Complement factor B inhibitors and uses thereof

Abstract

Provided herein are compounds of formula (I) and pharmaceutical compositions thereof that are useful for treating diseases or disorders mediated by complement factor B. [Formula 1] TIFF2025511100000139.tif32170

Description

[Technical field]

[0001] The present disclosure relates to inhibition of the alternative complement pathway, and in particular to inhibition of factor B in patients suffering from conditions and diseases associated with alternative complement pathway activation, such as age-related macular degeneration, diabetic retinopathy and related eye diseases. [Background technology]

[0002] The complement system is a key component of the innate immune system and comprises a group of proteins that normally exist in an inactive state. These proteins are organized into three activation pathways: the classical pathway, the lectin pathway, and the alternative pathway (VM Holers, In Clinical Immunology: Principles and Practice, ed. RRRich, Mosby Press; 1996, 363-391). Molecules from microorganisms, antibodies, or cellular components can activate these pathways, leading to the formation of protease complexes known as C3 convertase and C5 convertase. The classical pathway is a calcium / magnesium-dependent cascade that is usually activated by the formation of antigen-antibody complexes. It can also be activated antibody-independently by the binding of C-reactive protein complexed to a ligand 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 susceptible surfaces (e.g., cell wall polysaccharides of yeast and bacteria, as well as certain biopolymer materials).

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

[0004] Macular degeneration is a clinical term used to describe a family of diseases characterized by progressive loss of central vision associated with abnormalities in Bruch's membrane, choroid, neural retina, and / or retinal pigment epithelium. At the center of the retina is the macula, which is approximately 1 / 3 to 1 / 2 cm in diameter. The macula provides detailed vision, especially in the center (fovea), due to a higher density of cones and a higher ratio of ganglion cells to photoreceptor cells. The blood vessels, ganglion cells, inner nuclear layer and cells, and plexiform layer are all displaced laterally (rather than resting on top of the photoreceptor cells), thereby allowing a more direct pathway for light to the cones. Under the retina are the choroid, parts of the uvea, and the retinal pigment epithelium (RPE), which lies between the neural retina and the choroid. The choroidal blood vessels provide nourishment to the retina and its photoreceptor cells.

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

[0006] Neovascular AMD is characterized by abnormal growth of blood vessels under the macula and vascular leakage, leading to retinal displacement, bleeding, and scarring. This leads to loss of vision over weeks to years. Cases of neovascular AMD stem from intermediate or advanced dry AMD. The neovascular form accounts for 85% of legal blindness due to AMD. In neovascular AMD, abnormal blood vessels leak fluid and blood, resulting in the formation of scar tissue that destroys the central retina.

[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. Published studies suggest that CNV is caused by complement activation in a mouse laser model (Bora PS, J. Immunol. 2005; 174; 491-497).

[0008] Human genetic evidence implicates the complement system, particularly the alternative pathway, in the pathogenesis of age-related macular degeneration (AMD). A significant association has been found between AMD and polymorphisms in 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 US A. 2005 May 17;102(20):7227-32; Haines JL,et al. Complement factor H variant increases the 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.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. 2008 May 21;3(5):e2199), and most recently in 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.2009 Jul;50(7):3386-93.Epub 2009 Feb 21). Taken together, genetic variants in alternative pathway components CFH, CFB and C3 can predict clinical outcome in almost 80% of cases.

[0009] Currently, there is no proven medical treatment for dry AMD, and many patients with neovascular AMD become legally blind despite current treatment with anti-VEGF agents such as Lucentis. It would therefore be desirable to provide a therapeutic agent for the treatment or prevention of complement-mediated diseases, and particularly for the treatment of AMD. Summary of the Invention

[0010] The present disclosure provides compounds that modulate and / or inhibit the activation of the alternative complement pathway. 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] Compounds of the present disclosure inhibit or suppress the amplification of the complement system caused by C3 activation, regardless of the initial mechanism of activation (including, for example, activation of the classical, lectin or alternative pathways).

[0012] The present disclosure also relates to compounds effective as factor B modulators, pharma- ceutically acceptable salts thereof, compositions thereof, and their uses in the treatment of the conditions and purposes detailed herein.

[0013] The present disclosure provides in a first aspect a compound of formula (I) [ka] or a pharma- ceutically acceptable salt thereof, wherein m is 0, 1, 2, or 3; n is 0, 1, 2, or 3, with the proviso that m and n are not both 0; R is hydrogen, halogen, C 1 ~C 4 Alkyl, haloC 1 ~C 4 Alkyl or hydroxy C 1 ~C 4 is alkyl; R 1 is hydrogen, halogen, hydroxy, C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 3 ~C 6 Cycloalkyl, C 1 ~C 6 Alkoxy, HaloC 1 ~C 6 Alkyl, haloC 3 ~C 6 Cycloalkyl, HaloC 1 ~C 6 Alkoxy, Hydroxy C 1 ~C 6 Alkyl, Hydroxy C 3 ~C 6 Cycloalkyl Amino C 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxy C 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxy C 1 ~C 6 Alkoxy, C 3 ~C 6 Cycloalkyl C 1 ~C 6 Alkoxy, HaloC 1 ~C 6 Alkoxy, -SC 1 ~C 6 Alkyl, -S(O)C1 ~C 6 Alkyl, -S(O) 2 C 1 ~C 6 Alkyl, CH 2 NHC(O)C 1 ~C 4 Alkyl or -OCH 2 C(O)R 1a and; R 1a is hydroxy, C 1 ~C 6 Alkoxy, amino or mono- and di-C 1 ~C 6 is alkylamino; R 2 is C 1 ~C 3 Alkyl, C 3 Cycloalkyl, C 1 ~C 3 Alkoxy, Hydroxy C 1 ~C 6 alkyl or halogen, where C 1 ~C 3 Alkyl, C 3 Cycloalkyl, or C 1 ~C 3 The alkoxy 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, where heteroaryl is a 5- to 10-membered heteroaryl having 1, 2 or 3 ring heteroatoms independently selected from N, O, or S, and phenyl or heteroaryl is unsubstituted or has one R 5 and 0, 1 or 2 R 5’ has been replaced by; R 5 -CO 2 R 5b , -CON(R 5c ) 2 , C 1 ~C6 Alkyl, C 1 ~C 6 Alkoxy C 1 ~C 6 Alkyl, -CH 2 CO 2 R 5b , -CH 2 CON(R 5c ) 2 , -C(O)NHSO 2 C 1 ~C 4 Alkyl, -SO 2 NHC(O)C 1 ~C 4 Alkyl, -SO 2 N(H) m (C 1 ~C 4 Alkyl) 2-m , -SO 2 C 1 ~C 4 5- to 6-membered heteroaryl having 1 to 4 heteroatoms independently selected from alkyl, cyano, hydroxy, halogen, N, O, and S, and N, O, and S(O) q wherein the 5- to 6-membered heteroaryl and the 4- to 6-membered heterocyclyl are unsubstituted or selected from 1, 2, or 3 R 5a has been replaced by; Each R 5a is fluoro, hydroxyl, and C which is unsubstituted or substituted by -COOH or 1, 2, or 3 fluoro; 1 ~C 6 independently selected from alkyl; Here, R 5 When R is a 4- to 6-membered heterocyclyl, two R 5a rather than fluoro and hydroxyl substituted at the same positions; Each R 5b is hydrogen or C 1 ~C 5 independently selected from alkyl; Each R 5c is hydrogen, unsubstituted or halogen, hydroxy or C 1~C 4 Alkyl-substituted C 1 ~C 4 independently selected from alkyl; Each R 5’ is HaroC 1 ~C 4 Alkyl, C 1 ~C 4 Alkoxy, HaloC 1 ~C 4 Alkoxy, halogen, cyanomethyl, hydroxy C 1 ~C 6 Alkyl, and C 3 ~C 5 independently selected from the group consisting of cycloalkyl; W is O, C(R 6 ) 2 , or NR 7 and; R 6 represents, at each occurrence, hydrogen, halogen, hydroxy, amino, mono- and di-C 1 ~C 4 Alkylamino, C 1 ~C 6 Alkyl, haloC 1 ~C 6 Alkyl, Hydroxy C 1 ~C 6 Alkyl, Cyano C 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxy or haloC 1 ~C 6 or two R 6 in combination with the carbon atom to which they are attached form a spirocyclic carbocycle having 3 to 6 ring atoms, where the spirocyclic carbocycle is unsubstituted or substituted with halogen, C 1 ~C 6 Alkyl or C 1 ~C 6 alkoxy; or two R 6 in combination with the carbon atom to which they are attached, N, O, or S(O) qand forming a spirocyclic heterocycle having 1 or 2 ring heteroatoms independently selected from 1 ~C 6 Alkyl, haloC 1 ~C 6 Alkyl, C 3 ~C 6 Cycloalkyl, HaloC 3 ~C 6 is substituted by cycloalkyl; q is 0, 1, or 2; R 7 is hydrogen, C 1 ~C 6 Alkyl, haloC 1 ~C 6 Alkyl, Hydroxy C 2 ~C 6 Alkyl, C 3 ~C 6 Cycloalkyl, C 3 ~C 6 Cycloalkyl C 1 ~C 3 Alkyl, haloC 3 ~C 6 Cycloalkyl, C 1 ~C 6 Alkoxy C 1 ~C 6 Alkyl, haloC 1 ~C 6 Alkoxy C 1 ~C 6 Alkyl, aryl, N, O, and S(O) q or a 4- to 6-membered heterocyclyl having 1 to 2 heteroatoms independently selected from N, O, and S, 1 ~C 6 Alkyl is unsubstituted or includes N, O, and S(O). qand each of the 4- to 6-membered heterocyclyl groups is unsubstituted or substituted with 1, 2, or 3 halogen atoms, and each of the aryl or heteroaryl groups is unsubstituted or substituted with halo, C. 1 ~C 6 Alkyl, haloC 1 ~C 6 Alkyl, C 3 ~C 5 Cycloalkyl, HaloC 3 ~C 5 is substituted by cycloalkyl; Each R 8 are independently hydrogen, halogen, C 1 ~C 4 Alkyl, haloC 1 ~C 4 alkyl or two R 8 together with the carbon atom to which they are attached, C 3 ~C 5 Cycloalkyl or haloC 3 ~C 5 Forms a cycloalkyl.

[0014] In a second aspect, there is provided a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable carrier or excipient.

[0015] In a third aspect, there is provided 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 a pharma- ceutically acceptable salt thereof.

[0016] In a further aspect, there is provided a method of modulating the alternative complement pathway activity in a subject, comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharma- ceutically acceptable salt thereof.

[0017] In a further aspect, there is provided a method of treating a disease or disorder mediated by complement activation, in particular by activation of the alternative complement pathway, in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharma- ceutically acceptable salt thereof.

[0018] In a further aspect, there is provided a method of treating a disease or disorder affected by modulation of the alternative complement pathway comprising administering to a subject a therapeutically effective amount of a compound of formula (I) or a pharma- ceutically acceptable salt thereof.

[0019] In a further aspect, there is provided a method of treating a disease or disorder associated with dysregulation of the alternative complement pathway, comprising administering to a subject a therapeutically effective amount of a compound of formula (I) or a pharma- ceutical acceptable salt thereof.

[0020] In a further aspect, there is provided a method of inhibiting expression or activity of complement factor B comprising administering to a subject a compound of formula (I) or a pharma- ceutically acceptable salt thereof.

[0021] In a further aspect, there is provided a method of treating age-related macular degeneration comprising administering to a subject in need thereof a composition comprising an effective amount of a compound of formula (I) or a pharma- ceutically acceptable salt thereof.

[0022] In a further aspect, there is provided a compound of formula (I) or a pharma- ceutically acceptable salt thereof for use as a medicament.

[0023] In a further aspect, there is provided a compound of formula (I) or a pharma- ceutically acceptable salt thereof for use in inhibiting the expression or activity of complement factor B in a subject in need thereof.

[0024] In a further aspect, there is provided a compound of formula (I) or a pharma- ceutically acceptable salt thereof for use in the treatment of a disease or disorder associated with dysregulation of the alternative complement pathway.

[0025] In a further aspect, there is provided the use of a compound of formula (I) or a pharma- ceutically acceptable salt thereof in the manufacture of a medicament for the treatment of a disease or disorder mediated by complement activation or activation of the alternative complement pathway.

[0026] In a further aspect, there is provided the use of a compound of formula (I) or a pharma- ceutically acceptable salt thereof for the treatment of a disease or disorder mediated by complement activation or activation of the alternative complement pathway.

[0027] In a further aspect, there is provided the use of a compound of formula (I) or a pharma- ceutically acceptable salt thereof for treating a disease or disorder affected by modulation of the alternative complement pathway. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0028] As mentioned above, the present disclosure provides compounds that modulate factor B activation and / or factor B-mediated signaling of the complement system. Such compounds may be used in vitro or in vivo to modulate factor B activity in a variety of contexts. The compounds disclosed herein are effective as factor B modulators and / or inhibitors. Without wishing to be bound by any theory, the disclosed compounds are effective in treating factor B-related disorders, such as age-related macular degeneration, geographic atrophy, diabetic retinopathy, uveitis, retinitis pigmentosa, macular edema, Behcet's uveitis, multifocal choroiditis, Vogt-Koyanagi-Harada syndrome, intermediate uveitis, birdshot choroiditis, sympathetic ophthalmia, ocular bifurcation pemphigoid, ocular pemphigus, nonarteritic ischemic optic neuropathy, postoperative inflammation, retinal vein occlusion, glaucoma, Doyne honeycomb retinal dystrophy / Malattia leventinese, Sorsby fundus dystrophy, late onset retinal macular dystrophy, North Neurological disorders such as carolina macular dystrophy, Stargardt disease, corneal inflammation, multiple sclerosis, 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, and drug-induced neurotoxicity;Disorders of inappropriate or undesirable complement activation, e.g. hemodialysis complications, hyperacute allograft rejection, xenograft rejection, interleukin-2 induced toxicity during IL-2 treatment, inflammatory disorders, paroxysmal nocturnal hemoglobinuria, C3 glomerulonephritis (including compact deposits 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 E. coli hemolytic uremic syndrome) , peritonitis, CD55 deficiency with complement hyperactivation, vasculopathic thrombosis, 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 respiratory distress syndrome (ARDS), myocarditis, post-ischemic reperfusion state, myocardial infarction, balloon angioplasty, post-pump syndrome in cardiopulmonary or renal bypass, atelectasis, pulmonary edema ... rheumatoid arteriosclerosis, hemodialysis, kidney damage, acute kidney injury, mesenteric artery reperfusion after aortic reconstruction, infection or sepsis; COVID-19, immune complex disorders and autoimmune diseases, rheumatoid arthritis, osteoarthritis, spondyloarthropathy, 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, fibrous dust disease, pulmonary fibrosis, It is believed to be capable of treating asthma, allergies, bronchoconstriction, hypersensitivity pneumonitis, parasitic diseases, Goodpasture's syndrome, pulmonary vasculitis, pauciimmune vasculitis, antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), Buerger's vasculitis, cryoglobulinemia, Kawasaki's disease, Takayasu's arteritis, cryoglobulinemia, immune complex-associated inflammation, antiphospholipid syndrome, glomerulonephritis, and obesity; immune thrombocytopenia, cold agglutinin disease, warm autoimmune hemolytic anemia (wAIHA), thrombotic thrombocytopenic purpura (TTP), abdominal aortic aneurysm, and Graves' disease;

[0029] definition Unless otherwise specified, the terms "compounds of the disclosure", "compounds of this disclosure" or "compounds of this disclosure" refer to compounds of Formula (I), (IA), (IB), (IC), exemplified compounds, salts thereof, particularly pharma- ceutically acceptable salts thereof, hydrates, solvates, and all stereoisomers (including diastereoisomers and enantiomers), rotamers, tautomers and isotopically labeled compounds (including deuterium substitutions) and inherently formed moieties.

[0030] In the groups, radicals or moieties defined below, the number of carbon atoms is often specified preceding the group, e.g., C 1 ~C 10 Alkyl means an alkyl group or radical having 1 to 10 carbon atoms.

[0031] Additionally, use of terms designating univalent radicals where a divalent radical is appropriate should be construed to designate the respective divalent radical, and vice versa. Unless otherwise specified, normal definitions of terms control, and normal stable valences are presumed and achieved in all formulas and groups. The articles "a" and "an" refer to one or more (e.g., at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element.

[0032] The term "and / or" means "and" or "or" unless otherwise indicated.

[0033] The term "substituted" means that the specified group or moiety bears one or more suitable substituents, and the substituents may be attached to the specified group or moiety at one or more positions. For example, an aryl substituted with a cycloalkyl may indicate that the cycloalkyl is bonded or fused to the aryl and is connected to an atom of the aryl by sharing two or more common atoms.

[0034] As used herein, the term "C 1 ~C 6"Alkyl" refers to a straight or branched hydrocarbon chain radical consisting exclusively of carbon and hydrogen atoms, containing no unsaturation, having from 1 to 6 carbon atoms and attached to the remainder of the molecule by a single bond. 1 ~C 3 Alkyl and C 1 ~C 4 The term alkyl is to be interpreted accordingly. 1 ~C 6 Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, 1-methylethyl (iso-propyl), n-butyl, 1-methylpropyl (sec-butyl), 2-methylpropyl (iso-butyl), 1,1-dimethylethyl (tert-butyl), n-pentyl, and n-hexyl. 1 ~C 6 Alkyl is a cycloalkyl group attached to an alkyl group, e.g., [ka] Also includes.

[0035] As used herein, the term "C 1 ~C 6 "Alkoxy" is a group represented by the formula -OR a R refers to the group a is the C 1 ~C 6 It is an alkyl group. 1 ~C 6 Examples of alkoxyl include, but are not limited to, methoxy, ethoxy, propoxy, iso-propoxy, butoxy, iso-butoxy, tert-butoxy, sec-butoxy, pentoxy and hexoxy.

[0036] The terms "halogen" or "halo" mean fluorine, chlorine, bromine or iodine.

[0037] As used herein, the term "cycloalkyl" means a monocyclic or polycyclic saturated or partially unsaturated carbocyclic ring containing 3 to 18 carbon atoms, in which there are no delocalized pi electrons shared between the ring carbons (aromaticity). 3 ~C 5 The term polycyclic includes bridged (e.g., norbornane), fused (e.g., decalin) and spirocyclic cycloalkyls. Preferably, cycloalkyls, such as C 3 ~C 5 Cycloalkyl is a monocyclic hydrocarbon group of 3 to 5 carbon atoms.

[0038] Examples of cycloalkyl groups include, but are not limited to, cyclopropenyl, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, bicyclo[1.1.1]pentanyl, and derivatives thereof.

[0039] C 3 ~C 5 Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, and cyclopentyl.

[0040] "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), where there are no delocalized pi-electrons (aromaticity) shared between ring carbons or heteroatoms. The term "4-6 membered heterocyclyl" is to be interpreted accordingly. The heterocyclyl ring structure may be substituted with one or more substituents. The substituents may themselves be optionally substituted. The heterocyclyl may be attached via a carbon atom or a heteroatom. The term polycyclic encompasses bridged, fused and spirocyclic heterocyclyls.

[0041] Examples of heterocyclyl rings include, but are not limited to, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, oxazolinyl, isoxazolinyl, oxazolidinyl, thiazolidinyl, pyranyl, thiopyranyl, tetrahydropyranyl, dioxalinyl, piperidinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S-dioxide, piperazinyl, azepinyl. , oxepinyl, diazepinyl, tropanyl, oxazolidinonyl, 1,4-dioxanyl, dihydrofuranyl, 1,3-dioxolanyl, imidazolidinyl, dihydroisoxazolinyl, pyrrolinyl, pyrazolinyl, oxazepinyl, dithiolanyl, homotropanyl, dihydropyranyl (e.g., 3,6-dihydro-2H-pyranyl), oxaspiroheptanyl (e.g., 2-oxaspiro[3.3]heptan-6-yl), and the like.

[0042] Examples of 4- to 6-membered heterocyclyls include, but are not limited to, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, piperazinyl, dihydroisoxazolinyl, tetrahydropyranyl, morpholinyl, dihydropyranyl (e.g., 3,6-dihydro-2H-pyranyl), and oxaspiroheptanyl (e.g., 2-oxaspiro[3.3]heptan-6-yl).

[0043] As used herein, the term "heteroaryl" is intended to include monocyclic heteroaromatic rings. 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, azepinyl, azesinyl, and the like.

[0044] Heteroaryl is also intended to include bicyclic heteroaromatic 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, thiazolopyridinyl, thiazolopyrimidinyl, imidazothiazolyl, triazolopyridinyl, triazolopyrimidinyl, and the like.

[0045] Heteroaryl is also intended to include polycyclic heteroaromatic 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.

[0046] The heteroaryl ring structure may be substituted with one or more substituents. The substituents may themselves be optionally substituted. The heteroaryl ring may be attached via a carbon atom or a heteroatom.

[0047] The term "5- or 6-membered heteroaryl" should be construed accordingly.

[0048] Examples of 5- or 6-membered heteroaryls include, but are not limited to, furan, indolyl, pyridinyl, pyrimidinyl, pyridinonyl, 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, thiophenyl, thiadiazolyl (e.g., 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl), pyrazinyl, isoxazolopyridinyl, dihydropyridoxazinyl, and tetrazolyl. The term "5- or 6-membered heteroaryl ring having 1 to 2 heteroatoms independently selected from N, O and S" should be construed accordingly.

[0049] As used herein, "modulator" refers to a compound of the present disclosure that modulates, decreases, or reduces the level of, for example, a particular protein, such as complement factor B. The amount of modulated particular protein, such as complement factor B, can be measured by comparing the amount of particular protein, such as complement factor B, remaining after treatment with a compound of the present disclosure compared to the initial amount or level of the particular protein, such as complement factor B, present when measured prior to treatment with a compound of the present disclosure.

[0050] As used herein, "inhibitor" refers to a compound of the present disclosure that inhibits or reduces the activity of at least one component of a complement pathway, e.g., the compound inhibits the binding of one component to another component of the pathway. For example, the complement pathway is the alternative complement pathway. For example, a component of the complement pathway is complement factor B.

[0051] As used herein, the term "inhibition" or "inhibiting" refers to the reduction or suppression of a given condition, symptom, or disorder, or disease, or a significant decrease in the baseline activity of a biological activity or process.

[0052] The term "effective amount" of a compound described herein refers to that amount of a therapeutic compound that is necessary or sufficient to perform its intended function in a mammal. The effective amount of a therapeutic compound may vary depending on factors such as the amount of causative agent 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.

[0053] Thus, the term "therapeutically effective amount" of a compound of the present disclosure refers to an amount of a compound of the present disclosure that induces a biological or medical response in a subject, such as a reduction or inhibition of an enzyme or protein activity, improves symptoms, alleviates a condition, slows the progression of a disease, or prevents a disease. 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 ameliorate a condition, disorder, or disease that is (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 the activity of complement factor B; or (3) reduce or inhibit the expression of complement factor B. 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 the activity of complement factor B; or at least partially reduce or inhibit the expression of complement factor B.

[0054] As used herein, the terms "treat", "treating" or "treatment", in reference to a disease or disorder, in some embodiments refers to reversing the disease or disorder (i.e., delaying or arresting or reducing the onset of the disease or at least one of its clinical symptoms). In another embodiment, "treat", "treating" or "treatment" refers to alleviating or reversing at least one physical parameter, including those that may not be discernible by the patient. In yet another embodiment, "treat", "treating" or "treatment" refers to modulating the disease or disorder physically (e.g., stabilization of a discernible symptom), physiologically (e.g., stabilization of a physical parameter), or both. In yet another embodiment, "treat", "treating" or "treatment" refers to preventing or delaying the onset, or occurrence, or progression of the disease or disorder or a symptom thereof.

[0055] As used herein, the term "subject" or "patient" refers to humans and non-human mammals, including, but not limited to, primates, rabbits, pigs, horses, dogs, cats, sheep, and cattle. In certain embodiments, the subject or patient is a human. In some embodiments, the term "patient" or "subject" refers to a human suffering from a condition (i.e., disease or disorder) described herein and who would benefit from a treatment. As used herein, a subject is "in need of" a treatment if such a subject (patient) would benefit from such treatment biologically, medically, or in quality of life. In certain embodiments, the subject is an adult human at least about 18 years of age. In certain embodiments, the subject is an adult human between about 18 and about 75 years of age. In some embodiments, the subject is a human child up to about 18 years of age.

[0056] As used herein, the terms "prevent", "preventing" or "prevention" of any disease or disorder refers to the prophylactic treatment of a disease or disorder; or delaying the onset or progression of said disease or disorder.

[0057] As used herein, a subject is "in need of" a treatment if such subject would benefit biologically, medically, or in quality of life from such treatment.

[0058] As used herein, the term "about" refers to a range of values ​​of + / - 10% of the specified value.

[0059] As used herein, in the context of this disclosure (and particularly in the context of the claims), the terms "a," "an," "the," and similar terms are intended to encompass both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context.

[0060] As used herein, the term "pharmaceutically acceptable carrier" refers to a substance useful in the preparation or use of a pharmaceutical composition, and includes, for example, suitable excipients, solvents, dispersion media, surfactants, antioxidants, preservatives, isotonicity agents, buffers, emulsifiers, absorption delaying agents, salts, drug stabilizers, binders, additives, disintegrants, lubricants, wetting agents, sweeteners, flavoring agents, 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).

[0061] Various enumerated embodiments of the present disclosure are described herein, and it will be recognized that the features specified in each embodiment can be combined with other specified features to provide further embodiments of the present disclosure.

[0062] Enumerated Embodiments Embodiment 1. Formula (I) [ka] (In the formula, m is 0, 1, 2, or 3; n is 0, 1, 2, or 3, with the proviso that m and n are not both 0; R is hydrogen, halogen, C 1 ~C 4 Alkyl, haloC 1 ~C 4 Alkyl or hydroxy C 1 ~C 4 is alkyl; R 1 is hydrogen, halogen, hydroxy, C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 3 ~C 6 Cycloalkyl, C 1 ~C 6 Alkoxy, HaloC 1 ~C 6 Alkyl, haloC3 ~C 6 Cycloalkyl, HaloC 1 ~C 6 Alkoxy, Hydroxy C 1 ~C 6 Alkyl, Hydroxy C 3 ~C 6 Cycloalkyl Amino C 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxy C 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxy C 1 ~C 6 Alkoxy, C 3 ~C 6 Cycloalkyl C 1 ~C 6 Alkoxy, HaloC 1 ~C 6 Alkoxy, -SC 1 ~C 6 Alkyl, -S(O)C 1 ~C 6 Alkyl, -S(O) 2 C 1 ~C 6 Alkyl, CH 2 NHC(O)C 1 ~C 4 Alkyl or -OCH 2 C(O)R 1a and; R 1a is hydroxy, C 1 ~C 6 Alkoxy, amino or mono- and di-C 1 ~C 6 is alkylamino; R 2 is C 1 ~C 3 Alkyl, C 3 Cycloalkyl, C 1 ~C 3 Alkoxy, Hydroxy C 1 ~C 6 alkyl or halogen, where C 1 ~C 3 Alkyl, C 3Cycloalkyl, or C 1 ~C 3 The alkoxy 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, where heteroaryl is a 5- to 10-membered heteroaryl having 1, 2 or 3 ring heteroatoms independently selected from N, O, or S, and phenyl or heteroaryl is unsubstituted or has one R 5 and 0, 1 or 2 R 5’ has been replaced by; R 5 -CO 2 R 5b , -CON(R 5c ) 2 , C 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxy C 1 ~C 6 Alkyl, -CH 2 CO 2 R 5b , -CH 2 CON(R 5c ) 2 , -C(O)NHSO 2 C 1 ~C 4 Alkyl, -SO 2 NHC(O)C 1 ~C 4 Alkyl, -SO 2 N(H) m (C 1 ~C 4 Alkyl) 2-m , -SO 2 C 1 ~C 4 5- to 6-membered heteroaryl having 1 to 4 heteroatoms independently selected from alkyl, cyano, hydroxy, halogen, N, O, and S, and N, O, and S(O) qwherein the 5- to 6-membered heteroaryl and the 4- to 6-membered heterocyclyl are unsubstituted or selected from 1, 2, or 3 R 5a has been replaced by; Each R 5a is fluoro, hydroxyl, and C which is unsubstituted or substituted by -COOH or 1, 2, or 3 fluoro; 1 ~C 6 independently selected from alkyl; Here, R 5 When R is a 4- to 6-membered heterocyclyl, two R 5a rather than fluoro and hydroxyl substituted at the same positions; Each R 5b is hydrogen or C 1 ~C 5 independently selected from alkyl; Each R 5c is hydrogen, unsubstituted or halogen, hydroxy or C 1 ~C 4 Alkyl-substituted C 1 ~C 4 independently selected from alkyl; Each R 5’ is HaroC 1 ~C 4 Alkyl, C 1 ~C 4 Alkoxy, HaloC 1 ~C 4 Alkoxy, halogen, cyanomethyl, hydroxyC 1 ~C 6 Alkyl, and C 3 ~C 5 independently selected from the group consisting of cycloalkyl; W is O, C(R 6 ) 2 , or NR 7 and; R 6 represents, at each occurrence, hydrogen, halogen, hydroxy, amino, mono- and di-C 1 ~C 4 Alkylamino, C 1 ~C6 Alkyl, haloC 1 ~C 6 Alkyl, Hydroxy C 1 ~C 6 Alkyl, Cyano C 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxy or haloC 1 ~C 6 or two R 6 in combination with the carbon atom to which they are attached form a spirocyclic carbocycle having 3 to 6 ring atoms, where the spirocyclic carbocycle is unsubstituted or substituted with halogen, C 1 ~C 6 Alkyl or C 1 ~C 6 alkoxy; or two R 6 in combination with the carbon atom to which they are attached, N, O, or S(O) q and forming a spirocyclic heterocycle having 1 or 2 ring heteroatoms independently selected from 1 ~C 6 Alkyl, haloC 1 ~C 6 Alkyl, C 3 ~C 6 Cycloalkyl, HaloC 3 ~C 6 is substituted by cycloalkyl; q is 0, 1, or 2; R 7 is hydrogen, C 1 ~C 6 Alkyl, haloC 1 ~C 6 Alkyl, Hydroxy C 2 ~C 6 Alkyl, C 3 ~C 6 Cycloalkyl, C 3 ~C 6 Cycloalkyl C 1 ~C 3 Alkyl, haloC3 ~C 6 Cycloalkyl, C 1 ~C 6 Alkoxy C 1 ~C 6 Alkyl, haloC 1 ~C 6 Alkoxy C 1 ~C 6 Alkyl, aryl, N, O, and S(O) q or a 4- to 6-membered heterocyclyl having 1 to 2 heteroatoms independently selected from N, O, and S, 1 ~C 6 Alkyl is unsubstituted or includes N, O, and S(O). q and each of the 4- to 6-membered heterocyclyl groups is unsubstituted or substituted with 1, 2, or 3 halogen atoms, and each of the aryl or heteroaryl groups is unsubstituted or substituted with halo, C. 1 ~C 6 Alkyl, haloC 1 ~C 6 Alkyl, C 3 ~C 5 Cycloalkyl, HaloC 3 ~C 5 substituted by cycloalkyl; Each R 8 are independently hydrogen, halogen, C 1 ~C 4 Alkyl, haloC 1 ~C 4 alkyl or two R 8 together with the carbon atom to which they are attached, C 3 ~C 5 Cycloalkyl or haloC 3 ~C 5 forming a cycloalkyl or a pharma- ceutically acceptable salt thereof.

[0063] Embodiment 2. Formula (IA) [ka] wherein A is selected from phenyl, furanyl, thiophenyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, pyrazolyl, imidazolyl, pyridyl, triazolyl, tetrazolyl, oxadiazolyl, isoxadiazolyl, pyrimidinyl, pyrazinyl, and pyridazinyl. 2. A compound of formula (I) as defined in embodiment 1, or a pharma- ceutically acceptable salt thereof.

[0064] Embodiment 3. Formula (IB) [ka] wherein A is selected from phenyl, furanyl, thiophenyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, pyrazolyl, imidazolyl, pyridyl, triazolyl, tetrazolyl, oxadiazolyl, isoxadiazolyl, pyrimidinyl, pyrazinyl, and pyridazinyl. or a pharma- ceutically acceptable salt thereof.

[0065] Embodiment 4.A is [ka] or a pharma- ceutically acceptable salt thereof.

[0066] Embodiment 5. W is C(R 6 ) 2 , or NR 7 or a pharma- ceutically acceptable salt thereof.

[0067] Embodiment 6. W is C(R 6 ) 2 or a pharma- ceutically acceptable salt thereof.

[0068] In embodiment 7, W is NR 7 or a pharma- ceutically acceptable salt thereof.

[0069] Embodiment 8.R 7 is C 1 ~C 6 Alkyl, haloC 1 ~C 6 Alkyl, C 3 ~C 6 Cycloalkyl or haloC 3 ~C 6 The compound according to any one of the preceding embodiments, wherein R is cycloalkyl; or a pharma- ceutically acceptable salt thereof.

[0070] Embodiment 9. A compound according to any one of the preceding embodiments, or a pharma- ceutically acceptable salt thereof, wherein A is a phenyl ring.

[0071] Embodiment 10.R 5 is substituted at the para position of the phenyl ring, or a pharma- ceutically acceptable salt thereof.

[0072] Embodiment 11. Formula (IC): [ka] 11. The compound according to embodiment 10, or a pharma- ceutically acceptable salt thereof.

[0073] Embodiment 12. Formula (ID): [ka] or a pharma- ceutically acceptable salt thereof.

[0074] Embodiment 13.R 1 is hydrogen, halogen, C 1 ~C 6 Alkyl, C 3 ~C 6Cycloalkyl and C 1 ~C 6 The compound according to any one of the preceding embodiments, wherein said compound is selected from alkoxy, or a pharma- ceutically acceptable salt thereof.

[0075] Embodiment 14.R 2 is selected from halogen, methyl, ethyl, and cyclopropyl, or a pharma- ceutically acceptable salt thereof.

[0076] Embodiment 15.R 2 is selected from methyl, ethyl, and cyclopropyl, or a pharma- ceutically acceptable salt thereof.

[0077] Embodiment 16.R 2 is methyl, or a pharma- ceutically acceptable salt thereof.

[0078] Embodiment 17. R is hydrogen, halogen, or C 1 ~C 4 The compound according to any one of the preceding embodiments, or a pharma- ceutically acceptable salt thereof, wherein: R is alkyl;

[0079] Embodiment 18.R 3 is hydrogen or chloro, or a pharma- ceutically acceptable salt thereof.

[0080] Embodiment 19.R 3 is hydrogen, or a pharma- ceutically acceptable salt thereof.

[0081] Embodiment 20.R 5 is hydrogen, -CO 2 R 5b , -CON(R 5c ) 2 , C 1 ~C 6 Alkyl, -CH 2 CO 2 R5b , -CH 2 CON(R 5c ) 2 , -C(O)NHSO 2 C 1 ~C 4 Alkyl, -SO 2 NHC(O)C 1 ~C 4 Alkyl, -SO 2 N(H) m (C 1 ~C 4 Alkyl) 2-m , -SO 2 C 1 ~C 4 Alkyl, cyano, halogen, hydroxy C 1 ~C 6 Alkyl, C 3 ~C 5 cycloalkyl, 5- to 6-membered heteroaryl having 1 to 4 heteroatoms independently selected from N, O, and S, and 4- to 6-membered heterocyclyl having 1 to 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 have one or two R 5a or a pharma- ceutically acceptable salt thereof.

[0082] Embodiment 21.R 5 -CO 2 H, hydroxy C 1 ~C 6 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 selected from 0-1 R 5a or a pharma- ceutically acceptable salt thereof.

[0083] Embodiment 22.R 5 CO 2 H, hydroxy C 1 ~C 6and selected from alkyl, 5-membered heteroaryl having two N heteroatoms, and 4- to 6-membered heterocyclyl having one O heteroatom, wherein the 4- to 6-membered heterocyclyl is unsubstituted or has one R 5a is replaced by R 5a is hydroxyl, or a pharma- ceutically acceptable salt thereof.

[0084] Embodiment 23.R 5 -CO 2 H, or a pharma- ceutically acceptable salt thereof.

[0085] Embodiment 24.R 5 is tetrazolyl, or a pharma- ceutically acceptable salt thereof.

[0086] Embodiment 25.R 4 is HaroC 1 ~C 4 one or two R independently selected from the group consisting of alkyl and halogen; 5’ or a pharma- ceutically acceptable salt thereof.

[0087] Embodiment 26.R 6 represents, in each occurrence, hydrogen, halogen, haloC 1 ~C 6 Alkoxy, C 1 ~C 6 or two R 6 in combination with the carbon atom to which they are attached form a spirocyclic carbocycle having 3 to 6 ring atoms, where the spirocyclic carbocycle is unsubstituted or substituted with a halogen or C 1 ~C 6 The compound according to any one of the preceding embodiments, or a pharma- ceutically acceptable salt thereof, substituted by 1 or 2 substituents selected from alkoxy.

[0088] Embodiment 27. A compound according to any one of the preceding embodiments, provided that both m and n are not 3.

[0089] 28. 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-tetrazol-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 or a pharma- ceutically acceptable salt thereof.

[0090] 29.

[0091] [Table 1]

[0092] [Table 2]

[0093] [Table 3]

[0094] [Table 4]

[0095] [Table 5]

[0096] [Table 6]

[0097] [Table 7] or a pharma- ceutically acceptable salt thereof.

[0098] Embodiment 30. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of the preceding embodiments, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier or excipient.

[0099] Embodiment 31. A method for treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to any one of embodiments 1 to 29, or a pharma- ceutically acceptable salt thereof.

[0100] Embodiment 32. A method for modulating the alternative complement pathway activity in a subject, comprising administering to the subject a therapeutically effective amount of a compound according to any one of embodiments 1 to 29, or a pharma- ceutically acceptable salt thereof.

[0101] Embodiment 33. A method of treating a disease or disorder mediated by complement activation, in particular by activation of the alternative complement pathway, in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to any one of embodiments 1 to 29, or a pharma- ceutically acceptable salt thereof.

[0102] Embodiment 34. A method for treating a disease or disorder affected by modulation of the alternative complement pathway, comprising administering to a subject a therapeutically effective amount of a compound according to any one of embodiments 1 to 29, or a pharma- ceutically acceptable salt thereof.

[0103] Embodiment 35. A method for treating a disease or disorder associated with dysregulation of the alternative complement pathway, comprising administering to a subject a therapeutically effective amount of a compound according to any one of embodiments 1 to 29, or a pharma- ceutically acceptable salt thereof.

[0104] Embodiment 36. A method for inhibiting expression or activity of complement factor B, comprising administering to a subject a compound according to any one of embodiments 1 to 29, or a pharma- ceutically acceptable salt thereof.

[0105] Embodiment 37. The disease or disorder is selected from the group consisting of age-related macular degeneration, geographic atrophy, diabetic retinopathy, uveitis, retinitis pigmentosa, macular edema, Behcet's uveitis, multifocal choroiditis, Vogt-Koyanagi-Harada syndrome, intermediate uveitis, birdshot choroiditis, sympathetic ophthalmia, ocular bifurcation pemphigoid, ocular pemphigus, nonarteritic ischemic optic neuropathy, postoperative inflammation, retinal vein occlusion, glaucoma, Doyne honeycomb retinal dystrophy / Malattia leventinese, Sorsby fundus dystrophy, late onset retinal macular dystrophy, North neurological disorders such as carolina macular dystrophy, Stargardt's disease, corneal inflammation, multiple sclerosis, 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 of inappropriate or undesirable complement activation, such as hemodialysis complications, hyperacute allograft rejection, xenograft rejection, interleukin-2 induced toxicity during IL-2 treatment, inflammatory disorders, paroxysmal nocturnal hemoglobinuria, C3 glomerulonephritis (including compact deposits and C3 glomerulonephritis), immune complex membranoproliferative glomerulonephritis (IC-MPGN), IgA nephropathy, membranous nephropathy including idiopathic membranous nephropathy, diabetic nephropathy, non-small cell lung cancer, and idiopathic nephropathy. typical hemolytic uraemic syndrome (aHUS), hemolytic uraemic syndrome, STEC-HUS (Shiga toxin producing E. coli hemolytic uraemic syndrome), peritonitis, CD55 deficiency with complement hyperactivation, vasculopathic thrombosis, protein-losing enteropathy (CHAPLE syndrome), inflammatory or autoimmune diseases such as Crohn's disease, neuromyelitis optica (NMO), IgA vasculitis (previously known as Henoch-Schönlein purpura or HSP), CHAPLE syndrome, hematopoietic stem cell transplantation-associated thrombotic microangiopathy (HSCT-TMA), adult respiratory distress syndrome (ARDS), myocarditis, post-ischemic reperfusion state, myocardial infarction, balloon angioplasty, post-pump syndrome in cardiopulmonary or renal bypass, atherosclerosis, hemodialysis, kidney injury, acute kidney injury, mesenteric artery reperfusion after aortic reconstruction, infection or sepsis;COVID-19, immune complex disorders and autoimmune diseases, rheumatoid arthritis, osteoarthritis, spondyloarthropathy, 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, fibrous dust disease, pulmonary fibrosis, asthma, allergies, bronchoconstriction, hypersensitivity pneumonitis, parasitic diseases, Goodpasture's disease The method according to any one of embodiments 31 and 33-35, wherein the disease is selected from the group consisting of pulmonary vasculitis, pauciimmune vasculitis, antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), Buerger's vasculitis, cryoglobulinemia, Kawasaki disease, Takayasu's arteritis, cryoglobulinemia, immune complex-associated inflammation, antiphospholipid syndrome, glomerulonephritis and obesity; immune thrombocytopenia, cold agglutinin disease, warm autoimmune hemolytic anemia (wAIHA), thrombotic thrombocytopenic purpura (TTP), abdominal aortic aneurysm and Graves' disease;

[0106] Embodiment 38. A method for treating age-related macular degeneration, 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 pharma- ceutically acceptable salt thereof.

[0107] Embodiment 39. A compound according to any one of embodiments 1 to 29, or a pharma- ceutically acceptable salt thereof, for use as a medicament.

[0108] Embodiment 40. A compound according to any one of embodiments 1 to 29, or a pharma- ceutically acceptable salt thereof, for use in inhibiting the expression or activity of complement factor B in a subject in need thereof.

[0109] Embodiment 41. A compound according to any one of embodiments 1 to 29 or a pharma- ceutically acceptable salt thereof for use in the treatment of a disease or disorder associated with dysregulation of the alternative complement pathway.

[0110] Embodiment 42. The disease or disorder is selected from the group consisting of age-related macular degeneration, geographic atrophy, diabetic retinopathy, uveitis, retinitis pigmentosa, macular edema, Behcet's uveitis, multifocal choroiditis, Vogt-Koyanagi-Harada syndrome, intermediate uveitis, birdshot retina-choroiditis, sympathetic ophthalmia, ocular bisymptomatic pemphigoid, ocular pemphigus, nonarteritic ischemic optic neuropathy, postoperative inflammation, retinal vein occlusion, glaucoma, Doyne honeycomb retinal dystrophy / Malattia leventinese, Sorsby fundus dystrophy, late onset retinal macular dystrophy, North neurological disorders such as carolina macular dystrophy, Stargardt's disease, corneal inflammation, multiple sclerosis, 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 of inappropriate or undesirable complement activation, such as hemodialysis complications, hyperacute allograft rejection, xenograft rejection, interleukin-2 induced toxicity during IL-2 treatment, inflammatory disorders, paroxysmal nocturnal hemoglobinuria, C3 glomerulonephritis (including compact deposits and C3 glomerulonephritis), immune complex membranoproliferative glomerulonephritis (IC-MPGN), IgA nephropathy, membranous nephropathy including idiopathic membranous nephropathy, diabetic nephropathy, non-small cell lung cancer, and idiopathic nephropathy. typical hemolytic uraemic syndrome (aHUS), hemolytic uraemic syndrome, STEC-HUS (Shiga toxin producing E. coli hemolytic uraemic syndrome), peritonitis, CD55 deficiency with complement hyperactivation, vasculopathic thrombosis, protein-losing enteropathy (CHAPLE syndrome), inflammatory or autoimmune diseases such as Crohn's disease, neuromyelitis optica (NMO), IgA vasculitis (previously known as Henoch-Schönlein purpura or HSP), CHAPLE syndrome, hematopoietic stem cell transplantation-associated thrombotic microangiopathy (HSCT-TMA), adult respiratory distress syndrome (ARDS), myocarditis, post-ischemic reperfusion state, myocardial infarction, balloon angioplasty, post-pump syndrome in cardiopulmonary or renal bypass, atherosclerosis, hemodialysis, kidney injury, acute kidney injury, mesenteric artery reperfusion after aortic reconstruction, infection or sepsis;COVID-19, immune complex disorders and autoimmune diseases, rheumatoid arthritis, osteoarthritis, spondyloarthropathy, 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, fibrous dust disease, pulmonary fibrosis, asthma, allergies, bronchoconstriction, hypersensitivity pneumonitis, parasitic diseases, Goodpasture's syndrome, lung The compound or a pharmacologic acceptable salt thereof for use according to embodiment 41, selected from vasculitis, pauciimmune vasculitis, antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), Buerger's vasculitis, cryoglobulinemia, Kawasaki's disease, Takayasu's arteritis, cryoglobulinemia, immune complex-associated inflammation, antiphospholipid syndrome, glomerulonephritis and obesity; immune thrombocytopenia, cold agglutinin disease, warm autoimmune hemolytic anemia (wAIHA), thrombotic thrombocytopenic purpura (TTP), abdominal aortic aneurysm, and Graves' disease;

[0111] Embodiment 43. Use of a compound according to any one of embodiments 1 to 29 or a pharma- ceutically acceptable salt thereof in the manufacture of a medicament for the treatment of a disease or disorder mediated by complement activation or activation of the alternative complement pathway.

[0112] Embodiment 44. Age-related macular degeneration, geographic atrophy, diabetic retinopathy, uveitis, retinitis pigmentosa, macular edema, Behcet's uveitis, multifocal choroiditis, Vogt-Koyanagi-Harada syndrome, intermediate uveitis, birdshot retina-choroiditis, sympathetic ophthalmia, ocular bisymptomatic pemphigoid, ocular pemphigus, nonarteritic ischemic optic neuropathy, postoperative inflammation, retinal vein occlusion, glaucoma, Doyne honeycomb retinal dystrophy / Malattia leventinese, Sorsby fundus dystrophy, late-onset retinal macular dystrophy, North neurological disorders such as carolina macular dystrophy, Stargardt's disease, corneal inflammation, multiple sclerosis, 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 of inappropriate or undesirable complement activation, such as hemodialysis complications, hyperacute allograft rejection, xenograft rejection, interleukin-2 induced toxicity during IL-2 treatment, inflammatory disorders, paroxysmal nocturnal hemoglobinuria, C3 glomerulonephritis (including compact deposits and C3 glomerulonephritis), immune complex membranoproliferative glomerulonephritis (IC-MPGN), IgA nephropathy, membranous nephropathy including idiopathic membranous nephropathy, diabetic nephropathy, non-small cell lung cancer, and idiopathic nephropathy. typical hemolytic uraemic syndrome (aHUS), hemolytic uraemic syndrome, STEC-HUS (Shiga toxin producing E. coli hemolytic uraemic syndrome), peritonitis, CD55 deficiency with complement hyperactivation, vasculopathic thrombosis, protein-losing enteropathy (CHAPLE syndrome), inflammatory or autoimmune diseases such as Crohn's disease, neuromyelitis optica (NMO), IgA vasculitis (previously known as Henoch-Schönlein purpura or HSP), CHAPLE syndrome, hematopoietic stem cell transplantation-associated thrombotic microangiopathy (HSCT-TMA), adult respiratory distress syndrome (ARDS), myocarditis, post-ischemic reperfusion state, myocardial infarction, balloon angioplasty, post-pump syndrome in cardiopulmonary or renal bypass, atherosclerosis, hemodialysis, kidney injury, acute kidney injury, mesenteric artery reperfusion after aortic reconstruction, infection or sepsis;COVID-19, immune complex disorders and autoimmune diseases, rheumatoid arthritis, osteoarthritis, spondyloarthropathy, 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, fibrous dust disease, pulmonary fibrosis, asthma, allergies, bronchoconstriction, hypersensitivity pneumonitis, parasitosis, Goodpasture's syndrome, pulmonary vasculitis, pauci-immune vasculitis, anti-inflammatory drugs ... Use of a compound according to any one of embodiments 1 to 29 or a pharma- ceutically acceptable salt thereof in the manufacture of a medicament for the treatment of a disease or disorder selected from neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), Buerger's vasculitis, cryoglobulinemia, Kawasaki disease, Takayasu's arteritis, cryoglobulinemia, immune complex-associated inflammation, antiphospholipid syndrome, glomerulonephritis and obesity; immune thrombocytopenia, cold agglutinin disease, warm autoimmune hemolytic anemia (wAIHA), thrombotic thrombocytopenic purpura (TTP), abdominal aortic aneurysm, and Graves' disease.

[0113] Embodiment 45. Use of a compound according to any one of embodiments 1 to 29 or a pharma- ceutically acceptable salt thereof for treating a disease or disorder mediated by complement activation or activation of the alternative complement pathway.

[0114] Embodiment 46. Use of a compound according to any one of embodiments 1 to 29 or a pharma- ceutically acceptable salt thereof for treating a disease or disorder affected by modulation of the alternative complement pathway.

[0115] Embodiment 47. Age-related macular degeneration, geographic atrophy, diabetic retinopathy, uveitis, retinitis pigmentosa, macular edema, Behcet's uveitis, multifocal choroiditis, Vogt-Koyanagi-Harada syndrome, intermediate uveitis, birdshot retina-choroiditis, sympathetic ophthalmia, ocular bisymptomatic pemphigoid, ocular pemphigus, nonarteritic ischemic optic neuropathy, postoperative inflammation, retinal vein occlusion, glaucoma, Doyne honeycomb retinal dystrophy / Malattia leventinese, Sorsby fundus dystrophy, late-onset retinal macular dystrophy, North neurological disorders such as carolina macular dystrophy, Stargardt's disease, corneal inflammation, multiple sclerosis, 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 of inappropriate or undesirable complement activation, such as hemodialysis complications, hyperacute allograft rejection, xenograft rejection, interleukin-2 induced toxicity during IL-2 treatment, inflammatory disorders, paroxysmal nocturnal hemoglobinuria, C3 glomerulonephritis (including compact deposits and C3 glomerulonephritis), immune complex membranoproliferative glomerulonephritis (IC-MPGN), IgA nephropathy, membranous nephropathy including idiopathic membranous nephropathy, diabetic nephropathy, non-small cell lung cancer, and idiopathic nephropathy. typical hemolytic uraemic syndrome (aHUS), hemolytic uraemic syndrome, STEC-HUS (Shiga toxin producing E. coli hemolytic uraemic syndrome), peritonitis, CD55 deficiency with complement hyperactivation, vasculopathic thrombosis, protein-losing enteropathy (CHAPLE syndrome), inflammatory or autoimmune diseases such as Crohn's disease, neuromyelitis optica (NMO), IgA vasculitis (previously known as Henoch-Schönlein purpura or HSP), CHAPLE syndrome, hematopoietic stem cell transplantation-associated thrombotic microangiopathy (HSCT-TMA), adult respiratory distress syndrome (ARDS), myocarditis, post-ischemic reperfusion state, myocardial infarction, balloon angioplasty, post-pump syndrome in cardiopulmonary or renal bypass, atherosclerosis, hemodialysis, kidney injury, acute kidney injury, mesenteric artery reperfusion after aortic reconstruction, infection or sepsis;COVID-19, immune complex disorders and autoimmune diseases, rheumatoid arthritis, osteoarthritis, spondyloarthropathy, 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, fibrous dust disease, pulmonary fibrosis, asthma, allergies, bronchoconstriction, hypersensitivity pneumonitis, parasitosis, Goodpasture's syndrome, pulmonary vasculitis, pneumonia, pulmonary vascular inflammation, pulmonary vascular disease ... Use of a compound according to any one of embodiments 1 to 29 or a pharmacologic acceptable salt thereof for the treatment of a disease or disorder selected from: vasculitis, antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), Buerger's vasculitis, cryoglobulinemia, Kawasaki disease, Takayasu's arteritis, cryoglobulinemia, immune complex-associated inflammation, antiphospholipid syndrome, glomerulonephritis and obesity; immune thrombocytopenia, cold agglutinin disease, warm autoimmune hemolytic anemia (wAIHA), thrombotic thrombocytopenic purpura (TTP), abdominal aortic aneurysm, and Graves' disease.

[0116] Embodiment 48. Use of a compound according to any one of embodiments 1 to 29 or a pharma- ceutically acceptable salt thereof for treating age-related macular degeneration.

[0117] Embodiment 49. A pharmaceutical combination comprising a compound according to any one of embodiments 1 to 29 or a pharma- ceutically acceptable salt thereof, and one or more further therapeutic agents.

[0118] Depending on the selection of starting materials and procedures, the compounds may exist in one of the possible isomeric forms or as mixtures thereof, for example as pure optical isomers or as isomeric mixtures, for example racemates and diastereomeric mixtures, depending on the number of asymmetric centers. The present disclosure is meant 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. When the compounds contain di- or trisubstituted cycloalkyl, the cycloalkyl substituent may have a cis or trans configuration. The present disclosure includes cis and trans configurations of substituted cycloalkyl groups, for example, cyclobutyl groups, as well as mixtures thereof. All tautomeric forms are also intended to be included. In particular, when the heteroaryl ring containing N as a ring atom is a 2-pyridone, tautomers are included in which, for example, the carbonyl is shown as hydroxy (e.g., 2-hydroxypyridine).

[0119] Separation of cis and trans isomers can be achieved by methods known to those skilled in the art, such as chromatographic methods involving tools such as HPLC (High Performance Liquid Chromatography), thin layer chromatography, SFC (Supercritical Fluid Chromatography), GC (Gas Chromatography) or recrystallization techniques.

[0120] Pharmaceutically acceptable salts As used herein, the term "salt" or "salts" refers to acid addition salts or base addition salts of the compounds of the present disclosure. "Salt" specifically includes "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 physically or otherwise undesirable. The compounds of the present disclosure may be capable of forming acid salts and / or base salts due to the presence of amino and / or carboxyl groups or groups similar thereto.

[0121] 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 an HCl or formate salt.

[0122] 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.

[0123] 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. Particular organic amines include isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine and tromethamine.

[0124] In another aspect, the present disclosure provides an acid salt, such as acetate, ascorbate, adipate, aspartate, benzoate, besylate, bromide / hydrobromide, bicarbonate / carbonate, bisulfate / sulfate, camphorsulfonate, caprate, chloride / hydrochloride, chlortheophyllonate, citrate, ethanedisulfonate, fumarate, gluceptate, gluconate, glucuronate, glutamate, glutarate, glycolate, hippurate, hydroiodide / iodide, isethionate, lactate, lactobionate, laurate ... In one embodiment, the compound is provided in the form of a salt of the formula (I) of the formula (I): aryl sulfate, malate, maleate, malonate, mandelate, mesylate, methylsulfate, mucate, naphthoate, napsylate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate, polygalacturonate, propionate, sebacate, stearate, succinate, sulfosalicylate, sulfate, tartrate, tosylate, triphenylacetate, trifluoroacetate or xinafoate.

[0125] In another aspect, the disclosure provides compounds in the form of a sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, copper, isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine, or tromethamine salt.

[0126] Isotopically labeled compounds Any formula shown herein is also intended to represent unlabeled and isotopically labeled forms of the compound.Isotopically labeled compounds have the structure shown by the formula shown herein, except that one or more atoms are replaced by an atom with a selected atomic mass or mass number.Examples of isotopes that can be incorporated into the compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine, chlorine and iodine, such as isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine, chlorine and iodine, respectively. 2 H, 3 H, 11 C. 13 C. 14 C. 18 O. 15N, 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, including those that contain radioactive isotopes, e.g. 3 H and 14 C is present or among them non-radioactive isotopes, e.g. 2 H and 13 Such isotope-labeled compounds are useful for metabolic studies ( 14 C), reaction kinetic 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 radioactive treatment of patients. 18 F compounds may be particularly desirable for PET or SPECT studies. Isotopically labeled compounds of formula (I) or sub-formulas thereof may generally be prepared by conventional techniques known to those skilled in the art or by processes similar to those described in the accompanying examples and general schemes, substituting appropriate isotopically labeled reagents for previously used non-labeled reagents.

[0127] In addition, the heavier isotopes, especially deuterium (i.e. 2Substitution with H or D) may provide certain therapeutic benefits resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements or improved therapeutic index. It is understood in this context that deuterium is considered as a substituent of a compound of formula (I) or any of its subformulas. The concentration of such heavier isotopes, particularly deuterium, may be defined by the isotopic enrichment factor. The term "isotopic enrichment factor" as used herein refers to the ratio between the isotopic abundance and the natural abundance of a particular isotope. When a substituent in a compound of the disclosure is designated as deuterium, such compounds have 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).

[0128] Pharmaceutically acceptable solvates according to the present disclosure include those in which the solvent of crystallization may be isotopically substituted, e.g., D 2 O, d 6 -Acetone, d 6 -Contains DMSO.

[0129] Compounds of the present disclosure, i.e., compounds of formula (I), (IA), (IB), that contain groups capable of acting as donors and / or acceptors for hydrogen bonds, may be capable of forming co-crystals with suitable co-crystal formers. These co-crystals may be prepared from compounds of formula (I) or its sub-formulas by known co-crystal formation procedures. Such procedures include grinding, heating, co-subliming, co-melting, or contacting compounds of (I), (IA), (IB) with a crystal former under crystallization conditions in solution, and isolating the co-crystals formed thereby. Suitable co-crystal formers include those described in WO 2004 / 078163.

[0130] All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples or exemplary language (e.g., "etc.") provided herein is intended merely to better elucidate the disclosure and does not pose a limitation on the scope of the disclosure as otherwise claimed.

[0131] The asymmetric centers (e.g., carbons, etc.) of the compounds of the present disclosure can be present in racemic or enantiomerically enriched configurations, such as (R)-, (S)-, or (R,S)-configurations. In certain embodiments, e.g., as 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 chiral 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 can be present in racemic mixtures or in enantiomerically enriched form or in enantiopure form or as mixtures of diastereoisomers.

[0132] In one embodiment, there is provided compounds of formula (I) or pharma- ceutically acceptable salts thereof, which are present in at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess.

[0133] In one embodiment, there is provided compounds of formula (I) or pharma- ceutically acceptable salts thereof, which are present in diastereomeric excess of at least 90%, in diastereomeric excess of at least 95%, or in diastereomeric excess of at least 99%.

[0134] In one embodiment, the compound of formula (I) has the formula (IA) [ka] or a pharma- ceutically acceptable salt thereof, wherein A is selected from phenyl, furanyl, thiophenyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, pyrazolyl, imidazolyl, pyridyl, triazolyl, tetrazolyl, oxadiazolyl, isoxadiazolyl, pyrimidinyl, pyrazinyl, and pyridazinyl; R, R 1 , R 2 , R 3 , R 5 , R 6 , R 8 , W, m, n, and p are defined according to embodiment 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 of embodiments 1-26.

[0135] In another embodiment, the compound of formula (I) has the formula (IB) [ka] or a pharma- ceutically acceptable salt thereof, wherein A is selected from phenyl, furanyl, thiophenyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, pyrazolyl, imidazolyl, pyridyl, triazolyl, tetrazolyl, oxadiazolyl, isoxadiazolyl, pyrimidinyl, pyrazinyl, and pyridazinyl; R, R 1 , R 2 , R 3 , R 5 , R 6 , R 8 , W, m, n, and p are defined according to embodiment 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 of embodiments 1-26.

[0136] In another embodiment, the compound of formula (I) has the formula (IC) [ka] or a pharma- ceutically acceptable salt thereof, 1 , R 2 , R 3 , R 5 , R 6 , R 8 , W, and p are defined according to embodiment 1. In particular, R, R 1 , R 2 , R 5 , R 6 , R 8 , W, and p may be defined according to any of the embodiments 1-26.

[0137] In another embodiment, the compound of formula (I) has the formula (ID): [ka] or a pharma- ceutically acceptable salt thereof, wherein R, R 1 , R 2 , R 5 , R 7 and R 8 is defined according to embodiment 1. In particular, R, R 1 , R 2 , R 5 , R 7 and R 8 can be defined according to any of the first to twenty-sixth embodiments.

[0138] In the formula of the present application, C-sp 3 Above terms [ka] indicates the absolute stereochemical configuration (R) or (S). 3 Above terms [ka] indicates the absolute stereochemical configuration (R) or (S). 3 Above terms [ka] represents a covalent bond and the stereochemical configuration of the bond is not defined. 3 Above terms [ka] includes either the (S) or (R) configuration of each chiral center. Additionally, mixtures may exist. Thus, mixtures of stereoisomers, e.g., mixtures of enantiomers, e.g., racemates and / or mixtures of diastereoisomers, are encompassed by the present disclosure.

[0139] For the avoidance of doubt, [ka] When a compound structure is drawn with an undefined stereochemical configuration for any R group, as represented by:

[0140] For the avoidance of doubt, in any of the formulas in this application, R 5 When a group is shown attached to ring A, it is R 5 It means that the group can be attached via a carbon atom or a heteroatom, such as nitrogen.

[0141] For the avoidance of doubt, compound structures depicted herein may, where appropriate, exist in their zwitterionic form.

[0142] 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, such as substantially pure geometric (cis or trans) stereoisomers, diastereomers, optical isomers, racemates, or mixtures thereof.

[0143] Any resulting mixtures of stereoisomers can be separated on the basis of the physical chemical differences of the constituents into pure or substantially pure geometric or optical isomers, diastereomers, racemates, for example, by chromatography and / or fractional crystallization.

[0144] Any resulting racemates of the compounds or intermediates of the present disclosure can be resolved into their optical isomers (enantiomers) by known methods, for example by separation of their diastereomeric salts obtained with optically active acids or bases and liberating the optically active acidic or basic compounds. In particular, basic moieties can be used in this way to resolve the compounds of the present disclosure into their optical antipodes, for example by fractional crystallization of salts formed with optically active acids, for example tartaric acid, dibenzoyltartaric acid, diacetyltartaric acid, di-O,O'-p-toluoyltartaric acid, mandelic acid, malic acid or camphor-10-sulfonic acid. The racemates or racemic intermediates of the present disclosure can also be resolved by chiral chromatography, for example by high pressure liquid chromatography (HPLC) using a chiral adsorbent.

[0145] Furthermore, the compounds of the present disclosure, including their salts, may be obtained in the form of their hydrates or may include other solvents used for their crystallization. The compounds of the present disclosure may inherently or intentionally form solvates with pharma-ceutically acceptable solvents, including water; thus, the present disclosure is intended to encompass both solvated and unsolvated forms. The term "solvate" refers to a molecular complex of the compounds of the present disclosure (including its pharma-ceutically acceptable salts) with one or more solvent molecules. Such solvent molecules are those commonly used in pharmaceutical technology, known to be harmless to the recipient, such as water, ethanol, etc. The term "hydrate" refers to a complex in which the solvent molecule is water. The presence of solvates can be identified by those skilled in the art by tools, such as NMR.

[0146] Compounds of the present disclosure, including their salts, hydrates and solvates, may inherently or by design form polymorphs.

[0147] Method of production The compounds of the present disclosure can be prepared in a number of ways well known to those skilled in the art of organic synthesis. By way of example, the compounds of the present disclosure can be synthesized using the methods described below, together with synthetic methods known in the art of organic synthetic chemistry, or variations thereof as will be appreciated by those skilled in the art.

[0148] In general, compounds of formula (I) can be prepared according to the schemes provided below.

[0149] The compounds provided herein can be prepared according to the following examples. In the following scheme, R, R 1 , R 2 , R 3 , R 5 , R 6 , R 8 , W, m, n and p are defined according to enumerated embodiment 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 embodiments 1-23. PG refers to a protecting group. Suitable protecting groups are known to those skilled in the art, and the same or different protecting groups can be used in any scheme. Further definitions are provided as applicable to the following general scheme.

[0150] General Scheme 1 [ka] Examples S1-10 can be prepared as outlined in general scheme 1. Arylation of ketone S1-2 with aryl bromide S1-1 can be carried out using Buchwald coupling conditions. The resulting intermediate S1-3 can be deprotected to give intermediate S1-4, which can then be reacted with a suitable electrophile, such as an alkyl halide or triflate, in the presence of 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 is carried out using 9-BBN to give boronate S1-7. This is coupled to 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 give intermediate S1-9, which is then deprotected to give final example S1-10.

[0151] General Scheme 2 [ka] Examples S2-15 can be prepared as outlined in general Scheme 2.

[0152] Beta-ketoester S2-1 can be converted to vinyl triflate S2-2 using trifluoromethanesulfonic anhydride and base. Suzuki coupling with boronic acid or ester S2-3 gives S2-4. Hydrogenation of the alkene provides S2-5 and base-mediated epimerization gives S2-6, which has a trans configuration between adjacent stereocenters. Reduction of the ester with a reducing agent such as lithium borohydride provides primary alcohol S2-7, where R 5 When X' is also an ester, the reduction is chemoselective towards the alkyl ester. The alcohol can be converted to the primary halide S2-8 (e.g., X' = Br) using electrophiles such as carbon tetrabromide. Palladium-catalyzed borylation gives the boronic ester S2-9, which is then converted to S2-10 using potassium bifluoride. BF 3 The K-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 intermediate S2-12. Intermediate S2-12 can be selectively deprotected to give intermediate S2-13, which can then be reacted with a suitable electrophile, such as an alkyl halide or triflate, in the presence of a base, or with a suitable aldehyde or ketone in the presence of a reducing agent, such as sodium triacetoxyboronhydride or sodium cyanoborohydride, to give S2-14. Deprotection gives the final example S2-15.

[0153] In a further aspect, the present disclosure provides a process for preparing a compound of formula (I), in free form or in pharma- ceutically acceptable salt form, comprising the steps described above.

[0154] Pharmaceutical Compositions In another aspect, the present disclosure provides pharmaceutical compositions comprising one or more compounds described herein, or pharma- ceutically acceptable salts thereof, and one or more pharma- ceutically acceptable carriers.

[0155] In further embodiments, the composition comprises at least one or two pharma- ceutically acceptable carriers, such as those described herein.For purposes of this disclosure, unless otherwise specified, solvates and hydrates are generally considered to be compositions.

[0156] The compounds of formula (I) and its subformulas described herein may be administered alone or as the active ingredient of a pharmaceutical composition.Thus, provided herein are pharmaceutical compositions comprising a compound of formula (I) or its subformulas, or a pharma- ceutically acceptable salt thereof, and one or more pharma- ceutically acceptable carriers.

[0157] Methods for preparing various pharmaceutical compositions are known to those skilled in the art and may be described, for example, in Handbook of Pharmaceutical Excipients, American Pharmaceutical Association (current edition); Pharmaceutical Dosage Forms Tablets (Lieberman, Lachman and Schwartz, editors) current edition, published by Marcel Dekker, Inc. and Remington's Pharmaceutical Sciences (Arthur Osol, editor), 1553-1593 (current edition).

[0158] Pharmaceutical compositions can be formulated for a particular route of administration, such as oral, topical, parenteral, and rectal administration. Furthermore, pharmaceutical compositions of the present disclosure can be made in solid form (including but not limited to capsules, tablets, pills, granules, powders, or suppositories) or liquid form (including but not limited to solutions, gels, suspensions, or emulsions). The pharmaceutical compositions can be subjected to conventional pharmaceutical operations, such as sterilization, and / or can contain conventional inert excipients, lubricants or buffers, as well as adjuvants, such as preservatives, stabilizers, wetting agents, emulsifiers, and buffers.

[0159] Typically, the pharmaceutical composition comprises: a) excipients, such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine; b) lubricants, such as silica, talc, stearic acid, its magnesium or calcium salts and / or polyethylene glycol; c) binders, such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone; d) disintegrants, such as starch, agar, alginic acid or its sodium salt or effervescent mixtures; and e) Absorbents, colouring agents, flavouring agents and sweetening agents The active ingredient is a tablet or gelatin capsule containing one or more of the following:

[0160] In one embodiment, the pharmaceutical composition is a capsule containing only the active ingredient.

[0161] Tablets may be film coated or enteric coated by methods known in the art.

[0162] The mode of administration and pharmaceutical composition are closely related to the therapeutic amount of the compound or composition that is desired and effective for a given treatment application. The pharmaceutical compositions provided herein can be formulated for ocular, ocular, topical and transdermal administration. In certain embodiments, the pharmaceutical compositions provided herein are suitable for ocular administration. To prepare pharmaceutical compositions, the active ingredient can be mixed with one or more pharma- ceutically acceptable carriers by conventional pharmaceutical compounding techniques. The carrier can take a wide variety of forms depending on the form of preparation desired for administration.

[0163] Suitable compositions for oral administration include an effective amount of the compounds of the present disclosure 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. Oral compositions can be prepared by any method known in the art for the manufacture of pharmaceutical compositions, and such compositions can contain one or more agents selected from the group consisting of sweeteners, flavoring agents, coloring agents and preservatives to provide pharma-ceutically elegant and palatable preparations. Tablets can contain the active ingredient mixed with non-toxic pharma-ceutically acceptable additives suitable for the manufacture of tablets. These additives are, for example, inert excipients such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents such as corn starch or alginic acid; binders such as starch, gelatin or acacia; and lubricants such as magnesium stearate, stearic acid or talc. The tablets are uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract, thereby achieving a sustained action over a longer period of time.For example, a time-delay material such as glyceryl monostearate or glyceryl distearate can be used.Formulations for oral use can be presented as hard gelatin capsules (wherein the active ingredient is mixed with an inert solid excipient such as calcium carbonate, calcium phosphate or kaolin) or as soft gelatin capsules (wherein the active ingredient is mixed with water or an oil medium such as peanut oil, liquid paraffin or olive oil).

[0164] Certain injectable compositions are aqueous isotonic solutions or suspensions, and suppositories are advantageously prepared from fatty emulsions or suspensions. The compositions may be sterilized and / or contain adjuvants, such as preservatives, stabilizing agents, wetting agents or emulsifying agents, dissolution promoters, salts for regulating osmotic pressure and / or buffers. In addition, they may also contain other therapeutically valuable substances. The compositions are prepared by conventional mixing, granulating or coating methods, respectively, and contain about 0.1-75% of the active ingredient, or about 1-50% of the active ingredient.

[0165] Suitable compositions for transdermal application include an effective amount of the compound of the present disclosure with suitable carrier.Carriers suitable for transdermal delivery include absorbable pharmacologically acceptable solvents that support passage through the host's skin.For example, transdermal devices are in the form of bandages that include a backing component, a reservoir that contains the compound, optionally with a carrier, a rate-limiting barrier that optionally delivers the compound to the host's skin at a controlled, predetermined rate over a long period of time, and a means for fixing the device to the skin.

[0166] For example, suitable compositions for topical application to the skin and eyes include aqueous solutions, suspensions, ointments, creams, gels, or sprayable formulations, e.g., for delivery by aerosol. Such topical delivery systems are particularly suitable for dermal application, e.g., for the treatment of skin cancer, and for prophylactic use, e.g., in sun creams, lotions, sprays, etc. As such, they are particularly suitable for topical use, including cosmetic formulations, well known in the art. Such may contain solubilizers, stabilizers, tonicity enhancers, buffers, and preservatives.

[0167] As used herein, topical application may also refer to inhalation or intranasal application, which may be conveniently delivered in the form of a dry powder from a dry powder inhaler (alone, in mixtures, e.g., as a dry blend with lactose or mixed component particles, e.g., with phospholipids) or an aerosol spray presentation from a pressurized container, pump, spray, atomizer or nebulizer, with or without the use of a suitable propellant.

[0168] In certain embodiments, the pharmaceutical compositions provided herein are formulated as solutions, suspensions, gels, creams, ointments, liposomes, ocular inserts, or other pharmaceutical compositions suitable for topical administration to the ocular surface, cornea, eyelids, eye margin, eyelashes, and / or eyelid margin, in certain embodiments, for delivery of the composition to the eye. In some embodiments, a liquid (aqueous or non-aqueous) solution may be used. In certain embodiments, the pharmaceutical compositions are formulated as eye drops for topical administration to the ocular surface, cornea, eyelids, eyelid margin, eyelashes, and / or eyelid margin, in order to deliver the composition to the eye. Application of the pharmaceutical composition may be performed by an applicator for delivery of the formulation to the eye, such as the subject's finger, Weck-Cel®, Q-tip®, or other device capable of delivering the formulation to the eyelid, eyelashes, and / or eyelid margin. The pharmaceutical compositions provided herein can be viscous or semi-viscous; liquid, solid or semi-solid; aqueous or non-aqueous, depending on the site of application, the dose, the solubility of the drug, and a variety of other factors considered by one of skill in the art.

[0169] Any of a variety of carriers may be used in the pharmaceutical compositions provided herein. In one embodiment, the pharma- ceutically acceptable carrier is a non-aqueous carrier (e.g., an oil or oil mixture) having a viscosity ranging from about 50 cps to about 1000 cps, about 50 cps to about 500 cps, about 50 cps to about 200 cps, or about 60 cps to about 120 cps. In certain embodiments, the non-aqueous carrier comprises an oil, such as vegetable oil, silicone oil, mineral oil, or any combination thereof. In some embodiments, the carrier may be liquid paraffin, white petrolatum, refined lanolin, gelling hydrocarbon, polyethylene glycol, hydrophilic ointment base, white ointment base, water-absorbing ointment base, macrogol ointment base, simple ointment base, and the like. In certain embodiments, the pharmaceutical compositions may include monomeric polyols such as glycerol, propylene glycol and ethylene glycol, polymeric polyols such as polyethylene glycol, cellulose esters such as hydroxypropylmethylcellulose, sodium carboxymethylcellulose and hydroxypropylcellulose; dextrans such as dextran 70; water soluble proteins such as gelatin, polymers such as polyvinyl alcohol, polyvinylpyrrolidone and povidone; carbomers such as carbomer 934P, carbomer 941, carbomer 940 and carbomer 974P; and gums such as HP guar.

[0170] Additional additives may be optionally included in the pharmaceutical compositions provided herein. Examples of additional additives include, for example, tonicity enhancers, preservatives, solubilizers, non-toxic additives, demulcents, sequestering agents, pH adjusters, cosolvents, viscosity builders, and combinations thereof.

[0171] The pharmaceutical compositions of the present disclosure may be in the form of an aqueous suspension or solution. In one embodiment, the aqueous pharmaceutical composition of the present disclosure is in the form of an aqueous suspension.

[0172] Aqueous pharmaceutical compositions according to the present disclosure can be prepared using standard procedures familiar to those skilled in the art, for example by mixing the various components, suitably at ambient temperature and atmospheric pressure, hi one embodiment, the aqueous pharmaceutical composition of the present disclosure is suitable for administration to the eye.

[0173] In further embodiments, the pharmaceutical composition of the present disclosure is in the form of an eye ointment, eye gel, eye cream, or eye drops.

[0174] In a further embodiment, the pharmaceutical composition of the present disclosure is administered locally to the eye of a subject.

[0175] The compounds of formula (I), in free form or in the form of a pharma- ceutically acceptable salt, exhibit valuable pharmacological properties, such as complement factor B modulating properties, as shown in in vitro tests such as those provided in the Examples, and are therefore of use for therapy or as research chemicals, e.g. for use as tool compounds.

[0176] Further properties of the disclosed compounds include good potency in the biological assays described herein, a favorable safety profile, and favorable pharmacokinetic properties.

[0177] Diseases and Disorders and Methods of Use In a further aspect, the disclosure provides a compound of formula (I) or a pharma- ceutically acceptable salt thereof, for use in therapy.

[0178] In a further aspect, the disclosure provides a compound of formula (I) or a pharma- ceutically acceptable salt thereof for use in the treatment of a disease or disorder in which a requirement for complement factor B has been demonstrated. In one embodiment, the disease or disorder is affected by inhibition of complement factor B activity.

[0179] The compounds of formula (I) and their pharma- ceutically acceptable salts have complement factor B modulating and / or inhibiting activity and are useful in the treatment of certain diseases or disorders, such as age-related macular degeneration, geographic atrophy, diabetic retinopathy, uveitis, retinitis pigmentosa, macular edema, Behcet's uveitis, multifocal choroiditis, Vogt-Koyanagi-Harada syndrome, intermediate uveitis, birdshot retina-choroiditis, sympathetic ophthalmia, ocular bisymptomatic pemphigoid, ocular pemphigus, non-arteritic ischemic optic neuropathy, postoperative inflammation, retinal vein occlusion, glaucoma, Doyne honeycomb retinal dystrophy / Malattia leventinese, Sorsby fundus dystrophy, late onset retinal macular dystrophy, North neurological disorders such as carolina macular dystrophy, Stargardt's disease, corneal inflammation, multiple sclerosis, 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 of inappropriate or undesirable complement activation, such as hemodialysis complications, hyperacute allograft rejection, xenograft rejection, interleukin-2 induced toxicity during IL-2 treatment, inflammatory disorders, paroxysmal nocturnal hemoglobinuria, C3 glomerulonephritis (including compact deposits and C3 glomerulonephritis), immune complex membranoproliferative glomerulonephritis (IC-MPGN), IgA nephropathy, membranous nephropathy including idiopathic membranous nephropathy, diabetic nephropathy, non-small cell lung cancer, and idiopathic nephropathy. typical hemolytic uraemic syndrome (aHUS), hemolytic uraemic syndrome, STEC-HUS (Shiga toxin producing E. coli hemolytic uraemic syndrome), peritonitis, CD55 deficiency with complement hyperactivation, vasculopathic thrombosis, protein-losing enteropathy (CHAPLE syndrome), inflammatory or autoimmune diseases such as Crohn's disease, neuromyelitis optica (NMO), IgA vasculitis (previously known as Henoch-Schönlein purpura or HSP), CHAPLE syndrome, hematopoietic stem cell transplantation-associated thrombotic microangiopathy (HSCT-TMA), adult respiratory distress syndrome (ARDS), myocarditis, post-ischemic reperfusion state, myocardial infarction, balloon angioplasty, post-pump syndrome in cardiopulmonary or renal bypass, atherosclerosis, hemodialysis, kidney injury, acute kidney injury, mesenteric artery reperfusion after aortic reconstruction, infection or sepsis;COVID-19, immune complex disorders and autoimmune diseases, rheumatoid arthritis, osteoarthritis, spondyloarthropathy, 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, fibrous dust disease, pulmonary fibrosis, asthma, allergies, bronchoconstriction, hypersensitivity pneumonitis, parasitic diseases, Goodpasture's syndrome, lung It is believed that the compound may be used to treat or prevent a disease or disorder selected from: vasculitis, pauciimmuno-vasculitis, antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), Buerger's vasculitis, cryoglobulinemia, Kawasaki disease, Takayasu's arteritis, cryoglobulinemia, immune complex-associated inflammation, antiphospholipid syndrome, glomerulonephritis, and obesity; immune thrombocytopenia, cold agglutinin disease, warm autoimmune hemolytic anemia (wAIHA), thrombotic thrombocytopenic purpura (TTP), abdominal aortic aneurysm, and Graves' disease;

[0180] In view of their activity as complement factor B modulators or inhibitors, the compounds of formula (I) and subformulas thereof, in free or pharma- ceutically acceptable salt form, are useful in the treatment of conditions treatable by inhibition of complement factor B activity. In one aspect, the disclosure provides a method of treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or a subformula thereof, or a pharma- ceutically acceptable salt thereof.

[0181] In another aspect, the disclosure provides a method of modulating the alternative complement pathway activity in a subject, comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or a subformula thereof, or a pharma- ceutically acceptable salt thereof.

[0182] In another aspect, the disclosure provides a method of treating a disease or disorder mediated by complement activation, in particular by activation of the alternative complement pathway, in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or a subformula thereof, or a pharma- ceutically acceptable salt thereof.

[0183] In another aspect, the disclosure provides a method of treating a disease or disorder affected by modulation of the alternative complement pathway, comprising administering to a subject a therapeutically effective amount of a compound of formula (I) or a subformula thereof, or a pharma- ceutically acceptable salt thereof.

[0184] In another aspect, the disclosure provides a method of treating a disease or disorder associated with dysregulation of the alternative complement pathway, comprising administering to a subject a therapeutically effective amount of a compound of formula (I) or a subformula thereof, or a pharma- ceutically acceptable salt thereof.

[0185] In another aspect, the disclosure provides a method of inhibiting expression or activity of complement factor B, comprising administering to a subject a compound of formula (I) or a subformula thereof, or a pharma- ceutically acceptable salt thereof.

[0186] In another aspect, the present disclosure relates to the treatment of age-related macular degeneration, geographic atrophy, diabetic retinopathy, uveitis, retinitis pigmentosa, macular edema, Behcet's uveitis, multifocal choroiditis, Vogt-Koyanagi-Harada syndrome, intermediate uveitis, birdshot choroiditis, sympathetic ophthalmia, ocular bifurcation pemphigoid, ocular pemphigus, non-arteritic ischemic optic neuropathy, postoperative inflammation, retinal vein occlusion, glaucoma, Doyne honeycomb retinal dystrophy / Malattia leventinese, Sorsby fundus dystrophy, late onset retinal macular dystrophy, North neurological disorders such as carolina macular dystrophy, Stargardt's disease, corneal inflammation, multiple sclerosis, 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 of inappropriate or undesirable complement activation, such as hemodialysis complications, hyperacute allograft rejection, xenograft rejection, interleukin-2 induced toxicity during IL-2 treatment, inflammatory disorders, paroxysmal nocturnal hemoglobinuria, C3 glomerulonephritis (including compact deposits and C3 glomerulonephritis), immune complex membranoproliferative glomerulonephritis (IC-MPGN), IgA nephropathy, membranous nephropathy including idiopathic membranous nephropathy, diabetic nephropathy, non-small cell lung cancer, and idiopathic nephropathy. typical hemolytic uraemic syndrome (aHUS), hemolytic uraemic syndrome, STEC-HUS (Shiga toxin producing E. coli hemolytic uraemic syndrome), peritonitis, CD55 deficiency with complement hyperactivation, vasculopathic thrombosis, protein-losing enteropathy (CHAPLE syndrome), inflammatory or autoimmune diseases such as Crohn's disease, neuromyelitis optica (NMO), IgA vasculitis (previously known as Henoch-Schönlein purpura or HSP), CHAPLE syndrome, hematopoietic stem cell transplantation-associated thrombotic microangiopathy (HSCT-TMA), adult respiratory distress syndrome (ARDS), myocarditis, post-ischemic reperfusion state, myocardial infarction, balloon angioplasty, post-pump syndrome in cardiopulmonary or renal bypass, atherosclerosis, hemodialysis, kidney injury, acute kidney injury, mesenteric artery reperfusion after aortic reconstruction, infection or sepsis;COVID-19, immune complex disorders and autoimmune diseases, rheumatoid arthritis, osteoarthritis, spondyloarthropathy, 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, fibrous dust disease, pulmonary fibrosis, asthma, allergies, bronchoconstriction, hypersensitivity pneumonitis, parasitic diseases, good pathology The present invention provides a method for treating a disease or disorder selected from Charr's syndrome, pulmonary vasculitis, pauciimmune vasculitis, antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), Buerger's vasculitis, cryoglobulinemia, Kawasaki disease, Takayasu's arteritis, cryoglobulinemia, immune complex-associated inflammation, antiphospholipid syndrome, glomerulonephritis, and obesity; immune thrombocytopenia, cold agglutinin disease, warm autoimmune hemolytic anemia (wAIHA), thrombotic thrombocytopenic purpura (TTP), abdominal aortic aneurysm, and Graves' disease;

[0187] In certain aspects, methods are provided for the treatment of diseases associated with increased activity of the C3 amplification loop of the complement pathway. In certain embodiments, methods are provided for treating or preventing complement-mediated diseases in which complement activation is induced by antibody-antigen interactions, by components of autoimmune diseases, or by ischemic injury.

[0188] In certain embodiments, the present disclosure provides a method for treating or preventing age-related macular degeneration (AMD) by administering an effective amount of a compound of formula (I) of the present disclosure to a subject in need thereof. In certain embodiments, patients who are currently asymptomatic but at risk of developing symptomatic macular degeneration-related disorders are suitable for administration with a compound of the present disclosure. Methods for treating or preventing AMD include methods for treating or preventing one or more symptoms or aspects of AMD selected from, but not limited to, ocular drusen formation, inflammation of the eye or ocular tissue, loss of photoreceptor cells, loss of vision or loss of visual field), neovascularization (including CNV), retinal detachment, photoreceptor degeneration, RPE degeneration, retinal degeneration, chorioretinal degeneration, cone degeneration, retinal dysfunction, damage to the retina in response to light exposure, damage to Bruch's membrane, and / or loss of RPE function.

[0189] The compound of formula (I) of the present disclosure can be used, inter alia, to prevent the onset of AMD, to prevent the progression of early AMD to neovascular AMD or advanced AMD, including geographic atrophy, to delay and / or prevent the progression of geographic atrophy, to treat or prevent macular edema from AMD or other conditions (e.g., diabetic retinopathy, uveitis, or after surgical or non-surgical trauma), to prevent or reduce vision loss from AMD, and to improve vision loss due to existing early or advanced AMD.It can also be used in combination with anti-VEGF therapy to treat patients with neovascular AMD or to prevent neovascular AMD.

[0190] All of the above embodiments relating to the method of treatment of the above diseases include A compound of formula (I) or any sub-formula thereof or a pharma- ceutically acceptable salt thereof for use in the treatment of the above mentioned diseases according to the present disclosure; Use of a compound of formula (I) or any sub-formula or a pharma- ceutically acceptable salt thereof in the manufacture of a medicament for the treatment of the above diseases according to the present disclosure; Use of a compound of formula (I) or any of its sub-formulas or a pharma- ceutically acceptable salt thereof for the treatment of the above-mentioned diseases according to the present disclosure; and A pharmaceutical composition comprising a compound of formula (I) or any sub-formula thereof or a pharma- ceutically acceptable salt thereof and one or more pharma- ceutically acceptable carriers for use in the treatment of the above-mentioned diseases according to the present disclosure. are equally applicable to

[0191] Dosage The pharmaceutical composition or combination of the present disclosure may be in a unit dosage of about 1-1000 mg of active ingredient for a subject weighing about 50-70 kg. The therapeutically effective dosage of the compound, pharmaceutical composition or combination thereof depends on the species, weight, age and individual condition of the subject, the disorder or disease being treated or its severity.

[0192] The above-mentioned dosage properties are demonstrable in in vitro and in vivo tests, preferably using mammals, such as mice, rats, dogs, monkeys or isolated organs, tissues and preparations thereof. The compounds of the present disclosure can be applied in vitro in the form of solutions, e.g. aqueous solutions, and in vivo, e.g. enterally, parenterally, preferably intravenously, as a suspension or in aqueous solution. The dosage in vitro is about 10 -3 Molar concentration ~ 10 -9 The therapeutically effective amount in vivo may range, for example, from about 0.1 to 500 mg / kg, depending on the route of administration.

[0193] The therapeutically effective dosage of the compound, pharmaceutical composition or combination thereof will depend on the species, weight, age and individual condition of the subject, the disorder or disease to be treated or its severity.

[0194] The activity of compounds according to the present disclosure can be assessed by the in vitro methods described in the Examples.

[0195] Combination therapy In another aspect, the disclosure provides a pharmaceutical combination comprising a compound of formula (I) or a sub-formula thereof or a pharma- ceutically acceptable salt thereof and one or more further therapeutic agents for simultaneous, separate or sequential use in therapy.

[0196] The compounds of the present disclosure may be administered simultaneously with, before or after one or more other therapeutic agents. The compounds of the present disclosure may be administered separately by the same or different administration route or together in the same pharmaceutical composition with other agents. The therapeutic agent is, for example, a compound, peptide, antibody, antibody fragment or nucleic acid that is therapeutically active or enhances therapeutic activity when administered to a patient in combination with the compounds of the present disclosure. Thus, in one embodiment, the present disclosure provides a combination comprising a therapeutically effective amount of a compound of formula or its subformula or a pharma- ceutically acceptable salt thereof and one or more therapeutically active agents.

[0197] In certain embodiments, the compound of formula (I) or a subformula thereof or a pharma- ceutically acceptable salt thereof may be administered together with a further therapeutic agent.

[0198] The pharmaceutical compositions of the present disclosure, for example those comprising a compound of formula (I), can be administered alone or in combination with other molecules known to have beneficial effects on retinal attachment or retinal tissue damage, including molecules capable of inhibiting tissue repair and regeneration and / or inflammation. Examples of useful cofactors include complement inhibitors (e.g., Factor D, inhibitors of C5a receptor and antibodies or Fabs against C5, C3, Properidin, Factor H, etc.), anti-VEGF agents (e.g., antibodies or FABs against VEGF, e.g., Lucentis or Avastin), basic fibroblast growth factor (bFGF), ciliary neurotrophic factor (CNTF), axokine (a mutein 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, 30 kD survival factor, taurine and vitamin A. Other useful cofactors include symptom-relieving cofactors, including antiseptics, antibiotics, antivirals and antifungals, as well as analgesics and anesthetics. Agents suitable for combination treatment with the compounds of the present disclosure include agents known in the art that can modulate the activity of complement components.

[0199] In some embodiments, the present disclosure provides combination therapy for preventing and / or treating AMD or another complement-associated eye disease as described above using a compound of the present disclosure and an anti-angiogenic, e.g., anti-VEGF agent (including Lucentis Avastin and VEGF-R2 inhibitors, including pazopanib, sutent, nifanib and the VEGF-R2 inhibitors disclosed in WO 2010 / 066684) or photodynamic therapy (e.g., verteporfin).

[0200] In some embodiments, the present disclosure provides combination therapy for preventing and / or treating the above autoimmune diseases using a compound of the present disclosure and a B cell or T cell modulating agent (e.g., cyclosporine or an analog thereof, rapamycin, RAD001 or an analog thereof, etc.). In particular, for multiple sclerosis treatment, it may include a combination of a compound of the present disclosure with a second MS agent selected from fingolimod, cladribine, tisarubi, laquinimod, levi, avonex, etc. A non-limiting list of such agents includes cyclooxygenase-2 (COX-2) inhibitors, such as certain COX-2 inhibitors, e.g., celecoxib and rofecoxib; and nonsteroidal anti-inflammatory drugs (NSAIDs), such as acetylsalicylic acid and propionic acid derivatives; tricyclic antidepressants, such as Anafranil®, Asendin®, Aventyl®, Elavil®, Endep®, Norfranil®, Norpramin®, Pamelor®, Sinequan®, Surmontil®, Tipramine®, Tofranil®, Vivactil®, Tofranil-PM®; anticonvulsants, such as carbamazepine, oxcarbazepine and gabapentin; bradykinin B1 or B2 antagonists; and GABA antagonists. B Agonists include pharmaceutical agents effective in the treatment of diseases and conditions in which vanilloid receptor activation plays or is implicated as playing a role, including L-baclofen.

[0201] In certain embodiments, the additional therapeutic agent may include, for example, other compounds and antibodies that are useful for treating eye 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 fluorobexarotene.Other additional therapeutic agents include ophthalmic steroids, such as dexamethasone, fluocinolone, loteprednol, difluprednate, fluorometholone, prednisolone, prednisone, medrysone, triamcinolone, betamethasone, rimexolone or pharmaceutically acceptable salts thereof.In addition, other additional therapeutic agents include those that are used to target eye surface disease disorders, such as dry eye disease. Non-limiting examples of such additional therapeutic agents include Xiidra® (lifitegrast), Restasis® (cyclosporine), minocycline, doxycycline or other tetracycline antibiotics. Other examples include keratolytic agents such as selenium disulfide, salicylic acid, glycolic acid, and the like, or a pharma- ceutically acceptable salt thereof.

[0202] In certain embodiments, the additional therapeutic agent may include, for example, other compounds useful in the treatment of pain. In one embodiment, the compound of formula (I) or its subformulas or a pharma- ceutically acceptable salt thereof may be administered with an additional analgesic agent. Such analgesic agents may be NSAIDs (e.g., acetylsalicylic acid and propionic acid derivatives, e.g., Aleve®), opioids, or steroids.

[0203] Preparation of compounds It is understood that in the following description, combinations of substituents and / or variables of the depicted formula are permissible only if such combinations result in stable compounds.

[0204] It will also be appreciated by those skilled in the art that in the processes described below, functional groups of intermediate compounds may need to be protected by suitable protecting groups. Such functional groups include hydroxy, phenol, amino and carboxylic acid. Suitable protecting groups for hydroxy or phenol include trialkylsilyl or diarylalkylsilyl (e.g., tert-butyldimethylsilyl, tert-butyldiphenylsilyl or trimethylsilyl), tetrahydropyranyl, benzyl, substituted benzyl, methyl, and the like. Suitable protecting groups for amino, amidino and guanidino include t-butoxycarbonyl, benzyloxycarbonyl, and the like. Suitable protecting groups for carboxylic acid include alkyl, aryl or arylalkyl esters.

[0205] Protective groups can be added or removed according to standard techniques well known to those skilled in the art and as described herein. The use of protective groups is described in detail in JFW MacOmie, "Protective Groups in Organic Chemistry", Plenum Press, London and New York 1973; TW Greene and PG M Huts, "Greene's Protective Groups in Organic Synthesis", Fourth Edition, Wiley, New York 2007; PJ Kocienski, "Protecting Groups", Third Edition, Georg Thieme Verlag, Stuttgart and New York 2005; and "Methoden der organischen Chemie" (Methods of Organic Chemistry), Houben Weyl, 4th edition, Volume 15 / I, Georg Thieme Verlag, Stuttgart 1974.

[0206] The protecting group can also be a polymer resin, such as a Wang resin or a 2-chlorotrityl chloride resin.

[0207] The following reaction examples illustrate methods for making the compounds of the present disclosure. Those skilled in the art will understand that these compounds can be made by similar methods or methods known to those skilled in the art. In general, the starting building blocks and reagents can be obtained from sources such as, for example, Sigma Aldrich, Lancaster Synthesis, Inc., Maybridge, Matrix Scientific, TCI and Fluorochem USA, Strem, other commercial suppliers, or can be synthesized by sources known to those skilled in the art, or can be prepared as described in this disclosure.

[0208] Analytical methods, materials and instruments Reagents and solvents were used as received from commercial suppliers unless otherwise noted. Proton nuclear magnetic resonance (NMR) spectra were obtained on a Bruker Avance, Avance III, or Avance Neo spectrometer 400 MHz, a Varian Oxford 400 MHz, or a Varian Mercury 300 MHz spectrometer unless otherwise noted. Spectra are given in ppm (δ) and coupling constants, J, are reported in Hertz. Tetramethylsilane (TMS) was used as an internal standard. Chemical shifts are reported in ppm relative to dimethylsulfoxide (δ 2.50), methanol (δ 3.31), chloroform (δ 7.26), or other solvents as indicated in the NMR spectral data. A small amount of dry sample (2-5 mg) is dissolved in an appropriate deuterated solvent (1 mL). Chemical names were generated using ChemBioDraw Ultra v19 from CambridgeSoft.

[0209] Mass spectra (ESI-MS) were collected using a Waters System (Acquity UPLC and Micromass ZQ mass spectrometer) or an Agilent-1260Infinity (6120 Quadrupole); all masses reported are the m / z of the protonated parent ion unless otherwise reported. Samples were dissolved in an appropriate solvent, e.g., MeCN, DMSO, or MeOH, and injected directly onto the column using an automated sample processor.

[0210] Abbreviation 9-BBN 9-Borabicyclo[3.3.1]nonane ACN Acetonitrile AcOH Acetic acid aq Water-based Boc tert-Butyl carboxy br Broad c concentration CBr 4 Tetrabromomethane CO 2 carbon dioxide d doublet DAD Diode Array Detection DBU 1,8-Diazabicyclo[5.4.0]undec-7-ene DCE 1,2-dichloroethane DCM Dichloromethane dd Doublet of Doublets DIPEA Diisopropylethylamine DMAP N,N-Dimethylaminopyridine DMF N,N-Dimethylformamide DMSO Dimethyl sulfoxide ee enantiomeric excess eq equivalent EtOAc Ethyl acetate EtOH Ethanol h time H 2 hydrogen HCl Hydrochloric acid HPLC High Performance Liquid Chromatography IPA Isopropanol KHF 2 Potassium hydrogen fluoride K 2 CO 3 Potassium carbonate K 3 PO 4 Potassium phosphate, tribasic LC-MS Liquid Chromatography and Mass Spectrometry m multiplet m / z mass-to-charge ratio MeOH Methanol Me-THF 2-Methyltetrahydrofuran MgSO 4 Magnesium sulfate min MS mass spectrometry N 2 nitrogen NaCNBH 3 Sodium cyanoborohydride Na 2 CO 3 Sodium carbonate NaHCO 3 Sodium bicarbonate Na 2 SO 4 Sodium sulfate NaOH Sodium hydroxide NH 4 OH Ammonium hydroxide NMR nuclear magnetic resonance NP normal phase org organic Pd 2 (dba) 3 Tris(dibenzylideneacetone)dipalladium(0) PdCl 2 (dppf) 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride PdCl 2 (dtbpf) [1,1'-bis(di-tert-butylphosphino)ferrocene]palladium(II) dichloride PE Petroleum Ether PPh 3 Triphenylphosphine ppm parts per million rac Racemic RM reaction mixture RP Reverse Phase Rt retention time RT room temperature s singlet sat. saturation scCO 2 Supercritical Carbon Dioxide SFC Supercritical Fluid Chromatography SiO2 silica gel soln. solution t triplet TBAF Tetra-n-butylammonium fluoride TBME Methyl tert-butyl ether tBu tertiary butyl tert-Bu tertiary butyl tert-BuOH tert-butanol TFA Trifluoroacetic acid TFAA Trifluoroacetic anhydride Tf Trifluoromethanesulfonate THF Tetrahydrofuran TLC Thin Layer Chromatography UPLC Ultra High Performance Liquid Chromatography Xantphos 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene Xphos Pd G2 Chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) wt% Weight percent

[0211] Intermediates Intermediate I-1: tert-Butyl 4-bromo-5,7-dimethyl-1H-indole-1-carboxylate [ka] DMAP (242 mg, 1.98 mmol) was added to a suspension of 4-bromo-5,7-dimethyl-1H-indole (CAS number 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 on silica gel (330 g) using an automated purification system (NP; Teledyne ISCO®; collection at 256 / 294 nm; flow rate 200 mL / min; eluent: heptane + 0-4.5% EtOAc in 23 min) to give the title compound as off-white crystals (9.05 g) after concentration under reduced pressure at 50 °C. LC-MS Method B-2: Rt = 8.55 min; MS m / z [M-Boc+H] + =223.9 / 225.9.

[0212] Intermediate I-2: tert-Butyl 4-bromo-5-methoxy-7-methyl-1H-indole-1-carboxylate [ka] DMAP (25.95 mg, 212.4 μmol) was added to a solution of 4-bromo-5-methoxy-7-methyl-1H-indole (CAS number 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 on silica gel (40 g) using an automated purification system (NP; Teledyne ISCO®; collection at 256 / 294 nm; flow rate 40 mL / min; eluent: heptane + 0.0-8.7% EtOAc in 15.2 min) to give 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.

[0213] Intermediate I-3: tert-Butyl 4-bromo-5-cyclopropyl-7-methyl-1H-indole-1-carboxylate [ka] Step 1: 2-Cyclopropyl-4-methyl-5-nitroaniline (Intermediate I-3-1) [ka] Dioxane (200 mL) and H 2 A solution of 2-bromo-4-methyl-5-nitroaniline (CAS no. 102169-99-3, 50 g, 268.74 mmol) in 2O (66 mL) was treated with cyclopropylboronic acid (CAS no. 411235-57-9, 11.15 g, 129.84 mmol), K 3 PO 4 (55.12 g, 260 mmol), and Pd(dppf)Cl 2 -DCM (3.53 g, 4.33 mmol) was added. The resulting mixture was stirred at 90° C. for 16 h. The RM was filtered and the filtrate was extracted with EtOAc (3×200 mL) and diluted with Na 2 SO 4 The mixture was dried over 100 ml, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (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-d 6 )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)

[0214] Step 2: 1-Bromo-2-cyclopropyl-4-methyl-5-nitrobenzene (Intermediate I-3-2) [ka] A solution of 2-cyclopropyl-4-methyl-5-nitroaniline (Intermediate I-3-1, 120 g, 624.3 mmol) and tert-butyl nitrite (83.66 g, 378.58 mmol) in MeCN (1.2 L) was stirred at 0° C. for 0.5 h. To this mixture was added CuBr 2 (83.66 g, 378.58 mmol) was added at 0° C. and stirring was continued for 2 h at about 25° C. The RM was dissolved in H 2 The mixture was diluted with O (1 L) and extracted with EtOAc (3×500 mL). The combined organic layers were washed with brine (1 L) and 2 SO 4 Drying by filtration and concentration under reduced pressure afforded 1-bromo-2-cyclopropyl-4-methyl-5-nitrobenzene (120 g) 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).

[0215] Step 3: 4-Bromo-5-cyclopropyl-7-methyl-1H-indole (Intermediate I-3-3) [ka] 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) at −78° C. After the addition was complete, the RM was stirred at −40° C. for 2 h. The RM was cooled to 100° C. and cooled to 37° C. for 1 h. 2 The mixture was quenched with O (3 L) and extracted with EtOAc (3×3 L). The combined organic layers were washed with brine (5 L) and added Na 2 SO 4The mixture was dried over 100 ml, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (EtOAc / PE=0 / 100-10 / 90) to give 4-bromo-5-cyclopropyl-7-methyl-1H-indole (35 g) as a yellow solid. 1 H NMR(400MHz,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=0.8Hz,3H),2.26(tt,J=5.3,8.5Hz,1H),1.05-0.98(m,2H),0.74-0.66(m,2H).

[0216] Step 4: tert-Butyl 4-bromo-5-cyclopropyl-7-methyl-1H-indole-1-carboxylate (Intermediate I-3) 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. 1 ,N 1 -Dimethylethane-1,2-diamine (105 mL) was added and the mixture was stirred at 25° C. for 10 min. The mixture was diluted with H 2 The mixture was diluted with 2×O (100 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine (100 mL) and 2 SO 4 Drying over rt, filtration and concentration under reduced pressure afforded tert-butyl 4-bromo-5-cyclopropyl-7-methyl-1H-indole-1-carboxylate (38 g) as a yellow solid which was used directly without further purification. 1 H NMR(400MHz,chloroform-d)δ[ppm]7.54(d,J=3.8Hz,1H),6.67(s,1H),6.65(d,J=3.8Hz,1H),2 .56(s,3H),2.22(tt,J=5.3,8.5Hz,1H),1.64(s,9H),1.06-0.97(m,2H),0.76-0.66(m,2H).

[0217] The following intermediates were synthesized from the appropriate starting materials by applying similar methods as above.

[0218] Intermediate I-4: tert-Butyl 4-bromo-7-methyl-1H-indole-1-carboxylate [ka] Intermediate I-4 was prepared from 4-bromo-7-methyl-1H-indole (CAS number 936092-87-4). 1 H NMR (400MHz, chloroform-d) δ[ppm]7.62(d,J=3.8Hz,1H),7.29(s,1H),6.93(d,J=9.9Hz,1H),6.65(d,J=3.8Hz,1H),2.61(s,3H),1.67(s,9H).

[0219] Intermediate I-5: tert-Butyl 4-bromo-5-fluoro-7-methyl-1H-indole-1-carboxylate [ka] Intermediate I-5 was prepared from 1-bromo-2-fluoro-4-methyl-5-nitrobenzene (CAS number 224185-19-7). 1 H NMR (400MHz, chloroform-d) δ[ppm]7.62(d,J=3.8Hz,1H),6.93(d,J=9.9Hz,1H),6.65(d,J=3.8Hz,1H),2.61(s,3H),1.67(s,9H).

[0220] Intermediate I-6: tert-Butyl 4-bromo-5-chloro-7-methyl-1H-indole-1-carboxylate [ka] Intermediate I-6 was prepared from 1-bromo-2-chloro-4-methyl-5-nitrobenzene (CAS number 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).

[0221] Intermediate I-7: tert-Butyl 4-bromo-5,7-dichloro-1H-indole-1-carboxylate [ka] Intermediate I-7 was prepared from 1-bromo-2,4-dichloro-5-nitrobenzene (CAS number 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).

[0222] Intermediate I-8: tert-Butyl 4-bromo-3-chloro-5,7-dimethyl-1H-indole-1-carboxylate [ka] Step 1: 4-Bromo-3-chloro-5,7-dimethyl-1H-indole (Intermediate I-8-1) [ka] To a solution of 4-bromo-5,7-dimethyl-1H-indole (CAS no. 1167056-53-2, 345 mg, 1.54 mmol) in DMF (4.0 mL) at 0° C. was added a solution of N-chlorosuccinimide (246.7 mg, 1.85 mg) in DMF (1 mL) dropwise. The RM was stirred at 0° C. for an additional 10 min before being cooled to 10° C. 2The mixture was diluted with O. The formed precipitate was filtered off and dried under reduced pressure. Purification by column chromatography on silica gel (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).

[0223] Step 2: tert-Butyl 4-bromo-3-chloro-5,7-dimethyl-1H-indole-1-carboxylate (Intermediate I-8) Intermediate I-8 was prepared from intermediate I-8-1 following a similar method as described above for intermediate I-1. 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).

[0224] Intermediate A-1: ​​Methyl 4-(4-methylene-1-(2,2,2-trifluoroethyl)piperidin-3-yl)benzoate [ka] Step 1: tert-Butyl 3-(4-(methoxycarbonyl)phenyl)-4-oxopiperidine-1-carboxylate (Intermediate A-1-1) [ka] K 3 PO 4(40.86 g, 15.94 mL, 192.5 mmol) was added to a solution of tert-butyl 4-oxopiperidine-1-carboxylate (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 was then cooled to 5° C. for 24 hours. 2 It was evacuated and refilled twice with Pd 2 (dba) 3 (1.533 g, 1.674 mmol) was added and the mixture was rehydrated with N 2 Evacuate / refill twice with N 2 Heated to 80° C. under atmosphere overnight. The RM was cooled to RT and partitioned between toluene and water. The slurry was filtered through Celite and the filtrate was diluted with saturated NaHCO 3 The combined organic layers were washed with MgSO 4 The mixture was dried over 1000 ml, filtered, and the volatiles were removed under reduced pressure at 50° C. The resulting residue was purified on silica gel (330 g) using an automated purification system (NP; Teledyne ISCO®; monitoring at 250 nm; flow rate 200 mL / min; eluent: heptane + 5-40% EtOAc in 31.0 min), then re-purified on silica gel (330 g) using an automated purification system (normal phase; Teledyne ISCO®; monitoring at 250 nm; flow rate 200 mL / min; eluent: dichloromethane + 0.0-4.7% EtOAc in 26.2 min), then re-purified on two RediSep C18 columns (360 g each) using an automated purification system (Teledyne ISCO®; collection at 240 nm; flow rate 150 mL / min; eluent: water + 25-60% ACN). The pure fractions were combined and the ACN was removed under reduced pressure at 50 °C to give a water slurry. The mixture was extracted with DCM (3x) and the combined organic layers were washed with MgSO 4 Drying over 100° C., filtration and removal of volatiles under reduced pressure at 50° C. afforded the title compound as a white solid (9.20 g). LC-MS Method B-1: Rt=1.02 min; MS m / z [MH] - =332.0.

[0225] Step 2: Methyl 4-(4-oxopiperidin-3-yl)benzoate (Intermediate A-1-2) [ka] tert-Butyl 3-(4-(methoxycarbonyl)phenyl)-4-oxopiperidine-1-carboxylate (Intermediate A-1-1, 9.20 g, 27.6 mmol) was treated with HCl (4 M in dioxane, 140.0 mL). The initial solution became a thick white suspension, which was stirred at RT for 60 min. Approximately 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 (3×) and dried under reduced pressure at 50° C. to give the title compound as an off-white solid (HCl salt, 7.60 g, approx. 85% purity). 1 H NMR (400MHz, DMSO-d 6 )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 .1,7.9Hz,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 overlapped with DMSO peak).

[0226] Step 3: Methyl 4-(4-oxo-1-(2,2,2-trifluoroethyl)piperidin-3-yl)benzoate (Intermediate A-1-3) [ka] 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, approx. 85% purity) in ACN (93 mL). 2,2,2-Trifluoroethyl trifluoromethanesulfonate (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 diluted with MgSO 4 Drying over 100° C., filtration and removal of volatiles under reduced pressure at 50° C. gave an orange oil which was purified on silica gel (220 g) using an automated purification system (NP; Teledyne ISCO®; collection at 245 / 260 nm; flow rate 150 mL / min; eluent: heptane + 5.0-30% EtOAc in 24 min) to give the title compound as a yellow oil (7.29 g) after concentration under reduced pressure. LC-MS Method B-1: Rt=0.95 min; MS m / z [M+H] + =316.3.

[0227] Step 4: Methyl 4-(4-methylene-1-(2,2,2-trifluoroethyl)piperidin-3-yl)benzoate (Intermediate A-1) [ka] A suspension of zinc dust (9.63 g, 147.3 mmol) in THF (160 mL) was carefully rinsed with N 2The RM was evacuated / backfilled twice with 500 rpm. Diiodomethane (21.92 g, 6.60 mL, 81.83 mmol) was added dropwise. The RM was stirred at RT for 30 min. The RM was then cooled to 0-5 °C and titanium tetrachloride (1 M in DCM, 16.37 mL, 16.37 mmol) was added dropwise while maintaining the temperature below 18 °C. Once the exothermic reaction had ceased, the suspension was stirred at ambient temperature without a cooling bath for an additional 30 min. A solution of methyl 4-(4-oxo-1-(2,2,2-trifluoroethyl)piperidin-3-yl)benzoate (Intermediate A-1-3, 5.160 g, 16.37 mmol) in THF (10.3 mL) was added dropwise. The RM was stirred at RT for 1.5 h and then resuspended in well-stirred saturated NaHCO 3 Poured into a mixture of aqueous solution and TBME. The resulting slurry was filtered through Celite and the solid was washed with TBME (3x). The layers of the filtrate were separated and washed with brine and TBME. The combined organic layers were washed with MgSO 4 The mixture was dried over 1000 ml, filtered and the volatiles were removed under reduced pressure at 50° C. The resulting residue was purified on silica gel (220 g) using an automated purification system (NP; Teledyne ISCO®; collection at 238 / 254 nm; flow rate 150 mL / min; eluent: heptane + 30-70% DCM in 29.0 min). Pure fractions were combined and the volatiles were removed under reduced pressure at 50° C. to give the title compound as a colorless oil that solidified on standing (3.27 g). LC-MS Method B-1: Rt=1.42 min; MS m / z [M+H] + =314.1.

[0228] Intermediate A-2: tert-Butyl (3R,4R)-3-(4-(tert-butoxycarbonyl)phenyl)-4-(hydroxymethyl)piperidine-1-carboxylate [ka] Step 1: 1-(tert-butyl) 4-ethyl 5-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1,4(2H)-dicarboxylate (Intermediate A-2-1) [ka] N 2 To a stirred solution of 1-(tert-butyl) 4-ethyl 3-oxopiperidine-1,4-dicarboxylate (CAS no. 71233-25-5, 30.23 g, 111.4 mmol) in DCM (893 mL) at −78° C. under atmospheric pressure, DIPEA (18.72 g, 144.8 mmol) was slowly added, followed by the addition of Tf 2 O (37.72 g, 22.59 mL, 133.7 mmol) was added dropwise. The resulting mixture was stirred at RT for about 1 h. The RM was diluted with DCM (150 mL) and saturated NaHCO 3 The separated aqueous layer was extracted with DCM (300 mL) and the combined organic phase was washed with Na 2 SO 4 The mixture was passed through a plug of Florisil® 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.

[0229] Step 2: 1-(tert-butyl) 4-ethyl 5-(4-(tert-butoxycarbonyl)phenyl)-3,6-dihydropyridine-1,4(2H)-dicarboxylate (Intermediate A-2-2) [ka] H 2 K in O (248.4 mL) 3 PO 4A solution of (70.94 g, 334.2 mmol) 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). 2 The mixture was evacuated and refilled twice with PdCl 2 (dtbpf) (3.63 g, 5.57 mmol) was added and the mixture was again treated with N 2 The RM was stirred at 40° C. for about 16 h. The RM was filtered through Florisil® and the filtrate was diluted with EtOAc and saturated NaHCO 3 The separated organic layer was partitioned between aqueous sodium hydroxide (700 mL each) and saturated NaHCO 3 The separated aqueous layer was extracted with EtOAc (700 mL). The combined organic layers were washed with Na 2 SO 4 The mixture was dried over hexane, filtered, and the volume of the filtrate was reduced to about 1 / 3 under reduced pressure. The mixture was stirred over Silicycle SiliaMet®-S DMT (20 g) for about 1 hour, filtered, and the filtrate was concentrated under reduced pressure. The crude material was purified by column chromatography on silica gel [750 g, EtOAc / heptane=0 / 100 to 70 / 30] to provide 1-(tert-butyl) 4-ethyl 5-(4-(tert-butoxycarbonyl)phenyl)-3,6-dihydropyridine-1,4(2H)-dicarboxylate (37.28 g) as a pale yellow oil that solidified on 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).

[0230] Step 3: Racemic 1-(tert-butyl)4-ethyl (3R * ,4S * )-3-(4-(tert-butoxycarbonyl)phenyl)piperidine-1,4-dicarboxylate (Intermediate A-2-3) [ka] 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% wet, 863.1 mg) in EtOH (150 mL) was degassed and then shaken under hydrogen atmosphere (45 psi; 500 mL Parr bottle) at ambient temperature for about 14 h. The mixture was filtered through a Celite® pad (2×) and the pad was rinsed / washed with EtOH. The filtrate was concentrated under reduced pressure and the resulting residue was purified by column chromatography on silica gel [80 g, EtOAc / heptane=0 / 100 to 60 / 40] to give racemic 1-(tert-butyl) 4-ethyl (3R * ,4S * )-3-(4-(tert-butoxycarbonyl)phenyl)piperidine-1,4-dicarboxylate (2.94 g) was obtained as a white solid. 1 H NMR(400MHz,chloroform-d)δ[ppm]7.92-7.84(m,2H),7.28-7.24(m,2H),4.02(dd,J=13.3,8.1Hz,1H),3.93(dddd,J=18.0,10.9,7.1,3.7Hz,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=7.2Hz,3H).

[0231] Step 4: Racemic 1-(tert-butyl)4-ethyl (3R * ,4R* )-3-(4-(tert-butoxycarbonyl)phenyl)piperidine-1,4-dicarboxylate (Intermediate A-2-4) [ka] Racemic 1-(tert-butyl)4-ethyl (3R * ,4S * A solution of 2.53 g of 4-(tert-butoxycarbonyl)phenyl)piperidine-1,4-dicarboxylate (Intermediate A-2-3, 5.84 mmol) was dissolved in N 2 The RM was cooled to RT and stirred overnight before being concentrated under reduced pressure to approximately ½ its volume. The resulting mixture was purged with saturated KH 2 PO 4 The mixture was diluted with Me-THF (60 mL) and brine (20 mL) and then extracted with Me-THF (2×60 mL). The combined organic layers were washed with brine (20 mL) and diluted with Na 2 SO 4 The mixture was dried over 1000 ml, filtered and concentrated under reduced pressure to give two phases. The residue was diluted with Me-THF and the separated organic phase was washed with Na 2 SO 4 The mixture was dried over water again, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel [40 g, EtOAc / heptane=0 / 100 to 80 / 20] to give racemic 1-(tert-butyl)-4-ethyl (3R * ,4R * )-3-(4-(tert-butoxycarbonyl)phenyl)piperidine-1,4-dicarboxylate (1.93 g; containing approximately 3% of the bis-ethyl ester) was provided as a colorless oil that solidified on standing. 1H NMR(400MHz,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=7.1Hz,3H).

[0232] Step 5: Racemic tert-butyl (3R * ,4R * )-3-(4-(tert-butoxycarbonyl)phenyl)-4-(hydroxymethyl)piperidine-1-carboxylate (Intermediate A-2-5) [ka] Racemic 1-(tert-butyl)4-ethyl (3R * ,4R * A solution of 1.92 g (4.43 mmol) of 4-(tert-butoxycarbonyl)-3-(4-(tert-butoxycarbonyl)phenyl)piperidine-1,4-dicarboxylate (Intermediate A-2-4) in freshly prepared LiBH 4 A solution (2M, 5.54 mL, 11.07 mmol) was added at 0° C. The mixture was stirred at ambient temperature and warmed to 35° C. for about 14 h. LiBH in MeOH (50 uL) and THF was added. 4 Solution (2M, 1 mL, 2.0 mmol) was added and stirring was continued for 2 h. The RM was cooled to 0° C. and saturated KH 2 PO 4 The mixture was carefully diluted with aqueous solution (80 mL) and brine (30 mL). The separated aqueous layer was extracted with EtOAc (2×60 mL, 30 mL). The combined organic layers were washed with Na 2 SO 4 The mixture was dried over 100 ml of ethyl acetate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel [40 g, EtOAc / heptane=0 / 100 to 60 / 40] to give racemic tert-butyl (3R * ,4R* )-3-(4-(tert-butoxycarbonyl)phenyl)-4-(hydroxymethyl)piperidine-1-carboxylate (1.22 g) was afforded as a white solid, and intermediate A-2-4 (335 mg) was recovered. 1 H 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). Thirty-two of the 33 protons were reported.

[0233] Step 6: tert-Butyl (3R,4R-3-(4-(tert-butoxycarbonyl)phenyl)-4-(hydroxymethyl)piperidine-1-carboxylate (Intermediate A-2) and tert-Butyl (3S,4S-3-(4-(tert-butoxycarbonyl)phenyl)-4-(hydroxymethyl)piperidine-1-carboxylate (Intermediate A-2-6) Enantiomer separation and analysis according to method SFC-3: Racemic tert-butyl (3R * ,4R * )-3-(4-(tert-butoxycarbonyl)phenyl)-4-(hydroxymethyl)piperidine-1-carboxylate (Intermediate A-2-5, 3.70 g) provided the following: 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=2.35 min; 99.5% ee. Intermediate A-2-6 (peak 2): 1.73 g, white solid. LC-MS method B-1: Rt=1.30 min; MS m / z[M+Na] + = 414.2; Analytical chiral HPLC: Rt = 1.42 min; 99.5% ee.

[0234] Intermediate rac-A-3: Racemic tert-butyl (3R *,4S * )-3-(4-cyanophenyl)-4-(hydroxymethyl)pyrrolidine-1-carboxylate [ka] Racemic (3S * ,4R * )-1-(tert-butoxycarbonyl)-4-(4-cyanophenyl)pyrrolidine-3-carboxylic acid (CAS number 1217702-50-5, 1.03 g, 3.25 mmol) was dissolved in THF (10 mL) and cooled to 0 °C. Borane-methyl sulfide complex (0.61 mL, 6.5 mmol) was added dropwise and the RM was stirred at 0 °C for 30 min, then stirring was continued at RT for 3 h. The mixture was cooled to 0 °C, quenched with MeOH (10 mL) and the resulting mixture was concentrated under reduced pressure. The residue was purified by chromatography on silica gel (24 g, EtOAc / heptane = 0 / 100 to 80 / 20) to give the racemic tert-butyl (3R * ,4S * )-3-(4-cyanophenyl)-4-(hydroxymethyl)pyrrolidine-1-carboxylate (1.01 g) was obtained 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. 9Hz,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).

[0235] Intermediate A-4: tert-Butyl (3R,4R)-3-(4-(tert-butoxycarbonyl)phenyl)-4-(hydroxymethyl)azepane-1-carboxylate [ka] Step 1: 1-(tert-butyl) 4-ethyl (3R,4R)-3-(4-(tert-butoxycarbonyl)phenyl)azepane-1,4-dicarboxylate (Intermediate A-4-1) [ka] Step 1-a: 1-(tert-butyl) 4-ethyl 2,5,6,7-tetrahydro-1H-azepine-1,4-dicarboxylate (CAS no. 2254213-29-9; prepared from 1-tert-butyl 4-ethyl 3-oxoazepane-1,4-dicarboxylate, CAS no. 98977-38-9, Tetrahedron in degassed MeOH / water (4 / 1, 50 mL) As described in Lett. 2018, 59, 4611; to a solution of 2.370 g, 8.799 mmol), (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 no. 850409-83-5, 68.20 mg, 0.264 mmol), 1,1,3,3-tetramethylguanidine (608.1 mg, 5.280 mmol) and acetylacetonatobis(ethylene)rhodium(I) (CAS no. 12082-47-2, 68.14 mg, 0.264 mmol) were added. The yellow solution was cooled to 100° C. for 2 h. 2 Heat under atmosphere to an internal temperature of 65° C. and stir for 45 min. The mixture is allowed to cool to RT and then diluted with TBME (100 mL) and brine (100 mL). The separated organic layer is washed with brine (100 mL) and the separated aqueous layer is washed with TBME (100 mL). The combined organic layers are washed with Na 2 SO 4The mixture was dried over 100 ml, filtered and concentrated under reduced pressure at 45° C. The residue was purified by column chromatography on silica gel (220 g, EtOAc / heptane=0 / 100 to 50 / 50) to afford 1-(tert-butyl) 4-ethyl (3R)-3-(4-(tert-butoxycarbonyl)phenyl)azepane-1,4-dicarboxylate (4.10 g) as a yellow oil in 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.

[0236] Step 1-b: To a solution of the trans / cis mixture from step 1-a 1-(tert-butyl) 4-ethyl (3R)-3-(4-(tert-butoxycarbonyl)phenyl)azepane-1,4-dicarboxylate (4.10 g, 9.16 mmol) in THF (80 mL) at an internal temperature of -60 °C, a solution of potassium tert-butoxide in THF (1 M, 4.58 mL, 4.58 mmol) was added dropwise over 1 min. The RM was stirred at -60 °C for 30 min and then saturated NaHCO 3 The mixture was poured into a stirred mixture of aqueous solution (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 washed with Na 2 SO 4 Drying over 100° C., filtration and concentration under reduced pressure at 45° C. provided concentrated 1-(tert-butyl) 4-ethyl (3R,4R)-3-(4-(tert-butoxycarbonyl)phenyl)azepane-1,4-dicarboxylate (4.11 g) as a pale yellow oil in a trans / cis mixture in a ratio of 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.

[0237] Step 2: tert-Butyl (3R,4R)-3-(4-(tert-butoxycarbonyl)phenyl)-4-(hydroxymethyl)azepane-1-carboxylate (Intermediate A-4) Step 2-a: To a solution of concentrated 1-(tert-butyl)4-ethyl(3R,4R)-3-(4-(tert-butoxycarbonyl)phenyl)azepane-1,4-dicarboxylate (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 (2 M, 11.45 mL, 22.9 mmol) was added dropwise over 2 min. The RM was heated to 35-38 °C (internal temperature) and stirred overnight. To the RM, additional MeOH (926 μL) was added 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 approximately 10° C. and diluted with TBME (100 mL) and saturated NaHCO 3 Pour into the stirred mixture of aqueous solution (100 mL) and stir at ambient temperature for 15 min. The separated organic phase was washed with saturated NaHCO 3 The combined organic layer was washed with NaCl (100 mL) and brine (100 mL), and the separated aqueous layer was washed with TBME (100 mL). 2 SO 4 The mixture was dried over 100 ml of ethyl acetate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (220 g, EtOAc / heptane=15 / 85-100 / 0) to provide concentrated tert-butyl (3R,4R)-3-(4-(tert-butoxycarbonyl)phenyl)-4-(hydroxymethyl)azepane-1-carboxylate (2.81 g) as a white foam. LC-MS Method B-1: Rt=1.31 min; MS m / z[M-Boc+H] + =306.4.

[0238] Step 2-b: Chiral purification and analysis according to method SFC-2: Concentrated tert-butyl (3R,4R)-3-(4-(tert-butoxycarbonyl)phenyl)-4-(hydroxymethyl)azepane-1-carboxylate (2.75 g) from 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. 1 H NMR (600MHz, DMSO-d 6 )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),2.91-2.8 5(m,1H),2.67-2.59(m,1H),2.08-2.00(m,1H),2.00-1.95(m,1H),1.76-1.71(m,2H),1.54(s,9H),1.42-1.37(m,9H),1.30-1.15(m,1H).

[0239] Intermediate A-5: tert-Butyl (4R,5R)-4-(4-(tert-butoxycarbonyl)phenyl)-5-(hydroxymethyl)azepane-1-carboxylate [ka] Intermediate A-5 was prepared following the method described for Intermediate A-4 herein above using 1-(tert-butyl) 4-ethyl 2,3,6,7-tetrahydro-1H-azepine-1,4-dicarboxylate (CAS number 912444-89-4). Chiral purification and analysis according to method SFC-5: LC-MS method B-2: Rt=6.41 min; MS m / z[M-Boc+H] + =306.2. Chiral HPLC method: Rt=2.79 min; 100% ee. 1 H NMR (600MHz, DMSO-d 6 )δ[ppm]7.81(dd,J=8.3,2.7Hz,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 overlapping 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).

[0240] Intermediate A-6: Benzyl (3R,4R)-3-(4-cyanophenyl)-4-(hydroxymethyl)piperidine-1-carboxylate [ka] Step 1: 1-Benzyl 4-methyl 3-(4-carbamoylphenyl)piperidine-1,4-dicarboxylate (Intermediate A-6-1) [ka] Intermediate A-6-1 was prepared according to the method (step 1-a) described for intermediate A-4 above using 1-benzyl 4-methyl 3,6-dihydropyridine-1,4(2H)-dicarboxylate (CAS no. 1784422-91-8) and (4-carbamoylphenyl)boronic acid (CAS no. 123088-59-5). LC-MS Method B-2: Rt=3.95 / 4.09 min (diastereomeric mixture); MS m / z [M+H] + =397.1.

[0241] Step 2: 1-Benzyl 4-methyl 3-(4-cyanophenyl)piperidine-1,4-dicarboxylate (Intermediate A-6-2) [ka] To a solution of cis / trans mixture of 1-benzyl 4-methyl 3-(4-carbamoylphenyl)piperidine-1,4-dicarboxylate (Intermediate A-6-1, 4.250 g, 10.72 mmol) and TEA (4.339 g, 42.88 mmol) in DCM (150 mL) at 0-5 °C was added TFAA (4.50 g, 21.44 mmol) dropwise over approximately 5 min. The RM was stirred at 0-5 °C for an additional 5 min, the ice bath was removed, and stirring was continued at ambient temperature for approximately 1 h. The mixture was diluted with saturated NaHCO 3 Pour into aqueous solution (200 mL) of NaHCO 3 and stir vigorously for 5 min. The separated organic phase was washed with saturated NaHCO 3 3 The combined organic layers were washed with Na 2 SO 4 The mixture was dried over 100° C., filtered and concentrated under reduced pressure at 45° C. The residue was purified by column chromatography on silica gel (220 g, EtOAc / heptane=15 / 85-100 / 00) to provide 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.

[0242] Step 3: Benzyl (3R,4R)-3-(4-cyanophenyl)-4-(hydroxymethyl)piperidine-1-carboxylate (Intermediate A-6) Intermediate A-6 was prepared following the methods, steps 1-a and 2 described for intermediate A-4 herein above. Chiral purification and analysis according to method SFC-6: LC-MS method B-2: Rt=4.50 min; MS m / z[M+H] + =351.2. Chiral HPLC method: Rt=1.88 min; 100% ee. 1 H NMR (500MHz, DMSO-d 6 ) δ [ppm] 1 H NMR (500MHz, DMSO-d 6 )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=13.1H) z,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).

[0243] Intermediate A-7: Benzyl (3R,4R)-3-(4-bromophenyl)-4-(hydroxymethyl)piperidine-1-carboxylate [ka] Intermediate A-7 was prepared according to the method described for intermediate A-4 herein above using 1-benzyl 4-methyl 3,6-dihydropyridine-1,4(2H)-dicarboxylate (CAS no. 1784422-91-8) and (4-bromophenyl)boronic acid (CAS no. 5467-74-3). Chiral purification and analysis according to method SFC-7: LC-MS method B-2: Rt=6.11 min; MS m / z[M+H] + =404.0. Chiral HPLC method: Rt=1.54 min; 100% ee. 1 H NMR (500MHz, DMSO-d 6)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).

[0244] Intermediate A-8: Benzyl (3R,4R)-3-(4-(1H-pyrazol-1-yl)phenyl)-4-(hydroxymethyl)piperidine-1-carboxylate [ka] 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 stirred at RT for 1 h. 2 Copper iodide (170.5 mg, 0.895 mmol) was added and the mixture was flushed with N 2 The RM was stirred at 120° C. for 3 days. The mixture was cooled to RT, diluted with TBME and water, and filtered through Celite®. The layers of the filtrate were separated, the organic phase was washed with 1M aqueous NaOH, water, brine, and the aqueous phase was extracted with TBME. The combined organic layers were washed with MgSO 4The mixture was dried over 100° C., filtered and the volatiles were removed under reduced pressure at 50° C. The residue was purified by column chromatography on silica gel (80 g, heptane / EtOAc=90 / 10 to 30 / 70) to provide benzyl (3R,4R)-3-(4-(1H-pyrazol-1-yl)phenyl)-4-(hydroxymethyl)piperidine-1-carboxylate (1.06 g) as a yellow oil. LC-MS Method B-1: Rt=1.01 min; MS m / z[M+H] + =392.2.

[0245] Intermediate A-9: tert-Butyl (3R,4R)-4-(hydroxymethyl)-3-(1-methyl-1H-pyrazol-4-yl)piperidine-1-carboxylate [ka] Step 1: 1-(tert-butyl) 4-ethyl 5-(1-methyl-1H-pyrazol-4-yl)-3,6-dihydropyridine-1,4(2H)-dicarboxylate (Intermediate A-9-1) [ka] Dioxane (50 mL) and H 2 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 no. 847818-55-7, 4.55 g, 21.9 mmol), and cesium carbonate (9.5 g, 29.2 mmol) in 2H (6 mL) was heated at 40° C. for 1 hour at 40° C. for 2 hours at 40° C. 2 The mixture was degassed at 40° C. for 30 min. XPhos Pd G2 (CAS number 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 filtered through Celite® and washed with water. The organic phase was washed with Na 2 SO 4Drying over, concentration and purification by chromatography on silica gel (40 g, MeOH / DCM 0-10%) provided 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.

[0246] Step 2: Racemic 1-(tert-butyl)4-ethyl (3R * ,4S * )-3-(1-methyl-1H-pyrazol-4-yl)piperidine-1,4-dicarboxylate (Intermediate A-9-2) [ka] A mixture of 1-(tert-butyl) 4-ethyl 5-(1-methyl-1H-pyrazol-4-yl)-3,6-dihydropyridine-1,4(2H)-dicarboxylate (Intermediate A-9-1) and platinum oxide (10 wt% on carbon, 5 g) in EtOH (48 mL) was stirred under 1 atm hydrogen pressure at RT for 16 h. The RM was filtered through a pad of Celite®, concentrated, and purified by chromatography on silica gel (40 g, EtOAc / heptane 0-20%) to give racemic 1-(tert-butyl) 4-ethyl (3R * ,4S * )-3-(1-methyl-1H-pyrazol-4-yl)piperidine-1,4-dicarboxylate (4.1 g) was obtained as a yellow oil. LC-MS Method A-1: ​​Rt=1.78 min; MS m / z[M+H] + =338.5.

[0247] Step 3: Racemic 1-(tert-butyl)4-ethyl (3R * ,4R * )-3-(1-methyl-1H-pyrazol-4-yl)piperidine-1,4-dicarboxylate (Intermediate A-9-3) [ka] Racemic 1-(tert-butyl)4-ethyl (3R * ,4R * To a solution of 1-methyl-1H-pyrazol-4-yl)piperidine-1,4-dicarboxylate (Intermediate A-9-2, 3.2 g, 9.78 mmol) was added DBU (4.1 mL, 29.34 mmol). The mixture was stirred at RM110° C. for 16 h and then quenched with water. The mixture was extracted with EtOAc. The organic phase was washed with Na 2 SO 4 The mixture was dried over 1000 ml, concentrated under reduced pressure and purified by chromatography on silica gel (40 g, EtOAc / heptane 0-20%) to give the racemic 1-(tert-butyl)4-ethyl (3R * ,4R * )-3-(1-methyl-1H-pyrazol-4-yl)piperidine-1,4-dicarboxylate was obtained as a colorless oil 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.

[0248] Step 4: tert-Butyl (3R,4R)-4-(hydroxymethyl)-3-(1-methyl-1H-pyrazol-4-yl)piperidine-1-carboxylate (Intermediate A-9) [ka] Racemic 1-(tert-butyl)4-ethyl (3R * ,4R * A solution of 1-methyl-1H-pyrazol-4-yl)piperidine-1,4-dicarboxylate (Intermediate A-9-3, as a mixture with Intermediate A-9-2, 3 g, 8.89 mmol) was dissolved in N 2Cooled to 0° C. under atmosphere. Lithium aluminum hydride solution (1M 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 diluted with H 2 O was added. The organic phase was cooled and the aqueous phase was extracted with EtOAc. The combined organic phase was washed with Na 2 SO 4 Dry and concentrate to give the racemic tert-butyl (3R * ,4R * )-4-(hydroxymethyl)-3-(1-methyl-1H-pyrazol-4-yl)piperidine-1-carboxylate with racemic tert-butyl (3R * ,4S * )-4-(hydroxymethyl)-3-(1-methyl-1H-pyrazol-4-yl)piperidine-1-carboxylate. Chiral purification and analysis according to method C-10: LC-MS method A-1: ​​Rt=1.70 min; MS m / z[M+H] + =296.5. Chiral HPLC method: Rt = 3.61 min; 97.9% ee. 1 H NMR (400MHz, DMSO-d 6 )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)3.30-3.24(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)

[0249] Intermediate F-1: Potassium (((3R,4R)-1-(tert-butoxycarbonyl)-3-(4-(tert-butoxycarbonyl)phenyl)piperidin-4-yl)methyl)trifluoroborate [ka] Step 1: tert-Butyl (3R,4R)-4-(bromomethyl)-3-(4-(tert-butoxycarbonyl)phenyl)piperidine-1-carboxylate (Intermediate F-1-1) [ka] A suspension of tert-butyl (3R,4R)-3-(4-(tert-butoxycarbonyl)phenyl)-4-(hydroxymethyl)-piperidine-1-carboxylate (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 PPh 3 (1.420 g, 5.412 mmol) was added. The mixture was cooled to 3° C. and CBr 4 (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 PPh 3 (328mg) and CBr 4 (414 mg) was added and stirring was continued at RT for 90 min. Volatiles were removed under reduced pressure at 35 °C. The residue was purified on silica gel (40 g) using an automated purification system (NP; Teledyne ISCO®; collection at 245 / 260 nm; flow rate 40 mL / min; eluent: heptane + 5.0-25% EtOAc in 20 min) to provide 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.

[0250] Step 2: 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) [ka] 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(pinacolato)diborane (2.121 g, 8.352 mmol) in tert-BuOH (10.50 mL) was added water (875.6 mg, 875.6 μL, 48.59 mmol). The mixture was purified by N 2 Bis(1,1-dimethylethyl)(methyl)phosphine tetrafluoroborate (CAS number 479094-62-7, 135.6 mg, 546.7 μmol), Pd 2 (dba) 3 (83.43 mg, 91.11 μmol) and K 3 PO 4 (1.289 g, 6.074 mmol) was subsequently added. 2 Evacuate / refill twice with N 2 The mixture was cooled to RT, diluted with TBME and added NH 4 Poured into a well-stirred mixture of aqueous Cl (10 wt%, 10 mL) and TBME (10 mL). The resulting black slurry was filtered through Celite® and the solids were rinsed with TBME (2×). The layers of the filtrate were separated and washed with brine and TBME. The combined organic layers were washed with MgSO 4The mixture was dried over silica gel (40 g) using an automated purification system (NP; Teledyne ISCO®; collection at 250 / 260 nm; flow rate 40 mL / min; eluent: heptane + 3.0-19.5% EtOAc in 15 min) to provide 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 as a yellow foam (1.35 g). LC-MS Method B-2: Rt=8.14 min; MS m / z [M-Boc+H-tBu+H] + =346.4.

[0251] Step 3: Potassium (((3R,4R)-1-(tert-butoxycarbonyl)-3-(4-(tert-butoxycarbonyl)phenyl)piperidin-4-yl)methyl)trifluoroborate (Intermediate F-1) 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. 2 KHF in O (10.0 mL) 2 A solution of (950.0 mg, 439.0 μL, 12.16 mmol) was added via addition funnel and additional MeOH (5 mL) was added and stirred steadily. After stirring at RT for 90 min, the RM was diluted with MeOH, evaporated to dryness, the residue was dissolved 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 filtrate volatiles 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.

[0252] Intermediate rac-F-2: Racemic Potassium (((3S * ,4R * )-1-(tert-butoxycarbonyl)-4-(4-cyanophenyl)pyrrolidin-3-yl)methyl)trifluoroborate [ka] Step 1: Racemic tert-butyl (3S * ,4R * )-3-(Bromomethyl)-4-(4-cyanophenyl)pyrrolidine-1-carboxylate (intermediate rac-F-2-1) [ka] Racemic tert-butyl (3R * ,4S * )-3-(4-cyanophenyl)-4-(hydroxymethyl)pyrrolidine-1-carboxylate (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 and CBr 4 (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 chromatography on silica gel (40 g, EtOAc / heptane=0 / 100 to 60 / 40) to obtain racemic tert-butyl (3S * ,4R * )-3-(bromomethyl)-4-(4-cyanophenyl)pyrrolidine-1-carboxylate (977 mg) was obtained as a colorless oil. LCMS Method C-1: RT=1.17 min; MS m / z[M-tBu+H] + =311.2. 1H 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).

[0253] Step 2: Racemic tert-butyl (3R * ,4S * )-3-(4-cyanophenyl)-4-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl)pyrrolidine-1-carboxylate (intermediate rac-F-2-2) [ka] In vial, N 2 Racemic tert-butyl (3S * ,4R * )-3-(bromomethyl)-4-(4-cyanophenyl)pyrrolidine-1-carboxylate (intermediate rac-F-2-1, 777 mg, 2.13 mmol), bis(pinacolato)diboron (902 mg, 3.55 mmol), K 3 PO 4 (993mg, 4.68mmol), Pd 2 (dba) 3 (58 mg, 64 μmol) and bis(1,1-dimethylethyl)(methyl)phosphine tetrafluoroborate (95 mg, 38 μmol) were added tert-BuOH (7 mL) and water (0.6 mL). 2 The mixture was purged with 0.5 mL of 10 ... 3The separated aqueous layer was extracted with DCM (3x). The combined organic layers were dried over an Isolute® Phase Separator and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (24 g, EtOAc / heptane = 0 / 100 to 50 / 50) to give the enriched racemic tert-butyl (3R * ,4S * )-3-(4-cyanophenyl)-4-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl)pyrrolidine-1-carboxylate (937.0 mg) was obtained, 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.

[0254] Step 3: Racemic Potassium (((3S * ,4R * )-1-(tert-butoxycarbonyl)-4-(4-cyanophenyl)pyrrolidin-3-yl)methyl)trifluoroborate (intermediate rac-F-2) Enriched racemic tert-butyl (3R * ,4S * )-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 H 2 KHF in O (4.0 mL) 2 A solution of (710 mg, 328 μL, 9.09 mmol) 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 dissolved in Et 2 The precipitate was filtered off and triturated with Et 2 O and dried under vacuum at 40 °C to give the title compound (634 mg) as a pale yellow solid. 1 H NMR (400MHz, DMSO-d 6)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,1H),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).

[0255] Intermediate F-3: Potassium (((3R,4R)-1-(tert-butoxycarbonyl)-3-(4-(tert-butoxycarbonyl)phenyl)azepan-4-yl)methyl)trifluoroborate [ka] Intermediate F-3 was prepared according to the method described for Intermediate F-1 herein above using Intermediate A-4. LC-MS Method B-2: Rt=6.42 min; MS m / z [M-K+Na] - =478.1.

[0256] Intermediate F-4: Potassium (((4R,5R)-1-(tert-butoxycarbonyl)-5-(4-(tert-butoxycarbonyl)phenyl)azepan-4-yl)methyl)trifluoroborate [ka] Intermediate F-4 was prepared according to the method described for Intermediate F-1 herein above using Intermediate A-5. LC-MS Method B-2: Rt=6.59 min; MS m / z [M-K+Na] - =478.4.

[0257] Intermediate F-5: Potassium (((3R,4R)-1-((benzyloxy)carbonyl)-3-(4-cyanophenyl)piperidin-4-yl)methyl)trifluoroborate [ka] Intermediate F-5 was prepared according to the method described for Intermediate F-1 herein above using Intermediate A-6. LC-MS Method B-2: Rt=4.73 min; MS m / z [M-K+Na] - =423.2.

[0258] Intermediate F-6: Potassium (((3R,4R)-3-(4-(1H-pyrazol-1-yl)phenyl)-1-((benzyloxy)carbonyl)piperidin-4-yl)methyl)trifluoroborate [ka] Intermediate F-6 was prepared according to the method described for Intermediate F-1 herein above using Intermediate A-8. LC-MS Method B-2: Rt=4.98 min; MS m / z [M-K+Na] - =464.3.

[0259] Intermediate F-7: Potassium (((3R,4R)-1-(tert-butoxycarbonyl)-3-(1-methyl-1H-pyrazol-4-yl)piperidin-4-yl)methyl)trifluoroborate [ka] Intermediate F-7 was prepared according to the method described for Intermediate F-1 herein above using Intermediate A-9. LC-MS Method B-2: Rt=3.59 min; MS m / z [M-K+Na] - =368.2.

[0260] 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 [ka] 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 diluted with N 2 The RM was evacuated / backfilled twice with 9-BBN (0.5 M in THF, 8.82 mL, 4.41 mmol) was added slowly and the RM was stirred at 50° C. for 4 h in a capped vial. The RM was then cooled to RT. 3 PO 4 A degassed solution of (2.553 g, 12.03 mmol) of tert-butyl 4-bromo-5,7-dimethyl-1H-indole-1-carboxylate (Intermediate I-1, 1.30 g, 4.01 mmol) and PdCl was then added slowly to the mixture. 2 (dtbpf) (130.7 mg, 200.5 μmol) was added as a solid. The mixture was then cooled to 5° C. 2 The RM was evacuated / backfilled with 50° C. and the capped vial was stirred at 50° C. for 2 h. The RM was allowed to cool to RT and then partitioned between water and TBME. The layers were separated and washed with brine and TBME. The combined organic layers were washed with MgSO 4 The mixture was dried over ice, filtered, and the volatiles were removed under reduced pressure at 50° C. to give a brown oil, which was purified on silica gel (220 g) using an automated purification system (NP; Teledyne ISCO®; collection at 245 / 263 nm; flow rate 150 mL / min; eluent: heptane + 1-9.7% EtOAc in 25.9 min). Pure fractions were combined and the volatiles were removed under reduced pressure at 50° C. to give a) recovered starting material (Intermediate A-1, 308 mg) and b) the cis isomer as a white foam (1.34 g); LC-MS Method B-2: Rt=9.19 min; MS m / z[M+H] + =559.2; 1 H NMR (400MHz, DMSO-d 6) 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) as an amber oil (211 mg);LC-MS method B-2:Rt=8.92 min;MS m / z[M+H]+= 559.4; 1 H NMR (400MHz, DMSO-d 6 )δ[ppm]7.97(d,J=8.2Hz,2H),7.58-7.51(m,3H),6.81(s,1H),6.47(d,J= 3.8Hz,1H),3.86(s,3H),3.24-3.09(m,2H),2.92-2.78(m,3H),2.59-2.45 (partially overlapped with m,2H,DMSO peak),2.43-2.37(m,4H),2.30-2.21(m,1H),2.09(s,3 H),1.89-1.77(m,1H),1.57(s,9H),1.51-1.37(m,1H),1.29-1.20(m,1H).

[0261] 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 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 [ka] 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). Volatiles were removed under reduced pressure at 50° C. and the residue was triturated multiple times with hexanes and DCM, then dried under reduced pressure at 50° C. to provide: 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 = 3.62 min; 96.6% ee.

[0262] 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 [ka] Intermediate rac-B-4 was prepared according to the method described for intermediate rac-B-4 above, 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.

[0263] 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 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 [ka] Enantiomeric separation and analysis of intermediate rac-B-4 according to method SFC-8: 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 = 1.12 min; 99.5% ee. 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.

[0264] 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 [ka] A diastereomeric mixture of intermediate rac-B-7 was prepared following the method described for intermediate rac-B-4 herein above 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.

[0265] 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 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 [ka] Diastereomeric and enantiomeric separation and analysis of the intermediate rac-B-7 of the diastereomeric mixture according to method SFC-9: 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 = 1.67 min; 99.5% ee. Intermediate B-9 (Peak 4): White foam. LC-MS method B-2: Rt=8.51 min; MS m / z[M+H] +=575.3 Analytical chiral HPLC: Rt = 2.72 min; 99.5% ee. Before use in the next reaction, the isolated peak 4 was re-purified by column chromatography on silica gel (12 g, heptane / EtOAc = 100 / 0 to 88 / 12).

[0266] Intermediate B-10: tert-Butyl 4-(((3R,4R)-1-(tert-butoxycarbonyl)-3-(4-(tert-butoxycarbonyl)phenyl)piperidin-4-yl)methyl)-5,7-dimethyl-1H-indole-1-carboxylate [ka] 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. 3 PO 4 (1.470 g, 6.924 mmol) was added. The mixture was then heated under N 2 The mixture was evacuated and refilled with PdCl. 2 (dppf) (153.5 mg, 209.8 μmol) was added and the mixture was treated with N 2 The RM was stirred in a capped vial at 95° C. overnight, then cooled to RT, diluted with TBME / water and filtered through Celite®. The layers of the filtrate were separated and washed with brine and TBME. The combined organic layers were washed with MgSO 4The mixture was dried over silica gel (40 g) using an automated purification system (NP; Teledyne ISCO®; collection at 245 / 260 nm; flow rate 40 mL / min; eluent: heptane + 0-9.6% EtOAc in 20 min) to provide 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.

[0267] Intermediate B-11: tert-Butyl 4-(((3R,4R)-3-(4-(tert-butoxycarbonyl)phenyl)piperidin-4-yl)methyl)-5,7-dimethyl-1H-indole-1-carboxylate [ka] 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 an additional 140 min. Na 2 CO 3 The RM was poured into a well-stirred mixture of aqueous solution (10 wt%) and EtOAc. The layers were separated and washed with EtOAc and brine. The combined organic layers were washed with MgSO 4The mixture was dried over silica gel, filtered and concentrated under reduced pressure at 50 °C. The residue was purified by automated purification system (NP; Teledyne ISCO®; collection at 233 / 263 nm; flow rate 35 mL / min; eluent: DCM + 0-10% {EtOH / NH 4 Purification on silica gel (24 g) using 25% OH water = 9 / 1) provided 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.

[0268] Intermediate B-12: tert-Butyl 4-(((3R,4R)-3-(4-(tert-butoxycarbonyl)phenyl)-1-methylpiperidin-4-yl)methyl)-5,7-dimethyl-1H-indole-1-carboxylate [ka] Aqueous formaldehyde (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) and sodium cyanoborohydride (18.66 mg, 296.9 μmol) was added and the RM was stirred for 1 h. The mixture was diluted with TBME and saturated NaHCO 3 Partition between aqueous solution and water, separate the layers and wash with brine and TBME. The combined organic layers were washed with MgSO 4The mixture was dried over 100° C., 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 60 F254, 0.5 mm; UV detection; eluent: DCM / MeOH=92 / 8; elution of bands 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 as a white foam (68.6 mg). LC-MS Method B-2: Rt=6.41 min; MS m / z[M+H] + =533.3.

[0269] Intermediate B-13: tert-Butyl 4-(((3R,4R)-3-(4-(tert-butoxycarbonyl)phenyl)-1-(2-fluoroethyl)piperidin-4-yl)methyl)-5,7-dimethyl-1H-indole-1-carboxylate [ka] 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 washed with MgSO 4Drying over 100° C., filtration and removal of volatiles under reduced pressure at 50° C. gave a yellow oil, which was purified by preparative TLC (MERCK 1.05744.0001, PLC silica gel 60 F254, 0.5 mm; eluent: DCM / MeOH=94 / 6; elution of bands with DCM / MeOH=90 / 10). The filtrate's volatiles 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.

[0270] Intermediate B-14: tert-Butyl 4-(((3R,4R)-3-(4-(tert-butoxycarbonyl)phenyl)-1-ethylpiperidin-4-yl)methyl)-5,7-dimethyl-1H-indole-1-carboxylate [ka] 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 in a capped vial at 45 °C for 6 h. The mixture was allowed to cool to RT and then partitioned between TBME and water. The layers were separated and washed with brine and TBME. The combined organic layers were washed with MgSO 4The mixture was dried over 100° C., 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 60 F254, 0.5 mm; UV detection; eluent=DCM / MeOH 95 / 5; elution of bands 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.

[0271] Intermediate B-15: tert-Butyl 4-(((3R,4R)-3-(4-cyanophenyl)piperidin-4-yl)methyl)-5,7-dimethyl-1H-indole-1-carboxylate [ka] 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 diluted with H 2The mixture was stirred under atmosphere (balloon) for about 2.5 hours. The mixture was filtered through Celite and the solid was 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 charcoal before filtering through Celite® and rinsing 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 (400MHz, DMSO-d 6 ) 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). Thirty-two of the 33 Hs were reported.

[0272] Intermediate rac-B-16: Racemic tert-butyl 4-(((3S * ,4R * )-1-(tert-butoxycarbonyl)-4-(4-cyanophenyl)pyrrolidin-3-yl)methyl)-5,7-dimethyl-1H-indole-1-carboxylate [ka] In a vial, tert-butyl 4-bromo-5,7-dimethyl-1H-indole-1-carboxylate (Intermediate I-1, 27 mg, 83 μmol), racemic potassium (((3S *,4R * )-1-(tert-butoxycarbonyl)-4-(4-cyanophenyl)pyrrolidin-3-yl)methyl)trifluoroborate (intermediate rac-F-2, 21 mg, 53 μmol), K 3 PO 4 (34 mg, 161 μmol), and PdCl 2 (dppf)-CH 2 Cl 2 The adduct (6.1 mg, 7.5 μmol) was 2 Toluene (0.5 mL) and water (125 μL) were added under 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 (3×) and the combined organic layers were dried over an Isolute® Phase Separator and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (40 g, EtOAc / heptane=0 / 100 to 50 / 50) to give the racemic tert-butyl 4-(((3S * ,4R * )-1-(tert-butoxycarbonyl)-4-(4-cyanophenyl)pyrrolidin-3-yl)methyl)-5,7-dimethyl-1H-indole-1-carboxylate (19.8 mg) was obtained. LC-MS Method C-1: RT=1.48 min; MS m / z[M-tBu+H] + =474.3.

[0273] Intermediate rac-B-17: Racemic tert-butyl 4-(((3S * ,4R * )-4-(4-cyanophenyl)pyrrolidin-3-yl)methyl)-5,7-dimethyl-1H-indole-1-carboxylate [ka] 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 and washed with saturated NaHCO 3 Wash with aqueous solution, dry with an Isolute® Phase Separator and concentrate to give the 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) was obtained as a pale yellow oil. LC-MS Method C-1: RT=1.00 min; MS m / z[M+H] + =430.4.

[0274] Intermediate rac-B-18: Racemic tert-butyl 4-(((3S * ,4R * )-4-(4-cyanophenyl)-1-methylpyrrolidin-3-yl)methyl)-5,7-dimethyl-1H-indole-1-carboxylate [ka] Crude concentrated racemic tert-butyl 4-(((3S * ,4R *To )-4-(4-cyanophenyl)pyrrolidin-3-yl)methyl)-5,7-dimethyl-1H-indole-1-carboxylate (intermediate rac-B-17, 73 mg) was added a solution of formaldehyde in water (37 wt%, 2.0 mL). The mixture was stirred at RT for 15 min before 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 dissolved in DCM and saturated NaHCO 3 The separated aqueous layer was extracted with DCM (3x) and the combined organic layers were dried over an Isolute® phase separator and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (12 g, {EtOAc / EtOH 3 / 1} / heptane = 0 / 100 to 100 / 0) to give the racemic tert-butyl 4-(((3S * ,4R * )-4-(4-cyanophenyl)-1-methylpyrrolidin-3-yl)methyl)-5,7-dimethyl-1H-indole-1-carboxylate (48 mg) was obtained as a pale yellow oil. LC-MS Method C-1: RT=0.90 min; MS m / z[M+H] + =444.5.

[0275] The following examples were synthesized from the appropriate starting materials by applying methods similar to those described in the above examples.

[0276] [Table 8]

[0277] [Table 9]

[0278] [Table 10]

[0279]

Table 11

[0280]

Table 12

[0281]

Table 13

[0282]

Table 14

[0283]

Table 15

[0284]

Table 16

[0285]

Table 17

[0286]

Table 18

[0287]

Table 19

[0288]

Table 20

[0289] [Table 21]

[0290] [Table 22]

[0291] [Table 23]

[0292] [Table 24]

[0293] [Table 25] EXAMPLES

[0294] 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 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 washed with MgSO 4The mixture was dried over silica gel (12 g) using an automated purification system (NP; Teledyne ISCO®; collection at 240 / 269 nm; flow rate 30 mL / min; eluent: DCM+0-4.7% MeOH in 9.4 min). Pure fractions were combined and the volatiles were removed under reduced pressure at 50° C. to give the title compound (72.9 mg) as an off-white foam.

[0295] 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 Example 2 (72.8 mg, off-white foam) was prepared similarly to Example 1 as described above 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).

[0296] Example Ex-8: 4-((3R,4R)-4-((5,7-dimethyl-1H-indol-4-yl)methyl)-1-methylpiperidin-3-yl)benzoic acid 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., which resulted in a clear solution, and stirring was continued at 55° C. for 23 h. The RM was allowed to cool 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 (3×). The combined organic layers were washed with MgSO 4 It was dried over ice, 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.

[0297] Example Ex-10: 4-((3R,4R)-4-((5,7-dimethyl-1H-indol-4-yl)methyl)-1-ethylpiperidin-3-yl)benzoic acid 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 an additional 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 brought into solution with MeOH and NH 4Direct purification by preparative HPLC on an XBridge C18 column (30 × 100 mm, 5 μm) eluted with 5–60% ACN in OH water (0.1%) provided 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.

[0298] Example Ex-12: 4-((3R,4R)-4-((5,7-dimethyl-1H-indol-4-yl)methyl)-1-(2-fluoroethyl)piperidin-3-yl)benzoic acid 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) was added TFA (0.3 mL). The RM was stirred at RT for 1 h, diluted with DCE and volatiles were removed under reduced pressure at 40 °C. The crude residue was purified on a C18 (26 g) using an automated purification system (RP, Teledyne ISCO®; collection at 220 / 270 nm; flow rate 35 mL / min; eluent: water + 10-60% ACN in 10 min). Pure fractions were combined and ACN was removed under reduced pressure at 50 °C. The resulting aqueous slurry was freeze-dried overnight to give the title compound as a white solid (16.8mg).

[0299] Example Ex-15: 4-((3R,4R)-4-((5,7-dimethyl-1H-indol-4-yl)methyl)-1-(2-hydroxy-2-methylpropyl)piperidin-3-yl)benzoic acid 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 2 drops of water were added and NH 4 The mixture was purified by preparative HPLC on an XBridge C18 column (30 × 100 mm, 5 μm) eluting with 5% to 28% ACN in OH water (0.1%) to provide, after lyophilization, 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.

[0300] Examples Ex-24 and Ex-25: 4-((3R,4S)-4-((5,7-dimethyl-1H-indol-4-yl)methyl)-1-methylpyrrolidin-3-yl)benzoic acid and 4-((3S,4R)-4-((5,7-dimethyl-1H-indol-4-yl)methyl)-1-methylpyrrolidin-3-yl)benzoic acid Step 1-a: Racemic tert-butyl 4-(((3S) in IPA (2.5 mL) * ,4R * To a solution of 4-(4-cyanophenyl)-1-methylpyrrolidin-3-yl)methyl)-5,7-dimethyl-1H-indole-1-carboxylate (intermediate rac-B-18, 48 mg, 19 μmol), aqueous KOH (5 M, 250 μL, 1.25 mmol) and water (1.0 mL) were added. Microwave irradiation (Biotage® Initiator +) to 150° C. for 4.5 h. Additional aqueous KOH (5 M, 75 μL) was added and the RM was heated using microwave irradiation (Biotage® Initiator + Heating was continued at 150° C. for 3 h and then at 165° C. for 1 h. The mixture was concentrated under reduced pressure and NH 4 The crude residue was purified by preparative HPLC on an XBridge C18 OBD column (30 × 50 mm, 5 μm) eluted with 5%–20% ACN in OH water (5 mM) to give racemic 4-((3R * ,4S * )-4-((5,7-dimethyl-1H-indol-4-yl)methyl)-1-methylpyrrolidin-3-yl)benzoic acid (23.4 mg) was provided as a white solid. LC-MS Method C-1: RT=0.70 min; MS m / z[M+H] + =363.2.

[0301] Step 1-b: Enantiomer separation and analysis 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) provided: 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 = 3.02 min; 98.6% ee.

[0302] Example Ex-42: 4-(((3R,4R)-3-(4-(1H-tetrazol-5-yl)phenyl)-1-methylpiperidin-4-yl)methyl)-5,7-dimethyl-1H-indole 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) was added sodium azide (16.13 mg, 248.1 μmol) and ammonium chloride (12.39 mg, 231.6 μmol) and the resulting mixture was stirred in a capped vial at 100° C. for approximately 1.5 days. The RM was cooled to RT and added MeOH (2.0 mL) and K 2 CO 3 (325 mesh, 114.3 mg, 827.1 μmol) was added. Heating was continued at 55° C. for 18 h and stirring was continued at ambient temperature for approximately 2 days. The mixture was diluted with MeOH and concentrated HCl (12 M, 137.9 uL, 1.654 mmol) was added and the resulting mixture was concentrated under reduced pressure at 50° C. to a slurry. Water was added and NH 4 The mixture was purified by preparative HPLC on an XBridge C18 column (30 × 100 mm, 5 μm) eluting with 5%–36.2% ACN in OH water (0.1%) to afford 4-(((3R,4R)-3-(4-(1H-tetrazol-5-yl)phenyl)-1-methylpiperidin-4-yl)methyl)-5,7-dimethyl-1H-indole (26.1 mg) as a pale yellow fluffy solid after concentration under reduced pressure and subsequent lyophilization.

[0303] Example Ex-44: 4-((3R,4R)-4-((5,7-dimethyl-1H-indol-4-yl)methyl)-1-methylpiperidin-3-yl)benzonitrile 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 added Na 2 CO 3The layers were then separated and the aqueous layer was extracted with DCM (2x). The combined organic layers were washed with MgSO 4 The mixture was dried over 1000 ml, filtered and concentrated under reduced pressure at 50° C. Preparative TLC plates (MERCK 1.05744.0001, PLC silica gel 60 F254, 0.5 mm; DCM / {MeOH / NH 4 The residue was purified by elution with 5% COOH (25%, 9 / 1}=92 / 8) to provide 4-((3R,4R)-4-((5,7-dimethyl-1H-indol-4-yl)methyl)-1-methylpiperidin-3-yl)benzonitrile (12.8 mg) as a white foam.

[0304] Example Ex-52: 5,7-Dimethyl-4-(((3R,4R)-1-methyl-3-(1-methyl-1H-pyrazol-4-yl)piperidin-4-yl)methyl)-1H-indole 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 K 2 CO 3 (325 mesh, 50.2 mg, 363 μmol) was added 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 washed with MgSO 4 The mixture was dried over 100° C., filtered and concentrated under reduced pressure at 50° C. Preparative TLC plates (MERCK 1.05744.0001, PLC silica gel 60 F254, 0.5 mm; DCM / (MeOH:NH 4 The residue was purified by elution with 0.5% hexanes (OH) 25% 9:1)=88 / 12) to provide 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.

[0305] Example Ex-58 Racemic 4-((3R * ,4S * )-4-((5,7-dimethyl-1H-indol-4-yl)methyl)-1-methylpyrrolidin-3-yl)benzamide Racemic tert-butyl 4-(((3S) in tert-amyl alcohol (2.5 mL) * ,4R * To a solution of )-4-(4-cyanophenyl)-1-methylpyrrolidin-3-yl)methyl)-5,7-dimethyl-1H-indole-1-carboxylate (intermediate rac-B-18, 68 mg, 15 μmol), aqueous NaOH (1 M, 1.2 mL, 1.20 mmol) was added. Microwave irradiation (Biotage® Initiator + ) the RM was heated at 110° C. for 84 h and then at 160° C. for 2 h. Solid lithium hydroxide (50 mg, 2.09 mmol) was added and microwave irradiation (Biotage® Initiator + The RM was heated at 165 °C for 16 h with NH 4 The crude residue was purified by preparative HPLC on an XBridge C18 OBD column (30 × 50 mm, 5 μm) eluting with 10% to 0% AC in OH water (5 mM) to give racemic 4-((3R * ,4S * )-4-((5,7-dimethyl-1H-indol-4-yl)methyl)-1-methylpyrrolidin-3-yl)benzamide (3.0 mg) was provided as an off-white solid. LC-MS Method C-3: Rt=0.92 min; [M+H] + =362.4

[0306] Example Ex-59 4-((3R,4S)-4-((5-cyclopropyl-7-methyl-1H-indol-4-yl)methyl)-1-methylpyrrolidin-3-yl)benzoic acid Step 1-a: Racemic 4-((3R * ,4S *)-4-((5-cyclopropyl-7-methyl-1H-indol-4-yl)methyl)-1-methylpyrrolidin-3-yl)benzoic acid is the racemic tert-butyl 4-(((3S * ,4R * Prepared according to step 1-a of the method described for Example Ex-24 herein above using 4-(4-cyanophenyl)-1-methylpyrrolidin-3-yl)methyl)-5-cyclopropyl-7-methyl-1H-indole-1-carboxylate (Intermediate B-87).

[0307] Step 1-b: Enantiomer separation and analysis 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 = 3.10 min; 95.9% ee.

[0308] Example Ex-60 4-(((3S,4R)-4-(4-(2H-tetrazol-5-yl)phenyl)-1-methylpyrrolidin-3-yl)methyl)-5,7-dimethyl-1H-indole Step 1-a: Racemic 4-(((3S * ,4R * )-4-(4-(2H-tetrazol-5-yl)phenyl)-1-methylpyrrolidin-3-yl)methyl)-5,7-dimethyl-1H-indole is the racemic tert-butyl 4-(((3S * ,4R * Prepared according to the method described for Example Ex-42 herein above using 4-(4-cyanophenyl)-1-methylpyrrolidin-3-yl)methyl)-5-cyclopropyl-7-methyl-1H-indole-1-carboxylate (intermediate rac-B-18).

[0309] Step 1-b: Enantiomer separation and analysis according to method SFC-13: Racemic 4-(((3S * ,4R * )-4-(4-(2H-tetrazol-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 = 3.48 min; 98.9% ee.

[0310] The following table includes examples that have been described above and those that have been synthesized using the appropriate starting materials and applying similar methods described in the above examples.

[0311] [Table 26]

[0312] [Table 27]

[0313] [Table 28]

[0314] [Table 29]

[0315] [Table 30]

[0316] [Table 31]

[0317] [Table 32]

[0318] [Table 33]

[0319] [Table 34]

[0320] [Table 35]

[0321] [Table 36]

[0322] [Table 37]

[0323] [Table 38]

[0324] [Table 39]

[0325] [Table 40]

[0326] LC-MS method Method A-1: Column: Acquity UPLC BEH C18, 2.1 x 50 mm column, 1.7 μm Column temperature: 40℃ Eluent: A: Water + FA (0.1%) B:ACN Flow rate: 0.8mL / min Gradient: Time / B%: 0.01 / 5; 0.3 / 5; 0.5 / 100; 1.8 / 100; 2.0 / 5; 3.0 / 5 (ternary method)

[0327] Method A-2: Column: Waters XBridge C18, 3.0 x 50 mm column, 3.5 μm Column temperature: 40℃ Eluent: A: Water + FA (0.1%) B:ACN Flow rate: 1.0mL / min Gradient: Time / B%:0.01 / 10;0.2 / 10 4.5 / 95;8.5 / 95;8.5 / 10;10.0 / 10;(decimal)

[0328] Method B-1: Column: CORTECS C18+, 2.1 x 50mm column, 2.7μm Column temperature: 80℃ Eluent: A: water + 0.05% FA + 3.75 mM ammonium acetate NH 4 (CH 3 CO 2 ) B: IPA + 0.05% FA Flow rate: 1.0mL / min 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.

[0329] Method B-2: Column: Acquity UPLC BEH C18, 2.1 x 100mm column, 1.7μm Column temperature: 80℃ Eluent: A: Water + 0.05% FA + 3.75 mM ammonium acetate B: IPA + 0.05% FA Flow rate: 0.4mL / min Gradient: Pre-run with 5% B in 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.

[0330] Method C-1: Column: Acquity UPLC BEH C18, 2.1 x 30 mm column, 1.7 μm Column temperature: 50℃ Eluent: A: water + 0.1% FA B: ACN + 0.1% FA Flow rate: 1.0mL / min Gradient: 2% B until 0.1 min; 2% to 98% B until 1.5 min, 98% B until 1.8 min.

[0331] Method C-2: Column: Acquity UPLC BEH C18, 2.1 x 30 mm column, 1.7 μm Column temperature: 50℃ Eluent: A: 5 mM NH in water 4 OH B: 5 mM NH in ACN 4 OH Flow rate: 1.0mL / min Gradient: 2% B until 0.1 min; 2% to 98% B until 1.5 min, 98% B until 1.8 min.

[0332] Method C-3: Column: Acquity UPLC BEH C18, 2.1 x 30 mm column, 1.7 μm Column temperature: 50℃ Eluent: A: 0.1% FA in water B: 0.1% FA in ACN Flow rate: 1.0mL / min Gradient: 2% to 98% B until 4.40 min, 98% B until 5.15 min.

[0333] Method C-4: Column: Acquity UPLC BEH C18, 2.1 x 30 mm column, 1.7 μm Column temperature: 50℃ Eluent: A: 5 mM NH in water 4 OH B: 5 mM NH in ACN4 OH Flow rate: 1.0mL / min Gradient: 2% to 98% B until 4.40 min, 98% B until 5.15 min.

[0334] Chiral HPLC Method Method SFC-1: Preparative Chiral HPLC Equipment: Sepiatec prep SFC-100 Column: Chiralpak AD, 250mm x 30mm 5μm Eluent: A: 0.05% NH in 15% IPA 3 B: 85% scCO 2 (Isocratic) Flow rate: 110.0mL / min Detection: UV230nm Injection volume: 3×1.30mL Oven temperature: 40℃ Pressure: 120 bar

[0335] Analytical Chiral HPLC Instrument: Analytical SFC-MS Waters UPC2 Injection: 5μL Mobile phase: A: 0.05% NH in 12% IPA 3 B: 88% scCO 2 (Isocratic) Flow rate: 3mL / min Column: Chiralpak AD (4.6mm×100mm 5μm) Detection UV: DAD Oven temperature: 40℃ Pressure: 1800psi

[0336] Method SFC-2: Preparative Chiral HPLC Equipment: Sepiatec prep SFC-100 Column: Chiralpak IH, 250×30mm 5μm Eluent: A: 0.05% NH in 11% IPA 3B: 89% scCO 2 (Isocratic) Flow rate: 90.0mL / min Detection: UV239nm Injection volume: 55×1.00mL Oven temperature: 40℃ Pressure: 130 bar

[0337] Analytical Chiral HPLC Instrument: Analytical SFC-MS Waters UPC2 Injection: 5μL Mobile phase: A: 0.05% NH in 10% IPA 3 B: 90% scCO 2 (Isocratic) Flow rate: 3mL / min Column: Chiralpak IH (4.6mm×100mm 5μm) Detection UV: DAD Oven temperature: 40℃ Pressure: 1800psi

[0338] Method SFC-3: Preparative Chiral HPLC Equipment: Sepiatec prep SFC-250 Column: Chiralpak IG, 250×30mm 5μm Eluent: A: 0.05% NH in 55% MeOH / IPA 50 / 50 3 B: 45% scCO 2 (Isocratic) Flow rate: 80mL / min Detection: UV240nm Injection volume: 38×2.0mL Oven temperature: 40℃ Pressure: 120 bar

[0339] Analytical Chiral HPLC Instrument: Analytical SFC-MS Waters UPC2 Injection: 5μL Mobile phase: A: 0.05% NH in 50% MeOH / IPA 50 / 50 3 B: 50% scCO 2 (Isocratic) Flow rate: 3.0mL / min Column: Chiralpak IG (4.6×100mm 5μm) Detection UV: DAD Oven temperature: 40℃ Pressure: 1800psi

[0340] Method SFC-4: Preparative Chiral HPLC Instrument: Waters THAR80 system Column: Chiralpak IG, 21×250mm 5μm Eluent: A: 45% 10 mM NH 3 A: MeOH containing 55% scCO 2 (Isocratic) Flow rate: 80g / min Detection: UV270nm Injection volume: 4×3.0mL Oven temperature: RT Pressure: 125 bar

[0341] Analytical Chiral HPLC Instrument: Analytical SFC-MS Waters UPC2 Injection: 3μL Mobile phase: A:CO 2 B: 5~55% 0.1% NH 3 Containing MeOH Flow rate: 2.5mL / min Column: Chiralpak IG-3 (3×100mm 3μm) Detection UV: DAD Oven temperature: 40℃ Pressure: 1800psi

[0342] Method SFC-5: Preparative Chiral SFC Equipment: Sepiatec SFC 100 Column: 2×Chiralcel oz in a raw, 250×30mm 5μm Eluent: A: 0.05% NH in 22% MeOH 3 B: 78% scCO 2 (Isocratic) Flow rate: 105mL / min Detection: UV235nm Injection volume: 3.5mL Oven temperature: 40℃ Pressure: 100 bar

[0343] Analytical Chiral SFC Instrument: Analytical SFC-MS Waters UPC2 Injection: 5μL Mobile phase: A: 0.05% NH in 12% MeOH 3 B: 88% scCO 2 (Isocratic) Flow rate: 3mL / min Column: Chiralcel Oz (4.6×100mm 5μm) Detection UV: DAD 235nm Oven temperature: 40℃ Pressure: 1800psi

[0344] Method SFC-6: Preparative Chiral SFC Equipment: Sepiatec SFC 100 Column: Chiralpak IG, 250×50mm 5μm Eluent: A: 0.05% NH in 55% IPA 3 B: 45% scCO 2 (Isocratic) Flow rate: 120mL / min Detection: UV235nm Injection volume: 1.2mL Oven temperature: 40℃ Pressure: 120 bar

[0345] Analytical Chiral SFC Instrument: Analytical SFC-MS Waters UPC2 Injection: 5μL Mobile phase: A: 0.05% NH in 40% IPA 3 B: 60% scCO 2 (Isocratic) Flow rate: 3mL / min Column: Chiralpak AD (4.6×100mm 5μm) Detection UV: DAD 235nm Oven temperature: 40℃ Pressure: 1800psi

[0346] Method SFC-7: Preparative Chiral SFC Equipment: Sepiatec SFC 100 Column: Chiralpak AD-H, 250×30mm 5μm Eluent: A: 0.05% NH in 42% IPA 3 B: 58% scCO 2 (Isocratic) Flow rate: 80mL / min Detection: UV220nm Injection volume: 3.5mL Oven temperature: 40℃ Pressure: 120 bar

[0347] Analytical Chiral SFC Instrument: Analytical SFC-MS Waters UPC2 Injection: 5μL Mobile phase: A: 0.05% NH in 40% IPA 3 B: 60% scCO 2 (Isocratic) Flow rate: 3mL / min Column: Chiralpak AD (4.6×100mm 5μm) Detection UV: DAD 220nm Oven temperature: 40℃ Pressure: 1800psi

[0348] Method SFC-8: Preparative Chiral HPLC Equipment: Sepiatec prep SFC-100 Column: Chiralpak AD, 250×30mm 5μm Eluent: A: 0.05% NH in 20% IPA 3 B: 80% scCO 2 (Isocratic) Flow rate: 80mL / min Detection: UV235nm Injection volume: 23×1.10mL Oven temperature: 40℃ Pressure: 120 bar

[0349] Analytical Chiral HPLC Instrument: Analytical SFC-MS Waters UPC2 Injection: 5μL Mobile phase: A: 0.05% NH in 20% IPA 3 B: 80% scCO 2 (Isocratic) Flow rate: 3mL / min Column: Chiralpak AD (4.6×100mm 5μm) Detection UV: DAD Oven temperature: 40℃ Pressure: 1800psi

[0350] Method SFC-9: Preparative Chiral HPLC Equipment: Sepiatec prep SFC-100 Column: Chiralpak IC, 250×30mm 5μm Eluent: A: 0.05% NH in 15% MeOH 3 B: 85% scCO 2 (Isocratic) Flow rate: 80mL / min Detection: UV240nm Injection volume: 28×0.80mL Oven temperature: 40℃ Pressure: 130 bar

[0351] Analytical Chiral HPLC Instrument: Analytical SFC-MS Waters UPC2 Injection: 5μL Mobile phase: A: 0.05% NH in 10% MeOH 3 B: 90% scCO 2 (Isocratic) Flow rate: 3mL / min Column: Chiralpak IK (4.6mm x 100mm 5μm) Detection UV: DAD Oven temperature: 40℃ Pressure: 1800psi

[0352] Method C-10: Preparative Chiral HPLC Instrument: Agilent 1260 Infinity Column: Chiralpak IG, 250×21mm, 5μm Eluent: A: 40% n-hexane, B: 60% EtOH / MeOH=1 / 1 (isocratic) Flow rate: 15.0mL / min Detection: 210nm Oven / column temperature: 23℃ Pressure: 80 bar

[0353] Analytical Chiral HPLC Instrument: Agilent, 1260 infinity II Injection: 10μL Mobile phase: A: 50% n-Hexane, B: 0.1% DEA in 50% EtOH / MeOH=70 / 30 (isocratic) Flow rate: 1mL / min Column: Chiralpak IG (4.6×150mm 5μm) Detection UV: DAD Oven / column temperature: 25℃ Pressure: 400 bar

[0354] Method SFC-11: Preparative Chiral HPLC Instrument: Waters SFC-100 (equipped with ABsys GmbH upgrade) Column: Chiralpak IG, 250×30mm 5μm Eluent: A: 0.05% NH in 35-45% MeOH 3 B: 65-55% scCO 2 Flow rate: 110.0mL / min Detection: DAD Injection volume: 3×1.30mL Oven temperature: 50℃ Pressure: 120 bar

[0355] Analytical Chiral HPLC Instrument: Analytical SFC-MS Waters UPC2 Injection: 5μL Mobile phase: A: 0.05% NH in 38% MeOH 3 B: 62% scCO 2 (Isocratic) Flow rate: 3mL / min Column: Chiralpak IG (4.6×100mm 5μm) Detection UV: DAD Oven temperature: 40℃ Pressure: 1800psi

[0356] Method SFC-12: Preparative Chiral HPLC Equipment: Sepiatec prep SFC-100 Column: Chiralpak IC, 250×21mm 5μm Eluent: A: 40% 10 mM NH in 4:1 MeOH / ACN 3 B: 60% scCO 2 (Isocratic) Flow rate: 80g / min Detection: UV272nm Injection volume: 13×2mL Oven temperature: 40℃ Pressure: 100 bar

[0357] Analytical Chiral HPLC Instrument: Analytical SFC-MS Waters UPC2 Injection: 5μL Mobile phase: A: 0.1% TEA in 4:1 MeOH / ACN, B: scCO 2 0.1% TEA in medium; 5-55% A-B gradient over 5 min Flow rate: 2.5mL / min Column: Chiralpak IC (3×100mm 3μm) Detection UV: DAD Oven temperature: 40℃ Pressure: 1800psi

[0358] Method SFC-13: Preparative Chiral HPLC Equipment: Sepiatec prep SFC-100 Column: Chiralpak IE, 250×21mm 5μm Eluent: A: 10 mM NH in 45% MeOH 3 B: 55% scCO 2 (Isocratic) Flow rate: 80g / min Detection: UV248nm Injection volume: 5×1mL Oven temperature: 40℃ Pressure: 125 bar

[0359] Analytical Chiral HPLC Instrument: Analytical SFC-MS Waters UPC2 Injection: 5μL Mobile phase: A: 0.1% NH in MeOH 3 , B: scCO 2 5-55% A-B gradient over 5 min Flow rate: 2.5mL / min Column: Chiralpak IE (3×100mm 3μm) Detection UV: DAD Oven temperature: 40℃ Pressure: 1800psi

[0360] Biological Data Determination of complement factor B inhibition Biological Example 1: Human Complement Factor B ELISA Assay CVF-Bb complex 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 a concentration of 3 nM was diluted in 10 mM MgCl 2 The cells were incubated with various concentrations of test compounds for 1 h at RT in PBS pH 7.4 containing 0.05% (w / v) CHAPS. Human complement C3 substrate purified from plasma was added to a final concentration of 1 μM. After 1 h of incubation at RT, the enzymatic reaction was stopped by adding a cocktail of concentrated pan-protease inhibitors. The product of the reaction, 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 test compound concentration.

[0361] Biological Example 2: Human Complement Factor B TR-FRET Assay 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)amino)-6-oxohexyl)-3,3-dimethyl-5-sulfoindoline-2-yl Recombinant human Factor B (expressed in Drosophila cells and purified using standard methods) labeled with (75 nm)-3H-indol-1-ium (prepared for 240 nm active Factor B as described in WO 2015 / 009616 when tested using the assay of Biological Example 1) was incubated with various concentrations of test compound in 20 mM Tris / HCl, pH 7.4, 0.005% (v / v) Tween 20 for up to 2 hours at RT.

[0362] The decrease in fluorescence intensity over time 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. IC from the percentage inhibition of displacement 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-sulfoindolin-2-ylidene)penta-1,3-dien-1-yl)-1-ethyl-3,3-dimethyl-5-sulfo-3H-indol-1-ium (240 nm active factor B when tested using the assay of Biological Example 1) as a function of test compound concentration. 50 values ​​were calculated.

[0363] Compounds of the present disclosure are active in inhibiting factor B. The data in Table 1 were collected using the assay of Biological Example 2.

[0364] [Table 41]

[0365] [Table 42]

[0366] [Table 43]

[0367] Compounds of the present disclosure have an IC of -micromolar 50 Thus, the compounds of the present disclosure may be useful in treating diseases and / or disorders described herein, such as diseases / disorders mediated by complement factor B.

[0368] All publications and patent documents cited in this specification are incorporated by reference as if each such publication or document was specifically and individually indicated to be incorporated by reference. The present disclosure and embodiments thereof have been described in detail. However, the scope of the disclosure is not intended to be limited to the particular embodiments of any process, manufacture, composition, compound, means, method and / or step described herein. Various modifications, substitutions and changes can be made to the disclosed materials without departing from the spirit and / or essential characteristics of the present disclosure. Thus, those skilled in the art will readily recognize from this disclosure that subsequent modifications, substitutions and / or changes that perform substantially the same function or achieve substantially the same result as the embodiments described herein can be utilized by such related embodiments of the present disclosure. Thus, it is intended that the following claims include within their scope modifications, substitutions and changes to the processes, manufacture, composition, compound, means, method and / or step disclosed herein. The claims should not be read as being limited to the described order or elements unless stated to that effect. It should be understood that various changes in form and detail can be made without departing from the scope of the appended claims.

Claims

1. Formula (I) 【Chemistry 1】 (In the formula, m is 0, 1, 2, or 3; n is 0, 1, 2, or 3, with the proviso that m and n are not both 0; R is hydrogen, halogen, C １ ~C ４ Alkyl, haloC １ ~C ４ Alkyl or hydroxy C １ ~C ４ is alkyl; R １ is hydrogen, halogen, hydroxy, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C ３ ~C ６ Cycloalkyl, C １ ~C ６ Alkoxy, HaloC １ ~C ６ Alkyl, haloC ３ ~C ６ Cycloalkyl, haloC １ ~C ６ Alkoxy, Hydroxy C １ ~C ６ Alkyl, Hydroxy C ３ ~C ６ Cycloalkyl Amino C １ ~C ６ Alkyl, C １ ~C ６ Alkoxy C １ ~C ６ Alkyl, C １ ~C ６ Alkoxy C １ ~C ６ Alkoxy, C ３ ~C ６ Cycloalkyl C １ ~C ６ Alkoxy, HaloC １ ~C ６ Alkoxy, -S-C １ ~C ６ Alkyl, -S(O)C １ ~C ６ Alkyl, -S(O) ２ C １ ~C ６ Alkyl, CH ２ NHC(O)C １ ~C ４ Alkyl or -OCH ２ C(O)R １ａ and R １ａ is hydroxy, C １ ~C ６ Alkoxy, amino or mono- and di-C １ ~C ６ alkylamino; R ２ is C １ ~C ３ Alkyl, C ３ Cycloalkyl, C １ ~C ３ Alkoxy, Hydroxy C １ ~C ６ alkyl or halogen, １ ~C ３ Alkyl, C ３ Cycloalkyl, or C １ ~C ３ The alkoxy 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, where said heteroaryl is a 5- to 10-membered heteroaryl having 1, 2 or 3 ring heteroatoms independently selected from N, O, or S, and said phenyl or heteroaryl is unsubstituted or has one R ５ and 0, 1 or 2 R ５’ is replaced by; R ５ is -CO ２ R ５ｂ , -CON(R ５ｃ ) ２ , C １ ~C ６ Alkyl, C １ ~C ６ Alkoxy C １ ~C ６ Alkyl, -CH ２ CO ２ R ５ｂ , -CH ２ CON (R ５ｃ ) ２ , -C(O)NHSO ２ C １ ~C ４ Alkyl, -SO ２ NHC(O)C １ ~C ４ Alkyl, -SO ２ N (H) ｍ (C １ ~C ４ Alkyl) ２－ｍ , -SO ２ C １ ~C ４ 5- to 6-membered heteroaryl having 1 to 4 heteroatoms independently selected from alkyl, cyano, hydroxy, halogen, N, O, and S, and N, O, and S(O) ｑ and wherein the 5- to 6-membered heteroaryl and 4- to 6-membered heterocyclyl are unsubstituted or have 1, 2, or 3 R ５ａ is replaced by; Each R ５ａ is fluoro, hydroxyl, and C which is unsubstituted or substituted by —COOH or 1, 2, or 3 fluoro. １ ~C ６ independently selected from alkyl; Here, R ５ When R is a 4- to 6-membered heterocyclyl, two R ５ａ is not fluoro and hydroxyl substituted at the same positions; Each R ５ｂ is hydrogen or C １ ~C ５ independently selected from alkyl; Each R ５ｃ is hydrogen, unsubstituted or halogen, hydroxy or C １ ~C ４ C substituted with alkyl １ ~C ４ independently selected from alkyl; Each R ５’ is, HaroC １ ~C ４ Alkyl, C １ ~C ４ Alkoxy, HaloC １ ~C ４ Alkoxy, halogen, cyanomethyl, hydroxy C １ ~C ６ Alkyl, and C ３ ~C ５ cycloalkyl; W is O, C(R ６ ) ２ , or NR ７ and R ６ represents, at each occurrence, hydrogen, halogen, hydroxy, amino, mono- and di-C １ ~C ４ Alkylamino, C １ ~C ６ Alkyl, haloC １ ~C ６ Alkyl, Hydroxy C １ ~C ６ Alkyl, Cyano C １ ~C ６ Alkyl, C １ ~C ６ Alkoxy or haloC １ ~C ６ or two R ６ in combination with the carbon atom to which they are attached form a spirocyclic carbocycle having 3 to 6 ring atoms, wherein said spirocyclic carbocycle is unsubstituted or substituted with halogen, C １ ~C ６ Alkyl, or C １ ~C ６ alkoxy; or two R ６ in combination with the carbon atom to which they are attached, N, O, or S(O) ｑ and forming a spirocyclic heterocycle having 1 or 2 ring heteroatoms independently selected from the group consisting of: １ ~C ６ Alkyl, haloC １ ~C ６ Alkyl, C ３ ~C ６ Cycloalkyl, haloC ３ ~C ６ is substituted by cycloalkyl; q is 0, 1, or 2; R ７ is hydrogen, C １ ~C ６ Alkyl, haloC １ ~C ６ Alkyl, Hydroxy C ２ ~C ６ Alkyl, C ３ ~C ６ Cycloalkyl, C ３ ~C ６ Cycloalkyl C １ ~C ３ Alkyl, haloC ３ ~C ６ Cycloalkyl, C １ ~C ６ Alkoxy C １ ~C ６ Alkyl, haloC １ ~C ６ Alkoxy C １ ~C ６ Alkyl, aryl, N, O, and S(O) ｑ or a 4- to 6-membered heterocyclyl having 1 to 2 heteroatoms independently selected from N, O, and S, wherein １ ~C ６ Alkyl is unsubstituted or includes N, O, and S(O) ｑ and wherein the 4- to 6-membered heterocyclyl is unsubstituted or substituted by 1, 2, or 3 halogens; and wherein the aryl or heteroaryl is unsubstituted or substituted by halo, C １ ~C ６ Alkyl, haloC １ ~C ６ Alkyl, C ３ ~C ５ Cycloalkyl, haloC ３ ~C ５ is substituted by cycloalkyl; Each R ８ are independently hydrogen, halogen, C １ ~C ４ Alkyl, haloC １ ~C ４ alkyl or two R ８ together with the carbon atom to which they are attached, C ３ ~C ５ Cycloalkyl or haloC ３ ~C ５ forming a cycloalkyl or a pharma- ceutically acceptable salt thereof.

2. Formula (IA) 【Chemistry 2】 wherein A is selected from phenyl, furanyl, thiophenyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, pyrazolyl, imidazolyl, pyridyl, triazolyl, tetrazolyl, oxadiazolyl, isoxadiazolyl, pyrimidinyl, pyrazinyl, and pyridazinyl.

2. A compound of formula (I) according to claim 1, or a pharma- ceutically acceptable salt thereof.

3. Formula (IB) 【Chemistry 3】 wherein A is selected from phenyl, furanyl, thiophenyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, pyrazolyl, imidazolyl, pyridyl, triazolyl, tetrazolyl, oxadiazolyl, isoxadiazolyl, pyrimidinyl, pyrazinyl, and pyridazinyl.

2. A compound of formula (I) according to claim 1, or a pharma- ceutically acceptable salt thereof.

4. A is, 【Chemistry 4】 The compound (IA) or (IB) according to claim 2 or 3, or a pharma- ceutically acceptable salt thereof, selected from:

5. W is C(R ６ ) ２ , or NR ７ 5. The compound according to any one of claims 1 to 4, wherein:

6. W is C(R ６ ) ２ 6. The compound according to any one of claims 1 to 5, wherein:

7. W is NR ７ 7. The compound according to any one of claims 1 to 6, wherein:

8. R ７ is C １ ~C ６ Alkyl, haloC １ ~C ６ Alkyl, C ３ ~C ６ Cycloalkyl or haloC ３ ~C ６ 8. The compound of any one of claims 1 to 7, or a pharma- ceutically acceptable salt thereof, which is cycloalkyl.

9. 9. The compound of any one of claims 1 to 8, or a pharma- ceutically acceptable salt thereof, wherein A is a phenyl ring.

10. R ５ is substituted at the para position of the phenyl ring, or a pharma- ceutically acceptable salt thereof.

11. Formula (IC): 【Chemistry 5】 11. A compound of formula (I) according to claim 9 or 10, or a pharma- ceutically acceptable salt thereof.

12. Formula (ID): 【Chemistry 6】 12. The compound according to any one of claims 1 to 11, or a pharma- ceutically acceptable salt thereof.

13. R １ is hydrogen, halogen, C １ ~C ６ Alkyl, C ３ ~C ６ Cycloalkyl, and C １ ~C ６ 13. The compound of any one of claims 1 to 12, or a pharma- ceutically acceptable salt thereof, selected from alkoxy.

14. R ２ 14. The compound of any one of claims 1 to 13, or a pharma- ceutically acceptable salt thereof, wherein is selected from halogen, methyl, ethyl, and cyclopropyl.

15. R ２ is selected from methyl, ethyl, and cyclopropyl; or a pharma- ceutically acceptable salt thereof.

16. R ２ is methyl; or a pharma- ceutically acceptable salt thereof.

17. R is hydrogen, halogen, or C １ ~C ４ 17. The compound of any one of claims 1 to 16, or a pharma- ceutically acceptable salt thereof, wherein: R is an alkyl group;

18. R ３ is hydrogen or chloro; or a pharma- ceutically acceptable salt thereof.

19. R ３ The compound according to any one of claims 1 to 18, or a pharma- ceutically acceptable salt thereof, wherein:

20. R ５ is hydrogen, -CO ２ R ５ｂ , -CON(R ５ｃ ) ２ , C １ ~C ６ Alkyl, -CH ２ CO ２ R ５ｂ , -CH ２ CON (R ５ｃ ) ２ , -C(O)NHSO ２ C １ ~C ４ Alkyl, -SO ２ NHC(O)C １ ~C ４ Alkyl, -SO ２ N (H) ｍ (C １ ~C ４ Alkyl) ２－ｍ , -SO ２ C １ ~C ４ Alkyl, cyano, halogen, hydroxy C １ ~C ６ Alkyl, C ３ ~C ５ cycloalkyl, 5- to 6-membered heteroaryl having 1 to 4 heteroatoms independently selected from N, O, and S, and 4- to 6-membered heterocyclyl having 1 to 2 heteroatoms independently selected from N, O, and S, wherein said 5- to 6-membered heteroaryl and 4- to 6-membered heterocyclyl are unsubstituted or are selected from one or two R ５ａ 20. The compound of any one of claims 1 to 19, substituted by: or a pharma- ceutically acceptable salt thereof.

21. R ５ is -CO ２ H, hydroxy C １ ~C ６ alkyl, 5- to 6-membered heteroaryl having 1 to 4 heteroatoms independently selected from N, O, and S, and 4- to 6-membered heterocyclyl having 1 O heteroatom, wherein said 4- to 6-membered heterocyclyl is selected from 0 to 1 R ５ａ 21. The compound of any one of claims 1 to 20, substituted by: or a pharma- ceutically acceptable salt thereof.

22. R ５ CO ２ H, hydroxy C １ ~C ６ and selected from alkyl, 5-membered heteroaryl having two N heteroatoms, and 4- to 6-membered heterocyclyl having one O heteroatom, wherein said 4- to 6-membered heterocyclyl is unsubstituted or has one R ５ａ and R ５ａ is hydroxyl; or a pharma- ceutically acceptable salt thereof.

23. R ５ is -CO ２ H; or a pharma- ceutically acceptable salt thereof.

24. R ５ is tetrazolyl; or a pharma- ceutically acceptable salt thereof.

25. R ４ is, HaroC １ ~C ４ one or two R independently selected from the group consisting of alkyl and halogen; ５’ 25. The compound of any one of claims 1 to 24, or a pharma- ceutically acceptable salt thereof, substituted by:

26. R ６ represents, in each occurrence, hydrogen, halogen, haloC １ ~C ６ Alkoxy, C １ ~C ６ or two R ６ in combination with the carbon atom to which they are attached form a spirocyclic carbocycle having 3 to 6 ring atoms, wherein said spirocyclic carbocycle is unsubstituted or substituted with a halogen or C １ ~C ６ 26. The compound of any one of claims 1 to 25, or a pharma- ceutically acceptable salt thereof, substituted by 1 or 2 substituents selected from alkoxy.

27. 27. The compound of any one of claims 1 to 26, or a pharma- ceutically acceptable salt thereof, provided that both m and n are not 3.

28. 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-tetrazol-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 2. The compound of formula (I) according to claim 1, selected from:

29. 【Table 1】 【Table 2】 【Table 3】 【Table 4】 【Table 5】 【Table 6】 2. The compound of formula (I) according to claim 1, selected from:

30. 30. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 29, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier or excipient.

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

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

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

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

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

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

37. The disease or disorder includes age-related macular degeneration, geographic atrophy, diabetic retinopathy, uveitis, retinitis pigmentosa, macular edema, Behcet's uveitis, multifocal choroiditis, Vogt-Koyanagi-Harada syndrome, intermediate uveitis, scattershot chorioretinitis, sympathetic ophthalmia, ocular cicatricial pemphigoid, ocular pemphigus, non-arteritic ischemic optic neuropathy, postoperative inflammation, retinal vein occlusion, glaucoma, Doyne honeycomb retinal dystrophy / Malattia's ophthalmopathy, and / or other conditions. leventinese, Sorsby fundus degeneration, late onset retinal macular dystrophy, North Carolina macular dystrophy, Stargardt's disease, keratitis, neurological disorders such as multiple sclerosis, stroke, Guillain-Barre 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 of inappropriate or undesirable complement activation such as hemodialysis complications, hyperacute allograft rejection, xenograft rejection, interleukin-2 induced toxicity during IL-2 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 E. coli hemolytic uremic syndrome), peritonitis, CD55 deficiency with complement hyperactivation, vasculopathic thrombosis, 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 respiratory distress syndrome (ARDS), myocarditis, post-ischemic reperfusion state, myocardial infarction, balloon angioplasty, post-pump syndrome in cardiopulmonary or renal bypass surgery, atherosclerosis, hemodialysis, renal ischemia, acute kidney injury Mesenteric artery reperfusion, infection or sepsis after aortic reconstruction;COVID-19, immune complex disorders and autoimmune diseases, rheumatoid arthritis, osteoarthritis, spondyloarthropathy, 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 pneumoconiosis, pulmonary fibrosis, asthma, allergies, bronchoconstriction, hypersensitivity pneumonitis, parasitic diseases, Goodpasture's syndrome, The method of any one of claims 31 and 33-35, wherein the disease is selected from pulmonary vasculitis, Pauci-immune vasculitis, antineutrophil cytoplasmic antibody (ANCA) associated vasculitis (AAV), Buerger vasculitis, cryoglobulinemia, Kawasaki disease, Takayasu's arteritis, cryoglobulinemia, immune complex associated inflammation, antiphospholipid syndrome, glomerulonephritis and obesity; immune thrombocytopenia, cold agglutinin disease, warm autoimmune hemolytic anemia (wAIHA), thrombotic thrombocytopenic purpura (TTP), abdominal aortic aneurysm and Graves' disease.

38. 30. A method for treating age-related macular degeneration, 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 pharma- ceutically acceptable salt thereof.

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

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

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

42. The disease or disorder includes age-related macular degeneration, geographic atrophy, diabetic retinopathy, uveitis, retinitis pigmentosa, macular edema, Behcet's uveitis, multifocal choroiditis, Vogt-Koyanagi-Harada syndrome, intermediate uveitis, scattershot chorioretinitis, sympathetic ophthalmia, ocular cicatricial pemphigoid, ocular pemphigus, non-arteritic ischemic optic neuropathy, postoperative inflammation, retinal vein occlusion, glaucoma, Doyne honeycomb retinal dystrophy / Malattia's ophthalmopathy, and / or other conditions. leventinese, Sorsby fundus degeneration, late onset retinal macular dystrophy, North Carolina macular dystrophy, Stargardt's disease, keratitis, neurological disorders such as multiple sclerosis, stroke, Guillain-Barre 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 of inappropriate or undesirable complement activation such as hemodialysis complications, hyperacute allograft rejection, xenograft rejection, interleukin-2 induced toxicity during IL-2 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 E. coli hemolytic uremic syndrome), peritonitis, CD55 deficiency with complement hyperactivation, vasculopathic thrombosis, 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 respiratory distress syndrome (ARDS), myocarditis, post-ischemic reperfusion state, myocardial infarction, balloon angioplasty, post-pump syndrome in cardiopulmonary or renal bypass surgery, atherosclerosis, hemodialysis, renal ischemia, acute kidney injury Mesenteric artery reperfusion, infection or sepsis after aortic reconstruction;COVID-19, immune complex disorders and autoimmune diseases, rheumatoid arthritis, osteoarthritis, spondyloarthropathy, 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 pneumoconiosis, pulmonary fibrosis, asthma, allergies, bronchoconstriction, hypersensitivity pneumonitis, parasitic diseases, Goodpasture's syndrome, pulmonary vasculitis 42. The compound for use according to claim 41, or a pharmacologic acceptable salt thereof, selected from: Pauci-immune vasculitis, antineutrophil cytoplasmic antibody (ANCA) associated vasculitis (AAV), Buerger vasculitis, cryoglobulinemia, Kawasaki disease, Takayasu arteritis, cryoglobulinemia, immune complex associated inflammation, antiphospholipid syndrome, glomerulonephritis and obesity; immune thrombocytopenia, cold agglutinin disease, warm autoimmune hemolytic anemia (wAIHA), thrombotic thrombocytopenic purpura (TTP), abdominal aortic aneurysm, and Graves' disease;

43. 30. Use of a compound according to any one of claims 1 to 29, or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a disease or disorder mediated by complement activation or activation of the alternative complement pathway.

44. Age-related macular degeneration, geographic atrophy, diabetic retinopathy, uveitis, retinitis pigmentosa, macular edema, Behcet's uveitis, multifocal choroiditis, Vogt-Koyanagi-Harada syndrome, intermediate uveitis, scattershot chorioretinitis, sympathetic ophthalmia, ocular cicatricial pemphigoid, ocular pemphigus, non-arteritic ischemic optic neuropathy, postoperative inflammation, retinal vein occlusion, glaucoma, Doyne honeycomb retinal dystrophy / Malattia leventinese, Sorsby fundus degeneration, late onset retinal macular dystrophy, North Carolina macular dystrophy, Stargardt's disease, keratitis, neurological disorders such as multiple sclerosis, stroke, Guillain-Barre 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 of inappropriate or undesirable complement activation such as hemodialysis complications, hyperacute allograft rejection, xenograft rejection, interleukin-2 induced toxicity during IL-2 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 E. coli hemolytic uremic syndrome), peritonitis, CD55 deficiency with complement hyperactivation, vasculopathic thrombosis, 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 respiratory distress syndrome (ARDS), myocarditis, post-ischemic reperfusion state, myocardial infarction, balloon angioplasty, post-pump syndrome in cardiopulmonary or renal bypass surgery, atherosclerosis, hemodialysis, renal ischemia, acute kidney injury Mesenteric artery reperfusion, infection or sepsis after aortic reconstruction;COVID-19, immune complex disorders and autoimmune diseases, rheumatoid arthritis, osteoarthritis, spondyloarthropathy, 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 pneumoconiosis, pulmonary fibrosis, asthma, allergy, bronchoconstriction, hypersensitivity pneumonitis, parasitic diseases, Goodpasture's syndrome, pulmonary vasculitis, Pauci-immune type Use of a compound according to any one of claims 1 to 29, or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for treating a disease or disorder selected from vasculitis, antineutrophil cytoplasmic antibody (ANCA) associated vasculitis (AAV), Buerger vasculitis, cryoglobulinemia, Kawasaki disease, Takayasu arteritis, cryoglobulinemia, immune complex-associated inflammation, antiphospholipid syndrome, glomerulonephritis and obesity; immune thrombocytopenia, cold agglutinin disease, warm autoimmune hemolytic anemia (wAIHA), thrombotic thrombocytopenic purpura (TTP), abdominal aortic aneurysm, and Graves' disease.

45. 30. Use of a compound according to any one of claims 1 to 29, or a pharma- ceutically acceptable salt thereof, for treating a disease or disorder mediated by complement activation or activation of the alternative complement pathway.

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

47. Age-related macular degeneration, geographic atrophy, diabetic retinopathy, uveitis, retinitis pigmentosa, macular edema, Behcet's uveitis, multifocal choroiditis, Vogt-Koyanagi-Harada syndrome, intermediate uveitis, scattershot chorioretinitis, sympathetic ophthalmia, ocular cicatricial pemphigoid, ocular pemphigus, non-arteritic ischemic optic neuropathy, postoperative inflammation, retinal vein occlusion, glaucoma, Doyne honeycomb retinal dystrophy / Malattia leventinese, Sorsby fundus degeneration, late onset retinal macular dystrophy, North Carolina macular dystrophy, Stargardt's disease, keratitis, neurological disorders such as multiple sclerosis, stroke, Guillain-Barre 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 of inappropriate or undesirable complement activation such as hemodialysis complications, hyperacute allograft rejection, xenograft rejection, interleukin-2 induced toxicity during IL-2 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 E. coli hemolytic uremic syndrome), peritonitis, CD55 deficiency with complement hyperactivation, vasculopathic thrombosis, 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 respiratory distress syndrome (ARDS), myocarditis, post-ischemic reperfusion state, myocardial infarction, balloon angioplasty, post-pump syndrome in cardiopulmonary or renal bypass surgery, atherosclerosis, hemodialysis, renal ischemia, acute kidney injury Mesenteric artery reperfusion, infection or sepsis after aortic reconstruction;COVID-19, immune complex disorders and autoimmune diseases, rheumatoid arthritis, osteoarthritis, spondyloarthropathy, 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 pneumoconiosis, pulmonary fibrosis, asthma, allergy, bronchoconstriction, hypersensitivity pneumonitis, parasitic diseases, Goodpasture's syndrome, pulmonary vasculitis, Pauci-imm Use of a compound according to any one of claims 1 to 29, or a pharmacologic acceptable salt thereof, for treating a disease or disorder selected from Une-type vasculitis, antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), Buerger vasculitis, cryoglobulinemia, Kawasaki disease, Takayasu's arteritis, cryoglobulinemia, immune complex-associated inflammation, antiphospholipid syndrome, glomerulonephritis and obesity; immune thrombocytopenia, cold agglutinin disease, warm autoimmune hemolytic anemia (wAIHA), thrombotic thrombocytopenic purpura (TTP), abdominal aortic aneurysm, and Graves' disease.

48. 30. Use of a compound according to any one of claims 1 to 29, or a pharma- ceutically acceptable salt thereof, for treating age-related macular degeneration.

49. 30. A pharmaceutical combination comprising a compound according to any one of claims 1 to 29, or a pharma- ceutically acceptable salt thereof, and one or more further therapeutic agents.

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