced pressure to obtain compound 13-e (colorless oil) as a crude product. The crude product was directly used in the next step without purification. LC-MS m / z (ESI) = 621.5 [M+H] + .

[0424] Step 6: Preparation of (S)-4-(7-(5-methoxy-7-methyl-1H-indol-4-yl)methyl)-2- (oxetanylsulfanyl)-7-azaspiro[3.5]non-6-yl)benzoic acid (Compound 13)

[0425] Compound 13-e obtained in the previous step was dissolved in a mixture of 3 mL of THF and 2 mL of methanol, and lithium hydroxide (24 mg, 1.00 mmol) was added, and the reaction was allowed to proceed at 70°C for 4 h. After filtration, the filtrate was adjusted to pH 7 with dilute hydrochloric acid, and purified by Agilent InfinityLab Poroshell 120 HP H-C18, 21.2*150mm*4μm column (acetonitrile / 0.1% NH3-H2O in H2O: 10%-90%, 20 mL / min, retention time 6.8 min) to obtain compound 13 (6 mg, white solid). LC-MS m / z (ESI) = 507.8 [M+H] + ; 1H NMR (500 MHz, DMSO-d6) δ 10.82 (s, 1H), 7.96 (s, 2H), 7.62 (s, 2H), 7.24 (m, 1H), 6.65 (s, 1H), 6.45 (d, 1H), 4.84 (t, 2H), 4.40 (t, 2H), 4.14 (dt, 1H), 3.80 - 3.00 (m, 7H), 2.70 - 2.45 (m, 2H), 2.41 (s, 3H), 2.10 - 1.50 (m, 8H) ppm.

[0426] Example 14: Preparation of (S)-4-(7-((5-methoxy-7-methyl-lH-indol-4-yl)methyl)-2- (methylthio)-7-azaspiro[3.5]nonan-6-yl-2-d)benzoic acid (Compound 14)

[0427] First Step: Preparation of (S)-6-(4-(methoxycarbonyl)phenyl)-2-(methylthio)-7- azaspiro[3.5]nonane-7-carboxylate benzyl ester-2-d (14-a)

[0428] Compound 4c (3.74 g, 7.98 mmol) was added to a 100 mL single-neck flask, 30 mL of methanol was added, followed by the addition of methyl iodide (1 mL, 15.96 mmol), and then lithium hydroxide (0.29 g, 11.97 mmol), and stirred at 25 °C for 2 hours. 50 mL of ethyl acetate was added, washed with 150 mL of saturated sodium chloride three times, dried with anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure, and purified by silica gel column (ethyl acetate: petroleum ether = 1:3) to obtain compound 14-a (3.0 g, yellow oil). LC-MS m / z (ESI) = 440.9 [M+H] + .

[0429] Second Step: Preparation of methyl (S)-4-(2-(methylthio)-7-azaspiro[3.5]nonan-6-yl-2- d)benzoate (14-b)

[0430] Compound 14-a (3.0 g, 6.80 mmol) was added to a 100 mL single-neck flask, 20 mL of acetonitrile was added, and the temperature was lowered to 0 °C, followed by the addition of trimethylsilyl iodide (3 mL, 20.43 mmol), and stirred at 0 °C for 30 minutes. Quench with methanol, extract with 30 mL of petroleum ether three times, adjust the pH of the aqueous phase to 7-8 with potassium carbonate aqueous solution, add 20 mL of ethyl acetate, wash with 100 mL of saturated sodium chloride three times, dry with anhydrous sodium sulfate, concentrate the organic phase under reduced pressure, and purify by silica gel column (methanol: dichloromethane = 1:10) to obtain compound 14-b (2 g, yellow solid). LC-MS m / z (ESI) = 306.9 [M+H] + .

[0431] Step 3: Preparation of (S)-5-methoxy-4-((6-(4-(methoxy carbonyl)phenyl)-2- (methylthio)-7-azaspiro[3.5]nonan-7-yl-2-d)methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (14-c)

[0432] Compound 14-b (900 mg, 2.94 mmol) was added to a 100 mL single-neck flask, 10 mL DMF was added, intermediate 2 (2.87 g, 4.40 mmol), cesium carbonate (1.56 g, 8.81 mmol) were added, and stirring was performed at 80 °C for 2 hours. 20 mL ethyl acetate was added, and the mixture was washed with 50 mL saturated sodium chloride three times, dried over anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure. Purification was performed on a silica gel column (ethyl acetate: petroleum ether = 1:10) to obtain compound 14-c (737 mg, yellow solid). LC-MS m / z (ESI) = 580.0 [M+H] + .

[0433] Step 4: Preparation of (S)-4-(7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-2- (methylthio)-7-azaspiro[3.5]nonan-6-yl-2-d)benzoic acid (compound 14)

[0434] Compound 14-c obtained in the previous step was added to a 50 mL single-neck flask, 5 mL THF, 5 mL methanol, 3 mL pure water were added, lithium hydroxide (304 mg, 12.71 mmol) was added, and stirring was performed at 80 °C for 3 hours. The pH was adjusted to 7 with dilute hydrochloric acid, filtered, and purified by preparative liquid chromatography (instrument: Shimadzu LC-20AP; column: Agilent InfinityLab Poroshell 120HPH-C18, 21.2*150mm*4μm; gradient conditions: acetonitrile / 0.1% NH3-H2O in H2O: 10%-60%, 20 mL / min, retention time 6.5 min) to obtain compound 14 (410 mg, white solid). 410 mg of compound 14 was subjected to chiral resolution under the conditions shown in Table 13.

[0435] Table 13

[0436] Compound 14A (139 mg, retention time 9.0 min) was obtained, LC-MS m / z (ESI) = 465.8 [M+H] + . 1H NMR (500 MHz, DMSO-d6) δ 10.82 (s, 1H), 7.88 (d, 2H), 7.46 (d, 2H), 7.24 (t, 1H), 6.64 (s, 1H), 6.47 - 6.43 (m, 1H), 3.70 (s, 3H), 3.52 (d, 1H), 3.09 (dd, 2H), 2.63 (dd, 1H), 2.44 (dd, 1H), 2.41 (s, 3H), 2.33 - 2.27 (m, 1H), 2.00 (d, 1H), 1.98 (s, 3H), 1.81 (d, 1H), 1.71 - 1.57 (m, 4H), 1.35 (dd, 1H) ppm.

[0437] Compound 14B (94.2 mg, retention time 12.0 min), LC-MS m / z (ESI) = 466.0 [M+H] + . 1 H NMR (500 MHz, DMSO-d6) δ 10.82 (s, 1H), 7.97 (d, 2H), 7.67 (d, 2H), 7.25 (t, 1H), 6.65 (s, 1H), 6.45 - 6.42 (m, 1H), 3.70 (s, 3H), 3.51 (d, 1H), 3.22 (d, 1H), 3.14 (d, 1H), 2.60 - 2.55 (m, 1H), 2.44 (s, 1H), 2.41 (s, 3H), 1.98 (s, 4H), 1.92 (d, 1H), 1.87 - 1.80 (m, 1H), 1.70 (dd, 2H), 1.56 - 1.46 (m, 2H), 1.44 - 1.34 (m, 1H) ppm.

[0438] Example 15: Preparation of (S)-4-(7-((5-methoxy-7-methyl-lH-indol-4-yl)methyl-d2)-2- (methylthio)-7-azaspiro[3.5]nonan-6-yl-2-d)benzoic acid (Compound 15)

[0439] First Step: Preparation of (S)-5-methoxy-4-((6-(4-(methoxy carbonyl)phenyl)-2- (methylthio)-7-azaspiro[3.5]nonan-7-yl-2-d)methyl-d2)-7-methyl-lH-indole-1-carboxylic acid tert-butyl ester (15-a)

[0440] Compound 14-b (900 mg, 2.94 mmol) was taken in 100 mL flask, 10 mL DMF was added, intermediate 4 (2.87 g, 4.40 mmol), cesium carbonate (1.57 g, 8.81 mmol) was added, stirred at 80 °C for 2 h. 20 mL ethyl acetate was added, washed with 50 mL saturated sodium chloride three times, dried over anhydrous sodium sulfate, the organic phase was concentrated under reduced pressure, purified by silica gel column (ethyl acetate: petroleum ether = 1:10) to get the title compound compound 15-a (900 mg, yellow solid). LC-MS m / z (ESI) = 582.0 [M+H] + .

[0441] Second Step: Preparation of (S)-4-(7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl-d2)-2- (methylthio)-7-azaspiro[3.5]nonan-6-yl-2-d)benzoic acid (Compound 15)

[0442] The compound 15-a obtained in the previous step was taken in 50 mL flask, 5 mL THF, 5 mL methanol, 3 mL pure water was added, lithium hydroxide (370 mg, 15.47 mmol) was added, stirred at 80 °C for 3 h. The pH was adjusted to 7 with dilute hydrochloric acid, filtered, and purified by preparative liquid chromatography (instrument: Shimadzu LC-20AP; column: Agilent InfinityLab Poroshell 120HPH-C18, 21.2*150mm*4μm; gradient condition: acetonitrile / 0.1%NH3-H2O in H2O: 10%-90%, 20 mL / min, retention time 6.3 min) to get compound 15 (440 mg, white solid). 440 mg of compound 15 was taken for chiral resolution, the conditions are shown in Table 14.

[0443] Table 14

[0444] Compound 15A (158 mg, retention time 9.2 min) was obtained, LC-MS m / z (ESI) = 468.0 [M+H] + . 1H NMR (500 MHz, DMSO-d6) δ 10.82 (s, 1H), 7.88 (d, 2H), 7.46 (d, 2H), 7.24 (t, 1H), 6.64 (s, 1H), 6.47 - 6.43 (m, 1H), 3.70 (s, 3H), 3.52 (d, 1H), 3.09 (dd, 1H), 2.63 (dd, 1H), 2.44 (dd, 1H), 2.41 (s, 3H), 2.33 - 2.27 (m, 1H), 1.98 (s, 3H), 1.81 (d, 1H), 1.71 - 1.57 (m, 4H), 1.35 (dd, 1H) ppm.

[0445] Compound 15B (94.6 mg, retention time 12.3 min), LC-MS m / z (ESI) = 468.0 [M+H] + . 1 H NMR (500 MHz, DMSO-d6) δ 10.80 (s, 1H), 7.96 (d, 2H), 7.66 (d, 2H), 7.22 (d, 1H), 6.63 (d, 1H), 6.41 (d, 1H), 3.69 (s, 3H), 3.22 (d, 1H), 2.60 - 2.54 (m, 2H), 2.41 (s, 3H), 1.98 (d, 4H), 1.92 (d, 1H), 1.83 (d, 1H), 1.69 (dd, 2H), 1.57 - 1.45 (m, 2H), 1.39 (t, 1H) ppm.

[0446] Example 16: Preparation of (S)-4-(7-(5-methoxy-7-methyl-lH-indole-4-carbonyl)-2-(methylthio)-7- azaspiro[3.5]nonan-6-yl)benzoic acid (Compound 16)

[0447] First Step: Preparation of tert-butyl 4-(chlorocarbonyl)-5-methoxy-7-methyl-lH-indole-l- carboxylate (16-b)

[0448] Intermediate 16-a (1.21 g, 3.96 mmol) was added to a 50 mL single neck flask, 10 mL DMF was added, (chloromethylidene)dimethylammonium chloride (560 mg, 4.36 mmol) was added portionwise slowly under ice bath, the reaction was stirred at room temperature for 2 hours. The reaction solution of compound 16-b was used directly for the next step.

[0449] Second Step: Preparation of tert-butyl (S)-5-methoxy-4-(6-(4-(methoxy carbonyl)phenyl)-2-(methylthio)-7- azaspiro[3.5]nonane-7-carbonyl)-7-methyl-lH-indole-l-carboxylate (16-c)

[0450] To the reaction solution of compound 16-b, intermediate 1e (570 mg, 1.87 mmol) was added, triethylamine (1.1 mL, 7.46 mmol) was added, stirred at room temperature for 2 hours. 6 mL of dichloromethane was added, washed with 20 mL of saturated sodium chloride for three times, dried with anhydrous sodium sulfate, the organic phase was concentrated under reduced pressure, purified by silica gel column (ethyl acetate: petroleum ether = 1:3) to obtain compound 16-c (920 mg, yield 79%, white solid). LC-MS m / z (ESI) = 593.1 [M+H] + .

[0451] Third step: preparation of (S)-4-(7-(5-methoxy-7-methyl-1H-indole-4-carbonyl)-2-(ylthio)-7- azaspiro[3.5]nonan-6-yl)benzoic acid (compound 16)

[0452] Compound 16-c (920 mg, 1.55 mmol) was added to a 50 mL single-neck flask, 4 mL of THF, 4 mL of methanol, 2 mL of pure water were added, lithium hydroxide (372 mg, 15.52 mmol) was added, stirred at 70°C for 3 hours under nitrogen protection. Cool to room temperature, adjust the pH to about 7 with dilute hydrochloric acid in an ice bath, Agilent InifinityLab Poroshell 120HPH C18, 21.2*150mm*4um (acetonitrile / H2O+0.1% ammonia water: 10%-90%, 20mL / min, retention time 5.3min) to obtain compound 16 (480 mg, white solid, yield 64%). LC-MS m / z (ESI) = 478.9 [M+H] + .

[0453] Chiral resolution of compound 16480 mg (instrument: SHIMADZU LC-30ADsf; column: Chiralpak AD-3 50 x 4.6 mm I.D., particle size 3 um; mobile phase: A = CO2, B = IPA + CAN (0.05% DEA); gradient: 60% B; wavelength: 220 nm; flow rate 3.0 ml / min) to obtain compound 16-A (235 mg, retention time: 1.59 min), LC-MS m / z (ESI) = 478.9 [M+H] + . 1H NMR (500 MHz, CD3OD) δ 8.11 - 7.85 (m, 2H), 7.73 - 7.38 (m, 2H), 7.38 - 7.31 (m, 1H), 6.90 - 6.56 (m, 1H), 6.37 - 6.32 (m, 1H), 6.25 - 6.05 (m, 1H), 4.14 - 3.85 (m, 2H), 3.64 - 3.52 (m, 1H), 3.48 - 3.34 (m, 1H), 3.31 - 3.13 (m, 2H), 2.82 - 2.66 (m, 1H), 2.61 - 2.43 (m, 3H), 2.23 - 1.97 (m, 2H), 1.96 - 1.83 (m, 4H), 1.83 - 1.60 (m, 2H), 1.49 - 1.26 (m, 2H) ppm.

[0454] Compound 16-B (158 mg, retention time: 2.09 min), LC-MS m / z (ESI) = 478.9 [M+H] + ; 1 H NMR (500 MHz, CD3OD) δ 8.10 - 7.83 (m, 2H), 7.72 - 7.35 (m, 2H), 7.35 - 7.07 (m, 1H), 6.91 - 6.54 (m, 1H), 6.37 - 6.06 (m, 2H), 4.02 - 3.88 (m, 2H), 3.60 - 3.45 (m, 1H), 3.40 - 3.34 (m, 1H), 3.31 - 3.06 (m, 2H), 2.85 - 2.63 (m, 1H), 2.62 - 2.45 (m, 3H), 2.39 - 2.03 (m, 2H), 1.99 - 1.90 (m, 3H), 1.89 - 1.65 (m, 3H), 1.65 - 1.37 (m, 2H) ppm.

[0455] Example 17: Preparation of (S)-4-(7-((5-(dimethylamino)-7-methyl-lH-indol-4- yl)methyl)-2-(methylthio)-7-azaspiro[3.5]nonan-6-yl)benzoic acid (Compound 17)

[0456] First Step: Preparation of 5-(dimethylamino)-4-formyl-7-methyl-lH-indole- 1-carboxylate tert-butyl ester (17-b)

[0457] 30 mL microwave tube was added sequentially compound 17-a (500.0 mg, 1.48 mmol), dioxane (10 mL), tris(dibenzylideneacetone)dipalladium (406.15 mg, 0.44 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (513.27 mg, 0.89 mmol), cesium carbonate (1.20 g, 3.70 mmol) and dimethylamine (3.69 mL, 7.39 mmol, 2N), 130 °C microwave reaction for 0.5 h; concentrated under reduced pressure, silica gel column purification (ethyl acetate: petroleum ether = 1:5) to give compound 17-b (420 mg, yield 93%, light yellow solid). LC-MS m / z (ESI) = 303.3 [M+H] + .

[0458] Second Step: Preparation of (S)-5-(dimethylamino)-4-((6-(4- (methoxycarbonyl)phenyl)-2-(methylthio)-7-azaspiro[3.5]non-7-yl)methyl)-7- methyl-1H-indole-1-carboxylic acid tert-butyl ester (17-c)

[0459] 50 mL single neck flask was added sequentially 17-b (650.0 mg, 2.15 mmol), dichloroethane (13 mL), acetic acid (129.0 mg, 2.15 mmol) and intermediate 1e (656.0 mg, 2.05 mmol), 45 °C stirring for 12 h, then added sodium triacetoxyborohydride (684.6 mg, 3.23 mmol) in batches, 45 °C stirring reaction for 16 h. After the reaction was completed, water (20 mL) was added to quench, extracted with ethyl acetate (50 mL), the organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, purified by silica gel column (ethyl acetate: petroleum ether = 1:5) to give compound 17-c (800.0 mg, yield 63.0%, yellow solid). LC-MS m / z (ESI) = 592.3 [M+H] + .

[0460] Third Step: Preparation of (S)-4-(7-((5-(dimethylamino)-7-methyl-1H-indol-4-yl)methyl)- 2-(methylthio)-7-azaspiro[3.5]nonan-6-yl)benzoic acid (compound 17)

[0461] 50 mL single-necked flask was charged with 17-c (800.0 mg, 1.35 mmol), methanol (4 mL), tetrahydrofuran (4 mL), water (2 mL) and lithium hydroxide (162.0 mg, 6.75 mmol), nitrogen protection, 75 °C stirring reaction for 4 h. After the reaction was completed, it was allowed to stand at room temperature, adjusted to pH = 4 with hydrochloric acid, and purified by preparative liquid chromatography (instrument: Shimadzu LC-20AP; column: Agilent InfinityLab Poroshell 120HPH-C18, 21.2*150mm*4pm; gradient conditions: acetonitrile / 0.1% NH3-H2O in H2O: 10%-80%, 20 mL / min, retention time 6.577 min) to give compound 17 (275 mg, yield 42.6%, white solid). LC-MS m / z (ESI) = 478.2 [M+H] + . 275 mg of compound 17 was resolved by chiral resolution, and the conditions are shown in Table 15.

[0462] Table 15

[0463] Compound 17-A (109.4 mg, retention time 1.97 min) was obtained, LC-MS m / z (ESI) = 478.4 [M+H] + . 1 H NMR (500 MHz, MeOD) d 8.05 (d, 2H), 7.62 (d, 2H), 7.36 (d, 1H), 7.12 (s, 1H), 6.55 (d, 1H), 4.18 (s, 1H), 4.07 (d, 1H), 3.95 (s, 1H), 3.48 - 3.39 (m, 1H), 3.22 - 3.09 (m, 1H), 2.89 (s, 6H), 2.51 (m, 5H), 2.28 (m, 2H), 2.16 - 1.73 (m, 8H) ppm.

[0464] Compound 17-B (85.5 mg, retention time 2.59 min), LC-MS m / z (ESI) = 478.5 [M+H] + . 1H NMR (500 MHz, MeOD) δ 8.06 (d, 2H), 7.64 (d, 2H), 7.36 (d, 1H), 7.12 (s, 1H), 6.54 (d, 1H), 4.21 (d, 1H), 4.12 - 3.96 (m, 2H), 3.46 (m, 1H), 3.12 (d, 1H), 2.89 (s, 6H), 2.79 - 2.71 (m, 1H), 2.63 (t, 1H), 2.52 (s, 3H), 2.34 - 2.18 (m, 3H), 2.05 (s, 3H), 1.95 - 1.84 (m, 4H) ppm.

[0465] Bioassay Example One: In vitro enzymatic method to detect the inhibition rate of FB activity by the compound

[0466] I. Experimental materials and instruments

[0467] 1. Recombinant human complement factor D protein (R&D system, 1824-SE-010, 10 μg)

[0468] 2. Recombinant human complement factor B protein (Yiqi God, 17064-H08H, 100 μg)

[0469] 3. Human complement C3 protein (Yiqi God, 13182-H08H, 100 μg)

[0470] 4. Human complement C3a detection kit (Invitrogen, BMS2089, 96T)

[0471] 5. Cobra venom factor (CVF) (Quidel, A600)

[0472] 6. Zwittergent surfactant (CHAPS) (Sigma, C3023-5G, 5 g / bottle)

[0473] 7. Magnesium chloride solution (Sigma, M1028-100ML, 100 mL / bottle)

[0474] 8. Reaction buffer (PBS pH 7.4, 10 mM MgCl2, 0.05% CHAPS)

[0475] 9. Multifunctional enzyme marker (BMG, VANTAstar).

[0476] II. Solution preparation:

[0477] 1. The stock concentration of recombinant human complement factor D protein (26 kDa) is 0.44 mg / mL, i.e. 1.69 x 10 4 nM.

[0478] (1) Sub-packaging to avoid repeated freeze-thawing; (2) -70℃ can be stored for 6 months; (3) After opening, it can be stored at -70℃ for 3 months.

[0479] 2. Recombinant human complement factor B protein (84.5 kDa) stock concentration: 0.25 mg / mL, i.e. 2.96 μM.

[0480] (1) Sub-packaging to avoid repeated freeze-thawing; (2) -20℃ to -80℃ can be stored for 12 months; (3) Use 400 μL sterile water to dissolve and prepare 0.25 mg / mL.

[0481] 3. Human complement C3 protein (186.43 kDa) stock concentration: 0.25 mg / mL, i.e. 1.341 μM.

[0482] (1) Sub-packaging to avoid repeated freeze-thawing; (2) -20℃ to -80℃ can be stored for 12 months; (3) Use 400 μL sterile water to dissolve and prepare 0.25 mg / mL.

[0483] 4. Cobra venom factor (149 kDa) stock concentration: 1.0 mg / mL, i.e. 6.7 μM.

[0484] (1) Sub-packaging to avoid repeated freeze-thawing; (2) Store below -70℃; (3) Concentration: 1.0 mg / mL.

[0485] 5. C3 reaction buffer (PBS pH 7.4, 10 mM MgCl2, 0.05% CHAPS) is prepared at 10 mL and stored at 4℃.

[0486] III. Experimental procedure

[0487] 1. Obtain CVF-Bb by shearing reaction of human complement factor B protein:

[0488] Add FD protein at a final concentration of 300 nM, FB protein at 1 μM and CVF protein at 1 μM in C3 reaction buffer to a final volume of 10 μL, mix well and incubate at 37℃ for 3 h to obtain 300 nM CVF-Bb (enzyme and protein are stored at -80℃).

[0489] 2. Preparation of test compounds:

[0490] Dilute 20 mM test compounds dissolved in DMSO with C3 reaction buffer to 10 μM, 3.333 μM, 1.111 μM, 0.370 μM, 0.123 μM, 0.0411 μM, 0.0137 μM, 0.00457 μM, 0.00152 μM and 0.00051 μM, and the blank well is 0.05% DMSO, and the DMSO content in all test compound solutions is controlled at 0.05%.

[0491] 3. C3 protein cleavage reaction to obtain C3a protein:

[0492] (1) 10 μL reaction system was prepared using 0.2 mL EP tube, 8.8 μL C3 reaction buffer was added, 0.2 μL CVF-Bb with a concentration of 300 nM was added, and 1 μL of the above-mentioned test compound diluted in C3 reaction buffer and blank control were added, and incubated at 37°C for 1 h.

[0493] (2) C3 diluted with C3 reaction buffer to a final concentration of 500 nM was added to the reaction system to make the final system volume 20 μL, and after mixing, it was reacted at 37°C for 2 h, and only 500 nM C3 was contained in the reaction mixture as a negative control.

[0494] 4. Inhibition of FB by test compound was detected using human C3a detection kit:

[0495] (1) After the well plate in the C3a kit was taken out, it needed to be placed in an aluminum foil packaging bag and stored at 2-8°C in the dark; (2) The well plate was washed with 200 μL wash buffer for 10-15 s twice; (3) 10 μL C3 protein cleavage reaction mixture was added; (4) The membrane was sealed, and overnight incubation was performed at 4°C with shaking at 100 rpm using a well plate shaker; (5) Biotin-Conjugate was prepared (diluted with 1x assay buffer 1:100, used within 30 min); (6) The well plate was washed with wash buffer 6 times, 200 μL / well; (7) 100 μL of diluted Biotin-Conjugate was added to all wells including blank, the membrane was sealed, and incubated at room temperature for 1 h with shaking at 100 rpm using a well plate shaker; (8) Streptavidin-HRP was prepared (diluted with 1x assay buffer 1:100, used within 30 min); (9) The well plate was washed with wash buffer 6 times; (10) 100 μL of diluted Streptavidin-HRP was added to all wells including blank; (11) The membrane was sealed, and incubated at room temperature for 1 h with shaking; (12) The well plate was washed with wash buffer 6 times; (13) 100 μL TMB Substrate Solution was added to all wells; (14) The membrane was sealed, and incubated at room temperature for 10-15 min (in the dark); (15) Stop solution was added when the highest standard sample had formed a deep blue color; (16) 100 μL Stop Solution was quickly added to all wells, and immediately detected; (17) Readings were taken at 450 nm wavelength using a microplate reader.

[0496] 5. Inhibition rate calculation:

[0497] The inhibition rate of the compound on the FB activity was calculated using the following formula:

[0498] Inhibition rate = [1- (C 受试化合物 -C 阴性对照孔 ) / (C 空白孔 -C 阴性对照孔 )] x 100%.

[0499] The inhibition curve was drawn according to the compound concentration and the corresponding inhibition rate by using the GraphPad Prism software, and the half-inhibition rate (IC 50 ) of each tested compound on the Fb protein was calculated, and the results are shown in Table 16, wherein the structure of the control compound LNP023 is as follows:

[0500] Table 16. IC 50

[0501] A represents: IC 50 <50nM; B represents: 50nM≤IC 50 <200nM; C represents: 200nM≤IC 50 ≤1000nM; D represents: IC 50 >1000nM.

[0502] Conclusion: The compound of the present application has obvious inhibitory effect on FB activity.

[0503] Biological test example two: mouse pharmacokinetic test

[0504] Test purpose: In this test, the test substance was administered to male C57 / 6J mice by single-dose intravenous injection or gavage, the concentration of the test substance in the mouse plasma was determined, and the pharmacokinetic characteristics of the test substance in the mouse body were evaluated.

[0505] Test animals: Male C57 / 6J mice, 18-22 g, 6-8 weeks old, 3 per compound. Purchased from Zhejiang Weitong Lihua Experimental Animal Technology Co., Ltd.

[0506] Test method:

[0507] 1. Blank solvent preparation: Take an appropriate amount of MC (methyl cellulose), add the theoretical amount of ultrapure water, and fully stir to obtain 0.5% MC liquid.

[0508] 2. Preparation of administration preparation:

[0509] (1) for intragastric administration: weigh the appropriate amount of test substance (converted purity and salt factor), add the prescribed amount of 0.5% MC solvent, vortex and mix to obtain the preparation of the specified theoretical concentration. Prepare fresh before use.

[0510] (2) for intravenous injection: weigh the appropriate amount of test substance (converted purity and salt factor), add the prescribed amount of normal saline (if not soluble, add 5% DMSO), vortex and mix to obtain the preparation of the specified theoretical concentration. Prepare fresh before use.

[0511] 3. Test animal administration: as shown in Table 17, on the test day, male C57 mice were randomly grouped, and 3 mice were used for each compound. The mice were fasted overnight but not deprived of water the day before administration, and food was restored 4 hours after administration.

[0512] Table 17

[0513] 4. Sampling: At each time point (0.25h, 0.5h, 1h, 2h, 4h, 8h, 24h after administration), about 300μL of blood sample was collected into an anticoagulant tube containing EDTA-K2 anticoagulant, and plasma was obtained by centrifugation within 60 minutes. The whole blood sample was placed on ice before centrifugation, and a total of 21x3 plasma samples were collected. All collected plasma samples were stored on dry ice or in a freezer until analysis.

[0514] 5. Detection: For each detection, at least one set of standard curve and QC samples were prepared using blank plasma to quantify the test samples, and at least 3 / 4 of the number of standard curve samples had an accuracy within 80%-120% of the true concentration (the accuracy of LLOQ should be within 75%-125%).

[0515] 6. The results are shown in Table 18:

[0516] Table 18

[0517] NT: not detected

[0518] Conclusion: The oral absorption characteristics of the compounds of the present application in mice are good, and the half-lives and exposure amounts of multiple compounds are higher than those of the control compounds.

[0519] Biological Test Example Three: Rat Ocular Fundus Tissue Pharmacokinetic Test

[0520] Test Purpose: This test measures the concentration of test substance in rat plasma, retina and choroid by single-dose intragastric administration of test substance to SD rats, and evaluates the pharmacokinetic characteristics of test substance in rats and ocular fundus tissue.

[0521] Test animals: Male SD rats, more than 180 g, 6-8 weeks old, 21 / compound. Purchased from Zhejiang Vintone Lihua Experimental Animal Technology Co., Ltd.

[0522] Test method:

[0523] 1. Blank solvent preparation: Take an appropriate amount of MC, add the theoretical amount of ultrapure water, fully stir and mix to obtain 0.5% MC liquid.

[0524] 2. Preparation of administration preparation: Weigh an appropriate amount of test substance (converted purity and salt coefficient), add the prescription amount of 0.5% MC solvent, vortex and mix to obtain the specified theoretical concentration of the preparation. Prepare immediately before use.

[0525] 3. Test animal administration: As shown in Table 19, on the test day, SD rats were randomly divided by weight, and 21 SD rats were allocated to each compound. The rats were fasted overnight but not deprived of water the day before administration, and food was restored 4 hours after administration.

[0526] Table 19

[0527] 4. Sampling: At each time point (0.25h, 0.5h, 1h, 2h, 4h, 8h, 24h after administration), about 300μL of blood sample was collected into an anticoagulant tube containing EDTA-K2 anticoagulant, and plasma was obtained by centrifugation within 60 minutes. The whole blood sample was placed on ice before centrifugation. After the blood sample was collected, the animals were euthanized by CO2 inhalation, and the left and right eye retinas (combined) and choroids (combined) were collected (the surface of the tissue was rinsed with normal saline before weighing and the surface moisture of the tissue was absorbed with filter paper). A total of 21x3 plasma samples, 21x3 retinal sample boxes, and 21x3 choroidal samples were collected. All collected plasma, retinal sample boxes, and choroidal samples were stored on dry ice or in a freezer until analysis.

[0528] 5. Detection: At least one set of standard curve and QC samples were prepared using blank plasma and blank eye tissue homogenate liquid for each detection to quantitatively determine the test samples, and at least 3 / 4 of the standard curve samples had an accuracy of 80%-120% of the true concentration (the accuracy of LLOQ should be within the range of 75%-125%).

[0529] 6. The results are shown in Table 20:

[0530] Table 20

[0531] Conclusion: The compound of the present application has good drug exposure in the rat retina and choroid after oral administration in rats, and the C max and AUC compared to the control compound are significantly improved, indicating that the compound of the present application can be used for eye diseases.

[0532] Bioassay Example Four: Inhibition of FB activity by compounds using human serum complement activation method

[0533] I. Experimental Materials and Instruments

[0534] 1. Mixed human serum (Precision Biological, at least 10 individual sera mixed)

[0535] 2. Complement System Alternative Pathway (SVAR, COMPLAP330RUO)

[0536] 3. Microplate Reader (Molecular Devices, SpectraMax plus 384)

[0537] II. Experimental Steps

[0538] 4. Dilute the mixed human serum 10-fold with Diluent AP as sample diluent.

[0539] 5. Dilute the candidate compound with the sample diluent in gradient, starting concentration is 3000nM, 3-fold gradient dilution with 7 dilution points.

[0540] 6. The positive diluent is used as positive control, and the negative control provided by the kit is used as negative control.

[0541] 7. Add the negative control, positive control and sample diluent to the 96-well plate provided by the kit, and incubate at 37°C for 60 min.

[0542] 8. After incubation, wash each well with 200n of the positive control and sample diluent for 4 times.

[0543] 9. Add 100n of the positive control and sample diluent to the reagent provided in each well (alkaline phosphatase-labeled antibody), and incubate at room temperature for 30 min.

[0544] 10. Wash each well with 200n of the labeled antibody for 4 times at room temperature.

[0545] 11. Add 100n of the labeled antibody to each well, and incubate at room temperature for 20-30 min.

[0546] 12. Detect the absorbance at 405nm in the microplate reader.

[0547] III. Inhibition rate calculation

[0548] 1. Calculate Response% = 100 * (Sample - Mean of Negative Control) / (Mean of Positive Control - Mean of Negative Control).

[0549] 2. Bring the Response% value into prism 9.0 software using the log(inhibitor) vs. response - Variable slope (four parameters) method to fit the curve and obtain the corresponding IC 50 value.

[0550] Table 21. IC values of each test compound for inhibiting the activity of human serum complement 50

[0551] Conclusion: The compound of the present application has obvious inhibitory activity on the activation of human serum alternative pathway, which is better than the control compound LNP023.

[0552] It will be apparent to those skilled in the art that the present contents are not limited to the foregoing illustrative embodiments, but can be embodied in other specific forms without departing from the essential characteristics thereof. Therefore, it is intended that the embodiments be considered in all respects as illustrative and not restrictive, and that reference be made to the appended claims rather than the foregoing examples, and all changes which come within the meaning and range of equivalency of the claims are intended to be embraced therein.

Claims

1. A compound containing an indole group, having a structure as shown in Formula (I), or a stereoisomer, tautomer, nitride, solvate, metabolite, pharmaceutically acceptable salt, or prodrug of Formula (I), wherein, R 1 R is H, alkyl, haloalkyl, heteroalkyl, or cycloalkyl; R 2 , R 3 , R 4 , R 5 , R 6 , R 8 , R 9 , R 10 , R 12 and R 13 are each independently hydrogen, deuterium, halogen, hydroxyl, amino, cyano, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkylalkyl, alkoxy, alkoxyalkyl, hydroxyalkyl, or cycloalkyl; R 7 is hydrogen, deuterium, halogen, hydroxyl, amino, cyano, alkyl, haloalkyl, heteroalkyl, cycloalkylalkyl, alkoxyalkyl, hydroxyalkyl, cycloalkyl, -N(R a R b )2, or -OR 16 ; R 16 is alkyl, haloalkyl, heteroalkyl, cycloalkylalkyl, alkoxy, alkoxyalkyl, hydroxyalkyl, or cycloalkyl; R a and R b each independently is selected from the group consisting of hydrogen, alkyl, haloalkyl, hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl, haloalkylalkyl, alkenylalkyl, alkynylalkyl; R 3 , R 8 and the carbon atom to which they are attached form a 5-7 membered carbocyclic or 5-7 membered heterocyclic ring; R 8 , R 13 and the carbon atom to which they are attached form a 3-7 membered nitrogen-containing heterocyclic ring; R 14 and R 15 each independently is hydrogen, deuterium, alkyl or halogen; or R 14 , R 15 and the carbon atom to which they are attached together form C(=O); A is -(CH2) m -S-R 11 , heterocyclyl, cycloalkyl, aryl, heteroaryl or -SF5; R 11 is hydrogen, deuterium, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkylalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl; m is 0, 1, 2, 3, 4, or 5; n is 0, 1, 2, or 3; 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 , R 16 , R a , and R b are independently optionally substituted with 1, 2, 3, or 4 substituents selected from deuterium, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, cycloalkyl.

2. The compound of claim 1, wherein, R 1 is H, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 heteroalkyl or C 3-8 cycloalkyl; and / or, R 4 , R 5 , R 9 , and R 12 are each independently hydrogen, deuterium, halogen, hydroxyl, amino, cyano, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 heteroalkyl, C 3-8 cycloalkyl C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxy C 1-6 alkyl, C 1-6 hydroxyalkyl, or C 3-8 cycloalkyl; and / or, R 7 is hydrogen, deuterium, halogen, hydroxyl, amino, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 heteroalkyl, C 3-8 cycloalkyl C 1-6 alkyl, C 1-6 alkoxy C 1-6 alkyl, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, -N(R a R b ) or -OR 16 ; R a and R b are each independently selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl C 1-6 alkyl, C 1-6 alkoxy C 1-6 alkyl, C 1-6 haloalkyl C 1-6 alkyl, C 2-6 alkenyl C 1-6 alkyl, C 2-6 alkynyl C 1-6 alkyl; R 16 is C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 heteroalkyl, C 3-8 cycloalkyl C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxy C 1-6 alkyl, C 1-6 hydroxyalkyl or C 3-8 cycloalkyl, preferably C 1-6 alkyl, C 3-8 cycloalkyl C 1-6 alkyl or C 3-8 cycloalkyl; R 1 , R 4 , R 5 , R 7 , R 9 , R 12 , R 16 , R a , and R b in the groups C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 heteroalkyl, C 3-8 cycloalkyl C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxy C 1-6 alkyl, C 1-6 hydroxyalkyl, or C 3-8 cycloalkyl are independently optionally substituted with 1, 2, 3, or 4 substituents selected from deuterium, F, Cl, Br, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl.

3. The compound of claim 1 or 2, wherein, R 1 is H, methyl, ethyl, n-propyl, i-propyl or t-butyl; and / or, R 7 For hydrogen, deuterium, -N(R) a R b ) or -OR 16 ;R a and R b Each is independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl; R 16 The compounds are methyl, ethyl, n-propyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; and / or, R 4 R 5 R 9 and R 12 Each of the following C groups is independently substituted with hydrogen, deuterium, F, Cl, Br, I, hydroxyl, amino, cyano, methyl, ethyl, n-propyl, isopropyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, or cyclopropyl. 1-3 Alkyl, methoxy, ethoxy, n-propoxy, isopropoxy, methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, methoxyn-propyl, methoxyisopropyl, ethoxypropyl, ethoxyisopropyl, isopropoxymethyl, isopropoxyethyl, n-propoxymethyl, propoxyethyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; R 1 R 4 R 5 R 9 R 12 R 16 R a and R b The C-substituted compounds described herein are methyl, ethyl, n-propyl, isopropyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, and cyclopropyl. 1-3 Alkyl, methoxy, ethoxy, n-propoxy, isopropoxy, methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, methoxyn-propyl, methoxyisopropyl, ethoxypropyl, ethoxyisopropyl, isopropoxymethyl, isopropoxyethyl, n-propoxymethyl, propoxyethyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl are independently and optionally separated by 1, 2, 3, or 4 elements selected from deuterium, F, Cl, Br, amino, hydroxyl, cyano, nitro, C 1-3 It is substituted by alkyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl substituents.

4. The compound of claim 1, wherein, The compounds have a structure according to Formula (II), (II’), or are stereoisomers, tautomers, nitroso forms, solvates, metabolites, pharmaceutically acceptable salts or prodrugs of the compounds of Formula (II), (II’), R 2 , R 3 , R 6 , R 8 , R 10 , R 13 , R 14 , R 15 , R 16 , R a , R b , A, n are as defined in formula (I); R 16 is C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 heteroalkyl, C 3-8 cycloalkyl C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxy C 1-6 alkyl, C 1-6 hydroxyalkyl or C 3-8 cycloalkyl; R 16 is C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 heteroalkyl, C 3-8 cycloalkyl C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxy C 1-6 alkyl, C 1-6 hydroxyalkyl or C 3-8 cycloalkyl optionally substituted with 1, 2, 3 or 4 substituents selected from deuterium, F, Cl, Br, amino, hydroxyl, cyano, nitro, C 1-3 alkyl or C 3-6 cycloalkyl.

5. The compound of claim 1 or 4, wherein, R 2 , R 3 , R 6 , R 8 , R 10 , and R 13 are each independently hydrogen, deuterium, halogen, hydroxyl, amino, cyano, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 heteroalkyl, C 3-6 cycloalkyl C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxy C 1-6 alkyl, C 1-6 hydroxyalkyl, or C 3-6 cycloalkyl; and / or, R 14 and R 15 each independently is hydrogen, deuterium, C 1-6 alkyl, halogen; or R 14 , R 15 and the carbon atom to which they are attached form C(=O); R 2 , R 3 , R 6 , R 8 , R 10 , R 13 , R 14 , and R 15 in the groups C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 heteroalkyl, C 3-6 cycloalkyl C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxy C 1-6 alkyl, C 1-6 hydroxyalkyl, or C 3-6 cycloalkyl are independently optionally substituted with 1, 2, 3, or 4 substituents selected from deuterium, F, Cl, Br, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl; R 3 , R 8 and the carbon atom to which they are attached form a 5-7 membered carbocyclic or 5-7 membered heterocyclic ring; R 8 R 13 and the carbon atom to which they are attached form a 5-7 membered nitrogen heterocycle.

6. The compound of claim 5, wherein, R 2 , R 3 , R 6 , R 8 , R 10 , and R 13 are each independently hydrogen, deuterium, F, Cl, Br, I, hydroxyl, amino, cyano, methyl, ethyl, n-propyl, i-propyl, ethenyl, propenyl, allyl, ethynyl, propynyl, propargyl, C 1-3 propynyl, propargyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; and / or, R 14 and R 15 each independently is hydrogen, deuterium, methyl, ethyl, n-propyl, i-propyl, F, CI or Br; or R 14 , R 15 and the carbon atom to which they are attached together form C(=O); R 2 , R 3 , R 6 , R 8 , R 10 , R 13 , R 14 , and R 15 in the methyl, ethyl, n-propyl, isopropyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, cyclopropyl substituted C 1-3 alkyl, methoxy, ethoxy, n-propoxy, isopropoxy, methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, methoxy-n-propyl, methoxyisopropyl, ethoxypropyl, ethoxyisopropyl, isopropoxymethyl, isopropoxyethyl, n-propoxymethyl, propoxyethyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl are independently optionally substituted with 1, 2, 3, or 4 substituents selected from deuterium, F, Cl, Br, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl; R 3 , R 8 and the carbon atom to which they are attached form a 5-7 membered carbocyclic or 5-7 membered heterocyclic ring; Optionally, R 8 , R 13 and the carbon atom to which they are attached form a 5-7 membered nitrogen heterocycle.

7. The compound according to any one of claims 1-6, wherein, A is -(CH2) m -S-R 11 , C 1-9 heterocyclyl, C 3-6 cycloalkyl, C 6-10 aryl, C 1-9 heteroaryl or -SF5; R 11 is hydrogen, deuterium, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 1-9 heterocyclyl, C 1-9 heterocyclyl, C 1-6 alkyl, C 6-10 aryl, C 6-10 aryl, C 1-6 alkyl, C 1-9 heteroaryl, or C 1-9 heteroaryl, C 1-6 alkyl; R 11 is C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 1-9 heterocyclyl, C 1-9 heterocyclyl, C 1-6 alkyl, C 6-10 aryl, C 6-10 aryl, C 1-6 alkyl, C 1-9 heteroaryl, or C 1-9 heteroaryl, C 1-6 independently optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of deuterium, F, Cl, Br, amino, hydroxyl, cyano, C 1-3 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl; m is 0, 1, 2, 3, 4, or 5.

8. The compound of claim 7, wherein, R 11 is hydrogen, deuterium, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, C 1-3 alkyl, C 3-6 cycloalkyl, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, C 1-4 heterocyclyl, C 2-6 heterocyclyl, C 1-3 alkyl, phenyl, phenylC 1-3 alkyl, C 3-6 heteroaryl or C 3-6 heteroaryl, C 1-3 alkyl; R 11 the C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, C 1-4 heterocyclyl, C 2-6 heterocyclyl, C 1-3 alkyl, phenyl, phenylC 1-3 alkyl, C 3-6 heteroaryl or C 3-6 heteroaryl, C 1-3 alkyl is independently optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of deuterium, F, Cl, Br, amino, hydroxyl, cyano, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl.

9. The compound according to any one of claims 1-8, wherein, said compound having a structure according to Formula (III), (III'), (IV), (IV'), (V), (V'), (VI), or a stereoisomer, tautomer, nitroso, solvate, metabolite, pharmaceutically acceptable salt, or prodrug of a structure according to Formula (III), (III'), (IV), (IV'), (V), (V'), (VI), in formulae (III), (III'), (IV), (IV'), (V), (V') and (VI), R 2 , R 3 , R 6 , R 8 , R 10 , R 11 , R 14 , R 15 , R 16 , R a and R b are defined as in formula (I), formula (II), formula (II'). In formulae (V) and (V’), X is a bond, O, NR 17 or CR 18 R 19 ; R 17 is H, C 1-6 alkyl, C 1-6 deuteroalkyl, or C 1-6 haloalkyl; R 18 and R 19 are each independently hydrogen, deuterium, halogen, C 1-6 alkyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, 3-6 membered cycloalkyl, or 3-7 membered heterocyclyl; n is 0, 1, 2, or 3.

10. The compound of claim 9, wherein, In formulae (III), (III'), (IV), (IV'), (V), (V') and (VI), R 2 , R 3 , R 6 , R 8 and R 10 are each independently hydrogen, deuterium, halogen, hydroxyl, amino, cyano, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 heteroalkyl, C 3-6 cycloalkyl C 1-6 alkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl or C 3-6 cycloalkyl; R 2 , R 3 , R 6 , R 8 and R 10 are each independently C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 heteroalkyl, C 3-6 cycloalkyl C 1-6 alkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl or C 3-6 cycloalkyl independently optionally substituted with 1, 2, 3 or 4 substituents selected from deuterium, F, Cl, Br, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 3-6 cycloalkyl; and / or, Each R 11 Independent of hydrogen, deuterium, and C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 3-6 cycloalkyl C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-9 Heterocyclic group, C 1-9 Heterocyclic C 1-6 Alkyl, C 6-10 Aryl, C 6-10 Aryl C 1-6 Alkyl, C 1-9 heteroaryl or C 1-9 heteroaryl C 1-6 Alkyl; R 11 The C mentioned in 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 3-6 cycloalkyl C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-9 Heterocyclic group, C 1-9 Heterocyclic C 1-6 Alkyl, C 6-10 Aryl, C 6-10 Aryl C 1-6 Alkyl, C 1-9 heteroaryl or C 1-9 heteroaryl C 1-6 Alkyl groups are independently and optionally surrounded by 1, 2, 3, or 4 groups selected from deuterium, F, Cl, Br, amino, hydroxyl, cyano, C 1-3 Alkyl, C 3-6 Substituents of cycloalkyl groups; and / or, R 14 and R 15 each independently is hydrogen, deuterium, C 1-6 alkyl, F, CI or Br; or R 14 , R 15 and the carbon atom to which they are attached together form C(=0); and / or, each R is independently C 16 is independently C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 heteroalkyl, C 3-8 cycloalkyl C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxy C 1-6 alkyl, C 1-6 hydroxyalkyl or C 3-8 cycloalkyl, R 16 optionally substituted with 1, 2, 3, or 4 substituents selected from deuterium, F, Cl, Br, amino, hydroxyl, cyano, nitro, C 1-3 alkyl or C 3-6 cycloalkyl; and / or, In formulae (V) and (V’), X is a bond, O, NR 17 or CR 18 R 19 ; R 17 is H, C 1-3 alkyl, C 1-3 deuteroalkyl, C 1-3 haloalkyl; R 18 and R 19 are each independently hydrogen, deuterium, F, Cl, Br, C 1-3 alkyl, C 1-3 deuteroalkyl, C 1-3 haloalkyl, 3-6 membered cycloalkyl, or 3-7 membered heterocyclyl; n is 0, 1, 2, or 3.

11. The compound of claim 9 or 10, wherein, R 2 , R 3 , R 6 , R 8 , and R 10 are each independently hydrogen, deuterium, halogen, hydroxyl, amino, cyano, methyl, ethyl, n-propyl, i-propyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, C 1-3 alkyl, methoxy, ethoxy, n-propoxy, i-propoxy, hydroxymethyl, hydroxyethyl, hydroxypropyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; R 2 , R 3 , R 6 , R 8 , and R 10 independently of one another are each independently hydrogen, deuterium, halogen, hydroxyl, amino, cyano, methyl, ethyl, n-propyl, i-propyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, C 1-3 alkyl, methoxy, ethoxy, n-propoxy, i-propoxy, hydroxymethyl, hydroxyethyl, hydroxypropyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl independently optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of deuterium, F, Cl, Br, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl; and / or, Each R 11 Independent of hydrogen, deuterium, and C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy C 1-3 Alkyl, C 3-6 cycloalkyl C 1-3 Alkyl, C 3-6 cycloalkyl, C 1-4 Heterocyclic group, C 1-4 Heterocyclic C 1-3 Alkyl, phenyl, phenyl C 1-3 Alkyl, C 1-6 heteroaryl or C 1-6 heteroaryl C 1-6 Alkyl group, preferably C 1-3 Alkyl, C 3-6 cycloalkyl or C 1-4 Heterocyclic group; the C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy C 1-3 Alkyl, C 3-6 cycloalkyl C 1-3 Alkyl, C 3-6 cycloalkyl, C 1-4 Heterocyclic group, C 1-4 Heterocyclic C 1-3 Alkyl, phenyl, phenyl C 1-3 Alkyl, C 1-6 heteroaryl or C 1-6 heteroaryl C 1-6 Alkyl groups are independently and optionally surrounded by 1, 2, 3, or 4 groups selected from deuterium, F, Cl, Br, amino, hydroxyl, cyano, C 1-3 Alkyl, C 3-6 Substituents of cycloalkyl groups; and / or, R 14 and R 15 each independently is hydrogen, deuterium, C 1-3 alkyl, F, Cl or Br; or R 14 , R 15 and the carbon atom to which they are attached together form C(=O); and / or, Each R 16 Independently for C 1-6 Alkyl groups or C atoms substituted with 1, 2, 3 or 4 deuterium atoms. 1-6 Alkyl; and / or, In formulae (V) and (V’), X is a bond or CR 18 R 19 ; R 18 and R 19 are each independently H, methyl, ethyl, propyl, C 1-3 alkyl substituted with 1, 2 or 3 deuterium, C 1-3 alkyl substituted with 1, 2 or 3 fluorine; n is 0, 1, 2, or 3.

12. The compound of any one of claims 1-11, wherein, said compound having a structure according to Formula (I-1), (I-2), (I-3), (I-4), (I-5), (I-6), (I-7), (I-8), (I-9), (I-10), (I-11), (I-12), (I-13), (I-14), or a stereoisomer, tautomer, nitroso, solvate, metabolite, pharmaceutically acceptable salt, or prodrug of a structure according to Formula (I-1), (I-2), (I-3), (I-4), (I-5), (I-6), (I-7), (I-8), (I-9), (I-10), (I-11), (I-12), (I-13), (I-14), In the formulae (I-1), (I-2), (I-3), (I-4), (I-5), (I-6), (I-7), (I-8), (I-9), (I-10), (I-11), (I-12), (I-13), (I-14), R 2 , R 3 , R 8 , R 10 , R 11 , R 14 , R 15 , R 16 , R a , and R b are defined as in the formulae (I), (II), (II'), (III), (III'), (IV), (IV'), (V), (V') and (VI).

13. The compound of any one of claims 1-12, wherein, R 1 is hydrogen; and / or, R 2 and R 3 each independently is hydrogen, deuterium, C 1-3 alkyl or deuterated C 1-3 alkyl, preferably hydrogen, deuterium, methyl or deuterated methyl; and / or, R 4 and R 5 each independently is hydrogen or deuterium; and / or; R 6 is C 1-3 alkyl or deuterated C 1-3 alkyl, preferably methyl or deuterated methyl; and / or; R 9 , R 12 , and R 13 are each hydrogen; and / or; R 8 is hydrogen, deuterium, C 1-3 alkyl or deuterated C 1-3 alkyl, preferably H, methyl or deuterated methyl; and / or; R 10 is hydrogen, deuterium, C 1-3 alkyl or deuterated C 1-3 alkyl, preferably hydrogen or deuterium; and / or, R 11 is C 1-3 alkyl, C 1-3 haloalkyl, C 3-6 cycloalkyl, C 1-4 heterocyclyl, or deuterated C 1-3 alkyl, preferably methyl, trifluoromethyl, deuterated methyl, cyclopropyl, cyclobutyl, oxiranyl or oxetanyl; and / or; R 14 and R 15 each independently is hydrogen or deuterium; or R 14 , R 15 and the carbon atom to which they are attached together form C(=O); and / or, R a and R b each independently is selected from hydrogen, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl or t-butyl; R 16 is C 1-3 alkyl, deuterated C 1-3 alkyl, fluorinated C 1-3 alkyl, preferably methyl, deuterated methyl or fluorinated methyl.

14. The compound of any one of claims 1-13, wherein, The compounds have one of the following structures, or a stereoisomer, tautomer, nitroso, solvate, metabolite, pharmaceutically acceptable salt, or prodrug thereof, 15. A pharmaceutical composition comprising a compound of any one of claims 1-14, and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle, or a combination thereof.

16. Use of a compound of any one of claims 1-14 or a pharmaceutical composition of claim 15 in the manufacture of a medicament for a disease associated with or mediated by complement Factor B.

17. The use of claim 16, wherein the disease is selected from glomerulopathy, hemolytic uremic syndrome, atypical hemolytic uremic syndrome, paroxysmal nocturnal hemoglobinuria, age-related macular degeneration, geographic atrophy, diabetic retinopathy, uveitis, retinitis pigmentosa, macular edema, uveitis caused by Behcet's syndrome, multifocal choroiditis, Vogt-Koyanagi-Harada syndrome, birdshot retinochoroiditis, sympathetic ophthalmia, ocular cicatricial pemphigoid, ocular pemphigus, non-arteritic ischemic optic neuropathy, post-surgical inflammation, retinal vein occlusion, neurological disorders, multiple sclerosis, stroke, Guillain-Barre syndrome, traumatic brain injury, Parkinson's disease, inappropriate or undesirable complement activation disorders, hemodialysis complications, hyperacute allograft rejection, xenograft rejection, interleukin-2 induced toxicity during IL-2 therapy, Crohn's disease, adult respiratory distress syndrome, myocarditis, post-ischemic reperfusion disorders, myocardial infarction, balloon angioplasty, post-pump syndrome in cardiopulmonary bypass or renal bypass surgery, atherosclerosis, hemodialysis, renal ischemia, aortic reconstruction, mesenteric arterial reperfusion following infectious disease or sepsis, systemic lupus erythematosus, systemic lupus erythematosus nephritis, proliferative nephritis, liver fibrosis, hemolytic anemia, myasthenia gravis, tissue regeneration, nerve regeneration, dyspnea, hemoptysis, acute respiratory distress syndrome, asthma, chronic obstructive pulmonary disease, pulmonary emphysema, pulmonary embolism and infarction, pneumonia, fibrosis-causing dust diseases, pulmonary fibrosis, asthma, allergy, bronchoconstriction, parasitic diseases, Goodpasture's syndrome, pulmonary vasculitis, pauci-immune vasculitis, immune complex-related inflammation, antiphospholipid syndrome, and obesity. Preferably, the disease is selected from the group consisting of age-related macular degeneration, geographic atrophy, diabetic retinopathy, uveitis, retinitis pigmentosa, macular edema, uveitis caused by Behcet's syndrome, multifocal choroiditis, birdshot retinochoroiditis, sympathetic ophthalmia, ocular cicatricial pemphigoid, ocular pemphigus, non-arteritic ischemic optic neuropathy, post-surgical inflammation, retinal vein occlusion, C3 glomerulopathy, immunoglobulin A nephropathy, membranous glomerulonephritis, atypical hemolytic uremic syndrome (aHUS), and paroxysmal nocturnal hemoglobinuria (PNH).

18. A method of inhibiting or modulating the activity of complement Factor B in a cell, comprising contacting the cell with an effective amount of a compound of any one of claims 1-14 or a pharmaceutical composition of claim 15.

19. A method of inhibiting or modulating the activity of complement Factor B in a subject, comprising administering to the subject an effective amount of a compound of any one of claims 1-14 or a pharmaceutical composition of claim 15.

20. A method of preventing, treating, ameliorating, or modulating a disease associated with or mediated by complement Factor B, comprising administering to a patient an effective amount of a compound of any one of claims 1-14 or a pharmaceutical composition of claim 15.

21. The method of claim 20, wherein the disease is selected from one or more of the following: glomerulopathy, hemolytic uremic syndrome, atypical hemolytic uremic syndrome, paroxysmal nocturnal hemoglobinuria, age-related macular degeneration, geographic atrophy, diabetic retinopathy, uveitis, retinitis pigmentosa, macular edema, uveitis caused by Behcet's syndrome, multifocal choroiditis, Vogt-Koyanagi-Harada syndrome, birdshot retinochoroiditis, sympathetic ophthalmia, ocular cicatricial pemphigoid, ocular pemphigus, non-arteritic ischemic optic neuropathy, post-surgical inflammation, retinal vein occlusion, neurological disorders, multiple sclerosis, stroke, Guillain-Barre syndrome, traumatic brain injury, Parkinson's disease, disorders of inappropriate or unwanted complement activation, hemodialysis complications, hyperacute allograft rejection, xenograft rejection, interleukin-2-induced toxicity during IL-2 therapy, Crohn's disease, adult respiratory distress syndrome, myocarditis, post-ischemic reperfusion disorders, myocardial infarction, balloon angioplasty, post-pump syndrome in cardiopulmonary bypass or renal bypass surgery, atherosclerosis, hemodialysis, renal ischemia, aortic reconstruction, mesenteric arterial reperfusion following infectious disease or sepsis, systemic lupus erythematosus, systemic lupus erythematosus nephritis, proliferative nephritis, liver fibrosis, hemolytic anemia, myasthenia gravis, tissue regeneration, nerve regeneration, dyspnea, hemoptysis, acute respiratory distress syndrome, asthma, chronic obstructive pulmonary disease, emphysema, pulmonary embolism and infarction, pneumonia, fibrotic dust diseases, pulmonary fibrosis, asthma, allergy, bronchoconstriction, parasitic diseases, Goodpasture's syndrome, pulmonary vasculitis, pauci-immune vasculitis, immune complex-related inflammation, antiphospholipid syndrome, and obesity; Preferably, the disease is selected from age-related macular degeneration, geographic atrophy, diabetic retinopathy, uveitis, retinitis pigmentosa, macular edema, uveitis caused by Behcet's syndrome, multifocal choroiditis, birdshot retinochoroiditis, sympathetic ophthalmia, ocular cicatricial pemphigoid, ocular pemphigus, non-arteritic ischemic optic neuropathy, post-surgical inflammation, retinal vein occlusion, C3 glomerulopathy, immunoglobulin A nephropathy, membranous glomerulonephritis, atypical hemolytic uremic syndrome (aHUS), and paroxysmal nocturnal hemoglobinuria (PNH).

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