Complement factor B inhibitors and uses thereof

Abstract

Provided herein are compounds having formula (I) and pharmaceutical compositions thereof useful in the treatment of diseases or disorders mediated by complement factor B. # imgabs0 #

Description

Technical Field

[0001] The present disclosure relates to the inhibition of the alternative complement pathway, particularly Factor B, in patients with disorders and diseases associated with activation of the alternative complement pathway, such as age-related macular degeneration, diabetic retinopathy, and related ophthalmic diseases. Background Art

[0002] The complement system is an important component of the innate immune system and contains a series of proteins that are normally present in an inactive state. These proteins are organized into three activation pathways: the classical pathway, the lectin pathway, and the alternative pathway (VM Holers, Clinical Immunology: Principles and Practice, ed.: RRR Rich, Mosby Press; 1996, 363-391). Molecules, antibodies, or cellular components from microorganisms can activate these pathways, leading to the formation of protease complexes called C3-convertase and C5-convertase. The classical pathway is a calcium / magnesium-dependent cascade that is normally activated by the formation of antigen-antibody complexes. It can also be activated in an antibody-independent manner by binding to ligand-complexed C-reactive protein and by many pathogens (including Gram-negative bacteria). The alternative pathway is a magnesium-dependent cascade that is activated by the deposition and activation of C3 on certain sensitive surfaces (e.g., cell wall polysaccharides of yeast and bacteria, and certain biopolymer materials).

[0003] Factor B may be a suitable target for inhibiting amplification of this complement pathway because its typical plasma concentration in humans is about 200 μg / mL (or about 2 μM) and it has been shown to be a key enzyme in activating the alternative complement pathway (PH Lesavre and HJ Müller-Eberhard. J. Exp. Med. [Journal of Experimental Medicine], 1978; 148: 1498-1510; JA Volanakis et al., New Eng. J. Med. [New England Journal of Medicine], 1985; 312: 395-401).

[0004] Macular degeneration is a clinical term used to describe a class of diseases characterized by the progressive loss of central vision associated with abnormalities of Bruch's membrane, choroid, neural retina and / or retinal pigment epithelium. The center of the retina is the macula, which is about 1 / 3 to 1 / 2 cm in diameter. The macula provides detailed vision, particularly in the center (fovea), because the cone density is higher, and because the ratio of ganglion cells to photoreceptors is high. Blood vessels, ganglion cells, inner nuclear layer and cells, and plexiform layers are all located on the side (not staying above the photoreceptors), so that light reaches the cones by a more direct path. Below the retina is the choroid (a part of the uveal bundle) and the retinal pigment epithelium (RPE), which is located between the neural retina and the choroid. Choroidal blood vessels provide nutrition to the retina and its visual cells.

[0005] Age-related macular degeneration (AMD) is the most common form of macular degeneration, associated with progressive loss of visual acuity, color vision changes, and abnormal dark adaptation and sensitivity in the central part of the visual field. The two main clinical manifestations of AMD are described as dry or atrophic forms and neovascular or exudative forms. The dry form is associated with atrophic cell death in the central retina or macula, which is required for fine vision used in activities such as reading, driving, or recognizing faces. About 10%-20% of these AMD patients develop into a second form of AMD, called neovascular AMD (also referred to as wet AMD).

[0006] Neovascular AMD is characterized by abnormal growth and vascular leakage of blood vessels under the macula, resulting in retinal displacement, bleeding and scarring. This will cause vision to decline over a period of weeks to years. Neovascular AMD cases originate from mid- or late-stage dry AMD. The neovascular form accounts for 85% of legal blindness caused by AMD. In neovascular AMD, scar tissue that destroys the central retina is formed as abnormal blood vessels leak fluid and blood.

[0007] The new blood vessels in neovascular AMD usually originate from the choroid and are called choroidal neovascularization (CNV). The pathogenesis of new choroidal vessels is poorly understood, but factors such as inflammation, ischemia, and local production of angiogenic factors are thought to be important. A published study showed that CNV was caused by complement activation in a mouse laser model (Bora PS, J. Immunol. 2005; 174; 491-497).

[0008] Human genetic evidence suggests that the complement system, particularly the alternative pathway, is involved in the pathogenesis of age-related macular degeneration (AMD). Significant associations have been found between AMD and polymorphisms of the following complement factors: complement factor H (CFH) (Edwards AO et al. Complement factor H polymorphism and age-related macular degeneration. Science. 2005 Apr 15;308(5720):421-4; Hageman GS et al. A common haplotype in the complement regulatory gene factor H (HF1 / CFH) predisposes individuals to age-related macular degeneration. Proc Natl Acad Sci U SA. 2005 May 17;102(20):7227-32; Haines JL et al. Complement factor H variant increases the risk of age-related macular degeneration. degeneration[Complement factor H variant increases risk of age-related macular degeneration]. Science. 2005 Apr 15;308(5720):419-21; Klein RJ et al. Complement factor H polymorphism in age-related macular degeneration. Science. 2005 Apr 15;308(5720):385-9; Lau LI et al. Association of the Y402H polymorphism in complement factor H gene and neovascular age-related macular degeneration in Chinese patients. Invest Ophthalmol Vis Sci.Investig Ophthalmol Vis Sci. 2006 Aug;47(8):3242-6; Simonelli F et al. Polymorphism p.402Y>H in the complement factor H protein is a risk factor for age-related macular degeneration in an Italian population. Br J Ophthalmol. 2006 Sep;90(9):1142-5; and Zareparsi S et al. Strong association of the Y402H variant in complement factor H at 1q32 with susceptibility to age-related macular degeneration. Am J Hum Genet. 2005 Jul;77(1):149-53.), complement factor B (CFB) and complement C2 (Gold B et al. Variation in factor B (BF) and complement component 2 (C2) genes is associated with age-related macular degeneration. Nat Genet. 2006 Apr;38(4):458-62 and Jakobsdottir J et al. C2 and CFB genes in age-related maculopathy and joint action with CFH and LOC387715 genes. PLoS One.[Public Library of Science ONE] 2008 May 21;3(5):e2199), and more recently complement C3 (Despriet DD et al. Complement component C3 and risk of age-related macular degeneration. Ophthalmology. 2009 Mar;116(3):474-480.e2; Maller JB et al. Variation in complement factor 3 is associated with risk of age-related macular degeneration. Nat Genet. 2007 Oct;39(10):1200-1 and Park KH et al. Complement component 3 (C3) haplotypes and risk of advanced age-related macular degeneration. Invest Ophthalmol Vis. Sci. Investigative Ophthalmology & Visual Science 2009 Jul;50(7):3386-93. Epub 2009 Feb 21.). In conclusion, genetic variation in the alternative pathway components CFH, CFB, and C3 can predict clinical outcome in nearly 80% of cases.

[0009] Currently, there is no effective drug therapy for dry AMD, and despite current treatment with anti-VEGF agents such as Lucentis, many patients with neovascular AMD remain legally blind.Therefore, there is a need to provide therapeutic agents for treating or preventing complement-mediated diseases, particularly for treating AMD. Summary of the invention

[0010] The present disclosure provides compounds that modulate and / or inhibit complement alternative pathway activation. In certain embodiments, the present disclosure provides compounds that modulate and / or inhibit factor B activity and / or factor B-mediated complement pathway activation. Such factor B modulators are preferably high affinity factor B inhibitors that inhibit the catalytic activity of complement factor B, such as primate factor B and especially human factor B.

[0011] The compounds of the present disclosure inhibit or suppress amplification of the complement system resulting from C3 activation, regardless of the initial activation mechanism (including, for example, activation of the classical, lectin, or alternative pathways).

[0012] The present disclosure also relates to compounds effective as Factor B modulators, pharmaceutically acceptable salts thereof, compositions thereof, and their use in therapy for the conditions and purposes detailed herein.

[0013] In a first aspect, the present disclosure provides a compound having formula (I) or a pharmaceutically acceptable salt thereof,

[0014]

[0015] Where: m is 0, 1, 2 or 3; N is 0, 1, 2 or 3, provided that m and n are not 0 at the same time;

[0016] R is hydrogen, halogen, C1-C4 alkyl, halogenated C1-C4 alkyl, or hydroxy C1-C4 alkyl;

[0017] R 1 is hydrogen, halogen, hydroxy, C1-C6 alkyl, C2-C6 alkenyl, C3-C6 cycloalkyl, C1-C6 alkoxy, halo-C1-C6 alkyl, halo-C3-C6 cycloalkyl, halo-C1-C6 alkoxy, hydroxy-C1-C6 alkyl, hydroxy-C3-C6 cycloalkylamino-C1-C6 alkyl, C1-C6 alkoxy-C1-C6 alkyl, C1-C6 alkoxy-C1-C6 alkoxy, C3-C6 cycloalkyl-C1-C6 alkoxy, halo-C1-C6 alkoxy, -S-C1-C6 alkyl, -S(O)C1-C6 alkyl, -S(O)2C1-C6 alkyl, CH2NHC(O)C1-C4 alkyl, or -OCH2C(O)R 1a ;

[0018] R 1a is hydroxy, C1-C6 alkoxy, amino or mono- and di-C1-C6 alkylamino;

[0019] R 2 is C1-C3 alkyl, C3 cycloalkyl, C1-C3 alkoxy, hydroxyC1-C6 alkyl, or halogen, wherein the C1-C3 alkyl, C3 cycloalkyl, or C1-C3 alkyl is unsubstituted or substituted with 1, 2, or 3 halogen substituents;

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

[0021] R 3 is hydrogen, halogen or cyano;

[0022] R 4 is phenyl, naphthyl or heteroaryl, wherein the heteroaryl is a 5- to 10-membered heteroaryl having 1, 2 or 3 ring heteroatoms independently selected from N, O or S, and wherein the phenyl or heteroaryl is unsubstituted or replaced by 1 R 5substituted by 0, 1 or 2 R 5’ Replace;

[0023] R 5 Selected from -CO2R 5b 、-CON(R 5c )2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl, -CH2CO2R 5b 、-CH2CON(R 5c )2, -C(O)NHSO2C1-C4 alkyl, -SO2NHC(O)C1-C4 alkyl, -SO2N(H) m (C1-C4 alkyl) 2-m , -SO2C1-C4 alkyl, cyano, hydroxyl, halogen, 5- to 6-membered heteroaryl having 1 to 4 heteroatoms independently selected from N, O and S, and 4- to 6-membered heteroaryl having 1 to 4 heteroatoms independently selected from N, O and S(O) q wherein the 5- to 6-membered heteroaryl and the 4- to 6-membered heterocyclic group are unsubstituted or replaced by 1, 2 or 3 R 5a replace;

[0024] Each R 5a Independently selected from fluorine, hydroxyl and C1-C6 alkyl which is unsubstituted or substituted with -COOH or 1, 2 or 3 fluorines;

[0025] Among them, when R 5 When it is a 4- to 6-membered heterocyclic group, the two R 5a Fluorine and hydroxyl are not substituted at the same position;

[0026] Each R 5b Independently selected from hydrogen or C1-C5 alkyl;

[0027] Each R 5c independently selected from hydrogen, C1-C4 alkyl which is unsubstituted or substituted by halogen, hydroxyl or C1-C4 alkyl;

[0028] Each R 5’ independently selected from the group consisting of halogenated C1-C4 alkyl, C1-C4 alkoxy, halogenated C1-C4 alkoxy, halogen, cyanomethyl, hydroxy C1-C6 alkyl, and C3-C5 cycloalkyl;

[0029] W is O, C (R 6 )2 or NR 7 ;

[0030] R 6Each occurrence is independently selected from the group consisting of hydrogen, halogen, hydroxy, amino, mono- and di-C1-C4 alkylamino, C1-C6 alkyl, halo-C1-C6 alkyl, hydroxy C1-C6 alkyl, cyano C1-C6 alkyl, C1-C6 alkoxy, or halo-C1-C6 alkoxy; or two R 6 Combined with the carbon atoms to which they are attached, they form a spirocyclic carbocycle having 3 to 6 ring atoms, wherein the spirocyclic carbocycle is unsubstituted or substituted with 1 or 2 substituents selected from halogen, C1-C6 alkyl, or C1-C6 alkoxy; or two R 6 Combined with the carbon atoms to which they are attached, they form a group having independently selected from N, O or S(O) q 1 or 2 ring heteroatoms of spirocyclic heterocycle, wherein the spirocyclic heterocycle is unsubstituted or substituted with 1 or 2 halogen substituents, C1-C6 alkyl, halo-C1-C6 alkyl, C3-C6 cycloalkyl, halo-C3-C6 cycloalkyl;

[0031] q is 0, 1, or 2;

[0032] R 7 is hydrogen, C1-C6 alkyl, halogenated C1-C6 alkyl, hydroxy C2-C6 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl C1-C3 alkyl, halogenated C3-C6 cycloalkyl, C1-C6 alkoxy C1-C6 alkyl, halogenated C1-C6 alkoxy C1-C6 alkyl, aryl, 4- to 6-membered alkyl radicals independently selected from N, O and S(O) q or a 5- to 6-membered heteroaryl group having 1-4 heteroatoms independently selected from N, O and S, wherein the C1-C6 alkyl group is unsubstituted or replaced by a 4- to 6-membered heteroaryl group having 1-2 heteroatoms independently selected from N, O and S(O) q wherein the 4- to 6-membered heterocyclic group is unsubstituted or substituted by 1, 2 or 3 halogens, and further wherein the aryl or heteroaryl is unsubstituted or substituted by halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C5 cycloalkyl, halogenated C3-C5 cycloalkyl;

[0033] Each R 8 are independently hydrogen, halogen, C1-C4 alkyl, halogenated C1-C4 alkyl, or two R 8 Together with the carbon atom to which they are attached, they form a C3-C5 cycloalkyl group or a halogenated C3-C5 cycloalkyl group.

[0034] In a second aspect, a pharmaceutical composition is provided, comprising a therapeutically effective amount of a compound having formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

[0035] In a third aspect, provided is a method of treating or preventing a disease or disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound having formula (I) or a pharmaceutically acceptable salt thereof.

[0036] In an additional aspect, provided is a method of modulating complement alternative pathway activity in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound having formula (I) or a pharmaceutically acceptable salt thereof.

[0037] In another aspect, provided is a method for treating a disease or disorder mediated by complement activation, particularly complement alternative pathway activation, in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound having formula (I) or a pharmaceutically acceptable salt thereof.

[0038] In additional aspects, provided are methods of treating a disease or disorder affected by modulation of the complement alternative pathway, the method comprising administering to a subject a therapeutically effective amount of a compound having formula (I) or a pharmaceutically acceptable salt thereof.

[0039] In additional aspects, provided are methods of treating a disease or disorder associated with dysregulation of the complement alternative pathway, the method comprising administering to a subject a therapeutically effective amount of a compound having formula (I) or a pharmaceutically acceptable salt thereof.

[0040] In an additional aspect, provided is a method of inhibiting the expression or activity of complement factor B, the method comprising administering to a subject a compound having formula (I) or a pharmaceutically acceptable salt thereof.

[0041] In another aspect, provided is a method of treating age-related macular degeneration, the method comprising administering to a subject in need thereof an effective amount of a composition comprising a compound having formula (I) or a pharmaceutically acceptable salt thereof.

[0042] In a further aspect, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof for use as a medicament.

[0043] In a further aspect, provided is a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in inhibiting the expression or activity of complement factor B in a subject in need thereof.

[0044] In a further aspect, provided is a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in treating a disease or disorder associated with dysregulation of the complement alternative pathway.

[0045] In a further aspect, there is provided use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating a disease or disorder mediated by complement activation or complement alternative pathway activation.

[0046] In a further aspect, there is provided the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for treating a disease or disorder mediated by complement activation or complement alternative pathway activation.

[0047] In a further aspect, there is provided the use of a compound having formula (I) or a pharmaceutically acceptable salt thereof for treating a disease or disorder affected by modulation of the complement alternative pathway. DETAILED DESCRIPTION

[0048] As noted above, the present disclosure provides compounds that modulate Factor B activation and / or Factor B-mediated signaling of the complement system. Such compounds can be used in vitro or in vivo to modulate Factor B activity in a variety of settings. The compounds disclosed herein can be useful as Factor B modulators and / or inhibitors. Without wishing to be bound by any theory, it is believed that the disclosed compounds can treat disorders associated with factor B, including treatment of age-related macular degeneration, geographic atrophy, diabetic retinopathy, uveitis, retinitis pigmentosa, macular edema, Behcet's uveitis, multifocal choroiditis, Vogt-Koyangi-Harada syndrome, intermediate uveitis, birdshot retinochoroiditis, sympathetic ophthalmia, ocular cicatricial pemphigoid, ocular pemphigus, nonarteritic ischemic optic neuropathy, postoperative inflammation, retinal vein occlusion, glaucoma, Doynehoneycomb retinal dystrophy / Malattia leventinese, Sorsby fundus dystrophy, late onset macular dystrophy, North carolina macular dystrophy, Stargardt macular dystrophy, disease), keratitis, multiple sclerosis and other neurological disorders, stroke, Guillain Barré Syndrome, spinal cord injury, traumatic brain injury, Parkinson's disease, Alzheimer's disease, schizophrenia, amyotrophic lateral sclerosis (ALS), Huntington's disease, multifocal motor neuropathy, autism spectrum disorder, schizophrenia, drug-induced neurotoxicity;Disorders with inappropriate or adverse complement activation, such as complications of hemodialysis, hyperacute allograft rejection, xenograft rejection, IL-2-induced toxicity during interleukin-2 therapy, inflammatory disorders, paroxysmal nocturnal hemoglobinuria, C3 glomerulonephritis (including dense deposit disease and C3 glomerulonephritis), immune complex membranoproliferative glomerulonephritis (IC-MPGN), IgA nephropathy, membranous nephropathy including idiopathic membranous nephropathy, diabetic nephropathy, atypical hemolytic uremic syndrome ( aHUS), hemolytic uremic syndrome, STEC-HUS (Shiga toxin-producing Escherichia coli hemolytic uremic syndrome), periodontitis, excessive complement activation due to CD55 deficiency, vasculothrombosis, protein-losing enteropathy (CHAPLE syndrome), inflammatory or autoimmune diseases such as Crohn's disease, neuromyelitis optica (NMO), IgA vasculitis (formerly Henoch-Schönlein purpura or HSP), CHAPLE syndrome, hematopoietic stem cell transplant-associated thrombotic microangiopathy (HSCT-TMA), adult respiratory distress syndrome (ARDS), myocarditis, post-ischemia-reperfusion syndrome, myocardial infarction, balloon angioplasty, post-pump syndrome during cardiopulmonary bypass or renal bypass, atherosclerosis, hemodialysis, renal ischemia, acute kidney injury, mesenteric artery reperfusion after aortic reconstruction, infectious diseases or sepsis; COVID-19, immune complex disorders and autoimmune diseases, rheumatoid arthritis, osteoarthritis, spondyloarthropathies, psoriatic arthritis, systemic Systemic lupus erythematosus (SLE), lupus nephritis, SLE nephritis, proliferative nephritis, myasthenia gravis, liver fibrosis, hemolytic anemia, tissue regeneration, nerve regeneration, dyspnea, hemoptysis, acute respiratory distress syndrome (ARDS), asthma, chronic obstructive pulmonary disease (COPD), emphysema, pulmonary embolism and infarction, pneumonia, fibrosing pneumococcal disease, pulmonary fibrosis, asthma, allergy, bronchoconstriction, hypersensitivity pneumonitis, parasitic diseases, Goodpasture's syndrome (Goodpasture's Syndrome), pulmonary vasculitis, Pauci-immune vasculitis, antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), Buerger's vasculitis, cryoglobulinemia, Kawasaki disease, Takayasu arteritis, cryoglobulinemia, immune complex-associated inflammation, antiphospholipid syndrome, glomerulonephritis, and obesity; immune thrombocytopenia, cold agglutinin disease, warm antibody autoimmune hemolytic anemia (wAIHA), thrombotic thrombocytopenic purpura (TTP), and abdominal aortic aneurysm, as well as Graves' disease.

[0049] definition

[0050] Unless otherwise indicated, the term "compounds of the present disclosure / compounds of the disclosure / compound of the disclosure" refers to compounds of formula (I), (IA), (IB), (IC), exemplified compounds, salts thereof, particularly pharmaceutically acceptable salts, hydrates, solvates thereof, and all stereoisomers (including diastereomers and enantiomers), rotamers, tautomers and isotopically labeled compounds (including deuterium substitution) and inherently formed moieties.

[0051] In the groups, radicals or moieties defined below, the number of carbon atoms is usually indicated before the group, e.g. C1-C 10 The alkyl group means an alkyl group having 1 to 10 carbon atoms.

[0052] In addition, the use of terms representing monovalent groups where divalent groups are appropriate should be understood to represent the corresponding divalent groups, and vice versa. Unless otherwise specified, the conventional definitions of the term controls and the valence of conventional stable atoms are assumed and are reflected in all formulas and groups. The article "a / an" refers to one or more than one (e.g., at least one) of the grammatical objects of the article. For example, "an element" means one element or more than one element.

[0053] Unless otherwise indicated, the term "and / or" means "and" or "or".

[0054] The term "substituted" means that the specified group or moiety carries one or more suitable substituents, wherein these substituents may be attached to the specified group or moiety at one or more positions. For example, an aryl substituted by a cycloalkyl group may indicate that the cycloalkyl group is attached to an atom of the aryl group either by a bond or by being fused to the aryl group and sharing two or more common atoms.

[0055] As used herein, the term "C1-C6 alkyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having one to six carbon atoms, and attached to the rest of the molecule by a single bond. The terms C1-C3 alkyl and C1-C4 alkyl should be interpreted accordingly. Examples of C1-C6 alkyl include, but are not limited to, methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, 1-methylpropyl (sec-butyl), 2-methylpropyl (isobutyl), 1,1-dimethylethyl (tert-butyl), n-pentyl, and n-hexyl. As used herein, C1-C6 alkyl also includes cycloalkyl groups attached to the alkyl group, for example,

[0056] As used herein, the term "C1-C6 alkoxy" refers to a group having the formula -OR a A group in which R a is a C1-C6 alkyl group as generally defined above. Examples of C1-C6 alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, sec-butoxy, pentyloxy, and hexyloxy.

[0057] The term "halogen" or "halo" means fluorine, chlorine, bromine, or iodine.

[0058] As used herein, the term "cycloalkyl" means a monocyclic or polycyclic saturated or partially unsaturated carbocyclic ring containing 3-18 carbon atoms, wherein there are no shared delocalized π electrons (aromaticity) between the ring carbons. The term "C3-C5 cycloalkyl" should be interpreted accordingly. The term polycyclic encompasses bridged (e.g., norbornane), fused (e.g., decalin) and spirocyclic cycloalkyls. Preferably, cycloalkyl, e.g., C3-C5 cycloalkyl, is a monocyclic hydrocarbon group having 3 to 5 carbon atoms.

[0059] Examples of cycloalkyl groups include, but are not limited to, cyclopropenyl, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, bicyclo[1.1.1]pentanyl, and derivatives thereof.

[0060] Examples of C3-C5 cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, and cyclopentyl.

[0061] "Heterocyclyl" means a saturated or partially saturated monocyclic or polycyclic ring containing carbon and at least one heteroatom selected from oxygen, nitrogen and sulfur (O, N and S), and wherein there are no shared delocalized π electrons (aromaticity) between the ring carbons or heteroatoms. The term "4- to 6-membered heterocyclyl" should be interpreted accordingly. The heterocyclyl ring structure can be substituted by one or more substituents. These substituents themselves can be optionally substituted. The heterocyclyl can be bonded via carbon atoms or heteroatoms. The term polycyclic encompasses bridged, fused and spirocyclic heterocyclyls.

[0062] Examples of heterocyclyl rings include, but are not limited to, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, oxazolinyl, isoxazolinyl, oxazolidinyl, thiazolidinyl, pyranyl, thiopyranyl, tetrahydropyranyl, dioxolinyl, piperidinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S-dioxide, piperazinyl, aza Oxalic acid Base, diazepine 1,4-dioxanyl, dihydrofuranyl, 1,3-dioxolanyl, imidazolidinyl, dihydroisoxazolinyl, pyrrolinyl, pyrazolinyl, oxazepine 1-H-pyranyl, 2-oxaspiro[3.3]heptane-6-yl, 2-oxaspiro[3.3]heptan ...

[0063] Examples of 4- to 6-membered heterocyclyl groups include, but are not limited to, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, piperazinyl, dihydroisoxazolinyl, tetrahydropyranyl, morpholinyl, dihydropyranyl (e.g., 3,6-dihydro-2H-pyranyl), and oxaspiroheptanyl (e.g., 2-oxaspiro[3.3]heptan-6-yl).

[0064] As used herein, the term "heteroaryl" is intended to include monocyclic heterocyclic aromatic rings containing one or more heteroatoms selected from oxygen, nitrogen and sulfur (O, N and S). Representative examples are pyrrolyl, furanyl, thienyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isothiazolyl, isoxazolyl, triazolyl (e.g., 1,2,4-triazolyl), oxadiazolyl (e.g., 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl), thiadiazolyl (e.g., 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl), tetrazolyl, pyranyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, thiadiazinyl, aza Base, azecinyl, etc.

[0065] Heteroaryl is also intended to include bicyclic heterocyclic aromatic rings containing one or more heteroatoms selected from oxygen, nitrogen and sulfur (O, N and S). Representative examples are indolyl, isoindolyl, benzofuranyl, benzothiophenyl, indazolyl, benzopyranyl, benzimidazolyl, benzothiazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl, benzoxazinyl, benzotriazolyl, naphthyridinyl, phthalazinyl, pteridinyl, purinyl, quinazolinyl, cinnolinyl, quinolinyl, isoquinolinyl, quinoxalinyl, oxazolopyridinyl, isoxazolopyridinyl, pyrrolopyridinyl, furopyridinyl, thienopyridinyl, imidazopyridinyl, imidazopyrimidinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, pyrazolotriazinyl, triazolopyridinyl, triazolopyrimidinyl, imidazothiazolyl, triazolopyridinyl, triazolopyrimidinyl, and the like.

[0066] Heteroaryl is also intended to include polycyclic heterocyclic aromatic rings containing one or more heteroatoms selected from oxygen, nitrogen and sulfur (O, N and S). Representative examples are carbazolyl, phenoxazinyl, phenazinyl, acridinyl, phenothiazinyl, carbolinyl, phenanthrolinyl and the like.

[0067] The heteroaryl ring structure may be substituted with one or more substituents. These substituents themselves may be optionally substituted. The heteroaryl ring may be bonded via a carbon atom or a heteroatom.

[0068] The term "5- or 6-membered heteroaryl" should be interpreted accordingly.

[0069] Examples of 5 or 6-membered heteroaryl groups include, but are not limited to, furan, indolyl, pyridyl, pyrimidyl, pyridonyl, pyridazinyl, triazolyl (e.g., 1,2,4-triazolyl), pyrazolyl, thiazolyl, oxazolyl, isoxazolyl, pyrrolyl, oxadiazolyl (e.g., 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl), imidazolyl, thienyl, thiadiazolyl (e.g., 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl), pyrazinyl, isoxazolopyridyl, dihydropyridooxazinyl, and tetrazolyl. The term "5 or 6-membered heteroaryl ring having 1-2 heteroatoms independently selected from N, O, and S" should be interpreted accordingly.

[0070] As used herein, "modulator" means, for example, a compound of the disclosure, which modulates, decreases, or reduces the level of a specific protein, such as complement factor B. The amount of a specific protein (e.g., complement factor B) that is modulated can be measured by comparing the amount of the specific protein (e.g., complement factor B) remaining after treatment with a compound of the disclosure to the initial amount or level of the specific protein (e.g., complement factor B) present measured prior to treatment with a compound of the disclosure.

[0071] As used herein, "inhibitor" means, for example, a compound of the present disclosure that inhibits or reduces the activity of at least one component of a complement pathway, for example, the compound inhibits the binding of one component of the pathway to another component. For example, the complement pathway is the alternative complement pathway. For example, a component of the complement pathway is complement factor B.

[0072] As used herein, the terms "inhibit," "inhibition," or "inhibiting" refer to reducing or suppressing a given condition, symptom, or disorder, or disease, or a significant decrease in the basal activity of a biological activity or process.

[0073] The term "effective amount" of a compound described herein refers to the amount of a therapeutic compound that is necessary or sufficient to achieve its intended function in a mammal. The effective amount of a therapeutic compound may vary depending on factors such as the amount of pathogen already present in the mammal, the age, sex, and weight of the mammal, and the ability of the therapeutic compound of the present disclosure to treat a condition in which complement factor B plays a role.

[0074] Therefore, the term "therapeutically effective amount" of a compound of the present disclosure refers to the amount of a compound of the present disclosure that will cause a biological or medical response in a subject (e.g., reduction or inhibition of enzyme or protein activity, or improvement of symptoms, alleviation of symptoms, slowing or delaying disease progression, or prevention of disease, etc.). In one embodiment, the term "therapeutically effective amount" refers to an amount of a compound of the present disclosure that, when administered to a subject, is effective to (1) at least partially alleviate, prevent and / or improve the following conditions or disorders or diseases: (i) mediated by complement factor B, or (ii) associated with complement factor B activity, or (iii) characterized by complement factor B activity (normal or abnormal): (2) reduce or inhibit complement factor B activity; or (3) reduce or inhibit complement factor B expression. In another embodiment, the term "therapeutically effective amount" refers to an amount of a compound of the present disclosure that, when administered to a cell, or tissue, or non-cellular biological material, or medium, is effective to at least partially reduce or inhibit complement factor B activity; or at least partially reduce or inhibit complement factor B expression.

[0075] As used herein, with respect to a disease or disorder, the term "treat, treating or treatment" in some embodiments refers to alleviating a disease or disorder (i.e., slowing down or preventing or reducing the development of a disease or at least one clinical symptom thereof). In another embodiment, "treat, treating or treatment" refers to alleviating or improving at least one physical parameter, including those that cannot be discerned by the patient. In yet another embodiment, "treat, treating or treatment" refers to regulating a disease or disorder physically (e.g., stabilization of discernible symptoms), physiologically (e.g., stabilization of physical parameters), or both. In yet another embodiment, "treat, treating or treatment" refers to preventing or delaying the onset or development or progression of a disease or disorder or its symptoms.

[0076] As used herein, the term "subject" or "patient" refers to human and non-human mammals, including but not limited to primates, rabbits, pigs, horses, dogs, cats, sheep and cattle. In specific embodiments, the subject or patient is a human. In certain embodiments, the term "patient" or "subject" refers to a person suffering from a condition (i.e., a disease or disorder) described herein and who will benefit from treatment. As used herein, if the subject (patient) will benefit from treatment biologically, medically or in terms of quality of life, such subject is "in need" of such treatment. In specific embodiments, the subject is an adult of at least about 18 years old. In specific embodiments, the subject is an adult from about 18 to about 75 years old. In certain embodiments, the subject is a human child of up to about 18 years old.

[0077] As used herein, the terms "prevent," "preventing," or "prevention" of any disease or disorder refers to prophylactic treatment of the disease or disorder; or delaying the onset or progression of the disease or disorder.

[0078] As used herein, a subject is "in need" of a treatment if the subject would benefit biologically, medically, or in quality of life from such treatment.

[0079] As used herein, the term "about" refers to a range of values ​​that is + / - 10% of the specified value.

[0080] As used herein, the terms "a", "an", "the" and similar terms used in the context of the disclosure (especially in the context of the claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context.

[0081] As used herein, the term "pharmaceutically acceptable carrier" refers to a substance useful in preparing or using a pharmaceutical composition and includes, for example, suitable diluents, solvents, dispersion media, surfactants, antioxidants, preservatives, isotonic agents, buffers, emulsifiers, absorption delaying agents, salts, drug stabilizers, binders, excipients, disintegrants, lubricants, wetting agents, sweeteners, flavorings, dyes, and combinations thereof, as known to those skilled in the art (see, for example, Remington The Science and Practice of Pharmacy, 22nd ed. Pharmaceutical Press, 2013, pp. 1049-1070).

[0082] A number of enumerated embodiments of the present disclosure are described herein. It should be appreciated that the features specified in each embodiment can be combined with other specified features to provide additional embodiments of the present disclosure.

[0083] Examples of Examples

[0084] Example 1. A compound having formula (I) or a pharmaceutically acceptable salt thereof,

[0085]

[0086] Where: m is 0, 1, 2 or 3; N is 0, 1, 2 or 3, provided that m and n are not 0 at the same time;

[0087] R is hydrogen, halogen, C1-C4 alkyl, halogenated C1-C4 alkyl, or hydroxy C1-C4 alkyl;

[0088] R 1 is hydrogen, halogen, hydroxy, C1-C6 alkyl, C2-C6 alkenyl, C3-C6 cycloalkyl, C1-C6 alkoxy, halo-C1-C6 alkyl, halo-C3-C6 cycloalkyl, halo-C1-C6 alkoxy, hydroxy-C1-C6 alkyl, hydroxy-C3-C6 cycloalkylamino-C1-C6 alkyl, C1-C6 alkoxy-C1-C6 alkyl, C1-C6 alkoxy-C1-C6 alkoxy, C3-C6 cycloalkyl-C1-C6 alkoxy, halo-C1-C6 alkoxy, -S-C1-C6 alkyl, -S(O)C1-C6 alkyl, -S(O)2C1-C6 alkyl, CH2NHC(O)C1-C4 alkyl, or -OCH2C(O)R 1a ;

[0089] R 1a is hydroxy, C1-C6 alkoxy, amino or mono- and di-C1-C6 alkylamino;

[0090] R 2 is C1-C3 alkyl, C3 cycloalkyl, C1-C3 alkoxy, hydroxyC1-C6 alkyl, or halogen, wherein the C1-C3 alkyl, C3 cycloalkyl, or C1-C3 alkyl is unsubstituted or substituted with 1, 2, or 3 halogen substituents;

[0091] p is 0, 1, 2, or 3;

[0092] R 3 is hydrogen, halogen or cyano;

[0093] R 4 is phenyl, naphthyl or heteroaryl, wherein the heteroaryl is a 5- to 10-membered heteroaryl having 1, 2 or 3 ring heteroatoms independently selected from N, O or S, and wherein the phenyl or heteroaryl is unsubstituted or replaced by 1 R 5 substituted by 0, 1 or 2 R 5’ Replace;

[0094] R 5 Selected from -CO2R 5b 、-CON(R 5c )2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl, -CH2CO2R 5b 、-CH2CON(R 5c )2, -C(O)NHSO2C1-C4 alkyl, -SO2NHC(O)C1-C4 alkyl, -SO2N(H) m (C1-C4 alkyl) 2-m , -SO2C1-C4 alkyl, cyano, hydroxyl, halogen, 5- to 6-membered heteroaryl having 1 to 4 heteroatoms independently selected from N, O and S, and 4- to 6-membered heteroaryl having 1 to 4 heteroatoms independently selected from N, O and S(O) q wherein the 5- to 6-membered heteroaryl and the 4- to 6-membered heterocyclic group are unsubstituted or replaced by 1, 2 or 3 R 5a replace;

[0095] Each R 5a Independently selected from fluorine, hydroxyl and C1-C6 alkyl which is unsubstituted or substituted with -COOH or 1, 2 or 3 fluorines;

[0096] Among them, when R 5 When it is a 4- to 6-membered heterocyclic group, the two R 5a Fluorine and hydroxyl are not substituted at the same position;

[0097] Each R 5b Independently selected from hydrogen or C1-C5 alkyl;

[0098] Each R 5c independently selected from hydrogen, C1-C4 alkyl which is unsubstituted or substituted by halogen, hydroxyl or C1-C4 alkyl;

[0099] Each R 5’ independently selected from the group consisting of halogenated C1-C4 alkyl, C1-C4 alkoxy, halogenated C1-C4 alkoxy, halogen, cyanomethyl, hydroxy C1-C6 alkyl, and C3-C5 cycloalkyl;

[0100] W is O, C (R 6 )2 or NR 7 ;

[0101] R 6 Each occurrence is independently selected from the group consisting of hydrogen, halogen, hydroxy, amino, mono- and di-C1-C4 alkylamino, C1-C6 alkyl, halo-C1-C6 alkyl, hydroxy C1-C6 alkyl, cyano C1-C6 alkyl, C1-C6 alkoxy, or halo-C1-C6 alkoxy; or two R 6Combined with the carbon atoms to which they are attached, they form a spirocyclic carbocycle having 3 to 6 ring atoms, wherein the spirocyclic carbocycle is unsubstituted or substituted with 1 or 2 substituents selected from halogen, C1-C6 alkyl, or C1-C6 alkoxy; or two R 6 Combined with the carbon atoms to which they are attached, they form a group having independently selected from N, O or S(O) q 1 or 2 ring heteroatoms of spirocyclic heterocycle, wherein the spirocyclic heterocycle is unsubstituted or substituted with 1 or 2 halogen substituents, C1-C6 alkyl, halo-C1-C6 alkyl, C3-C6 cycloalkyl, halo-C3-C6 cycloalkyl;

[0102] q is 0, 1, or 2;

[0103] R 7 is hydrogen, C1-C6 alkyl, halogenated C1-C6 alkyl, hydroxy C2-C6 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl C1-C3 alkyl, halogenated C3-C6 cycloalkyl, C1-C6 alkoxy C1-C6 alkyl, halogenated C1-C6 alkoxy C1-C6 alkyl, aryl, 4- to 6-membered alkyl radicals independently selected from N, O and S(O) q a heterocyclic group having 1 to 2 heteroatoms or a 5- to 6-membered heteroaryl group having 1 to 4 heteroatoms independently selected from N, O and S, wherein the C1-C6 alkyl group is unsubstituted or substituted with a 4- to 6-membered heterocyclic group having 1 to 2 heteroatoms independently selected from N, O and S(O)q, wherein the 4- to 6-membered heterocyclic group is unsubstituted or substituted with 1, 2 or 3 halogens, further wherein the aryl or heteroaryl group is unsubstituted or substituted with halo, C1-C6 alkyl, halo-substituted C1-C6 alkyl, C3-C5 cycloalkyl, halo-substituted C3-C5 cycloalkyl;

[0104] Each R 8 are independently hydrogen, halogen, C1-C4 alkyl, halogenated C1-C4 alkyl, or two R 8 Together with the carbon atom to which they are attached, they form a C3-C5 cycloalkyl group or a halogenated C3-C5 cycloalkyl group.

[0105] Embodiment 2. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to Embodiment 1, having formula (IA)

[0106]

[0107] wherein A is selected from the group consisting of phenyl, furanyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, pyrazolyl, imidazolyl, pyridinyl, triazolyl, tetrazolyl, oxadiazolyl, isoxadiazolyl, pyrimidinyl, pyrazinyl and pyridazinyl.

[0108] Example 3. Compound IA or a pharmaceutically acceptable salt thereof according to Example 1, having formula (IB)

[0109]

[0110] wherein A is selected from the group consisting of phenyl, furanyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, pyrazolyl, imidazolyl, pyridinyl, triazolyl, tetrazolyl, oxadiazolyl, isoxadiazolyl, pyrimidinyl, pyrazinyl and pyridazinyl.

[0111] Embodiment 4. The compound according to Embodiment 2 or 3 or a pharmaceutically acceptable salt thereof, wherein A is selected from:

[0112]

[0113] Embodiment 5. A compound according to any one of the preceding embodiments or a pharmaceutically acceptable salt thereof, wherein W is C(R 6 )2 or NR 7 .

[0114] Embodiment 6. A compound according to any one of the preceding embodiments or a pharmaceutically acceptable salt thereof, wherein W is C(R 6 )2.

[0115] Embodiment 7. A compound according to any one of the preceding embodiments or a pharmaceutically acceptable salt thereof, wherein W is NR 7 .

[0116] Embodiment 8. A compound according to any one of the preceding embodiments or a pharmaceutically acceptable salt thereof, wherein R 7 It is a C1-C6 alkyl group, a halogenated C1-C6 alkyl group, a C3-C6 cycloalkyl group, or a halogenated C3-C6 cycloalkyl group.

[0117] Embodiment 9. The compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein A is a benzene ring.

[0118] Embodiment 10. The compound according to Embodiment 9 or a pharmaceutically acceptable salt thereof, wherein R 5 It is substituted at the para position of the benzene ring.

[0119] Embodiment 11. The compound according to Embodiment 10 or a pharmaceutically acceptable salt thereof, having formula (IC):

[0120]

[0121] Embodiment 12. A compound according to any one of the preceding embodiments or a pharmaceutically acceptable salt thereof, having formula (ID):

[0122]

[0123] Embodiment 13. A compound according to any one of the preceding embodiments or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from hydrogen, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, and C1-C6 alkoxy.

[0124] Embodiment 14. A compound according to any one of the preceding embodiments or a pharmaceutically acceptable salt thereof, wherein R 2 Selected from halogen, methyl, ethyl and cyclopropyl.

[0125] Embodiment 15. A compound according to any one of the preceding embodiments or a pharmaceutically acceptable salt thereof, wherein R 2 Selected from methyl, ethyl and cyclopropyl.

[0126] Embodiment 16. A compound according to any one of the preceding embodiments or a pharmaceutically acceptable salt thereof, wherein R 2 It's methyl.

[0127] Embodiment 17. The compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R is hydrogen, halogen, or C1-C4 alkyl.

[0128] Embodiment 18. A compound according to any one of the preceding embodiments or a pharmaceutically acceptable salt thereof, wherein R 3 It is hydrogen or chlorine.

[0129] Embodiment 19. A compound according to any one of the preceding embodiments or a pharmaceutically acceptable salt thereof, wherein R 3 It's hydrogen.

[0130] Embodiment 20. A compound according to any one of the preceding embodiments or a pharmaceutically acceptable salt thereof, wherein R 5 independently selected from hydrogen, -CO2R 5b 、-CON(R 5c )2, C1-C6 alkyl, -CH2CO2R 5b 、-CH2CON(R 5c )2, -C(O)NHSO2C1-C4 alkyl, -SO2NHC(O)C1-C4 alkyl, -SO2N(H) m (C1-C4 alkyl) 2-m, -SO2C1-C4 alkyl, cyano, halogen, hydroxyC1-C6 alkyl, C3-C5 cycloalkyl, 5- to 6-membered heteroaryl having 1-4 heteroatoms independently selected from N, O and S, and 4- to 6-membered heterocyclyl having 1-2 heteroatoms independently selected from N, O and S, wherein the 5- to 6-membered heteroaryl and the 4- to 6-membered heterocyclyl are unsubstituted or replaced by 1 or 2 R 5a replace.

[0131] Embodiment 21. A compound according to any one of the preceding embodiments or a pharmaceutically acceptable salt thereof, wherein R 5 is selected from -CO2H, hydroxy C1-C6 alkyl, 5- to 6-membered heteroaryl having 1-4 heteroatoms independently selected from N, O and S, and 4- to 6-membered heterocyclyl having 1 O heteroatom, wherein the 4- to 6-membered heterocyclyl is surrounded by 0-1 R 5a replace.

[0132] Embodiment 22. A compound according to any one of the preceding embodiments or a pharmaceutically acceptable salt thereof, wherein R 5 is selected from CO2H, hydroxy C1-C6 alkyl, 5-membered heteroaryl having 2 N heteroatoms, and 4- to 6-membered heterocyclic group having 1 O heteroatom, wherein the 4- to 6-membered heterocyclic group is unsubstituted or substituted with 1 R 5a Substitution, where R 5a It's a hydroxyl group.

[0133] Embodiment 23. The compound according to Embodiment 18 or a pharmaceutically acceptable salt thereof, wherein R 5 It is -CO2H.

[0134] Embodiment 24. A compound according to any one of the preceding embodiments or a pharmaceutically acceptable salt thereof, wherein R 5 It is a tetrazolyl group.

[0135] Embodiment 25. A compound according to any one of the preceding embodiments or a pharmaceutically acceptable salt thereof, wherein R 4 1 or 2 R independently selected from the group consisting of halogenated C1-C4 alkyl and halogen 5’ replace.

[0136] Embodiment 26. A compound according to any one of the preceding embodiments or a pharmaceutically acceptable salt thereof, wherein R 6 Each occurrence is independently selected from the group consisting of hydrogen, halogen, halogenated C1-C6 alkoxy, C1-C6 alkoxy, or two R 6Combined with the carbon atoms to which they are attached they form a spirocyclic carbocycle having 3 to 6 ring atoms, wherein the spirocyclic carbocycle is unsubstituted or substituted with 1 or 2 substituents selected from halogen or C1-C6 alkoxy.

[0137] Embodiment 27. The compound according to any one of the preceding embodiments, provided that m and n are not 3 at the same time.

[0138] Embodiment 28. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to Embodiment 1 is selected from:

[0139] 4-((3R,4R)-4-((5,7-dimethyl-1H-indol-4-yl)methyl)-1-(2,2,2-trifluoroethyl)piperidin-3-yl)benzoic acid;

[0140] 4-(4-((5,7-dimethyl-1H-indol-4-yl)methyl)-1-(2,2,2-trifluoroethyl)piperidin-3-yl)benzoic acid;

[0141] 4-((3R,4R)-4-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-1-(2,2,2-trifluoroethyl)piperidin-3-yl)benzoic acid;

[0142] 4-(4-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-1-(2,2,2-trifluoroethyl)piperidin-3-yl)benzoic acid;

[0143] 4-((3R,4R)-4-((5,7-dimethyl-1H-indol-4-yl)methyl)-1-methylpiperidin-3-yl)benzoic acid;

[0144] 4-(4-((5,7-dimethyl-1H-indol-4-yl)methyl)-1-methylpiperidin-3-yl)benzoic acid;

[0145] 4-((3R,4R)-4-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-1-methylpiperidin-3-yl)benzoic acid;

[0146] 4-(4-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-1-methylpiperidin-3-yl)benzoic acid;

[0147] 4-((3R,4R)-1-(2,2-difluoroethyl)-4-((5,7-dimethyl-1H-indol-4-yl)methyl)piperidin-3-yl)benzoic acid;

[0148] 4-(1-(2,2-difluoroethyl)-4-((5,7-dimethyl-1H-indol-4-yl)methyl)piperidin-3-yl)benzoic acid;

[0149] 4-((3R,4R)-4-((5-cyclopropyl-7-methyl-1H-indol-4-yl)methyl)-1-(2,2,2-trifluoroethyl)piperidin-3-yl)benzoic acid;

[0150] 4-(4-((5-cyclopropyl-7-methyl-1H-indol-4-yl)methyl)-1-(2,2,2-trifluoroethyl)piperidin-3-yl)benzoic acid;

[0151] 4-((3R,4R)-4-((5,7-dimethyl-1H-indol-4-yl)methyl)-1-(2-fluoroethyl)piperidin-3-yl)benzoic acid;

[0152] 4-(4-((5,7-dimethyl-1H-indol-4-yl)methyl)-1-(2-fluoroethyl)piperidin-3-yl)benzoic acid;

[0153] 4-((3R,4R)-4-((5-cyclopropyl-7-methyl-1H-indol-4-yl)methyl)-1-methylpiperidin-3-yl)benzoic acid;

[0154] 4-(4-((5-cyclopropyl-7-methyl-1H-indol-4-yl)methyl)-1-methylpiperidin-3-yl)benzoic acid;

[0155] 4-((3R,4R)-4-((5,7-dimethyl-1H-indol-4-yl)methyl)-1-isobutylpiperidin-3-yl)benzoic acid;

[0156] 4-(4-((5,7-dimethyl-1H-indol-4-yl)methyl)-1-isobutylpiperidin-3-yl)benzoic acid;

[0157] 4-((3R,4R)-1-(cyclopropylmethyl)-4-((5,7-dimethyl-1H-indol-4-yl)methyl)piperidin-3-yl)benzoic acid;

[0158] 4-(1-(Cyclopropylmethyl)-4-((5,7-dimethyl-1H-indol-4-yl)methyl)piperidin-3-yl)benzoic acid;

[0159] 4-((3R,4R)-4-((5,7-dimethyl-1H-indol-4-yl)methyl)-1-(2-methoxyethyl)piperidin-3-yl)benzoic acid;

[0160] 4-(4-((5,7-dimethyl-1H-indol-4-yl)methyl)-1-(2-methoxyethyl)piperidin-3-yl)benzoic acid;

[0161] 4-(((3R,4R)-3-(4-(1H-tetrazol-5-yl)phenyl)-1-(2,2,2-trifluoroethyl)piperidin-4-yl)methyl)-5,7-dimethyl-1H-indole;

[0162] 4-((3-(4-(1H-tetrazol-5-yl)phenyl)-1-(2,2,2-trifluoroethyl)piperidin-4-yl)methyl)-5,7-dimethyl-1H-indole;

[0163] 4-((1R,2S)-2-((5,7-dimethyl-1H-indol-4-yl)methyl)-5,5-difluorocyclohexyl)benzoic acid;

[0164] 4-(2-((5,7-dimethyl-1H-indol-4-yl)methyl)-5,5-difluorocyclohexyl)benzoic acid;

[0165] 4-((6R,7S)-7-((5,7-dimethyl-1H-indol-4-yl)methyl)spiro[3.5]nonan-6-yl)benzoic acid;

[0166] 4-(7-((5,7-dimethyl-1H-indol-4-yl)methyl)spiro[3.5]nonan-6-yl)benzoic acid;

[0167] 4-((6R,7S)-7-((5,7-dimethyl-1H-indol-4-yl)methyl)-2,2-difluorospiro[3.5]nonan-6-yl)benzoic acid;

[0168] 4-(7-((5,7-dimethyl-1H-indol-4-yl)methyl)-2,2-difluorospiro[3.5]nonan-6-yl)benzoic acid;

[0169] 4-((1R,2S,5S)-2-((5,7-dimethyl-1H-indol-4-yl)methyl)-5-ethoxycyclohexyl)benzoic acid;

[0170] 4-(2-((5,7-dimethyl-1H-indol-4-yl)methyl)-5-ethoxycyclohexyl)benzoic acid;

[0171] 4-((1R,2S,5S)-5-(2,2-difluoroethoxy)-2-((5,7-dimethyl-1H-indol-4-yl)methyl)cyclohexyl)benzoic acid;

[0172] 4-(5-(2,2-difluoroethoxy)-2-((5,7-dimethyl-1H-indol-4-yl)methyl)cyclohexyl)benzoic acid;

[0173] 4-((1R,2S,5S)-5-(cyclopropylmethoxy)-2-((5,7-dimethyl-1H-indol-4-yl)methyl)cyclohexyl)benzoic acid;

[0174] 4-(5-(Cyclopropylmethoxy)-2-((5,7-dimethyl-1H-indol-4-yl)methyl)cyclohexyl)benzoic acid;

[0175] 4-((3R,4S)-4-((5,7-dimethyl-1H-indol-4-yl)methyl)-1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)benzoic acid;

[0176] 4-(4-((5,7-dimethyl-1H-indol-4-yl)methyl)-1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)benzoic acid;

[0177] 4-((3R,4S)-4-((5,7-dimethyl-1H-indol-4-yl)methyl)-1-(2,2,2-trifluoroethyl)azepan-3-yl)benzoic acid;

[0178] 4-(4-((5,7-dimethyl-1H-indol-4-yl)methyl)-1-(2,2,2-trifluoroethyl)azepan-3-yl)benzoic acid;

[0179] 2-(4-((3R,4R)-4-((5,7-dimethyl-1H-indol-4-yl)methyl)-1-(2,2,2-trifluoroethyl)piperidin-3-yl)-1H-pyrazol-1-yl)acetic acid;

[0180] 2-(4-(4-((5,7-dimethyl-1H-indol-4-yl)methyl)-1-(2,2,2-trifluoroethyl)piperidin-3-yl)-1H-pyrazol-1-yl)acetic acid;

[0181] 4-(((3R,4R)-3-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)-1-(2,2,2-trifluoroethyl)piperidin-4-yl)methyl)-5,7-dimethyl-1H-indole;

[0182] 4-((3-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)-1-(2,2,2-trifluoroethyl)piperidin-4-yl)methyl)-5,7-dimethyl-1H-indole;

[0183] 4-((3R,4R)-4-((5,7-dimethyl-1H-indol-4-yl)methyl)piperidin-3-yl)benzoic acid;

[0184] 4-(4-((5,7-dimethyl-1H-indol-4-yl)methyl)piperidin-3-yl)benzoic acid;

[0185] 4-((3R,4R)-4-((5,7-dimethyl-1H-indol-4-yl)methyl)-1-ethylpiperidin-3-yl)benzoic acid;

[0186] 4-(-((5,7-dimethyl-1H-indol-4-yl)methyl)-1-ethylpiperidin-3-yl)benzoic acid;

[0187] 4-((3R,4R)-4-((5,7-dimethyl-1H-indol-4-yl)methyl)-1-isopropylpiperidin-3-yl)benzoic acid;

[0188] 4-(4-((5,7-dimethyl-1H-indol-4-yl)methyl)-1-isopropylpiperidin-3-yl)benzoic acid;

[0189] 4-((3R,4R)-4-((5,7-dimethyl-1H-indol-4-yl)methyl)-1-(2-hydroxy-2-methylpropyl)piperidin-3-yl)benzoic acid;

[0190] 4-(4-((5,7-dimethyl-1H-indol-4-yl)methyl)-1-(2-hydroxy-2-methylpropyl)piperidin-3-yl)benzoic acid;

[0191] 4-((3R,4R)-4-((5,7-dimethyl-1H-indol-4-yl)methyl)-1-((3-fluorooxetan-3-yl)methyl)piperidin-3-yl)benzoic acid;

[0192] 4-(4-((5,7-dimethyl-1H-indol-4-yl)methyl)-1-((3-fluorooxetan-3-yl)methyl)piperidin-3-yl)benzoic acid;

[0193] 4-((3R,4R)-1-(3,3-difluorocyclobutyl)-4-((5,7-dimethyl-1H-indol-4-yl)methyl)piperidin-3-yl)benzoic acid;

[0194] 4-(1-(3,3-difluorocyclobutyl)-4-((5,7-dimethyl-1H-indol-4-yl)methyl)piperidin-3-yl)benzoic acid;

[0195] 4-((3R,4R)-4-((5,7-dimethyl-1H-indol-4-yl)methyl)-1-(2-(trifluoromethoxy)ethyl)piperidin-3-yl)benzoic acid;

[0196] 4-(4-((5,7-dimethyl-1H-indol-4-yl)methyl)-1-(2-(trifluoromethoxy)ethyl)piperidin-3-yl)benzoic acid;

[0197] 4-((3R,4R)-4-((5,7-dimethyl-1H-indol-4-yl)methyl)-1-propylpiperidin-3-yl)benzoic acid;

[0198] 4-(4-((5,7-dimethyl-1H-indol-4-yl)methyl)-1-propylpiperidin-3-yl)benzoic acid;

[0199] 4-((3R,4R)-4-((5,7-dimethyl-1H-indol-4-yl)methyl)-1-(oxetan-3-yl)piperidin-3-yl)benzoic acid;

[0200] 4-(4-((5,7-dimethyl-1H-indol-4-yl)methyl)-1-(oxetan-3-yl)piperidin-3-yl)benzoic acid;

[0201] 4-((3R,4R)-4-((5,7-dimethyl-1H-indol-4-yl)methyl)-1-((1r,3R)-3-fluorocyclobutyl)piperidin-3-yl)benzoic acid;

[0202] 4-(4-((5,7-dimethyl-1H-indol-4-yl)methyl)-1-(3-fluorocyclobutyl)piperidin-3-yl)benzoic acid;

[0203] 4-((3R,4R)-1-(3,3-difluoropropyl)-4-((5,7-dimethyl-1H-indol-4-yl)methyl)piperidin-3-yl)benzoic acid;

[0204] 4-(1-(3,3-difluoropropyl)-4-((5,7-dimethyl-1H-indol-4-yl)methyl)piperidin-3-yl)benzoic acid;

[0205] 4-((3R,4S)-4-((5,7-dimethyl-1H-indol-4-yl)methyl)-1-methylpyrrolidin-3-yl)benzoic acid;

[0206] 4-(4-((5,7-dimethyl-1H-indol-4-yl)methyl)-1-methylpyrrolidin-3-yl)benzoic acid;

[0207] 4-((3R,4R)-4-((5,7-dimethyl-1H-indol-4-yl)methyl)-1-methylpiperidin-3-yl)benzonitrile;

[0208] 4-(4-((5,7-dimethyl-1H-indol-4-yl)methyl)-1-methylpiperidin-3-yl)benzonitrile;

[0209] 4-((3R,4S)-4-((5,7-dimethyl-1H-indol-4-yl)methyl)-1-methylazepan-3-yl)benzoic acid;

[0210] 4-(4-((5,7-dimethyl-1H-indol-4-yl)methyl)-1-methylazepan-3-yl)benzoic acid;

[0211] 4-(4-((5,7-dimethyl-1H-indol-4-yl)methyl)-1-(2,2,2-trifluoroethyl)azepan-3-yl)benzoic acid;

[0212] 4-((3R,4S)-4-((5,7-dimethyl-1H-indol-4-yl)methyl)-1-ethylazepan-3-yl)benzoic acid;

[0213] 4-(4-((5,7-dimethyl-1H-indol-4-yl)methyl)-1-ethylazepan-3-yl)benzoic acid;

[0214] 4-((4R,5R)-5-((5,7-dimethyl-1H-indol-4-yl)methyl)-1-methylazepan-4-yl)benzoic acid;

[0215] 4-(5-((5,7-dimethyl-1H-indol-4-yl)methyl)-1-methylazepan-4-yl)benzoic acid;

[0216] 4-((3R,4R)-4-((5-fluoro-7-methyl-1H-indol-4-yl)methyl)-1-methylpiperidin-3-yl)benzoic acid;

[0217] 4-(4-((5-fluoro-7-methyl-1H-indol-4-yl)methyl)-1-methylpiperidin-3-yl)benzoic acid;

[0218] 4-((4R,5R)-1-(3,3-difluoropropyl)-5-((5,7-dimethyl-1H-indol-4-yl)methyl)azepan-4-yl)benzoic acid;

[0219] 4-(1-(3,3-difluoropropyl)-5-((5,7-dimethyl-1H-indol-4-yl)methyl)azepan-4-yl)benzoic acid;

[0220] 4-((3R,4R)-1-methyl-4-((7-methyl-1H-indol-4-yl)methyl)piperidin-3-yl)benzoic acid;

[0221] 4-(1-methyl-4-((7-methyl-1H-indol-4-yl)methyl)piperidin-3-yl)benzoic acid;

[0222] 4-((3R,4R)-4-((5-chloro-7-methyl-1H-indol-4-yl)methyl)-1-methylpiperidin-3-yl)benzoic acid;

[0223] 4-(4-((5-chloro-7-methyl-1H-indol-4-yl)methyl)-1-methylpiperidin-3-yl)benzoic acid;

[0224] 4-((3R,4R)-4-((5,7-dichloro-1H-indol-4-yl)methyl)-1-methylpiperidin-3-yl)benzoic acid;

[0225] 4-(4-((5,7-dichloro-1H-indol-4-yl)methyl)-1-methylpiperidin-3-yl)benzoic acid;

[0226] 4-((3R,4R)-4-((7-chloro-5-methyl-1H-indol-4-yl)methyl)-1-methylpiperidin-3-yl)benzoic acid;

[0227] 4-(4-((7-chloro-5-methyl-1H-indol-4-yl)methyl)-1-methylpiperidin-3-yl)benzoic acid;

[0228] 4-((3R,4R)-4-((3-chloro-5,7-dimethyl-1H-indol-4-yl)methyl)-1-methylpiperidin-3-yl)benzoic acid;

[0229] 4-(4-((3-chloro-5,7-dimethyl-1H-indol-4-yl)methyl)-1-methylpiperidin-3-yl)benzoic acid;

[0230] 4-((3R,4R)-1-(3,3-difluoropropyl)-4-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-3-yl)benzoic acid;

[0231] 4-(1-(3,3-difluoropropyl)-4-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-3-yl)benzoic acid;

[0232] 4-(((3R,4R)-3-(4-(1H-tetrazol-5-yl)phenyl)-1-methylpiperidin-4-yl)methyl)-5,7-dimethyl-1H-indole;

[0233] 4-((3-(4-(1H-tetrazol-5-yl)phenyl)-1-methylpiperidin-4-yl)methyl)-5,7-dimethyl-1H-indole;

[0234] 4-((3R,4R)-4-((5,7-dimethyl-1H-indol-4-yl)methyl)-1-(2,2,2-trifluoroethyl)piperidin-3-yl)benzonitrile;

[0235] 4-(4-((5,7-dimethyl-1H-indol-4-yl)methyl)-1-(2,2,2-trifluoroethyl)piperidin-3-yl)benzonitrile;

[0236] 4-(((3R,4R)-3-(4-(1H-pyrazol-1-yl)phenyl)-1-methylpiperidin-4-yl)methyl)-5,7-dimethyl-1H-indole;

[0237] 4-((3-(4-(1H-pyrazol-1-yl)phenyl)-1-methylpiperidin-4-yl)methyl)-5,7-dimethyl-1H-indole;

[0238] 4-(((3R,4R)-3-(4-(1H-pyrazol-1-yl)phenyl)-1-(2,2,2-trifluoroethyl)piperidin-4-yl)methyl)-5,7-dimethyl-1H-indole;

[0239] 4-((3-(4-(1H-pyrazol-1-yl)phenyl)-1-(2,2,2-trifluoroethyl)piperidin-4-yl)methyl)-5,7-dimethyl-1H-indole;

[0240] 4-(((3R,4R)-3-(4-(1H-pyrazol-1-yl)phenyl)-1-(3,3-difluoropropyl)piperidin-4-yl)methyl)-5,7-dimethyl-1H-indole;

[0241] 4-((3-(4-(1H-pyrazol-1-yl)phenyl)-1-(3,3-difluoropropyl)piperidin-4-yl)methyl)-5,7-dimethyl-1H-indole;

[0242] 4-(((3R,4R)-3-(4-(1H-pyrazol-1-yl)phenyl)-1-((3-fluorooxetan-3-yl)methyl)piperidin-4-yl)methyl)-5,7-dimethyl-1H-indole;

[0243] 4-((3-(4-(1H-pyrazol-1-yl)phenyl)-1-((3-fluorooxetan-3-yl)methyl)piperidin-4-yl)methyl)-5,7-dimethyl-1H-indole;

[0244] 4-(((3R,4R)-3-(4-(1H-pyrazol-1-yl)phenyl)-1-(oxetan-3-yl)piperidin-4-yl)methyl)-5,7-dimethyl-1H-indole;

[0245] 4-((3-(4-(1H-pyrazol-1-yl)phenyl)-1-(oxetan-3-yl)piperidin-4-yl)methyl)-5,7-dimethyl-1H-indole;

[0246] 4-(((3R,4R)-3-(4-(1H-pyrazol-1-yl)phenyl)-1-(1,3-difluoropropan-2-yl)piperidin-4-yl)methyl)-5,7-dimethyl-1H-indole;

[0247] 4-((3-(4-(1H-pyrazol-1-yl)phenyl)-1-(1,3-difluoropropan-2-yl)piperidin-4-yl)methyl)-5,7-dimethyl-1H-indole;

[0248] 5,7-Dimethyl-4-(((3R,4R)-1-methyl-3-(1-methyl-1H-pyrazol-4-yl)piperidin-4-yl)methyl)-1H-indole;

[0249] 5,7-Dimethyl-4-((1-methyl-3-(1-methyl-1H-pyrazol-4-yl)piperidin-4-yl)methyl)-1H-indole;

[0250] 5,7-Dimethyl-4-(((3R,4R)-3-(1-methyl-1H-pyrazol-4-yl)-1-(2,2,2-trifluoroethyl)piperidin-4-yl)methyl)-1H-indole;

[0251] 5,7-Dimethyl-4-((3-(1-methyl-1H-pyrazol-4-yl)-1-(2,2,2-trifluoroethyl)piperidin-4-yl)methyl)-1H-indole;

[0252] 4-(((3R,4R)-1-(2-fluoroethyl)-3-(1-methyl-1H-pyrazol-4-yl)piperidin-4-yl)methyl)-5,7-dimethyl-1H-indole;

[0253] 4-((1-(2-fluoroethyl)-3-(1-methyl-1H-pyrazol-4-yl)piperidin-4-yl)methyl)-5,7-dimethyl-1H-indole;

[0254] 4-(((3R,4R)-1-(2,2-difluoroethyl)-3-(1-methyl-1H-pyrazol-4-yl)piperidin-4-yl)methyl)-5,7-dimethyl-1H-indole;

[0255] 4-((1-(2,2-difluoroethyl)-3-(1-methyl-1H-pyrazol-4-yl)piperidin-4-yl)methyl)-5,7-dimethyl-1H-indole;

[0256] 4-(((3R,4R)-1-(3,3-difluoropropyl)-3-(1-methyl-1H-pyrazol-4-yl)piperidin-4-yl)methyl)-5,7-dimethyl-1H-indole;

[0257] 4-((1-(3,3-difluoropropyl)-3-(1-methyl-1H-pyrazol-4-yl)piperidin-4-yl)methyl)-5,7-dimethyl-1H-indole;

[0258] 4-(((3R,4R)-1-(1,3-difluoropropan-2-yl)-3-(1-methyl-1H-pyrazol-4-yl)piperidin-4-yl)methyl)-5,7-dimethyl-1H-indole;

[0259] 4-((1-(1,3-difluoropropan-2-yl)-3-(1-methyl-1H-pyrazol-4-yl)piperidin-4-yl)methyl)-5,7-dimethyl-1H-indole;

[0260] 4-((3R,4S)-4-((5,7-dimethyl-1H-indol-4-yl)methyl)-1-methylpyrrolidin-3-yl)benzamide;

[0261] 4-(4-((5,7-dimethyl-1H-indol-4-yl)methyl)-1-methylpyrrolidin-3-yl)benzamide;

[0262] 4-((3R,4S)-4-((5-cyclopropyl-7-methyl-1H-indol-4-yl)methyl)-1-methylpyrrolidin-3-yl)benzoic acid;

[0263] 4-(4-((5-cyclopropyl-7-methyl-1H-indol-4-yl)methyl)-1-methylpyrrolidin-3-yl)benzoic acid;

[0264] 4-(((3S,4R)-4-(4-(1H-tetrazol-5-yl)phenyl)-1-methylpyrrolidin-3-yl)methyl)-5,7-dimethyl-1H-indole;

[0265] 4-((4-(4-(1H-tetrazol-5-yl)phenyl)-1-methylpyrrolidin-3-yl)methyl)-5,7-dimethyl-1H-indole;

[0266] 4-(((3S,4R)-4-(4-(1H-tetrazolyl-5-yl)phenyl)-1-ethylpyrrolidin-3-yl)methyl)-5-cyclopropyl-7-methyl-1H-indole; and

[0267] 4-((4-(4-(1H-tetrazol-5-yl)phenyl)-1-ethylpyrrolidin-3-yl)methyl)-5-cyclopropyl-7-methyl-1H-indole.

[0268] Embodiment 29. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to Embodiment 1 is selected from:

[0269]

[0270]

[0271]

[0272]

[0273]

[0274]

[0275] Embodiment 30. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of the preceding embodiments or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

[0276] Embodiment 31. A method of treating or preventing a disease or disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound according to any one of Embodiments 1 to 29, or a pharmaceutically acceptable salt thereof.

[0277] Embodiment 32. A method of modulating complement alternative pathway activity in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound according to any one of embodiments 1 to 29, or a pharmaceutically acceptable salt thereof.

[0278] Embodiment 33. A method of treating a disease or disorder mediated by complement activation, particularly complement alternative pathway activation, in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound according to any one of Embodiments 1 to 29, or a pharmaceutically acceptable salt thereof.

[0279] Embodiment 34. A method of treating a disease or disorder affected by modulation of the complement alternative pathway, the method comprising administering to the subject a therapeutically effective amount of a compound according to any one of Embodiments 1 to 29, or a pharmaceutically acceptable salt thereof.

[0280] Embodiment 35. A method of treating a disease or disorder associated with dysregulation of the complement alternative pathway, the method comprising administering to the subject a therapeutically effective amount of a compound according to any one of Embodiments 1 to 29, or a pharmaceutically acceptable salt thereof.

[0281] Embodiment 36. A method of inhibiting complement factor B expression or activity, the method comprising administering to a subject a compound according to any one of embodiments 1 to 29 or a pharmaceutically acceptable salt thereof.

[0282] Embodiment 37. The method of any one of embodiments 31 and 33 to 35, wherein the disease or disorder is selected from age-related macular degeneration, geographic atrophy, diabetic retinopathy, uveitis, retinitis pigmentosa, macular edema, Behcet's uveitis, multifocal choroiditis, Voigt-Koyanagi-Harada syndrome, intermediate uveitis, birdshot retinochoroiditis, sympathetic eye inflammation, ocular cicatricial pemphigoid, ocular pemphigus, non-arteritic ischemic optic neuropathy, postoperative inflammation, retinal vein occlusion, glaucoma, multi-cause honeycomb retinal dystrophy / Malattialeven tinese, Sorsby fundus dystrophy, late onset macular dystrophy, North Carolina macular dystrophy, fundus xanthophy, keratitis, multiple sclerosis and other neurological disorders, stroke, Guillain-Barré syndrome, spinal cord injury, traumatic brain injury, Parkinson's disease, Alzheimer's disease, schizophrenia, amyotrophic lateral sclerosis (ALS), Huntington's disease, multifocal motor neuropathy, autism spectrum disorder, schizophrenia, drug-induced neurotoxicity; disorders with inappropriate or adverse complement activation, such as complications of hemodialysis, hyperacute allograft rejection, xenograft rejection, interleukin- 2 IL-2-induced toxicity during treatment, inflammatory disorders, paroxysmal nocturnal hemoglobinuria, C3 glomerulonephritis (including dense deposit disease and C3 glomerulonephritis), immune complex membranoproliferative glomerulonephritis (IC-MPGN), IgA nephropathy, membranous nephropathy including idiopathic membranous nephropathy, diabetic nephropathy, atypical hemolytic uremic syndrome (aHUS), hemolytic uremic syndrome, STEC-HUS (Shiga toxin-producing Escherichia coli hemolytic uremic syndrome), periodontitis, CD55 deficiency leading to excessive complement activation, vasculothrombosis, protein-losing enteropathy inflammatory or autoimmune diseases such as Crohn's disease, neuromyelitis optica (NMO), IgA vasculitis (formerly known as Henoch-Schönlein purpura or HSP), CHAPLE syndrome, hematopoietic stem cell transplant-associated thrombotic microangiopathy (HSCT-TMA), adult-onset respiratory distress syndrome (ARDS), myocarditis, post-ischemia-reperfusion syndrome, myocardial infarction, balloon angioplasty, post-pump syndrome during cardiopulmonary bypass or renal bypass, atherosclerosis, hemodialysis, renal ischemia, acute kidney injury, mesenteric artery reperfusion after aortic reconstruction, infectious disease, or sepsis;COVID-19, immune complex disorders and autoimmune diseases, rheumatoid arthritis, osteoarthritis, spondyloarthropathies, psoriatic arthritis, systemic lupus erythematosus (SLE), lupus nephritis, SLE nephritis, proliferative nephritis, myasthenia gravis, liver fibrosis, hemolytic anemia, tissue regeneration, nerve regeneration, dyspnea, hemoptysis, acute respiratory distress syndrome (ARDS), asthma, chronic obstructive pulmonary disease (COPD), emphysema, pulmonary embolism and infarction, pneumonia, fibrosing pneumococcal disease, pulmonary fibrosis, asthma, allergy, bronchitis contraction, hypersensitivity pneumonitis, parasitic diseases, Goodpasture's syndrome, pulmonary vasculitis, microimmune vasculitis, antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), Burger's vasculitis, cryoglobulinemia, Kawasaki disease, Takayasu arteritis, cryoglobulinemia, immune complex-associated inflammation, antiphospholipid syndrome, glomerulonephritis, and obesity; immune thrombocytopenia, cold agglutinin disease, warm antibody autoimmune hemolytic anemia (wAIHA), thrombotic thrombocytopenic purpura (TTP), and abdominal aortic aneurysm, as well as Graves' disease. ;

[0283] Embodiment 38. A method of treating age-related macular degeneration, the method comprising administering to a subject in need thereof an effective amount of a composition comprising a compound according to any one of Embodiments 1 to 29 or a pharmaceutically acceptable salt thereof.

[0284] Embodiment 39. A compound according to any one of Embodiments 1 to 29, or a pharmaceutically acceptable salt thereof, for use as a medicament.

[0285] Embodiment 40. A compound according to any one of Embodiments 1 to 29, or a pharmaceutically acceptable salt thereof, for use in inhibiting the expression or activity of complement factor B in a subject in need thereof.

[0286] Embodiment 41. A compound according to any one of Embodiments 1 to 29, or a pharmaceutically acceptable salt thereof, for use in treating a disease or disorder associated with dysregulation of the complement alternative pathway.

[0287] Embodiment 42. A compound for use according to embodiment 41 or a pharmaceutically acceptable salt thereof, wherein the disease or disorder is selected from age-related macular degeneration, geographic atrophy, diabetic retinopathy, uveitis, retinitis pigmentosa, macular edema, Behcet's uveitis, multifocal choroiditis, Voigt-Koyanagi-Harada syndrome, intermediate uveitis, birdshot retinochoroiditis, sympathetic ophthalmia, ocular cicatricial pemphigoid, ocular pemphigus, non-arteritic ischemic optic neuropathy, postoperative inflammation, retinal vein occlusion, glaucoma, multi-cause honeycomb retinal dystrophy / Malattialev entinese, Sorsby fundus dystrophy, late onset macular dystrophy, North Carolina macular dystrophy, fundus xanthophy, keratitis, multiple sclerosis and other neurological disorders, stroke, Guillain-Barré syndrome, spinal cord injury, traumatic brain injury, Parkinson's disease, Alzheimer's disease, schizophrenia, amyotrophic lateral sclerosis (ALS), Huntington's disease, multifocal motor neuropathy, autism spectrum disorder, schizophrenia, drug-induced neurotoxicity; disorders with inappropriate or adverse complement activation, such as complications of hemodialysis, hyperacute allograft rejection, xenograft rejection, interleukin IL-2-induced toxicity during IL-2 therapy, inflammatory disorders, paroxysmal nocturnal hemoglobinuria, C3 glomerulonephritis (including dense deposit disease and C3 glomerulonephritis), immune complex membranoproliferative glomerulonephritis (IC-MPGN), IgA nephropathy, membranous nephropathy including idiopathic membranous nephropathy, diabetic nephropathy, atypical hemolytic uremic syndrome (aHUS), hemolytic uremic syndrome, STEC-HUS (Shiga toxin-producing Escherichia coli hemolytic uremic syndrome), periodontitis, CD55 deficiency leading to excessive complement activation, vasculothrombosis, protein-losing Enteropathy (CHAPLE syndrome), inflammatory or autoimmune diseases such as Crohn's disease, neuromyelitis optica (NMO), IgA vasculitis (formerly known as Henoch-Schönlein purpura or HSP), CHAPLE syndrome, hematopoietic stem cell transplant-associated thrombotic microangiopathy (HSCT-TMA), adult-onset respiratory distress syndrome (ARDS), myocarditis, post-ischemia-reperfusion syndrome, myocardial infarction, balloon angioplasty, post-pump syndrome during cardiopulmonary bypass or renal bypass, atherosclerosis, hemodialysis, renal ischemia, acute kidney injury, mesenteric artery reperfusion after aortic reconstruction, infectious disease, or sepsis;COVID-19, immune complex disorders and autoimmune diseases, rheumatoid arthritis, osteoarthritis, spondyloarthropathies, psoriatic arthritis, systemic lupus erythematosus (SLE), lupus nephritis, SLE nephritis, proliferative nephritis, myasthenia gravis, liver fibrosis, hemolytic anemia, tissue regeneration, nerve regeneration, dyspnea, hemoptysis, acute respiratory distress syndrome (ARDS), asthma, chronic obstructive pulmonary disease (COPD), emphysema, pulmonary embolism and infarction, pneumonia, fibrosing pneumococcal disease, pulmonary fibrosis, asthma, allergy, bronchitis contraction, hypersensitivity pneumonitis, parasitic diseases, Goodpasture's syndrome, pulmonary vasculitis, microimmune vasculitis, antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), Burger's vasculitis, cryoglobulinemia, Kawasaki disease, Takayasu arteritis, cryoglobulinemia, immune complex-associated inflammation, antiphospholipid syndrome, glomerulonephritis, and obesity; immune thrombocytopenia, cold agglutinin disease, warm antibody autoimmune hemolytic anemia (wAIHA), thrombotic thrombocytopenic purpura (TTP), and abdominal aortic aneurysm, as well as Graves' disease. ;

[0288] Embodiment 43. Use of a compound according to any one of Embodiments 1 to 29, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for treating a disease or disorder mediated by complement activation or complement alternative pathway activation.

[0289] Embodiment 44. Use of a compound according to any one of Embodiments 1 to 29 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for treating a disease or disorder selected from the group consisting of age-related macular degeneration, geographic atrophy, diabetic retinopathy, uveitis, retinitis pigmentosa, macular edema, Behcet's uveitis, multifocal choroiditis, Voigt-Koyanagi-Harada syndrome, intermediate uveitis, birdshot retinochoroiditis, sympathetic ophthalmia, ocular cicatricial pemphigoid, ocular pemphigus, non-arteritic ischemic optic neuropathy, postoperative inflammation, retinal vein occlusion, glaucoma, multi-cause honeycomb retinal dystrophy / Malattia leventinese, Sorsby fundus dystrophy, late-onset retinal macular dystrophy, North Carolina macular dystrophy, fundus xanthophy, keratitis, multiple sclerosis and other neurological disorders, stroke, Guillain-Barré syndrome, spinal cord injury, traumatic brain injury, Parkinson's disease, Alzheimer's disease, schizophrenia, amyotrophic lateral sclerosis (ALS), Huntington's disease, multifocal motor neuropathy, autism spectrum disorder, schizophrenia, drug-induced neurotoxicity; disorders with inappropriate or adverse complement activation, such as complications of hemodialysis, hyperacute allograft rejection, xenograft rejection, IL-2-induced toxicity during interleukin-2 therapy, inflammatory disorders, paroxysmal nocturnal hemoglobinuria, C3 glomerulonephritis (including dense deposit disease and C3 glomerulonephritis), immune complex membranoproliferative glomerulonephritis (IC-MPGN), IgA nephropathy, including idiopathic membranous nephropathy Membranous nephropathy, diabetic nephropathy, atypical hemolytic uremic syndrome (aHUS), hemolytic uremic syndrome, STEC-HUS (Shiga toxin-producing Escherichia coli hemolytic uremic syndrome), periodontitis, excessive complement activation due to CD55 deficiency, vasculothrombosis, protein-losing enteropathy (CHAPLE syndrome), inflammatory or autoimmune diseases such as Crohn's disease, neuromyelitis optica (NMO), IgA vasculitis (formerly known as Henoch-Schönlein purpura or HSP), CHAPLE syndrome, hematopoietic stem cell transplant-associated thrombotic microangiopathy (HSCT-TMA), adult-onset respiratory distress syndrome (ARDS), myocarditis, post-ischemia-reperfusion syndrome, myocardial infarction, balloon angioplasty, post-pump syndrome during cardiopulmonary bypass or renal bypass, atherosclerosis, hemodialysis, renal ischemia, acute kidney injury, mesenteric artery reperfusion after aortic reconstruction, infectious disease, or sepsis;COVID-19, immune complex disorders and autoimmune diseases, rheumatoid arthritis, osteoarthritis, spondyloarthropathies, psoriatic arthritis, systemic lupus erythematosus (SLE), lupus nephritis, SLE nephritis, proliferative nephritis, myasthenia gravis, liver fibrosis, hemolytic anemia, tissue regeneration, nerve regeneration, dyspnea, hemoptysis, acute respiratory distress syndrome (ARDS), asthma, chronic obstructive pulmonary disease (COPD), emphysema, pulmonary embolism and infarction, pneumonia, fibrosing pneumococcal disease, pulmonary fibrosis, asthma, allergy, bronchitis contraction, hypersensitivity pneumonitis, parasitic diseases, Goodpasture's syndrome, pulmonary vasculitis, microimmune vasculitis, antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), Burger's vasculitis, cryoglobulinemia, Kawasaki disease, Takayasu arteritis, cryoglobulinemia, immune complex-associated inflammation, antiphospholipid syndrome, glomerulonephritis, and obesity; immune thrombocytopenia, cold agglutinin disease, warm antibody autoimmune hemolytic anemia (wAIHA), thrombotic thrombocytopenic purpura (TTP), and abdominal aortic aneurysm, as well as Graves' disease. ;

[0290] Embodiment 45. Use of a compound according to any one of Embodiments 1 to 29, or a pharmaceutically acceptable salt thereof, for treating a disease or disorder mediated by complement activation or complement alternative pathway activation.

[0291] Embodiment 46. Use of a compound according to any one of Embodiments 1 to 29, or a pharmaceutically acceptable salt thereof, for treating a disease or disorder affected by modulation of the complement alternative pathway.

[0292] Embodiment 47. Use of a compound according to any one of Embodiments 1 to 29 or a pharmaceutically acceptable salt thereof for treating a disease or disorder selected from the group consisting of age-related macular degeneration, geographic atrophy, diabetic retinopathy, uveitis, retinitis pigmentosa, macular edema, Behcet's uveitis, multifocal choroiditis, Voigt-Koyanagi-Harada syndrome, intermediate uveitis, birdshot retinochoroiditis, sympathetic ophthalmia, ocular cicatricial pemphigoid, ocular pemphigus, non-arteritic ischemic optic neuropathy, postoperative inflammation, retinal vein occlusion, glaucoma, multi-cause honeycomb retinal dystrophy / Malattia leventinese, Sorsby fundus dystrophy, late-onset retinal macular dystrophy, North Carolina macular dystrophy, fundus xanthophy, keratitis, multiple sclerosis and other neurological disorders, stroke, Guillain-Barré syndrome, spinal cord injury, traumatic brain injury, Parkinson's disease, Alzheimer's disease, schizophrenia, amyotrophic lateral sclerosis (ALS), Huntington's disease, multifocal motor neuropathy, autism spectrum disorder, schizophrenia, drug-induced neurotoxicity; disorders with inappropriate or adverse complement activation, such as complications of hemodialysis, hyperacute allograft rejection, xenograft rejection, IL-2-induced toxicity during interleukin-2 therapy, inflammatory disorders, paroxysmal nocturnal hemoglobinuria, C3 glomerulonephritis (including dense deposit disease and C3 glomerulonephritis), immune complex membranoproliferative glomerulonephritis (IC-MPGN), IgA nephropathy, including idiopathic membranous nephropathy Membranous nephropathy, diabetic nephropathy, atypical hemolytic uremic syndrome (aHUS), hemolytic uremic syndrome, STEC-HUS (Shiga toxin-producing Escherichia coli hemolytic uremic syndrome), periodontitis, excessive complement activation due to CD55 deficiency, vasculothrombosis, protein-losing enteropathy (CHAPLE syndrome), inflammatory or autoimmune diseases such as Crohn's disease, neuromyelitis optica (NMO), IgA vasculitis (formerly known as Henoch-Schönlein purpura or HSP), CHAPLE syndrome, hematopoietic stem cell transplant-associated thrombotic microangiopathy (HSCT-TMA), adult-onset respiratory distress syndrome (ARDS), myocarditis, post-ischemia-reperfusion syndrome, myocardial infarction, balloon angioplasty, post-pump syndrome during cardiopulmonary bypass or renal bypass, atherosclerosis, hemodialysis, renal ischemia, acute kidney injury, mesenteric artery reperfusion after aortic reconstruction, infectious disease, or sepsis;COVID-19, immune complex disorders and autoimmune diseases, rheumatoid arthritis, osteoarthritis, spondyloarthropathies, psoriatic arthritis, systemic lupus erythematosus (SLE), lupus nephritis, SLE nephritis, proliferative nephritis, myasthenia gravis, liver fibrosis, hemolytic anemia, tissue regeneration, nerve regeneration, dyspnea, hemoptysis, acute respiratory distress syndrome (ARDS), asthma, chronic obstructive pulmonary disease (COPD), emphysema, pulmonary embolism and infarction, pneumonia, fibrosing pneumococcal disease, pulmonary fibrosis, asthma, allergy, bronchitis contraction, hypersensitivity pneumonitis, parasitic diseases, Goodpasture's syndrome, pulmonary vasculitis, microimmune vasculitis, antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), Burger's vasculitis, cryoglobulinemia, Kawasaki disease, Takayasu arteritis, cryoglobulinemia, immune complex-associated inflammation, antiphospholipid syndrome, glomerulonephritis, and obesity; immune thrombocytopenia, cold agglutinin disease, warm antibody autoimmune hemolytic anemia (wAIHA), thrombotic thrombocytopenic purpura (TTP), and abdominal aortic aneurysm, as well as Graves' disease. ;

[0293] Embodiment 48. Use of a compound according to any one of Embodiments 1 to 29 or a pharmaceutically acceptable salt thereof for treating age-related macular degeneration.

[0294] Embodiment 49. A pharmaceutical combination comprising a compound according to any one of Embodiments 1 to 29 or a pharmaceutically acceptable salt thereof, and one or more additional therapeutic agents.

[0295] Depending on the choice of starting materials and procedures, the compound may exist in possible isomeric forms or as a mixture thereof (e.g., as a pure optical isomer or as a mixture of isomers, such as a racemate and a diastereomeric mixture), depending on the number of asymmetric centers. The present disclosure is intended to include all such possible isomers, including racemic mixtures, enantiomerically enriched mixtures, diastereomeric mixtures, and optically pure forms. Optically active (R)- and (S)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a disubstituted or trisubstituted cycloalkyl, the one or more cycloalkyl substituents may have a cis or trans configuration. The present disclosure includes cis and trans configurations of substituted cycloalkyl groups (e.g., cyclobutyl groups) and mixtures thereof. All tautomeric forms are also intended to be included. In particular, when the heteroaryl ring containing N as a ring atom is 2-pyridone, for example, tautomers in which the carbonyl group is described as a hydroxyl group (e.g., 2-hydroxypyridine) are included.

[0296] Separation of cis and trans isomers can be achieved according to methods known to those skilled in the art such as chromatography using tools such as HPLC (high performance liquid chromatography), thin layer chromatography, SFC (supercritical fluid chromatography), GC (gas chromatography) or recrystallization techniques.

[0297] Pharmaceutically acceptable salts

[0298] As used herein, the term "salt" or "salts" refers to an acid addition salt or a base addition salt of a compound of the present disclosure. "Salts" particularly include "pharmaceutically acceptable salts". The term "pharmaceutically acceptable salts" refers to salts that retain the biological effectiveness and properties of the compounds of the present disclosure and are typically not biologically or otherwise undesirable. Due to the presence of amino and / or carboxyl groups or groups similar thereto, the compounds of the present disclosure are capable of forming acid salts and / or base salts.

[0299] Pharmaceutically acceptable acid addition salts can be formed with inorganic and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc. 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, toluenesulfonic acid, sulfosalicylic acid, formic acid, trifluoroacetic acid, etc. In one embodiment, the compound of formula (I) is in the form of HCl or formate.

[0300] Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, ammonium salts and metals from columns I to XII of the periodic table. In certain embodiments, salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include ammonium, potassium, sodium, calcium, and magnesium salts.

[0301] Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines; substituted amines (including naturally occurring substituted amines); cyclic amines; basic ion exchange resins, etc. Certain organic amines include isopropylamine, benzathine, choline, diethanolamine, diethylamine, lysine, meglumine, piperazine, and tromethamine.

[0302] In another aspect, the disclosure provides compounds in the form of acetate, ascorbate, adipate, aspartate, benzoate, benzenesulfonate, bromide / hydrobromide, bicarbonate / carbonate, bisulfate / sulfate, camphorsulfonate, decanoate, chloride / hydrochloride, chlortheophyllonate, citrate, edisylate, fumarate, glucoheptonate, gluconate, glucuronate, glutamate, glutarate, glycolate, hippurate, hydroiodide / iodide, isethionate The invention can be in the form of a salt, lactate, lactobionate, dodecylsulfate, malate, maleate, malonate, mandelate, methanesulfonate, methylsulfate, mucate, naphthoate, naphthoate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate / hydrogenphosphate / dihydrogenphosphate, polygalacturonate, propionate, sebacate, stearate, succinate, sulfosalicylate, sulfate, tartrate, toluenesulfonate, trifenatate, trifluoroacetate or xinafoate.

[0303] In another aspect, the disclosure provides compounds in the form of sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, copper, isopropylamine, benzathine, choline, diethanolamine, diethylamine, lysine, meglumine, piperazine or tromethamine salt forms.

[0304] Isotope-labeled compounds

[0305] Any formula given herein is also intended to represent non-labeled forms of the compound as well as isotopically labeled forms. An isotopically labeled compound has a structure depicted by the formula given herein, except that one or more atoms are replaced by atoms having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine, chlorine, and iodine, for example, 2 H. 3 H. 11 C. 13 C. 14 C. 18 O. 15 N. 18 F. 17 O. 18 O. 35 S. 36 Cl, 123 I. 124 I. 125 I. The present disclosure includes various isotopically labeled compounds as defined herein, for example, compounds into which a radioactive isotope (e.g. 3 H and 14C), or compounds into which non-radioactive isotopes (e.g. 2 H and 13 C). Such isotope-labeled compounds can be used for metabolic studies (using 14 C) reaction kinetics studies (e.g. 2 H or 3 H), detection or imaging techniques, such as positron emission tomography (PET) or single photon emission computed tomography (SPECT), including drug or substrate tissue distribution assays, or radiation therapy for patients. In particular, 18 F compounds may be particularly desirable for PET or SPECT studies. Isotopically labeled compounds of formula (I) or subformulae thereof can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and general schemes, using an appropriate isotopically labeled reagent in place of the unlabeled previously used reagent.

[0306] In addition, the use of heavier isotopes, especially deuterium (i.e. 2 H or D) can provide certain therapeutic advantages derived from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements or improved therapeutic index). It should be understood that deuterium in this context is considered to be a substituent of a compound having any of formula (I) or its subformulae. The concentration of such heavier isotopes (particularly deuterium) can be defined by an isotopic enrichment factor. As used herein, the term "isotopic enrichment factor" means the ratio between the isotopic abundance and the natural abundance of a specified isotope. If a substituent in a compound of the disclosure indicates deuterium, such 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).

[0307] Pharmaceutically acceptable solvates according to the present disclosure include those wherein the solvent of crystallization may be isotopically substituted, for example, D2O, d6-acetone, d6-DMSO.

[0308] The compounds of the present disclosure, i.e. compounds of formula (I), (IA), (IB) containing groups capable of acting as hydrogen bond donors and / or acceptors, are capable of forming co-crystals with suitable co-crystal formers. These co-crystals can be prepared from compounds of formula (I) or a subformula thereof by known co-crystal forming procedures. Such procedures include grinding, heating, co-subliming, co-melting or contacting in solution a compound of formula (I), (IA), (IB) with a co-crystal former under crystallization conditions and isolating the co-crystals thus formed. Suitable co-crystal formers include those described in WO 2004 / 078163.

[0309] All methods described herein can be performed in any suitable order, unless otherwise indicated herein or otherwise clearly contradictory to the context. The use of any and all examples or exemplary language (such as "for example") provided herein is intended only to better illustrate this disclosure, without limiting the scope of this disclosure otherwise claimed.

[0310] Any asymmetric center (e.g., carbon, etc.) of one or more compounds of the present disclosure can exist in a racemic or enantiomerically enriched form, for example, (R)-, (S)-, or (R, S)-configuration. In certain embodiments, for example, in a mixture of enantiomers, each asymmetric center is present in at least 10% enantiomeric excess, at least 20% enantiomeric excess, at least 30% enantiomeric excess, at least 40% enantiomeric excess, at least 50% enantiomeric excess, 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. In certain embodiments, for example, in enantiomerically enriched form, each asymmetric center is present in at least 50% enantiomeric excess, 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. Thus, the compounds of the present disclosure may exist as a racemic mixture or in enantiomerically enriched or enantiomeric form, or as a mixture of diastereomers.

[0311] In one embodiment, there is provided a compound having formula (I) or a pharmaceutically acceptable salt thereof present in at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess.

[0312] In one embodiment, there is provided a compound having formula (I) or a pharmaceutically acceptable salt thereof present in at least 90% diastereomeric excess, at least 95% diastereomeric excess, or at least 99% diastereomeric excess.

[0313] In one embodiment, the compound of formula (I) is a compound of formula (IA) or a pharmaceutically acceptable salt thereof:

[0314]

[0315] wherein A is selected from the group consisting of phenyl, furanyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, pyrazolyl, imidazolyl, pyridinyl, triazolyl, tetrazolyl, oxadiazolyl, isoxadiazolyl, pyrimidinyl, pyrazinyl and pyridazinyl, and wherein R, R 1 , R 2 , R 3 , R 5 , R 6 , R 8 , W, m, n, and p are defined according to Example 1. In particular, R, R 1 , R 2 , R 3 , R 5 , R 6 , R 8 , W, m, n, and p may be defined according to any one of Examples 1 to 26.

[0316] In another embodiment, the compound of formula (I) is a compound of formula (IB) or a pharmaceutically acceptable salt thereof:

[0317]

[0318] wherein A is selected from phenyl, furanyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, pyrazolyl, imidazolyl, pyridinyl, triazolyl, tetrazolyl, oxadiazolyl, isoxadiazolyl, pyrimidinyl, pyrazinyl and pyridazinyl, wherein R, R 1 , R 2 , R 3 , R 5 , R 6 , R 8 , W, m, n, and p are defined according to Example 1. In particular, R, R 1 , R 2 , R 3 , R 5 , R 6 , R 8 , W, m, n, and p may be defined according to any one of Examples 1 to 26.

[0319] In another embodiment, the compound of formula (I) is a compound of formula (IC) or a pharmaceutically acceptable salt thereof:

[0320]

[0321] Among them, R 1 , R 2 , R 3 , R 5 , R 6 , R 8 , W, and p are defined according to Example 1. In particular, R, R 1 , R 2 , R 5 , R 6 , R 8 , W, and p may be defined according to any one of Examples 1 to 26.

[0322] In another embodiment, the compound of formula (I) is a compound of formula (ID) or a pharmaceutically acceptable salt thereof:

[0323]

[0324] Among them, R 1 , R 2 , R 5 , R 7 , and R 8 As defined in Example 1. In particular, R, R 1 , R 2 , R 5 , R 7 , and R 8 May be defined according to any one of Embodiments 1 to 26.

[0325] In the formula of the present application, in C-sp 3 Terminology Indicates absolute stereochemistry, (R) or (S). In the formulae of the present application, in the C-sp 3 Terminology Indicates absolute stereochemistry, (R) or (S). In the formulae of the present application, in the C-sp 3 Terminology represents a covalent bond where the stereochemistry of the bond is not defined. This means that 3 Terminology This includes the (S) configuration or the (R) configuration of the respective chiral center. In addition, mixtures may also be present. Therefore, the present disclosure encompasses mixtures of stereoisomers, such as mixtures of enantiomers (such as racemates), and / or mixtures of diastereomers.

[0326] For the avoidance of doubt, when depicting a compound structure with unspecified stereochemistry, for any R group, the By this is meant that an asymmetric center has the (R)- or (S)-configuration, or is present as a mixture thereof and is so stated.

[0327] For the avoidance of doubt, in any formula of the present application, when R 5 When a group is shown attached to ring A, this means that one or more R 5 The radicals may be bonded via a carbon atom or a heteroatom such as nitrogen.

[0328] For the avoidance of doubt, compound structures shown herein may exist in their zwitterionic form where appropriate.

[0329] Thus, as used herein, the compounds of the present disclosure may be in the form of one of the possible stereoisomers, rotamers, atropisomers, tautomers, or mixtures thereof, for example, in the form of substantially pure geometric (cis or trans) stereoisomers, diastereomers, optical isomers, racemates, or mixtures thereof.

[0330] Any resulting mixtures of stereoisomers can be separated on the basis of the physicochemical differences of the components, into the pure or substantially pure geometric or optical isomers, diastereomers, racemates, for example, by chromatography and / or fractional crystallization.

[0331] Any obtained compound of the present disclosure or the racemate of intermediate can be split into optical isomers (enantiomers) by known methods, for example, by separating its diastereomeric salt obtained with optically active acid or alkali, and releasing optically active acidic or basic compounds. In particular, the compound of the present disclosure can be split into their optical enantiomers using an alkaline moiety, for example, by fractional crystallization with optically active acid, such as tartaric acid, dibenzoyltartaric acid, diacetyltartaric acid, two-O, O'-toluoyltartaric acid, mandelic acid, malic acid or camphor-10-sulfonic acid formed salts to split. The racemic compound of the present disclosure or racemic intermediate can also be split by chiral chromatography (for example, using high pressure liquid chromatography (HPLC) of chiral adsorbent).

[0332] In addition, the compounds disclosed herein (including their salts) can also be obtained in the form of their hydrates, or include other solvents for their crystallization. The compounds disclosed herein can inherently or by design form solvates with pharmaceutically acceptable solvents (including water); therefore, it is intended that the disclosure includes both solvated and non-solvated forms. The term "solvate" refers to a molecular complex of the disclosed compound (including its pharmaceutically acceptable salt) and one or more solvent molecules. Such solvent molecules (e.g., water, ethanol, etc.) are those commonly used in the pharmaceutical field, and it is known that they are harmless to the recipient. The term "hydrate" refers to a complex in which the solvent molecule is water. Those skilled in the art can use tools (e.g., NMR) to identify the presence of solvates.

[0333] The compounds of the present disclosure (including salts, hydrates and solvates thereof) may inherently or by design form polymorphs.

[0334] Preparation method

[0335] The compounds of the present disclosure can be prepared in many ways well known to those skilled in the art of organic synthesis. For example, the compounds of the present disclosure can be synthesized using the following methods, as well as synthetic methods known in the field of synthetic organic chemistry, or variations thereof as understood by those skilled in the art.

[0336] Generally, compounds having formula (I) can be prepared according to the schemes provided below.

[0337] The compounds provided herein can be prepared according to the following examples. In the following schemes, R, R 1 , R 2 , R 3 , R 5 , R 6 , R 8 , W, m, n, and p are defined according to Example 1. In one embodiment, R, R 1 , R 2 , R 3 , R 5 , R 6 , R 8 , W, m, n, and p are defined according to any one of the enumerated Examples 1 to 23. PG refers to a protecting group. Suitable protecting groups are known to those skilled in the art, and the same or different protecting groups may be used in any scheme. Other definitions applicable are provided in the following general schemes.

[0338] General solution 1

[0339]

[0340] Example S1-10 can be prepared as outlined in General Scheme 1. Arylation of ketone S1-2 with aryl bromide S1-1 can be performed using Buchwald coupling conditions. The resulting intermediate S1-3 can be deprotected to give intermediate S1-4, which in turn can be reacted with a suitable electrophile (e.g., alkyl halide or triflate) in the presence of a base to give S1-5. Conversion of S1-5 to the corresponding methylene derivative S1-6 can be achieved by Wittig olefination or using diiodomethane, titanium tetrachloride, and zinc. Hydroboration of the resulting S1-6 with 9-BBN affords the boronate S1-7, which is coupled with the N-protected 4-Br indole derivative S1-8 (prepared by reacting the corresponding unprotected indole with a suitable electrophile in the presence of DMAP) using Suzuki coupling to afford the intermediate S1-9, which is then deprotected to afford the final example S1-10.

[0341] General Solution 2

[0342]

[0343] Example S2-15 can be prepared as outlined in General Scheme 2.

[0344] The β-ketoester S2-1 can be converted to the vinyl triflate S2-2 with triflic anhydride and base. Suzuki coupling with boronic acid or ester S2-3 affords S2-4. Hydrogenation of the olefin provides S2-5, and base-mediated epimerization affords S2-6 in the trans configuration between the ortho stereocenters. Ester reduction with a reducing agent such as lithium borohydride affords the primary alcohol S2-7, where R 5 When also an ester, the reduction is chemoselective for the alkyl ester. Using an electrophile such as carbon tetrabromide, the alcohol can be converted to the primary halide S2-8, e.g., X'=Br. Palladium-catalyzed borylation provides the boronate ester S2-9, which is then converted to S2-10 using potassium difluoride. The BF3K-salt S2-10 is coupled to the N-protected 4-Br indole derivative S2-11 (prepared by reacting the corresponding unprotected indole with a suitable electrophile in the presence of DMAP) using Suzuki coupling to give the intermediate S2-12. Intermediate S2-12 can be selectively deprotected to give intermediate S2-13, which in turn can be reacted with a suitable electrophile such as an alkyl halide or triflate in the presence of a base or a suitable aldehyde or ketone in the presence of a reducing agent such as sodium triacetoxyborohydride or sodium cyanoborohydride to give S2-14. Deprotection gives the final example S2-15.

[0345] In a further aspect, the present disclosure provides a method for preparing a compound of formula (I) in free form or in pharmaceutically acceptable salt form, the method comprising the steps as described above.

[0346] Pharmaceutical composition

[0347] In another aspect, the present disclosure provides a pharmaceutical composition comprising one or more compounds described herein, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

[0348] In further embodiments, the composition comprises at least one or two pharmaceutically acceptable carriers (such as those described herein).For the purposes of this disclosure, solvates and hydrates are generally considered to be compositions unless otherwise specified.

[0349] The compounds of formula (I) and its subformulae described herein can be administered alone or as an active ingredient of a pharmaceutical composition. Therefore, provided herein is a pharmaceutical composition comprising a compound of formula (I) or its subformulae or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers.

[0350] Methods for preparing various pharmaceutical compositions are known to those skilled in the art and may be described, for example, in the American Pharmaceutical Association's Handbook of Pharmaceutical Excipients (current edition); Pharmaceutical Dosage Forms Tablets (Lieberman, Lachman and Schwartz, eds.), current edition, published by Marcel Dekker, Inc.; and Remington's Pharmaceutical Sciences (Arthur Osol, ed.), 1553-1593 (current edition).

[0351] The pharmaceutical composition can be formulated for specific administration routes, such as oral administration, topical administration, parenteral administration, and rectal administration, etc. In addition, the pharmaceutical composition of the present disclosure can be made in solid form (including but not limited to capsules, tablets, pills, granules, powders, or suppositories) or in liquid form (including but not limited to solutions, gels, suspensions, or emulsions). The pharmaceutical composition can be subjected to conventional pharmaceutical operations, such as sterilization and / or can contain conventional inert diluents, lubricants, or buffers, and adjuvants (such as preservatives, stabilizers, wetting agents, emulsifiers, and buffers, etc.).

[0352] Typically, the pharmaceutical composition is a tablet or gelatin capsule containing the active ingredient and one or more of the following:

[0353] a) diluents, for example, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine;

[0354] b) lubricants, for example, silicon dioxide, talc, stearic acid, its magnesium or calcium salts and / or polyethylene glycol;

[0355] c) binders, for example, magnesium aluminum silicate, starch paste, gelatin, gum tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone;

[0356] d) disintegrants, for example, starch, agar, alginic acid or its sodium salt or effervescent mixtures; and

[0357] e) Adsorbents, colorants, flavoring agents and sweeteners.

[0358] In one embodiment, the pharmaceutical composition is a capsule containing only the active ingredient.

[0359] Tablets may be film-coated or enteric-coated according to methods known in the art.

[0360] Modes of administration and pharmaceutical compositions are closely related to the therapeutic amount of the desired and effective compound or composition for a given therapeutic application. The pharmaceutical compositions provided herein can be formulated for ophthalmology, eye, topical and transdermal administration. In a specific embodiment, the pharmaceutical compositions provided herein are suitable for ophthalmic administration. In order to prepare the pharmaceutical composition, the active ingredient can be mixed with one or more pharmaceutically acceptable carriers according to conventional pharmaceutical compounding techniques. The carrier can be in various forms, depending on the form of the formulation required for administration.

[0361] Suitable compositions for oral administration include an effective amount of the disclosed compounds in the form of tablets, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs, solutions or solid dispersions. Compositions intended for oral use are prepared according to any method known in the art for making pharmaceutical compositions, and such compositions may contain one or more agents selected from the group consisting of sweeteners, flavoring agents, colorants and preservatives to provide pharmaceutically refined and palatable preparations. Tablets may contain active ingredients mixed with non-toxic, pharmaceutically acceptable excipients suitable for making tablets. These excipients are, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating agents and disintegrants such as corn starch or alginic acid; binders such as starch, gelatin or gum arabic; and lubricants such as magnesium stearate, stearic acid or talc. Tablets are uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract, thereby providing sustained action over a longer period of time. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. Formulations for oral use may be presented as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent (e.g., calcium carbonate, calcium phosphate or kaolin), or as soft gelatin capsules in which the active ingredient is mixed with water or an oil medium (e.g., peanut oil, liquid paraffin or olive oil).

[0362] Some injectable compositions are aqueous isotonic solutions or suspensions, and suppositories are advantageously prepared from fat emulsions or suspensions. The compositions may be sterilized and / or contain adjuvants (e.g., preservatives, stabilizers, wetting agents or emulsifiers, solution promoters, salts and / or buffers for regulating osmotic pressure). In addition, they may also contain other therapeutically valuable substances. The compositions are prepared according to conventional mixing, granulation or coating methods, respectively, and contain about 0.1%-75%, or contain about 1%-50% of active ingredient.

[0363] Suitable compositions for transdermal applications include an effective amount of a compound of the disclosure and a suitable carrier. Carriers suitable for transdermal delivery include absorbable pharmacologically acceptable solvents that aid passage through the host's skin. For example, a transdermal device is in the form of a bandage comprising a liner, a reservoir containing the compound and optionally a carrier, a rate-controlling barrier that delivers the compound to the host's skin at a controlled and predetermined rate over an extended period of time, and a device for securing the device to the skin.

[0364] Compositions suitable for topical application (e.g., to the skin and eyes) include aqueous solutions, suspensions, ointments, creams, gels or sprayable formulations, e.g., for delivery by aerosols, etc. Such topical delivery systems will be particularly suitable for dermal applications, e.g., for the treatment of skin cancer, e.g., for preventive use in sunscreens, lotions, sprays, etc. It is therefore particularly suitable for use in topical applications, including cosmetics, formulations well known in the art. Such systems may contain solubilizers, stabilizers, tonicity enhancers, buffers and preservatives.

[0365] As used herein, topical application may also refer to inhalation or intranasal application. They may be conveniently delivered in the form of dry powders (alone as a mixture, e.g., a dry blend with lactose, or mixed component particles, e.g., mixed with a phospholipid) from a dry powder inhaler with or without a suitable propellant, or in the form of an aerosol spray from a pressurized container, pump, spray, nebulizer or atomizer.

[0366] In certain embodiments, the pharmaceutical compositions provided herein are formulated into solutions, suspensions, gels, creams, ointments, liposomes, ocular inserts, or other pharmaceutical compositions suitable for topical application to the ocular surface, cornea, eyelids, eyelid margins, eyelashes, and / or eyelid margins in specific embodiments to deliver the composition to the eye. In some embodiments, liquid (aqueous or non-aqueous) solutions may be used. In certain embodiments, the pharmaceutical compositions are formulated into eye drops for topical application to the ocular surface, cornea, eyelids, eyelid margins, eyelashes, and / or eyelid margins to deliver the composition to the eye. The application of the pharmaceutical composition may be with an applicator such as the subject's finger, Or other devices capable of delivering the formulation to the eyelids, eyelashes and / or eyelid margins, so as to deliver the formulation to the eye. The pharmaceutical compositions provided herein can be viscous or semi-viscous; liquid, solid or semi-solid; aqueous or non-aqueous, depending on the application site, dosage, solubility of the drug, and various other factors considered by those skilled in the art.

[0367] Any of a variety of carriers can be used in pharmaceutical compositions provided herein. In one embodiment, a pharmaceutically acceptable carrier is a non-aqueous carrier (e.g., oil or oil mixture) having a viscosity in the range of about 50cps to about 1000cps, about 50cps to about 500cps, about 50cps to about 200cps, or about 60cps to about 120cps. In certain embodiments, the non-aqueous carrier includes oil, such as vegetable oil, silicone oil, mineral oil, or any combination thereof. In certain embodiments, the carrier can be liquid paraffin, white vaseline, purified lanolin, gelled hydrocarbons, polyethylene glycol, hydrophilic ointment base, white ointment base, absorbent ointment base, polyethylene glycol ointment base, simple ointment base, etc. In certain embodiments, the pharmaceutical composition may include monomeric polyols such as glycerol, propylene glycol, and ethylene glycol; polymeric polyols such as polyethylene glycol; cellulose esters such as hydroxypropyl methylcellulose, sodium carboxymethylcellulose, and hydroxypropyl cellulose; dextran such as dextran 70; water-soluble proteins such as gelatin; polymers such as polyvinyl alcohol, polyvinyl pyrrolidone, and povidone; carbomers such as carbomer 934P, carbomer 941, carbomer 940, and carbomer 974P; and gums such as HP-guar gum.

[0368] Other excipients may be optionally included in the pharmaceutical compositions provided herein. Examples of other excipients include, for example, tonicity enhancers, preservatives, solubilizers, non-toxic excipients, demulcents, chelating agents, pH adjusters, cosolvents, viscosity building agents, and combinations thereof.

[0369] The pharmaceutical composition of the present disclosure may be in the form of an aqueous suspension or a water solution. In one embodiment, the aqueous pharmaceutical composition of the present disclosure is in the form of an aqueous suspension.

[0370] Aqueous pharmaceutical compositions according to the present disclosure can be prepared using standard procedures familiar to those skilled in the art, for example by appropriately mixing the various components at ambient temperature and atmospheric pressure. In one embodiment, the aqueous pharmaceutical compositions of the present disclosure are suitable for ocular administration.

[0371] In further embodiments, the pharmaceutical compositions of the present disclosure are in the form of eye ointment, eye gel, eye cream or eye drops.

[0372] In further embodiments, the pharmaceutical compositions of the present disclosure are administered topically to a subject in the eye.

[0373] The compounds of formula (I) in free form or in pharmaceutically acceptable salt form exhibit valuable pharmacological properties, such as complement factor B modulating properties, e.g., as shown in the in vitro tests provided in the Examples, and are therefore indicated for use in therapy or as research chemicals, e.g., as tool compounds.

[0374] Additional properties of the disclosed compounds include good potency in the biological assays described herein, a favorable safety profile, and favorable pharmacokinetic properties.

[0375] Diseases and disorders and methods of use

[0376] In a further aspect, the disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in therapy.

[0377] In additional aspects, the disclosure provides a compound having formula (I) or a pharmaceutically acceptable salt thereof for use in treating a disease or disorder for which complement factor B is indicated. In one embodiment, the disease or disorder is affected by inhibition of complement factor B activity.

[0378] The compounds of formula (I) and pharmaceutically acceptable salts thereof have complement factor B modulating and / or inhibiting activity and are considered to have potential use for treating or preventing certain diseases or disorders such as age-related macular degeneration, geographic atrophy, diabetic retinopathy, uveitis, retinitis pigmentosa, macular edema, Behcet's uveitis, multifocal choroiditis, Voigt-Koyanagi-Harada syndrome, intermediate uveitis, birdshot retinochoroiditis, sympathetic ophthalmia, ocular cicatricial pemphigoid, ocular pemphigus, non-arteritic ischemic optic neuropathy, postoperative inflammation, retinal vein occlusion, glaucoma, multifocal honeycomb retinal dystrophy / Malattia leventinese, Sorsby fundus dystrophy, late-onset retinal macular dystrophy, North Carolina macular dystrophy, fundus xanthophy, keratitis, multiple sclerosis and other neurological disorders, stroke, Guillain-Barré syndrome, spinal cord injury, traumatic brain injury, Parkinson's disease, Alzheimer's disease, schizophrenia, amyotrophic lateral sclerosis (ALS), Huntington's disease, multifocal motor neuropathy, autism spectrum disorder, schizophrenia, drug-induced neurotoxicity; disorders with inappropriate or adverse complement activation, such as complications of hemodialysis, hyperacute allograft rejection, xenograft rejection, IL-2-induced toxicity during interleukin-2 therapy, inflammatory disorders, paroxysmal nocturnal hemoglobinuria, C3 glomerulonephritis (including dense deposit disease and C3 glomerulonephritis), immune complex membranoproliferative glomerulonephritis (IC-MPGN), IgA nephropathy, including idiopathic membranous nephropathy Membranous nephropathy, diabetic nephropathy, atypical hemolytic uremic syndrome (aHUS), hemolytic uremic syndrome, STEC-HUS (Shiga toxin-producing Escherichia coli hemolytic uremic syndrome), periodontitis, excessive complement activation due to CD55 deficiency, vasculothrombosis, protein-losing enteropathy (CHAPLE syndrome), inflammatory or autoimmune diseases such as Crohn's disease, neuromyelitis optica (NMO), IgA vasculitis (formerly known as Henoch-Schönlein purpura or HSP), CHAPLE syndrome, hematopoietic stem cell transplant-associated thrombotic microangiopathy (HSCT-TMA), adult-onset respiratory distress syndrome (ARDS), myocarditis, post-ischemia-reperfusion syndrome, myocardial infarction, balloon angioplasty, post-pump syndrome during cardiopulmonary bypass or renal bypass, atherosclerosis, hemodialysis, renal ischemia, acute kidney injury, mesenteric artery reperfusion after aortic reconstruction, infectious disease, or sepsis;COVID-19, immune complex disorders and autoimmune diseases, rheumatoid arthritis, osteoarthritis, spondyloarthropathies, psoriatic arthritis, systemic lupus erythematosus (SLE), lupus nephritis, SLE nephritis, proliferative nephritis, myasthenia gravis, liver fibrosis, hemolytic anemia, tissue regeneration, nerve regeneration, dyspnea, hemoptysis, acute respiratory distress syndrome (ARDS), asthma, chronic obstructive pulmonary disease (COPD), emphysema, pulmonary embolism and infarction, pneumonia, fibrosing pneumococcal disease, pulmonary fibrosis, asthma, allergy, bronchitis contraction, hypersensitivity pneumonitis, parasitic diseases, Goodpasture's syndrome, pulmonary vasculitis, microimmune vasculitis, antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), Burger's vasculitis, cryoglobulinemia, Kawasaki disease, Takayasu arteritis, cryoglobulinemia, immune complex-associated inflammation, antiphospholipid syndrome, glomerulonephritis, and obesity; immune thrombocytopenia, cold agglutinin disease, warm antibody autoimmune hemolytic anemia (wAIHA), thrombotic thrombocytopenic purpura (TTP), and abdominal aortic aneurysm, as well as Graves' disease. ;

[0379] In view of their activity as complement factor B modulators or inhibitors, compounds of formula (I) and subformulae thereof, in free or pharmaceutically acceptable salt form, are useful for treating conditions treatable by inhibiting the activity of complement factor B. In one aspect, the disclosure provides a method of treating or preventing a disease or disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or subformulae thereof, or a pharmaceutically acceptable salt thereof.

[0380] In another aspect, the disclosure provides a method of modulating complement alternative pathway activity in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound having Formula (I) or a subformula thereof, or a pharmaceutically acceptable salt thereof.

[0381] In another aspect, the present disclosure provides a method for treating a disease or disorder mediated by complement activation, particularly by complement alternative pathway activation, in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound having formula (I) or a subformula thereof, or a pharmaceutically acceptable salt thereof.

[0382] In another aspect, the disclosure provides a method of treating a disease or disorder affected by modulation of the complement alternative pathway, the method comprising administering to a subject a therapeutically effective amount of a compound having Formula (I) or a subformula thereof, or a pharmaceutically acceptable salt thereof.

[0383] In another aspect, the disclosure provides a method of treating a disease or disorder associated with dysregulation of the complement alternative pathway, the method comprising administering to a subject a therapeutically effective amount of a compound having Formula (I) or a subformula thereof, or a pharmaceutically acceptable salt thereof.

[0384] In another aspect, the disclosure provides a method of inhibiting the expression or activity of complement factor B, the method comprising administering to a subject a compound having formula (I) or a subformula thereof, or a pharmaceutically acceptable salt thereof.

[0385] In another aspect, the disclosure provides a method of treating a disease or disorder selected from the group consisting of age-related macular degeneration, geographic atrophy, diabetic retinopathy, uveitis, retinitis pigmentosa, macular edema, Behcet's uveitis, multifocal choroiditis, Voigt-Koyanagi-Harada syndrome, intermediate uveitis, birdshot retinochoroiditis, sympathetic ophthalmia, ocular cicatricial pemphigoid, ocular pemphigus, nonarteritic ischemic optic neuropathy, postoperative inflammation, retinal vein occlusion, glaucoma, multifactorial honeycomb retinal dystrophy / Malattia leventinese, Sorsby fundus dystrophy, late-onset retinal macular dystrophy, North Carolina macular dystrophy, fundus xanthophy, keratitis, multiple sclerosis and other neurological disorders, stroke, Guillain-Barré syndrome, spinal cord injury, traumatic brain injury, Parkinson's disease, Alzheimer's disease, schizophrenia, amyotrophic lateral sclerosis (ALS), Huntington's disease, multifocal motor neuropathy, autism spectrum disorder, schizophrenia, drug-induced neurotoxicity; disorders with inappropriate or adverse complement activation, such as complications of hemodialysis, hyperacute allograft rejection, xenograft rejection, IL-2-induced toxicity during interleukin-2 therapy, inflammatory disorders, paroxysmal nocturnal hemoglobinuria, C3 glomerulonephritis (including dense deposit disease and C3 glomerulonephritis), immune complex membranoproliferative glomerulonephritis (IC-MPGN), IgA nephropathy, including idiopathic membranous nephropathy Membranous nephropathy, diabetic nephropathy, atypical hemolytic uremic syndrome (aHUS), hemolytic uremic syndrome, STEC-HUS (Shiga toxin-producing Escherichia coli hemolytic uremic syndrome), periodontitis, excessive complement activation due to CD55 deficiency, vasculothrombosis, protein-losing enteropathy (CHAPLE syndrome), inflammatory or autoimmune diseases such as Crohn's disease, neuromyelitis optica (NMO), IgA vasculitis (formerly known as Henoch-Schönlein purpura or HSP), CHAPLE syndrome, hematopoietic stem cell transplant-associated thrombotic microangiopathy (HSCT-TMA), adult-onset respiratory distress syndrome (ARDS), myocarditis, post-ischemia-reperfusion syndrome, myocardial infarction, balloon angioplasty, post-pump syndrome during cardiopulmonary bypass or renal bypass, atherosclerosis, hemodialysis, renal ischemia, acute kidney injury, mesenteric artery reperfusion after aortic reconstruction, infectious disease, or sepsis;COVID-19, immune complex disorders and autoimmune diseases, rheumatoid arthritis, osteoarthritis, spondyloarthropathies, psoriatic arthritis, systemic lupus erythematosus (SLE), lupus nephritis, SLE nephritis, proliferative nephritis, myasthenia gravis, liver fibrosis, hemolytic anemia, tissue regeneration, nerve regeneration, dyspnea, hemoptysis, acute respiratory distress syndrome (ARDS), asthma, chronic obstructive pulmonary disease (COPD), emphysema, pulmonary embolism and infarction, pneumonia, fibrosing pneumococcal disease, pulmonary fibrosis, asthma, allergy, bronchitis contraction, hypersensitivity pneumonitis, parasitic diseases, Goodpasture's syndrome, pulmonary vasculitis, microimmune vasculitis, antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), Burger's vasculitis, cryoglobulinemia, Kawasaki disease, Takayasu arteritis, cryoglobulinemia, immune complex-associated inflammation, antiphospholipid syndrome, glomerulonephritis, and obesity; immune thrombocytopenia, cold agglutinin disease, warm antibody autoimmune hemolytic anemia (wAIHA), thrombotic thrombocytopenic purpura (TTP), and abdominal aortic aneurysm, as well as Graves' disease. ;

[0386] In certain aspects, methods for treating diseases associated with increased activity of the C3 amplification loop in the complement pathway are provided. In certain embodiments, methods for treating or preventing complement-mediated diseases are provided, wherein complement activation is induced by antibody-antigen interactions, components of autoimmune diseases, or ischemic injury.

[0387] In certain embodiments, the disclosure provides a method for treating or preventing age-related macular degeneration (AMD), which is carried out by applying an effective amount of the present disclosure to a subject in need thereof. In certain embodiments, the compound of the present disclosure is suitable for applying the present disclosure in patients with risk of a disorder related to symptomatic macular degeneration. The method for treating or preventing AMD includes but is not limited to treating or preventing AMD selected from one or more symptoms or aspects thereof: eye drusen formation, eye or eye tissue inflammation, photoreceptor cell loss, vision loss (including visual acuity or visual field loss), neovascularization (including CNV), retinal detachment, photoreceptor cell degeneration, RPE degeneration, retinal degeneration, chorioretinal degeneration, cone degeneration, retinal dysfunction, light exposure reactive retinal damage, Bruch's membrane damage and / or RPE function loss.

[0388] The compound with formula (I) disclosed herein is particularly useful for preventing the onset of AMD, preventing early AMD from progressing to late forms of AMD (including neovascular AMD or geographic atrophy), slowing down and / or preventing the progression of geographic atrophy, treating or preventing macular edema caused by AMD or other conditions (such as diabetic retinopathy, uveitis, or postoperative or non-surgical trauma), preventing or reducing vision loss caused by AMD, and improving vision loss caused by pre-existing early or late AMD. It can also be used in combination with anti-VEGF therapy for the treatment of neovascular AMD patients or for preventing neovascular AMD.

[0389] All of the aforementioned embodiments relating to methods of treating the aforementioned diseases also apply to:

[0390] A compound having formula (I) or a subformula thereof, or a pharmaceutically acceptable salt thereof, for use in treating the aforementioned diseases according to the present disclosure;

[0391] Use of a compound of formula (I) or its subformulae or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating the aforementioned diseases according to the present disclosure;

[0392] Use of a compound of formula (I) or its subformulae or a pharmaceutically acceptable salt thereof for treating the aforementioned diseases according to the present disclosure; and

[0393] A pharmaceutical composition comprising a compound having formula (I) or its subformulae or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers is used in the treatment of the aforementioned diseases according to the present disclosure.

[0394] dose

[0395] The pharmaceutical composition or combination of the present disclosure may be a unit dose of about 1-1000 mg of one or more active ingredients for a subject of about 50-70 kg. The therapeutically effective dose of the compound, pharmaceutical composition, or combination thereof depends on the species, weight, age, and individual condition, disorder, or disease being treated or its severity.

[0396] The above dosage characteristics can be demonstrated in in vitro and in vivo tests using advantageous mammals (e.g., mice, rats, dogs, monkeys) or their isolated organs, tissues and preparations. The compounds disclosed herein can be applied in vitro in the form of solutions (e.g., aqueous solutions), and in vivo in the form of enteral, parenteral (advantageously, intravenous), for example, suspensions or aqueous solutions. In vitro doses can be about 10 -3 Moore and 10 -9 The in vivo therapeutically effective amount may vary, for example, within the range of about 0.1-500 mg / kg depending on the route of administration.

[0397] The therapeutically effective dose of the compound, pharmaceutical composition, or combination thereof depends on the subject's species, weight, age, and the individual condition, disorder or disease being treated or its severity.

[0398] The activity of the compounds according to the present disclosure can be assessed by the in vitro methods described in the Examples.

[0399] Combination therapy

[0400] In another aspect, the disclosure provides a pharmaceutical combination comprising a compound of formula (I) or a subformula thereof, or a pharmaceutically acceptable salt thereof, and one or more additional therapeutic agents for simultaneous, separate or sequential use in therapy.

[0401] The compounds of the present disclosure can be administered simultaneously with one or more other therapeutic agents or before or after the one or more therapeutic agents. The compounds of the present disclosure can be administered separately by the same or different routes of administration, or administered together in the same pharmaceutical composition as other medicaments. The therapeutic agent is, for example, a chemical compound, a peptide, an antibody, an antibody fragment or a nucleic acid, which has therapeutic activity or enhances therapeutic activity when administered to a patient in combination with the compounds of the present disclosure. Therefore, in one embodiment, the present disclosure provides a combination comprising a therapeutically effective amount of a compound having formula (I) or its subformula or a pharmaceutically acceptable salt thereof, and one or more therapeutically active agents.

[0402] In certain embodiments, a compound of formula (I) or a subformula thereof, or a pharmaceutically acceptable salt thereof, may be administered with an additional therapeutic agent.

[0403] The pharmaceutical compositions of the present disclosure (e.g., pharmaceutical compositions comprising compounds of formula (I)) can be administered alone or in combination with other molecules known to have beneficial effects on retinal attachment or damaged retinal tissue, including molecules capable of tissue repair and regeneration and / or inhibiting inflammation. Examples of useful cofactors include complement inhibitors (e.g., factor D, C5a receptors and antibodies or inhibitors of Fabs to C5, C3, properdin, factor H, etc.), anti-VEGF agents (e.g., antibodies or FABs to VEGF, such as ranibizumab or Avastin), basic fibroblast growth factor (bFGF), ciliary neurotrophic factor (CNTF), axokine (a mutant protein of CNTF), leukemia inhibitory factor (LIF), neurotrophin 3 (NT-3), neurotrophin-4 (NT-4), nerve growth factor (NGF), insulin-like growth factor II, prostaglandin E2, 30kD survival factor, taurine, and vitamin A. Other useful cofactors include symptomatic cofactors, including antibacterial, antibiotic, antiviral and antifungal agents and analgesics and anesthetics.Agents suitable for combination therapy with the compounds of the disclosure include those known in the art that are capable of modulating the activity of complement components.

[0404] In some embodiments, the disclosure provides a combination therapy for preventing and / or treating AMD or another complement-associated ocular disease as described above, which combination therapy uses a compound of the disclosure and an anti-angiogenic agent, such as an anti-VEGF agent (including ranibizumab, Avastin, and VEGF-R2 inhibitors, including pazopanib, sunitinib, inifanib, and the VEGF-R2 inhibitors disclosed in WO 2010 / 066684) or photodynamic therapy (such as verteporfin).

[0405] In some embodiments, the present disclosure provides a combination therapy for preventing and / or treating an autoimmune disease as described above, the combination therapy using a compound of the present disclosure and a B cell or T cell modulator (e.g., cyclosporine or its analogs, rapamycin, RAD001 or its analogs, etc.). In particular, therapy for multiple sclerosis may include a combination of a compound of the present disclosure and a second MS agent selected from fingolimod, cladribine, tysarbi, laquinimod, rebif, avonex, etc. A non-limiting list of such agents includes agents effective for treating the following diseases and conditions in which activation of vanilloid receptors plays a role or involves activation of vanilloid receptors, including cyclooxygenase-2 (COX-2) inhibitors, such as specific COX-2 inhibitors, such as celecoxib and rofecoxib; and nonsteroidal anti-inflammatory drugs (NSAIDs), such as acetylsalicylic acid and propionic acid derivatives; tricyclic antidepressants, such as Anticonvulsants, such as carbamazepine, oxcarbazepine, and gabapentin; bradykinin B1 or B2 antagonists; and GABA B Agonists, such as L-baclofen.

[0406] In certain embodiments, other therapeutic agents may include, for example, other compounds and antibodies that can be used to treat ocular disorders. A non-limiting list of such agents includes retinoid X receptor agonists, such as vitamin A, retinoic acid, phytanic acid, lithocholic acid, bexarotene, docosahexaenoic acid, or flubexarotene. Other additional therapeutic agents are ophthalmic steroids, such as dexamethasone, fluocinolone, loteprednol, difluprednate, fluorometholone, prednisolone, prednisone, medecinolone, triamcinolone, betamethasone, rimexolone, or a pharmaceutically acceptable salt thereof. In addition, other additional therapeutic agents include those for targeting ocular surface diseases such as dry eye. Non-limiting examples of such additional therapeutic agents include (lifitegrast), (cyclosporine), minocycline, doxycycline or other tetracycline antibiotics. Other examples include keratolytic agents such as selenium sulfide, salicylic acid, glycolic acid, etc., or pharmaceutically acceptable salts thereof.

[0407] In certain embodiments, the other therapeutic agent may include, for example, other compounds useful for treating pain. In one embodiment, the compound of formula (I) or its subformulae or a pharmaceutically acceptable salt thereof may be administered with an additional analgesic. Such analgesics may be NSAIDs (e.g., acetylsalicylic acid and propionic acid derivatives, such as ), opioids, or steroids.

[0408] Preparation of compounds

[0409] It is understood that in the following description, combinations of substituents and / or variables of the depicted formulas are permissible only if such combinations result in stable compounds.

[0410] It will also be appreciated by those skilled in the art that in the methods described below, the functional groups of the intermediate compounds may need to be protected by suitable protecting groups. Such functional groups include hydroxyl, phenol, amino and carboxylic acid. Suitable protecting groups for hydroxyl or phenol include trialkylsilyl or diarylalkylsilyl (e.g., tert-butyldimethylsilyl, tert-butyldiphenylsilyl or trimethylsilyl), tetrahydropyranyl, benzyl, substituted benzyl, methyl, etc. Suitable protecting groups for amino, amidino and guanidino include tert-butyloxycarbonyl, benzyloxycarbonyl, etc. Suitable protecting groups for carboxylic acids include alkyl esters, aryl esters or arylalkyl esters.

[0411] Protecting groups can be added or removed according to standard techniques, which are well known to those skilled in the art and are described herein. The use of protecting groups is described in detail in JFW McOmie, "Protective Groups in Organic Chemistry", Plenum Press, London and New York 1973; TW Greene and PGM Wuts, "Greene's Protective Groups in Organic Synthesis", 4th edition, Wiley, New York 2007; PJ Kocienski, "Protecting Groups", 3rd edition, Georg Thieme Verlag, Stuttgart and New York 2005; and in "Methoden der organischen Chemie" (Methods of Organic Chemistry), Houben Weyl, 4th edition, Volume 15 / I, Georg Thieme Verlag, Stuttgart 1974.

[0412] The protecting group may also be a polymer resin, such as Wang resin or 2-chlorotrityl-chloride resin.

[0413] The following reaction examples illustrate the method for preparing the disclosed compounds. It should be appreciated that those skilled in the art will be able to manufacture these compounds by similar methods or by methods known to those skilled in the art. Generally speaking, starting components and reagents can be obtained from the following sources, such as Sigma Aldrich, Lancaster Synthesis, Inc., Maybridge, Matrix Scientific, TCI, Fluorochem USA, Strem, other commercial suppliers, or can be synthesized according to sources known to those skilled in the art, or prepared according to the disclosure.

[0414] Analytical methods, materials and instruments

[0415] Unless otherwise noted, reagents and solvents received from commercial suppliers were used. Unless otherwise noted, proton nuclear magnetic resonance (NMR) spectra were obtained on Bruker Avance, Avance III or Avance Neo spectrometers (400MHz), Varian Oxford 400MHz or Varian Mercury 300MHz spectrometers. Spectra are given in ppm (δ), and coupling constants J are reported in Hertz. Tetramethylsilane (TMS) is used as an internal standard. Chemical shifts are reported in ppm relative to dimethyl sulfoxide (δ 2.50), methanol (δ 3.31), chloroform (δ 7.26) or other solvents shown in NMR spectral data. A small amount of dried sample (2-5mg) was dissolved in an appropriate deuterated solvent (1mL). Chemical names are generated using ChemBioDraw Ultra v19 from Cambridge Software (CambridgeSoft).

[0416] Mass spectra (ESI-MS) were collected using a Waters system (Acquity UPLC and Micromass ZQ spectrometer) or an Agilent-1260 Infinity (6120 quadrupole); all masses reported are the m / z of the protonated parent ion unless otherwise stated. The sample was dissolved in a suitable solvent (such as MeCN, DMSO, or MeOH) and injected directly into the column using an automated sample processor.

[0417] abbreviation

[0418] 9-BBN 9-Borabicyclo[3.3.1]nonane

[0419] ACN Acetonitrile

[0420] AcOH Acetic acid

[0421] aq water-based

[0422] Boc tert-butylcarboxyl

[0423] br Broad Peak

[0424] c Concentration

[0425] CBr4 Tetrabromomethane

[0426] CO2 Carbon dioxide

[0427] d Doublet

[0428] DAD Diode Array Detection

[0429] DBU 1,8-diazabicyclo[5.4.0]undec-7-ene

[0430] DCE 1,2-Dichloroethane

[0431] DCM Dichloromethane

[0432] dd double peak

[0433] DIPEA Diisopropylethylamine

[0434] DMAP N,N-Dimethylaminopyridine

[0435] DMF N,N-Dimethylformamide

[0436] DMSO Dimethyl sulfoxide

[0437] ee enantiomeric excess

[0438] eq equivalent

[0439] EtOAc Ethyl acetate

[0440] EtOH

[0441] h hour

[0442] H2 Hydrogen

[0443] HCl

[0444] HPLC High Performance Liquid Chromatography

[0445] IPA Isopropyl Alcohol

[0446] KHF2 Potassium Hydrogen Fluoride

[0447] K2CO3 Potassium carbonate

[0448] K3PO4 Tripotassium Phosphate

[0449] LC-MS Liquid chromatography and mass spectrometry

[0450] m multiplet

[0451] m / z mass-to-charge ratio

[0452] MeOH Methanol

[0453] Me-THF 2-Methyltetrahydrofuran

[0454] MgSO4 Magnesium sulfate

[0455] min

[0456] MS mass spectrometry

[0457] N2 Nitrogen

[0458] NaCNBH3 Sodium cyanoborohydride

[0459] Na2CO3 Sodium carbonate

[0460] NaHCO3 Sodium bicarbonate

[0461] Na2SO4 Sodium sulfate

[0462] NaOH Sodium hydroxide

[0463] NH4OH Ammonium Hydroxide

[0464] NMR Nuclear Magnetic Resonance

[0465] NP Normal Phase

[0466] org organic

[0467] Pd2(dba)3 tris(dibenzylideneacetone)dipalladium(0)

[0468] PdCl2(dppf) 1,1'-Bis(diphenylphosphino)ferrocene-palladium(II) chloride

[0469] PdCl2(dtbpf) [1,1'-Bis(di-tert-butylphosphino)ferrocene]palladium(II) dichloride

[0470] PE Petroleum Ether

[0471] PPh3 Triphenylphosphine

[0472] ppm parts per million

[0473] rac racemic

[0474] RM reaction mixture

[0475] RP Invert

[0476] Rt retention time

[0477] RT Room temperature

[0478] s Single peak

[0479] sat. saturated

[0480] scCO2 Supercritical Carbon Dioxide

[0481] SFC Supercritical Fluid Chromatography

[0482] SiO2 Silica Gel

[0483] soln. solution

[0484] t Triplet

[0485] TBAF Tetra-n-butylammonium fluoride

[0486] TBME tert-butyl methyl ether

[0487] tBu tert-butyl

[0488] tert-Bu tert-butyl

[0489] tert-BuOH tert-butyl alcohol

[0490] TFA Trifluoroacetic acid

[0491] TFAA Trifluoroacetic anhydride

[0492] Tf triflate

[0493] THF Tetrahydrofuran

[0494] TLC Thin layer chromatography

[0495] UPLC Ultra-Performance Liquid Chromatography

[0496] Xantphos 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene

[0497] Xphos Pd G2 Chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II)

[0498] wt% weight percentage

[0499] Intermediates

[0500] Intermediate I-1:

[0501] 4-Bromo-5,7-dimethyl-1H-indole-1-carboxylic acid tert-butyl ester

[0502]

[0503] DMAP (242 mg, 1.98 mmol) was added to a suspension of 4-bromo-5,7-dimethyl-1H-indole (CAS# 1167056-53-2, 8.87 g, 39.6 mmol) and di-tert-butyl dicarbonate (10.4 g, 47.5 mmol) in DCM (122 mL). The RM was stirred at RT for 40 min and then evaporated to dryness to give a brown residue which was purified over silica gel (330 g) using an automated purification system (NP; Teledyne Collect at 256 / 294 nm; flow rate: 200 mL / min; eluent: heptane + 0 to 4.5% EtOAc added over 23 min) to obtain the title compound after concentration under reduced pressure at 50°C as off-white crystals (9.05 g). LC-MS method B-2: Rt = 8.55 min; MS m / z [M-Boc+H] + =223.9 / 225.9.

[0504] Intermediate I-2:

[0505] 4-Bromo-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester

[0506]

[0507] DMAP (25.95 mg, 212.4 μmol) was added to a solution of 4-bromo-5-methoxy-7-methyl-1H-indole (CAS#1352393-65-7, 1.020 g, 4.248 mmol) and di-tert-butyl dicarbonate (1.113 g, 1.17 mL, 5.098 mmol) in DCM (14 mL). The RM was stirred at RT for 2 h and then concentrated to dryness under reduced pressure. The residue was purified over silica gel (40 g) using an automated purification system (NP; Teledyne Collect at 256 / 294 nm; flow rate: 40 mL / min; eluent: heptane + 0.0 to 8.7% EtOAc added over 15.2 min) to obtain the title compound as a colorless oil (1.42 g) after concentration under reduced pressure at 50°C. LC-MS method B-1: Rt = 1.54 min; MS m / z [M+H] +=340.0 / 342.0.

[0508] Intermediate I-3:

[0509] 4-Bromo-5-cyclopropyl-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester

[0510]

[0511] Step 1: 2-Cyclopropyl-4-methyl-5-nitroaniline (Intermediate I-3-1)

[0512]

[0513] To a solution of 2-bromo-4-methyl-5-nitroaniline (CAS#102169-99-3, 50 g, 268.74 mmol) in dioxane (200 mL) and H2O (66 mL) was added cyclopropylboronic acid (CAS#411235-57-9 11.15 g, 129.84 mmol), K3PO4 (55.12 g, 260 mmol), and Pd(dppf)Cl2-DCM (3.53 g, 4.33 mmol). The resulting mixture was stirred at 90°C for 16 h. The RM was filtered and the filtrate was extracted with EtOAc (3 x 200 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / PE=0 / 100 to 30 / 70) to give 2-cyclopropyl-4-methyl-5-nitroaniline (12.0 g) as a black solid. 1 H NMR(400MHz,DMSO-d6)δ[ppm]7.27(s,1H),6.81(s,1H),5.48–5.39(m,2H),2. 33(s,3H),1.75(tt,J=5.4,8.3Hz,1H),0.97–0.88(m,2H),0.65–0.56(m,2H).

[0514] Step 2: 1-Bromo-2-cyclopropyl-4-methyl-5-nitrobenzene (Intermediate I-3-2)

[0515]

[0516] The solution of 2-cyclopropyl-4-methyl-5-nitroaniline (intermediate I-3-1, 120g, 624.3mmol) and tert-butyl nitrite (83.66g, 378.58mmol) in MeCN (1.2L) was stirred at 0°C for 0.5h. At 0°C, CuBr (83.66g, 378.58mmol) was added to the mixture, and stirring was continued for 2h at about 25°C. RM was diluted with H2O (1L), then extracted with EtOAc (3x500mL). The combined organic layer was washed with brine (1L), passed through Na2SO4, dried, filtered, and concentrated under reduced pressure to obtain 1-bromo-2-cyclopropyl-4-methyl-5-nitrobenzene (120g) as a yellow solid, which was used in the next step without further purification. 1 H NMR (400 MHz, CHLOROFORM-d) δ [ppm] 8.23 ​​(s, 1H), 6.80 (s, 1H), 2.54 (s, 3H), 2.22 (tt, J = 5.3, 8.4 Hz, 1H), 1.18–1.11 (m, 2H), 0.81–0.74 (m, 2H).

[0517] Step 3: 4-Bromo-5-cyclopropyl-7-methyl-1H-indole (Intermediate I-3-3)

[0518]

[0519] At -78 ° C, to a solution of 1-bromo-2-cyclopropyl-4-methyl-5-nitrobenzene (intermediate I-3-2, 117 g, 144.5 mmol) in THF (1.2 L) was added vinylmagnesium bromide (3.2 L, 3.20 mol). After the addition was complete, RM was stirred at -40 ° C for 2 h. RM was quenched with H2O (3 L) and then extracted with EtOAc (3 x 3 L). The combined organic layers were washed with brine (5 L), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / PE=0 / 100 to 10 / 90) to obtain 4-bromo-5-cyclopropyl-7-methyl-1H-indole (35 g) as a yellow solid. 1 H NMR (400 MHz, CHLOROFORM-d) δ [ppm] 8.12 (br s, 1H), 7.25–2.22 (m, 1H), 6.64–6.58 (m, 2H), 2.43 (d, J = 0.8 Hz, 3H), 2.26 (tt, J = 5.3, 8.5 Hz, 1H), 1.05–0.98 (m, 2H), 0.74–0.66 (m, 2H).

[0520] Step 4: tert-Butyl 4-bromo-5-cyclopropyl-7-methyl-1H-indole-1-carboxylate (Intermediate I-3)

[0521] To a mixture of 4-bromo-5-cyclopropyl-7-methyl-1H-indole (35 g, 126 mmol) and di-tert-butyl dicarbonate (148.24 g, 700 mmol) was added DMAP (1.68 g, 14 mmol). The RM was stirred at 40 °C for 2 h and then cooled to 25 °C. N 1 ,N 1 -dimethylethane-1,2-diamine (105mL) and the mixture was stirred at 25 ° C for 10min. The mixture was diluted with H2O (100mL) and then extracted with EtOAc (3x 50mL). The combined organic layer was washed with brine (100mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give tert-butyl 4-bromo-5-cyclopropyl-7-methyl-1H-indole-1-carboxylate (38g) as a yellow solid, which was used directly without further purification. 1 H NMR (400 MHz, CHLOROFORM-d) δ [ppm] 7.54 (d, J = 3.8 Hz, 1H), 6.67 (s, 1H), 6.65 (d, J = 3.8 Hz, 1H), 2.56 (s, 3H), 2.22 (tt, J = 5.3, 8.5 Hz, 1H), 1.64 (s, 9H), 1.06–0.97 (m, 2H), 0.76–0.66 (m, 2H).

[0522] The following intermediates were synthesized from appropriate starting materials by applying similar methods as described above:

[0523] Intermediate I-4:

[0524] 4-Bromo-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester

[0525]

[0526] Intermediate 1-4 was prepared from 4-bromo-7-methyl-1H-indole (CAS# 936092-87-4). 1 HNMR (400 MHz, CHLOROFORM-d) δ [ppm] 7.62 (d, J = 3.8 Hz, 1H), 7.29 (s, 1H), 6.93 (d, J = 9.9 Hz, 1H), 6.65 (d, J = 3.8 Hz, 1H), 2.61 (s, 3H), 1.67 (s, 9H).

[0527] Intermediate I-5:

[0528] 4-Bromo-5-fluoro-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester

[0529]

[0530] Intermediate 1-5 was prepared from 1-bromo-2-fluoro-4-methyl-5-nitrobenzene (CAS# 224185-19-7). 1 H NMR (400MHz, chloroform-d) δ [ppm] 7.62 (d, J = 3.8 Hz, 1H), 6.93 (d, J = 9.9 Hz, 1H), 6.65 (d, J = 3.8 Hz, 1H), 2.61 (s, 3H), 1.67 (s, 9H).

[0531] Intermediate I-6:

[0532] 4-Bromo-5-chloro-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester

[0533]

[0534] Intermediate 1-6 was prepared from 1-bromo-2-chloro-4-methyl-5-nitrobenzene (CAS# 1126367-34-7). 1 H NMR (400 MHz, CHLOROFORM-d) δ [ppm] 7.49 (d, J = 3.6 Hz, 1H), 7.14–7.05 (m, 1H), 6.55 (d, J = 3.8 Hz, 1H), 2.50 (d, J = 0.8 Hz, 3H), 1.56 (s, 9H).

[0535] Intermediate I-7:

[0536] 4-Bromo-5,7-dichloro-1H-indole-1-carboxylic acid tert-butyl ester

[0537]

[0538] Intermediate 1-7 was prepared from 1-bromo-2,4-dichloro-5-nitrobenzene (CAS# 65001-80-1). 1 H NMR (400 MHz, CHLOROFORM-d) δ [ppm] 7.54 (d, J = 3.7 Hz, 1H), 7.35 (s, 1H), 6.59 (d, J = 3.7 Hz, 1H), 1.58 (s, 9H).

[0539] Intermediate I-8:

[0540] 4-Bromo-3-chloro-5,7-dimethyl-1H-indole-1-carboxylic acid tert-butyl ester

[0541]

[0542] Step 1: 4-Bromo-3-chloro-5,7-dimethyl-1H-indole (Intermediate I-8-1)

[0543]

[0544] At 0 ° C, to a solution of 4-bromo-5,7-dimethyl-1H-indole (CAS#1167056-53-2, 345 mg, 1.54 mmol) in DMF (4.0 mL) was added dropwise a solution of N-chlorosuccinimide (246.7 mg, 1.85 mg) in DMF (1 mL). The RM was stirred at 0 ° C for another 10 min and then diluted with H2O. The formed precipitate was filtered off and dried under reduced pressure. Purification by silica gel column chromatography (heptane / EtOAc=80 / 20) provided 4-bromo-3-chloro-5,7-dimethyl-1H-indole (185 mg) as a dark green solid. 1 H NMR (400 MHz, CHLOROFORM-d) δ [ppm] 7.97 (s, 1H), 7.18 (d, J = 2.7 Hz, 1H), 6.92 (s, 1H), 2.48 (s, 3H), 2.39 (s, 3H).

[0545] Step 2: tert-Butyl 4-bromo-3-chloro-5,7-dimethyl-1H-indole-1-carboxylate (Intermediate I-8)

[0546] Intermediate I-8 was prepared from intermediate I-8-1 in a similar manner as intermediate I-1 above. 1 H NMR (400 MHz, CHLOROFORM-d) δ [ppm] 7.54 (s, 1H), 7.05 (s, 1H), 2.51 (s, 3H), 2.47 (s, 3H), 1.65 (s, 9H).

[0547] Intermediate A-1: ​​methyl 4-(4-methylene-1-(2,2,2-trifluoroethyl)piperidin-3-yl)benzoate

[0548]

[0549] Step 1: tert-Butyl 3-(4-(methoxycarbonyl)phenyl)-4-oxopiperidine-1-carboxylate (Intermediate A-1-1)

[0550]

[0551] K3PO4 (40.86 g, 15.94 mL, 192.5 mmol) is added to a solution of tert-butyl 4-oxopiperidine-1-formate (30.02 g, 150.7 mmol), methyl 4-bromobenzoate (18.0 g, 83.7 mmol) and Xantphos (2.131 g, 3.68 mmol) in toluene (160 mL). The mixture is evacuated / backfilled twice with N2. Pd2(dba)3 (1.533 g, 1.674 mmol) is added, and the mixture is evacuated / backfilled twice with N2 again, then heated to 80 °C overnight under N2 atmosphere. RM is cooled to RT and distributed between toluene and water. The slurry is filtered through diatomaceous earth, and the filtrate is washed with saturated NaHCO3 aqueous solution, brine and toluene. The combined organic layer is dried over MgSO4, filtered and volatiles are removed under reduced pressure at 50 °C. The obtained residue was purified by silica gel (330 g) using an automated purification system (NP; Teledyne Monitored at 250 nm; flow rate: 200 mL / min; eluent: heptane + 5% to 40% EtOAc added in 31.0 min), then repurified over silica gel (330 g), and then repurified using an automated purification system (normal phase; Teledyne Monitored at 250 nm; flow rate: 200 mL / min; eluent: dichloromethane + 0.0 to 4.7% EtOAc added in 26.2 min), then purified on RediSep C18 columns (360 g each) using an automated purification system (Teledyne Collect at 240nm; flow rate: 150mL / min; eluent: water + 25% to 60% ACN) was repurified in two portions. The pure fractions were combined and the ACN was removed under reduced pressure at 50°C to give an aqueous slurry. The mixture was extracted with DCM (3x), the combined organic layers were dried over MgSO4, filtered and the volatiles were removed under reduced pressure at 50°C to give the title compound as a white solid (9.20g). LC-MS Method B-1: Rt = 1.02min; MS m / z [MH] - =332.0.

[0552] Step 2: Methyl 4-(4-oxopiperidin-3-yl)benzoate (Intermediate A-1-2)

[0553]

[0554] Tert-butyl 3-(4-(methoxycarbonyl)phenyl)-4-oxopiperidine-1-carboxylate (Intermediate A-1-1, 9.20 g, 27.6 mmol) was treated with HCl (4M in dioxane, 140.0 mL). The initial solution became a viscous white suspension, which was stirred at RT for 60 min. About 3 / 4 of the volatiles were removed under reduced pressure at 50 °C to give a slurry in dioxane. The mixture was diluted with TBME and filtered. The solid was washed with TBME (3x) and dried under reduced pressure at 50 °C to give the title compound (HCl salt, 7.60 g, about 85% purity) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6) δ [ppm] 9.94–9.54 (s, 2H), 7.97–7.92 (m, 2H), 7.41–7.35 (m, 2H), 4.33 (dd, J = 11.1, 7.9 Hz, 1H), 3.86 (s, 3H), 3.69–3.59 (m, 3H), 3.57–3.47 (m, 1H), 3.06–2.93 (m 1H), 2.63–2.49 (m, 1H, partially overlaps with DMSO peak).

[0555] Step 3: Methyl 4-(4-oxo-1-(2,2,2-trifluoroethyl)piperidin-3-yl)benzoate (Intermediate A-1-3)

[0556]

[0557] DIPEA (10.83 g, 14.6 mL, 83.8 mmol) was added to a suspension of methyl 4-(4-oxopiperidin-3-yl)benzoate HCl salt (Intermediate A-1-2, 7.60 g, about 85% purity) in ACN (93 mL). 2,2,2-Trifluoroethyl triflate (6.90 mL, 47.9 mmol) was added and the RM was stirred at 50 °C overnight and then cooled to RT. The volatiles were removed under reduced pressure at 50 °C and the residue was partitioned between TBME and water. The layers were separated and washed with brine and TBME. The combined organic layers were dried over MgSO4, filtered and the volatiles were removed under reduced pressure at 50 °C to give an orange oil which was purified over silica gel (220 g) using an automated purification system (NP; Teledyne Collect at 245 / 260 nm; flow rate: 150 mL / min; eluent: heptane + 5.0 to 30% EtOAc added over 24 min) and concentrate under reduced pressure to give the title compound (7.29 g) as a yellow oil. LC-MS method B-1: Rt = 0.95 min; MS m / z [M+H] + =316.3.

[0558] Step 4: Methyl 4-(4-methylene-1-(2,2,2-trifluoroethyl)piperidin-3-yl)benzoate (Intermediate A-1)

[0559]

[0560] The suspension of zinc powder (9.63g, 147.3mmol) in THF (160mL) was carefully evacuated / backfilled twice with N2. Diiodomethane (21.92g, 6.60mL, 81.83mmol) was added dropwise. RM was stirred at RT for 30min. Then RM was cooled to 0 to 5°C, and titanium tetrachloride (1M in DCM, 16.37mL, 16.37mmol) was added dropwise while keeping the temperature below 18°C. After the exothermic reaction stopped, the suspension was stirred for another 30min at ambient temperature without a cooling bath. A solution of 4-(4-oxo-1-(2,2,2-trifluoroethyl)piperidin-3-yl)methyl benzoate (intermediate A-1-3, 5.160g, 16.37mmol) in THF (10.3mL) was added dropwise. The RM was stirred at RT for 1.5 h and then poured into a well stirred mixture of saturated aqueous NaHCO3 and TBME. The resulting slurry was filtered through celite and the solids were washed with TBME (3x). The filtrate layers were separated and washed with brine and TBME. The combined organic layers were dried over MgSO4, filtered and the volatiles were removed under reduced pressure at 50 °C. The resulting residue was purified over silica gel (220 g) using an automated purification system (NP; Teledyne Collect at 238 / 254 nm; Flow rate: 150 mL / min; Eluent: Heptane + 30% to 70% DCM added in 29.0 min). Pure fractions were combined and volatiles were removed under reduced pressure at 50 °C to give the title compound as a colorless oil which solidified upon standing (3.27 g). LC-MS method B-1: Rt = 1.42 min; MS m / z [M+H] + =314.1.

[0561] Intermediate A-2:

[0562] (3R,4R)-tert-butyl 3-(4-(tert-Butyloxycarbonyl)phenyl)-4-(hydroxymethyl)piperidine-1-carboxylate

[0563]

[0564] Step 1: 1-(tert-butyl)4-ethyl 5-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1,4(2H)-dicarboxylate (Intermediate A-2-1)

[0565]

[0566] To a stirred solution of 1-(tert-butyl) 4-ethyl 3-oxopiperidine-1,4-dicarboxylate (CAS#71233-25-5, 30.23 g, 111.4 mmol) in DCM (893 mL) was slowly added dropwise DIPEA (18.72 g, 144.8 mmol) and Tf2O (37.72 g, 22.59 mL, 133.7 mmol) at -78 °C under N2 atmosphere. The resulting mixture was stirred at RT for about 1 h. The RM was diluted with DCM (150 mL) and washed with a saturated aqueous solution of NaHCO3 (300 mL). The separated aqueous layer was extracted with DCM (300 mL) and the combined organic phases were dried over Na2SO4. The mixture was passed through The solution was plugged and concentrated under reduced pressure to give crude 1-(tert-butyl)4-ethyl 5-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1,4(2H)-dicarboxylate, which was used directly without further purification. LC-MS method C-1: Rt = 1.29 min; MS m / z [M-Boc+H] + =304.1.

[0567] Step 2: 1-(tert-butyl)4-ethyl 5-(4-(tert-butoxycarbonyl)phenyl)-3,6-dihydropyridine-1,4(2H)-dicarboxylate (Intermediate A-2-2)

[0568]

[0569] A solution of K3PO4 (70.94 g, 334.2 mmol) in H2O (248.4 mL) was added to a solution of crude 1-(tert-butyl)4-ethyl 5-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1,4(2H)-dicarboxylate (Intermediate A-2-1, 44.94 g) and (4-(tert-butoxycarbonyl)phenyl)boronic acid (32.16 g, 144.8 mmol) in dioxane (922 mL). The mixture was evacuated / backfilled with N2 twice. PdCl2(dtbpf) (3.63 g, 5.57 mmol) was added and the mixture was evacuated with N2 again. The RM was stirred at 40 °C for about 16 h. The RM was purified by The mixture was filtered and the filtrate was partitioned between EtOAc and saturated aqueous NaHCO3 (700 mL each). The separated organic layer was washed with saturated aqueous NaHCO3 and brine. The separated aqueous layer was extracted with EtOAc (700 mL). The combined organic layers were dried over Na2SO4, filtered, and the filtrate was reduced to about 1 / 3 of its volume under reduced pressure. The mixture was subjected to Silicycle -SDMT (20 g) was stirred for about 1 h, filtered, and the filtrate was concentrated under reduced pressure. The crude material was purified by silica gel column chromatography [750 g, EtOAc / heptane=0 / 100 to 70 / 30] to give 5-(4-(tert-butoxycarbonyl)phenyl)-3,6-dihydropyridine-1,4(2H)-dicarboxylic acid 1-(tert-butyl)4-ethyl ester (37.28 g) as a light yellow oil, which solidified after standing. 1 H NMR(400MHz, chloroform-d)δ[ppm]7.96(d,J=7.9Hz,2H),7.23(d,J=8.4Hz,2H),4.18–4.07(m,2H),3.92(q,J =7.1Hz,2H),3.66–3.55(m,2H),2.60–2.51(m,2H),1.59(s,9H),1.48(s,9H),0.91(t,J=7.1Hz,3H).

[0570] Step 3: Racemic (3R*, 4S*)-3-(4-(tert-butyloxycarbonyl)phenyl)piperidine-1,4-dicarboxylic acid 1-(tert-butyl) 4-ethyl ester (Intermediate A-2-3)

[0571]

[0572] A mixture of (tert-butyl) 4-ethyl 5-(4-(tert-butoxycarbonyl)phenyl)-3,6-dihydropyridine-1,4(2H)-dicarboxylate (Intermediate A-2-2, 3.50 g, 8.11 mmol) and Pd / C (10 wt %, Degussa type, 50% moisture, 863.1 mg) in EtOH (150 mL) was degassed and then shaken at ambient temperature under a hydrogen atmosphere (45 psi; 500 mL Parr bottle) for about 14 h. The mixture was stirred for 14 h at room temperature. The pad was filtered through 4% paraformaldehyde (2x), and the pad was then rinsed / washed with EtOH. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography [80 g, EtOAc / heptane=0 / 100 to 60 / 40] to give racemic (3R*, 4S*)-3-(4-(tert-butoxycarbonyl)phenyl)piperidine-1,4-dicarboxylic acid 1-(tert-butyl) 4-ethyl ester (2.94 g) as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ [ppm] 7.92–7.84 (m, 2H), 7.28–7.24 (m, 2H), 4.02 (dd, J = 13.3, 8.1 Hz, 1H), 3.93 (dddd, J = 18.0, 10.9, 7.1, 3.7 Hz, 2H), 3.84–3.66 (m, 2H), 3.59–3.48 (m, 1H), 3.21–3.13 (m, 1H), 3.02–2.93 (m, 1H), 2.04–1.93 (m, 1H), 1.90–1.82 (m, 1H), 1.58 (s, 9H), 1.44 (s, 9H), 1.05 (t, J = 7.2 Hz, 3H).

[0573] Step 4: Racemic (3R*, 4R*)-3-(4-(tert-butyloxycarbonyl)phenyl)piperidine-1,4-dicarboxylic acid 1-(tert-butyl) 4-ethyl ester (Intermediate A-2-4)

[0574]

[0575] A solution of racemic (3R*, 4S*)-3-(4-(tert-butyloxycarbonyl)phenyl)piperidine-1,4-dicarboxylic acid 1-(tert-butyl) 4-ethyl ester (Intermediate A-2-3, 2.53 g, 5.84 mmol) in degassed EtOH (60 mL) was purged with N2. A solution of sodium ethoxide in EtOH (436 μL, 21 wt%, 1.167 mmol) was added and the resulting mixture was stirred at 50 °C for about 8 h. The RM was cooled to RT, stirred overnight, and then concentrated under reduced pressure to about 1 / 2 of its volume. The resulting mixture was diluted with a saturated aqueous solution of KH2PO4 (60 mL) and brine (20 mL), then extracted with Me-THF (2x 60 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to produce two phases. The residue was diluted with Me-THF, and the separated organic phase was dried over Na2SO4 again, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography [40 g, EtOAc / heptane=0 / 100 to 80 / 20] to obtain racemic (3R*, 4R*)-3-(4-(tert-butoxycarbonyl)phenyl)piperidine-1,4-dicarboxylic acid 1-(tert-butyl) 4-ethyl ester (1.93 g; containing about 3% of diethyl ester) as a colorless oil, which solidified after standing. 1H NMR (400 MHz, CHLOROFORM-d) δ [ppm] 7.93–7.91 (m, 2H), 7.28–7.25 (m, 2H), 4.39–4.04 (m, 2H), 3.98–3.85 (m, 2H), 3.03–2.97 (m, 1H), 2.84–2.65 (m, 3H), 2.01–1.96 (m, 1H), 1.81–1.70 (m, 1H), 1.57 (s, 9H), 1.45 (s, 9H), 0.99 (t, J = 7.1 Hz, 3H).

[0576] Step 5: Racemic (3R*, 4R*)-3-(4-(tert-butoxycarbonyl)phenyl)-4-(hydroxymethyl)piperidine-1-carboxylic acid tert-butyl ester (Intermediate A-2-5)

[0577]

[0578] To a solution of racemic (3R*, 4R*)-3-(4-(tert-butyloxycarbonyl)phenyl)piperidine-1,4-dicarboxylic acid 1-(tert-butyl) 4-ethyl ester (Intermediate A-2-4, 1.92 g, 4.43 mmol) in THF (23 mL) and MeOH (269 μL, 6.643 mmol) at 0°C was added a freshly prepared solution of LiBH4 in THF (2M, 5.54 mL, 11.07 mmol). The mixture was stirred at ambient temperature and warmed to 35°C for about 14 h. MeOH (50 uL) and a solution of LiBH4 in THF (2M, 1 mL, 2.0 mmol) were added and stirring was continued for 2 h. The RM was cooled to 0°C and carefully diluted with a saturated aqueous solution of KH2PO4 (80 mL) and brine (30 mL). The separated aqueous layer was extracted with EtOAc (2x 60 mL, 30 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography [40 g, EtOAc / heptane = 0 / 100 to 60 / 40] to give racemic (3R *, 4R *)-3-(4-(tert-butoxycarbonyl)phenyl)-4-(hydroxymethyl)piperidine-1-carboxylic acid tert-butyl ester (1.22 g) and recovered intermediate A-2-4 (335 mg) as a white solid. 1H NMR (400 MHz, chloroform-d) δ [ppm] 7.95–7.93 (m, 2H), 7.26 (d, J = 8.4 Hz, 2H), 4.37–4.04 (m, 2H), 3.44–3.40 (m, 1H), 3.27–3.23 (m, 1H), 2.86–2.73 (m, 2H), 2.62–2.55 (m, 1H), 1.97–1.87 (m, 2H), 1.59 (s, 9H), 1.48–1.07 (m, 10H). 32 of 33 protons reported.

[0579] Step 6: (3R, 4R-3-(4-(tert-butoxycarbonyl)phenyl)-4-(hydroxymethyl)piperidine-1-carboxylic acid tert-butyl ester (Intermediate A-2) and (3S, 4S-3-(4-(tert-butoxycarbonyl)phenyl)-4-(hydroxymethyl)piperidine-1-carboxylic acid tert-butyl ester (Intermediate A-2-6)

[0580] Enantiomer separation and analysis according to method SFC-3: Racemic (3R*, 4R*)-tert-butyl 3-(4-(tert-butoxycarbonyl)phenyl)-4-(hydroxymethyl)piperidine-1-carboxylate (Intermediate A-2-5, 3.70 g) afforded Intermediate A-2 (peak 1): 1.70 g, white solid. LC-MS method B-1: Rt = 1.31 min; MS m / z [M+Na] + =414.3; analytical chiral HPLC: Rt=2.35min; 99.5%ee. Intermediate A-2-6 (peak 2): 1.73g, white solid. LC-MS method B-1: Rt=1.30min; MS m / z[M+Na] + =414.2; analytical chiral HPLC: Rt=1.42min; 99.5%ee.

[0581] Intermediate rac-A-3:

[0582] Racemic (3R*,4S*)-3-(4-cyanophenyl)-4-(hydroxymethyl)pyrrolidine-1-carboxylic acid tert-butyl ester

[0583]

[0584] Racemic (3S *, 4R *) -1- (tert-butoxycarbonyl) -4- (4- cyanophenyl) pyrrolidine -3- carboxylic acid (CAS # 1217702-50-5, 1.03g, 3.25mmol) was dissolved in THF (10mL) and cooled to 0 ° C. Borane-dimethyl sulfide complex (0.61mL, 6.5mmol) was added dropwise, and the RM was stirred at 0 ° C for 30min, and then continued to stir at RT for 3h. The mixture was cooled to 0 ° C, quenched with MeOH (10mL), and the resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (24g, EtOAc / heptane = 0 / 100 to 80 / 20) to give racemic (3R *, 4S *) -3- (4- cyanophenyl) -4- (hydroxymethyl) pyrrolidine -1- carboxylic acid tert-butyl ester (1.01g) as a white solid. LCMS method C-2: RT = 0.93 min; MS m / z [M-tBu+H] + =246.9. 1 H NMR(400MHz, chloroform-d)δ[ppm]7.68–7.60(m,2H),7.43–7.34(m,2H),3.87(dd,J=11.0,7.9Hz,1H),3.77(dd,J=11.0,7.9H z,1H),3.68(dd,J=10.8,4.7Hz,1H),3.57(dd,J=10.8,6.3Hz,1H),3.46–3.19(m,3H),2.62–2.41(m,1H),1.49(s,9H).

[0585] Intermediate A-4:

[0586] tert-Butyl (3R,4R)-3-(4-(tert-Butoxycarbonyl)phenyl)-4-(hydroxymethyl)azepane-1-carboxylate

[0587]

[0588] Step 1: 1-(tert-butyl)4-ethyl(3R,4R)-3-(4-(tert-butoxycarbonyl)phenyl)azepane-1,4-dicarboxylate (Intermediate A-4-1)

[0589]

[0590] Step 1-a: 2,5,6,7-tetrahydro-1H-azepine-1,4-dicarboxylic acid 1-(tert-butyl) 4-ethyl ester (CAS#2254213-29-9; prepared from 3-oxoazepane-1,4-dicarboxylic acid 1-tert-butyl 4-ethyl ester, CAS#98977-38-9, similar to Tetrahedron [Tetrahedron Express] 2018, 59, 4611; 2.370 g, 8.799 mmol) was added to a solution of (4-(tert-butoxycarbonyl)phenyl)boronic acid (3.517 g, 15.84 mmol), (1S, 4S)-2,5-diphenylbicyclo[2.2.2]octa-2,5-diene (CAS#850409-83-5, 68.20 mg, 0.264 mmol), 1,1,3,3-tetramethylguanidine (608.1 mg, 5.280 mmol) and acetylacetonatoacylbis(ethylene)rhodium (I) (CAS#12082-47-2, 68.14 mg, 0.264 mmol) in degassed MeOH / water (4 / 1, 50 mL). The yellow solution was heated to 65°C internal temperature under N2 atmosphere and stirred for 45 min. The mixture was cooled to RT and then diluted with TBME (100 mL) and brine (100 mL). The separated organic layer was washed with brine (100 mL), and the separated aqueous layer was washed with TBME (100 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure at 45°C. The residue was purified by silica gel column chromatography (220 g, EtOAc / heptane=0 / 100 to 50 / 50) to give (3R)-3-(4-(tert-butoxycarbonyl)phenyl)azepane-1,4-dicarboxylic acid 1-(tert-butyl) 4-ethyl ester (4.10 g) as a yellow oil and a trans / cis mixture in a ratio of 65 / 35. LC-MS method B-1: Rt=1.49 / 1.54 min; MS m / z[M-Boc+H] + =348.4 / 348.3.

[0591] Step 1-b: To a solution of the trans / cis mixture of step 1-a, (3R)-3-(4-(tert-butyloxycarbonyl)phenyl)azepane-1,4-dicarboxylic acid 1-(tert-butyl) 4-ethyl ester (4.10 g, 9.16 mmol) in THF (80 mL), a solution of potassium tert-butoxide in THF (1 M, 4.58 mL, 4.58 mmol) was added dropwise over 1 min at -60 °C internal temperature. The RM was stirred at -60 °C for 30 min and then poured into a stirred mixture of saturated aqueous NaHCO3 (100 mL) and TBME (100 mL). After stirring for 2 min, the separated organic layer was washed with brine (100 mL) and the separated aqueous layer was extracted with TBME (100 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure at 45°C to give enriched (3R,4R)-3-(4-(tert-butyloxycarbonyl)phenyl)azepane-1,4-dicarboxylic acid 1-(tert-butyl)4-ethyl ester (4.11 g) as a light yellow oil in a trans / cis mixture (ratio 94 / 6), which was used directly without further purification. LC-MS method B-1: Rt = 1.51 / 1.46 min; MS m / z [M-Boc+H] + =348.3 / 348.3.

[0592] Step 2: (3R,4R)-3-(4-(tert-butoxycarbonyl)phenyl)-4-(hydroxymethyl)azepane-1-carboxylic acid tert-butyl ester (Intermediate A-4)

[0593] Step 2-a: To a solution of enriched (3R,4R)-3-(4-(tert-butyloxycarbonyl)phenyl)azepane-1,4-dicarboxylic acid 1-(tert-butyl) 4-ethyl ester (Intermediate A-4-1, 4.10 g, 9.17 mmol) in THF (50 mL) was added MeOH (926 μL, 22.90 mmol). The mixture was cooled to 0 °C and then a solution of lithium borohydride in THF (2M, 11.45 mL, 22.9 mmol) was added dropwise over 2 min. The RM was heated to 35 °C-38 °C (internal temperature) and stirred overnight. More MeOH (926 μL) was added to the RM and stirring was continued at 38 °C for 1 h. Additional MeOH (926 μL) was added and stirring was continued at 38 °C for another 1 h. The RM was cooled to about 10 ° C, poured into a stirred mixture of TBME (100 mL) and NaHCO3 saturated aqueous solution (100 mL), and stirred at ambient temperature for 15 min. The separated organic phase was washed with NaHCO3 saturated aqueous solution (100 mL) and brine (100 mL), and the separated aqueous layer was washed with TBME (100 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (220 g, EtOAc / heptane=15 / 85 to 100 / 0) to give enriched (3R, 4R)-3-(4-(tert-butoxycarbonyl)phenyl)-4-(hydroxymethyl)azepane-1-carboxylic acid tert-butyl ester (2.81 g) as a white foam. LC-MS method B-1: Rt=1.31 min; MS m / z[M-Boc+H] + =306.4.

[0594] Step 2-b: Chiral purification and analysis according to method SFC-2: Enriched (3R,4R)-tert-butyl 3-(4-(tert-butoxycarbonyl)phenyl)-4-(hydroxymethyl)azepane-1-carboxylate (2.75 g) of step 2-a provided intermediate A4 (2.29 g) as a white crystalline material. LC-MS method B-2: Rt = 6.33 min; MS m / z [M-Boc+H-tBu+H] + = 250.1. Chiral HPLC method SFC-2: Rt = 2.11 min; 100% ee. 1H NMR(600MHz,DMSO-d6)δ[ppm]7.86–7.81(m,2H),7.33(d,J=8.03Hz,2H),4 .37–4.30(m,1H),3.73–3.56(m,1H),3.46–3.39(m,1H),3.18–3.00(m,3H) ,2.91–2.85(m,1H),2.67–2.59(m,1H),2.08–2.00(m,1H),2.00–1.95(m,1 H),1.76–1.71(m,2H),1.54(s,9H),1.42–1.37(m,9H),1.30–1.15(m,1H).

[0595] Intermediate A-5:

[0596] (4R,5R)-tert-butyl 4-(4-(tert-Butoxycarbonyl)phenyl)-5-(hydroxymethyl)azepane-1-carboxylate

[0597]

[0598] Intermediate A-5 was prepared according to the method described above for Intermediate A-4 using 2,3,6,7-tetrahydro-1H-azepine-1,4-dicarboxylic acid 1-(tert-butyl) 4-ethyl ester (CAS#912444-89-4).

[0599] Chiral purification and analysis according to method SFC-5:

[0600] LC-MS method B-2: Rt = 6.41 min; MS m / z [M-Boc+H] + =306.2.

[0601] Chiral HPLC method: Rt = 2.79 min; 100% ee.

[0602] 1H NMR (600 MHz, DMSO-d6) δ [ppm] 7.81 (dd, J = 8.3, 2.7 Hz, 2H), 7.35–7.18 (m, 2H), 4.39–4.28 (m, 1H), 3.71–3.49 (m, 2H), 3.41–3.30 (m, 1H, partially overlapped with water peak), 3.26–3.12 (m, 1H), 3.00–2.91 (m, 1H), 2 .84–2.77 (m, 1H), 2.55–2.47 (m, 1H, partially overlapped with the solvent peak), 2.08 (d, J=4.3 Hz, 1H), 1.87–1.77 (m, 1H), 1.77–1.72 (m, 1H), 1.72–1.67 (m, 1H), 1.64–1.55 (m, 1H), 1.53 (s, 9H), 1.41 (d, J=12.1 Hz, 9H).

[0603] Intermediate A-6:

[0604] (3R,4R)-3-(4-Cyanophenyl)-4-(hydroxymethyl)piperidine-1-carboxylic acid benzyl ester

[0605]

[0606] Step 1: 1-Benzyl 4-methyl 3-(4-carbamoylphenyl)piperidine-1,4-dicarboxylate (Intermediate A-6-1)

[0607]

[0608] Intermediate A-6-1 was prepared according to the method described above for Intermediate A-4 (step 1-a) using 1-benzyl 4-methyl 3,6-dihydropyridine-1,4(2H)-dicarboxylate (CAS#1784422-91-8) and (4-carbamoylphenyl)boronic acid (CAS#123088-59-5). LC-MS method B-2: Rt=3.95 / 4.09min (diastereoisomer mixture); MS m / z[M+H] + =397.1.

[0609] Step 2: 1-Benzyl 4-methyl 3-(4-cyanophenyl)piperidine-1,4-dicarboxylate (Intermediate A-6-2)

[0610]

[0611] To a solution of a cis / trans mixture of 3-(4-carbamoylphenyl)piperidine-1,4-dicarboxylic acid 1-benzyl 4-methyl ester (Intermediate A-6-1, 4.250 g, 10.72 mmol) and TEA (4.339 g, 42.88 mmol) in DCM (150 mL) was added TFAA (4.50 g, 21.44 mmol) dropwise at 0 to 5 ° C in about 5 min. The RM was stirred for another 5 min at 0 to 5 ° C, the ice bath was removed, and stirring was continued at ambient temperature for about 1 h. The mixture was poured into a saturated aqueous solution of NaHCO (200 mL) and stirred vigorously for 5 min. The separated organic phase was washed with a saturated aqueous solution of NaHCO (100 mL), and the aqueous layer was washed with DCM (100 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure at 45 ° C. The residue was purified by silica gel column chromatography (220 g, EtOAc / heptane=15 / 85 to 100 / 00) to give a cis / trans mixture of 1-benzyl 4-methyl 3-(4-cyanophenyl)piperidine-1,4-dicarboxylate (4.28 g) as a yellow oil. LC-MS method B-2: Rt=4.93 / 5.04 min; MS m / z [M+H] + =379.3.

[0612] Step 3: (3R,4R)-3-(4-cyanophenyl)-4-(hydroxymethyl)piperidine-1-carboxylic acid benzyl ester (Intermediate A-6)

[0613] Intermediate A-6 was prepared according to steps 1-a and 2 of the method described above for intermediate A-4.

[0614] Chiral purification and analysis according to method SFC-6:

[0615] LC-MS method B-2: Rt = 4.50 min; MS m / z [M+H] + =351.2.

[0616] Chiral HPLC method: Rt = 1.88 min; 100% ee.

[0617] 1 H NMR (500 MHz, DMSO-d6) δ [ppm] 1H NMR(500MHz, DMSO-d6)δ[ppm]7.79(d,J=7.7Hz,2H),7.48(d,J=7.8Hz,2H),7.44–7.25(m,5H),5.09(s,2H),4.43–4.34(m,1H),4.13( d,J=13.1Hz,1H),4.00–3.83(m,1H),3.14–3.07(m,1H),3.06–2.83(m,3H),2.64–2.56(m,1H),1.99–1.80(m,2H),1.44–1.22(m,1H).

[0618] Intermediate A-7:

[0619] (3R,4R)-3-(4-Bromophenyl)-4-(hydroxymethyl)piperidine-1-carboxylic acid benzyl ester

[0620]

[0621] Intermediate A-7 was prepared according to the method described above for Intermediate A-4 using 1-benzyl 4-methyl 3,6-dihydropyridine-1,4(2H)-dicarboxylate (CAS#1784422-91-8) and (4-bromophenyl)boronic acid (CAS#5467-74-3).

[0622] Chiral purification and analysis according to method SFC-7:

[0623] LC-MS method B-2: Rt = 6.11 min; MS m / z [M+H] + =404.0.

[0624] Chiral HPLC method: Rt = 1.54 min; 100% ee.

[0625] 1 H NMR(500MHz, DMSO-d6)δ[ppm]7.50(d,J=8.0Hz,2H),7.43–7.27(m,5H),7.22(d,J=7.9Hz,2H),5.08(s,2H),4.38–4.29(m,1H),4.23–4.05(m,1H), 3.90(d,J=12.8Hz,1H),3.12(ddd,J=10.6,4.8,2.8Hz,1H),3.04–2.79(m ,3H),2.46(dd,J=11.3,4.2Hz,1H),1.94–1.75(m,2H),1.42–1.20(m,1H).

[0626] Intermediate A-8:

[0627] (3R,4R)-3-(4-(1H-pyrazol-1-yl)phenyl)-4-(hydroxymethyl)piperidine-1-carboxylic acid benzyl ester

[0628]

[0629] A mixture of benzyl (3R,4R)-3-(4-bromophenyl)-4-(hydroxymethyl)piperidine-1-carboxylate (Intermediate A-7, 1.810 g, 4.477 mmol), 1H-pyrazole (914.4 mg, 13.43 mmol), rac-trans-N,N'dimethylcyclohexane-1,2-diamine (254.7 mg, 0.895 mmol), cesium carbonate (4.376, 13.43 mmol) and DMF (18.0 mL) in a sealed vial was evacuated / backfilled twice with N2. Copper iodide (170.5 mg, 0.895 mmol) was added and the mixture was evacuated / backfilled with N2 again. The RM was stirred at 120 °C over 3 days. The mixture was cooled to RT, diluted with TBME and water, and purified by chromatography on a column chromatography column. Filter. The filtrate layers were separated, the organic phase was washed with 1M NaOH aqueous solution, water, and brine, and the aqueous phase was extracted with TBME. The combined organic layers were dried over MgSO4, filtered, and the volatiles were removed under reduced pressure at 50°C. The residue was purified by silica gel column chromatography (80 g, heptane / EtOAc=90 / 10 to 30 / 70) to give (3R,4R)-3-(4-(1H-pyrazol-1-yl)phenyl)-4-(hydroxymethyl)piperidine-1-carboxylic acid benzyl ester (1.06 g) as a yellow oil. LC-MS method B-1: Rt=1.01 min; MS m / z[M+H] + =392.2.

[0630] Intermediate A-9:

[0631] (3R,4R)-tert-butyl 4-(hydroxymethyl)-3-(1-methyl-1H-pyrazol-4-yl)piperidine-1-carboxylate

[0632]

[0633] Step 1: 5-(1-methyl-1H-pyrazol-4-yl)-3,6-dihydropyridine-1,4(2H)-dicarboxylic acid 1-(tert-butyl) 4-ethyl ester (Intermediate A-9-1)

[0634]

[0635] A solution of 1-(tert-butyl)4-ethyl 5-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1,4(2H)-dicarboxylate (Intermediate A-2-1, 5.9 g, 14.64 mmol), (1-methyl-1H-pyrazol-4-yl)boronic acid (CAS#847818-55-7, 4.55 g, 21.9 mmol), and cesium carbonate (9.5 g, 29.2 mmol) in dioxane (50 mL) and H2O (6 mL) was degassed with N2 for 30 min. XPhos Pd G2 (CAS#1310584-14-5, 0.57 g, 0.73 mmol) was added, and the RM was stirred at 80 °C for 12 h. The mixture was stirred by Filtered and washed with water. The organic phase was dried over Na2SO4, concentrated, and purified via silica gel chromatography (40 g, MeOH / DCM 0-10%) to give 1-(tert-butyl)4-ethyl 5-(1-methyl-1H-pyrazol-4-yl)-3,6-dihydropyridine-1,4(2H)-dicarboxylate (4.8 g) as a yellow oil. LC-MS Method A-1: ​​Rt = 1.69 min; MS m / z [M+H] + =336.9.

[0636] Step 2: Racemic (3R*, 4S*)-3-(1-methyl-1H-pyrazol-4-yl)piperidine-1,4-dicarboxylic acid 1-(tert-butyl) 4-ethyl ester (Intermediate A-9-2)

[0637]

[0638] A mixture of 5-(1-methyl-1H-pyrazol-4-yl)-3,6-dihydropyridine-1,4(2H)-dicarboxylic acid 1-(tert-butyl)-4-ethyl ester (Intermediate A-9-1) and platinum oxide (10 wt%, based on carbon, 5 g) in EtOH (48 mL) was stirred at 1 atm hydrogen pressure for 16 h at RT. The RM was stirred by The mixture was filtered through a pad of 4% paraformaldehyde, concentrated, and purified via silica gel chromatography (40 g, EtOAc / heptane 0-20%) to yield racemic (3R*, 4S*)-3-(1-methyl-1H-pyrazol-4-yl)piperidine-1,4-dicarboxylic acid 1-(tert-butyl)4-ethyl ester (4.1 g) as a yellow oil. LC-MS Method A-1: ​​Rt = 1.78 min; MS m / z [M+H] + =338.5.

[0639] Step 3: Racemic (3R*, 4R*)-3-(1-methyl-1H-pyrazol-4-yl)piperidine-1,4-dicarboxylic acid 1-(tert-butyl) 4-ethyl ester (Intermediate A-9-3)

[0640]

[0641] To a solution of racemic (3R*, 4R*)-3-(1-methyl-1H-pyrazol-4-yl)piperidine-1,4-dicarboxylic acid 1-(tert-butyl) 4-ethyl ester (Intermediate A-9-2, 3.2 g, 9.78 mmol) in toluene (30 mL) was added DBU (4.1 mL, 29.34 mmol). The RM was stirred at 110 °C for 16 h and then quenched with water. The mixture was extracted with EtOAc. The organic phase was dried over Na2SO4, concentrated under reduced pressure, and purified by silica gel chromatography (40 g, EtOAc / heptane 0-20%) to yield racemic (3R*, 4R*)-3-(1-methyl-1H-pyrazol-4-yl)piperidine-1,4-dicarboxylic acid 1-(tert-butyl) 4-ethyl ester as a colorless oil and as a diastereomeric mixture with the recovered intermediate A-9-2, which was used directly without further purification. LC-MS method A-2: Rt = 2.28 min; MS m / z [M+H] + =338.2.

[0642] Step 4:

[0643] (3R,4R)-4-(Hydroxymethyl)-3-(1-methyl-1H-pyrazol-4-yl)piperidine-1-carboxylic acid tert-butyl ester (Intermediate A-9)

[0644]

[0645] A solution of racemic (3R*, 4R*)-3-(1-methyl-1H-pyrazol-4-yl)piperidine-1,4-dicarboxylic acid 1-(tert-butyl) 4-ethyl ester (Intermediate A-9-3, as a mixture with Intermediate A-9-2, 3 g, 8.89 mmol) in THF (30 mL) was cooled to 0°C under N2 atmosphere. Lithium aluminum hydride solution (1 M in THF, 10 mL, 10 mmol) was added and the RM was stirred at 0°C for 2 h. The mixture was quenched with EtOAc at 0°C and then H2O was added. The organic phase was collected and the aqueous phase was extracted with EtOAc. The combined organic phases were dried over Na2SO4 and concentrated to yield racemic (3R*,4R*)-tert-butyl 4-(hydroxymethyl)-3-(1-methyl-1H-pyrazol-4-yl)piperidine-1-carboxylate as a mixture with racemic (3R*,4S*)-tert-butyl 4-(hydroxymethyl)-3-(1-methyl-1H-pyrazol-4-yl)piperidine-1-carboxylate.

[0646] Chiral purification and analysis according to method C-10:

[0647] LC-MS method A-1: ​​Rt = 1.70 min; MS m / z [M+H] + =296.5.

[0648] Chiral HPLC method: Rt = 3.61 min; 97.9% ee.

[0649] 1 H NMR(400MHz,DMSO-d6)δ[ppm]7.51(s,1H),7.27(s,1H),4.32–4.28(m,1H)4.06–3.95(m,1H),3.93–3.82(m,1H),3.77(s,3H)3.30–3.2 4(m,1H),3.12-3.02(m,1H)2.86–2.62(m,2H),2.39–2.28(m,1H),1.73–1.83(m,1H),1.59–1.45(m,1H),1.38(s,9H),1.29–1.22(m,1H)

[0650] Intermediate F-1:

[0651] Potassium (((3R,4R)-1-(tert-butoxycarbonyl)-3-(4-(tert-butoxycarbonyl)phenyl)piperidin-4-yl)methyl)trifluoroborate

[0652]

[0653] Step 1: (3R,4R)-4-(bromomethyl)-3-(4-(tert-butoxycarbonyl)phenyl)piperidine-1-carboxylic acid tert-butyl ester (Intermediate F-1-1)

[0654]

[0655] A suspension of (3R,4R)-3-(4-(tert-butoxycarbonyl)phenyl)-4-(hydroxymethyl)-piperidine-1-carboxylic acid tert-butyl ester (Intermediate A-2, 1.630 g, 4.163 mmol) in ACN (64.5 mL) and DCM (5.0 mL) was dissolved by heating the mixture to about 45 °C. The mixture was cooled to RT and PPh3 (1.420 g, 5.412 mmol) was added. The mixture was cooled to 3 °C and CBr4 (1.795 g, 5.412 mmol) was added in one portion. The RM was stirred in an ice bath for 30 min and then at RT for 2 h 45 min. Additional PPh3 (328 mg) and CBr4 (414 mg) were added and stirring was continued at RT for 90 min. The volatiles were removed under reduced pressure at 35 °C. The residue was purified over silica gel (40 g) using an automated purification system (NP; Teledyne Collect at 245 / 260 nm; Flow rate: 40 mL / min; Eluent: Heptane + 5.0% to 25% EtOAc added over 20 min) to give tert-butyl (3R,4R)-4-(bromomethyl)-3-(4-(tert-butoxycarbonyl)phenyl)piperidine-1-carboxylate (1.38 g) as a colorless oil. LC-MS Method B-2: Rt = 7.95 min; MS m / z [M-tBu+H-tBu+H] + =342.0 / 344.0.

[0656] Step 2: (3R,4R)-3-(4-(tert-butoxycarbonyl)phenyl)-4-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl)piperidine-1-carboxylic acid tert-butyl ester (Intermediate F-1-2)

[0657]

[0658] Water (875.6 mg, 875.6 μL, 48.59 mmol) was added to a mixture of tert-butyl (3R,4R)-4-(bromomethyl)-3-(4-(tert-butoxycarbonyl)phenyl)piperidine-1-carboxylate (Intermediate F-1-1, 1.380 g, 3.037 mmol) and bis(pinacol)diborane (2.121 g, 8.352 mmol) in tert-BuOH (10.50 mL). The mixture was evacuated / backfilled with N2. Bis(1,1-dimethylethyl)(methyl)phosphinetetrafluoroborate (CAS#479094-62-7, 135.6 mg, 546.7 μmol), Pd2(dba)3 (83.43 mg, 91.11 μmol) and K3PO4 (1.289 g, 6.074 mmol) were then added. The RM was evacuated / backfilled twice with N2 and heated at 65°C under N2 atmosphere overnight. The mixture was cooled to RT, diluted with TBME, and poured into a well stirred mixture of aqueous NH4Cl (10 wt%, 10 mL) and TBME (10 mL). The resulting slurry was purified by The solid was filtered and rinsed with TBME (2x). The filtrate layers were separated and washed with brine and TBME. The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure at 50°C. The residue was purified over silica gel (40 g) using an automated purification system (NP; Teledyne Collect at 250 / 260 nm; Flow rate: 40 mL / min; Eluent: Heptane + 3.0% to 19.5% EtOAc added over 15 min) to give (3R,4R)-tert-butyl 3-(4-(tert-butoxycarbonyl)phenyl)-4-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl)piperidine-1-carboxylate (1.35 g) as a yellow foam. LC-MS Method B-2: Rt = 8.14 min; MS m / z [M-Boc+H-tBu+H] + =346.4.

[0659] Step 3: Potassium (((3R,4R)-1-(tert-butoxycarbonyl)-3-(4-(tert-butoxycarbonyl)phenyl)piperidin-4-yl)methyl)trifluoroborate (Intermediate F-1)

[0660] A solution of tert-butyl (3R,4R)-3-(4-(tert-butoxycarbonyl)phenyl)-4-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl)piperidine-1-carboxylate (Intermediate F-1-2, 1.220 g, 2.433 mmol) in MeOH (20.0 mL) was placed in a water bath at RT. A solution of KHF2 (950.0 mg, 439.0 μL, 12.16 mmol) in H2O (10.0 mL) was added via a dropping funnel and additional MeOH (5 mL) was added to ensure stirring. After stirring at RT for 90 min, the RM was diluted with MeOH, evaporated to dryness, the residue was taken up in MeOH and the volatiles were removed under reduced pressure at 50 °C. The crude yellow solid was suspended in acetone, heated to 50°C, sonicated, filtered, and the volatiles in the filtrate were removed under reduced pressure at 50°C to give potassium (((3R,4R)-1-(tert-butoxycarbonyl)-3-(4-(tert-butoxycarbonyl)phenyl)piperidin-4-yl)methyl)trifluoroborate (1.13 g) as an off-white solid. LC-MS method B-2: Rt = 6.40 min; MS m / z [M-K+Na] - =464.3.

[0661] Intermediate rac-F-2:

[0662] Racemic (((3S*,4R*)-1-(tert-Butyloxycarbonyl)-4-(4-cyanophenyl)pyrrolidin-3-yl)methyl) potassium trifluoroborate

[0663]

[0664] Step 1: Racemic (3S*,4R*)-tert-butyl 3-(bromomethyl)-4-(4-cyanophenyl)pyrrolidine-1-carboxylate (intermediate rac-F-2-1)

[0665]

[0666] Racemic (3R *, 4S *) -3- (4-cyanophenyl) -4- (hydroxymethyl) pyrrolidine-1-carboxylic acid tert-butyl ester (intermediate rac-A-3, 984 mg, 3.25 mmol) was dissolved in DCM (10 mL) and triphenylphosphine (1.11 g, 4.23 mmol) was added. The RM was cooled to 0 ° C, CBr4 (1.40 g, 4.23 mmol) was added, and the RM was stirred at 0 ° C for 10 min and then at RT for 2 h. The RM was concentrated under reduced pressure and the residue was purified by silica gel chromatography (40 g, EtOAc / heptane = 0 / 100 to 60 / 40) to give racemic (3S *, 4R *) -3- (bromomethyl) -4- (4-cyanophenyl) pyrrolidine-1-carboxylic acid tert-butyl ester (977 mg) as a colorless oil. LCMS method C-1: RT = 1.17 min; MS m / z [M-tBu+H] + =311.2. 1 H NMR (400 MHz, CHLOROFORM-d) δ [ppm] 7.71–7.63 (m, 2H), 7.44–7.35 (m, 2H), 3.97–3.86 (m, 1H), 3.87–3.78 (m, 1H), 3.51–3.40 (m, 2H), 3.40–3.22 (m, 3H), 2.70–2.56 (m, 1H), 1.45 (s, 9H).

[0667] Step 2: Racemic (3R*,4S*)-tert-butyl 3-(4-cyanophenyl)-4-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl)pyrrolidine-1-carboxylate (intermediate rac-F-2-2)

[0668]

[0669] In a vial, under N2 atmosphere, tert-BuOH (7 mL) and water (0.6 mL) were added to racemic (3S*, 4R*)-tert-butyl 3-(bromomethyl)-4-(4-cyanophenyl)pyrrolidine-1-carboxylate (intermediate rac-F-2-1, 777 mg, 2.13 mmol), bis(pinacol)diboron (902 mg, 3.55 mmol), K3PO4 (993 mg, 4.68 mmol), Pd2(dba)3 (58 mg, 64 μmol) and bis(1,1-dimethylethyl)(methyl)phosphine tetrafluoroborate (95 mg, 38 μmol). The RM was purged with N2 and then stirred at 65 °C overnight. The RM was filtered through a syringe filter ( 0.45 mm PTFE w / GMF 25 mm diameter) and then the filtrate was diluted with DCM and saturated aqueous NaHCO3. The separated aqueous layer was extracted with DCM (3x). The combined organic layers were passed through The phase separator was dried and concentrated under reduced pressure. The residue was purified by silica gel chromatography (24 g, EtOAc / heptane=0 / 100 to 50 / 50) to obtain enriched racemic (3R*,4S*)-3-(4-cyanophenyl)-4-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester (937.0 mg), which was used directly in the next step without further purification. LCMS method C-1: RT=1.17 min; MS m / z[M-Boc+H] + =313.2.

[0670] Step 3: Racemic (((3S*,4R*)-1-(tert-butoxycarbonyl)-4-(4-cyanophenyl)pyrrolidin-3-yl)methyl)potassium trifluoroborate (intermediate rac-F-2)

[0671] The enriched racemic (3R*,4S*)-tert-butyl 3-(4-cyanophenyl)-4-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl)pyrrolidine-1-carboxylate (intermediate rac-F-2-2, 937 mg, 2.27 mmol) was dissolved in MeOH (8.0 mL) and a solution of KHF2 (710 mg, 328 μL, 9.09 mmol) in H2O (4.0 mL) was added. The RM was stirred at RT for 2 h and then concentrated under reduced pressure. The residue was suspended in a solution of MeOH / acetone (20 / 80), filtered, and the solid was rinsed twice with MeOH / acetone (20 / 80). The filtrate was concentrated under reduced pressure and the resulting residue was triturated with Et2O at ambient temperature. The precipitate was filtered off, washed with Et2O, and dried under reduced pressure at 40°C to give the title compound (634 mg) as a pale yellow solid. 1 H NMR(400MHz,DMSO-d6)δ[ppm]7.83–7.62(m,2H),7.56–7.31(m,2H),3.67–3.53(m,2H),3.21–3.09(m,1 H),2.87–2.69(m,2H),2.13–1.97(m,1H),1.45–1.35(m,9H),0.10–-0.08(m,1H),-0.13–-0.36(m,1H).

[0672] Intermediate F-3:

[0673] Potassium (((3R,4R)-1-(tert-butoxycarbonyl)-3-(4-(tert-butoxycarbonyl)phenyl)azepan-4-yl)methyl)trifluoroborate

[0674]

[0675] Intermediate F-3 was prepared according to the method described above for Intermediate F-1 using Intermediate A-4. LC-MS method B-2: Rt = 6.42 min; MS m / z [M-K+Na] - =478.1.

[0676] Intermediate F-4:

[0677] Potassium (((4R,5R)-1-(tert-butoxycarbonyl)-5-(4-(tert-butoxycarbonyl)phenyl)azepan-4-yl)methyl)trifluoroborate

[0678]

[0679] Intermediate F-4 was prepared according to the method described above for Intermediate F-1 using Intermediate A-5. LC-MS method B-2: Rt = 6.59 min; MS m / z [M-K+Na] - =478.4.

[0680] Intermediate F-5:

[0681] Potassium (((3R,4R)-1-((Benzyloxy)carbonyl)-3-(4-cyanophenyl)piperidin-4-yl)methyl)trifluoroborate

[0682]

[0683] Intermediate F-5 was prepared according to the method described above for Intermediate F-1 using Intermediate A-6. LC-MS method B-2: Rt = 4.73 min; MS m / z [M-K+Na] - =423.2.

[0684] Intermediate F-6:

[0685] Potassium (((3R,4R)-3-(4-(1H-pyrazol-1-yl)phenyl)-1-((benzyloxy)carbonyl)piperidin-4-yl)methyl)trifluoroborate

[0686]

[0687] Intermediate F-6 was prepared according to the method described above for Intermediate F-1 using Intermediate A-8. LC-MS method B-2: Rt = 4.98 min; MS m / z [M-K+Na] -=464.3.

[0688] Intermediate F-7:

[0689] Potassium (((3R,4R)-1-(tert-Butyloxycarbonyl)-3-(1-methyl-1H-pyrazol-4-yl)piperidin-4-yl)methyl)trifluoroborate

[0690]

[0691] Intermediate F-7 was prepared according to the method described above for Intermediate F-1 using Intermediate A-9. LC-MS method B-2: Rt = 3.59 min; MS m / z [M-K+Na] - =368.2.

[0692] Intermediate rac-B-1: tert-butyl 4-(((3RS,4RS)-3-(4-(methoxycarbonyl)phenyl)-1-(2,2,2-trifluoroethyl)piperidin-4-yl)methyl)-5,7-dimethyl-1H-indole-1-carboxylate

[0693]

[0694] A solution of methyl 4-(4-methylene-1-(2,2,2-trifluoroethyl)piperidin-3-yl)benzoate (intermediate A-1, 1.382 g, 4.41 mmol) in THF (16.0 mL) was evacuated / backfilled twice with N2. 9-BBN (0.5 M in THF, 8.82 mL, 4.41 mmol) was slowly added and the RM was stirred at 50 ° C for 4 h in a capped vial. The RM was then cooled to RT. A degassed solution of K3PO4 (2.553 g, 12.03 mmol) in water (8.00 mL) was slowly added to the mixture. 4-bromo-5,7-dimethyl-1H-indole-1-carboxylic acid tert-butyl ester (intermediate I-1, 1.30 g, 4.01 mmol) and PdCl2(dtbpf) (130.7 mg, 200.5 μmol) were then added as solids. The mixture was evacuated / backfilled with N2 and the capped vial was stirred at 50°C for 2h. The RM was cooled to RT and then partitioned between water and TBME. The layers were separated and washed with brine and TBME. The combined organic layers were dried over MgSO4, filtered and the volatiles were removed under reduced pressure at 50°C to give a brown oil which was purified over silica gel (220 g) using an automated purification system (NP; Teledyne Collect at 245 / 263 nm; Flow rate: 150 mL / min; Eluent: Heptane + 1% to 9.7% EtOAc added in 25.9 min). Pure fractions were combined and volatiles were removed under reduced pressure at 50 °C to give a) recovered starting material (Intermediate A-1, 308 mg) and b) a white foam Cis-isomer (1.34 g); LC-MS method B-2: Rt = 9.19 min; MS m / z [M+H] + =559.2; 1 H NMR (400 MHz, DMSO-d6) δ [ppm] 7.95 (d, J = 8.1 Hz, 2H), 7.74 (d, J = 8.1 Hz, 2H), 7.50 (d, J = 3.8 Hz, 1H), 6.82 (s, 1H), 6.28 (d, J = 3.8 Hz, 1H), 3.86 (s, 3H), 3.30–3.09 (m, 4H), 2.98–2.90 (m, 1H), 2.84 (dd, J = 11.4, 3.5 Hz, 1H), 2.56–2.49 (m, 1H, partially overlapped with DMSO peak), 2.48–2.30 (m, 5H), 2.04 (s, 4H), 1.56 (s, 9H), 1.43–1.30 (m, 2H); c) the title compound ( Trans-isomer ) (211 mg); LC-MS method B-2: Rt = 8.92 min; MS m / z [M+H] + = 559.4; 1 H NMR (400 MHz, DMSO-d6) δ [ppm] 7.97 (d, J = 8.2 Hz, 2H), 7.58–7.51 (m, 3H), 6.81 (s, 1H), 6.47 (d, J = 3.8 Hz, 1H), 3.86 (s, 3H), 3.24–3.09 (m, 2H), 2.92–2.78 (m, 3H), 2.59–2.45 (m, 2H, partially overlapped with DMSO peak), 2.43–2.37 (m, 4H), 2.30–2.21 (m, 1H), 2.09 (s, 3H), 1.89–1.77 (m, 1H), 1.57 (s, 9H), 1.51–1.37 (m, 1H), 1.29–1.20 (m, 1H).

[0695] Intermediate B-2: tert-butyl 4-(((3S,4S)-3-(4-(methoxycarbonyl)phenyl)-1-(2,2,2-trifluoroethyl)piperidin-4-yl)methyl)-5,7-dimethyl-1H-indole-1-carboxylate and

[0696] Intermediate B-3: tert-butyl 4-(((3R,4R)-3-(4-(methoxycarbonyl)phenyl)-1-(2,2,2-trifluoroethyl)piperidin-4-yl)methyl)-5,7-dimethyl-1H-indole-1-carboxylate

[0697]

[0698] Enantiomer separation and analysis according to method SFC-1: tert-butyl 4-(((3RS,4RS)-3-(4-(methoxycarbonyl)phenyl)-1-(2,2,2-trifluoroethyl)piperidin-4-yl)methyl)-5,7-dimethyl-1H-indole-1-carboxylate (intermediate rac-B-1, 210 mg, 375.9 μmol). The volatiles were removed under reduced pressure at 50°C and the residue was triturated several times with hexane and DCM and then dried under reduced pressure at 50°C to give: Intermediate B-2 (peak 1): 96.3 mg, white foam. LC-MS method B-2: Rt = 9.01 min; MS m / z [M+H] + =559.3; analytical chiral HPLC: Rt=3.19 min; 99.5% ee. Intermediate B-3 (peak 2), 107.7 mg, amber oil. LC-MS method B-2: Rt=9.04 min; MS m / z [M+H] + =559.2; analytical chiral HPLC: Rt=3.62min; 96.6%ee.

[0699] Intermediate rac-B-4: tert-butyl 5-cyclopropyl-4-(((3RS,4RS)-3-(4-(methoxycarbonyl)phenyl)-1-(2,2,2-trifluoroethyl)piperidin-4-yl)methyl)-7-methyl-1H-indole-1-carboxylate

[0700]

[0701] Intermediate rac-B-4 was prepared according to the method described above for intermediate rac-B-4 using methyl 4-(4-methylene-1-(2,2,2-trifluoroethyl)piperidin-3-yl)benzoate (Intermediate A-1) and tert-butyl 4-bromo-5-cyclopropyl-7-methyl-1H-indole-1-carboxylate (Intermediate I-3). LC-MS method B-2: Rt = 9.17 min; MS m / z [M+H] + =585.4.

[0702] Intermediate B-5: tert-butyl 5-cyclopropyl-4-(((3S,4S)-3-(4-(methoxycarbonyl)phenyl)-1-(2,2,2-trifluoroethyl)piperidin-4-yl)methyl)-7-methyl-1H-indole-1-carboxylate and

[0703] Intermediate B-6: tert-butyl 5-cyclopropyl-4-(((3R,4R)-3-(4-(methoxycarbonyl)phenyl)-1-(2,2,2-trifluoroethyl)piperidin-4-yl)methyl)-7-methyl-1H-indole-1-carboxylate

[0704] Enantiomer separation and analysis of intermediate rac-B-4 according to method SFC-8:

[0705] Intermediate B-5 (peak 1): off-white foam. LC-MS method B-2: Rt = 9.11 min; MS m / z [M+H] + =585.4; analytical chiral HPLC: Rt=1.12min; 99.5%ee.

[0706] Intermediate B-6 (peak 2): off-white. LC-MS method B-2: Rt = 9.17 min; MS m / z [M+H] + =585.3 Analytical chiral HPLC: Rt=1.52 min; 99.5% ee.

[0707] Intermediate rac-B-7: tert-butyl 5-methoxy-4-((3-(4-(methoxycarbonyl)phenyl)-1-(2,2,2-trifluoroethyl)piperidin-4-yl)methyl)-7-methyl-1H-indole-1-carboxylate

[0708]

[0709]

[0710] The diastereomeric mixture of intermediate rac-B-7 was prepared according to the method described above for intermediate rac-B-4 using methyl 4-(4-methylene-1-(2,2,2-trifluoroethyl)piperidin-3-yl)benzoate (Intermediate A-1) and tert-butyl 4-bromo-5-methoxy-7-methyl-1H-indole-1-carboxylate (Intermediate I-2). LC-MS method B-2: Rt = 8.44 min; MS m / z [M+H] + =575.3.

[0711] Intermediate B-8: tert-butyl 5-methoxy-4-(((3S,4S)-3-(4-(methoxycarbonyl)phenyl)-1-(2,2,2-trifluoroethyl)piperidin-4-yl)methyl)-7-methyl-1H-indole-1-carboxylate and

[0712] Intermediate B-9: tert-butyl 5-methoxy-4-(((3R,4R)-3-(4-(methoxycarbonyl)phenyl)-1-(2,2,2-trifluoroethyl)piperidin-4-yl)methyl)-7-methyl-1H-indole-1-carboxylate

[0713]

[0714] Separation and analysis of diastereoisomers and enantiomers of the intermediate rac-B-7 from a diastereomeric mixture according to method SFC-9:

[0715] Intermediate B-8 (peak 1): white foam. LC-MS method B-2: Rt = 8.51 min; MS m / z [M+H] + =575.3; analytical chiral HPLC: Rt=1.67min; 99.5%ee.

[0716] Intermediate B-9 (peak 4): white foam. LC-MS method B-2: Rt = 8.51 min; MS m / z [M+H] + =575.3Analytical chiral HPLC: Rt=2.72 min; 99.5% ee. The isolated peak 4 was re-purified by silica gel column chromatography (12 g, heptane / EtOAc=100 / 0 to 88 / 12) and then used in the next reaction.

[0717] Intermediate B-10:

[0718] 4-(((3R,4R)-1-(tert-Butyloxycarbonyl)-3-(4-(tert-Butyloxycarbonyl)phenyl)piperidin-4-yl)methyl)-5,7-dimethyl-1H-indole-1-carboxylic acid tert-butyl ester

[0719]

[0720] A mixture of potassium (((3R,4R)-1-(tert-butoxycarbonyl)-3-(4-(tert-butoxycarbonyl)phenyl)piperidin-4-yl)methyl)trifluoroborate (Intermediate F-1, 1.010 g, 2.098 mmol) and tert-butyl 4-bromo-5,7-dimethyl-1H-indole-1-carboxylate (Intermediate I-1, 884.3 mg, 2.727 mmol) in toluene (16.60 mL) was placed in a vial. A solution of K3PO4 (1.470 g, 6.924 mmol) in water (4.15 mL) was added. The mixture was evacuated / backfilled with N2. PdCl2(dppf) (153.5 mg, 209.8 μmol) was added and the mixture was evacuated / backfilled with N2 again. The RM was stirred in a capped vial at 95 °C overnight, then cooled to RT, diluted with TBME / water, and Filter. The filtrate layers were separated and washed with brine and TBME. The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure at 50°C. The residue was purified over silica gel (40 g) using an automated purification system (NP; Teledyne Collect at 245 / 260 nm; Flow rate: 40 mL / min; Eluent: Heptane + 0 to 9.6% EtOAc over 20 min) to give tert-butyl 4-(((3R,4R)-1-(tert-butoxycarbonyl)-3-(4-(tert-butoxycarbonyl)phenyl)piperidin-4-yl)methyl)-5,7-dimethyl-1H-indole-1-carboxylate (1.03 g) as an off-white foam. LC-MS Method B-2: Rt = 9.48 min; MS m / z [M+H] + 619.3.

[0721] Intermediate B-11:

[0722] 4-(((3R,4R)-3-(4-(tert-Butyloxycarbonyl)phenyl)piperidin-4-yl)methyl)-5,7-dimethyl-1H-indole-1-carboxylic acid tert-butyl ester

[0723]

[0724] HCl in 1,4-dioxane (4M, 3.085 mL, 12.34 mmol) was added to a solution of tert-butyl 4-(((3R,4R)-1-(tert-butoxycarbonyl)-3-(4-(tert-butoxycarbonyl)phenyl)piperidin-4-yl)methyl)-5,7-dimethyl-1H-indole-1-carboxylate (Intermediate B-10, 509.0 mg, 822.5 μmol) in dioxane (15.0 mL). The RM was stirred at RT for 70 min, additional HCl in dioxane (4M, 3.03 mL, 12.12 mmol) was added, and stirring was continued for another 140 min. The RM was poured into a well stirred mixture of aqueous Na2CO3 (10 wt%) and EtOAc. The layers were combined and washed with EtOAc and brine. The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure at 50 °C. The residue was purified by silica gel (24 g) using an automated purification system (NP; Teledyne Collect at 233 / 263 nm; flow rate: 35 mL / min; eluent: DCM + 0 to 10% {EtOH / NH4OH aqueous solution 25% = 9 / 1}) was added within 25 min to give tert-butyl 4-(((3R,4R)-3-(4-(tert-butoxycarbonyl)phenyl)piperidin-4-yl)methyl)-5,7-dimethyl-1H-indole-1-carboxylate (263 mg) as a slightly amber foam. LC-MS method B-1: Rt = 1.44 min; MS m / z [M+H] + =519.3.

[0725] Intermediate B-12:

[0726] 4-(((3R,4R)-3-(4-(tert-Butoxycarbonyl)phenyl)-1-methylpiperidin-4-yl)methyl)-5,7-dimethyl-1H-indole-1-carboxylic acid tert-butyl ester

[0727]

[0728] Aqueous formaldehyde solution (37% wt, 110.5 μL, 1.484 mmol) was added to a solution of tert-butyl 4-(((3R,4R)-3-(4-(tert-butoxycarbonyl)phenyl)piperidin-4-yl)methyl)-5,7-dimethyl-1H-indole-1-carboxylate (Intermediate B-11, 77.0 mg, 148.4 μmol) in MeOH (1.70 mL). AcOH (13.37 mg, 12.75 μL, 222.7 μmol) was added. The RM was placed in a water bath (RT), sodium cyanoborohydride (18.66 mg, 296.9 μmol) was added, and the RM was stirred for 1 h. The mixture was partitioned between TBME and saturated aqueous NaHCO3 and water; the layers were separated and washed with brine and TBME. The combined organic layers were dried over MgSO4, filtered, and the volatiles were removed under reduced pressure at 50°C. The residue was purified by preparative TLC (MERCK 1.05744.0001, PLC silica gel 60F254, 0.5 mm; UV detection; eluent: DCM / MeOH=92 / 8; bands eluted with DCM / MeOH=92 / 8 and 80 / 20) to give tert-butyl 4-(((3R,4R)-3-(4-(tert-butoxycarbonyl)phenyl)-1-methylpiperidin-4-yl)methyl)-5,7-dimethyl-1H-indole-1-carboxylate (68.6 mg) as a white foam. LC-MS method B-2: Rt=6.41 min; MS m / z[M+H] + =533.3.

[0729] Intermediate B-13:

[0730] 4-(((3R,4R)-3-(4-(tert-Butoxycarbonyl)phenyl)-1-(2-fluoroethyl)piperidin-4-yl)methyl)-5,7-dimethyl-1H-indole-1-carboxylic acid tert-butyl ester

[0731]

[0732] A solution of tert-butyl 4-(((3R,4R)-3-(4-(tert-butoxycarbonyl)phenyl)piperidin-4-yl)methyl)-5,7-dimethyl-1H-indole-1-carboxylate (Intermediate B-11, 50.0 mg, 96.4 μmol) in ACN (0.5 mL) was placed in a microwave vial. DIPEA (31.15 mg, 42.0 μL, 241.0 μmol) and 1-fluoro-2-iodoethane (41.92 mg, 19.63 μL, 241.0 μmol) were added. The capped vial was stirred at 45 °C for 24 h. The RM was cooled to RT and partitioned between TBME and water. The layers were separated and washed with brine and TBME. The combined organic layers were dried over MgSO4, filtered and the volatiles were removed under reduced pressure at 50°C to give a yellow oil, which was purified by preparative TLC (MERCK 1.05744.0001, PLC silica gel 60F254, 0.5 mm; eluent: DCM / MeOH=94 / 6; band eluted with DCM / MeOH=90 / 10). The volatiles of the filtrate were removed under reduced pressure at 50°C to give tert-butyl 4-(((3R,4R)-3-(4-(tert-butoxycarbonyl)phenyl)-1-(2-fluoroethyl)piperidin-4-yl)methyl)-5,7-dimethyl-1H-indole-1-carboxylate (49.5 mg) as a white foam. LC-MS method B-1: Rt=1.34 min; MS m / z[M+H] + =565.4.

[0733] Intermediate B-14:

[0734] 4-(((3R,4R)-3-(4-(tert-Butoxycarbonyl)phenyl)-1-ethylpiperidin-4-yl)methyl)-5,7-dimethyl-1H-indole-1-carboxylic acid tert-butyl ester

[0735]

[0736] To a solution of tert-butyl 4-(((3R,4R)-3-(4-(tert-butoxycarbonyl)phenyl)piperidin-4-yl)methyl)-5,7-dimethyl-1H-indole-1-carboxylate (Intermediate B-11) (50.0 mg, 96.4 μmol) in ACN (0.50 mL) was added DIPEA (31.15 mg, 42 μL, 241 μmol) and iodoethane (37.59 mg, 19.42 μL, 241.0 μmol). The RM was stirred at 45 °C for 6 h in a capped vial. The mixture was cooled to RT and partitioned between TBME and water. The layers were separated and washed with brine and TBME. The combined organic layers were dried over MgSO4, filtered, and the volatiles were removed under reduced pressure at 50 °C. The residue was purified by preparative TLC (MERCK 1.05744.0001, PLC silica gel 60F254, 0.5 mm; UV detection; eluent = DCM / MeOH 95 / 5; band eluted with DCM / MeOH = 85 / 15) to give tert-butyl 4-(((3R,4R)-3-(4-(tert-butoxycarbonyl)phenyl)-1-ethylpiperidin-4-yl)methyl)-5,7-dimethyl-1H-indole-1-carboxylate (30.2 mg) as a white foam. LC-MS method B-2: Rt = 6.28 min; MS m / z [M+H] + =547.5.

[0737] Intermediate B-15:

[0738] 4-(((3R,4R)-3-(4-cyanophenyl)piperidin-4-yl)methyl)-5,7-dimethyl-1H-indole-1-carboxylic acid tert-butyl ester

[0739] A mixture of tert-butyl 4-(((3R,4R)-1-((benzyloxy)carbonyl)-3-(4-cyanophenyl)piperidin-4-yl)methyl)-5,7-dimethyl-1H-indole-1-carboxylate (Intermediate B-66, 565 mg, 978 μmol), Pd / C (72.85 mg, 10% wt, 68.4 μmol) and EtOH (20 mL) was stirred under H2 atmosphere (balloon) for about 2.5 h. The mixture was filtered through celite and the solids were rinsed with DCM (3x). The volatiles of the filtrate were removed under reduced pressure at 50 °C. The residue was dissolved in TBME and the resulting solution was treated with activated carbon and then purified by Filter and rinse the solid with TBME (2x). The filtrate was diluted with n-hexane and concentrated under reduced pressure at 50°C to give crude tert-butyl 4-(((3R,4R)-1-((benzyloxy)carbonyl)-3-(4-cyanophenyl)piperidin-4-yl)methyl)-5,7-dimethyl-1H-indole-1-carboxylate (421 mg) as an off-white foam, which was used directly in the next step without further purification. LC-MS method B-2: Rt = 5.00 min; [M+H] + =444.3. 1 H NMR (400 MHz, DMSO-d6) δ [ppm] 7.80 (d, J = 7.9 Hz, 2H), 7.57 (d, J = 8.0 Hz, 2H), 7.52 (d, J = 3.7 Hz, 1H), 6.81 (s, 1H), 6.41 (d, J = 3.8 Hz, 1H), 2.91–2.79 (m, 2H), 2.65–2.55 (m, 2H), 2.47–2.42 (m, 1H), 2.42–2.30 (m, 5H), 2.10 (s, 3H), 1.99–1.87 (m, 1H), 1.57 (s, 9H), 1.26–1.20 (m, 2H). 32 of 33H reported.

[0740] Intermediate rac-B-16:

[0741] Racemic tert-butyl 4-(((3S*,4R*)-1-(tert-butoxycarbonyl)-4-(4-cyanophenyl)pyrrolidin-3-yl)methyl)-5,7-dimethyl-1H-indole-1-carboxylate

[0742]

[0743] Toluene (0.5 mL) and water (125 μL) were added to tert-butyl 4-bromo-5,7-dimethyl-1H-indole-1-carboxylate (Intermediate I-1, 27 mg, 83 μmol), racemic (((3S*,4R*)-1-(tert-butoxycarbonyl)-4-(4-cyanophenyl)pyrrolidin-3-yl)methyl) potassium trifluoroborate (Intermediate rac-F-2, 21 mg, 53 μmol), K3PO4 (34 mg, 161 μmol) and PdCl2(dppf)-CH2Cl2 adduct (6.1 mg, 7.5 μmol) in a vial under N2 atmosphere, and the mixture was heated at 95 °C overnight. The RM was allowed to cool to RT and then diluted with water. The mixture was extracted with DCM (3x) and the combined organic layers were washed with water. The phase separator was dried and concentrated under reduced pressure. The residue was purified by silica gel chromatography (40 g, EtOAc / heptane=0 / 100 to 50 / 50) to obtain racemic 4-(((3S*,4R*)-1-(tert-butoxycarbonyl)-4-(4-cyanophenyl)pyrrolidin-3-yl)methyl)-5,7-dimethyl-1H-indole-1-carboxylic acid tert-butyl ester (19.8 mg). LC-MS method C-1: RT=1.48 min; MS m / z[M-tBu+H] + =474.3.

[0744] Intermediate rac-B-17:

[0745] Racemic 4-(((3S*,4R*)-4-(4-cyanophenyl)pyrrolidin-3-yl)methyl)-5,7-dimethyl-1H-indole-1-carboxylic acid tert-butyl ester

[0746]

[0747] Racemic tert-butyl 4-(((3S*,4R*)-1-(tert-butoxycarbonyl)-4-(4-cyanophenyl)pyrrolidin-3-yl)methyl)-5,7-dimethyl-1H-indole-1-carboxylate (intermediate rac-B-16, 91 mg) was suspended in MeOH (2.0 mL) and HCl in dioxane (4 M, 0.5 mL, 2 mmol) was added. The RM was stirred at RT for 4 h and then concentrated under reduced pressure. The residue was dissolved in DCM, washed with saturated aqueous NaHCO3 and washed with 4% paraformaldehyde. Phase separator drying and concentration gave crude racemic tert-butyl 4-(((3S*,4R*)-4-(4-cyanophenyl)pyrrolidin-3-yl)methyl)-5,7-dimethyl-1H-indole-1-carboxylate (73 mg; partially contaminated with its indole NH form) as a light yellow oil. LC-MS method C-1: RT = 1.00 min; MS m / z [M+H] + =430.4.

[0748] Intermediate rac-B-18:

[0749] Racemic 4-(((3S*,4R*)-4-(4-cyanophenyl)-1-methylpyrrolidin-3-yl)methyl)-5,7-dimethyl-1H-indole-1-carboxylic acid tert-butyl ester

[0750]

[0751] To the crude and enriched racemic tert-butyl 4-(((3S*,4R*)-4-(4-cyanophenyl)pyrrolidin-3-yl)methyl)-5,7-dimethyl-1H-indole-1-carboxylate (intermediate rac-B-17, 73 mg) in MeOH (2.0 mL) and acetic acid (30 μL, 524 μmol) was added aqueous formaldehyde (37 wt%, 2.0 mL). The mixture was stirred at RT for 15 min, then sodium triacetoxyborohydride (144 mg, 680 μmol) was added. The RM was stirred at RT overnight. Additional aqueous formaldehyde (37 wt%, 1.0 mL) and sodium triacetoxyborohydride (100 mg, 472 μmol) were added and the RM was stirred at RT for 4 h. The mixture was concentrated under reduced pressure and the residue was diluted with DCM and saturated aqueous NaHCO3. The separated aqueous layer was extracted with DCM (3x) and the combined organic layers were washed with 4% 4-nitropropane-1,4-diol-1,4-diol-1,4-diol-1,4-diol-1,4-diol-1,4-diol-1,4-diol-1,4-diol-1,4-diol-1,4-diol-1,4-diol-1,4-diol-1,4-diol-1,4-diol-1,4-diol-1,4-diol-1,4-diol-1,4-diol-1,4-diol-1 The phase separator was dried and concentrated under reduced pressure. The residue was purified by silica gel chromatography (12 g, {EtOAc / EtOH 3 / 1} / heptane=0 / 100 to 100 / 0) to give racemic 4-(((3S*,4R*)-4-(4-cyanophenyl)-1-methylpyrrolidin-3-yl)methyl)-5,7-dimethyl-1H-indole-1-carboxylic acid tert-butyl ester (48 mg) as a light yellow oil. LC-MS method C-1: RT=0.90 min; MS m / z[M+H] + =444.5.

[0752] The following examples were synthesized from appropriate starting materials by applying analogous methods described in the above examples.

[0753]

[0754]

[0755]

[0756]

[0757]

[0758]

[0759]

[0760]

[0761]

[0762]

[0763]

[0764]

[0765]

[0766]

[0767]

[0768]

[0769]

[0770]

[0771]

[0772]

[0773]

[0774]

[0775] Examples

[0776] Example Ex-1: 4-((3R,4R)-4-((5,7-dimethyl-1H-indol-4-yl)methyl)-1-(2,2,2-trifluoroethyl)piperidin-3-yl)benzoic acid

[0777] Aqueous NaOH (4M, 482 μL, 1.928 mmol) was added to a solution of tert-butyl 4-(((3R,4R)-3-(4-(methoxycarbonyl)phenyl)-1-(2,2,2-trifluoroethyl)piperidin-4-yl)methyl)-5,7-dimethyl-1H-indole-1-carboxylate (Intermediate B-3, 107.7 mg, 192.8 μmol) in MeOH (1.00 mL) and THF (0.70 mL). The RM was heated to 50 °C for 4.5 h, then cooled to RT and diluted with aqueous HCl (4M, 482 μL, 1.928 mmol). EtOAc, brine and a small amount of water were added. The layers were separated and washed with brine and EtOAc. The combined organic layers were dried over MgSO4, filtered and the volatiles were removed under reduced pressure at 50°C to give a slightly yellow oil which was purified on silica gel (12 g) using an automated purification system (NP; Teledyne Collect at 240 / 269 nm; flow rate: 30 mL / min; eluent: DCM + 0 to 4.7% MeOH added over 9.4 min). Pure fractions were combined and volatiles were removed under reduced pressure at 50 °C to give the title compound as an off-white foam (72.9 mg).

[0778] Example 2: 4-((3S,4S)-4-((5,7-dimethyl-1H-indol-4-yl)methyl)-1-(2,2,2-trifluoro-ethyl)piperidin-3-yl)benzoic acid

[0779] Example 2 (72.8 mg, off-white foam) was prepared similarly as described in Example 1 using tert-butyl 4-(((3S,4S)-3-(4-(methoxycarbonyl)phenyl)-1-(2,2,2-trifluoroethyl)piperidin-4-yl)methyl)-5,7-dimethyl-1H-indole-1-carboxylate (Intermediate B-2, 96.3 mg).

[0780] Example Ex-8:

[0781] 4-((3R,4R)-4-((5,7-dimethyl-1H-indol-4-yl)methyl)-1-methylpiperidin-3-yl)benzoic acid

[0782] Aqueous NaOH (4M, 511.5 μL, 2.046 mmol) was added to a solution of tert-butyl 4-(((3R,4R)-3-(4-(tert-butoxycarbonyl)phenyl)-1-methylpiperidin-4-yl)methyl)-5,7-dimethyl-1H-indole-1-carboxylate (Intermediate B-11, 109.0 mg, 204.6 μmol) in MeOH (1.8 mL) and THF (0.5 mL). The resulting milky RM was heated to 55 °C to form a clear solution and stirring was continued at 55 °C for 23 h. The RM was cooled to RT and quenched with aqueous HCl (4M, 511.5 μL, 2.046 mmol). EtOAc, brine and a small amount of water were added. The layers were separated, Me-THF was added, the layers were separated and the aqueous layer was washed with Me-THF (3x). The combined organic layers were dried over MgSO4, filtered and the volatiles were removed under reduced pressure at 50°C. The residue was triturated with ACN / water (9 / 1), filtered and the solid was dried under reduced pressure at 50°C to give the title compound (57.5 mg) as a white solid.

[0783] Example Ex-10:

[0784] 4-((3R,4R)-4-((5,7-dimethyl-1H-indol-4-yl)methyl)-1-ethylpiperidin-3-yl)benzoic acid

[0785] Aqueous NaOH (4M, 138.1 μL, 552.4 μmol) was added to a solution of tert-butyl 4-(((3R, 4R)-3-(4-(tert-butoxycarbonyl)phenyl)-1-ethylpiperidin-4-yl)methyl)-5,7-dimethyl-1H-indole-1-carboxylate (Intermediate B-14, 30.2 mg, 55.2 μmol) in MeOH (0.60 mL) and THF (0.20 mL). The RM was stirred at RT for 48 h and then at 50 °C for another 24 h. The mixture was cooled to RT and quenched with aqueous HCl (4M, 138 μL, 552.4 μmol) and then diluted with MeOH. Most of the volatiles were removed under reduced pressure at 50 °C. The resulting slurry was added to a MeOH solution and directly purified by preparative HPLC on an XBridge C18 column (30 x 100 mm, 5 μm) eluting with 5% to 60% ACN (0.1%) in aqueous NH4OH to afford 4-((3R,4R)-4-((5,7-dimethyl-1H-indol-4-yl)methyl)-1-ethylpiperidin-3-yl)benzoic acid (17.8 mg) as a white solid after concentration under reduced pressure.

[0786] Example Ex-12:

[0787] 4-((3R,4R)-4-((5,7-dimethyl-1H-indol-4-yl)methyl)-1-(2-fluoroethyl)piperidin-3-yl)benzoic acid

[0788] TFA (0.3 mL) was added to a solution of tert-butyl 4-(((3R,4R)-3-(4-(tert-butoxycarbonyl)phenyl)-1-(2-fluoroethyl)piperidin-4-yl)methyl)-5,7-dimethyl-1H-indole-1-carboxylate (Intermediate B-13, 48.0 mg, 84.99 μmol) in DCM (0.9 mL). The RM was stirred at RT for 1 h, diluted with DCE, and the volatiles were removed under reduced pressure at 40 °C. The crude residue was purified over C18 (26 g) using an automated purification system (RP, Teledyne Collect at 220 / 270 nm; flow rate: 35 mL / min; eluent: water + 10% to 60% ACN added over 10 min). Pure fractions were combined and ACN was removed under reduced pressure at 50° C. The resulting aqueous slurry was lyophilized overnight to give the title compound as a white solid (16.8 mg).

[0789] Example Ex-15:

[0790] 4-((3R,4R)-4-((5,7-dimethyl-1H-indol-4-yl)methyl)-1-(2-hydroxy-2-methylpropyl)piperidin-3-yl)benzoic acid

[0791] To a solution of tert-butyl 4-(((3R,4R)-3-(4-(tert-butoxycarbonyl)phenyl)-1-(2-hydroxy-2-methylpropyl)piperidin-4-yl)methyl)-5,7-dimethyl-1H-indole-1-carboxylate (Intermediate B-22, 69.0 mg, 116.8 mmol) in MeOH (0.80 mL) and THF (0.30 mL) was added aqueous NaOH (4 M, 292 uL, 1.168 mmol), and the resulting RM was stirred at 50 °C overnight. To the mixture was added aqueous HCl (4 M, 297 uL, 1.168 mmol) and MeOH, and the resulting mixture was concentrated under reduced pressure to a slurry. Additional MeOH and two drops of water were added, and the mixture was purified by preparative HPLC on an XBridge C18 column (30 x 100 mm, 5 μm) eluting with 5% to 28% ACN in aqueous NH4OH (0.1%) to give 4-((3R,4R)-4-((5,7-dimethyl-1H-indol-4-yl)methyl)-1-(2-hydroxy-2-methylpropyl)piperidin-3-yl)benzoic acid (43.8 mg) as a white solid after lyophilization.

[0792] Example Ex-24 and Example Ex-25:

[0793] 4-((3R,4S)-4-((5,7-dimethyl-1H-indol-4-yl)methyl)-1-methylpyrrolidin-3-yl)benzoic acid and

[0794] 4-((3S,4R)-4-((5,7-dimethyl-1H-indol-4-yl)methyl)-1-methylpyrrolidin-3-yl)benzoic acid

[0795] Step 1-a: To a solution of racemic tert-butyl 4-(((3S*,4R*)-4-(4-cyanophenyl)-1-methylpyrrolidin-3-yl)methyl)-5,7-dimethyl-1H-indole-1-carboxylate (intermediate rac-B-18, 48 mg, 19 μmol) in IPA (2.5 mL) was added aqueous KOH (5 M, 250 μL, 1.25 mmol) and water (1.0 mL). The mixture was irradiated using microwaves ( Initiator + ) The RM was heated at 150 °C for 4.5 h. Additional aqueous KOH (5 M, 75 μL) was added and heating at 150 °C was continued for 3 h, then irradiated using microwaves ( Initiator +) was heated at 165°C for 1 h. The mixture was concentrated under reduced pressure and the crude residue was purified by preparative HPLC on an XBridge C18 OBD column (30 x 50 mm, 5 μm) eluting with 5% to 20% ACN in aqueous NH4OH (5 mM) to afford racemic 4-((3R*,4S*)-4-((5,7-dimethyl-1H-indol-4-yl)methyl)-1-methylpyrrolidin-3-yl)benzoic acid (23.4 mg) as a white solid. LC-MS Method C-1: RT = 0.70 min; MS m / z [M+H] + =363.2.

[0796] Step 1-b : Separation and analysis of enantiomers according to method SFC-4: Racemic 4-((3R*,4S*)-4-((5,7-dimethyl-1H-indol-4-yl)methyl)-1-methylpyrrolidin-3-yl)benzoic acid (from step 1-a, above, 23 mg) gave Example Ex-25 (peak 1): 6.2 mg, white solid. LC-MS method C-3: Rt = 1.22 min; MS m / z [M+H] + =363.2; analytical chiral HPLC: Rt=2.35 min; 100% ee. Example Ex-24 (peak 2): 6.3 mg, white solid. LC-MS method C-3: Rt=1.24 min; MS m / z [M+H] + =363.2; analytical chiral HPLC: Rt=3.02min; 98.6%ee.

[0797] Example Ex-42:

[0798] 4-(((3R,4R)-3-(4-(1H-tetrazolyl-5-yl)phenyl)-1-methylpiperidin-4-yl)methyl)-5,7-dimethyl-1H-indole

[0799] Sodium azide (16.13 mg, 248.1 μmol) and ammonium chloride (12.39 mg, 231.6 μmol) were added to a solution of tert-butyl 4-(((3R,4R)-3-(4-cyanophenyl)-1-methylpiperidin-4-yl)methyl)-5,7-dimethyl-1H-indole-1-carboxylate (Intermediate B-67, 75.70 mg, 165.4 μmol) in DMF (0.750 mL), and the resulting mixture was stirred at 100 °C in a capped vial for about 1.5 days. The RM was cooled to RT, and MeOH (2.0 mL) and K2CO3 (325 mesh 114.3 mg, 827.1 μmol) were added. Heating was continued at 55 °C for 18 h, and stirring was continued at ambient temperature for about 2 days. The mixture was diluted with MeOH, concentrated HCl (12M, 137.9uL, 1.654mmol) was added, and the resulting mixture was concentrated to a slurry under reduced pressure at 50°C. Water was added and the mixture was purified by preparative HPLC on an XBridge C18 column (30 x 100mm, 5μm) eluting with 5% to 36.2% ACN in aqueous NH4OH (0.1%) to give 4-(((3R,4R)-3-(4-(1H-tetrazol-5-yl)phenyl)-1-methylpiperidin-4-yl)methyl)-5,7-dimethyl-1H-indole (26.1mg) as a light yellow fluffy solid after concentration under reduced pressure and then lyophilization.

[0800] Example Ex-44:

[0801] 4-((3R,4R)-4-((5,7-dimethyl-1H-indol-4-yl)methyl)-1-methylpiperidin-3-yl)benzonitrile

[0802] Tert-butyl 4-(((3R,4R)-3-(4-cyanophenyl)-1-methylpiperidin-4-yl)methyl)-5,7-dimethyl-1H-indole-1-carboxylate (Intermediate B-67, 22.0 mg, 48.07 μmol) was treated with DCM / TFA (3 / 1, 0.60 mL) and the resulting RM was stirred at RT for 30 min. The mixture was diluted with DCM and poured into aqueous Na2CO3 (10 wt%). The layers were then separated and the aqueous layer was extracted with DCM (2x). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure at 50 °C. The residue was purified by preparative TLC (MERCK 1.05744.0001, PLC silica gel 60F254, 0.5 mm; DCM / {MeOH / NH4OH 25%, 9 / 1}=92 / 8) to give 4-((3R,4R)-4-((5,7-dimethyl-1H-indol-4-yl)methyl)-1-methylpiperidin-3-yl)benzonitrile (12.8 mg) as a white foam.

[0803] Example Ex-52:

[0804] 5,7-Dimethyl-4-(((3R,4R)-1-methyl-3-(1-methyl-1H-pyrazol-4-yl)piperidin-4-yl)methyl)-1H-indole

[0805] To a solution of tert-butyl 5,7-dimethyl-4-(((3R,4R)-1-methyl-3-(1-methyl-1H-pyrazol-4-yl)piperidin-4-yl)methyl)-1H-indole-1-carboxylate (Intermediate B-77, 31.7 mg, 72.6 μmol) in MeOH (1.20 mL) was added K2CO3 (325 mesh, 50.2 mg, 363 μmol) and the resulting mixture was stirred at 50 °C overnight. The volatiles were removed under reduced pressure at 50 °C and the residue was partitioned between water and DCM. The separated aqueous layer was extracted with DCM (2x). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure at 50 °C. The residue was purified by preparative TLC plate (MERCK 1.05744.0001, PLC silica gel 60F254, 0.5 mm; DCM / (MeOH:NH4OH 25% 9:1)=88 / 12) to give 5,7-dimethyl-4-(((3R,4R)-1-methyl-3-(1-methyl-1H-pyrazol-4-yl)piperidin-4-yl)methyl)-1H-indole (21.0 mg) as an off-white solid.

[0806] Example Ex-58

[0807] Racemic 4-((3R*,4S*)-4-((5,7-dimethyl-1H-indol-4-yl)methyl)-1-methylpyrrolidin-3-yl)benzamide

[0808] To a solution of racemic tert-butyl 4-(((3S*,4R*)-4-(4-cyanophenyl)-1-methylpyrrolidin-3-yl)methyl)-5,7-dimethyl-1H-indole-1-carboxylate (intermediate rac-B-18, 68 mg, 15 μmol) in tert-amyl alcohol (2.5 mL) was added aqueous NaOH (1 M, 1.2 mL, 1.20 mmol). The RM was heated at 110 °C for 84 h and then irradiated using microwaves ( Initiator + ) was heated at 160°C for 2 h. Solid lithium hydroxide (50 mg, 2.09 mmol) was added and the mixture was irradiated with microwaves ( Initiator +)The RM was heated at 165 °C for 16 h. The mixture was concentrated under reduced pressure and the crude residue was purified by preparative HPLC on an XBridge C18 OBD column (30 x 50 mm, 5 μm) eluting with 10% to 0% ACN in aqueous NH4OH (5 mM) to afford racemic 4-((3R*,4S*)-4-((5,7-dimethyl-1H-indol-4-yl)methyl)-1-methylpyrrolidin-3-yl)benzamide (3.0 mg) as an off-white solid. LC-MS Method C-3: Rt = 0.92 min; [M+H] + =362.4

[0809] Example Ex-59

[0810] 4-((3R,4S)-4-((5-cyclopropyl-7-methyl-1H-indol-4-yl)methyl)-1-methylpyrrolidin-3-yl)benzoic acid

[0811] Step 1-a : Racemic 4-((3R*,4S*)-4-((5-cyclopropyl-7-methyl-1H-indol-4-yl)methyl)-1-methylpyrrolidin-3-yl)benzoic acid was prepared according to step 1-a of the method described above for Example Ex-24 using racemic 4-(((3S*,4R*)-4-(4-cyanophenyl)-1-methylpyrrolidin-3-yl)methyl)-5-cyclopropyl-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (Intermediate B-87).

[0812] Step 1-b : Separation and analysis of enantiomers according to method SFC-12: Racemic 4-((3R*,4S*)-4-((5-cyclopropyl-7-methyl-1H-indol-4-yl)methyl)-1-methylpyrrolidin-3-yl)benzoic acid (from step 1-a, above, 40 mg) provided Example Ex-59 (peak 2): 16.3 mg, white solid. LC-MS method C-3: Rt = 1.44 min; [M+H] + =389.3; Analytical chiral HPLC: Rt=3.10min; 95.9%ee.

[0813] Example Ex-60

[0814] 4-(((3S,4R)-4-(4-(2H-tetrazolyl-5-yl)phenyl)-1-methylpyrrolidin-3-yl)methyl)-5,7-dimethyl-1H-indole

[0815] Step 1-a: Racemic 4-(((3S*,4R*)-4-(4-(2H-tetrazol-5-yl)phenyl)-1-methylpyrrolidin-3-yl)methyl)-5,7-dimethyl-1H-indole was prepared according to the method described above for Example Ex-42 using racemic 4-(((3S*,4R*)-4-(4-cyanophenyl)-1-methylpyrrolidin-3-yl)methyl)-5-cyclopropyl-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (intermediate rac-B-18).

[0816] Step 1-b : Separation and analysis of enantiomers according to method SFC-13: Racemic 4-(((3S*,4R*)-4-(4-(2H-tetrazolyl-5-yl)phenyl)-1-methylpyrrolidin-3-yl)methyl)-5,7-dimethyl-1H-indole (25 mg) provided Example Ex-60 (peak 2): 3.5 mg, white solid. LC-MS method C-3: Rt = 1.15 min; [M+H] + =387.5; analytical chiral HPLC: Rt=3.48min; 98.9%ee.

[0817] The following table includes the above examples and those synthesized using appropriate starting materials and applying analogous methods described in the above examples.

[0818]

[0819]

[0820]

[0821]

[0822]

[0823]

[0824]

[0825]

[0826]

[0827]

[0828]

[0829]

[0830]

[0831]

[0832]

[0833]

[0834]

[0835]

[0836]

[0837]

[0838]

[0839]

[0840]

[0841]

[0842]

[0843]

[0844]

[0845]

[0846] LC-MS method

[0847] Method A-1:

[0848] Column: Acquity UPLC BEH C18, 2.1x 50mm column, 1.7μm Column temperature: 40℃

[0849] Eluent: A: water + FA (0.1%)

[0850] B:ACN

[0851] Flow rate: 0.8mL / min

[0852] Gradient: Time / %B: 0.01 / 5; 0.3 / 5; 0.5 / 100; 1.8 / 100; 2.0 / 5; 3.0 / 5 (3 min method)

[0853] Method A-2:

[0854] Column: Waters XBridge C18, 3.0 x 50 mm column, 3.5 μm

[0855] Column temperature: 40℃

[0856] Eluent: A: water + FA (0.1%)

[0857] B:ACN

[0858] Flow rate: 1.0mL / min

[0859] Gradient: Time / %B: 0.01 / 10; 0.2 / 10 4.5 / 95; 8.5 / 95; 8.5 / 10; 10.0 / 10; (10 min method)

[0860] Method B-1:

[0861] Column: CORTECS C18+, 2.1 x 50 mm column, 2.7 μm

[0862] Column temperature: 80℃

[0863] Eluent: A: water + 0.05% FA + 3.75mM ammonium acetate NH4 (CH3CO2)

[0864] B: IPA + 0.05% FA

[0865] Flow rate: 1.0mL / min

[0866] Gradient: initial 5% B; 5% to 50% B in 1.4 min, 50% to 98% B in 0.30 min; 98% B in 0.10 min.

[0867] Method B-2:

[0868] Column: Acquity UPLC BEH C18, 2.1 x 100 mm column, 1.7 μm

[0869] Column temperature: 80℃

[0870] Eluent: A: water + 0.05% FA + 3.75 mM ammonium acetate

[0871] B: IPA + 0.05% FA

[0872] Flow rate: 0.4mL / min

[0873] Gradient: pre-run with 5% B for 0.50 min; 5% to 60% B in 8.4 min, 60% to 98% B in 1.00 min; 98% B in 0.40 min.

[0874] Method C-1:

[0875] Column: Acquity UPLC BEH C18, 2.1 x 30 mm column, 1.7 μm

[0876] Column temperature: 50℃

[0877] Eluent: A: water + 0.1% FA

[0878] B: ACN + 0.1% FA

[0879] Flow rate: 1.0mL / min

[0880] Gradient: 2% B until 0.1 min; 2% to 98% B until 1.5 min, 98% B until 1.8 min.

[0881] Method C-2:

[0882] Column: Acquity UPLC BEH C18, 2.1 x 30 mm column, 1.7 μm

[0883] Column temperature: 50℃

[0884] Eluent: A: 5 mM NH4OH in water

[0885] B: 5 mM NH4OH in ACN

[0886] Flow rate: 1.0mL / min

[0887] Gradient: 2% B until 0.1 min; 2% to 98% B until 1.5 min, 98% B until 1.8 min.

[0888] Method C-3:

[0889] Column: Acquity UPLC BEH C18, 2.1 x 30 mm column, 1.7 μm

[0890] Column temperature: 50℃

[0891] Eluent: A: 0.1% FA in water

[0892] B: 0.1% FA in ACN

[0893] Flow rate: 1.0mL / min

[0894] Gradient: 2% to 98% B until 4.40 min, 98% B until 5.15 min.

[0895] Method C-4:

[0896] Column: Acquity UPLC BEH C18, 2.1 x 30 mm column, 1.7 μm

[0897] Column temperature: 50℃

[0898] Eluent: A: 5 mM NH4OH in water

[0899] B: 5 mM NH4OH in ACN

[0900] Flow rate: 1.0mL / min

[0901] Gradient: 2% to 98% B until 4.40 min, 98% B until 5.15 min.

[0902] Chiral HPLC Method

[0903] Method SFC-1:

[0904] Preparative Chiral HPLC

[0905] Instrument: Sepiatec prep SFC-100

[0906] Column: Chiralpak AD, 250mm x 30mm 5μm

[0907] Eluent: A: 15% 0.05% NH3 in IPA, B: 85% scCO2 (isocratic) Flow rate: 110.0 mL / min

[0908] Detection: UV 230nm

[0909] Injection volume: 3x 1.30mL

[0910] Column box temperature: 40°C

[0911] Pressure: 120 bar

[0912] Analytical Chiral HPLC

[0913] Instrument: Analytical SFC-MS Waters UPC2

[0914] Injection: 5μL

[0915] Mobile phase: A: 12% 0.05% NH3 in IPA, B: 88% scCO2 (isocratic) Flow rate: 3 mL / min

[0916] Column: Chiralpak AD (4.6mm x 100mm 5μm)

[0917] Detect UV: DAD

[0918] Column box temperature: 40°C

[0919] Pressure: 1800psi

[0920] Method SFC-2:

[0921] Preparative Chiral HPLC

[0922] Instrument: Sepiatec prep SFC-100

[0923] Column: Chiralpak IH, 250 x 30 mm 5 μm

[0924] Eluent: A: 11% 0.05% NH3 in IPA, B: 89% scCO2 (isocratic)

[0925] Flow rate: 90.0mL / min

[0926] Detection: UV 239nm

[0927] Injection volume: 55 x 1.00 mL

[0928] Column box temperature: 40°C

[0929] Pressure: 130 bar

[0930] Analytical Chiral HPLC

[0931] Instrument: Analytical SFC-MS Waters UPC2

[0932] Injection: 5μL

[0933] Mobile phase: A: 10% 0.05% NH3 in IPA, B: 90% scCO2 (isocratic)

[0934] Flow rate: 3mL / min

[0935] Column: Chiralpak IH (4.6mm x 100mm 5μm)

[0936] Detect UV: DAD

[0937] Column box temperature: 40°C

[0938] Pressure: 1800psi

[0939] Method SFC-3:

[0940] Preparative Chiral HPLC

[0941] Instrument: Sepiatec prep SFC-250

[0942] Column: Chiralpak IG, 250 x 30 mm 5 μm

[0943] Eluent: A: 55% 0.05% NH3 in MeOH / IPA 50 / 50, B: 45% scCO2 (isocratic)

[0944] Flow rate: 80mL / min

[0945] Detection: UV 240nm

[0946] Injection volume: 38 x 2.0 mL

[0947] Column box temperature: 40°C

[0948] Pressure: 120 bar

[0949] Analytical Chiral HPLC

[0950] Instrument: Analytical SFC-MS Waters UPC2

[0951] Injection: 5μL

[0952] Mobile phase: A: 50% 0.05% NH3 in MeOH / IPA 50 / 50, B: 50% scCO2 (isocratic)

[0953] Flow rate: 3.0mL / min

[0954] Column: Chiralpak IG (4.6 x 100 mm 5 μm)

[0955] Detect UV: DAD

[0956] Column box temperature: 40°C

[0957] Pressure: 1800psi

[0958] Method SFC-4:

[0959] Preparative Chiral HPLC

[0960] Instrument: Waters THAR80 systems

[0961] Column: Chiralpak IG, 21 x 250 mm 5 μm

[0962] Eluent: A: 45% MeOH w / 10mM NH3, B: 55% scCO2 (isocratic)

[0963] Flow rate: 80g / min

[0964] Detection: UV 270nm

[0965] Injection volume: 4x 3.0mL

[0966] Column oven temperature: RT

[0967] Pressure: 125 bar

[0968] Analytical Chiral HPLC

[0969] Instrument: Analytical SFC-MS Waters UPC2

[0970] Injection: 3μL

[0971] Mobile phase: A: CO2, B: 5% to 55% MeOH containing 0.1% NH3

[0972] Flow rate: 2.5mL / min

[0973] Column: Chiralpak IG-3 (3x 100mm 3μm)

[0974] Detect UV: DAD

[0975] Column box temperature: 40°C

[0976] Pressure: 1800psi

[0977] Method SFC-5:

[0978] Preparative Chiral SFC

[0979] Instrument: Sepiatec SFC 100

[0980] Column: 2x Chiralcel oz, single row, 250x 30mm 5μm

[0981] Eluent: A: 22% 0.05% NH3 in MeOH, B: 78% scCO2 (isocratic)

[0982] Flow rate: 105mL / min

[0983] Detection: UV 235nm

[0984] Injection volume: 3.5mL

[0985] Column box temperature: 40°C

[0986] Pressure: 100 bar

[0987] Analytical Chiral SFC

[0988] Instrument: Analytical SFC-MS Waters UPC2

[0989] Injection: 5μL

[0990] Mobile phase: A: 12% 0.05% NH3 in MeOH, B: 88% scCO2 (isocratic)

[0991] Flow rate: 3mL / min

[0992] Column: Chiralcel Oz (4.6 x 100 mm 5 μm)

[0993] UV detection: DAD 235nm

[0994] Column box temperature: 40°C

[0995] Pressure: 1800psi

[0996] Method SFC-6:

[0997] Preparative Chiral SFC

[0998] Instrument: Sepiatec SFC 100

[0999] Column: Chiralpak IG, 250 x 50 mm 5 μm

[1000] Eluent: A: 55% 0.05% NH3 in IPA, B: 45% scCO2 (isocratic)

[1001] Flow rate: 120mL / min

[1002] Detection: UV 235nm

[1003] Injection volume: 1.2mL

[1004] Column box temperature: 40°C

[1005] Pressure: 120 bar

[1006] Analytical Chiral SFC

[1007] Instrument: Analytical SFC-MS Waters UPC2

[1008] Injection: 5μL

[1009] Mobile phase: A: 40% 0.05% NH3 in IPA, B: 60% scCO2 (isocratic) Flow rate: 3 mL / min

[1010] Column: Chiralpak AD (4.6 x 100 mm 5 μm)

[1011] UV detection: DAD 235nm

[1012] Column box temperature: 40°C

[1013] Pressure: 1800psi

[1014] Method SFC-7:

[1015] Preparative Chiral SFC

[1016] Instrument: Sepiatec SFC 100

[1017] Column: Chiralpak AD-H, 250 x 30 mm 5 μm

[1018] Eluent: A: 42% 0.05% NH3 in IPA, B: 58% scCO2 (isocratic) Flow rate: 80 mL / min

[1019] Detection: UV 220nm

[1020] Injection volume: 3.5mL

[1021] Column box temperature: 40°C

[1022] Pressure: 120 bar

[1023] Analytical Chiral SFC

[1024] Instrument: Analytical SFC-MS Waters UPC2

[1025] Injection: 5μL

[1026] Mobile phase: A: 40% 0.05% NH3 in IPA, B: 60% scCO2 (isocratic) Flow rate: 3 mL / min

[1027] Column: Chiralpak AD (4.6 x 100 mm 5 μm)

[1028] UV detection: DAD 220nm

[1029] Column box temperature: 40°C

[1030] Pressure: 1800psi

[1031] Method SFC-8:

[1032] Preparative Chiral HPLC

[1033] Instrument: Sepiatec prep SFC-100

[1034] Column: Chiralpak AD, 250 x 30 mm 5 μm

[1035] Eluent: A: 20% 0.05% NH3 in IPA, B: 80% scCO2 (isocratic)

[1036] Flow rate: 80mL / min

[1037] Detection: UV 235nm

[1038] Injection volume: 23 x 1.10 mL

[1039] Column box temperature: 40°C

[1040] Pressure: 120 bar

[1041] Analytical Chiral HPLC

[1042] Instrument: Analytical SFC-MS Waters UPC2

[1043] Injection: 5μL

[1044] Mobile phase: A: 20% 0.05% NH3 in IPA, B: 80% scCO2 (isocratic)

[1045] Flow rate: 3mL / min

[1046] Column: Chiralpak AD (4.6 x 100 mm 5 μm)

[1047] Detect UV: DAD

[1048] Column box temperature: 40°C

[1049] Pressure: 1800psi

[1050] Method SFC-9:

[1051] Preparative Chiral HPLC

[1052] Instrument: Sepiatec prep SFC-100

[1053] Column: Chiralpak IC, 250 x 30 mm 5 μm

[1054] Eluent: A: 15% 0.05% NH3 in MeOH, B: 85% scCO2 (isocratic)

[1055] Flow rate: 80mL / min

[1056] Detection: UV 240nm

[1057] Injection volume: 28 x 0.80 mL

[1058] Column box temperature: 40°C

[1059] Pressure: 130 bar

[1060] Analytical Chiral HPLC

[1061] Instrument: Analytical SFC-MS Waters UPC2

[1062] Injection: 5μL

[1063] Mobile phase: A: 10% 0.05% NH3 in MeOH, B: 90% scCO2 (isocratic)

[1064] Flow rate: 3mL / min

[1065] Column: Chiralpak IK (4.6mm x 100mm 5μm)

[1066] Detect UV: DAD

[1067] Column box temperature: 40°C

[1068] Pressure: 1800psi

[1069] Method C-10:

[1070] Preparative Chiral HPLC

[1071] Instrument: Agilent 1260Infinity

[1072] Column: Chiralpak IG, 250 x 21 mm, 5 μm

[1073] Eluent: A: 40% n-hexane, B: 60% EtOH / MeOH=1 / 1 (isocratic)

[1074] Flow rate: 15.0mL / min

[1075] Detection: 210nm

[1076] Box / column temperature: 23°C

[1077] Pressure: 80 bar

[1078] Analytical Chiral HPLC

[1079] Instrument: Agilent, 1260infinity II

[1080] Injection: 10μL

[1081] Mobile phase: A: 50% n-hexane, B: 50% 0.1% DEA in EtOH / / MeOH = 70 / 30 (isocratic)

[1082] Flow rate: 1mL / min

[1083] Column: Chiralpak IG (4.6 x 150 mm 5 μm)

[1084] Detect UV: DAD

[1085] Box / column temperature: 25°C

[1086] Pressure: 400 bar

[1087] Method SFC-11:

[1088] Preparative Chiral HPLC

[1089] Instrument: Waters SFC-100 (with ABsys GmbH upgraded version)

[1090] Column: Chiralpak IG, 250 x 30 mm 5 μm

[1091] Eluent: A: 35%-45% 0.05% NH3 in MeOH, B: 65%-55% scCO2

[1092] Flow rate: 110.0mL / min

[1093] Detection: DAD

[1094] Injection volume: 3x 1.30mL

[1095] Column box temperature: 50°C

[1096] Pressure: 120 bar

[1097] Analytical Chiral HPLC

[1098] Instrument: Analytical SFC-MS Waters UPC2

[1099] Injection: 5μL

[1100] Mobile phase: A: 38% 0.05% NH3 in MeOH, B: 62% scCO2 (isocratic)

[1101] Flow rate: 3mL / min

[1102] Column: Chiralpak IG (4.6 x 100 mm 5 μm)

[1103] Detect UV: DAD

[1104] Column box temperature: 40°C

[1105] Pressure: 1800psi

[1106] Method SFC-12:

[1107] Preparative Chiral HPLC

[1108] Instrument: Sepiatec prep SFC-100

[1109] Column: Chiralpak IC, 250 x 21 mm 5 μm

[1110] Eluent: A: 40% 10 mM NH3 in 4:1 MeOH / ACN, B: 60% scCO2 (isocratic)

[1111] Flow rate: 80g / min

[1112] Detection: UV 272nm

[1113] Injection volume: 13 x 2 mL

[1114] Column box temperature: 40°C

[1115] Pressure: 100 bar

[1116] Analytical Chiral HPLC

[1117] Instrument: Analytical SFC-MS Waters UPC2

[1118] Injection: 5μL

[1119] Mobile phase: A: 0.1% TEA in 4:1 MeOH / ACN, B: 0.1% TEA in scCO2; 5%-55% A to B gradient in 5 min

[1120] Flow rate: 2.5mL / min

[1121] Column: Chiralpak IC (3x 100mm 3μm)

[1122] Detect UV: DAD

[1123] Column box temperature: 40°C

[1124] Pressure: 1800psi

[1125] Method SFC-13:

[1126] Preparative Chiral HPLC

[1127] Instrument: Sepiatec prep SFC-100

[1128] Column: Chiralpak IE, 250 x 21 mm 5 μm

[1129] Eluent: A: 45% 10 mM NH3 in MeOH, B: 55% scCO2 (isocratic)

[1130] Flow rate: 80g / min

[1131] Detection: UV 248nm

[1132] Injection volume: 5 x 1 mL

[1133] Column box temperature: 40°C

[1134] Pressure: 125 bar

[1135] Analytical Chiral HPLC

[1136] Instrument: Analytical SFC-MS Waters UPC2

[1137] Injection: 5μL

[1138] Mobile phase: A: 0.1% NH3 in MeOH, B: scCO2; gradient 5%-55% A to B in 5 min

[1139] Flow rate: 2.5mL / min

[1140] Column: Chiralpak IE (3x 100mm 3μm)

[1141] Detect UV: DAD

[1142] Column box temperature: 40°C

[1143] Pressure: 1800psi

[1144] Biological data

[1145] Complement factor B inhibition assay

[1146] Biological Example 1: Human complement factor B ELISA assay

[1147] CVF-Bb complex was prepared from purified cobra venom factor (1 μM), recombinant human complement factor B (expressed in Drosophila cells and purified using standard methods) and human complement factor D (expressed in E. coli, refolded and purified using standard methods). CVF-Bb complex at 3 nM concentration was incubated with different concentrations of test compounds at RT in PBS pH 7.4 containing 10 mM MgCl2 and 0.05% (w / v) CHAPS for 1 h. Human complement C3 substrate purified from plasma was added to a final concentration of 1 μM. After incubation at RT for 1 h, the enzyme reaction was terminated by adding a concentrated pan-protease inhibitor cocktail. The reaction product C3a was quantified by enzyme-linked immunosorbent assay. IC 50 Values ​​were calculated from the percentage inhibition of CVF-Bb activity as a function of the test compound concentration.

[1148] Biological Example 2: Human Complement Factor B TR-FRET Assay

[1149] Recombinant human factor B (expressed in Drosophila cells and purified using standard methods) labeled with biotin (10 nM), europium-labeled streptavidin (5 nM), and (+) or (-)-2-((1E,3E,5E)-5-(1-(6-((2-(3-(4-((R)-3-amino-3-phenylpropanoyl)-1-(4-amino-6,7-dimethoxyquinazolin-2-yl)piperazin-2-yl)phenoxy)ethyl =Then, 1-(4-(2-(4-(2-(4-(2-(4-(2-(4-(2-(4-(2-(4-(2-(4-(2-(4-(2-(4-(2-(4-(2-(4-(2-(4-(2-(4-(2-(4-(2-(4-(2-(4-(2-(4-(2-(4-(2-(4-(2-(4-(2-(4-(2-(4-(2-(4-(2-(4-(2-(4-(2-(4-(2-(4-(2-(4-(2-(4-(2-(4-(2-(4-(2-(4-(2-(4-(2-(4-(2-(4-(2-(4-(2-(4-(2-(4-(2-(4-(2-(4-(2-(4-(2-(4-(2-(4-(2-(4-(2-

[1150] The time-gated decrease in fluorescence intensity associated with competition between labeled and unlabeled Factor B ligand was recorded at both 620 nm and 665 nm 70 μs after excitation at 337 nm using a microplate spectrofluorometer. 50Values ​​were calculated from the percent inhibition of complement factor B-(+) or (-)-2-((1E,3E,5E)-5-(1-(6-((2-(3-(4-((R)-3-amino-3-phenylpropanoyl)-1-(4-amino-6,7-dimethoxyquinazolin-2-yl)piperazin-2-yl)phenoxy)ethyl)amino)-6-oxohexyl)-3,3-dimethyl-5-sulfoindol-2-ylidene)penta-1,3-dien-1-yl)-1-ethyl-3,3-dimethyl-5-sulfo-3H-indol-1-ium (240 nM activity against factor B when tested using the assay of Biological Example 1) displacement as a function of test compound concentration.

[1151] The compounds of the present disclosure have an inhibitory effect on Factor B. The data in Table 1 were collected using the assay of Biological Example 2.

[1152] Table 1:

[1153]

[1154]

[1155]

[1156]

[1157] The compounds disclosed herein are expressed as micromolar IC 50 The value inhibits complement factor B activity. Therefore, the compounds of the present disclosure can be used to treat the diseases and / or disorders described herein, such as diseases / disorders mediated by complement factor B.

[1158] All publications and patent documents cited herein are incorporated herein by reference, as if each such publication or document is explicitly and individually indicated to be incorporated herein by reference. The present disclosure and its embodiments have been described in detail. However, the scope of the present disclosure is not intended to be limited to any specific embodiment of the process, manufactured product, material composition, compound, means, method and / or step described in this specification. Various modifications, substitutions and changes can be made to the disclosed materials without departing from the spirit and / or essential features of the present disclosure. Therefore, it will be easily understood by a person of ordinary skill in the art from the present disclosure that subsequent modifications, substitutions and / or changes that perform substantially the same functions or achieve substantially the same results as the embodiments described herein can be utilized according to such relevant embodiments of the present disclosure. Therefore, the following claims are intended to cover within their scope modifications, substitutions and changes to the methods, manufactured products, material compositions, compounds, means, methods and / or steps disclosed herein. Unless otherwise specified, the claims should not be understood to be limited to the described order or elements. It should be understood that various changes can be made in form and detail without departing from the scope of the appended claims.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof, in: m is 0, 1, 2 or 3; N is 0, 1, 2 or 3, provided that m and n are not both 0; R is hydrogen, halogen, C1-C4 alkyl, halogenated C1-C4 alkyl, or hydroxy C1-C4 alkyl; R 1 is hydrogen, halogen, hydroxy, C1-C6 alkyl, C2-C6 alkenyl, C3-C6 cycloalkyl, C1-C6 alkoxy, halo-C1-C6 alkyl, halo-C3-C6 cycloalkyl, halo-C1-C6 alkoxy, hydroxy-C1-C6 alkyl, hydroxy-C3-C6 cycloalkylamino-C1-C6 alkyl, C1-C6 alkoxy-C1-C6 alkyl, C1-C6 alkoxy-C1-C6 alkoxy, C3-C6 cycloalkyl-C1-C6 alkoxy, halo-C1-C6 alkoxy, -S-C1-C6 alkyl, -S(O)C1-C6 alkyl, -S(O)2C1-C6 alkyl, CH2NHC(O)C1-C4 alkyl, or -OCH2C(O)R 1a ; R 1a is hydroxy, C1-C6 alkoxy, amino or mono- and di-C1-C6 alkylamino; R 2 is C1-C3 alkyl, C3 cycloalkyl, C1-C3 alkoxy, hydroxyC1-C6 alkyl, or halogen, wherein the C1-C3 alkyl, C3 cycloalkyl, or C1-C3 alkyl is unsubstituted or substituted with 1, 2, or 3 halogen substituents; p is 0, 1, 2, or 3; R 3 is hydrogen, halogen or cyano; R 4 is phenyl, naphthyl or heteroaryl, wherein the heteroaryl is a 5- to 10-membered heteroaryl having 1, 2 or 3 ring heteroatoms independently selected from N, O or S, and wherein the phenyl or heteroaryl is unsubstituted or replaced by 1 R 5 substituted by 0, 1 or 2 R 5’ Replace; R 5 Selected from -CO2R 5b 、-CON(R 5c )2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl, -CH2CO2R 5b 、-CH2CON(R 5c )2, -C(O)NHSO2C1-C4 alkyl, -SO2NHC(O)C1-C4 alkyl, -SO2N(H) m (C1-C4 alkyl) 2-m , -SO2C1-C4 alkyl, cyano, hydroxyl, halogen, 5- to 6-membered heteroaryl having 1 to 4 heteroatoms independently selected from N, O and S, and 4- to 6-membered heteroaryl having 1 to 4 heteroatoms independently selected from N, O and S(O) q wherein the 5- to 6-membered heteroaryl and the 4- to 6-membered heterocyclic group are unsubstituted or replaced by 1, 2 or 3 R 5a replace; Each R 5a Independently selected from fluorine, hydroxyl and C1-C6 alkyl which is unsubstituted or substituted with -COOH or 1, 2 or 3 fluorines; Among them, when R 5 When it is a 4- to 6-membered heterocyclic group, the two R 5a Fluorine and hydroxyl are not substituted at the same position; Each R 5b Independently selected from hydrogen or C1-C5 alkyl; Each R 5c independently selected from hydrogen, C1-C4 alkyl which is unsubstituted or substituted by halogen, hydroxyl or C1-C4 alkyl; Each R 5’ independently selected from the group consisting of halogenated C1-C4 alkyl, C1-C4 alkoxy, halogenated C1-C4 alkoxy, halogen, cyanomethyl, hydroxy C1-C6 alkyl, and C3-C5 cycloalkyl; W is O, C (R 6 )2 or NR 7 ; R 6 Each occurrence is independently selected from the group consisting of hydrogen, halogen, hydroxy, amino, mono- and di-C1-C4 alkylamino, C1-C6 alkyl, halo-C1-C6 alkyl, hydroxy C1-C6 alkyl, cyano C1-C6 alkyl, C1-C6 alkoxy, or halo-C1-C6 alkoxy; or two R 6 Combined with the carbon atoms to which they are attached, they form a spirocyclic carbocycle having 3 to 6 ring atoms, wherein the spirocyclic carbocycle is unsubstituted or substituted with 1 or 2 substituents selected from halogen, C1-C6 alkyl, or C1-C6 alkoxy; or two R 6 Combined with the carbon atoms to which they are attached, they form a group having independently selected from N, O or S(O) q 1 or 2 ring heteroatoms of spirocyclic heterocycle, wherein the spirocyclic heterocycle is unsubstituted or substituted with 1 or 2 halogen substituents, C1-C6 alkyl, halo-C1-C6 alkyl, C3-C6 cycloalkyl, halo-C3-C6 cycloalkyl; q is 0, 1, or 2; R 7 is hydrogen, C1-C6 alkyl, halogenated C1-C6 alkyl, hydroxy C2-C6 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl C1-C3 alkyl, halogenated C3-C6 cycloalkyl, C1-C6 alkoxy C1-C6 alkyl, halogenated C1-C6 alkoxy C1-C6 alkyl, aryl, 4- to 6-membered alkyl radicals independently selected from N, O and S(O) q or a 5- to 6-membered heteroaryl group having 1-4 heteroatoms independently selected from N, O and S, wherein the C1-C6 alkyl group is unsubstituted or replaced by a 4- to 6-membered heteroaryl group having 1-2 heteroatoms independently selected from N, O and S(O) q wherein the 4- to 6-membered heterocyclic group is unsubstituted or substituted with 1, 2 or 3 halogens, and further wherein the aryl or heteroaryl is unsubstituted or substituted with halo, C1-C6 alkyl, halo-C1-C6 alkyl, C3-C5 cycloalkyl, halo-C3-C5 cycloalkyl; Each R 8 are independently hydrogen, halogen, C1-C4 alkyl, halogenated C1-C4 alkyl, or two R 8 Together with the carbon atom to which they are attached, they form a C3-C5 cycloalkyl group or a halogenated C3-C5 cycloalkyl group.

2. The compound of claim 1 having formula (I) or a pharmaceutically acceptable salt thereof, having formula (IA) in, A is selected from the group consisting of phenyl, furanyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, pyrazolyl, imidazolyl, pyridinyl, triazolyl, tetrazolyl, oxadiazolyl, isoxadiazolyl, pyrimidinyl, pyrazinyl and pyridazinyl.

3. The compound of claim 1 having formula (I) or a pharmaceutically acceptable salt thereof, having formula (IB) in, A is selected from the group consisting of phenyl, furanyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, pyrazolyl, imidazolyl, pyridinyl, triazolyl, tetrazolyl, oxadiazolyl, isoxadiazolyl, pyrimidinyl, pyrazinyl and pyridazinyl.

4. The compound (IA) or (IB) according to claim 2 or 3, or a pharmaceutically acceptable salt thereof, wherein A is selected from:

5. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein W is C(R 6 )2 or NR 7 .

6. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein W is C(R 6 )2.

7. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein W is NR 7 .

8. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R 7 It is C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl or halogenated C3-C6 cycloalkyl.

9. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein A is a benzene ring.

10. The compound according to claim 9 or a pharmaceutically acceptable salt thereof, wherein R 5 The benzene ring is substituted at the para position.

11. The compound of claim 9 or 10 having formula (I) or a pharmaceutically acceptable salt thereof, having formula (IC):

12. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, having formula (ID):

13. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from hydrogen, halogen, C1-C6 alkyl, C3-C6 cycloalkyl and C1-C6 alkoxy.

14. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R 2 Selected from halogen, methyl, ethyl and cyclopropyl.

15. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R 2 Selected from methyl, ethyl and cyclopropyl.

16. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R 2 It's methyl.

17. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R is hydrogen, halogen or C1-C4 alkyl.

18. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R 3 It is hydrogen or chlorine.

19. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R 3 It's hydrogen.

20. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R 5 independently selected from hydrogen, -CO2R 5b 、-CON(R 5c )2, C1-C6 alkyl, -CH2CO2R 5b 、-CH2CON(R 5c )2, -C(O)NHSO2C1-C4 alkyl, -SO2NHC(O)C1-C4 alkyl, -SO2N(H) m (C1-C4 alkyl) 2-m , -SO2C1-C4 alkyl, cyano, halogen, hydroxyC1-C6 alkyl, C3-C5 cycloalkyl, 5- to 6-membered heteroaryl having 1-4 heteroatoms independently selected from N, O and S, and 4- to 6-membered heterocyclyl having 1-2 heteroatoms independently selected from N, O and S, wherein the 5- to 6-membered heteroaryl and the 4- to 6-membered heterocyclyl are unsubstituted or replaced by 1 or 2 R 5a replace.

21. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R 5 is selected from -CO2H, hydroxy C1-C6 alkyl, 5- to 6-membered heteroaryl having 1-4 heteroatoms independently selected from N, O and S, and 4- to 6-membered heterocyclyl having 1 O heteroatom, wherein the 4- to 6-membered heterocyclyl is replaced by 0-1 R 5a replace.

22. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R 5 is selected from CO2H, hydroxy C1-C6 alkyl, 5-membered heteroaryl having 2 N heteroatoms, and 4- to 6-membered heterocyclic group having 1 O heteroatom, wherein the 4- to 6-membered heterocyclic group is unsubstituted or substituted with 1 R 5a Substitution, where R 5a It's a hydroxyl group.

23. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R 5 It is –CO2H.

24. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R 5 It is a tetrazolyl group.

25. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R 4 1 or 2 R independently selected from the group consisting of halogenated C1-C4 alkyl and halogen 5’ replace.

26. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R 6 Each occurrence is independently selected from the group consisting of hydrogen, halogen, halogenated C1-C6 alkoxy, C1-C6 alkoxy, or two R 6 Combined with the carbon atoms to which they are attached they form a spirocyclic carbocycle having 3 to 6 ring atoms, wherein the spirocyclic carbocycle is unsubstituted or substituted with 1 or 2 substituents selected from halogen or C1-C6 alkoxy.

27. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, with the proviso that m and n are not 3 at the same time.

28. The compound of claim 1 having formula (I) or a pharmaceutically acceptable salt thereof, selected from: 4-((3R,4R)-4-((5,7-dimethyl-1H-indol-4-yl)methyl)-1-(2,2,2-trifluoroethyl)piperidin-3-yl)benzoic acid; 4-(4-((5,7-dimethyl-1H-indol-4-yl)methyl)-1-(2,2,2-trifluoroethyl)piperidin-3-yl)benzoic acid; 4-((3R,4R)-4-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-1-(2,2,2-trifluoroethyl)piperidin-3-yl)benzoic acid; 4-(4-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-1-(2,2,2-trifluoroethyl)piperidin-3-yl)benzoic acid; 4-((3R,4R)-4-((5,7-dimethyl-1H-indol-4-yl)methyl)-1-methylpiperidin-3-yl)benzoic acid; 4-(4-((5,7-dimethyl-1H-indol-4-yl)methyl)-1-methylpiperidin-3-yl)benzoic acid; 4-((3R,4R)-4-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-1-methylpiperidin-3-yl)benzoic acid; 4-(4-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-1-methylpiperidin-3-yl)benzoic acid; 4-((3R,4R)-1-(2,2-difluoroethyl)-4-((5,7-dimethyl-1H-indol-4-yl)methyl)piperidin-3-yl)benzoic acid; 4-(1-(2,2-difluoroethyl)-4-((5,7-dimethyl-1H-indol-4-yl)methyl)piperidin-3-yl)benzoic acid; 4-((3R,4R)-4-((5-cyclopropyl-7-methyl-1H-indol-4-yl)methyl)-1-(2,2,2-trifluoroethyl)piperidin-3-yl)benzoic acid; 4-(4-((5-cyclopropyl-7-methyl-1H-indol-4-yl)methyl)-1-(2,2,2-trifluoroethyl)piperidin-3-yl)benzoic acid; 4-((3R,4R)-4-((5,7-dimethyl-1H-indol-4-yl)methyl)-1-(2-fluoroethyl)piperidin-3-yl)benzoic acid; 4-(4-((5,7-dimethyl-1H-indol-4-yl)methyl)-1-(2-fluoroethyl)piperidin-3-yl)benzoic acid; 4-((3R,4R)-4-((5-cyclopropyl-7-methyl-1H-indol-4-yl)methyl)-1-methylpiperidin-3-yl)benzoic acid; 4-(4-((5-cyclopropyl-7-methyl-1H-indol-4-yl)methyl)-1-methylpiperidin-3-yl)benzoic acid; 4-((3R,4R)-4-((5,7-dimethyl-1H-indol-4-yl)methyl)-1-isobutylpiperidin-3-yl)benzoic acid; 4-(4-((5,7-dimethyl-1H-indol-4-yl)methyl)-1-isobutylpiperidin-3-yl)benzoic acid; 4-((3R,4R)-1-(cyclopropylmethyl)-4-((5,7-dimethyl-1H-indol-4-yl)methyl)piperidin-3-yl)benzoic acid; 4-(1-(Cyclopropylmethyl)-4-((5,7-dimethyl-1H-indol-4-yl)methyl)piperidin-3-yl)benzoic acid; 4-((3R,4R)-4-((5,7-dimethyl-1H-indol-4-yl)methyl)-1-(2-methoxyethyl)piperidin-3-yl)benzoic acid; 4-(4-((5,7-dimethyl-1H-indol-4-yl)methyl)-1-(2-methoxyethyl)piperidin-3-yl)benzoic acid; 4-(((3R,4R)-3-(4-(1H-tetrazol-5-yl)phenyl)-1-(2,2,2-trifluoroethyl)piperidin-4-yl)methyl)-5,7-dimethyl-1H-indole; 4-((3-(4-(1H-tetrazol-5-yl)phenyl)-1-(2,2,2-trifluoroethyl)piperidin-4-yl)methyl)-5,7-dimethyl-1H-indole; 4-((1R,2S)-2-((5,7-dimethyl-1H-indol-4-yl)methyl)-5,5-difluorocyclohexyl)benzoic acid; 4-(2-((5,7-dimethyl-1H-indol-4-yl)methyl)-5,5-difluorocyclohexyl)benzoic acid; 4-((6R,7S)-7-((5,7-dimethyl-1H-indol-4-yl)methyl)spiro[3.5]nonan-6-yl)benzoic acid; 4-(7-((5,7-dimethyl-1H-indol-4-yl)methyl)spiro[3.5]nonan-6-yl)benzoic acid; 4-((6R,7S)-7-((5,7-dimethyl-1H-indol-4-yl)methyl)-2,2-difluorospiro[3.5]nonan-6-yl)benzoic acid; 4-(7-((5,7-dimethyl-1H-indol-4-yl)methyl)-2,2-difluorospiro[3.5]nonan-6-yl)benzoic acid; 4-((1R,2S,5S)-2-((5,7-dimethyl-1H-indol-4-yl)methyl)-5-ethoxycyclohexyl)benzoic acid; 4-(2-((5,7-dimethyl-1H-indol-4-yl)methyl)-5-ethoxycyclohexyl)benzoic acid; 4-((1R,2S,5S)-5-(2,2-difluoroethoxy)-2-((5,7-dimethyl-1H-indol-4-yl)methyl)cyclohexyl)benzoic acid; 4-(5-(2,2-difluoroethoxy)-2-((5,7-dimethyl-1H-indol-4-yl)methyl)cyclohexyl)benzoic acid; 4-((1R,2S,5S)-5-(cyclopropylmethoxy)-2-((5,7-dimethyl-1H-indol-4-yl)methyl)cyclohexyl)benzoic acid; 4-(5-(Cyclopropylmethoxy)-2-((5,7-dimethyl-1H-indol-4-yl)methyl)cyclohexyl)benzoic acid; 4-((3R,4S)-4-((5,7-dimethyl-1H-indol-4-yl)methyl)-1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)benzoic acid; 4-(4-((5,7-dimethyl-1H-indol-4-yl)methyl)-1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)benzoic acid; 4-((3R,4S)-4-((5,7-dimethyl-1H-indol-4-yl)methyl)-1-(2,2,2-trifluoroethyl)azepan-3-yl)benzoic acid; 4-(4-((5,7-dimethyl-1H-indol-4-yl)methyl)-1-(2,2,2-trifluoroethyl)azepan-3-yl)benzoic acid; 2-(4-((3R,4R)-4-((5,7-dimethyl-1H-indol-4-yl)methyl)-1-(2,2,2-trifluoroethyl)piperidin-3-yl)-1H-pyrazol-1-yl)acetic acid; 2-(4-(4-((5,7-dimethyl-1H-indol-4-yl)methyl)-1-(2,2,2-trifluoroethyl)piperidin-3-yl)-1H-pyrazol-1-yl)acetic acid; 4-(((3R,4R)-3-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)-1-(2,2,2-trifluoroethyl)piperidin-4-yl)methyl)-5,7-dimethyl-1H-indole; 4-((3-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)-1-(2,2,2-trifluoroethyl)piperidin-4-yl)methyl)-5,7-dimethyl-1H-indole; 4-((3R,4R)-4-((5,7-dimethyl-1H-indol-4-yl)methyl)piperidin-3-yl)benzoic acid; 4-(4-((5,7-dimethyl-1H-indol-4-yl)methyl)piperidin-3-yl)benzoic acid; 4-((3R,4R)-4-((5,7-dimethyl-1H-indol-4-yl)methyl)-1-ethylpiperidin-3-yl)benzoic acid; 4-(-((5,7-dimethyl-1H-indol-4-yl)methyl)-1-ethylpiperidin-3-yl)benzoic acid; 4-((3R,4R)-4-((5,7-dimethyl-1H-indol-4-yl)methyl)-1-isopropylpiperidin-3-yl)benzoic acid; 4-(4-((5,7-dimethyl-1H-indol-4-yl)methyl)-1-isopropylpiperidin-3-yl)benzoic acid; 4-((3R,4R)-4-((5,7-dimethyl-1H-indol-4-yl)methyl)-1-(2-hydroxy-2-methylpropyl)piperidin-3-yl)benzoic acid; 4-(4-((5,7-dimethyl-1H-indol-4-yl)methyl)-1-(2-hydroxy-2-methylpropyl)piperidin-3-yl)benzoic acid; 4-((3R,4R)-4-((5,7-dimethyl-1H-indol-4-yl)methyl)-1-((3-fluorooxetan-3-yl)methyl)piperidin-3-yl)benzoic acid; 4-(4-((5,7-dimethyl-1H-indol-4-yl)methyl)-1-((3-fluorooxetan-3-yl)methyl)piperidin-3-yl)benzoic acid; 4-((3R,4R)-1-(3,3-difluorocyclobutyl)-4-((5,7-dimethyl-1H-indol-4-yl)methyl)piperidin-3-yl)benzoic acid; 4-(1-(3,3-difluorocyclobutyl)-4-((5,7-dimethyl-1H-indol-4-yl)methyl)piperidin-3-yl)benzoic acid; 4-((3R,4R)-4-((5,7-dimethyl-1H-indol-4-yl)methyl)-1-(2-(trifluoromethoxy)ethyl)piperidin-3-yl)benzoic acid; 4-(4-((5,7-dimethyl-1H-indol-4-yl)methyl)-1-(2-(trifluoromethoxy)ethyl)piperidin-3-yl)benzoic acid; 4-((3R,4R)-4-((5,7-dimethyl-1H-indol-4-yl)methyl)-1-propylpiperidin-3-yl)benzoic acid; 4-(4-((5,7-dimethyl-1H-indol-4-yl)methyl)-1-propylpiperidin-3-yl)benzoic acid; 4-((3R,4R)-4-((5,7-dimethyl-1H-indol-4-yl)methyl)-1-(oxetan-3-yl)piperidin-3-yl)benzoic acid; 4-(4-((5,7-dimethyl-1H-indol-4-yl)methyl)-1-(oxetan-3-yl)piperidin-3-yl)benzoic acid; 4-((3R,4R)-4-((5,7-dimethyl-1H-indol-4-yl)methyl)-1-((1r,3R)-3-fluorocyclobutyl)piperidin-3-yl)benzoic acid; 4-(4-((5,7-dimethyl-1H-indol-4-yl)methyl)-1-(3-fluorocyclobutyl)piperidin-3-yl)benzoic acid; 4-((3R,4R)-1-(3,3-difluoropropyl)-4-((5,7-dimethyl-1H-indol-4-yl)methyl)piperidin-3-yl)benzoic acid; 4-(1-(3,3-difluoropropyl)-4-((5,7-dimethyl-1H-indol-4-yl)methyl)piperidin-3-yl)benzoic acid; 4-((3R,4S)-4-((5,7-dimethyl-1H-indol-4-yl)methyl)-1-methylpyrrolidin-3-yl)benzoic acid; 4-(4-((5,7-dimethyl-1H-indol-4-yl)methyl)-1-methylpyrrolidin-3-yl)benzoic acid; 4-((3R,4R)-4-((5,7-dimethyl-1H-indol-4-yl)methyl)-1-methylpiperidin-3-yl)benzonitrile; 4-(4-((5,7-dimethyl-1H-indol-4-yl)methyl)-1-methylpiperidin-3-yl)benzonitrile; 4-((3R,4S)-4-((5,7-dimethyl-1H-indol-4-yl)methyl)-1-methylazepan-3-yl)benzoic acid; 4-(4-((5,7-dimethyl-1H-indol-4-yl)methyl)-1-methylazepan-3-yl)benzoic acid; 4-(4-((5,7-dimethyl-1H-indol-4-yl)methyl)-1-(2,2,2-trifluoroethyl)azepan-3-yl)benzoic acid; 4-((3R,4S)-4-((5,7-dimethyl-1H-indol-4-yl)methyl)-1-ethylazepan-3-yl)benzoic acid; 4-(4-((5,7-dimethyl-1H-indol-4-yl)methyl)-1-ethylazepan-3-yl)benzoic acid; 4-((4R,5R)-5-((5,7-dimethyl-1H-indol-4-yl)methyl)-1-methylazepan-4-yl)benzoic acid; 4-(5-((5,7-dimethyl-1H-indol-4-yl)methyl)-1-methylazepan-4-yl)benzoic acid; 4-((3R,4R)-4-((5-fluoro-7-methyl-1H-indol-4-yl)methyl)-1-methylpiperidin-3-yl)benzoic acid; 4-(4-((5-Fluoro-7-methyl-1H-indol-4-yl)methyl)-1-methylpiperidin-3-yl)benzoic acid; 4-((4R,5R)-1-(3,3-difluoropropyl)-5-((5,7-dimethyl-1H-indol-4-yl)methyl)azepan-4-yl)benzoic acid; 4-(1-(3,3-difluoropropyl)-5-((5,7-dimethyl-1H-indol-4-yl)methyl)azepan-4-yl)benzoic acid; 4-((3R,4R)-1-methyl-4-((7-methyl-1H-indol-4-yl)methyl)piperidin-3-yl)benzoic acid; 4-(1-methyl-4-((7-methyl-1H-indol-4-yl)methyl)piperidin-3-yl)benzoic acid; 4-((3R,4R)-4-((5-chloro-7-methyl-1H-indol-4-yl)methyl)-1-methylpiperidin-3-yl)benzoic acid; 4-(4-((5-chloro-7-methyl-1H-indol-4-yl)methyl)-1-methylpiperidin-3-yl)benzoic acid; 4-((3R,4R)-4-((5,7-dichloro-1H-indol-4-yl)methyl)-1-methylpiperidin-3-yl)benzoic acid; 4-(4-((5,7-dichloro-1H-indol-4-yl)methyl)-1-methylpiperidin-3-yl)benzoic acid; 4-((3R,4R)-4-((7-chloro-5-methyl-1H-indol-4-yl)methyl)-1-methylpiperidin-3-yl)benzoic acid; 4-(4-((7-chloro-5-methyl-1H-indol-4-yl)methyl)-1-methylpiperidin-3-yl)benzoic acid; 4-((3R,4R)-4-((3-chloro-5,7-dimethyl-1H-indol-4-yl)methyl)-1-methylpiperidin-3-yl)benzoic acid; 4-(4-((3-chloro-5,7-dimethyl-1H-indol-4-yl)methyl)-1-methylpiperidin-3-yl)benzoic acid; 4-((3R,4R)-1-(3,3-difluoropropyl)-4-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-3-yl)benzoic acid; 4-(1-(3,3-difluoropropyl)-4-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-3-yl)benzoic acid; 4-(((3R,4R)-3-(4-(1H-tetrazol-5-yl)phenyl)-1-methylpiperidin-4-yl)methyl)-5,7-dimethyl-1H-indole; 4-((3-(4-(1H-tetrazol-5-yl)phenyl)-1-methylpiperidin-4-yl)methyl)-5,7-dimethyl-1H-indole; 4-((3R,4R)-4-((5,7-dimethyl-1H-indol-4-yl)methyl)-1-(2,2,2-trifluoroethyl)piperidin-3-yl)benzonitrile; 4-(4-((5,7-dimethyl-1H-indol-4-yl)methyl)-1-(2,2,2-trifluoroethyl)piperidin-3-yl)benzonitrile; 4-(((3R,4R)-3-(4-(1H-pyrazol-1-yl)phenyl)-1-methylpiperidin-4-yl)methyl)-5,7-dimethyl-1H-indole; 4-((3-(4-(1H-pyrazol-1-yl)phenyl)-1-methylpiperidin-4-yl)methyl)-5,7-dimethyl-1H-indole; 4-(((3R,4R)-3-(4-(1H-pyrazol-1-yl)phenyl)-1-(2,2,2-trifluoroethyl)piperidin-4-yl)methyl)-5,7-dimethyl-1H-indole; 4-((3-(4-(1H-pyrazol-1-yl)phenyl)-1-(2,2,2-trifluoroethyl)piperidin-4-yl)methyl)-5,7-dimethyl-1H-indole; 4-(((3R,4R)-3-(4-(1H-pyrazol-1-yl)phenyl)-1-(3,3-difluoropropyl)piperidin-4-yl)methyl)-5,7-dimethyl-1H-indole; 4-((3-(4-(1H-pyrazol-1-yl)phenyl)-1-(3,3-difluoropropyl)piperidin-4-yl)methyl)-5,7-dimethyl-1H-indole; 4-(((3R,4R)-3-(4-(1H-pyrazol-1-yl)phenyl)-1-((3-fluorooxetan-3-yl)methyl)piperidin-4-yl)methyl)-5,7-dimethyl-1H-indole; 4-((3-(4-(1H-pyrazol-1-yl)phenyl)-1-((3-fluorooxetan-3-yl)methyl)piperidin-4-yl)methyl)-5,7-dimethyl-1H-indole; 4-(((3R,4R)-3-(4-(1H-pyrazol-1-yl)phenyl)-1-(oxetan-3-yl)piperidin-4-yl)methyl)-5,7-dimethyl-1H-indole; 4-((3-(4-(1H-pyrazol-1-yl)phenyl)-1-(oxetan-3-yl)piperidin-4-yl)methyl)-5,7-dimethyl-1H-indole; 4-(((3R,4R)-3-(4-(1H-pyrazol-1-yl)phenyl)-1-(1,3-difluoropropan-2-yl)piperidin-4-yl)methyl)-5,7-dimethyl-1H-indole; 4-((3-(4-(1H-pyrazol-1-yl)phenyl)-1-(1,3-difluoropropan-2-yl)piperidin-4-yl)methyl)-5,7-dimethyl-1H-indole; 5,7-Dimethyl-4-(((3R,4R)-1-methyl-3-(1-methyl-1H-pyrazol-4-yl)piperidin-4-yl)methyl)-1H-indole; 5,7-Dimethyl-4-((1-methyl-3-(1-methyl-1H-pyrazol-4-yl)piperidin-4-yl)methyl)-1H-indole; 5,7-Dimethyl-4-(((3R,4R)-3-(1-methyl-1H-pyrazol-4-yl)-1-(2,2,2-trifluoroethyl)piperidin-4-yl)methyl)-1H-indole; 5,7-Dimethyl-4-((3-(1-methyl-1H-pyrazol-4-yl)-1-(2,2,2-trifluoroethyl)piperidin-4-yl)methyl)-1H-indole; 4-(((3R,4R)-1-(2-fluoroethyl)-3-(1-methyl-1H-pyrazol-4-yl)piperidin-4-yl)methyl)-5,7-dimethyl-1H-indole; 4-((1-(2-fluoroethyl)-3-(1-methyl-1H-pyrazol-4-yl)piperidin-4-yl)methyl)-5,7-dimethyl-1H-indole; 4-(((3R,4R)-1-(2,2-difluoroethyl)-3-(1-methyl-1H-pyrazol-4-yl)piperidin-4-yl)methyl)-5,7-dimethyl-1H-indole; 4-((1-(2,2-difluoroethyl)-3-(1-methyl-1H-pyrazol-4-yl)piperidin-4-yl)methyl)-5,7-dimethyl-1H-indole; 4-(((3R,4R)-1-(3,3-difluoropropyl)-3-(1-methyl-1H-pyrazol-4-yl)piperidin-4-yl)methyl)-5,7-dimethyl-1H-indole; 4-((1-(3,3-difluoropropyl)-3-(1-methyl-1H-pyrazol-4-yl)piperidin-4-yl)methyl)-5,7-dimethyl-1H-indole; 4-(((3R,4R)-1-(1,3-difluoropropan-2-yl)-3-(1-methyl-1H-pyrazol-4-yl)piperidin-4-yl)methyl)-5,7-dimethyl-1H-indole; 4-((1-(1,3-difluoropropan-2-yl)-3-(1-methyl-1H-pyrazol-4-yl)piperidin-4-yl)methyl)-5,7-dimethyl-1H-indole; 4-((3R,4S)-4-((5,7-dimethyl-1H-indol-4-yl)methyl)-1-methylpyrrolidin-3-yl)benzamide; 4-(4-((5,7-dimethyl-1H-indol-4-yl)methyl)-1-methylpyrrolidin-3-yl)benzamide; 4-((3R,4S)-4-((5-cyclopropyl-7-methyl-1H-indol-4-yl)methyl)-1-methylpyrrolidin-3-yl)benzoic acid; 4-(4-((5-cyclopropyl-7-methyl-1H-indol-4-yl)methyl)-1-methylpyrrolidin-3-yl)benzoic acid; 4-(((3S,4R)-4-(4-(1H-tetrazol-5-yl)phenyl)-1-methylpyrrolidin-3-yl)methyl)-5,7-dimethyl-1H-indole; 4-((4-(4-(1H-tetrazol-5-yl)phenyl)-1-methylpyrrolidin-3-yl)methyl)-5,7-dimethyl-1H-indole; 4-(((3S,4R)-4-(4-(1H-tetrazolyl-5-yl)phenyl)-1-ethylpyrrolidin-3-yl)methyl)-5-cyclopropyl-7-methyl-1H-indole; and 4-((4-(4-(1H-tetrazol-5-yl)phenyl)-1-ethylpyrrolidin-3-yl)methyl)-5-cyclopropyl-7-methyl-1H-indole.

29. The compound of claim 1 having formula (I) or a pharmaceutically acceptable salt thereof, selected from:

30. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

31. A method of treating or preventing a disease or disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof.

32. A method of modulating complement alternative pathway activity in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof.

33. A method of treating a disease or disorder mediated by complement activation, particularly complement alternative pathway activation, in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof.

34. A method of treating a disease or disorder affected by modulation of the complement alternative pathway, the method comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof.

35. A method of treating a disease or disorder associated with dysregulation of the complement alternative pathway, the method comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof.

36. A method of inhibiting complement factor B expression or activity, the method comprising administering to a subject a compound according to any one of claims 1 to 29 or a pharmaceutically acceptable salt thereof.

37. The method of any one of claims 31 and 33 to 35, wherein the disease or disorder is selected from age-related macular degeneration, geographic atrophy, diabetic retinopathy, uveitis, retinitis pigmentosa, macular edema, Behcet's uveitis, multifocal choroiditis, Voigt-Koyanagi-Harada syndrome, intermediate uveitis, birdshot retinochoroiditis, sympathetic ophthalmia, ocular cicatricial pemphigoid, ocular pemphigus, nonarteritic ischemic optic neuropathy, postoperative inflammation, retinal vein occlusion, glaucoma, multifactorial honeycomb retinal dystrophy / Malattia leventinese, Sorsby fundus dystrophy, late-onset retinal macular dystrophy, North Carolina macular dystrophy, fundus xanthophy, keratitis, multiple sclerosis and other neurological disorders, stroke, Guillain-Barré syndrome, spinal cord injury, traumatic brain injury, Parkinson's disease, Alzheimer's disease, schizophrenia, amyotrophic lateral sclerosis (ALS), Huntington's disease, multifocal motor neuropathy, autism spectrum disorder, schizophrenia, drug-induced neurotoxicity; disorders with inappropriate or adverse complement activation, such as complications of hemodialysis, hyperacute allograft rejection, xenograft rejection, IL-2-induced toxicity during interleukin-2 therapy, inflammatory disorders, paroxysmal nocturnal hemoglobinuria, C3 glomerulonephritis (including dense deposit disease and C3 glomerulonephritis), immune complex membranoproliferative glomerulonephritis (IC-MPGN), IgA nephropathy, including idiopathic membranous nephropathy Membranous nephropathy, diabetic nephropathy, atypical hemolytic uremic syndrome (aHUS), hemolytic uremic syndrome, STEC-HUS (Shiga toxin-producing Escherichia coli hemolytic uremic syndrome), periodontitis, excessive complement activation due to CD55 deficiency, vasculothrombosis, protein-losing enteropathy (CHAPLE syndrome), inflammatory or autoimmune diseases such as Crohn's disease, neuromyelitis optica (NMO), IgA vasculitis (formerly known as Henoch-Schönlein purpura or HSP), CHAPLE syndrome, hematopoietic stem cell transplant-associated thrombotic microangiopathy (HSCT-TMA), adult-onset respiratory distress syndrome (ARDS), myocarditis, post-ischemia-reperfusion syndrome, myocardial infarction, balloon angioplasty, post-pump syndrome during cardiopulmonary bypass or renal bypass, atherosclerosis, hemodialysis, renal ischemia, acute kidney injury, mesenteric artery reperfusion after aortic reconstruction, infectious disease, or sepsis;COVID-19, immune complex disorders and autoimmune diseases, rheumatoid arthritis, osteoarthritis, spondyloarthropathies, psoriatic arthritis, systemic lupus erythematosus (SLE), lupus nephritis, SLE nephritis, proliferative nephritis, myasthenia gravis, liver fibrosis, hemolytic anemia, tissue regeneration, nerve regeneration, dyspnea, hemoptysis, acute respiratory distress syndrome (ARDS), asthma, chronic obstructive pulmonary disease (COPD), emphysema, pulmonary embolism and infarction, pneumonia, fibrosing pneumococcal disease, pulmonary fibrosis, asthma, allergy, bronchitis contraction, hypersensitivity pneumonitis, parasitic diseases, Goodpasture's syndrome, pulmonary vasculitis, microimmune vasculitis, antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), Burger's vasculitis, cryoglobulinemia, Kawasaki disease, Takayasu arteritis, cryoglobulinemia, immune complex-associated inflammation, antiphospholipid syndrome, glomerulonephritis, and obesity; immune thrombocytopenia, cold agglutinin disease, warm antibody autoimmune hemolytic anemia (wAIHA), thrombotic thrombocytopenic purpura (TTP), and abdominal aortic aneurysm, as well as Graves' disease. ; 38. A method for treating age-related macular degeneration, the method comprising administering to a subject in need thereof an effective amount of a composition comprising a compound according to any one of claims 1 to 29 or a pharmaceutically acceptable salt thereof.

39. A compound according to any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof, for use as a medicament.

40. A compound according to any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof, for use in inhibiting the expression or activity of complement factor B in a subject in need thereof.

41. A compound according to any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof, for use in treating a disease or disorder associated with dysregulation of the complement alternative pathway.

42. The compound for use according to claim 41, or a pharmaceutically acceptable salt thereof, wherein the disease or disorder is selected from age-related macular degeneration, geographic atrophy, diabetic retinopathy, uveitis, retinitis pigmentosa, macular edema, Behcet's uveitis, multifocal choroiditis, Voigt-Koyanagi-Harada syndrome, intermediate uveitis, birdshot retinochoroiditis, sympathetic ophthalmia, ocular cicatricial pemphigoid, ocular pemphigus, non-arteritic ischemic optic neuropathy, postoperative inflammation, retinal vein occlusion, glaucoma, multifactorial honeycomb retinal dystrophy / Malattialev entinese, Sorsby fundus dystrophy, late onset macular dystrophy, North Carolina macular dystrophy, fundus xanthophy, keratitis, multiple sclerosis and other neurological disorders, stroke, Guillain-Barré syndrome, spinal cord injury, traumatic brain injury, Parkinson's disease, Alzheimer's disease, schizophrenia, amyotrophic lateral sclerosis (ALS), Huntington's disease, multifocal motor neuropathy, autism spectrum disorder, schizophrenia, drug-induced neurotoxicity; disorders with inappropriate or adverse complement activation, such as complications of hemodialysis, hyperacute allograft rejection, xenograft rejection, interleukin IL-2-induced toxicity during IL-2 therapy, inflammatory disorders, paroxysmal nocturnal hemoglobinuria, C3 glomerulonephritis (including dense deposit disease and C3 glomerulonephritis), immune complex membranoproliferative glomerulonephritis (IC-MPGN), IgA nephropathy, membranous nephropathy including idiopathic membranous nephropathy, diabetic nephropathy, atypical hemolytic uremic syndrome (aHUS), hemolytic uremic syndrome, STEC-HUS (Shiga toxin-producing Escherichia coli hemolytic uremic syndrome), periodontitis, CD55 deficiency leading to excessive complement activation, vasculothrombosis, protein-losing Enteropathy (CHAPLE syndrome), inflammatory or autoimmune diseases such as Crohn's disease, neuromyelitis optica (NMO), IgA vasculitis (formerly known as Henoch-Schönlein purpura or HSP), CHAPLE syndrome, hematopoietic stem cell transplant-associated thrombotic microangiopathy (HSCT-TMA), adult-onset respiratory distress syndrome (ARDS), myocarditis, post-ischemia-reperfusion syndrome, myocardial infarction, balloon angioplasty, post-pump syndrome during cardiopulmonary bypass or renal bypass, atherosclerosis, hemodialysis, renal ischemia, acute kidney injury, mesenteric artery reperfusion after aortic reconstruction, infectious disease, or sepsis;COVID-19, immune complex disorders and autoimmune diseases, rheumatoid arthritis, osteoarthritis, spondyloarthropathies, psoriatic arthritis, systemic lupus erythematosus (SLE), lupus nephritis, SLE nephritis, proliferative nephritis, myasthenia gravis, liver fibrosis, hemolytic anemia, tissue regeneration, nerve regeneration, dyspnea, hemoptysis, acute respiratory distress syndrome (ARDS), asthma, chronic obstructive pulmonary disease (COPD), emphysema, pulmonary embolism and infarction, pneumonia, fibrosing pneumococcal disease, pulmonary fibrosis, asthma, allergy, bronchitis contraction, hypersensitivity pneumonitis, parasitic diseases, Goodpasture's syndrome, pulmonary vasculitis, microimmune vasculitis, antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), Burger's vasculitis, cryoglobulinemia, Kawasaki disease, Takayasu arteritis, cryoglobulinemia, immune complex-associated inflammation, antiphospholipid syndrome, glomerulonephritis, and obesity; immune thrombocytopenia, cold agglutinin disease, warm antibody autoimmune hemolytic anemia (wAIHA), thrombotic thrombocytopenic purpura (TTP), and abdominal aortic aneurysm, as well as Graves' disease. ; 43. Use of a compound according to any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating a disease or disorder mediated by complement activation or complement alternative pathway activation.

44. Use of a compound according to any one of claims 1 to 29 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating a disease or disorder selected from the group consisting of age-related macular degeneration, geographic atrophy, diabetic retinopathy, uveitis, retinitis pigmentosa, macular edema, Behcet's uveitis, multifocal choroiditis, Voigt-Koyanagi-Harada syndrome, intermediate uveitis, birdshot retinochoroiditis, sympathetic ophthalmia, ocular cicatricial pemphigoid, ocular pemphigus, non-arteritic ischemic optic neuropathy, postoperative inflammation, retinal vein occlusion, glaucoma, multi-cause honeycomb retinal dystrophy / Malattia leventinese, Sorsby fundus dystrophy, late-onset retinal macular dystrophy, North Carolina macular dystrophy, fundus xanthophy, keratitis, multiple sclerosis and other neurological disorders, stroke, Guillain-Barré syndrome, spinal cord injury, traumatic brain injury, Parkinson's disease, Alzheimer's disease, schizophrenia, amyotrophic lateral sclerosis (ALS), Huntington's disease, multifocal motor neuropathy, autism spectrum disorder, schizophrenia, drug-induced neurotoxicity; disorders with inappropriate or adverse complement activation, such as complications of hemodialysis, hyperacute allograft rejection, xenograft rejection, IL-2-induced toxicity during interleukin-2 therapy, inflammatory disorders, paroxysmal nocturnal hemoglobinuria, C3 glomerulonephritis (including dense deposit disease and C3 glomerulonephritis), immune complex membranoproliferative glomerulonephritis (IC-MPGN), IgA nephropathy, including idiopathic membranous nephropathy Membranous nephropathy, diabetic nephropathy, atypical hemolytic uremic syndrome (aHUS), hemolytic uremic syndrome, STEC-HUS (Shiga toxin-producing Escherichia coli hemolytic uremic syndrome), periodontitis, excessive complement activation due to CD55 deficiency, vasculothrombosis, protein-losing enteropathy (CHAPLE syndrome), inflammatory or autoimmune diseases such as Crohn's disease, neuromyelitis optica (NMO), IgA vasculitis (formerly known as Henoch-Schönlein purpura or HSP), CHAPLE syndrome, hematopoietic stem cell transplant-associated thrombotic microangiopathy (HSCT-TMA), adult-onset respiratory distress syndrome (ARDS), myocarditis, post-ischemia-reperfusion syndrome, myocardial infarction, balloon angioplasty, post-pump syndrome during cardiopulmonary bypass or renal bypass, atherosclerosis, hemodialysis, renal ischemia, acute kidney injury, mesenteric artery reperfusion after aortic reconstruction, infectious disease, or sepsis;COVID-19, immune complex disorders and autoimmune diseases, rheumatoid arthritis, osteoarthritis, spondyloarthropathies, psoriatic arthritis, systemic lupus erythematosus (SLE), lupus nephritis, SLE nephritis, proliferative nephritis, myasthenia gravis, liver fibrosis, hemolytic anemia, tissue regeneration, nerve regeneration, dyspnea, hemoptysis, acute respiratory distress syndrome (ARDS), asthma, chronic obstructive pulmonary disease (COPD), emphysema, pulmonary embolism and infarction, pneumonia, fibrosing pneumococcal disease, pulmonary fibrosis, asthma, allergy, bronchitis contraction, hypersensitivity pneumonitis, parasitic diseases, Goodpasture's syndrome, pulmonary vasculitis, microimmune vasculitis, antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), Burger's vasculitis, cryoglobulinemia, Kawasaki disease, Takayasu arteritis, cryoglobulinemia, immune complex-associated inflammation, antiphospholipid syndrome, glomerulonephritis, and obesity; immune thrombocytopenia, cold agglutinin disease, warm antibody autoimmune hemolytic anemia (wAIHA), thrombotic thrombocytopenic purpura (TTP), and abdominal aortic aneurysm, as well as Graves' disease. ; 45. Use of a compound according to any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof, for treating a disease or disorder mediated by complement activation or complement alternative pathway activation.

46. ​​Use of a compound according to any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof, for treating a disease or disorder affected by modulation of the complement alternative pathway.

47. Use of a compound according to any one of claims 1 to 29 or a pharmaceutically acceptable salt thereof for treating a disease or disorder selected from the group consisting of age-related macular degeneration, geographic atrophy, diabetic retinopathy, uveitis, retinitis pigmentosa, macular edema, Behcet's uveitis, multifocal choroiditis, Voigt-Koyanagi-Harada syndrome, intermediate uveitis, birdshot retinochoroiditis, sympathetic ophthalmia, ocular cicatricial pemphigoid, ocular pemphigus, non-arteritic ischemic optic neuropathy, postoperative inflammation, retinal vein occlusion, glaucoma, multi-cause honeycomb retinal dystrophy / Malattia leventinese, Sorsby fundus dystrophy, late-onset retinal macular dystrophy, North Carolina macular dystrophy, fundus xanthophy, keratitis, multiple sclerosis and other neurological disorders, stroke, Guillain-Barré syndrome, spinal cord injury, traumatic brain injury, Parkinson's disease, Alzheimer's disease, schizophrenia, amyotrophic lateral sclerosis (ALS), Huntington's disease, multifocal motor neuropathy, autism spectrum disorder, schizophrenia, drug-induced neurotoxicity; disorders with inappropriate or adverse complement activation, such as complications of hemodialysis, hyperacute allograft rejection, xenograft rejection, IL-2-induced toxicity during interleukin-2 therapy, inflammatory disorders, paroxysmal nocturnal hemoglobinuria, C3 glomerulonephritis (including dense deposit disease and C3 glomerulonephritis), immune complex membranoproliferative glomerulonephritis (IC-MPGN), IgA nephropathy, including idiopathic membranous nephropathy Membranous nephropathy, diabetic nephropathy, atypical hemolytic uremic syndrome (aHUS), hemolytic uremic syndrome, STEC-HUS (Shiga toxin-producing Escherichia coli hemolytic uremic syndrome), periodontitis, excessive complement activation due to CD55 deficiency, vasculothrombosis, protein-losing enteropathy (CHAPLE syndrome), inflammatory or autoimmune diseases such as Crohn's disease, neuromyelitis optica (NMO), IgA vasculitis (formerly known as Henoch-Schönlein purpura or HSP), CHAPLE syndrome, hematopoietic stem cell transplant-associated thrombotic microangiopathy (HSCT-TMA), adult-onset respiratory distress syndrome (ARDS), myocarditis, post-ischemia-reperfusion syndrome, myocardial infarction, balloon angioplasty, post-pump syndrome during cardiopulmonary bypass or renal bypass, atherosclerosis, hemodialysis, renal ischemia, acute kidney injury, mesenteric artery reperfusion after aortic reconstruction, infectious disease, or sepsis;COVID-19, immune complex disorders and autoimmune diseases, rheumatoid arthritis, osteoarthritis, spondyloarthropathies, psoriatic arthritis, systemic lupus erythematosus (SLE), lupus nephritis, SLE nephritis, proliferative nephritis, myasthenia gravis, liver fibrosis, hemolytic anemia, tissue regeneration, nerve regeneration, dyspnea, hemoptysis, acute respiratory distress syndrome (ARDS), asthma, chronic obstructive pulmonary disease (COPD), emphysema, pulmonary embolism and infarction, pneumonia, fibrosing pneumococcal disease, pulmonary fibrosis, asthma, allergy, bronchitis contraction, hypersensitivity pneumonitis, parasitic diseases, Goodpasture's syndrome, pulmonary vasculitis, microimmune vasculitis, antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), Burger's vasculitis, cryoglobulinemia, Kawasaki disease, Takayasu arteritis, cryoglobulinemia, immune complex-associated inflammation, antiphospholipid syndrome, glomerulonephritis, and obesity; immune thrombocytopenia, cold agglutinin disease, warm antibody autoimmune hemolytic anemia (wAIHA), thrombotic thrombocytopenic purpura (TTP), and abdominal aortic aneurysm, as well as Graves' disease. ; 48. Use of a compound according to any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof, for treating age-related macular degeneration.

49. A pharmaceutical combination comprising a compound according to any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof, and one or more additional therapeutic agents.

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