Spirocyclic piperidinyl derivatives as complement factor B inhibitors and their uses

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] JPEG2025504859000187.jpg44170

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) or a pharma- ceutically acceptable salt thereof: [ka] During the ceremony, X is O or CR X1 R X2 and; R 1 is selected from H, C1-C6 alkoxyl, C3-C5 cycloalkoxyl, C1-C6 alkyl, and C3-C5 cycloalkyl; C1-C6 alkoxyl, C1-C6 alkyl, and C3-C5 cycloalkyl are unsubstituted or substituted with 1 or 2 halogen substituents; R 2 is C1-C3 alkyl or C3 cycloalkyl, C1-C3 alkyl or C3 cycloalkyl is unsubstituted or substituted with 1 or 2 halogen substituents; R X1 is selected from hydrogen, fluoro, C1-C6 alkyl, and C3-C5 cycloalkyl; R X2 is selected from hydroxyl, fluoro, C1-C6 alkyl, and C3-C5 cycloalkyl; However, R X2 is hydroxyl, R X1 Isn't it fluoro; Or R X1 and R X2 form, in combination with the carbon atom to which they are attached, a spirocyclic carbocyclic ring having 3 to 5 ring atoms; A is a phenyl ring or a 5- or 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from N, O and S; Each R 5 H, -CO2R 5b , C1-C6 alkyl, CH2CO2R 5b, C1-C6 hydroxyalkyl, C3-C5 cycloalkyl, 5-6 membered heteroaryl having 1-4 heteroatoms independently selected from N, O and S, and 4-6 membered heterocyclyl having 1-2 heteroatoms independently selected from N, O and S, wherein C1-C6 hydroxyalkyl, C1-C6 alkyl, 5-6 membered heteroaryl and 4-6 membered heterocyclyl are unsubstituted or are substituted with 1 or 2 R 5a is replaced by; Each R 5a is independently selected from fluoro, hydroxyl, and C1-C6 alkyl; C1-C6 alkyl is unsubstituted or substituted with 1, 2 or 3 fluoro; R 5 When R is a 4- to 6-membered heterocyclyl, two R 5a is not fluoro and hydroxyl substituted at the same positions; and R 5b is selected from H or C1-C5 alkyl; m is 0 or 1; n is 0, 1 or 2; Both m and n are not 0; however, When X is O, m is 1 and n is 1 or 2.

[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- ceutical 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's disease, corneal inflammatory disease, 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 (compact deposits and C 3 including glomerulonephritis), IgA nephropathy, membranous nephropathy including idiopathic membranous nephropathy, diabetic nephropathy, atypical hemolytic uraemic syndrome, hemolytic uraemic syndrome, STEC-HUS (Shiga toxin producing E. coli hemolytic uraemic syndrome), peritonitis, CD55 deficiency with complement hyperactivation, vasculopathy thrombosis, protein-losing enteropathy (CHAPLE syndrome), inflammatory or autoimmune diseases such as Crohn's disease, adult respiratory distress syndrome, 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 including psoriatic arthritis, systemic lupus erythematosus (SLE), lupus nephritis, SLE nephritis, proliferative nephritis, 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, goodpasti It is believed that it may treat: Cardiovascular disease, pulmonary vasculitis, pauciimmune vasculitis including antineutrophil cytoplasmic antibody (ANCA) associated vasculitis, other vasculitis such as Henoch-Schnerein vasculitis, Buerger's vasculitis, cryoglobulinemia, Kawasaki disease, Takayasu's arteritis, 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), 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, for example, C1-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 "C1-C6 alkyl" refers to a straight or branched hydrocarbon chain radical consisting exclusively of carbon and hydrogen atoms, containing no unsaturation, having 1-6 carbon atoms, and attached to the remainder of the molecule by a single bond. The terms C1-C3 alkyl and C1-C4 alkyl shall be interpreted accordingly. Examples of C1-C6 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.

[0035] As used herein, the term "C1-C6 alkoxyl" refers to a group of the formula -OR a R refers to the group ais a C1-C6 alkyl group as generally defined above. Examples of C1-C6 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" refers to a monocyclic or polycyclic saturated or partially unsaturated carbocyclic ring containing 3 to 18 carbon atoms, where there are no delocalized pi-electrons (aromaticity) shared between ring carbons. The term "C3-C5 cycloalkyl" is to be interpreted accordingly. The term polycyclic encompasses bridged (e.g., norbornane), fused (e.g., decalin) and spirocyclic cycloalkyls. Preferably, cycloalkyl, e.g., C3-C5 cycloalkyl, is a monocyclic hydrocarbon group 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] Examples of C3-C5 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, X is O or CR X1 R X2 and; R 1 is selected from H, C1-C6 alkoxyl, C3-C5 cycloalkoxyl, C1-C6 alkyl, and C3-C5 cycloalkyl; C1-C6 alkoxyl, C1-C6 alkyl, and C3-C5 cycloalkyl are unsubstituted or substituted with 1 or 2 halogen substituents; R 2 is C1-C3 alkyl or C3 cycloalkyl, C1-C3 alkyl or C3 cycloalkyl is unsubstituted or substituted with 1 or 2 halogen substituents; R X1 is selected from hydrogen, fluoro, C1-C6 alkyl, and C3-C5 cycloalkyl; RX2 is selected from hydroxyl, fluoro, C1-C6 alkyl, and C3-C5 cycloalkyl; However, R X2 is hydroxyl, R X1 Isn't it fluoro; Or R X1 and R X2 form, in combination with the carbon atom to which they are attached, a spirocyclic carbocyclic ring having 3 to 5 ring atoms; A is a phenyl ring or a 5- or 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from N, O and S; Each R 5 H, -CO2R 5b , C1-C6 alkyl, CH2CO2R 5b , C1-C6 hydroxyalkyl, C3-C5 cycloalkyl, 5-6 membered heteroaryl having 1-4 heteroatoms independently selected from N, O and S, and 4-6 membered heterocyclyl having 1-2 heteroatoms independently selected from N, O and S, wherein C1-C6 hydroxyalkyl, C1-C6 alkyl, 5-6 membered heteroaryl and 4-6 membered heterocyclyl are unsubstituted or are substituted with 1 or 2 R 5a is replaced by; Each R 5a is independently selected from fluoro, hydroxyl, and C1-C6 alkyl; C1-C6 alkyl is unsubstituted or substituted with 1, 2 or 3 fluoro; R 5 When R is a 4- to 6-membered heterocyclyl, two R 5a is not fluoro and hydroxyl substituted at the same positions; and R 5b is selected from H or C1-C5 alkyl; m is 0 or 1; n is 0, 1 or 2; Both m and n are not 0; however, When X is O, m is 1 and n is 1 or 2. or a pharma- ceutically acceptable salt thereof.

[0063] Embodiment 2. Formula (IA) or (IB) [ka] 2. A compound of formula (I) as defined in embodiment 1, or a pharma- ceutically acceptable salt thereof.

[0064] Embodiment 3. Compound IA as defined in embodiment 2, or a pharma- ceutically acceptable salt thereof.

[0065] Embodiment 4.R 2 or a pharma- ceutically acceptable salt thereof. The compound according to any one of the preceding embodiments, wherein is selected from methyl, ethyl, and cyclopropyl.

[0066] Embodiment 5.R 2 is methyl; or a pharma- ceutically acceptable salt thereof.

[0067] Embodiment 6. A compound according to any one of the preceding embodiments, or a pharma- ceutically acceptable salt thereof, wherein A is a phenyl ring.

[0068] Embodiment 7.R 5 is substituted at the para position of the phenyl ring; or a pharma- ceutically acceptable salt thereof.

[0069] Embodiment 8. A compound according to any one of embodiments 1 to 5, wherein A is selected from furanyl, thiophenyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, pyrazolyl, imidazolyl, pyridyl, triazolyl, tetrazolyl, oxadiazolyl, isoxadiazolyl, pyrimidinyl, pyrazinyl and pyridazinyl; or a pharma- ceutically acceptable salt thereof.

[0070]

[0032] Embodiment 9.A comprises: [ka] or a pharma- ceutically acceptable salt thereof.

[0071] Embodiment 10. A has one R 5 is replaced by R 5 is selected from -COH, C1-C6 hydroxyalkyl, 5-6 membered heteroaryl having 1-4 heteroatoms independently selected from N, O and S, and 4-6 membered heterocyclyl having 1 O heteroatom, wherein the 4-6 membered heterocyclyl is unsubstituted or has 0-1 R 5a or a pharma- ceutically acceptable salt thereof.

[0072] Embodiment 11.R 5 CO2R 5b , C1-C6 hydroxyalkyl, 5-membered heteroaryl having two N heteroatoms, and 4-6-membered heterocyclyl having one O heteroatom, wherein the 4-6-membered heterocyclyl is unsubstituted or has one R 5a is replaced by R 5a is hydroxyl and R 5b is H; or a pharma- ceutically acceptable salt thereof.

[0073] Embodiment 12.R 5 or a pharma- ceutically acceptable salt thereof. The compound according to any one of the preceding embodiments, wherein is selected from -CO2H, tetrazole, and oxetane substituted with hydroxyl;

[0074] Embodiment 13.R 5 is -CO2H; or a pharma- ceutically acceptable salt thereof.

[0075] Embodiment 14.R 5 is tetrazole; or a pharma- ceutically acceptable salt thereof.

[0076] Embodiment 15.R1 or a pharma- ceutically acceptable salt thereof.

[0077] Embodiment 16.R 1 or a pharma- ceutically acceptable salt thereof.

[0078] Embodiment 17.R 1 or a pharma- ceutically acceptable salt thereof.

[0079] Embodiment 18.R X1 and R X2 or a pharma- ceutically acceptable salt thereof.

[0080] Embodiment 19.R X1 and R X2 are both fluoro, or fluoro and C1-C6 alkyl, or fluoro and H; or a pharma- ceutically acceptable salt thereof.

[0081] Embodiment 20. A compound according to any one of the preceding embodiments, or a pharma- ceutically acceptable salt thereof, wherein n is 1 or 2.

[0082] Embodiment 21. A compound according to any one of the preceding embodiments, wherein X is O; or a pharma- ceutically acceptable salt thereof.

[0083] 22.X is CR X1 R X2 21. The compound according to any one of embodiments 1 to 20, wherein:

[0084] Embodiment 23.R X1 is fluoro and R X2 is selected from fluoro and C1-C6 alkyl, such as methyl.

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

[0086] Embodiment 25. A composition selected from the following: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] A compound of formula (I) as defined in embodiment 1 or a pharma- ceutically acceptable salt thereof.

[0087] Embodiment 26. A compound according to any one of the preceding embodiments, or a pharma- ceutically acceptable salt thereof, wherein the compound is present in at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess.

[0088] Embodiment 27. A compound according to any one of the preceding embodiments, or a pharma- ceutically acceptable salt thereof, wherein the compound is present in at least 90% diastereomeric excess, at least 95% diastereomeric excess, or at least 99% diastereomeric excess.

[0089] Embodiment 28. 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.

[0090] Embodiment 29. 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 27, or a pharma- ceutically acceptable salt thereof.

[0091] Embodiment 30. 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 27, or a pharma- ceutically acceptable salt thereof.

[0092] Embodiment 31. 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 27, or a pharma- ceutically acceptable salt thereof.

[0093] Embodiment 32. 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 27, or a pharma- ceutically acceptable salt thereof.

[0094] Embodiment 33. 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 27, or a pharma- ceutically acceptable salt thereof.

[0095] Embodiment 34. 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 27, or a pharma- ceutically acceptable salt thereof.

[0096] Embodiment 35. 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 inflammatory disease, 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 (compact deposits and C 3 including glomerulonephritis), IgA nephropathy, membranous nephropathy including idiopathic membranous nephropathy, diabetic nephropathy, atypical hemolytic uraemic syndrome, hemolytic uraemic syndrome, STEC-HUS (Shiga toxin producing E. coli hemolytic uraemic syndrome), peritonitis, CD55 deficiency with complement hyperactivation, vasculopathy thrombosis, protein-losing enteropathy (CHAPLE syndrome), inflammatory or autoimmune diseases such as Crohn's disease, adult respiratory distress syndrome, 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 including psoriatic arthritis, systemic lupus erythematosus (SLE), lupus nephritis, SLE nephritis, proliferative nephritis, 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, pulmonary vasculitis , pauciimmune vasculitis, including antineutrophil cytoplasmic antibody (ANCA) associated vasculitis, other vasculitis, such as Henoch-Schnerein vasculitis, Buerger's vasculitis, cryoglobulinemia, Kawasaki disease, Takayasu's arteritis, 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.

[0097] Embodiment 36. 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 27 or a pharma- ceutically acceptable salt thereof.

[0098] Embodiment 37. A compound according to any one of embodiments 1 to 27, or a pharma- ceutically acceptable salt thereof, for use as a medicament.

[0099] Embodiment 38. A compound according to any one of embodiments 1 to 27, 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.

[0100] Embodiment 39. A compound according to any one of embodiments 1 to 27 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.

[0101] Embodiment 40. 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 inflammatory disease, 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 (compact deposits and C 3 including glomerulonephritis), IgA nephropathy, membranous nephropathy including idiopathic membranous nephropathy, diabetic nephropathy, atypical hemolytic uraemic syndrome, hemolytic uraemic syndrome, STEC-HUS (Shiga toxin producing E. coli hemolytic uraemic syndrome), peritonitis, CD55 deficiency with complement hyperactivation, vasculopathy thrombosis, protein-losing enteropathy (CHAPLE syndrome), inflammatory or autoimmune diseases such as Crohn's disease, adult respiratory distress syndrome, 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, spondyloarthropathies including psoriatic arthritis, systemic lupus erythematosus (SLE), lupus nephritis, SLE nephritis, proliferative nephritis, 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, antineutrophil leukemia, 39. The compound or a pharmacologic acceptable salt thereof for use according to embodiment 39, selected from: pauciimmune vasculitis, including antimyeloblastic cytoplasmic antibody (ANCA)-associated vasculitis, other vasculitis such as Henoch-Schnerein vasculitis, Buerger's vasculitis, cryoglobulinemia, Kawasaki's disease, Takayasu's arteritis, 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;

[0102] Embodiment 41. Use of a compound according to any one of embodiments 1 to 27, 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.

[0103] Embodiment 42. 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 inflammatory disease, 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 (compact deposits and C 3 including glomerulonephritis), IgA nephropathy, membranous nephropathy including idiopathic membranous nephropathy, diabetic nephropathy, atypical hemolytic uraemic syndrome, hemolytic uraemic syndrome, STEC-HUS (Shiga toxin producing E. coli hemolytic uraemic syndrome), peritonitis, CD55 deficiency with complement hyperactivation, vasculopathy thrombosis, protein-losing enteropathy (CHAPLE syndrome), inflammatory or autoimmune diseases such as Crohn's disease, adult respiratory distress syndrome, 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, spondyloarthropathies including psoriatic arthritis, systemic lupus erythematosus (SLE), lupus nephritis, SLE nephritis, proliferative nephritis, 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, antineutrophil cytoplasmic antibody (ANCA) related Use of a compound according to any one of embodiments 1 to 27 or a pharmacologic acceptable salt thereof in the manufacture of a medicament for the treatment of a disease or disorder selected from: pauciimmune vasculitis, including vasculitis, other vasculitis such as Henoch-Schnerein vasculitis, Buerger's vasculitis, cryoglobulinemia, Kawasaki's disease, Takayasu's arteritis, 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;

[0104] Embodiment 43. Use of a compound according to any one of embodiments 1 to 27 or a pharma- ceutically acceptable salt thereof for treating a disease or disorder mediated by complement activation or activation of the alternative complement pathway.

[0105] Embodiment 44. Use of a compound according to any one of embodiments 1 to 27 or a pharma- ceutically acceptable salt thereof for treating a disease or disorder affected by modulation of the alternative complement pathway.

[0106] Embodiment 45. 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 inflammatory disease, 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 (compact deposits and C 3 including glomerulonephritis), IgA nephropathy, membranous nephropathy including idiopathic membranous nephropathy, diabetic nephropathy, atypical hemolytic uraemic syndrome, hemolytic uraemic syndrome, STEC-HUS (Shiga toxin producing E. coli hemolytic uraemic syndrome), peritonitis, CD55 deficiency with complement hyperactivation, vasculopathy thrombosis, protein-losing enteropathy (CHAPLE syndrome), inflammatory or autoimmune diseases such as Crohn's disease, adult respiratory distress syndrome, 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, spondyloarthropathies including psoriatic arthritis, systemic lupus erythematosus (SLE), lupus nephritis, SLE nephritis, proliferative nephritis, 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, antineutrophil cytoplasmic antibodies (ANC) A) Use of a compound according to any one of embodiments 1 to 27 or a pharmacologic acceptable salt thereof for the treatment of a disease or disorder selected from: Pauci-immune vasculitis, including associated vasculitis, other vasculitis such as Henoch-Schnerein vasculitis, Bürger's vasculitis, cryoglobulinemia, Kawasaki disease, Takayasu's arteritis, 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;

[0107] Embodiment 46. Use of a compound according to any one of embodiments 1 to 27 or a pharma- ceutically acceptable salt thereof for treating age-related macular degeneration.

[0108] Embodiment 47. A pharmaceutical combination comprising a compound according to any one of embodiments 1 to 27 or a pharma- ceutically acceptable salt thereof, and one or more further therapeutic agents.

[0109] 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).

[0110] 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.

[0111] 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.

[0112] 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.

[0113] 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.

[0114] 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.

[0115] 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.

[0116] 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.

[0117] 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.

[0118] 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).

[0119] Pharmaceutically acceptable solvates in accordance with the present disclosure include those in which the solvent of crystallization may be isotopically substituted, eg, D2O, d6-acetone, d6-DMSO.

[0120] 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.

[0121] 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.

[0122] 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.

[0123] 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.

[0124] 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%.

[0125] In one embodiment, the compound of formula (I) has the formula (IA): [ka] or a pharma- ceutically acceptable salt thereof, wherein R1 , R 2 , R 5 , A, X, n and m are defined according to embodiment 1. In particular, R 1 , R 2 , R 5 , A, X, n and m may be defined according to any of embodiments 1-25.

[0126] In another embodiment, the compound of formula (I) has the formula (IB): [ka] or a pharma- ceutically acceptable salt thereof, wherein R 1 , R 2 , R 5 , A, X, n and m are defined according to embodiment 1. In particular, R 1 , R 2 , R 5 , A, X, n and m may be defined according to any of embodiments 1-25.

[0127] In the formula of the present application, C-sp 3 The above term " [ka] " indicates the absolute stereochemical configuration (R) or (S). In the formula of this application, C-sp 3 The above term " [ka] " indicates the absolute stereochemical configuration (R) or (S). In the formula of this application, C-sp 3 The above term " [ka] " represents a covalent bond and the stereochemical configuration of the bond is not defined. This is the case for C-sp 3 The above term " [ka] " is meant to include 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.

[0128] For the avoidance of doubt, [ka] When a compound structure is drawn with an undefined stereochemical configuration for any R group, as represented by:

[0129] 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.

[0130] For the avoidance of doubt, compound structures depicted herein may, where appropriate, exist in their zwitterionic form.

[0131] 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.

[0132] 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.

[0133] 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.

[0134] 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.

[0135] Compounds of the present disclosure, including their salts, hydrates and solvates, may inherently or by design form polymorphs.

[0136] 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.

[0137] In general, compounds of formula (I) can be prepared according to the schemes provided below.

[0138] The compounds provided herein can be prepared according to the following examples. In the following scheme, R 1 , R 2 , R 5 , A, X, n and m are defined according to enumerated embodiment 1. In one embodiment, R 1 , R 2 , R 5 , A, X, n and m are defined according to any one of the enumerated embodiments 1 to 25. 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.

[0139] General Scheme 1 [ka] Intermediates I-4 and I-5 can be prepared as outlined in general scheme 1. Indole W1 can be converted to I-4-1 utilizing Suzuki coupling with vinyl boronate. I-4-1 can be further converted to I-4-3 after aldehyde reduction with sodium borohydride and introduction of a TBS protecting group by electrophilic substitution with TBSCl and base. The alkene of I-4-3 can be reacted with Me3SiCF3 and potassium iodide at elevated temperature to access I-4-4. Intermediates I-4 and I-5 can be accessed by alcohol deprotection using TBAF followed by oxidation using MnO2.

[0140] General Scheme 2 [ka] Protected amines X2 can be prepared as outlined in general scheme 2. Commercially available secondary amines can be protected by reaction with a suitable electrophile (e.g., BocO). X a is X, C=O or a ketal (e.g., X a Ketals are selected from the group consisting of ketones (X is C(OMe)2) under acidic conditions. a is C=O) with methanol to provide

[0141] General Scheme 3 [ka] Amines such as X8 can be accessed as described by General Scheme 3. In General Scheme 3, R a is R 5 When is tetrazole, R a R except that is -CN 5 It has the same definition as X. a is as defined in General Scheme 2. Oxidation of X2 with ruthenium trichloride and sodium periodate gives lactam X3. Vinyl triflate X4 can be obtained by treatment with N-phenyl-bis(trifluoromethanesulfonimide) under basic conditions. X4 can be converted to X6 by palladium-catalyzed Suzuki coupling with an appropriate boronate. Alternatively, Miyura borylation of X4 can give X5, which can be further reacted with an appropriate aryl halide to give X6. Olefin reduction of X6 is achieved by hydrogenation. Deprotection of X7 can give X8.

[0142] General Scheme 4 [ka] X a The functionalization of amines X7a where R is C(OMe) is described in general Scheme 4. a is as defined in General Scheme 3. Ketal cleavage is achieved by hydrolysis under acidic conditions. The ketone can be further converted to X10, where the alcohol is reacted with sodium borohydride (R b =H, R c =OH) or by nucleophilic addition of organometallic reagents such as methylmagnesium bromide to give tertiary alcohols (R b =CH3, R c =OH) can be obtained. c =OHR c Conversion to =F can be accomplished using electrophilic fluorination or conversion of the alcohol to a leaving group followed by nucleophilic fluorination. Deprotection of X10 can provide X11 as described above.

[0143] General Scheme 5 [ka] The synthesis of amines X13 is described in general scheme 5. Ketones X12 are olefinated using the Wittig reagent. Cyclopropanation of B-11 is carried out as described above. Finally, deprotection of B-12 is carried out.

[0144] General Scheme 6 [ka] Indole aldehydes can be coupled with cyclic amines as shown above using reductive alkylation conditions, such as treatment with sodium triacetoxyborohydride in DCE, to afford Y1 as described in General Scheme 6. ais as defined in General Scheme 3. Alternatively, the hydroxy group in hydroxymethylindole W2 can be converted to a leaving group (LG, e.g. chloride) W3 by treatment with cyanuric chloride. W3 can be reacted with a cyclic amine in the presence of a base such as DIPEA in a solvent such as DMF at temperatures ranging from 0° C. to 50° C. to give Y1.

[0145] General Scheme 7 [ka] Compounds such as Z1 can be prepared according to general scheme 7. a is as defined in General Scheme 3. a is as defined in General Scheme 3. Deprotection of PG (PG=Boc) in compounds Y1-Z1 can be achieved by treatment with a hydroxide source such as KOH or LiOH in a suitable solvent system such as a mixture of THF / MeOH / water at temperatures ranging from RT to 50° C. a Deprotection of PG from Y1 in the case of =COOMe also leads to the simultaneous reaction of the -COOMe ester to give R e Further, when PG=Boc, Y1 can be treated with a suitable base such as potassium carbonate in a solvent such as methanol at a temperature up to 50° C. to provide Z1.

[0146] General Scheme 8 [ka] n R 5 Compounds such as Z1a, where R = tetrazole, can be prepared according to general scheme 8. a When =CN, Z1 can be converted to R by treatment with an azide-containing reagent such as sodium azide in the presence of a catalyst such as triethylamine hydrochloride in a suitable solvent. 5 can be converted to a tetrazole ring, Z1a.

[0147] 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.

[0148] 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.

[0149] In further embodiments, the composition comprises at least 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.

[0150] 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.

[0151] 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).

[0152] 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.

[0153] 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:

[0154] In one embodiment, the pharmaceutical composition is a capsule containing only the active ingredient.

[0155] Tablets may be film coated or enteric coated by methods known in the art.

[0156] 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.

[0157] 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).

[0158] 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.

[0159] 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.

[0160] 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.

[0161] 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.

[0162] 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.

[0163] 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.

[0164] 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.

[0165] 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.

[0166] 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.

[0167] 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.

[0168] In a further embodiment, the pharmaceutical composition of the present disclosure is administered locally to the eye of a subject.

[0169] 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.

[0170] Further properties of the disclosed compounds include good potency in the biological assays described herein, a favorable safety profile, and favorable pharmacokinetic properties.

[0171] 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.

[0172] 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.

[0173] 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 inflammatory disease, 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 (compact deposits and C 3 including glomerulonephritis), IgA nephropathy, membranous nephropathy including idiopathic membranous nephropathy, diabetic nephropathy, atypical hemolytic uraemic syndrome, hemolytic uraemic syndrome, STEC-HUS (Shiga toxin producing E. coli hemolytic uraemic syndrome), peritonitis, CD55 deficiency with complement hyperactivation, vasculopathy thrombosis, protein-losing enteropathy (CHAPLE syndrome), inflammatory or autoimmune diseases such as Crohn's disease, adult respiratory distress syndrome, 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, spondyloarthropathies including psoriatic arthritis, systemic lupus erythematosus (SLE), lupus nephritis, SLE nephritis, proliferative nephritis, 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, antineutrophil leukemia, It is believed that the compound may be used to treat or prevent a disease or disorder selected from: pauciimmuno-angiitis, including anti-myeloblastic cytoplasmic antibody (ANCA) associated vasculitis, other vasculitis such as Henoch-Schnerein vasculitis, Buerger's vasculitis, cryoglobulinemia, Kawasaki disease, Takayasu's arteritis, 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;

[0174] 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.

[0175] 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.

[0176] 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.

[0177] 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.

[0178] 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.

[0179] 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.

[0180] 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 inflammatory disease, 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 (compact deposits and C 3 including glomerulonephritis), IgA nephropathy, membranous nephropathy including idiopathic membranous nephropathy, diabetic nephropathy, atypical hemolytic uraemic syndrome, hemolytic uraemic syndrome, STEC-HUS (Shiga toxin producing E. coli hemolytic uraemic syndrome), peritonitis, CD55 deficiency with complement hyperactivation, vasculopathy thrombosis, protein-losing enteropathy (CHAPLE syndrome), inflammatory or autoimmune diseases such as Crohn's disease, adult respiratory distress syndrome, 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 including psoriatic arthritis, systemic lupus erythematosus (SLE), lupus nephritis, SLE nephritis, proliferative nephritis, 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, The present invention provides a method for treating a disease or disorder selected from pulmonary vasculitis, pauciimmune vasculitis including antineutrophil cytoplasmic antibody (ANCA) associated vasculitis, other vasculitis such as Henoch-Schnerein vasculitis, Buerger's vasculitis, cryoglobulinemia, Kawasaki disease, Takayasu's arteritis, 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;

[0181] 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.

[0182] 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.

[0183] 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.

[0184] 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

[0185] 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.

[0186] 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.

[0187] 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.

[0188] The activity of compounds according to the present disclosure can be assessed by the in vitro methods described in the Examples.

[0189] 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.

[0190] 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.

[0191] 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.

[0192] 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.

[0193] 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).

[0194] 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.

[0195] 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.

[0196] 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.

[0197] 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.

[0198] 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.

[0199] 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.

[0200] The protecting group can also be a polymer resin, such as a Wang resin or a 2-chlorotrityl chloride resin.

[0201] 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.

[0202] 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.

[0203] 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.

[0204] Abbreviation ACN Acetonitrile aq. Water-based Boc tertiary butyl carboxy br Broad c concentration CO2 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 de Diastereomeric excess DEA Diethanolamine DIPEA Diisopropylethylamine DMAP 4-N,N-Dimethylaminopyridine DMA N,N-Dimethylacetamide DMF N,N-Dimethylformamide DMSO Dimethyl sulfoxide dppf 1,1'-ferrocenediylbis(diphenylphosphine) ds diastereomer ELSD Evaporative Light Scattering Detector ee enantiomeric excess ent Enantiopure eq equivalent EtOAc Ethyl acetate EtOH Ethanol h time H2 Hydrogen HCl Hydrochloric acid HMDS 1,1,1,3,3,3-Hexamethyldisilazane HPLC High Performance Liquid Chromatography IPA Isopropanol K2CO3 Potassium Carbonate KI Potassium iodide KOtBu Potassium tert-butoxide K3PO4 Potassium phosphate, tribasic LC-MS Liquid Chromatography and Mass Spectrometry m multiplet m / z mass-to-charge ratio MeOH Methanol Me3SiCF3 Trimethyl(trifluoromethyl)silane 2-MeTHF 2-Methyltetrahydrofuran MgSO4 Magnesium Sulfate min MnO2 Manganese Dioxide MS mass spectrometry MTBE Methyl tert-butyl ether n-BuLi n-Butyl lithium N2 Nitrogen NaBH(OAc)3 Sodium triacetoxyborohydride NaBH4 Sodium borohydride Na2CO3 Sodium Carbonate NaHCO3 Sodium Bicarbonate NaI Sodium iodide NaIO4 Sodium Periodate NaOH Sodium hydroxide NaN3 Sodium Azide Na2SO4 Sodium Sulfate Na2S2O3 Sodium Thiosulfate NH4Cl Ammonium chloride NH4OH Ammonium hydroxide NH4(CH3CO2) Ammonium Acetate NMR nuclear magnetic resonance NP positive phase org.organic pa pro analysis Pd / C Palladium on Carbon PdCl2(PPh3)2 Bis(triphenylphosphine)palladium(II) dichloride PdCl2(dtbpf) [1,1'-bis(di-tert-butylphosphino)ferrocene]palladium(II) dichloride Pd2(dba)3 Bis(dibenzylideneacetone)dipalladium Pd(dppf)Cl2 [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride PE Petroleum Ether ppm parts per million rac Racemic RM reaction mixture RP Reverse Phase Rt retention time RT room temperature RuCl3 Ruthenium trichloride s singlet sat. saturation scCO2 Supercritical carbon dioxide SFC Supercritical Fluid Chromatography SiO2 Silica Gel soln. solution t triplet TBAF Tetra-n-butylammonium fluoride TBS tert-Butyldimethylsilyl TBSCl tert-Butyldimethylsilyl chloride tert-Bu tertiary butyl TFA Trifluoroacetic acid THF Tetrahydrofuran TLC Thin Layer Chromatography UPLC Ultra High Performance Liquid Chromatography wt% Weight percent Zn(CN)2 Zinc cyanide

[0205] The absolute configuration at the 2-position of the piperidine ring (S) has been tentatively assigned consistently to the more biologically active enantiomer. The absolute configuration of the compounds is further confirmed by X-ray crystallography of selected compounds. Stereochemical nomenclature was assigned using ChemDraw. Compounds with Chemical Abstracts registration numbers were either purchased from commercial suppliers or prepared by known methods.

[0206] Intermediates Intermediate I-1: tert-Butyl 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylate [ka] CAS 1481631-51-9

[0207] Intermediate I-2: tert-Butyl 4-formyl-5,7-dimethyl-1H-indole-1-carboxylate [ka] CAS 1644667-04-8

[0208] Intermediate I-3: tert-Butyl 5-cyclopropyl-4-formyl-7-methyl-1H-indole-1-carboxylate [ka] CAS 1628640-27-6

[0209] Intermediate I-4 and Intermediate I-5: tert-Butyl (R)-5-(2,2-difluorocyclopropyl)-4-formyl-7-methyl-1H-indole-1-carboxylate and tert-butyl (S)-5-(2,2-difluorocyclopropyl)-4-formyl-7-methyl-1H-indole-1-carboxylate [ka] Step 1: tert-Butyl 4-formyl-7-methyl-5-vinyl-1H-indole-1-carboxylate (Intermediate I-4-1) [ka] To a solution of tert-butyl 5-bromo-4-formyl-7-methyl-1H-indole-1-carboxylate (CAS 1628640-26-5, 2.0 g, 5.913 mmol) in degassed IPA (20 mL) was added potassium vinyl tetrafluoroborate (1.58 g, 11.82 mmol). The solvent was sparged with N2 for 10 min, then TEA (1.5 mL, 11.82 mmol) was added under N2 atmosphere. To this solution was added Pd(dppf)Cl2·DCM (0.24 g, 0.295 mmol). The mixture was flushed with N2 for 10 min and heated to 90 °C for 16 h. The RM was concentrated, diluted with water, and extracted with EtOAc (2x). The combined organic layers were washed with water, brine, dried over Na2SO4, and concentrated under reduced pressure. The crude residue was purified by column chromatography (NP, 6-8% EtOAc in hexanes). The product-containing fractions were combined and concentrated under reduced pressure to give the title compound as a brown solid (950 mg). 1 H NMR(300MHz,CDCl3)δ[ppm]10.6(s,1H),7.65(d,J=4.0Hz,1H),7.49(d,J=11.0Hz,1H),7.52-7.42(m,1H) ,7.24(d,J=7.2Hz,1H),5.65(d,J=17.4Hz,1H),5.54(dd,J=11.0,1.0Hz,1H),2.69,(s,3H),1.64(s,9H).

[0210] Step 2: tert-Butyl 4-(hydroxymethyl)-7-methyl-5-vinyl-1H-indole-1-carboxylate (Intermediate I-4-2) [ka] To a white suspension of tert-butyl 4-formyl-7-methyl-5-vinyl-1H-indole-1-carboxylate (intermediate I-4-1, 950 mg, 3.329 mmol) in MeOH (5.0 mL) was added NaBH4 (252 mg, 6.658 mmol) at 0° C. and the mixture was stirred at RT for 1 h. The mixture was concentrated under reduced pressure and the residue was diluted with water. The mixture was extracted with EtOAc (3×). The combined extracts were concentrated under reduced pressure to give the title compound as a white solid (920 mg). 1 H NMR(300MHz,CDCl3)δ[ppm]7.54(d,J=4.0Hz,1H),7.31(s,1H),7.18,(dd,J=17.4,11.0Hz,1H),6.72(d,J=4. 0Hz,1H),5.71(dd,J=17.4,1.0Hz,1H),5.35(dd,J=11.0,1.0Hz,1H),4.96(s,2H),2.63(s,3H),1.64(s,9H).

[0211] Step 3: tert-Butyl 4-(((tert-butyldimethylsilyl)oxy)methyl)-7-methyl-5-vinyl-1H-indole-1-carboxylate (Intermediate I-4-3) [ka] To a stirred solution of tert-butyl 4-(hydroxymethyl)-7-methyl-5-vinyl-1H-indole-1-carboxylate (Intermediate I-4-2, 900 mg, 3.131 mmol) in DCM (10 mL) was added TEA (1.21 mL, 9.395 mmol) and DMAP (0.11 g, 0.939 mmol). The mixture was stirred at RT for 30 min, TBSCl (1.41 g, 9.395 mmol) was added slowly, and the mixture was stirred at RT for 16 h. The RM was quenched with water, and the resulting mixture was extracted with EtOAc. The aqueous layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by chromatography (NP, 0-5% EtOAc in hexanes) to give the title product as a yellow solid (900 mg). 1H NMR(400MHz,CDCl3)δ[ppm]7.51(d,J=4.0Hz,1H),7.27(s,1H),7.17,(dd,J=17.4,11.0Hz,1H),6.7(d,4.0Hz ,1H),5.63(d,J=11.0Hz,1H),5.30(m,1H),4.96(s,2H),2.62,(s,3H),1.63(s,9H),0.89(s,9H),0.05(s,6H).

[0212] Step 4: tert-Butyl 4-(((tert-butyldimethylsilyl)oxy)methyl)-5-(2,2-difluorocyclopropyl)-7-methyl-1H-indole-1-carboxylate (Intermediate I-4-4) [ka] To a solution of tert-butyl 4-(((tert-butyldimethylsilyl)oxy)methyl)-7-methyl-5-vinyl-1H-indole-1-carboxylate (intermediate I-4-3, 900 mg, 2.240 mmol) in THF (15 mL) was added Me3SiCF3 (4.77 mg, 33.61 mmol) and NaI (0.743 g, 4.48 mmol) at RT. The RM was irradiated in a microwave at 120 °C for 1 h. The mixture was diluted with water and extracted with EtOAc (3x). The combined organic phase was washed with water, brine, dried over Na2SO4 and concentrated under reduced pressure to give the title compound as a light brown oil (950 mg). 1 H NMR(400MHz,CDCl3)δ[ppm]7.53(d,J=4.0Hz,1H),6.92(s,1H),6.71,(d,J=4.0Hz,1H),5.02(d,J=15.0Hz,1H),4.97(d,J=15.0Hz) ,1H),3.00-2.95(m,1H),2.59,(s,3H),1.86-1.80(m,1H),1.72-1.68(m,1H),1.66(s,9H),0.91(s,9H),0.10(s,3H),0.09(s,3H).

[0213] Step-5: tert-Butyl 5-(2,2-difluorocyclopropyl)-4-(hydroxymethyl)-7-methyl-1H-indole-1-carboxylate (Intermediate I-4-5) [ka] To a solution of tert-butyl 4-(((tert-butyldimethylsilyl)oxy)methyl)-5-(2,2-difluorocyclopropyl)-7-methyl-1H-indole-1-carboxylate (Intermediate I-4-4, 950 mg, 2.103 mmol) in THF (10 mL) was added TBAF (1.0 M in THF) (10 mL, 10.51 mmol) at RT. The RM was stirred at RT for 16 h. The mixture was diluted with water and extracted with EtOAc (3×). The combined organic layers were washed with water, aqueous brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give the racemic title compound. LC-MS Method A-1: ​​Rt=1.61 min; MS m / z [MH] - =335.9.

[0214] Step-6: tert-Butyl (S)-5-(2,2-difluorocyclopropyl)-4-formyl-7-methyl-1H-indole-1-carboxylate and tert-butyl (R)-5-(2,2-difluorocyclopropyl)-4-formyl-7-methyl-1H-indole-1-carboxylate (Intermediate I-4-6 and Intermediate I-4-7) [ka]

[0215] For chiral separation of intermediate I-4-6 and intermediate I-4-7 (1.03 g): Instrument: Agilent 1200; Column: Chiralpak IG 250 mm x 20 mm x 5 μm; Flow rate: 15 mL / min; Mobile phase: 90% A=Hexane, 10% B=EtOH:MeOH (1:1) (isocratic). Peak 1: Intermediate I-4-6. Isolated: 400 mg. Method SFC-16: Rt=5.40 / 30 min, ee 96%. Peak 2: Intermediate I-4-7. Isolated: 420 mg. Method SFC-16: Rt=5.93 / 30 min, ee 96%.

[0216] Step 7: tert-Butyl 5-(2,2-difluorocyclopropyl)-4-formyl-7-methyl-1H-indole-1-carboxylate (Intermediate I-4) To a solution of tert-butyl 5-(2,2-difluorocyclopropyl)-4-(hydroxymethyl)-7-methyl-1H-indole-1-carboxylate (intermediate I-4-6, 400 mg, 1.185 mmol) in 1,2-DCE (10 mL) was added MnO2 (4.12 g, 47.42 mmol) at RT. The RM was stirred at 50° C. for 2 h, cooled to RT, then filtered through Celite® and concentrated under reduced pressure. The crude material was purified by column chromatography on silica gel (2-4% EtOAc in hexanes). The product-containing fractions were combined and concentrated under reduced pressure to give the title compound as an off-white solid (313 mg). 1 H NMR (400 MHz, CDCl 3f )δ[ppm]10.61(s,1H),7.78(d,J=4.0Hz,1H),7.42(d,J=4.0Hz,1H),7.15(s,1H),3.42-3.36(m, 1H),2.66,(s,3H),2.08-2.01(m,1H),1.88-1.85(m,1H),1.66(s,9H).LC-MS method A-1: ​​Rt=1.70 min;MS m / z[M+H] + =336.1.

[0217] Intermediate I-5 was prepared following the method described for intermediate I-4 hereinabove using intermediate I-4-7 as the starting material. 1 H NMR(400MHz,CDCl3)δ[ppm]10.61(s,1H),7.78(d,J=4.0Hz,1H),7.42(d,J=4.0Hz,1H),7.15 (s,1H),3.42-3.34(m,1H),2.66,(s,3H),2.08-2.00(m,1H),1.88-1.85(m,1H),1.66(s,9H).

[0218] Intermediate I-6: tert-Butyl 4-(chloromethyl)-5-cyclopropyl-7-methyl-1H-indole-1-carboxylate [ka] CAS 1644667-08-2

[0219] Intermediate I-7: tert-Butyl 4-(chloromethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate [ka] Cyanuric chloride (189.8 mg, 1.029 mmol) was added to DCM (20 mL) and DMSO (0.1 mL) and the solvent was stirred for 10 min. tert-Butyl 4-(hydroxymethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (CAS 1644667-10-6, 500 mg, 1.716 mmol) was added slowly and the RM was stirred at RT for 2 h. The reaction was quenched with water and extracted three times with DCM. The combined extracts were dried over Na2SO4 and the solvent was removed under reduced pressure to give the title compound (550 mg). 1 H NMR(400MHz,CDCl3)δ[ppm]7.57(d,J=4.0Hz,1H),6.72(s,1H),6.62(d,J=4.0Hz,1H),4.92(s,2H),3.91(s,3H),2.63(s,3),1.62(s,9H).

[0220] Intermediate I-8: 7-Methyl-1H-indole-4-carbaldehyde [ka] A mixture of 1H-indol-4-yl-methanol (CAS no. 1074-85-7, 100 mg, 0.62 mmol) and MnO2 (216 mg, 2.48 mmol) in EtOAc (3 mL) was heated to 75° C. overnight. The RM was allowed to cool to RT and then filtered through Celite®, eluting with DCM. The filtrate was concentrated under reduced pressure and the residue was purified by chromatography on silica gel (NP, 0-70% EtOAc in heptane) to give the title compound (79 mg) as a white solid. LC-MS Method C-2: Rt=0.75 min, MS m / z [M+H] + =160.1.

[0221] Intermediate O-1: tert-Butyl 2,2-dimethoxy-6-(((trifluoromethyl)sulfonyl)oxy)-7-azaspiro[3.5]non-5-ene-7-carboxylate [ka] Step 1: tert-Butyl 2,2-dimethoxy-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate O-1-1) [ka] Camphorsulfonic acid (970 mg, 4.2 mmol) was added to a solution of tert-butyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate (20 g, 84 mmol) and trimethyl orthoformate (27 g, 27 mL, 0.25 mol) in MeOH. The RM was stirred at RT for 60 min. NaHCO3 (7.0 g, 84 mmol) was added and most of the MeOH was evaporated under reduced pressure at 50° C. The residue was partitioned between MTBE and water. The layers were separated and washed with brine and MTBE. The combined organic layers were dried over MgSO4, treated with activated charcoal and filtered through Celite®. The volatiles of the filtrate were removed under reduced pressure at 50° C. to give a colorless oil, which was treated with hexane and the volatiles were removed again under reduced pressure at 50° C. to give the title compound as a colorless oil (23.58 g). 1H NMR(400MHz,DMSO-d6)δ[ppm]3.25-3.19(m,4H),3.02(s,6H),1.86(s,4H),1.46-1.41(m,4H),1.38(s,9H).

[0222] Step 2: tert-Butyl 2,2-dimethoxy-6-oxo-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate O-1-2) [ka] NaIO4 (38.83 g, 181.5 mmol) was dissolved in water and RuCl3 (1.712 g, 550 μL, 8.252 mmol) was added under mechanical stirring to give an orange solution; NaHCO3 (6.933 g, 82.52 mmol) was added in portions (gas development). The mixture was vigorously stirred while EtOAc was added dropwise to a solution of tert-butyl 2,2-dimethoxy-7-azaspiro[3.5]nonane-7-carboxylate (23.55 g, 82.52 mmol) in EtOAc. The temperature was kept below 31 °C using a water bath. The RM was vigorously stirred at RT for 3 h 50 min and stirring was continued overnight. The RM was diluted with EtOAc and aqueous Na2S2O3 (10 wt%) was added. The mixture was filtered through Celite® and the black solid was washed with EtOAc. The layers of the filtrate were separated and washed with brine and EtOAc. The combined organic layers were dried over MgSO4, filtered and the volatiles were removed under reduced pressure at 50 °C.

[0223] The crude product was purified on silica gel (220 g) using an automated purification system (NP; Teledyne ISCO®; flow rate 150 mL / min, eluent: heptane + 5-35% EtOAc in 35 min). Product-containing fractions were combined and volatiles were removed under reduced pressure at 50° C. to give the title compound as a slightly yellow oil (17.26 g). LC-MS Method B-2: Rt=0.87 min; MS 300.3 [M+H] + .

[0224] Step 3: tert-Butyl 2,2-dimethoxy-6-(((trifluoromethyl)sulfonyl)oxy)-7-azaspiro[3.5]non-5-ene-7-carboxylate (Intermediate O-1) A solution of HMDS (12.10 g, 15.7 mL, 74.95 mmol) in 300 mL of THF was evacuated / backfilled with N2 twice. The solution was cooled to -75°C and n-BuLi (1.6 M in hexanes, 46.84 mL, 74.95 mmol) was added dropwise (exothermic, temperature should not exceed -65°C). The solution was then recooled to -75°C. A solution of intermediate O-1-2 (17.26 g, 57.65 mmol) in THF (40 mL) was added dropwise continuously. The resulting yellow solution was stirred at -75°C for 150 min. A solution of 1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (27.81 g, 77.83 mmol) in THF (50 m) was added dropwise. The cooling bath was removed and the RM was stirred for 40 min. The RM was poured into a well-stirred emulsion of 1M aqueous NaOH and MTBE. The layers were separated and washed with 1M aqueous NaOH, brine and MTBE. The combined organic layers were dried over K2CO3, filtered and the volatiles were removed under reduced pressure at 50 °C to give a slightly yellow oil.

[0225] The crude product was purified on silica gel (330 g) using an automated purification system (NP; Teledyne ISCO®); 245 nm + ELSD detector (flow rate 200 mL / min, eluent: heptane / Et3N 99:1 + 10-47.2% DCM / Et3N 99:1). Fractions were combined and volatiles were removed under reduced pressure at 50 °C to give the title compound as a slightly yellow oil (22.37 g). LC-MS Method B-2: Rt = 1.25 min; MS m / z [M-tertBu+H] + =376.2.

[0226] Intermediate O-2: tert-Butyl 2,2-difluoro-6-(((trifluoromethyl)sulfonyl)oxy)-7-azaspiro[3.5]non-5-ene-7-carboxylate [ka] Step 1: tert-Butyl 2,2-difluoro-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate O-2-1) [ka] To a solution of tert-butyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate (350 g, 1.46 mol) in CHCl (3.00 L) was added DAST (471 g, 2.93 mol, 386 mL) dropwise at 0° C. The RM was stirred at 25° C. for 48 h. The mixture was diluted with MeOH (0.70 L) at 0° C. and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (PE / EtOAc=100 / 1-100 / 5) to give the title compound (280 g) as a yellow liquid. 1 H NMR(400MHz, CDCl3)δ[ppm]3.39-3.24(m,4H),2.33(t,J=12.6Hz,4H),1.65-1.56(m,4H),1.44(s,9H).

[0227] Step 2: tert-Butyl 2,2-difluoro-6-oxo-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate O-2-2) [ka] To a solution of NaIO4 (504 g, 2.36 mol) in H2O (1.40 L) was added RuCl3 (22.2 g, 107 mmol, 7.15 mL) at 0 °C. Then, a solution of tert-butyl 2,2-difluoro-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate O-2-1, 280 g, 1.07 mol) in EtOAc (1.40 L) was added dropwise to the above mixture at 0 °C. The mixture was exposed to air and stirred at 18 °C for 16 h. The RM was filtered and extracted with EtOAc (3x). The combined organic layers were washed with 10% aqueous Na2S2O3 (3x), dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was diluted with MTBE and stirred at 0 °C for 1 h. The precipitated solid was filtered off and dried under reduced pressure to give the title compound (90.0 g) as a white solid. 1 H NMR(400MHz,CDCl3)δ[ppm]3.69-3.58(m,2H),2.64(s,2H),2.47(tt,J=12.2,2.0Hz,4H),1.96(t,J=6.0Hz,2H),1.52(s,9H).

[0228] Alternative preparation of tert-butyl 2,2-difluoro-6-oxo-7-azaspiro[3.5]nonane-7-carboxylate (intermediate O-2-2): To a solution of NaIO4 (504 g, 2.36 mol) in H2O (14.7 mL) was added RuCl3 (99 mg, 0.478 mmol). The solution containing orange, dark solid material was vigorously stirred and cooled by a water bath while a solution of tert-butyl 2,2-difluoro-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate O-2-1, 1.25 g, 4.78 mmol) in EtOAc (14.7 mL) was added dropwise. The RM was vigorously stirred overnight and then diluted with EtOAc and 10% aqueous Na2S2O3; the mixture was filtered through Celite® and the solid was washed with EtOAc. The layers of the filtrate were separated, washed with brine and extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure at 50 °C to give the crude title compound (1.28 g) as a white solid, which was used directly in the next reaction without further purification. LC-MS method B-1: Rt=0.81 min; MS m / z[M-tertBu+H] + =220.3.

[0229] Step 3: tert-Butyl 2,2-difluoro-6-(((trifluoromethyl)sulfonyl)oxy)-7-azaspiro[3.5]non-5-ene-7-carboxylate (Intermediate O-2) To a solution of HMDS (39.5 g, 245 mmol, 51.3 mL) in THF (712 mL) was added n-BuLi (2.5 M in hexane, 94.4 mL) under N2 atmosphere at -78 °C. Then, a solution of tert-butyl 2,2-difluoro-6-oxo-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate O-2-2, 50.0 g, 181 mmol) in THF (142 mL) was added dropwise to the above mixture. After stirring at -78 °C for 2 h, a solution of N-phenyl-bis(trifluoromethanesulfonimide) (87.6 g, 245 mmol) in THF (258 mL) was added dropwise. The cooling bath was removed and the mixture was stirred at 25 °C for another 8 h. The RM was poured into well-stirred 1M aqueous NaOH solution (300 mL) at 0° C., then extracted with EtOAc (3×1.0 L). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by RP-HPLC (ACN / water, 0.1% FA condition) to give the title compound (100 g) as a yellow liquid. 1 H NMR(400MHz,CDCl3)δ[ppm]5.25(s,1H),3.64-3.60(m,2H),2.74-2.62(m,2H),2.58-2.46(m,2H),1.93(td,J=2.8,5.2Hz,2H),1.50(s,9H). NOTE: Alternatively, the crude tert-butyl 2,2-difluoro-6-(((trifluoromethyl)sulfonyl)oxy)-7-azaspiro[3.5]non-5-ene-7-carboxylate (intermediate O-2) can be used directly in the next reaction without further purification.

[0230] To a solution of HMDS (83.1 g, 514 mmol, 107 mL) in 2-MeTHF (0.60 L), n-BuLi (2.5 M in hexane, 79.2 mmol, 198 mL) was added under N2 atmosphere at -78 °C. Then, a solution of tert-butyl 2,2-difluoro-6-oxo-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate O-2-2, 105 g, 381 mmol) in 2-MeTHF (0.40 L) was added dropwise to the above mixture. After stirring at -78 °C for 2 h, a solution of N-phenyl-bis(trifluoromethanesulfonimide) (183 g, 514 mmol) in 2-MeTHF (0.40 L) was added dropwise. The cooling bath was removed and the mixture was stirred at 18 °C for another 18 h. The RM was poured into a well-stirred 1M aqueous NaOH solution at 0° C. and then extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give the crude title compound (315 g) as a yellow oil, which was used directly in the next reaction without further purification.

[0231] Intermediate O-3: tert-Butyl 2,2-difluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7-azaspiro[3.5]non-5-ene-7-carboxylate [ka] A solution of tert-butyl 2,2-difluoro-6-(((trifluoromethyl)sulfonyl)oxy)-7-azaspiro[3.5]non-5-ene-7-carboxylate (Intermediate O-2, 7.970 g, 19.57 mmol), triphenylphosphine (307.9 mg, 1.174 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2 dioxaborolane) (7.453 g, 29.35 mmol) was evacuated and backfilled with N2. K2CO3 (325 mesh, 4.056 g, 29.35 mmol) and PdCl2(PPh3)2 (412 mg, 587 μmol) were added. The mixture was evacuated and backfilled with N2 again, heated to 90 °C and stirred under N2 atmosphere for 4 h. The RM was cooled to RT. The RM was diluted with MTBE and the mixture was filtered. The solid was washed with MTBE. Water was added to the filtrate and the layers were separated. They were washed with brine and MTBE. The combined organic layers were dried over MgSO4, filtered and the volatiles were removed under reduced pressure at 50° C. to give a yellow oil. The crude material was purified on silica gel (220 g) using heptane / EtOAc. The fractions were combined and the volatiles were removed under reduced pressure at 50° C. to give the title compound as an off-white solid (5.40 g, containing bis(pinacolato)diboron in an unquantifiable amount due to overlapping NMR signals), which was used in the next step without further purification. LC-MS Method B-1: Rt=1.38 min; MS m / z [M-Boc+H] + =286.3.

[0232] Intermediate O-4: tert-Butyl 6-(((trifluoromethyl)sulfonyl)oxy)-2-oxa-7-azaspiro[3.5]non-5-ene-7-carboxylate [ka] Step 1: tert-Butyl 6-oxo-2-oxa-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate O-4-1) [ka] NaIO4 (5.18 g, 24.2 mmol) was dissolved in water (26 mL) and RuCl3 (228 mg, 1.1 mmol) was added. The mixture was stirred vigorously and cooled by a water bath while a solution of tert-butyl 2-oxa-7-azaspiro[3.5]nonane-7-carboxylate (2.50 g, 11.0 mmol) in EtOAc (26 mL) was added dropwise. The RM was stirred vigorously overnight, then diluted with EtOAc and aqueous Na2S2O3 (10 wt%) was added. The mixture was filtered through Celite® and the black solid was washed with EtOAc. The layers of the filtrate were separated and washed with brine and EtOAc. The combined organic layers were dried over MgSO4, filtered and the volatiles were removed under reduced pressure at 50 °C to give an off-white solid that was triturated with hexane / MTBE 95 / 5. The suspension was sonicated and filtered. The solid was washed with hexane / MTBE 95 / 5 and dried under reduced pressure at 50° C. to give the title compound (1.86 g). LC-MS Method B-1: Rt=0.46 min; MS m / z [M-tertBu+H] + =186.1.

[0233] Step 2: tert-Butyl 6-(((trifluoromethyl)sulfonyl)oxy)-2-oxa-7-azaspiro[3.5]non-5-ene-7-carboxylate (Intermediate O-4) A solution of HMDS (261 mg, 1.616 mmol) in THF (2.6 mL) was evacuated / backfilled with N2 twice and cooled to -78 °C. n-BuLi (1.6 M in hexanes, 104 mL, 1.616 mmol) was added dropwise. The resulting clear, colorless solution was stirred in a dry ice bath for 5-10 min. This freshly prepared LiHMDS solution was then cannulated into a pre-cooled (-78 °C) solvent and degassed solution of tert-butyl 6-oxo-2-oxa-7-azaspiro[3.5]nonane-7-carboxylate (intermediate O-4-1, 300 mg, 1.243 mmol) in THF (3.7 mL). The RM was stirred for 120 min. A solution of 1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)-methanesulfonamide (600 mg, 1.678 mmol) in THF (1.6 mL) was added dropwise. The cooling bath was removed and the RM was stirred for 30 min and then poured onto a mixture of aqueous NaOH (c=1.0 mol / L) and MTBE under stirring. The layers were separated and washed with 0.5 M aqueous NaOH, brine and MTBE. The combined organic layers were dried over K2CO3, filtered and the volatiles were removed under reduced pressure at 50° C. to give a yellow oil which was purified on silica gel (12 g) by eluting with heptane / EtOAc (9 / 1 to 6 / 1) containing 1% Et3N. The pure fractions were combined and the volatiles were removed under reduced pressure at 50° C. to give the title compound as a colorless oil (464 mg). LC-MS method B-1: Rt=1.15 min; MS m / z[MH] - =372.2.

[0234] Intermediate O-5: tert-Butyl 2,2-dimethoxy-6-(4-(methoxycarbonyl)phenyl)-7-azaspiro[3.5]non-5-ene-7-carboxylate [ka] A solution of K3PO4 (33.02 g, 12.88 mL, 155.6 mmol) in water was added to a solution of tert-butyl 2,2-dimethoxy-6-(((trifluoromethyl)sulfonyl)oxy)-7-azaspiro[3.5]non-5-ene-7-carboxylate (Intermediate O-1, 22.37 g, 51.85 mmol) and (4-(methoxycarbonyl)phenyl)boronic acid (12.13 g, 67.41 mmol) in dioxane. The vigorously stirred emulsion was evacuated / backfilled with N2 twice. PdCl2(dtbpf) (1.690 g, 2.593 mmol) was added and the capped vial was stirred at 55 °C (bath temperature) for 65 min. Stirring was continued for an additional 30 min, after which an additional 0.1 eq. (933 mg) (4-(methoxycarbonyl)phenyl)boronic acid and 0.01 eq. (338 mg) PdCl2(dtbpf) were added and stirring was continued for an additional 30 min.

[0235] The RM was partitioned between water and EtOAc. The layers were separated and washed with saturated aqueous NaHCO3, brine, and EtOAc. The combined organic layers were dried over MgSO4, filtered, and the volatiles were removed under reduced pressure at 50 °C to give an amber oil, which was purified on silica gel (330 g) using an automated purification system (NP; Teledyne ISCO®; collection at 254 / 280 nm + ELSD detector; flow rate 200 mL / min; eluent: heptane:Et3N 99:1 + 5-22.2% EtOAc in 17.2 min). The fractions were combined and the volatiles were removed under reduced pressure at 50 °C to give an amber oil. This material was dissolved in hexane / MTBE 9 / 1 and treated with activated charcoal. The mixture was filtered through Celite® and the charcoal was washed with hexane / MTBE 9 / 1 (3x). The volatiles were removed under reduced pressure at 50° C. to give the title compound as a slightly amber oil (18.82 g) that solidified upon standing. LC-MS Method B-2: Rt=1.20 min; MS m / z [M+H] + =418.4.

[0236] Intermediate O-6: tert-Butyl 2,2-difluoro-6-(4-(methoxycarbonyl)phenyl)-7-azaspiro[3.5]non-5-ene-7-carboxylate [ka] To a solution of crude tert-butyl 2,2-difluoro-6-(((trifluoromethyl)sulfonyl)oxy)-7-azaspiro[3.5]non-5-ene-7-carboxylate (intermediate O-2, 155 g, 380 mmol, assuming 100% conversion) and (4-(methoxycarbonyl)phenyl)boronic acid (82.1 g, 456 mmol) in dioxane (1.20 L) was added a solution of K3PO4 (242 g, 1.14 mol) in HO (0.30 L) and PdCl2(dtbpf) (12.4 g, 19.0 mmol). The mixture was degassed under reduced pressure, purged with N2 three times, then stirred at 50 °C for 12 h. The RM was concentrated under reduced pressure to remove dioxane. The residue was diluted with water and extracted with EtOAc (3x). The combined organic layers were concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EtOAc=100 / 1 to 0 / 100). The crude product was purified by RP-HPLC (ACN / water, 0.1% FA condition) to give the title compound (80.0 g) as a white solid. 1 H NMR(400MHz,CDCl3)δ[ppm]7.99(d,J=8.4Hz,2H),7.36(d,J=8.4Hz,2H),5.33(s,1H),3.93(s,3H), 3.73(td,J=2.8,5.2Hz,2H),2.74-2.62(m,2H),2.56-2.46(m,2H),2.10-1.98(m,2H),1.07(s,9H).

[0237] Intermediate O-7: tert-Butyl 6-(4-(methoxycarbonyl)phenyl)-2-oxa-7-azaspiro[3.5]non-5-ene-7-carboxylate [ka] tert-Butyl 6-((((trifluoromethyl)sulfonyl)oxy)-2-oxa-7-azaspiro[3.5]non-5-ene-7-carboxylate (Intermediate O-4, 315 mg, 0.844 mmol) and (4-(methoxycarbonyl)phenyl)boronic acid (197 mg, 1.097 mmol) were dissolved in dioxane (5.6 mL). A solution of K3PO4 (537 mg, 2.53 mmol) in water (1.5 mL) was added. The mixture was evacuated and refilled with N2. PdCl2(dtbpf) (27.5 mg, 0.042 mg) was added and the mixture was evacuated / backfilled with N2 twice. The RM was then heated to 50 °C and stirred vigorously for 80 min. The RM was partitioned between water and EtAc. The layers were separated and washed with saturated aqueous NaHCO3, brine, and EtOAc. The combined organic layers were dried over MgSO4, filtered, and the volatiles were removed under reduced pressure at 50 °C to give an amber oil, which was purified on silica gel (24 g) using an automated purification system (NP; Teledyne ISCO®; collected at 280 nm; eluent: heptane + 10 to 26.3% EtOAc in 16.3 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 (242 mg). LC-MS Method B-1: Rt = 1.04 min; MS m / z [M-tertBu + H] + =304.3.

[0238] Intermediate rac-O-8: tert-Butyl 2,2-difluoro-7-(4-(methoxycarbonyl)phenyl)-8-azaspiro[4.5]dec-6-ene-8-carboxylate [ka] Intermediate rac-O-8 was prepared according to the method described for intermediate O-6 hereinabove using tert-butyl 2-oxo-8-azaspiro[4.5]decane-8-carboxylate (CAS number 1250994-14-9) as the starting material. LC-MS Method C-2: Rt=3.09 min; MS m / z [M-tertBu+H]+=352.1.

[0239] Intermediate (+)-O-9: (+)-tert-Butyl 2,2-difluoro-7-(4-(methoxycarbonyl)phenyl)-8-azaspiro[4.5]dec-6-ene-8-carboxylate and intermediate (-)-O-10: (-)-tert-Butyl 2,2-difluoro-7-(4-(methoxycarbonyl)phenyl)-8-azaspiro[4.5]dec-6-ene-8-carboxylate [ka] For SFC chiral purification of intermediate rac-O-8 (2.5 g): Instrument Thar 80 Prep SFC; Column: Chiralpak IE 21 x 250 mm 5 μm; Flow rate: 80 g / min; Co-solvent: 15% 1:1 MeOH:IPA in CO2; Detection: 300 nm; Backpressure set point: 125 bar; Injection size: 17.04 mg (14.2 mg / mL in MeOH). Peak 1: Intermediate (+)-O-9, isolated: 1.716g. Method SFC-1: Rt=1.14 min / 5.0 min, ee>99%. Specific rotation method OR1:[α] 25 @589nm = +5.57° (10.53mg of intermediate (+)-O-9 in 1mL DCM). Peak 2: Intermediate (-)-O-10, isolated: 1.748g. Method SFC-1: Rt=1.36 min / 5.0 min, ee 97%. Specific rotation method OR1:[α] 25 @589nm = -1.10° (10.018mg of intermediate (-)-O-10 in 1mL DCM).

[0240] Intermediate O-11: tert-Butyl 2,2-difluoro-6-(4-(3-hydroxyoxetan-3-yl)phenyl)-7-azaspiro[3.5]non-5-ene-7-carboxylate [ka] A solution of K3PO4 (945 mg, 369 μL, 4.454 mmol) in water (2.63 mL) was added to a solution of tert-butyl 2,2-difluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7-azaspiro[3.5]non-5-ene-7-carboxylate (Intermediate O-3, 572 mg, 1.485 mmol) and 3-(4-bromophenyl)oxetan-3-ol (510.2 mg, 2.227 mmol) in dioxane (9.90 mL). The well-stirred emulsion was evacuated / backfilled with N2 twice. PdCl2(dtbpf) (48.4 mg, 74.2 μmol) was added and the mixture was again evacuated / backfilled with N2 and then stirred at 50° C. for 40 min. The RM was cooled to RT and then partitioned between water and EtOAc. The layers were separated and washed with saturated aqueous NaHCO3, brine, and EtOAc. The combined organic layers were dried over MgSO4, filtered, and the volatiles were removed under reduced pressure at 50 °C. An amber solid was obtained. The crude product was dissolved in DCM and suspended in an ultrasonic bath. The suspension was filtered and the filtrate was purified on silica gel (24 g) using an automated purification system (NP; Teledyne ISCO®; collection at 257 / 275 nm; flow rate 35 mL / min; eluent: heptane + 5-26.4% (EtOAc:MeOH 95:5) in 18.1 min; gradient paused when product eluted). Fractions were combined and the volatiles were removed under reduced pressure at 50 °C to give the title compound as an amber oil (480 mg, containing approx. 17 wt % pinacol). LC-MS method B-1: Rt=1.10 min; MS m / z[M+H] + =408.4. The product was used in the next step without further purification.

[0241] Intermediate O-12: tert-Butyl 2,2-difluoro-6-(4-(2-hydroxypropan-2-yl)phenyl)-7-azaspiro[3.5]non-5-ene-7-carboxylate [ka] A solution of K3PO4 (945.4 mg, 368.7 μL, 4.454 mmol) in water (2.63 mL) was added to a solution of tert-butyl 2,2-difluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7-azaspiro[3.5]non-5-ene-7-carboxylate (Intermediate O-3, 572 mg, 1.485 mmol) and 2-(4-bromophenyl)propan-2-ol (479 mg, 2.227 mmol) in dioxane (9.90 mL). The well-stirred emulsion was evacuated / backfilled with N2 twice. PdCl2(dtbpf) (48.38 mg, 74.24 μmol) was added and the mixture was again evacuated / backfilled with N2 and then stirred at 50° C. for 50 min. The RM was cooled to RT and then partitioned between water and EtOAc. The layers were separated and washed with saturated aqueous NaHCO3, brine, and EtOAc. The combined organic layers were dried over MgSO4, filtered, and the volatiles were removed under reduced pressure at 50°C. An amber solid was obtained, which was dissolved in DCM and purified on silica gel (24 g) using an automated purification system (NP; Teledyne ISCO®; collection at 255 / 270 nm; flow rate 35 mL / min; eluent: heptane + 5-20.5% EtOAc in 16.1 min; gradient paused when product eluted). Pure fractions were combined and the volatiles removed under reduced pressure at 50°C to give the title compound as a slightly amber oil (344 mg). LC-MS method B-1: Rt=1.25 min; MS m / z[M-H2O+H]+=376.3; MS m / z[M-tertBu-H2O+H]+=320.2.

[0242] Intermediate O-13: tert-Butyl 8-(4-(1H-pyrazol-5-yl)phenyl)-2,2-difluoro-7-azaspiro[3.5]non-5-ene-7-carboxylate [ka] A solution of K3PO4 (826.4 mg, 322.3 μL, 3.893 mmol) in water (2.30 mL) was added to a solution of tert-butyl 2,2-difluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7-azaspiro[3.5]non-5-ene-7-carboxylate (Intermediate O-3, 500 mg, 1.298 mmol) and 5-(4-bromophenyl)-1H-pyrazole (434.3 mg, 1.947 mmol) in dioxane (8.65 mL). The well-stirred emulsion was evacuated / backfilled with N2 twice. PdCl2(dtbpf) (42.29 mg, 64.89 μmol) was added and the mixture was again evacuated / backfilled with N2 and then stirred at 50 °C for 40 min. The RM was cooled to RT and then partitioned between water and MTBE. The slurry was filtered through Celite® and the filtrate was transferred to a separatory funnel. The layers were separated and washed with saturated aqueous NaHCO3, brine and MTBE. The combined organic layers were dried over MgSO4, filtered and the volatiles were removed under reduced pressure at 50° C. An amber solid was obtained, which was purified on silica gel (40 g) using an automated purification system (NP; Teledyne ISCO®; collection at 254 / 280 nm; flow rate 40 mL / min; eluent: heptane + 10-40% EtOAc in 24.0 min). The fractions were combined and the volatiles were removed under reduced pressure at 50° C. to give the title compound as a slightly yellow oil (293 mg, containing approx. 17 wt % pinacol). LC-MS Method B-1: Rt=1.25 min; MS m / z [M-tertBu+H] + =346.2.

[0243] Intermediate O-14: tert-Butyl 6-(4-(1H-pyrazol-1-yl)phenyl)-2,2-difluoro-7-azaspiro[3.5]non-5-ene-7-carboxylate [ka] A solution of K3PO4 (661.1 mg, 257.9 μL, 3.115 mmol) in water (1.84 mL) was added to a solution of tert-butyl 2,2-difluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7-azaspiro[3.5]non-5-ene-7-carboxylate (Intermediate O-3, 400 mg, 1.038 mmol) and 1-(4-bromophenyl)-1H-pyrazole (347.4 mg, 1.557 mmol) in dioxane (6.92 mL). The well-stirred emulsion was evacuated / backfilled with N2 twice. PdCl2(dtbpf) (33.83 mg, 51.91 μmol) was added and the mixture was again evacuated / backfilled with N2 and then stirred at 50 °C for 50 min. The RM was cooled to RT and then partitioned between water and MTBE. The slurry was filtered through Celite® and the filtrate was transferred to a separatory funnel. The layers were separated and washed with saturated aqueous NaHCO3, brine and MTBE. The combined organic layers were dried over MgSO4, filtered and the volatiles were removed under reduced pressure at 50° C. An amber solid was obtained, which was dissolved in DCM and purified on silica gel (24 g) using an automated purification system (NP; Teledyne ISCO®; collection at 278 / 254 nm; flow rate 35 mL / min; eluent: heptane + 5-12.7% EtOAc in 15.4 min). Pure fractions were combined and the volatiles were removed under reduced pressure at 50° C. to give the title compound as a slightly yellow oil (234 mg). LC-MS Method B-1: Rt=1.35 min; MS m / z [M-tertBu+H]+=346.2.

[0244] Intermediate O-15: tert-Butyl 6-(4-cyanophenyl)-2,2-difluoro-7-azaspiro[3.5]non-5-ene-7-carboxylate [ka] A solution of K3PO4 (1.157 g, 451.2 μL, 5.451 mmol) in water (3.22 mL) was added to a solution of tert-butyl 2,2-difluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7-azaspiro[3.5]non-5-ene-7-carboxylate (Intermediate O-3, 700 mg, 1.817 mmol) and 4-bromobenzonitrile (496.1 mg, 2.725 mmol) in dioxane (12.11 mL). The well-stirred emulsion was evacuated / backfilled with N2 twice. PdCl2(dtbpf) (59.21 mg, 90.85 μmol) was added and the mixture was again evacuated / backfilled with N2 and then stirred at 50 °C for 50 min. The RM was cooled to RT and then partitioned between water and MTBE. The slurry was filtered through Celite® and the filtrate was transferred to a separatory funnel. The layers were separated and washed with saturated aqueous NaHCO3, brine and MTBE. The combined organic layers were dried over MgSO4, filtered and the volatiles were removed under reduced pressure at 50° C. An amber solid was obtained. The material was dissolved in hexane and filtered. The filtrate's volatiles were removed under reduced pressure at 50° C. to give an amber oil which was purified on silica gel (40 g) using an automated purification system (NP; Teledyne ISCO®; collection at 245 / 284 nm; flow rate 40 mL / min; eluent: heptane + 5-16.6% EtOAc in 15.5 min). The pure fractions were combined and the volatiles removed under reduced pressure at 50° C. to give the title compound as a slightly yellow oil (363 mg) which solidified on standing. 1 H NMR(400MHz,DMSO-d6)δ[ppm]7.84-7.77(m,2H),7.50-7.43(m,2H),5.55(s,1H),3 .67-3.59(m,2H),2.82-2.69(m,2H),2.56(m,2H),1.96-1.90(m,2H),1.02(s,9H).

[0245] Intermediate O-16: tert-Butyl 2,2-difluoro-6-phenyl-7-azaspiro[3.5]non-5-ene-7-carboxylate [ka] A solution of K3PO4 (843 mg, 328.8 μL, 3.971 mmol) in water (2.30 mL) was added to a solution of intermediate O-3 (510 mg, 1.324 mmol) and bromobenzene (353.3 mg, 2.250 mmol) in dioxane (8.65 mL). The well-stirred emulsion was evacuated / backfilled with N2 twice. PdCl2(dtbpf) (43.14 mg, 66.19 μmol) was added and the mixture was again evacuated / backfilled with N2, then stirred at 50 °C for 90 min. The RM was cooled to RT and then partitioned between water and MTBE. The slurry was filtered through Celite® and the filtrate was transferred to a separatory funnel. The layers were separated and washed with saturated aqueous NaHCO3, brine and MTBE. The combined organic layers were dried over MgSO4, filtered and the volatiles were removed under reduced pressure at 50°C. An amber oil was obtained. The crude product was dissolved in DCM and purified on silica gel (24 g) using an automated purification system (NP; Teledyne ISCO®; collection at 245 / 282 nm; flow rate 35 mL / min; eluent: heptane + 0-6.4% EtOAc in 12.7 min). Pure fractions were combined and the volatiles were removed under reduced pressure at 50°C to give the title compound (274 mg) as a slightly yellow oil. LC-MS Method B-1: Rt=1.47 min; MS m / z [M-tertBu+H] + =280.1.

[0246] Intermediate O-17: tert-Butyl 2,2-difluoro-6-(1-methyl-1H-pyrazol-4-yl)-7-azaspiro[3.5]non-5-ene-7-carboxylate [ka] A solution of K3PO4 (763.6 mg, 297.8 μL, 3.598 mmol) in water (2.13 mL) was added to a solution of intermediate O-3 (462 mg, 1.199 mmol) and 4-bromo-1-methyl-1H-pyrazole (290 mg, 1.799 mmol) in dioxane (7.99 mL). The well-stirred emulsion was evacuated / backfilled with N2 twice. PdCl2(dtbpf) (39.08 mg, 59.96 μmol) was added and the mixture was again evacuated / backfilled with N2, then stirred at 50 °C for 90 min. The RM was cooled to RT and then partitioned between water and MTBE. The slurry was filtered through Celite® and the filtrate was transferred to a separatory funnel. The layers were separated and washed with saturated aqueous NaHCO3, brine and MTBE. The combined organic layers were dried over MgSO4, filtered and the volatiles were removed under reduced pressure at 50°C. An amber solid was obtained, which was dissolved in DCM / hexane and purified on silica gel (24 g) using an automated purification system (NP; Teledyne ISCO®; collection at 278 / 254 nm; flow rate 35 mL / min; eluent: heptane + 5-12.7% EtOAc in 15.4 min). The purest fractions were combined and the volatiles were removed under reduced pressure at 50°C. The residue was triturated with hexane and DCM and the volatiles were removed again under reduced pressure at 50°C to give the title compound as amber crystals (138 mg). LC-MS Method B-1: Rt=1.06 min; MS m / z[M+H] + =340.3.

[0247] Intermediate rac-B-1: (RS)-tert-Butyl 2,2-dimethoxy-6-(4-(methoxycarbonyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate [ka] A solution of tert-butyl 2,2-dimethoxy-6-(4-(methoxycarbonyl)phenyl)-7-azaspiro[3.5]non-5-ene-7-carboxylate (Intermediate O-5, 18.8 g, 45.0 mmol) in EtOH / THF was placed under N2 atmosphere. Pd / C (2.40 g, 10 wt%, 2.25 mmol) was added and the RM was stirred under H2 atmosphere (balloon) for 120 min. The RM was flushed with N2 and diluted with DCM. The suspension was filtered through Celite® and rinsed with DCM (3x). The volatiles of the filtrate were removed under reduced pressure at 50° C. to give a colorless oil, which was purified on silica gel (330 g) using an automated purification system (NP; Teledyne ISCO®; collection at 240 / 254 nm; flow rate 200 mL / min; eluent: heptane:Et3N (99:1) + 5-16.8% EtOAc in 19.6 min). The fractions were combined and the volatiles were removed under reduced pressure at 50° C. to give the title compound as a colorless sticky oil (15.68 g). LC-MS Method B-2: Rt=1.18 min; MS m / z[M+H] + =420.4.

[0248] Intermediate rac-B-2: (RS)-tert-Butyl 6-(4-(methoxycarbonyl)phenyl)-2-oxo-7-azaspiro[3.5]nonane-7-carboxylate [ka] 2M aqueous HCl (46.72 mL, 93.44 mmol) was added to a solution of tert-butyl 2,2-dimethoxy-6-(4-(methoxycarbonyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (intermediate rac-B-1, 15.68 g, 37.38 mmol) in THF. The RM was stirred at RT for 90 min. Stirring was continued for 3 h. The RM was diluted with MTBE and brine. The separated layers were washed with brine and MTBE. The combined organic layers were dried over MgSO4, filtered and the volatiles were removed under reduced pressure at 50° C. to give the title compound (12.81 g) as a white sticky foam, which was used without further purification. LC-MS Method B-2: Rt=1.03 min; MS m / z [M+H] + =374.3.

[0249] Intermediate ds-rac-B-3: tert-Butyl 2-hydroxy-6-(4-(methoxycarbonyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (racemic mixture; 4 stereoisomers) [ka] NaBH4 (243 mg, 6.43 mmol) was added to a solution of tert-butyl 6-(4-(methoxycarbonyl)phenyl)-2-oxo-7-azaspiro[3.5]nonane-7-carboxylate (intermediate rac-B-2, 4.80 g, 12.9 mmol) in MeOH cooled to 0 °C. The RM was stirred in an ice bath for 20 min at RT. The RM was quenched with 1M aqueous HCl. EtOAc and more water were added and the layers were separated. The layers were washed with 1M aqueous HCl, brine and EtOAc. The combined organic layers were dried over MgSO4, filtered, and the volatiles were removed under reduced pressure at 50 °C to give a colorless oil, which was purified on silica gel (120 g) using an automated purification system (NP; Teledyne ISCO®; collection at 246 / 254 nm; flow rate 85 mL / min; eluent: heptane + 10-60% EtOAc in 20 min). Pure fractions were combined and the volatiles were removed under reduced pressure at 50 °C to give the title compound as a white foam (4.55 g, 55:45 diastereomeric mixture). LC-MS Method B-1: Rt = 1.04 min; MS m / z [M-Boc+H] + =276.3.

[0250] Intermediate ds-rac-B-4: tert-Butyl 2-hydroxy-6-(4-(methoxycarbonyl)phenyl)-2-methyl-7-azaspiro[3.5]nonane-7-carboxylate (racemic mixture; 4 stereoisomers) [ka] A solution of tert-butyl 6-(4-(methoxycarbonyl)phenyl)-2-oxo-7-azaspiro[3.5]nonane-7-carboxylate (intermediate rac-B-2, 1.57 g, 4.20 mmol) in THF was placed under N2 atmosphere and cooled to -78 °C. Methylmagnesium chloride (3 M in THF, 3.08 mL, 9.25 mmol) was added dropwise. The RM was then allowed to reach -20 °C before being poured into a well-stirred emulsion of 1 M aqueous HCl and MTBE. The layers were then separated and washed with brine and MTBE. The combined organic layers were dried over MgSO4, filtered, and the volatiles were removed under reduced pressure at 50 °C to give a colorless oil. The crude product was purified on silica gel (40 g) using an automated purification system (NP; Teledyne ISCO®; collection at 243 / 254 nm; flow rate 30 mL / min, eluent: DCM+0-32.2% MTBE in 20.2 min). Pure fractions were combined and volatiles were removed under reduced pressure at 50° C. to give the title compound as a white foam (1.54 g, 68:32 diastereomeric mixture). LC-MS method B-3: Rt=5.19 / 5.29 min (68 and 32% area); MS m / z [M-tertBu+H]+=334.2.

[0251] Intermediate ds-rac-B-5: tert-Butyl 2-fluoro-6-(4-(methoxycarbonyl)phenyl)-2-methyl-7-azaspiro[3.5]nonane-7-carboxylate (racemic mixture; 4 stereoisomers) [ka] A solution of tert-butyl 2-hydroxy-6-(4-(methoxycarbonyl)phenyl)-2-methyl-7-azaspiro[3.5]nonane-7-carboxylate (intermediate ds-rac-B-4, 402 mg, 1.03 mmol) in DCM was cooled to -78 °C. DAST (266 mg, 218 μL, 1.65 mmol) was added dropwise. The RM was allowed to warm to 0 °C and the mixture was stirred for 30 min. The RM was carefully poured portionwise into well-stirred saturated aqueous NaHCO3; the layers were separated and the aqueous layer was washed with DCM (2x). The combined organic layers were dried over K2CO3, filtered and the volatiles were removed under reduced pressure at 50 °C to give a colorless oil. The crude product was purified on silica gel (12 g) using an automated purification system (NP; Teledyne ISCO®; collection at 246 / 254 nm; flow rate 35 mL / min; eluent: heptane + 1-12% EtOAc in 15.6 min). Pure fractions were combined and volatiles were removed under reduced pressure at 50° C. to give the title compound (diastereomeric mixture with unknown composition) as a colorless oil (362 mg). LC-MS Method B-1: Rt=1.30 min, MS m / z [M+H] + =392.5, [M-tertBu+H] + =336.5.

[0252] Intermediate rac-B-6: (RS)-tert-Butyl 2,2-difluoro-6-(4-(methoxycarbonyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate [ka] Achiral hydrogenation: To a solution of compound tert-butyl 2,2-difluoro-6-(4-(methoxycarbonyl)phenyl)-7-azaspiro[3.5]non-5-ene-7-carboxylate (Intermediate O-6, 26.6 g, 67.6 mmol) in THF (130 mL) and EtOH (130 mL) was added Pd / C (2.70 g, 10 wt%) under N2 atmosphere. The suspension was degassed under reduced pressure and purged with H2 several times. The mixture was stirred under H2 (15 psi) at 25 °C for 1.5 h. The RM was filtered and the filtrate was concentrated under reduced pressure to give the crude title compound (26.3 g) as a white solid. 1 H NMR(400MHz,CDCl3)δ[ppm]8.00(d,J=8.4Hz,2H),7.24(d,J=8.0Hz,2H),5.42(br d,J=5.2Hz,1H),4.24-4.15(m,1H),3.90(s,3H),3.07-2.97(m,1H),2.40-2.27(m,3 H),2.10(dd,J=6.4,14.0Hz,1H),1.96-1.81(m,1H),1.77-1.68(m,3H),1.39(s,9H).

[0253] Chiral hydrogenation with (S,S)-iPr-DuPhos: A round-bottom flask in a glove box under N2 atmosphere was charged with Rh(COD)2BF4 (331 mg; 4 mol%, CAS 35138-22-8) and (S,S)-iPr-DuPhos (344 mg; 4 mol%, CAS 147253-69-8) followed by hexafluoro-IPA (8 mL; CAS 920-66-1, degassed with N2 and dried over 4 Å molecular sieves overnight). The mixture was stirred at RT for 1 h and then added to tert-butyl 2,2-difluoro-6-(4-(methoxycarbonyl)phenyl)-7-azaspiro[3.5]non-5-ene-7-carboxylate (Intermediate O-6, 8.0 g, 20.33 mmol) in an autoclave in the glove box followed by hexafluoro-IPA (32 mL). The RM was degassed with N2 and then hydrogenated under H2 atmosphere (15 bar) at 60 °C for 16-18 h. The RM was cooled to ambient temperature to give a solution of crude tert-butyl (S)-2,2-difluoro-6-(4-(methoxycarbonyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (70 and 87% ee; two different batches).

[0254] Intermediate (+)-B-7: tert-Butyl (R)-2,2-difluoro-6-(4-(methoxycarbonyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate [ka] and intermediate (-)-B-8: tert-Butyl (S)-2,2-difluoro-6-(4-(methoxycarbonyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate [ka] Chiral separation of crude racemic tert-butyl 2,2-difluoro-6-(4-(methoxycarbonyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (intermediate rac-B-6, 32 g) was carried out by chiral pretreatment SFC.

[0255] Preparative separation method: Instrument: Waters SFC prep 350; Column: REGIS(S,S)WHELK-O1 (250mm x 50mm, 10μm); Mobile phase: A for CO2 and B for EtOH (0.1% NH4OH); Gradient: B 35%; Flow rate: 200mL / min; Back pressure: 100 bar; Column temperature: 35°C; Wavelength: 220nm; Cycle time: approx. 3.85min; Sample preparation: Compounds were dissolved in approx. 300mL MeOH and DCM. Injection: 18mL per injection. Peak 1: Intermediate (+)-B-7, which is the first to elute from the column. Recovery yield: 12.5 g. Peak 2: Intermediate (-)-B-8, which elutes second from the column. Recovery yield: 13.1 g.

[0256] Analysis method: Instrument: Agilent-1260; Column: (S,S)Whelk-O1 50×4.6 mm ID, 3.5 μm; Mobile phase: Phase A for CO2, Phase B for MeOH (0.05% DEA); Gradient elution: 5%-40% B in A; Flow rate: 3 mL / min; Detector: DAD; Column temperature: 35 °C; Back pressure: 100 bar Peak 1: Intermediate (+)-B-7 Rt=0.887 min;>99% ee. Specific rotation method OR2:[α] 25 @589nm = +49.1° (11.5 mg of intermediate (+)-B-7 in 1.1 mL of DCM). 1 H NMR(400MHz,MeOD-d4)δ[ppm]8.01(d,J=8.44Hz,2H),7.35(d,J=8.08Hz,2H),5.42(br d,J=4.52Hz,1H),4.17(dt,J=13.88,3.56Hz,1H),3.90(s,3H),3.12(ddd,J=14.00,10.44,5.36Hz,1H) ,2.48-2.27(m,3H),2.12(dd,J=14.04,6.48Hz,1H),2.02-1.91(m,1H),1.79-1.68(m,3H),1.40(s,9H). Peak 2: Intermediate (-)-B-8 Rt=1.205 min; >99% ee. Specific rotation method OR2:[α] 25 @589nm = -49.1° (11.1 mg of intermediate (-)-B-8 in 1.1 mL of DCM). 1 H NMR(400MHz,MeOD-d4)δ[ppm]8.01(d,J=8.44Hz,2H),7.34(d,J=8.20Hz,2H),5.42(br d,J=4.64Hz,1H),4.17(dt,J=13.92,3.56Hz,1H),3.90(s,3H),3.12(ddd,J=14.00,10.40,5.44Hz,1H),2.49-2.28(m ,3H),2.12(dd,J=14.08,6.48Hz,1H),1.97(tdd,J=13.68,13.68,10.00,3.68Hz,1H),1.40(s,9H),1.78-1.67(m,3H).

[0257] Intermediate ds-rac-B-9: tert-Butyl 2-fluoro-6-(4-(methoxycarbonyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (racemic mixture; 4 stereoisomers) [ka] A solution of tert-butyl 2-hydroxy-6-(4-(methoxycarbonyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (intermediate ds-rac-B-3, 556 mg, 1.48 mmol) and 2,6-lutidine (793 mg, 858 μL, 7.40 mmol) in anhydrous DCM (5.5 mL) was cooled to −78° C. Trifluoromethanesulfonic anhydride (836 mg, 500 μL, 2.96 mmol) was added dropwise. The cooling bath was removed and the RM was stirred for 20 min. The RM was partitioned between MTBE and 1M aqueous HCl; the layers were separated and washed with 1M aqueous HCl, brine and MTBE. The combined organic layers were dried over MgSO4, filtered and the volatiles were removed under reduced pressure at 50° C. to give an orange oil. The material was dissolved in DCM (5 mL) and TBAF (2.96 mL of a 1 M solution in THF, 2.96 mmol) was added. The RM was stirred at RT for 60 min. The RM was partitioned between water and MTBE. The layers were separated and washed with water (2x), brine and MTBE. The combined organic layers were dried over MgSO4, filtered and the volatiles were removed under reduced pressure at 50°C to give a yellow oil. The crude product was purified on silica gel (24 g) using an automated purification system (NP; Teledyne ISCO®; collection at 241 / 254 nm; flow rate 35 mL / min, eluent: heptane + 1-15% EtOAc in 21.4 min). Pure fractions were combined and the volatiles were removed under reduced pressure at 50°C to give the title compound as a 55:45 diastereomeric mixture (284 mg). LC-MS method B-1: Rt=1.30 min; MS m / z[M+H] + =378.3.

[0258] Intermediate rac-B-10: (RS)-tert-Butyl 6-(4-(methoxycarbonyl)phenyl)-2-oxa-7-azaspiro[3.5]nonane-7-carboxylate [ka] A solution of tert-butyl 6-(4-(methoxycarbonyl)phenyl)-2-oxa-7-azaspiro[3.5]non-5-ene-7-carboxylate (Intermediate O-7, 236 mg, 0.657 mmol) in EtOH (4 mL) / THF (0.5 mL) was placed under N2 atmosphere. Pd / C (69.9 mg, 10 wt%, 0.066 mmol) was added and the RM was stirred under H2 atmosphere (balloon) for 60 min. The RM was purged with N2 and filtered through Celite®. The catalyst was washed with DCM (3x). The filtrate was evaporated to dryness under reduced pressure at 50°C to give the title compound as a colorless oil (228 mg) that solidified on standing. LC-MS Method B-1: Rt = 1.02 min; MS m / z [M+H] + =362.2.

[0259] Intermediate B-11: Benzyl (S)-2-(4-(methoxycarbonyl)phenyl)-4-methylenepiperidine-1-carboxylate [ka] To a stirred white suspension of methyltriphenylphosphonium iodide (990 mg, 2.45 mmol) in anhydrous THF (5 mL) was added a 1.0 M solution of KOtBu in THF (2.45 mL, 2.45 mmol) at 0 °C, and the resulting yellow mixture was stirred at 0 °C for 30 min. Then a solution of benzyl (S)-2-(4-(methoxycarbonyl)phenyl)-4-oxopiperidine-1-carboxylate (CAS 2408761-20-4, 300 mg, 0.816 mmol) in THF (5 mL) was added to the mixture at 0 °C. The ice bath was removed and the mixture was stirred at RT for 2 h. The mixture was quenched with water (20 mL) and extracted with EtOAc (2 x 25 mL). The combined organic phases were combined, dried over Na2SO4, and concentrated under reduced pressure. The crude residue was purified on silica gel (12 g) using an automated purification system (NP; heptane / EtOAc). The product-containing fractions were combined and concentrated to give the title compound (130 mg) as a sticky yellow solid. LC-MS Method A-1: ​​Rt=1.65 min; MS m / z[M+H] + =366.0.

[0260] Intermediate B-12 and Intermediate B-13: Benzyl (3S,5S)-1,1-difluoro-5-(4-(methoxycarbonyl)phenyl)-6-azaspiro[2.5]octane-6-carboxylate and benzyl (3R,5S)-1,1-difluoro-5-(4-(methoxycarbonyl)phenyl)-6-azaspiro[2.5]octane-6-carboxylate [ka] To a stirred solution of intermediate B-11 (130 mg, 0.355 mmol) in anhydrous THF (1 mL) was added trimethyl(trifluoromethyl)silane (253 mg, 1.778 mmol) and NaI (27 mg, 0.177 mmol) and the mixture was heated at 120° C. for 1 h. The reaction was quenched with water (10 mL) and extracted with EtOAc (2×25 mL). The organic phases were combined, dried over Na2SO4 and the solvent was removed under reduced pressure. The crude mixture of diastereomers was purified on silica gel using an automated purification system (NP; heptane / EtOAc). Pure fractions were combined and the volatiles were removed under reduced pressure to give the title compound (105 mg) as a mixture of approximately 10:1. LC-MS Method A-1: ​​Rt=1.64 min; MS m / z=416.0 [M+H] + .

[0261] Intermediate (+)-B-14(+): tert-Butyl (5S,7R)-2,2-difluoro-7-(4-(methoxycarbonyl)phenyl)-8-azaspiro[4.5]decane-8-carboxylate or tert-Butyl (5R,7R)-2,2-difluoro-7-(4-(methoxycarbonyl)phenyl)-8-azaspiro[4.5]decane-8-carboxylate [ka] and intermediate (-)-B-15(+): tert-Butyl (5S,7S)-2,2-difluoro-7-(4-(methoxycarbonyl)phenyl)-8-azaspiro[4.5]decane-8-carboxylate or tert-Butyl (5R,7S)-2,2-difluoro-7-(4-(methoxycarbonyl)phenyl)-8-azaspiro[4.5]decane-8-carboxylate [ka] Hydrogenation of (+)-tert-butyl 2,2-difluoro-7-(4-(methoxycarbonyl)phenyl)-8-azaspiro[4.5]dec-6-ene-8-carboxylate (intermediate (+)-O-9) gave intermediate (+)-B-14(+) and intermediate (-)-B-15(+):sol. To intermediate (+)-O-9 (510 mg, 1.25 mmol) in THF (10 mL) and EtOH (15 mL) in a Parr pressure bottle was added Pd / C (50 wt% wet form, 66.6 mg, 10 wt%, 0.0626 mmol). Hydrogenation was carried out under H2 atmosphere at 45 psi for 2-3 h. The solid was filtered off and rinsed / washed with EtOH (containing about 5% water). The filtrate was concentrated under reduced pressure and dried under vacuum to give the crude diastereomeric mixture of the title compounds as a white solid. LC-MS Method C-3: Rt=1.28 min; MS m / z [M-tertBu+H]+=354.3.

[0262] Diastereomer separation using SFC chiral separation method. Instrument: Thar 80 preparative SFC; Column: (S,S)Whelk-O1 21×250 mm 5 μm; Flow rate: 80 g / min; Co-solvent: 20% 1:1 MeOH:IPA in CO2; Detection: 270 nm; Backpressure set point: 125 bar; Injection size: 78 mg (15.6 mg / mL in 9:1 MeOH / DCM). Peak 1: Isolation of intermediate (+)-B-14(+): 320 mg. White solid. Method SFC-2: Rt=1.32 min, ee>99%. Specific rotation method OR-1:[α] 25 @589nm=+49.1° (10.914 mg of intermediate (+)-B-14(+) in 1 mL of MeOH). Peak 2: Intermediate (-)-B-15(+) isolated: 146 mg. White solid Method SFC-2: Rt=1.71 min, ee>99%. Specific rotation method OR-1: [α] 25 @589nm=-44.2° (10.696 mg of intermediate (-)-B-15(+) in 1 mL of MeOH).

[0263] Intermediate (+)-B-16(-): tert-Butyl (5S,7R)-2,2-difluoro-7-(4-(methoxycarbonyl)phenyl)-8-azaspiro[4.5]decane-8-carboxylate or tert-Butyl (5R,7R)-2,2-difluoro-7-(4-(methoxycarbonyl)phenyl)-8-azaspiro[4.5]decane-8-carboxylate [ka] and intermediate (-)-B-17(-): tert-Butyl (5S,7S)-2,2-difluoro-7-(4-(methoxycarbonyl)phenyl)-8-azaspiro[4.5]decane-8-carboxylate or tert-Butyl (5R,7S)-2,2-difluoro-7-(4-(methoxycarbonyl)phenyl)-8-azaspiro[4.5]decane-8-carboxylate [ka] Hydrogenation of (-)-tert-butyl 2,2-difluoro-7-(4-(methoxycarbonyl)phenyl)-8-azaspiro[4.5]dec-6-ene-8-carboxylate (intermediate (-)-O-10, 500 mg, 1.23 mmol) was carried out according to the method described for intermediate (+)-O-9 hereinabove to give a mixture of intermediate (+)-B-16(-) and intermediate (-)-B-17(-). LC-MS Method C-3: Rt=1.28 min; MS m / z [M-tertBu+H] + =354.3.

[0264] Diastereomer separation using SFC chiral separation method. Instrument: Thar 80 preparative SFC; Column: (S,S)Whelk-O1 21 x 250 mm 5 μm; Flow rate: 80 g / min; Co-solvent: 25% 1:1 MeOH:IPA in CO2; Detection: 270 nm; Backpressure set point: 125 bar; Injection size: 88.2 mg (14.7 mg / mL in 9:1 MeOH / DCM). Peak 1: Intermediate (+)-B-16(-) isolated: 149 mg. White solid Method SFC-2: Rt=1.30 min, ee>99%. Specific rotation method OR-1: [α] 25 @589nm=+44.5° (8.550 mg of intermediate (+)-B-16(-) in 1 mL of MeOH). Peak 2: Intermediate (-)-B-17(-) isolated: 330 mg. White solid Method SFC-2: Rt=1.73 min / 5.0 min, ee>99%. Specific rotation method OR-1: [α] 25 @589nm=-51.3° (10.230 mg of intermediate (-)-Boc-P-17(-) in 1 mL of MeOH).

[0265] Similar to tert-butyl (S)-2, 2-difluoro-6-(4-(methoxycarbonyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (intermediate (-)-B-8) was prepared, where the Boc-piperidine derivative with negative optical rotation was tentatively assigned to the (S)-configured benzylamine. The Boc-piperidine derivative with positive optical rotation was tentatively assigned to the (R)-configured benzylamine.

[0266] Intermediate rac-B-18: (RS)-tert-Butyl 2,2-difluoro-6-(4-(3-hydroxyoxetan-3-yl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate [ka] A solution of tert-butyl 2,2-difluoro-6-(4-(3-hydroxyoxetan-3-yl)phenyl)-7-azaspiro[3.5]non-5-ene-7-carboxylate (Intermediate O-11, 480 mg, 83 wt%, 978 μmol) in EtOH (10 mL) and THF (0.5 mL) was placed under a N2 atmosphere. Pd / C (104.1 mg, 10 wt%, 97.78 μmol) was added and the RM was then stirred under a H2 atmosphere (balloon) for 60 min. The RM was purged with N2 and filtered through Celite®. The catalyst was washed with DCM (3×). The volatiles of the filtrate were removed under reduced pressure at 50° C. to give a colorless oil. The crude product was purified on silica gel (24 g) using an automated purification system (NP; Teledyne ISCO®; 238 / 221 collection followed by 354 nm + ELSD detector; flow rate 35 mL / min; eluent: heptane + 5-24% (EtOAc:MeOH 95:5) in 22.1 min). Fractions were combined and volatiles were removed under reduced pressure at 50° C. to give the title compound as a colorless oil (370 mg). LC-MS Method B-1: Rt=1.12 min. MS m / z[M+H] + =410.4, [M-tertBu+H] + =354.3.

[0267] Intermediate rac-B-19: (RS)-tert-Butyl 2,2-difluoro-6-(4-(2-hydroxypropan-2-yl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate [ka] A solution of tert-butyl 2,2-difluoro-6-(4-(2-hydroxypropan-2-yl)phenyl)-7-azaspiro[3.5]non-5-ene-7-carboxylate (Intermediate O-12, 344.0 mg, 874.3 μmol) in EtOH (10.0 mL) and THF (0.50 mL) was placed under a N2 atmosphere. Pd / C (93.04 mg, 10 wt%, 87.43 μmol) was added and the RM was then stirred under a H2 atmosphere (balloon) for 60 min.

[0268] The RM was purged with N2 and filtered through Celite®. The catalyst was washed three times with DCM. The filtrate's volatiles were removed under reduced pressure at 50° C. to give a colorless oil, which was purified on silica gel (12 g) using an automated purification system (NP; Teledyne ISCO®; collection at 235 / 256 nm + ELSD detector used; flow rate 30 mL / min; eluent: heptane + 2-22.6% EtOAc in 17.9 min). Pure fractions were combined and volatiles were removed under reduced pressure at 50° C. to give the title compound (258 mg) as a colorless oil. LC-MS Method B-1: Rt=1.24 min; MS m / z [M-tertBu-H2O+H]+=322.3.

[0269] Intermediate rac-B-20: (RS)-tert-Butyl 6-(4-(1H-pyrazol-5-yl)phenyl)-2,2-difluoro-7-azaspiro[3.5]nonane-7-carboxylate [ka] A solution of tert-butyl 6-(4-(1H-pyrazol-1-yl)phenyl)-2,2-difluoro-7-azaspiro[3.5]non-5-ene-7-carboxylate (Intermediate O-13, 293.0 mg, 83 wt%, 605.8 μmol) in EtOH (7.0 mL) was placed under N2 atmosphere. Pd / C (64.47 mg, 10 wt%, 60.58 μmol) was added and the RM was then stirred under H2 atmosphere (balloon) for 75 min, and more Pd / C (65 mg, 10 wt%) was added. Stirring was continued for another 4 h. The RM was purged with N2 and filtered through Celite®. The solids were rinsed with DCM (3×). The filtrate volatiles were removed under reduced pressure at 50° C. to give a colorless oil, which was treated with hexanes. The volatiles were removed under reduced pressure at 50° C. to give a yellow oil. The crude product was purified on silica gel (12 g) using an automated purification system (NP; Teledyne ISCO®; collection at 257 / 280 nm; flow rate 30 mL / min; eluent: heptane + 5 to 34.7% EtOAc in 20.4 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 (249 mg). LC-MS Method B-1: Rt=1.24 min; MS m / z [M+H] + =404.2, [M-tertBu+H] + =348.2.

[0270] Intermediate rac-B-21: (RS)-tert-Butyl 6-(4-(1H-pyrazol-1-yl)phenyl)-2,2-difluoro-7-azaspiro[3.5]nonane-7-carboxylate [ka] A solution of tert-butyl 6-(4-(1H-pyrazol-1-yl)phenyl)-2,2-difluoro-7-azaspiro[3.5]non-5-ene-7-carboxylate (Intermediate O-14, 233.0 mg, 580.4 μmol) in EtOH (7.0 mL) was placed under N2 atmosphere. Pd / C (61.76 mg, 10 wt%, 58.04 μmol) was added and the RM was then stirred under H2 atmosphere (balloon) for 75 min. The RM was purged with N2 and filtered through Celite®. The solid was rinsed with DCM (3×) and the filtrate volatiles were removed under reduced pressure at 50° C. The resulting crude oil was treated with hexane and the solvent was removed again to give the title compound as a white solid (370 mg). LC-MS method B-1: Rt=1.28 min; MS m / z[M-tertBu+H]+=348.3.

[0271] Intermediate rac-B-22: (RS)-tert-Butyl 6-(4-cyanophenyl)-2,2-difluoro-7-azaspiro[3.5]nonane-7-carboxylate [ka] A solution of tert-butyl 6-(4-cyanophenyl)-2,2-difluoro-7-azaspiro[3.5]non-5-ene-7-carboxylate (Intermediate O-15, 335.0 mg, 929.5 μmol) in EtOAc (15.0 mL) was placed under N2 atmosphere. Pd / C (98.92 mg, 10 wt%, 92.95 μmol) was added and the RM was then stirred under H2 atmosphere (balloon) for 60 min. The RM was purged with N2, filtered through Celite®, and the solids were rinsed with DCM (3×). The volatiles of the filtrate were removed under reduced pressure at 50° C. to give a colorless oil, which was purified on silica gel (12 g) using an automated purification system (NP; Teledyne ISCO®; collection at 245 / 254 nm; flow rate 30 mL / min; eluent: heptane + 5-19% EtOAc in 11.2 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 (259 mg). LC-MS Method B-1: Rt=1.24 min; MS m / z [M-Boc+H] + =263.3.

[0272] Intermediate rac-B-23: (RS)-tert-Butyl 2,2-difluoro-6-phenyl-7-azaspiro[3.5]nonane-7-carboxylate [ka] A solution of tert-butyl 2,2-difluoro-6-phenyl-7-azaspiro[3.5]non-5-ene-7-carboxylate (Intermediate O-16, 274.0 mg, 817.0 μmol) in EtOH (7.0 mL) was placed under N2 atmosphere. Pd / C (86.94 mg, 10 wt%, 81.70 μmol) was added and the RM was then stirred under H2 atmosphere (balloon) for 90 min. The RM was purged with N2 and filtered through Celite®. The solids were rinsed with DCM (3×). The filtrate's volatiles were removed under reduced pressure at 50° C. to give a colorless oil, which was triturated with hexanes and dried. The crude product was purified on silica gel (12 g) using an automated purification system (NP; Teledyne ISCO®; collection at 254 nm + ELSD detector; flow rate 30 mL / min; eluent: heptane + 0-7.4% EtOAc in 12.3 min). Pure fractions were combined and volatiles were removed under reduced pressure at 50° C. to give the title compound as a colorless oil (242 mg). LC-MS Method B-1: Rt=1.44 min; MS m / z [M+H] + =338.3.

[0273] Intermediate rac-B-24: (RS)-tert-Butyl 2,2-difluoro-6-(1-methyl-1H-pyrazol-4-yl)-7-azaspiro[3.5]nonane-7-carboxylate [ka] A solution of tert-butyl 2,2-difluoro-6-(1-methyl-1H-pyrazol-4-yl)-7-azaspiro[3.5]non-5-ene-7-carboxylate (Intermediate O-17, 137.0 mg, 403.7 μmol) in EtOH (5.0 mL) was placed under N2 atmosphere. Pd / C (42.96 mg, 10 wt%, 40.37 μmol) was added and the RM was then stirred under H2 atmosphere (balloon) overnight, the RM was purged with N2 and filtered through Celite®. The solid was rinsed with EtOH (3×). The filtrate volatiles were removed under reduced pressure at 50° C. to give a grey oil. The residue was dissolved in EtOH (4 mL), placed under N2 atmosphere and Pd / C (80 mg, 10 wt%) was added. The RM was then stirred under H2 atmosphere (balloon) for 24 h. The RM was purged with N2 and filtered through Celite®. The solids were rinsed with DCM (3x). The filtrate's volatiles were removed under reduced pressure at 50°C. The residue was treated with hexanes and the volatiles were removed under reduced pressure at 50°C to give a colorless oil, which was purified on silica gel (12 g) using an automated purification system (NP; Teledyne ISCO®; collection at 257 / 280 nm; flow rate 30 mL / min; eluent: heptane + 10-90% EtOAc in 33.3 min). Pure fractions were combined, the volatiles were removed under reduced pressure at 50°C, treated with hexanes / DCM, and the solvent was removed again at 50°C to give the title compound as a colorless oil. LC-MS Method B-1: Rt=1.08 min; MS m / z [M+H] + =342.4.

[0274] Intermediate rac-B-25: tert-Butyl (RS)-6-(6-bromopyridin-3-yl)-2,2-difluoro-7-azaspiro[3.5]nonane-7-carboxylate [ka] Step 1: tert-Butyl (2-(1-(2-(6-bromopyridin-3-yl)-2-oxoethyl)-3,3-difluoro-cyclobutyl)ethyl)carbamate (intermediate rac-B-25-1) [ka] A solution of 2-bromo-5-iodopyridine (3.403 g, 11.99 mmol) in THF (30.0 mL) was evacuated / backfilled with N2 twice and cooled to -30 °C. A solution of isopropylmagnesium chloride lithium chloride complex in THF (1.30 M, 9.40 mL, 12.26 mmol) was added dropwise, and then the RM was stirred at -30 °C to -25 °C for 90 min. In a separate flask, tert-butyl 2,2-difluoro-6-oxo-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate O-2-2, 1.50 g, 5.45 mmol) was dissolved in THF (15.0 mL), evacuated and backfilled with N2 twice, and cooled to -78 °C. The freshly prepared Grignard solution described above was added via cannula using positive pressure of N2. The resulting yellow solution was stirred at -78°C for 20 min. The temperature was raised to -25°C, and then the RM was added to a well-stirred mixture of aqueous NH4Cl (10 wt%) and TBME. The layers were separated and washed with brine and TBME. The combined organic layers were dried over MgSO4, filtered, and the volatiles were removed under reduced pressure at 50°C. The residue was purified on silica gel (80 g) using an automated purification system (NP; Teledyne ISCO®; collection at 245 / 275 nm; flow rate 60 mL / min; eluent: heptane + 5-30% EtOAc in 27.4 min). Pure fractions were combined and the volatiles were removed under reduced pressure at 50°C to give the title compound (1.88 g) as a yellow oil. LC-MS Method B-6: Rt = 1.23 min; MS m / z [MH] - =430.9 / 433.0.

[0275] Step 2: 6-(6-bromopyridin-3-yl)-2,2-difluoro-7-azaspiro[3.5]nonane (intermediate rac-B-25-2) [ka] TFA (9.0 mL) was added to a solution of tert-butyl (2-(1-(2-(6-bromopyridin-3-yl)-2-oxoethyl)-3,3-difluoro-cyclobutyl)ethyl)carbamate (intermediate rac-B-25-1, 1.880 g, 87.5 wt%, 3.797 mmol) in DCM (27.0 mL). The RM was stirred at RT for 1 h. Volatiles were removed under reduced pressure at 50 °C. The residue was partitioned between DCM and saturated aqueous NaHCO3. The separated aqueous layer was washed twice with DCM. The combined organic layers were dried over MgSO4, filtered, and volatiles were removed under reduced pressure at 50 °C. The residue was dissolved in EtOH (15.0 mL) and the resulting solution was cooled to 0-5 °C. NaBH4 (287.2 mg, 7.593 mmol) was added in two portions over 10 min. The RM was stirred in an ice bath for an additional 50 min. The RM was carefully poured into a well-stirred mixture of EtOAc and water. The separated layers were washed with saturated aqueous NaHCO3, brine and EtOAc. The combined organic layers were dried over MgSO4, filtered and the volatiles were removed under reduced pressure at 50 °C. The residue was dissolved in DCM and purified on silica gel (40 g) using an automated purification system (NP; Teledyne ISCO®; collection at 254 / 268 nm; flow rate 40 mL / min; eluent: heptane + 10 to 77.5% {EtOAc / MeOH = 95 / 5} in 18.8 min). Pure fractions were combined and the volatiles were removed under reduced pressure at 50 °C to give the title compound (1.02 g) as white crystals. LC-MS Method B-6: Rt = 0.31 min; MS m / z [M+H] + =317.0 / 318.9.

[0276] Step 3: tert-Butyl 6-(6-bromopyridin-3-yl)-2,2-difluoro-7-azaspiro[3.5]nonane-7-carboxylate (intermediate rac-B-25) Triethylamine (493.1 mg, 679 μL, 4.873 mmol) and di-tert-butyl dicarbonate (930.6 mg, 4.264 mmol) were added to a solution of 6-(6-bromopyridin-3-yl)-2,2-difluoro-7-azaspiro[3.5]nonane (intermediate rac-B-25-2, 966.0 mg, 3.046 mmol) in DCM (10.0 mL) and the RM was stirred overnight. Volatiles were removed under reduced pressure at 50 °C to give a yellow oil, which was purified on silica gel (40 g) using an automated purification system (NP; Teledyne ISCO®; collection at 254 / 272 nm; flow rate 40 mL / min; eluent: heptane + 3.0 to 20.4% EtOAc in 18.3 min). Pure fractions were combined and the volatiles removed under reduced pressure at 50° C. to give the title compound (1.27 g) as a colorless oil. LC-MS Method B-6: Rt=1.30 min; MS m / z[M+H] + =417.0 / 419.1.

[0277] Intermediate rac-B-26: tert-Butyl (RS)-6-(6-cyanopyridin-3-yl)-2,2-difluoro-7-azaspiro[3.5]nonane-7-carboxylate [ka] A mixture of tert-butyl 6-(6-bromopyridin-3-yl)-2,2-difluoro-7-azaspiro[3.5]nonane-7-carboxylate (intermediate rac-B-25, 300 mg, 718.9 μmol), Zn(CN)2 (50.65 mg, 431.4 μmol), zinc powder (5.640 mg, 1.231 μL, 86.27 μmol) and dppf (15.94 mg, 28.76 μmol) in DMA (2.3 mL) was placed in a vial and evacuated / backfilled with N2 twice. Pd2(dba)3 (12.99 mg, 14.38 μmol) was added and the mixture was again evacuated / backfilled with N2. The capped vial was stirred at 105 °C for 70 min. The RM was cooled to RT and partitioned between TBME and water. The layers were separated and washed with water, brine and TBME. The combined organic layers were dried over MgSO4, filtered and the volatiles were removed under reduced pressure at 50°C. The residue was purified on silica gel (24 g) using an automated purification system (NP; Teledyne ISCO®; collection at 245 / 270 nm; flow rate 35 mL / min; eluent: heptane + 5-30% EtOAc in 17.8 min). Pure fractions were combined and the volatiles were removed under reduced pressure at 50°C to give the title compound (250 mg) as a colorless oil. LC-MS Method B-6: Rt = 1.10 min; MS m / z [M+H] + =364.1.

[0278] Intermediate rac-B-27: tert-Butyl (RS)-2,2-difluoro-6-(6-(methoxycarbonyl)pyridin-3-yl)-7-azaspiro[3.5]nonane-7-carboxylate [ka] A mixture of tert-butyl 6-(6-bromopyridin-3-yl)-2,2-difluoro-7-azaspiro[3.5]nonane-7-carboxylate (intermediate rac-B-25, 504.0 mg, 1.208 mmol), carbon monoxide-molybdenum (6:1; 318.9 mg, 1.208 mmol) and tri-tert-butylphosphonium tetrafluoroborate (70.08 mg, 241.6 μmol) in ACN (4.90 mL) and MeOH (1.23 mL) was placed in a vial and evacuated / backfilled with N twice. trans-Bis(acetato)bis[2-[bis(2-methylphenyl)phosphino]benzyl]dipalladium(II) (56.62 mg, 60.39 μmol) and DBU (275.8 mg, 273.1 μL, 1.812 mmol) were added and the mixture was again evacuated / backfilled with N2. The capped vial was heated at 75 °C for 21 h, then stirring was continued at RT for about 2 days. The RM was partitioned between TBME and water, the layers were separated and washed with water, brine and TBME. The combined organic layers were dried over MgSO4, filtered and the volatiles were removed under reduced pressure at 50 °C. The residue was purified on silica gel (24 g) using an automated purification system (NP; Teledyne ISCO®; collection at 245 / 270 nm; flow rate 35 mL / min; eluent: heptane + 10-50% EtOAc in 21.7 min). Pure fractions were combined and the volatiles were removed under reduced pressure at 50° C. to give the title compound (345.0 mg) as an off-white solid. LC-MS Method B-6: Rt=1.08 min; MS m / z[M+H] + =397.2.

[0279] Intermediate rac-P-1 and intermediate rac-P-2: Methyl 4-(2-hydroxy-2-methyl-7-azaspiro[3.5]nonan-6-yl)benzoate (Separation of racemic diastereomers; a mixture of two of each of two stereoisomers) [ka] tert-Butyl 2-hydroxy-6-(4-(methoxycarbonyl)phenyl)-2-methyl-7-azaspiro[3.5]nonane-7-carboxylate (intermediate ds-rac-B-4, 400 mg, 1.03 mmol) was dissolved in 4M HCl in dioxane (5 mL). The RM was stirred at RT for 50 min and then poured into a well-stirred mixture of 4M aqueous NaOH (5.5 mL), ice and DCM. The layers were separated and the aqueous layer was washed with DCM (3x). The combined organic layers were dried over K2CO3, filtered and the volatiles were removed under reduced pressure at 50 °C. The crude product was purified on silica gel (24 g) using an automated purification system (NP; Teledyne ISCO®; collection at 235 / 254 nm; flow rate 35 mL / min; eluent: DCM+0-7.6 (MeOH:NH4OH in water 25% 9:1) in 21.4 min). Pure fractions of the separated racemic diastereomers were combined and the volatiles removed under reduced pressure at 50 °C to give the title compound: The intermediate rac-P-1 was obtained as a white solid (62 mg) which eluted first from the column. LC-MS Method B-4: Rt=0.59 min; MS m / z[M+H] + =290.1. The second intermediate to elute from the column, rac-P-2, was obtained as a white solid (144 mg). LC-MS Method B-4: Rt=0.75 min; MS m / z[M+H] + =290.1.

[0280] Intermediate rac-P-3 and intermediate rac-P-4: Methyl 4-(2-fluoro-2-methyl-7-azaspiro[3.5]nonan-6-yl)benzoate (Separation of racemic diastereomers; a mixture of two of each of two stereoisomers) [ka] TFA (1.5 mL) was added to a solution of tert-butyl 2-fluoro-6-(4-(methoxycarbonyl)phenyl)-2-methyl-7-azaspiro[3.5]nonane-7-carboxylate (intermediate ds-rac-B-5, 535 mg, 1.37 mmol) in DCM (4.5 mL). The RM was stirred at RT for 45 min, diluted with DCE and the volatiles were removed under reduced pressure at 50 °C. The residue was partitioned between DCM and aqueous Na2CO3 (10 wt%), the layers were separated and the aqueous layer was washed with DCM (2x). The combined organic layers were dried over K2CO3, filtered and the volatiles were removed under reduced pressure at 50 °C to give a yellow oil. The crude product was purified on silica gel (24 g) using an automated purification system (NP; Teledyne ISCO®; collection at 235 / 254 nm; flow rate 35 mL / min; eluent: heptane + 25-80% (EtOAc:MeOH 95:5) in 25 min). Pure fractions of the separated racemic diastereomers were combined and the volatiles removed under reduced pressure at 50° C. to give the title compound: The intermediate rac-P-3 was the first to elute from the column as a slightly yellow oil (119 mg). LC-MS Method B-4: Rt=0.82 min; MS m / z[M+H] + =292.2. The intermediate rac-P-4, which was the second to elute from the column, was obtained as a white solid (227 mg). LC-MS Method B-4: Rt = 0.86 min; MS m / z [M+H] + =292.2.

[0281] Intermediate rac-P-5: (RS)-Methyl 4-(2,2-difluoro-7-azaspiro[3.5]nonan-6-yl)benzoate [ka] TFA (3 mL) was added to a solution of tert-butyl 2,2-difluoro-6-(4-(methoxycarbonyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (intermediate rac-B-6, 917 mg, 2.32 mmol) in DCM (9 mL). The RM was stirred at RT for 30 min and then diluted with DCE. Volatiles were removed under reduced pressure. The residue was partitioned between DCM and saturated aqueous NaHCO3. The separated aqueous layer was extracted with DCM (3x) and the combined organic layers were dried over Na2SO4, filtered off and concentrated under reduced pressure. The residue was dissolved in hexane and concentrated under reduced pressure at 50°C to give the title compound (684 mg) as a colorless solid, which was used directly without further purification. LC-MS Method B-1: Rt = 0.47 min; MS m / z [M+H] + =296.3.

[0282] Intermediate P-6: Methyl (S)-4-(2,2-difluoro-7-azaspiro[3.5]nonan-6-yl)benzoate [ka] TFA (70.7 mL) was added to a solution of tert-butyl (S)-2,2-difluoro-6-(4-(methoxycarbonyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate (-)-B-8, 20.8 g, 52.6 mmol) in DCM (212 mL). The RM was stirred at RT for 60 min. Volatiles were removed under reduced pressure at 50 °C. The residue was dissolved in DCM and saturated NaHCO3 solution was added portionwise to the well-stirred mixture.

[0283] The layers were separated and the aqueous layer was washed with DCM (3x). The combined organic layers were dried over Na2SO4, filtered and the volatiles were removed under reduced pressure at 50° to give a viscous dark yellow solid, which was purified on silica gel (220 g) using an automated purification system (NP; Teledyne ISCO®; collection at 234 / 254 nm; flow rate 150 mL / min; eluent: DCM+0-8% MeOH in 33.7 min). Pure fractions were combined, the volatiles removed under reduced pressure at 50°, triturated with DCM / hexanes and the solvent removed again under reduced pressure at 50° to give the title compound (12.79 g) as a pale yellow solid. LC-MS Method B-1: Rt=0.45 min; MS m / z[M+H] + =296.3.

[0284] Intermediate rac-P-7 and intermediate rac-P-8: Methyl 4-(2-fluoro-7-azaspiro[3.5]nonan-6-yl)benzoate (Separation of racemic diastereomers; a mixture of two of each of two stereoisomers) [ka] TFA (1 mL) was added to a solution of tert-butyl 2-fluoro-6-(4-(methoxycarbonyl)phenyl)-7-azaspiro-[3.5]nonane-7-carboxylate (intermediate ds-rac-B-9, 370 mg, 980 μmol) in DCM (3 mL). The RM was stirred at RT for 30 min, diluted with DCE and the volatiles were removed under reduced pressure at 50 °C. The residue was partitioned between DCM and aqueous Na2CO3 (10 wt%). The layers were separated and the aqueous layer was washed with DCM (2x). The combined organic layers were dried over K2CO3, filtered and the volatiles removed under reduced pressure at 50°C to give a yellow oil which was purified on silica gel (24 g) using an automated purification system (NP; Teledyne ISCO®; collection at 235 / 254 nm; flow rate 35 mL / min; eluent: heptane + 25-77.3% (EtOAc:MeOH / 95:5) in 22.6 min). Pure fractions of the separated racemic diastereomers were combined and the volatiles removed under reduced pressure at 50°C to give the title compound: The intermediate rac-P-7 was the first to elute from the column, afforded as a colorless oil (112 mg). LC-MS Method B-1: Rt=0.34 min; MS m / z[M+H] + =278.2. Intermediate rac-P-8 elutes second from the column as a slightly yellow oil (139 mg). LC-MS Method B-1: Rt=0.44 min; MS m / z[M+H] + =278.3.

[0285] Intermediate rac-P-9: (RS) 4-(2-oxa-7-azaspiro[3.5]nonan-6-yl)benzoate [ka] TFA (0.6 mL) was added to a solution of tert-butyl 6-(4-(methoxycarbonyl)phenyl)-2-oxa-7-azaspiro[3.5]nonane-7-carboxylate (intermediate rac-B-10, 226 mg, 0.625 mmol) in DCM (1.8 mL) and the RM was stirred for 50 min. The RM was diluted with DCE and evaporated to dryness. The residue was partitioned between DCM and saturated aqueous NaHCO3; the layers were separated and the aqueous layer was washed with DCM (3x). The combined organic layers were dried over Na2SO4, filtered and the volatiles were removed under reduced pressure at 50 °C to give an amber oil which was dissolved and purified by preparative TLC (MERCK 1.05744.0001, PLC silica gel 60 F254, 0.5 mm; eluent: DCM / (MeOH:NH4OH 25% 9:1) 88 / 12. The main band was scraped off the plate. The silica gel / compound mixture was suspended in DCM / (MeOH:NH4OH 25% 9:1) 85 / 15, sonicated and filtered. The residue was washed with DCM / (MeOH:NH4OH 25% 9:1) 85 / 15. The volatiles of the filtrate were removed under reduced pressure at 50 °C to give the title compound as a white fluffy solid (153 mg). LC-MS Method B-5: Rt = 0.47 min; MS m / z [M+H] + =262.1.

[0286] Intermediate P-10: Methyl 4-((5S,7R)-2,2-difluoro-8-azaspiro[4.5]decan-7-yl)benzoate or methyl 4-((5R,7R)-2,2-difluoro-8-azaspiro[4.5]decan-7-yl)benzoate [ka] Intermediate P-10 as its HCl salt was prepared according to the method described for Intermediate P-11 herein below using Intermediate (+)-B-14(+). LC-MS Method C-1: Rt=1.02 min; MS m / z [M+H] + =310.1.

[0287] Intermediate P-11: Methyl 4-((5S,7S)-2,2-difluoro-8-azaspiro[4.5]decan-7-yl)benzoate or methyl 4-((5R,7S)-2,2-difluoro-8-azaspiro[4.5]decan-7-yl)benzoate [ka] To intermediate (-)-B-15(+) (65 mg, 0.159 mmol) in 1,4-dioxane (0.5 mL) was slowly added HCl solution (4 M in 1,4-dioxane, 0.79 mL, 3.18 mmol). The mixture was stirred for about 2-3 h and then concentrated under reduced pressure. The residue was kept under reduced pressure overnight to give the crude title compound as its HCl salt as a white solid, which was used directly in the next step without further purification. LC-MS Method C-1: Rt=1.03 min; MS m / z[M+H] + =310.1.

[0288] Intermediate P-12: Methyl 4-((5S,7R)-2,2-difluoro-8-azaspiro[4.5]decan-7-yl)benzoate or methyl 4-((5R,7R)-2,2-difluoro-8-azaspiro[4.5]decan-7-yl)benzoate [ka] Intermediate P-12 as its HCl salt was prepared according to the method described for Intermediate P-11 hereinabove using Intermediate (+)-B-16(-). LC-MS Method C-1: Rt=1.03 min; MS m / z[M+H] + =310.1.

[0289] Intermediate P-13: Methyl 4-((5S,7S)-2,2-difluoro-8-azaspiro[4.5]decan-7-yl)benzoate or methyl 4-((5R,7S)-2,2-difluoro-8-azaspiro[4.5]decan-7-yl)benzoate [ka] Intermediate P-13 as its HCl salt was prepared according to the method described for Intermediate P-11 hereinabove using Intermediate (-)-B-17(-). LC-MS Method C-1: Rt=1.02 min; MS m / z[M+H] + =310.1.

[0290] Intermediate rac-P-14: (RS)-3-(4-(2,2-difluoro-7-azaspiro[3.5]nonan-6-yl)phenyl)oxetan-3-ol [ka] TFA (1.50 mL) was added to a solution of tert-butyl 2,2-difluoro-6-(4-(3-hydroxyoxetan-3-yl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (intermediate rac-B-18, 370.0 mg, 903.6 μmol) in DCM (6.0 mL). The RM was stirred at RT for 15 min. The RM was poured into a well-stirred aqueous Na2CO3 solution (10 wt%), the layers were separated, and the aqueous layer was washed with DCM (3×). The combined organic layers were dried over K2CO3, filtered, and the volatiles were removed under reduced pressure at 50 °C to give an off-white solid, which was purified on silica gel (12 g) using an automated purification system (NP; Teledyne ISCO®); collection at 218 / 262 nm + ELSD detector; flow rate 30 mL / min; eluent: DCM + 0-9.1 (EtOH:NH4OH 25% 9:1), 18.1 min. Pure fractions were combined and the volatiles were removed under reduced pressure at 50 °C to give the title compound as a white solid (235 mg). LC-MS Method B-1: Rt = 0.21 min; MS m / z [M+H] + =310.3.

[0291] Intermediate rac-P-15: (RS)-2-(4-(2,2-difluoro-7-azaspiro[3.5]nonan-6-yl)phenyl)propan-2-ol [ka] tert-Butyl 2,2-difluoro-6-(4-(2-hydroxypropan-2-yl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (intermediate rac-B-19, 256.0 mg, 647.3 μmol) was dissolved in 4 M HCl in dioxane (3.0 mL). The RM was stirred at RT for 15 min. The RM was poured into a well-stirred emulsion of water and DCM. The mixture was then carefully basified with solid Na2CO3 and the layers were separated. The aqueous layer was washed with DCM (3×). The combined organic layers were dried over K2CO3, filtered, and the volatiles were removed under reduced pressure at 50 °C to give a yellow oil, which was purified on silica gel (12 g) using an automated purification system (NP; Teledyne ISCO®; collection at 220 / 254 nm; flow rate 30 mL / min; eluent: DCM+0-9.9% (EtOH:NH4OH 25% 9:1) in 19.7 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 (149 mg). LC-MS Method B-1: Rt = 0.39 min; MS m / z [M+H] + =296.2.

[0292] Intermediate rac-P-16: (RS)-6-(4-(1H-pyrazol-5-yl)phenyl)-2,2-difluoro-7-azaspiro[3.5]nonane [ka] TFA (1.0 mL) was added to a solution of tert-butyl 6-(4-(1H-pyrazol-5-yl)phenyl)-2,2-difluoro-7-azaspiro[3.5]nonane-7-carboxylate (intermediate rac-B-20, 249.0 mg, ca. 95 wt%, 586.3 μmol) in DCM (3.0 mL). The RM was stirred at RT for 15 min and then poured into a well-stirred aqueous Na2CO3 solution (10 wt%). The layers were separated and the aqueous layer was washed with DCM (3×). The combined organic layers were dried over K2CO3, filtered, and the volatiles were removed under reduced pressure at 50 °C to give a colorless oil, which was purified on silica gel (12 g) using an automated purification system (NP; Teledyne ISCO®; collection at 254 / 280 nm; flow rate 30 mL / min; eluent: DCM+0-12.3% (EtOH:NH4OH 25% 9:1) in 17.3 min). Pure fractions were combined and the volatiles were removed under reduced pressure at 50 °C to give the title compound as a white foam (163 mg). LC-MS Method B-1: Rt = 0.42 min; MS m / z [M+H] + =304.2.

[0293] Intermediate rac-P-17: (RS)-6-(4-(1H-pyrazol-1-yl)phenyl)-2,2-difluoro-7-azaspiro[3.5]nonane [ka] TFA (1.0 mL) was added to a solution of tert-butyl 6-(4-(1H-pyrazol-1-yl)phenyl)-2,2-difluoro-7-azaspiro[3.5]nonane-7-carboxylate (intermediate rac-B-21, 226.0 mg, 560.1 μmol) in DCM (3.0 mL). The RM was stirred at RT for 30 min and then poured into a well-stirred aqueous Na2CO3 solution (10 wt%). The layers were separated and the aqueous layer was washed with DCM (3×). The combined organic layers were dried over K2CO3, filtered, and the volatiles were removed under reduced pressure at 50 °C to give a colorless oil, which was purified on silica gel (12 g) using an automated purification system (NP; Teledyne ISCO®; collection at 256 / 280 nm; flow rate 30 mL / min; eluent: DCM+0-10% (EtOH:NH4OH 25% 9:1) in 10 min). Pure fractions were combined and the volatiles were removed under reduced pressure at 50 °C to give the title compound as a white solid (159 mg). LC-MS Method B-1: Rt=0.46 min; MS m / z [M+H] + =304.3.

[0294] Intermediate rac-P-18: (RS)-4-(2,2-difluoro-7-azaspiro[3.5]nonan-6-yl)benzonitrile [ka] TFA (1.0 mL) was added to a solution of tert-butyl 6-(4-cyanophenyl)-2,2-difluoro-7-azaspiro[3.5]nonane-7-carboxylate (intermediate rac-B-22, 276.0 mg, 95 wt%, 723.5 μmol) in DCM (3.0 mL). The RM was stirred at RT for 30 min. The RM was poured into a well-stirred aqueous solution of Na2CO3 (10 wt%). The layers were then separated and the aqueous layer was washed with DCM (3×). The combined organic layers were dried over K2CO3, filtered, and the volatiles were removed under reduced pressure at 50° C., triturated with DCM / hexanes, and the solvent was removed again under reduced pressure at 50° C. to give the title compound as a white solid (188 mg). LC-MS Method B-1: Rt=0.27 min; MS m / z [M+H] +=263.1.

[0295] Intermediate rac-P-19: (RS)-2,2-Difluoro-6-phenyl-7-azaspiro[3.5]nonane [ka] TFA (0.75 mL) was added to a solution of tert-butyl 2,2-difluoro-6-phenyl-7-azaspiro[3.5]nonane-7-carboxylate (intermediate rac-B-23, 242.0 mg, 95 wt%, 681.4 μmol) in DCM (2.25 mL). The RM was stirred at RT for 30 min and then poured into a well-stirred aqueous Na2CO3 solution (10 wt%). The layers were then separated and the aqueous layer was washed with DCM (3×). The combined organic layers were dried over K2CO3, filtered, and the volatiles were removed under reduced pressure at 50 °C to give a colorless oil, which was purified on silica gel (12 g) using an automated purification system (NP; Teledyne ISCO®; collected at 215 / 254 nm, but all fractions were collected due to low UV activity; flow rate 30 mL / min; eluent: DCM+0-6.6% (EtOH:NH4OH 25% 9:1) in 9.9 min). Pure fractions were combined, the volatiles removed under reduced pressure at 50 °C, treated with hexane, and the solvent removed again under reduced pressure at 50 °C to give the title compound as a pale yellow liquid (137 mg). LC-MS Method B-1: Rt = 0.28 min; MS m / z [M+H] + =238.3.

[0296] Intermediate rac-P-20: (RS)-2,2-Difluoro-6-(1-methyl-1H-pyrazol-4-yl)-7-azaspiro[3.5]nonane [ka] TFA (0.50 mL) was added to a solution of tert-butyl 2,2-difluoro-6-(1-methyl-1H-pyrazol-4-yl)-7-azaspiro[3.5]nonane-7-carboxylate (intermediate rac-B-24, 127.0 mg, 372.0 μmol) in DCM (1.5 mL). The RM was stirred at RT for 40 min. The RM was poured into a well-stirred aqueous solution of Na2CO3 (10 wt%). The layers were then separated and the aqueous layer was washed with DCM (3×). The combined organic layers were dried over K2CO3, filtered and the volatiles were removed under reduced pressure at 50° C. to give the title compound as a pale yellow oil (90 mg), which was used in the next step without further purification. 1 H NMR(400MHz,DMSO-d6)δ[ppm]7.51(s,1H),7.30(s,1H),3.76(s,3H),3.44(dd,J=11.4,2 .5Hz,1H),2.88(m,1H),2.61-2.51(m,1H),2.48-2.36(m,2H),2.30(m,2H),2.12-2.02(br s,1H),1.78-1.72(m,1H),1.58-1.41(m,3H).

[0297] The following intermediates rac-P 21 to rac-P-26 were synthesized from intermediate O-3 and the appropriate aryl-bromide by applying the synthetic sequence of coupling, catalytic hydrogenation and Boc deprotection using methods similar to those described for the above intermediates.

[0298] Intermediate rac-P-21: (RS)-6-(1-(difluoromethyl)-1H-pyrazol-4-yl)-2,2-difluoro-7-azaspiro[3.5]nonane [ka] LC-MS method B-7: Rt=1.26 min; MS m / z[M+H] + =278.1.

[0299] Intermediate rac-P-22: (RS)-2,2-Difluoro-6-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)-7-azaspiro[3.5]nonane [ka] 1 H NMR(400MHz,DMSO-d6)δ[ppm]7.54(s,1H),7.34(s,1H),4.17(t,J=5.4Hz,2H),3.64(t,J=5.4Hz,2H),3.45(d,J=11.3Hz,1H),3.21(s,3 H),2.92-2.85(m,1H),2.61-2.51(m,1H),2.49-2.36(m,2H),2.37-2.26(m,2H),2.06(s,1H),1.76(d,J=12.6Hz,1H),1.58-1.41(m,3H).

[0300] Intermediate rac-P-23: Ethyl (RS)-2-(4-(2,2-difluoro-7-azaspiro[3.5]nonan-6-yl)-1H-pyrazol-1-yl)acetate [ka] 1 H NMR(400MHz,DMSO-d6)δ[ppm]7.59(s,1H),7.40(s,1H),4.98(s,2H),4.17-4.09(m,2H),3.53(dd,J=11.4,2.6Hz,1H),2.99-2.8 8(m,2H),2.64-2.56(m,1H),2.48-2.38(m,2H),2.37-2.29(m,2H),1.83-1.76(m,1H),1.58-1.51(m,2H),1.20(t,J=7.1Hz,4H).

[0301] Intermediate rac-P-24: (RS)-6-(4-(difluoromethyl)phenyl)-2,2-difluoro-7-azaspiro[3.5]nonane [ka] LC-MS method B-1: Rt=0.43 min; MS m / z[M+H] + =288.3.

[0302] Intermediate rac-P-25: Methyl (RS)-5-(2,2-difluoro-7-azaspiro[3.5]nonan-6-yl)picolinate [ka] LC-MS method B-6: Rt=0.24 min; MS m / z[M+H] + =297.0.

[0303] Intermediate rac-P-26: (RS)-5-(2,2-difluoro-7-azaspiro[3.5]nonan-6-yl)picolinonitrile [ka] LC-MS method B-6: Rt=0.18 min; MS m / z[M+H] + =264.3.

[0304] Intermediate P-27: [ka] To a solution of benzyl (5S)-1,1-difluoro-5-(4-(methoxycarbonyl)phenyl)-6-azaspiro[2.5]octane-6-carboxylate (Intermediate B-12 / B-13, 100 mg, 0.24 mmol) in MeOH (3 mL) under N2 atmosphere was added Pd / C (40 mg, 10 wt%). The solution was stirred under H2 atmosphere (balloon) for 3 h. The RM was purged with N2 and filtered through a pad of Celite® and rinsed with MeOH (20 mL). The filtrate was concentrated under reduced pressure to give the title compound (70 mg). LC-MS Method A-1: ​​Rt=0.31 min; MS m / z[M+H]+ =282.1.

[0305] Intermediate rac-A-1, Intermediate rac-A-2, Intermediate A-15, and Intermediate A-16: tert-Butyl 4-((2-hydroxy-6-(4-(methoxycarbonyl)phenyl)-2-methyl-7-azaspiro[3.5]non-7-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (Separation of racemic diastereomers; a mixture of two stereoisomers, one of which is separated into two single stereoisomers) [ka] Intermediate rac-A-2: Intermediate rac-P-2 (142 mg, 491 μmol) and tert-butyl 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylate (Intermediate I-1, 177 mg, 613 μmol) were dissolved in 3.5 mL of DCE. NaBH(OAc)3 (182 mg, 859 μmol) was added in two portions over 60 min. The RM was stirred at RT for a total of 36 h, with an additional 2×0.5 equiv (52 mg each) of NaBH(OAc)3 added every 8–14 h, then partitioned between EtOAc and saturated aqueous NaHCO3; the layers were separated and washed with saturated aqueous NaHCO3, brine, and EtOAc. The combined organic layers were dried over MgSO4, filtered, and the volatiles were removed under reduced pressure at 50° C. to give a colorless oil. The oil was redissolved in 1.5 mL of DCE and the RM was then treated again with NaBH(OAc)3 (182 mg, 859 μmol). After 7 h, 0.5 eq (52 mg) of NaBH(OAc)3 was added and the RM was stirred for another 24 h, diluted with MTBE and saturated NaHCO3 solution was added. The layers were separated and washed with saturated aqueous NaHCO3, brine and MTBE. The combined organic layers were dried over MgSO4, filtered and the volatiles were removed under reduced pressure at 50 °C to give a colorless oil. The crude product was purified on silica gel (12 g) using an automated purification system (NP; Teledyne ISCO®; collection at 242 / 254 nm; flow rate 30 mL / min; eluent: heptane + 10-35.9% EtOAc in 18.6 min). Pure fractions were combined and the volatiles removed under reduced pressure at 50° C. to give the title compound as a colorless oil that solidified on standing (171 mg). LC-MS Method B-1: Rt=1.03 min; MS m / z[M+H] + =563.5.

[0306] Enantiomer separation and analysis by method SFC-7 using 122 mg of racemic intermediate rac-A-2, followed by removal of the solvent under reduced pressure at 50° C., trituration with hexane and drying (under reduced pressure, 50° C.): Peak 1: (99.5% ee), Intermediate A-15, 48 mg, colorless oil. LC-MS method B-1: Rt=0.98 min. MS m / z[M+H]+ = 535.2. Analytical chiral HPLC (Method SFC-7): Rt = 1.42 min. Peak 2: (99.0% ee), Intermediate A-16, 47 mg, colorless oil. LC-MS method B-1: Rt=0.95 min. MS m / z[M+H] + = 535.4. Analytical chiral HPLC (Method SFC-7): Rt = 2.01 min.

[0307] Intermediate rac-A-1 was prepared according to the method described for intermediate rac-A-2 hereinabove using intermediate rac-P-1 (60 mg, 210 μmol) and tert-butyl 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylate (intermediate I-1, 75 mg, 260 μmol) to give racemic intermediate rac-A-1 (62 mg) as a colorless oil. LC-MS Method B-1: Rt=0.90 min; MS m / z[M+H] + =563.8. Racemic, not separated.

[0308] Intermediate A-3, Intermediate A-4, Intermediate A-5, and Intermediate A-6: tert-Butyl 4-((2-fluoro-6-(4-(methoxycarbonyl)phenyl)-2-methyl-7-azaspiro[3.5]nonan-7-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (Separation of racemic diastereomers, mixture of two stereoisomers each, both separated into two enantiomers each) [ka] A mixture of intermediate rac-P-3 (105 mg, 360 μmol) and tert-butyl 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylate (intermediate I-1, 130 mg, 450 μmol) was dissolved in DCE. NaBH(OAc)3 (134 mg, 631 μmol) was added in two portions over 40 min. The RM was stirred for 5 days followed by the addition of 4×0.5 equivalents (38 mg each) of NaBH(OAc)3. The RM was diluted with MTBE and saturated aqueous NaHCO3 was added. The layers were separated and washed with saturated aqueous NaHCO3, brine and MTBE. The combined organic layers were dried over MgSO4, filtered and the volatiles were removed under reduced pressure at 50° C. to give a slightly yellow oil. To remove unreacted aldehyde, the crude product was dissolved in 3 mL of EtOH, NaBH4 (13.6 mg, 360 μmol) was added, and the RM was stirred for 15 min. The RM was partitioned between MTBE, water, and brine. The layers were separated and washed with brine and MTBE. The combined organic layers were dried over MgSO4, filtered, and the volatiles were removed under reduced pressure at 50° C. to give a colorless oil.

[0309] The crude product was purified on silica gel (12 g) using an automated purification system (NP; Teledyne ISCO®; collection at 243 / 254 nm; flow rate 30 mL / min; eluent: heptane + 2-11.7% EtOAc in 11.8 min). Pure fractions were combined and volatiles were removed under reduced pressure at 50° C. to give the title compound (single diastereoisomer, racemic) as a white foam (167 mg). LC-MS Method B-1: Rt=1.12 min; MS m / z[M+H] + =565.8.

[0310] Enantiomer separation and analysis by method SFC-3, followed by removal of the solvent under reduced pressure at 50° C., trituration with hexane and drying (under reduced pressure, 50° C.): Peak 1: (99.5% ee), Intermediate A-3, 52.7 mg, white foam. LC-MS method B-1: Rt=1.23 min. MS m / z[M+H] + = 565.4. Analytical chiral HPLC (Method SFC-3): Rt = 1.29 min. Peak 2: (99.5% ee), Intermediate A-4, 52.9 mg, white foam. LC-MS method B-1: Rt=1.12 min. MS m / z[M+H] + = 565.8. Analytical chiral HPLC (Method SFC-3): Rt = 1.29 min.

[0311] Intermediate A-5 / Intermediate A-6 was prepared from Intermediate rac-P-4 (172 mg, 590 μmol) and tert-butyl 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylate (Intermediate I-1, 213 mg, 738 μmol) according to the method described for Intermediate A-3 / Intermediate A-4 above to give the title compound as a white foam (295 mg). LC-MS Method B-1: Rt=1.16 min; MS m / z[M+H] + =565.3.

[0312] Enantiomer separation and analysis by method SFC-4, followed by removal of the solvent under reduced pressure at 50° C., trituration with hexane and drying (under reduced pressure, 50° C.): Peak 1: (99.5% ee), Intermediate A-5, 112 mg, white foam. LC-MS Method B-1: Rt=1.14 min. MS m / z[M+H] + = 565.5. Analytical chiral HPLC (Method SFC-4): Rt = 1.46 min. Peak 2: (99.5% ee), Intermediate A-6, 116 mg, white foam. LC-MS method B-1: Rt=1.18 min. MS m / z[M+H] + = 565.3. Analytical chiral HPLC (Method SFC-4): Rt = 2.29 min.

[0313] Intermediate rac-A-78, Intermediate A-7 and Intermediate A-8: tert-Butyl 4-((2,2-difluoro-6-(4-(methoxycarbonyl)phenyl)-7-azaspiro[3.5]nonan-7-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate, tert-butyl (S)-4-((2,2-difluoro-6-(4-(methoxycarbonyl)phenyl)-7-azaspiro[3.5]nonan-7-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate, and tert-butyl (R)-4-((2,2-difluoro-6-(4-(methoxycarbonyl)phenyl)-7-azaspiro[3.5]nonan-7-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate [ka] Racemic tert-butyl 4-((2,2-difluoro-6-(4-(methoxycarbonyl)phenyl)-7-azaspiro[3.5]nonan-7-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate was prepared according to the methods described below for Intermediate A-21, methyl 4-(2,2-difluoro-7-azaspiro[3.5]nonan-6-yl)benzoate (Intermediate rac-P-5, 667 mg, 2.26 mmol) and tert-butyl 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylate (Intermediate I-1, 817 mg, 2.82 mmol) to give a racemic mixture of the title compound as a white foam (1.19 g). LC-MS Method B-1: Rt=1.18 min; MS m / z[M+H] + =569.4.

[0314] Enantiomer separation and analysis by method SFC-15 using 1.16 g racemic tert-butyl 4-((2,2-difluoro-6-(4-(methoxycarbonyl)phenyl)-7-azaspiro[3.5]nonan-7-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate, followed by removal of the solvent under reduced pressure at 50° C., trituration with hexane and drying under reduced pressure (50° C.): Peak 1: ((+)-isomer, 99.5% ee), intermediate A-7, 541 mg, white foam. LC-MS method B-1: Rt=1.20 min. MS m / z[M+H] + =569.6; Analytical chiral HPLC (Method SFC-15): Rt=1.19 min. Specific rotation method OR2:[α] 25 @589nm = +38.4° (in hexane). Peak 2: ((-)-isomer, 99.5% ee), intermediate A-8, 554 mg, white foam. LC-MS method B-1: Rt=1.21 min. MS m / z[M+H ]+ =569.6. Analytical chiral HPLC (Method SFC-15): Rt=2.24 min. Specific rotation method OR2:[α] 25 @589nm=-41.2°(in hexane).

[0315] Alternative preparation of tert-butyl (S)-4-((2,2-difluoro-6-(4-(methoxycarbonyl)phenyl)-7-azaspiro[3.5]non-7-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (Intermediate A-7): Methyl (S)-4-(2,2-difluoro-7-azaspiro[3.5]nonan-6-yl)benzoate (Intermediate P-6, 4.85 g, 16.4 mmol) and tert-butyl 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylate (Intermediate I-1, 5.94 g, 20.5 mmol) were dissolved in DCE (73 mL). NaBH(OAc)3 (6.09 g, 28.7 mmol) was added in 4 portions over 4 h. The RM was stirred for 1.5 h and additional NaBH(OAc)3 (870 mg) was added. The RM was stirred overnight, but the reaction was still incomplete, so additional NaBH(OAc)3 was added every 2 h (total: 5 x 870 mg). The RM was stirred overnight. The RM was carefully poured into well-stirred saturated aqueous NaHCO3; after CO2 evolution ceased, the mixture was transferred to a separatory funnel. The layers were separated and the aqueous layer was washed with DCM (2x). The combined organic layers were dried over MgSO4, filtered and the volatiles were removed under reduced pressure at 50 °C to give a yellow oil. The material was redissolved in 73 mL of DCE and NaBH(OAc)3 was added every 2 h (total: 4x 870 mg). The RM was finally stirred overnight. The RM was carefully poured into vigorously stirred saturated aqueous NaHCO3; after CO2 evolution ceased, MTBE was added and the layers were separated. The layers were washed with saturated aqueous NaHCO3, brine and MTBE. The combined organic layers were dried over MgSO4, filtered and the volatiles were removed under reduced pressure at 50 °C to give a slightly yellow oil which was dissolved in EtOH (50 mL) and NaBH4 (311 mg, 8.21 mmol) was added to reduce the residual aldehyde. The RM was stirred at ambient temperature for 20 min and then partitioned between MTBE, water, and brine. The layers were separated and washed with brine and MTBE. The combined organic layers were dried over MgSO4, filtered, and the volatiles were removed under reduced pressure at 50° C. to give a slightly amber foam (containing pure crude product and a small amount of transesterification to the ethyl ester). The crude product was dissolved in 100 mL of MTBE and 10 g of SiliaMetS thiol (PN R51030B from Silicycle Inc.; 40-63 μm, 1.40 mmol / g) was added. The vigorously stirred mixture was stirred at 50° C. for 4 h. The RM was then cooled to RT and filtered.The scavenger was washed with MTBE (2x) and the volatiles of the filtrate were removed under reduced pressure at 50°C to give a pale yellow foam. The crude product was purified on silica gel (330 g) using an automated purification system (NP; Teledyne ISCO®; collection at 254 / 275 nm; flow rate 200 mL / min, eluent: heptane + 2-42.7% EtOAc using a step gradient in 28.3 min). Pure fractions were combined and the volatiles were removed under reduced pressure at 50°C to give the title compound as a white foam (7.85 g) partially contaminated with the corresponding ethyl ester. LC-MS Method B-1: Rt = 1.23 min; MS m / z [M+H]. + = 569.4. Corresponding ethyl ester: Rt = 1.32 min [M+H] + 583.4.

[0316] Intermediate A-9, Intermediate A-10, Intermediate A-11, and Intermediate A-12: tert-Butyl 4-((2-fluoro-6-(4-(methoxycarbonyl)phenyl)-7-azaspiro[3.5]nonan-7-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (The racemic diastereomers were separated and then separated into single stereoisomers) [ka] Intermediate rac-P-8 (137 mg, 494 μmol) and tert-butyl 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylate (Intermediate I-1, 179 mg, 617 μmol) were dissolved in DCE. NaBH(OAc)3 (183 mg, 864 μmol) was added in three portions over 180 min. Every 8-14 h, an additional 4×0.5 equivalents (52 mg each) of NaBH(OAc)3 were added and the RM was stirred for a total of 58 h. The RM was diluted with MTBE and saturated aqueous NaHCO3 was added. The layers were separated and washed with saturated aqueous NaHCO3, brine and MTBE. The combined organic layers were dried over MgSO4, filtered and the volatiles were removed under reduced pressure at 50 °C to give a slightly yellow oil. To remove excess aldehyde, the crude product was dissolved in 3 mL of EtOH and NaBH4 (18.7 mg, 494 μmol) was added. The RM was stirred at RT for 15 min, then the RM was partitioned between MTBE, water and brine. The layers were separated and washed with brine and MTBE. The combined organic layers were dried over MgSO4, filtered and the volatiles were removed under reduced pressure at 50° C. to give a colorless oil. The crude product was purified on silica gel (12 g) using an automated purification system (NP; Teledyne ISCO®; collection at 240 / 254 nm; flow rate 30 mL / min; eluent: heptane + 2-12.9% EtOAc in 12.5 min). Pure fractions were combined and the volatiles were removed under reduced pressure at 50° C. to give the title compound as a white foam (217 mg). LC-MS method B-1: Rt=1.08 min; MS m / z[M+H] + =551.5.

[0317] Enantiomer separation and analysis by method SFC-12 using 215 mg of the racemic mixture, followed by removal of the solvent under reduced pressure at 50° C., trituration with hexane and drying (under reduced pressure, 50° C.): Peak 1: (99.5% ee), Intermediate A-9, 64 mg, white foam. LC-MS method B-1: Rt=1.05 min. MS m / z[M+H] + = 551.4. Analytical chiral HPLC (Method SFC-12): Rt = 1.65 min. Peak 2: (99.5% ee), Intermediate A-10, 64 mg, white foam. LC-MS method B-1: Rt=1.10 min. MS m / z[M+H] + = 551.5. Analytical chiral HPLC (Method SFC-12): Rt = 2.37 min.

[0318] Intermediate rac-P-7 (110 mg, 397 μmol) and tert-butyl 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylate (Intermediate I-1, 143 mg, 496 μmol) were dissolved in DCE. NaBH(OAc)3 (147 mg, 694 μmol) was added in three portions over 180 min. The RM was stirred for a total of 58 h with an additional 4×0.5 equivalents (42 mg each) of NaBH(OAc)3 added every 8-14 h. The RM was diluted with MTBE and saturated aqueous NaHCO3 was added. The layers were separated and washed with saturated aqueous NaHCO3, brine and MTBE. The combined organic layers were dried over MgSO4, filtered and the volatiles were removed under reduced pressure at 50 °C to give a slightly yellow solid. To remove unreacted intermediate I-1, the oil was dissolved in 2 mL of EtOH, NaBH4 (15.0 mg, 397 μmol) was added, and the RM was stirred at RT for 10 min. The RM was partitioned between MTBE, water, and some brine. The layers were separated and washed with brine and MTBE. The combined organic layers were dried over MgSO4, filtered, and the volatiles were removed under reduced pressure at 50 °C to give a colorless oil. The crude product was purified on silica gel (12 g) using an automated purification system (NP; Teledyne ISCO®; collection at 240 / 254 nm; flow rate 30 mL / min; eluent: heptane + 1-13.5% EtOAc in 13.2 min). Pure fractions were combined and the volatiles were removed under reduced pressure at 50 °C to give the title compound as a white foam (172 mg). LC-MS method B-1: Rt=1.14 min; MS m / z[M+H] + =551.4.

[0319] Enantiomer separation and analysis by method SFC-5 using 170 mg of the racemate, followed by removal of the solvent under reduced pressure at 50° C., trituration with hexane and drying under reduced pressure (50° C.): Peak 1: (99.5% ee), Intermediate A-11, 48 mg, white foam. LC-MS method B-1: Rt=1.07 min. MS m / z[M+H] + = 551.8. Analytical chiral HPLC (Method SFC-5): Rt = 2.24 min. Peak 2: (99.5% ee), Intermediate A-12, 48 mg, white foam. LC-MS method B-1: Rt=1.08 min. MS m / z[M+H] + = 551.8. Analytical chiral HPLC (Method SFC-5): Rt = 2.90 min.

[0320] Intermediate A-13 and Intermediate A-14: tert-Butyl (R)-5-methoxy-4-((6-(4-(methoxycarbonyl)phenyl)-2-oxa-7-azaspiro[3.5]nonan-7-yl)methyl)-7-methyl-1H-indole-1-carboxylate and tert-Butyl (S)-5-methoxy-4-((6-(4-(methoxycarbonyl)phenyl)-2-oxa-7-azaspiro[3.5]nonan-7-yl)methyl)-7-methyl-1H-indole-1-carboxylate [ka] A solution of methyl 4-(2-oxa-7-azaspiro[3.5]nonan-6-yl)benzoate (intermediate rac-P-9, 77 mg, 295 μmol) and tert-butyl 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylate (intermediate I-1, 102 mg, 354 μmol) in DCE (2 mL) was stirred at RT for 40 min. NaBH(OAc)3 (109 mg, 516 μmol) was added and every 8-48 h an additional 3×0.5 equiv (31 mg each) of NaBH(OAc)3 was added and the RM was stirred at RT for a total of 4 days. The RM was partitioned between saturated aqueous NaHCO3 and MTBE. The layers were separated and washed with saturated aqueous NaHCO3, brine and MTBE. The combined organic layers were dried over MgSO4, filtered and the volatiles were removed under reduced pressure at 50 °C to give a yellow oil. The crude product was purified on silica gel (12 g) using an automated purification system (NP; Teledyne ISCO®; collection at 229 / 254 nm; flow rate 30 mL / min; eluent: heptane + 5-20.6% (EtOAc:MeOH 95:5 in 15.6 min). Pure fractions were combined and volatiles were removed under reduced pressure at 50 °C to give racemic tert-butyl 5-methoxy-4-((6-(4-(methoxycarbonyl)phenyl)-2-oxa-7-azaspiro[3.5]nonan-7-yl)methyl)-7-methyl-1H-indole-1-carboxylate compound as a white foam (125 mg). LC-MS Method B-1: Rt = 1.00 min; MS m / z [M+H] + =535.3.

[0321] Enantiomer separation and analysis by method SFC-6 using 125 mg of the racemic mixture, followed by removal of the solvent under reduced pressure at 50° C., trituration with hexane and drying (under reduced pressure, 50° C.): Peak 1: (99.5% ee), Intermediate A-13, 52 mg, white foam. LC-MS method B-1: Rt=0.98 min. MS m / z[M+H] + = 535.2. Analytical chiral HPLC (Method SFC-6): Rt = 1.87 min. Peak 2: (99.5% ee), Intermediate A-14, 51 mg, white foam. LC-MS method B-1: Rt=0.95 min. MS m / z[M+H] + = 535.4. Analytical chiral HPLC (Method SFC-6): Rt = 3.89 min.

[0322] Intermediate A-17: tert-Butyl 4-(((5S,7R)-2,2-difluoro-7-(4-(methoxycarbonyl)phenyl)-8-azaspiro[4.5]decan-8-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate or tert-Butyl 4-(((5R,7R)-2,2-difluoro-7-(4-(methoxycarbonyl)phenyl)-8-azaspiro[4.5]decan-8-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate [ka] Intermediate P-10 was used to prepare intermediate A-17 according to the method described for intermediate A-18 herein below. LC-MS Method C-1: Rt=1.58 min; MS m / z [M-tertBu+Na+H] 2 +=274.1.

[0323] Intermediate A-18: tert-Butyl 4-(((5S,7S)-2,2-difluoro-7-(4-(methoxycarbonyl)phenyl)-8-azaspiro[4.5]decan-8-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate or tert-Butyl 4-(((5R,7S)-2,2-difluoro-7-(4-(methoxycarbonyl)phenyl)-8-azaspiro[4.5]decan-8-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate [ka] To a mixture of tert-butyl 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylate (intermediate I-1, 45.9 mg, 0.159 mmol) and crude intermediate P-11 hydrochloride (0.159 mmol) in DCM (1.58 mL) and under N2 atmosphere was added triethylamine (24.1 mg, 0.238 mmol). The mixture was stirred for about 15 min and NaBH(OAc)3 (50.5 mg, 0.238 mmol) was added in one portion. Stirring was continued for about 2 days. The RM was diluted with DCM and washed with saturated aqueous NaHCO3; the separated organic layer was washed with brine, dried over Na2SO4, filtered off and concentrated under reduced pressure to give the crude title compound. The crude material was used directly in the next reaction without further purification. LC-MS Method C-1: Rt=1.58 min; MS m / z [M-tertBu+Na+H] 2+ =274.1.

[0324] Intermediate A-19: tert-Butyl 4-(((5S,7R)-2,2-difluoro-7-(4-(methoxycarbonyl)phenyl)-8-azaspiro[4.5]decan-8-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate or tert-Butyl 4-(((5R,7R)-2,2-difluoro-7-(4-(methoxycarbonyl)phenyl)-8-azaspiro[4.5]decan-8-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate [ka] Intermediate P-12 was used to prepare intermediate A-19 according to the method described for intermediate A-18 herein above. LC-MS Method C-1: Rt=1.58 min; MS m / z [M-tertBu+Na+H] 2+ =274.1.

[0325] Intermediate A-20: tert-Butyl 4-(((5S,7S)-2,2-difluoro-7-(4-(methoxycarbonyl)phenyl)-8-azaspiro[4.5]decan-8-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate or tert-Butyl 4-(((5R,7S)-2,2-difluoro-7-(4-(methoxycarbonyl)phenyl)-8-azaspiro[4.5]decan-8-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate [ka] Intermediate P-13 was used to prepare intermediate A-20 according to the method described for intermediate A-18 herein above. LC-MS Method C-1: Rt=1.57 min; MS m / z [M-tertBu+Na+H] 2+ =274.1.

[0326] Intermediate A-21: tert-Butyl (S)-5-cyclopropyl-4-((2,2-difluoro-6-(4-(methoxycarbonyl)phenyl)-7-azaspiro[3.5]nonan-7-yl)methyl)-7-methyl-1H-indole-1-carboxylate [ka] Methyl (S)-4-(2,2-difluoro-7-azaspiro[3.5]nonan-6-yl)benzoate (Intermediate P-6, 519 mg, 1.76 mmol) and tert-butyl 5-cyclopropyl-4-formyl-7-methyl-1H-indole-1-carboxylate (Intermediate I-3, 631 mg, 2.11 mmol) were dissolved in DCE. NaBH(OAc)3 (652 mg, 3.08 mmol) was added in four portions over 4 h. After 4-14 h, 4×0.5 equiv (186 mg each) were added and the RM was stirred for a total of 51 h. The RM was diluted with MTBE and saturated aqueous NaHCO3 was added. The layers were separated and washed with saturated aqueous NaHCO3, brine and MTBE. The combined organic layers were dried over MgSO4, filtered and the volatiles were removed under reduced pressure at 50 °C to give a slightly yellow oil, which was dissolved in 8.9 mL of DCE and reacted with 0.5 eq (186 mg) of NaBH(OAc)3 for an additional 50 h, and another 0.5 eq (186 mg) of NaBH(OAc)3 was added. The RM was diluted with MTBE and saturated aqueous NaHCO3 was added. The layers were separated and washed with saturated aqueous NaHCO3, brine and MTBE. The combined organic layers were dried over MgSO4, filtered and the volatiles were removed under reduced pressure at 50 °C to give a slightly yellow oil. To remove unreacted aldehyde, the RM was dissolved in EtOH (10 mL) and NaBH4 (33.2 mg, 879 μmol) was added. The RM was stirred at RT for 30 min, diluted with MTBE and water and brine was added. The layers were separated and washed with brine and MTBE. The combined organic layers were dried over MgSO4, filtered, and the volatiles were removed under reduced pressure at 50°C to give a yellow oil. The crude product was purified on silica gel (40 g) using an automated purification system (NP; Teledyne ISCO®; collection at 246 / 254 nm; flow rate 40 mL / min; eluent: heptane + 1-23% EtOAc in 23 min). Pure fractions were combined and the volatiles were removed under reduced pressure at 50°C to give the title compound as a white foam (767 mg). LC-MS Method B-3: Rt = 8.34 min; MS m / z [M+H] + = 580.4 (contains small amounts of the corresponding ethyl ester) Rt = 8.70 min; MS m / z [M+H] +=593.5.

[0327] Intermediate A-22: tert-Butyl (S)-4-((2,2-difluoro-6-(4-(methoxycarbonyl)phenyl)-7-azaspiro[3.5]nonan-7-yl)methyl)-5,7-dimethyl-1H-indole-1-carboxylate [ka] Methyl (S)-4-(2,2-difluoro-7-azaspiro[3.5]nonan-6-yl)benzoate (Intermediate P-6, 70 mg, 0.24 mmol) and tert-butyl 4-formyl-5,7-dimethyl-1H-indole-1-carboxylate (Intermediate I-2, 78 mg, 0.28 mmol) were dissolved in DCE. NaBH(OAc)3 (88 mg, 0.41 mmol) was added in two portions over 60 min. After 4-14 h, 7×0.5 equiv (25 mg each) of triacetoxyborohydride was added and the RM was stirred for a total of 64 h. The RM was diluted with MTBE and saturated aqueous NaHCO3 was added. The layers were separated and washed with saturated aqueous NaHCO3, brine and MTBE. The combined organic layers were dried over MgSO4, filtered and the volatiles were removed under reduced pressure at 50 °C to give a slightly yellow oil. To reduce the unreacted intermediate I-2 and facilitate separation, the RM was dissolved in 1.5 mL of EtOH and NaBH4 (4.5 mg, 0.12 mmol) was added. The RM was stirred at RT for 10 min and then diluted with MTBE, water, and brine. The layers were separated and washed with brine and MTBE. The combined organic layers were dried over MgSO4, filtered, and the volatiles were removed under reduced pressure at 50 °C to give a yellow oil, which was purified on silica gel (12 g) using an automated purification system (NP; Teledyne ISCO®; collection at 238 / 254 nm; flow rate 30 mL / min; eluent: heptane + 1-8.5% EtOAc in 11.6 min). Pure fractions were combined and the volatiles were removed under reduced pressure at 50 °C to give the title compound as a white foam (93 mg). LC-MS Method B-1: Rt = 1.69 min; MS m / z [M+H] +=553.5.

[0328] Intermediate A-23: tert-Butyl 4-(((S)-2,2-difluoro-6-(4-(methoxycarbonyl)phenyl)-7-azaspiro[3.5]nonan-7-yl)methyl)-5-((R)-2,2-difluorocyclopropyl)-7-methyl-1H-indole-1-carboxylate or tert-Butyl 4-(((S)-2,2-difluoro-6-(4-(methoxycarbonyl)phenyl)-7-azaspiro[3.5]nonan-7-yl)methyl)-5-((S)-2,2-difluorocyclopropyl)-7-methyl-1H-indole-1-carboxylate [ka] Methyl (S)-4-(2,2-difluoro-7-azaspiro[3.5]nonan-6-yl)benzoate (intermediate P-6, 70.0 mg, 237.0 μmol) and intermediate I-4 (5.38 mg, 284.4 μmol) were dissolved in DCE. NaBH(OAc)3 (87.91 mg, 414.8 μmol) was added in four portions over 4 h. After 4-48 h, 7×0.5 equivalents (25 mg each) of NaBH(OAc)3 were added and the RM was stirred for a total of 6 days. The RM was diluted with MTBE and saturated aqueous NaHCO3 was added. The layers were separated and washed with saturated aqueous NaHCO3, brine and MTBE. The combined organic layers were dried over MgSO4, filtered and the volatiles were removed under reduced pressure at 50 °C to give a slightly yellow oil. The crude product was dissolved in EtOH (1.0 mL) and NaBH4 (6.73 mg, 177.8 μmol) was added to reduce excess aldehyde. The RM was stirred for 15 min and then diluted with MTBE, water and brine. The layers were separated and washed with brine and MTBE. The combined organic layers were dried over MgSO4, filtered and the volatiles were removed under reduced pressure at 50 °C to give a colorless oil, which was purified on silica gel (12 g) using an automated purification system (NP; Teledyne ISCO®; collection at 250 / 254 nm; flow rate 30 mL / min; eluent: heptane + 1-10.2% EtOAc in 13.1 min). Pure fractions were combined and the volatiles were removed under reduced pressure at 50 °C to give the title compound as a white foam (95 mg). LC-MS Method B-1: Rt = 1.73 min; MS m / z [M+H] + =615.4.

[0329] Intermediate A-24: tert-Butyl 4-(((S)-2,2-difluoro-6-(4-(methoxycarbonyl)phenyl)-7-azaspiro[3.5]nonan-7-yl)methyl)-5-((R)-2,2-difluorocyclopropyl)-7-methyl-1H-indole-1-carboxylate or tert-Butyl 4-(((S)-2,2-difluoro-6-(4-(methoxycarbonyl)phenyl)-7-azaspiro[3.5]nonan-7-yl)methyl)-5-((S)-2,2-difluorocyclopropyl)-7-methyl-1H-indole-1-carboxylate Intermediate A-24 was prepared similarly to its diastereomeric intermediate A-23 above using methyl (S)-4-(2,2-difluoro-7-azaspiro[3.5]nonan-6-yl)benzoate (Intermediate P-6, 70.0 mg, 237 μmol) and intermediate I-5 (87.4 mg, 260.7 μmol) to give intermediate A-24 as a white foam (83 mg). LC-MS Method B-1: Rt=1.70 min; MS m / z[M+H] + =615.5.

[0330] Intermediate rac-A-25: (RS)-tert-Butyl 5-cyclopropyl-4-((2,2-difluoro-6-(4-(3-hydroxyoxetan-3-yl)phenyl)-7-azaspiro[3.5]nonan-7-yl)methyl)-7-methyl-1H-indole-1-carboxylate [ka] A solution of 3-(4-(2,2-difluoro-7-azaspiro[3.5]nonan-6-yl)phenyl)oxetan-3-ol (intermediate rac-P-14, 109.2 mg, 353.0 μmol), tert-butyl 4-(chloromethyl)-5-cyclopropyl-7-methyl-1H-indole-1-carboxylate (intermediate I-6, 129.8 mg, 405.9 μmol) and DIPEA (91.3 mg, 123 μL, 706 μmol) was placed in a capped vial and the RM was stirred at 50° C. for 20 hours. The RM was partitioned between water and MTBE. The layers were separated and washed with brine and MTBE. The combined organic layers were dried over MgSO4, filtered and the volatiles were removed under reduced pressure at 50° C. The residue was purified on silica gel (12 g) using an automated purification system (NP; Teledyne ISCO®; collection at 250 / 272 nm; flow rate 30 mL / min; eluent: heptane + 2-32% EtOAc in 20 min). Pure fractions were combined and volatiles were removed under reduced pressure at 50° C. to give the title compound as a white foam (199 mg). LC-MS Method B-1: Rt=1.21 min; MS m / z [M+H] + =593.5.

[0331] Intermediate rac-A-26: (RS)-tert-Butyl 5-cyclopropyl-4-((2,2-difluoro-6-(4-(2-hydroxypropan-2-yl)phenyl)-7-azaspiro[3.5]nonan-7-yl)methyl)-7-methyl-1H-indole-1-carboxylate [ka] A solution of 2-(4-(2,2-difluoro-7-azaspiro[3.5]nonan-6-yl)phenyl)propan-2-ol (Intermediate rac-P-15, 112.0 mg, 379.2 μmol), tert-butyl 4-(chloromethyl)-5-cyclopropyl-7-methyl-1H-indole-1-carboxylate (Intermediate I-6, 139.5 mg, 436.1 μmol) and DIPEA (98.02 mg, 132 μL, 758.4 μmol) was placed in a capped vial and the RM was stirred at 50° C. overnight. The RM was partitioned between water and MTBE. The layers were separated and washed with brine and MTBE. The combined organic layers were dried over MgSO4, filtered, and the volatiles were removed under reduced pressure at 50°C to give a colorless oil, which was purified on silica gel (12 g) using an automated purification system (NP; Teledyne ISCO®; collection at 250 / 272 nm; flow rate 30 mL / min; eluent: heptane + 2-20.5% EtOAc in 13.2 min). Pure fractions were combined and the volatiles were removed under reduced pressure at 50°C to give the title compound as a white foam (218 mg). LC-MS Method B-1: Rt = 1.33 min; MS m / z [M+H] + =579.5.

[0332] Intermediate rac-A-27: (RS)-tert-Butyl 4-((6-(4-(1H-pyrazol-5-yl)phenyl)-2,2-difluoro-7-azaspiro[3.5]nonan-7-yl)methyl)-5-cyclopropyl-7-methyl-1H-indole-1-carboxylate [ka] A solution of 6-(4-(1H-pyrazol-5-yl)phenyl)-2,2-difluoro-7-azaspiro[3.5]nonane (intermediate rac-P-16, 110.0 mg, 362.6 μmol), tert-butyl 4-(chloromethyl)-5-cyclopropyl-7-methyl-1H-indole-1-carboxylate (intermediate I-6, 133.4 mg, 417.0 μmol) and DIPEA (93.73 mg, 126 μL, 725.2 μmol) was placed in a capped vial and the RM was stirred at 50° C. overnight. The RM was partitioned between water and MTBE. The layers were separated and washed with brine and MTBE. The combined organic layers were dried over MgSO4, filtered and the volatiles were removed under reduced pressure at 50° C. to give a colorless oil. The crude product was purified on silica gel (12 g) using an automated purification system (NP; Teledyne ISCO®; collection at 254 / 275 nm; flow rate 30 mL / min; eluent: heptane + 5-39.3% EtOAc in 15.2 min). Pure fractions were combined and volatiles were removed under reduced pressure at 50° C. to give the title compound as a white foam (190 mg). LC-MS Method B-1: Rt=1.37 min; MS m / z [M+H] + =587.4.

[0333] Intermediate rac-A-28: (RS)-tert-Butyl 4-((6-(4-(1H-pyrazol-1-yl)phenyl)-2,2-difluoro-7-azaspiro[3.5]nonan-7-yl)methyl)-5-cyclopropyl-7-methyl-1H-indole-1-carboxylate [ka] A solution of 6-(4-(1H-pyrazol-1-yl)phenyl)-2,2-difluoro-7-azaspiro[3.5]nonane (intermediate rac-P-17, 110.0 mg, 362.6 μmol), tert-butyl 4-(chloromethyl)-5-cyclopropyl-7-methyl-1H-indole-1-carboxylate (intermediate I-6, 133.4 mg, 417.0 μmol) and DIPEA (93.73 mg, 126 μL, 725.2 μmol) was placed in a capped vial and the RM was stirred at 50° C. overnight. The RM was diluted with water and MTBE. The layers were separated and washed with brine and MTBE. The combined organic layers were dried over MgSO4, filtered and the volatiles were removed under reduced pressure at 50° C. to give a colorless oil. The crude product was purified on silica gel (12 g) using an automated purification system (NP; Teledyne ISCO®; collection at 254 / 275 nm; flow rate 30 mL / min; eluent: heptane + 0-7.8% EtOAc in 20.1 min). Pure fractions were combined and volatiles were removed under reduced pressure at 50° C. to give the title compound as a white foam (209 mg). LC-MS Method B-1: Rt=1.53 min; MS m / z [M+H] + =587.5.

[0334] Intermediate rac-A-29: (RS)-tert-Butyl 4-((6-(4-cyanophenyl)-2,2-difluoro-7-azaspiro[3.5]nonan-7-yl)methyl)-5-cyclopropyl-7-methyl-1H-indole-1-carboxylate [ka] A solution of 4-(2,2-difluoro-7-azaspiro[3.5]nonan-6-yl)benzonitrile (intermediate rac-P-18, 137.0 mg, 522.3 μmol), tert-butyl 4-(chloromethyl)-5-cyclopropyl-7-methyl-1H-indole-1-carboxylate (intermediate I-6, 192.1 mg, 600.6 μmol) and DIPEA (135.0 mg, 182 μL, 1.045 mmol) was placed in a capped vial and the RM was stirred at 50° C. overnight. The RM was partitioned between water and MTBE. The layers were separated and washed with brine and MTBE. The combined organic layers were dried over MgSO4, filtered and the volatiles were removed under reduced pressure at 50° C. to give a colorless oil.

[0335] The crude product was purified on silica gel (24 g) using an automated purification system (NP; Teledyne ISCO®; collection at 254 / 275 nm; flow rate 35 mL / min; eluent: heptane 0-7.1% EtOAc + 17.7 min). The purest fractions were combined and the volatiles were removed under reduced pressure at 50° C. to give the title compound as a white foam (273 mg). LC-MS Method B-1: Rt=1.69 min; MS m / z [M+H] + =546.3.

[0336] Intermediate rac-A-30: (RS)-tert-Butyl 4-((2,2-difluoro-6-phenyl-7-azaspiro[3.5]nonan-7-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate [ka] 2,2-Difluoro-6-phenyl-7-azaspiro[3.5]nonane (intermediate rac-P-19, 68.50 mg, 288.7 μmol) and tert-butyl 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylate (intermediate I-1, 108.6 mg, 375.3 μmol) were dissolved in DCE. NaBH(OAc)3 (107.1 mg, 505.2 μmol) was added portionwise over 4 h. The RM was stirred for a total of 2.5 days with the addition of 7×0.5 equivalents of NaBH(OAc)3 (31 mg each) after 2.5-14 h. The RM was diluted with MTBE and saturated aqueous NaHCO3 was added. The layers were separated and washed with saturated aqueous NaHCO3, brine, and MTBE. The combined organic layers were dried over MgSO4, filtered, and the volatiles were removed under reduced pressure at 50 °C to give a slightly yellow oil. To reduce excess intermediate I-1 and facilitate separation, the crude material was dissolved in EtOH (2.0 mL) and NaBH4 (10.92 mg, 288.7 μmol) was added. The RM was stirred at RT for 10 min, then partitioned between MTBE, water, and brine. The layers were separated and washed with brine and MTBE. The combined organic layers were dried over MgSO4, filtered, and the volatiles were removed under reduced pressure at 50 °C to give a colorless oil, which was purified on a silica gel column (12 g) using an automated purification system (NP; Teledyne ISCO®; collection at 245 / 275 nm; flow rate 30 mL / min; eluent: heptane + 1.0-6.5% EtOAc in 12.3 min). Pure fractions were combined and the volatiles were removed under reduced pressure at 50° C. to give the title compound as a white foam (115 mg). LC-MS Method B-1: Rt=1.07 min; MS m / z[M+H] + =511.3.

[0337] Intermediate rac-A-31: (RS)-tert-Butyl 4-((2,2-difluoro-6-(1-methyl-1H-pyrazol-4-yl)-7-azaspiro[3.5]nonan-7-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate [ka] 2,2-Difluoro-6-(1-methyl-1H-pyrazol-4-yl)-7-azaspiro[3.5]nonane (intermediate rac-P-20, 89.50 mg, 370.9 μmol) and tert-butyl 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylate (intermediate I-1, 150.2 mg, 519.3 μmol) were dissolved in DCE (1.50 mL). NaBH(OAc)3 (137.6 mg, 649.1 μmol) was added in four portions over 4 h. An additional 0.5 equivalents (39 mg) of NaBH(OAc)3 was added and the RM was stirred for a total of 34 h after 4-14 h with 3× more 0.5 equivalents of NaBH(OAc)3 (39 mg each). The RM was diluted with DCE and saturated aqueous Na2CO3 (10 wt%). The layers were separated. The aqueous layer was extracted with DCE (2x). The combined organic layers were dried over MgSO4, filtered and the volatiles were removed under reduced pressure at 50°C to give a yellow oil. The material was redissolved in 1.5 mL DCE and 0.5 equivalents of NaBH(OAc)3 (39 mg) were added. The RM was added another 2x 0.5 equivalents of NaBH(OAc)3 (39 mg each) and stirred for a total of 21 h. The RM was diluted with MTBE and saturated aqueous NaHCO3 was added. The layers were separated and washed with saturated aqueous NaHCO3, brine and MTBE. The combined organic layers were dried over MgSO4, filtered and the volatiles were removed under reduced pressure at 50°C to give a yellow oil. The crude product was purified on silica gel (12 g) using an automated purification system (NP; Teledyne ISCO®; collection at 250 / 275 nm; flow rate 30 mL / min; eluent: heptane + 5-44.8% (EtOAc:MeOH 95:5) in 14.5 min). Pure fractions were combined and volatiles were removed under reduced pressure at 50° C. to give the title compound as white crystals (167 mg). LC-MS Method B-1: Rt=0.87 min; MS m / z [M+H] + =515.2.

[0338] Intermediate A-32 and Intermediate A-33: tert-Butyl (S)-4-((6-(1-(2-ethoxy-2-oxoethyl)-1H-pyrazol-4-yl)-2,2-difluoro-7-azaspiro[3.5]nonan-7-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate and tert-Butyl (R)-4-((6-(1-(2-ethoxy-2-oxoethyl)-1H-pyrazol-4-yl)-2,2-difluoro-7-azaspiro[3.5]nonan-7-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate [ka] Racemic tert-butyl 4-((6-(1-(2-ethoxy-2-oxoethyl)-1H-pyrazol-4-yl)-2,2-difluoro-7-azaspiro[3.5]nonan-7-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate was prepared similarly to the method described for intermediate rac-A-31 hereinabove using intermediate rac-P-23 and intermediate I-1. LC-MS Method B-6: Rt=0.88 min; MS m / z[M+H] + =587.2

[0339] Enantiomer separation and analysis of the racemic mixture by method SFC-22 gave: Peak 1: (99.3% ee), Intermediate A-32, 35.4 mg, yellow oil. LC-MS method B-6: Rt=0.86 min. MS m / z[M+H] + = 587.4. Analytical chiral HPLC (Method SFC-22): Rt = 1.59 min. Peak 2: (99.3% ee), Intermediate A-33, 34.0 mg, yellow oil. LC-MS method B-6: Rt=0.87 min. MS m / z[M+H] + = 587.3. Analytical chiral HPLC (Method SFC-22): Rt = 2.06 min.

[0340] Intermediate A-34 and Intermediate A-35: tert-Butyl (S)-4-((2,2-difluoro-6-(6-(methoxycarbonyl)pyridin-3-yl)-7-azaspiro[3.5]nonan-7-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate and tert-butyl (R)-4-((2,2-difluoro-6-(6-(methoxycarbonyl)pyridin-3-yl)-7-azaspiro[3.5]nonan-7-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate [ka] Racemic tert-butyl 4-((2,2-difluoro-6-(6-(methoxycarbonyl)pyridin-3-yl)-7-azaspiro[3.5]nonan-7-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate was prepared similarly to the method described for intermediate rac-A-78 herein above using intermediate rac-P-25 and intermediate I-1. LC-MS Method B-6: Rt=1.19 min; MS m / z [M+H] + =570.2

[0341] Enantiomer separation and analysis of the racemic mixture by method SFC-26 gave: Peak 1: (99.5% ee), Intermediate A-34, 80.4 mg, white. LC-MS method B-6: Rt=1.19 min. MS m / z[M+H] + = 570.2. Analytical chiral HPLC (Method SFC-26): Rt = 1.19 min. Peak 2: (98.5% ee), Intermediate A-35, 83.1 mg, white. LC-MS method B-6: Rt=1.20 min. MS m / z[M+H] + = 570.2. Analytical chiral HPLC (Method SFC-26): Rt = 1.79 min.

[0342] Intermediate A-36 and Intermediate A-37: tert-Butyl (S)-5-cyclopropyl-4-((2,2-difluoro-6-(6-(methoxycarbonyl)pyridin-3-yl)-7-azaspiro[3.5]nonan-7-yl)methyl)-7-methyl-1H-indole-1-carboxylate and tert-Butyl (R)-5-cyclopropyl-4-((2,2-difluoro-6-(6-(methoxycarbonyl)pyridin-3-yl)-7-azaspiro[3.5]nonan-7-yl)methyl)-7-methyl-1H-indole-1-carboxylate [ka] Racemic tert-butyl 5-cyclopropyl-4-((2,2-difluoro-6-(6-(methoxycarbonyl)pyridin-3-yl)-7-azaspiro[3.5]nonan-7-yl)methyl)-7-methyl-1H-indole-1-carboxylate was prepared similarly to the method described for intermediate rac-A-78 hereinabove using intermediate rac-P-25 and intermediate I-3. LC-MS Method B-6: Rt=1.65 min; MS m / z[M+H] + =580.3

[0343] Enantiomer separation and analysis of the racemic mixture by method SFC-27 gave: Peak 1: (99.5% ee), Intermediate A-36, 60.7 mg, white solid. LC-MS method B-6: Rt=1.64 min. MS m / z[M+H] + = 580.5. Analytical chiral HPLC (Method SFC-27): Rt = 2.79 min. Peak 2: (98.9% ee), Intermediate A-37, 63.1 mg, white solid. LC-MS method B-6: Rt=1.64 min. MS m / z[M+H] + = 580.3. Analytical chiral HPLC (Method SFC-27): Rt = 3.87 min.

[0344] Intermediate A-38 and Intermediate A-39: tert-Butyl (S)-4-((2,2-difluoro-6-(6-(methoxycarbonyl)pyridin-3-yl)-7-azaspiro[3.5]nonan-7-yl)methyl)-5,7-dimethyl-1H-indole-1-carboxylate and tert-Butyl (R)-4-((2,2-difluoro-6-(6-(methoxycarbonyl)pyridin-3-yl)-7-azaspiro[3.5]nonan-7-yl)methyl)-5,7-dimethyl-1H-indole-1-carboxylate [ka] Racemic tert-butyl 4-((2,2-difluoro-6-(6-(methoxycarbonyl)pyridin-3-yl)-7-azaspiro[3.5]nonan-7-yl)methyl)-5,7-dimethyl-1H-indole-1-carboxylate was prepared similarly to the method described for intermediate rac-A-78 hereinabove using intermediate rac-P-25 and intermediate I-2. LC-MS Method B-6: Rt=1.62 min; MS m / z[M+H] + =554.2

[0345] Enantiomer separation and analysis of the racemic mixture by method SFC-28 gave: Peak 1: (99.5% ee), Intermediate A-38, 69.9 mg, white foam. LC-MS method B-6: Rt=1.62 min. MS m / z[M+H] + = 554.1. Analytical chiral HPLC (Method SFC-28): Rt = 1.99 min. Peak 2: (99.5% ee), Intermediate A-39, 68.9 mg, white foam. LC-MS method B-6: Rt=1.62 min. MS m / z[M+H] + = 554.1. Analytical chiral HPLC (Method SFC-28): Rt = 2.72 min.

[0346] Compound example Example Ex-5: (S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzoic acid [ka] A solution of tert-butyl (S)-4-((2,2-difluoro-6-(4-(methoxycarbonyl)phenyl)-7-azaspiro[3.5]nonan-7-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (Intermediate A-7, 7.85 g, 13.8 mmol) in THF (60 mL) and MeOH (148 mL) was evacuated / backfilled with N2. 4M aqueous NaOH (34.5 mL, 138 mmol) was added. The mixture was again evacuated / backfilled with N2. The well-stirred RM was kept under N2 and heated to 50° C. to obtain a homogeneous solution and stirred for 21 h. The RM was cooled to RT and quenched with 4M aqueous HCl (5.03 g, 34.5 mL, 138 mmol). Approximately 50% of the volatiles (MeOH, THF) were removed under reduced pressure at 50° C. EtOAc, some water, and brine were added. The layers were separated and washed with brine and EtOAc. The combined organic layers were dried over MgSO4, filtered, and most of the volatiles were removed under reduced pressure at 50° C. to give a slightly amber foam. All solvents used in the following purification steps were of PA quality. The crude product was dissolved in DCM and a few drops of MeOH. Purified on silica gel (220 g) using an automated purification system (NP; Teledyne ISCO®; collection at 230 / 282 nm; flow rate 150 mL / min; eluent: DCM+2-17% MeOH in 29.2 min, isocratic gradient at end). Pure fractions were combined and the volatiles were removed under reduced pressure at 50° C. to give a slightly yellow foam that dissolved in EtOAc and as little MeOH as possible. The volatiles were again removed under reduced pressure at 50° C. The resulting semi-solid gum was redissolved in EtOAc and as little MeOH as possible. The volatiles were removed again under reduced pressure at 50° C.; this step was repeated twice, then the residue was dissolved in EtOAc and the mixture was concentrated under reduced pressure at 50° C. to a volume of about 40 mL. The mixture was cooled to RT and 100 mL of hexane was slowly added via a dropping funnel to precipitate the product. The resulting white suspension was sonicated and stirred for an additional 10 min. The suspension was then filtered and the filter cake was washed with ice-cold hexane / EtOAc 4 / 1. The filter cake was dried under reduced pressure at 50° C. to give the title compound as a white powder (5.96 g).LC-MS method B-3: Rt=2.34 min; MS m / z[M+H]. + =455.2.

[0347] Example Ex-6: (R)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzoic acid [ka] Aqueous 4M NaOH (492 μL) was added to a solution of tert-butyl (R)-4-((2,2-difluoro-6-(4-(methoxycarbonyl)phenyl)-7-azaspiro[3.5]nonan-7-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (Intermediate A-8, 111 mg, 195 μmol) in MeOH / THF (2.0 mL / 1.0 mL). The RM was stirred at 50° C. for 3 h 40 min. The RM was cooled to RT and quenched with aqueous 4M HCl (488 μL) and EtOAc, some water, and a few drops of brine were added. The layers were separated and washed with brine and EtOAc. The combined organic layers were dried over MgSO4, filtered, and the volatiles were removed under reduced pressure at 50° C. to give a milky oil. The mixture was dissolved in ACN / MeOH, the volatiles were removed under reduced pressure again at 50° C., and the residue was dried under reduced pressure at 50° C. to give the title compound as a grey foam, which was purified on a preparative TLC plate (MERCK 1.05744.0001, PLC silica gel 60 F254, 0.5 mm; eluent: DCM / MeOH 88 / 12). The main band (by UV) was scraped off the plate. The silica gel / compound mixture was suspended in DCM / MeOH 85 / 15, sonicated, and filtered. The silica gel was rinsed with DCM / MeOH 85 / 15. The volatiles of the filtrate were removed under reduced pressure at 50° C. to give the title compound as an off-white powder (80 mg). LC-MS Method B-3: Rt=2.30 min; MS m / z[M+H] + =455.4.

[0348] Example Ex-9: 4-(2-Fluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzoic acid (single stereoisomer 3) [ka] 4M aqueous NaOH (179 μL) was added to a solution of intermediate A-11 (49.2 mg, 89.3 μmol) in MeOH (1 mL) and THF (0.2 μL). The RM was stirred at 50 °C overnight, cooled to RT, and quenched with 4M aqueous HCl (179 μl). This solution was directly purified by preparative HPLC (Waters Xbridge C18 dimensions: 30 mm × 100 mm 5 μm; flow rate 50 mL / min; eluent A = water + 0.1% TFA; eluent B = ACN; gradient: 15 to 50% B in 12 min). Fractions containing the product were combined, volatiles were removed under reduced pressure at 40 °C, and the remaining aqueous solution was lyophilized to give the title compound as an off-white solid (44.3 mg). LC-MS Method B-1: Rt = 0.48 min; MS m / z [M+H] + =437.4.

[0349] Example Ex-18: 4-((5S,7S)-2,2-difluoro-8-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-8-azaspiro[4.5]decan-7-yl)benzoic acid or 4-((5R,7S)-2,2-difluoro-8-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-8-azaspiro[4.5]decan-7-yl)benzoic acid [ka] To a mixture of crude intermediate A-18 (61.8 mg, 0.106 mmol) in THF / MeOH (1.06 mL / 1.06 mL) was added 2N aqueous NaOH (1.06 mL, 2.12 mmol). The mixture was stirred at RT for about 15 min and then heated at 50° C. for about 3 h. Volatile solvents were removed under reduced pressure to about ½ of the original volume. The residue was diluted with water and ACN and purified by preparative HPLC on an XBridge C18 OBD column (30×50 mm, 5 μm) eluted with 15%-40% ACN (5 mM) in aqueous NH4OH to give the title compound (24 mg) as a white solid after lyophilization. LC-MS Method C-1: Rt=0.74 min; MS m / z[M+H] + =469.4.

[0350] Example Ex-21: (S)-4-(7-((5-cyclopropyl-7-methyl-1H-indol-4-yl)methyl)-2,2-difluoro-7-azaspiro[3.5]nonan-6-yl)benzoic acid [ka] 4M aqueous NaOH (3.31 mL, 13.3 mmol) was added to a solution of tert-butyl (S)-5-cyclopropyl-4-((2,2-difluoro-6-(4-(methoxycarbonyl)phenyl)-7-azaspiro[3.5]nonan-7-yl)methyl)-7-methyl-1H-indole-1-carboxylate (Intermediate A-21, 767 mg, 1.33 mmol) in MeOH / THF (9 mL, 5.3 mL). The RM was stirred at 50° C. overnight and then quenched with 4M aqueous HCl (3.31 mL, 13.3 mmol). EtOAc, water and a few drops of brine were added. The layers were separated and washed with brine and EtOAc. The combined organic layers were dried over MgSO4, filtered and the volatiles were removed under reduced pressure at 50° C. to give an off-white oil. The crude product was purified on silica gel (25 g) using an automated purification system (NP; Teledyne ISCO®; collection at 234 / 285 nm; flow rate 35 mL / min; eluent: DCM+0.5-13.9% MeOH in 18.5 min). Pure fractions were combined, the volatiles removed under reduced pressure at 50 °C, dissolved in ACN, the volatiles removed again under reduced pressure at 50 °C, and the product further dried under reduced pressure at 50 °C to give the title compound as an off-white powder (582 mg). LC-MS Method B-3: Rt=3.27 min; MS m / z=465.4.

[0351] Examples Ex-49, Ex-25 and Ex-26: 3-(4-(7-((5-cyclopropyl-7-methyl-1H-indol-4-yl)methyl)-2,2-difluoro-7-azaspiro[3.5]nonan-6-yl)phenyl)oxetan-3-ol, (S)-3-(4-(7-((5-cyclopropyl-7-methyl-1H-indol-4-yl)methyl)-2,2-difluoro-7-azaspiro[3.5]nonan-6-yl)phenyl)oxetan-3-ol and (R)-3-(4-(7-((5-cyclopropyl-7-methyl-1H-indol-4-yl)methyl)-2,2-difluoro-7-azaspiro[3.5]nonan-6-yl)phenyl)oxetan-3-ol [ka] Potassium carbonate 325 mesh (264.6 mg, 1.915 mmol) was added to a solution of racemic tert-butyl 5-cyclopropyl-4-((2,2-difluoro-6-(4-(3-hydroxyoxetan-3-yl)phenyl)-7-azaspiro[3.5]nonan-7-yl)methyl)-7-methyl-1H-indole-1-carboxylate (intermediate rac-A-25, 227.0 mg, 383.0 μmol) in MeOH (5.0 mL). The RM was stirred at 60° C. for about 10 h and then maintained without heating overnight. MeOH was removed under reduced pressure at 50° C. The resulting residue was partitioned between water and DCM. The layers were separated and the aqueous layer was washed with DCM (2×). The combined organic layers were dried over MgSO4, filtered, and the volatiles were removed under reduced pressure at 50° C. to give a white foam. The crude product was dissolved in DCM and distributed evenly between two TLC plates (MERCK 1.05744.0001, PLC silica gel 60 F254, 0.5 mm; eluent: DCM / MeOH 92 / 8). The main band (UV detection) was scraped off the plate. The silica gel / compound mixture was suspended in DCM / MeOH 85 / 15, sonicated and filtered. The silica gel was rinsed with DCM / MeOH 85 / 15. The filtrate was stripped of volatiles under reduced pressure at 50° C., dissolved in DCM / hexanes, the volatiles again stripped under reduced pressure at 50° C., and the material further dried under reduced pressure at 50° C. to give racemic 3-(4-(7-((5-cyclopropyl-7-methyl-1H-indol-4-yl)methyl)-2,2-difluoro-7-azaspiro[3.5]nonan-6-yl)phenyl)oxetan-3-ol (Example Ex-49) as an off-white solid. LC-MS Method B-1: Rt=0.58 min; MS m / z[M+H] + =493.4.

[0352] Enantiomer separation and analysis by method SFC-8 using 123 mg of racemic 3-(4-(7-((5-cyclopropyl-7-methyl-1H-indol-4-yl)methyl)-2,2-difluoro-7-azaspiro[3.5]nonan-6-yl)phenyl)oxetan-3-ol, followed by removal of the solvent under reduced pressure at 50° C. and trituration with hexanes+a few drops of DCM, followed by removal of the solvent under reduced pressure at 50° C. (repeated three times) and drying under reduced pressure at 50° C. gave the following: Peak 1: (99.5% ee), Example Ex-25, 54 mg, off-white powder. LC-MS method B-1: Rt=0.60 min. MS m / z[M+H] + = 493.3. Analytical chiral HPLC (Method SFC-8): Rt = 1.65 min. Peak 2: (99.5% ee), Example Ex-26, 52 mg, off-white powder. LC-MS method B-1: Rt=0.62 min. MS m / z[M+H] + = 493.3. Analytical chiral HPLC (Method SFC-8): Rt = 3.15 min.

[0353] Examples Ex-57, Ex-33 and Ex-34: 6-(4-(1H-tetrazol-5-yl)phenyl)-7-((5-cyclopropyl-7-methyl-1H-indol-4-yl)methyl)-2,2-difluoro-7-azaspiro[3.5]nonane, (S)-6-(4-(1H-tetrazol-5-yl)phenyl)-7-((5-cyclopropyl-7-methyl-1H-indol-4-yl)methyl)-2,2-difluoro-7-azaspiro[3.5]nonane and (R)-6-(4-(1H-tetrazol-5-yl)phenyl)-7-((5-cyclopropyl-7-methyl-1H-indol-4-yl)methyl)-2,2-difluoro-7-azaspiro[3.5]nonane [ka] NaN3 (42.20 mg, 649.1 μmol) and NH4Cl (32.24 mg, 602.7 μmol) were added to a solution of tert-butyl 4-((6-(4-cyanophenyl)-2,2-difluoro-7-azaspiro[3.5]nonan-7-yl)methyl)-5-cyclopropyl-7-methyl-1H-indole-1-carboxylate (intermediate rac-A-29, 253.0 mg, 463.7 μmol) in DMF (2.50 mL). The capped vial was stirred at 100° C. overnight and then cooled to RT. The RM was diluted with MeOH (5.0 mL) and K2CO3 (325 mesh, 320.4 mg, 2.318 mmol) was added. The RM was stirred at 60° C. for 8 h and then the RM was kept without heating overnight. To quench the base, concentrated HCl (ca. 12 M, 193.2 μL) was added. MeOH was removed under reduced pressure at 50 °C. The resulting suspension was filtered and the solid was washed with MeOH. The filtered solution was directly purified three times by RP-HPLC (Waters Xbridge C18 dimensions: 30 mm × 100 mm 5 μm; flow rate 50 mL / min; eluent A = water + 0.2% FA; eluent B = ACN; gradient: 15 to 39.7% B in 12 min; wavelength: 229 / 250 nm). The purest fractions were combined and ACN was removed under reduced pressure at 45 °C. The aqueous solution was lyophilized to give racemic 6-(4-(1H-tetrazol-5-yl)phenyl)-7-((5-cyclopropyl-7-methyl-1H-indol-4-yl)methyl)-2,2-difluoro-7-azaspiro[3.5]nonane (Example Ex-57, 107 mg) as a slightly red fluffy solid. LC-MS Method B-1: Rt=0.66 min; MS m / z=489.3 [M+H] + .

[0354] Enantiomer separation and analysis by method SFC-13 using 96 mg of racemic 6-(4-(1H-tetrazol-5-yl)phenyl)-7-((5-cyclopropyl-7-methyl-1H-indol-4-yl)methyl)-2,2-difluoro-7-azaspiro[3.5]nonane, followed by removal of the solvent under reduced pressure at 50° C., trituration with hexane / DCM (2×) followed by removal of the solvent under reduced pressure at 50° C., dissolving the sample in ACN / MeOH followed by removal of the solvent under reduced pressure at 50° C. and drying under reduced pressure at 50° C. gave the following: Peak 1: (99.5% ee), Example Ex-33, 38 mg, gray powder. LC-MS method B-1: Rt=0.68 min. MS m / z[M+H] + = 489.5. Analytical chiral HPLC (Method SFC-13): Rt = 1.13 min. Peak 2: (99.5% ee), Example Ex-34, 40 mg, grey, slightly green powder. LC-MS Method B-1: Rt=0.65 min. MS m / z[M+H] + = 489.3. Analytical chiral HPLC (Method SFC-13): Rt = 2.08 min.

[0355] The following examples were synthesized from the appropriate starting materials by applying similar methods as described in the above examples.

[0356] Examples Ex-37 and Ex-38: (S)-2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-6-phenyl-7-azaspiro[3.5]nonane and (R)-2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-6-phenyl-7-azaspiro[3.5]nonane

[0357] Enantiomer separation and analysis of racemic mixture Ex-35 by method SFC-18 gave: Peak 1: (99.5% ee), Example Ex-37, 19.4 mg, off-white foam. LC-MS Method B-6: Rt=0.66 min. MS m / z[M+H]+ = 411.3. Analytical chiral HPLC (Method SFC-18): Rt = 1.35 min. Peak 2: (99.5% ee), Example Ex-38, 21.0 mg, off-white foam. LC-MS Method B-6: Rt=0.66 min. MS m / z[M+H] + = 411.4. Analytical chiral HPLC (Method SFC-18): Rt = 2.06 min.

[0358] Example Ex-39 and Example Ex-40 (S)-2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-6-(1-methyl-1H-pyrazol-4-yl)-7-azaspiro[3.5]nonane and (R)-2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-6-(1-methyl-1H-pyrazol-4-yl)-7-azaspiro[3.5]nonane Racemic mixture Enantiomer separation and analysis by method SFC-19 of Example 36 gave: Peak 1: (99.5% ee), Example Ex-39, 35.2 mg, off-white foam. LC-MS Method B-6: Rt=0.49 min. MS m / z[M+H] + = 415.1. Analytical chiral HPLC (Method SFC-19): Rt = 1.31 min. Peak 2: (99.5% ee), Example Ex-40, 34.6 mg, off-white foam. LC-MS Method B-6: Rt=0.49 min. MS m / z[M+H] + = 415.1. Analytical chiral HPLC (Method SFC-19): Rt = 1.82 min.

[0359] Examples Ex-41 and Ex-42: (S)-6-(1-(difluoromethyl)-1H-pyrazol-4-yl)-2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonane and (R)-6-(1-(difluoromethyl)-1H-pyrazol-4-yl)-2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonane Intermediate 41-42: (RS)-6-(1-(difluoromethyl)-1H-pyrazol-4-yl)-2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonane [ka] Racemic (RS)-6-(1-(difluoromethyl)-1H-pyrazol-4-yl)-2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonane was prepared similarly to the method described for intermediate rac-A-31 hereinabove using intermediate rac-P-21 and intermediate I-1. LC-MS Method B-6: Rt=0.48 min; MS m / z[M+H] + =451.1

[0360] Enantiomeric separation and analysis of racemic intermediates 41-42 by method SFC-20 gave: Peak 1: (99.5% ee), Example Ex-41, 8.2 mg, yellow oil. LC-MS method B-6: Rt=0.45 min. MS m / z[M+H] + = 451.4. Analytical chiral HPLC (Method SFC-20): Rt = 1.23 min. Peak 2: (98.0% ee), Example Ex-42, 13.0 mg, yellow oil. LC-MS method B-6: Rt=0.44 min. MS m / z[M+H] + = 451.4. Analytical chiral HPLC (Method SFC-20): Rt = 1.48 min.

[0361] Examples Ex-43 and Ex-44: (R)-2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-6-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)-7-azaspiro[3.5]nonane and (S)-2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-6-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)-7-azaspiro[3.5]nonane Intermediate 43-44: (RS)-2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-6-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)-7-azaspiro[3.5]nonane [ka] Racemic (RS)-2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-6-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)-7-azaspiro[3.5]nonane was prepared similarly to the method described for intermediate rac-A-31 hereinabove using intermediate rac-P-22 and intermediate I-1. LC-MS Method B-6: Rt=0.46 min; MS m / z[M+H] + =459.4

[0362] Enantiomeric separation and analysis of racemic intermediates 43-44 by method SFC-21 gave: Peak 1: (99.5% ee), Example Ex-43, 71.2 mg, off-white foam. LC-MS Method B-6: Rt=0.48 min. MS m / z[M+H] + = 459.5. Analytical chiral HPLC (Method SFC-21): Rt = 1.05 min. Peak 2: (99.4% ee), Example Ex-44, 72.9 mg, off-white foam. LC-MS Method B-6: Rt=0.46 min. MS m / z[M+H] + = 459.2. Analytical chiral HPLC (Method SFC-21): Rt = 1.59 min.

[0363] Examples Ex-54, Ex-55 and Ex-56: (SR)-6-(4-(1H-tetrazol-5-yl)phenyl)-2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonane, (S)-6-(4-(1H-tetrazol-5-yl)phenyl)-2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonane and (R)-6-(4-(1H-tetrazol-5-yl)phenyl)-2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonane Racemic (SR)-6-(4-(1H-tetrazol-5-yl)phenyl)-2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonane was prepared similarly to the method described for Example Ex-57 hereinabove using intermediate rac-P-18 and intermediate I-1. Example Ex-54: LC-MS Method B-6: Rt=0.49 min; MS m / z [MH] - =477.2

[0364] Enantiomer separation and analysis of the provided racemic mixture Ex-54 by method SFC-23 gave: Peak 1: (99.5% ee), Example Ex-55, 61.9 mg, off-white solid. LC-MS Method B-6: Rt=0.52 min. MS m / z[M+H] + = 479.5. Analytical chiral HPLC (Method SFC-23): Rt = 1.03 min. Peak 2: (99.5% ee), Example Ex-56, 63.6 mg, off-white solid. LC-MS method B-6: Rt=0.55 min. MS m / z[M+H] + = 479.1. Analytical chiral HPLC (Method SFC-23): Rt = 1.60 min.

[0365] Example 58, Example Ex-59 and Example Ex-60: (SR)-6-(6-(1H-tetrazol-5-yl)pyridin-3-yl)-2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonane, (S)-6-(6-(1H-tetrazol-5-yl)pyridin-3-yl)-2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonane and (R)-6-(6-(1H-tetrazol-5-yl)pyridin-3-yl)-2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonane Racemic (SR)-6-(6-(1H-tetrazol-5-yl)pyridin-3-yl)-2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonane was prepared similarly to the method described for Example Ex-57 herein using intermediate rac-P-26 and intermediate I-1. Example Ex-58: LC-MS Method B-6: Rt=0.43 min; MS m / z[M+H] + =480.2

[0366] Enantiomer separation and analysis of racemic mixture Ex-58 by method SFC-24 gave: Peak 1: (99.5% ee), Example Ex-59, 57.8 mg, off-white powder. LC-MS method B-6: Rt=0.46 min. MS m / z[M+H] + = 480.1. Analytical chiral HPLC (Method SFC-24): Rt = 1.09 min. Peak 2: (99.5% ee), Example Ex-60, 55.0 mg, off-white powder. LC-MS Method B-6: Rt=0.43 min. MS m / z[M+H] + = 480.5. Analytical chiral HPLC (Method SFC-24): Rt = 2.08 min.

[0367] Examples Ex-61, Ex-62 and Ex-63: (SR)-6-(6-(1H-tetrazol-5-yl)pyridin-3-yl)-7-((5-cyclopropyl-7-methyl-1H-indol-4-yl)methyl)-2,2-difluoro-7-azaspiro[3.5]nonane, (S)-6-(6-(1H-tetrazol-5-yl)pyridin-3-yl)-7-((5-cyclopropyl-7-methyl-1H-indol-4-yl)methyl)-2,2-difluoro-7-azaspiro[3.5]nonane and (R)-6-(6-(1H-tetrazol-5-yl)pyridin-3-yl)-7-((5-cyclopropyl-7-methyl-1H-indol-4-yl)methyl)-2,2-difluoro-7-azaspiro[3.5]nonane Racemic (SR)-6-(6-(1H-tetrazol-5-yl)pyridin-3-yl)-7-((5-cyclopropyl-7-methyl-1H-indol-4-yl)methyl)-2,2-difluoro-7-azaspiro[3.5]nonane was prepared similarly to the method described for Example Ex-57 herein using intermediate rac-P-26 and intermediate I-3. Example Ex-61: LC-MS Method B-6: Rt=0.73 min; MS m / z[M+H] + =490.2

[0368] Enantiomer separation and analysis of the racemic mixture Example Ex-61 by method SFC-25 gave: Peak 1: (99.5% ee), Example Ex-62, 58.3 mg, amber solid. LC-MS method B-6: Rt=0.73 min. MS m / z[M+H] + = 490.2. Analytical chiral HPLC (Method SFC-25): Rt = 1.29 min. Peak 2: (99.5% ee), Example Ex-63, 57.3 mg, off-white solid. LC-MS method B-6: Rt=0.74 min. MS m / z[M+H] + = 490.3. Analytical chiral HPLC (Method SFC-25): Rt = 3.35 min.

[0369] Representative analytical data for exemplified compounds is summarized below. Coupling patterns reported are apparent coupling patterns provided by MNova NMR software.

[0370] [Table 1]

[0371] [Table 2]

[0372] [Table 3]

[0373] [Table 4]

[0374] [Table 5]

[0375] [Table 6]

[0376] [Table 7]

[0377] [Table 8]

[0378] [Table 9]

[0379] [Table 10]

[0380]

Table 11

[0381]

Table 12

[0382]

Table 13

[0383]

Table 14

[0384]

Table 15

[0385]

Table 16

[0386]

Table 17

[0387]

Table 18

[0388]

Table 19

[0389]

Table 20

[0390] [Table 21]

[0391] [Table 22]

[0392] [Table 23]

[0393] [Table 24]

[0394] Measurement of optical rotation Method OR1: Anton Paar MCP 200 polarimeter, serial #82006136, cylindrical glass cell with 100 mm path length at 25°C. The wavelength of light used was 589 nanometers (sodium D line). The optical rotation of the same cell filled with solvent was subtracted as a baseline. The final result was the average of 10 measurements. Method OR2: Perkin-Elmer 241 Polarimeter MC, serial #5126, 100 mm path length cylindrical glass cell. The wavelength of light used was 589 nanometers (sodium D line). The optical rotation of the same cell filled with solvent was subtracted as a baseline. The final result was the average of three measurements.

[0395] LC-MS method LC-MS method A-1: Column: Synergi 2.5μ (20×4.0mm), MAX-RP 100 A Mercury Column temperature: 40℃ Eluent: A: Water + FA (0.1%) B:ACN Flow rate: 2.0mL / min Gradient: Time / %B: 0.1 / 5; 0.5 / 5; 1.0 / 95; 1.5 / 95; 2.0 / 5; 3.0 / 5 (ternary method)

[0396] LC-MS method C-1: Column: Acquity UPLC BEH C18, 130Å 1.7μm, 2.1mm×30mm Column temperature: 50℃ Eluent: A: Water + NH4OH (5mM) B: ACN+NH4OH (5mM) Flow rate: 1.0mL / min Gradient: 2% to 98% B in 2.0 min

[0397] LC-MS method C-2: Column: Acquity UPLC BEH C18, 130Å 1.7μm, 2.1mm×50mm Column temperature: 50℃ Eluent: A: Water + NH4OH (5mM) B: ACN+NH4OH (5mM) Flow rate: 1.0mL / min Gradient: 2% to 98% B in 5.2 min

[0398] LC-MS method C-3: Column: ACQUITY UPLC BEH C18, 130Å, 1.7μm, 2.1mm×30mm Column temperature: 50℃ Eluent: A: Water + FA (0.1%) B: ACN+FA(0.1%) Flow rate: 1.0mL / min Gradient: 2% to 98% B in 2.0 min

[0399] LC-MS method B-1: Column: CORTECS C18+, 2.1 x 50mm column, 2.7μm Column temperature: 80℃ Eluent: A: Water+4.76% IPA+0.05% FA+3.75mM NH4(CH3CO2) B: IPA + 0.05% FA Flow rate: 1.0mL / min Gradient: initial 1% B; 1% to 50% B in 1.4 min, 50% to 98% B in 0.30 min; 98% B in 0.10 min.

[0400] LC-MS method B-2: Column: XBridge BEH, 2.1×50mm column, 2.5μm Column temperature: 80℃ Eluent: A: Water + 5mM NH4OH B: ACN+5mM NH4OH: Flow rate: 1.0mL / min Gradient: initial 2% B; 2% to 98% B in 1.40 min; 98% B in 0.40 min.

[0401] LC-MS method B-3: Column: Acquity UPLC BEH C18, 2.1 x 100mm column, 1.7μm Column temperature: 80℃ Eluent: A: Water+4.76% IPA+0.05% FA+3.75mM NH4(CH3CO2) B: IPA + 0.05% FA Flow rate: 0.4mL / min Gradient: pre-run at 1% B for 0.50 min; 1% to 60% B in 8.4 min, 60% to 98% B in 1.00 min; 98% B in 0.40 min.

[0402] LC-MS method B-4: Column: CORTECS C18+, 2.1 x 50mm column, 2.7μm Column temperature: 80℃ Eluent: A: Water+0.05% FA+3.75mM NH4(CH3CO2) B: IPA + 0.05% FA Flow rate: 1.0mL / min Gradient: initial 1% B; 1% to 98% B in 1.40 min; 98% B in 0.40 min.

[0403] LC-MS method B-5: Column: ACQUITY UPLC BEH C18, 2.1 x 50mm column, 1.7μm Column temperature: 80℃ Eluent: A: Water + 0.01% TFA B:ACN Flow rate: 1.0mL / min Gradient: initial 5% B; 5–98% B in 1.4 min.

[0404] LC-MS method B-6: Column: CORTECS C18+, 2.1 x 50mm column, 2.7μm Column temperature: 80℃ Eluent: A: Water+0.05% FA+3.75mM NH4(CH3CO2) 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.

[0405] LC-MS method B-7: Column: Acquity UPLC BEH C18, 2.1 x 100mm column, 1.7μm Column temperature: 80℃ Eluent: A: Water + 0.05% FA + 3.75mM ammonium acetate B: IPA + 0.05% FA Flow rate: 0.4mL / min Gradient: pre-run at 5% B for 0.50 min; 5% to 60% B in 8.4 min, 60% to 98% B in 1.00 min; 98% B in 0.40 min.

[0406] Chiral Preparative HPLC Method Waters automated purification system equipped with a PDA (photodiode array detector) and a single quadrupole mass detector with ESI ionization. device: Pump: Waters 2545 Fraction collector: Waters 2767 Reformer pump: Waters 515 Detector: Waters 2998 Mass spectrometry: Waters SQD-2 Column: Waters XBridge BEH C18 OBD 5μm 30×50mm Eluent: A: Water B:ACN Flow rate: 75mL / min Downtime: 6.5 minutes Column temperature: RT UV 210~400nm

[0407] Chiral HPLC Method Method SFC-1: Equipment: Waters Acquity UPC2 Column: Chiralpak IE-3 (3 μm) 3 mm × 100 mm Column temperature: 40℃ Eluent: A: 0.1% NH3 in MeOH / IPA (1 / 1) B: scCO2 Flow rate: 2.5mL / min Gradient: 5% B in 0.2 min, 5–55% B in 3.0 min Pressure: 1800psi

[0408] Method SFC-2: Equipment: Waters Acquity UPC2 Column: (S,S)Whelk-O1(3.5μm)3mm×100mm Column temperature: 40℃ Eluent: A: 0.1% NH3 in MeOH / IPA (1 / 1) B: scCO2 Flow rate: 2.5mL / min Gradient: 5% B in 0.2 min, 5–55% B in 3.0 min Pressure: 1800psi

[0409] Method SFC-3: Preparative Chiral HPLC Equipment: Sepiatec prep SFC-100 Column: Chiralpak AD, 250mm x 30mm 5μm Eluent: A: 0.05% NH3 in 20% MeOH, B: 80% scCO2 (isocratic) Flow rate: 90.0mL / min Detection: UV 234nm Injection volume: 2.3mL Oven temperature: 40℃ Pressure: 130bar

[0410] Analytical Chiral HPLC Instrument: Analytical SFC-MS Waters UPC2 Injection: 5μL Mobile phase: A: 0.1% NH3 in 20% IPA, B: 80% scCO2 (isocratic) Flow rate: 3mL / min Column: Chiralpak AD (4.6mm×100mm 5μm) Detection UV: DAD Oven temperature: 40℃ Pressure: 1800psi

[0411] Method SFC-4: Preparative Chiral HPLC Equipment: Sepiatec prep SFC-100 Column: Chiralpak AD, 250mm x 30mm 5μm Eluent: A: 0.05% NH3 in 22% MeOH, B: 78% scCO2 (isocratic) Flow rate: 90.0mL / min Detection: UV 234nm Injection volume: 2.5mL Oven temperature: 40℃ Pressure: 130bar

[0412] Analytical Chiral HPLC Instrument: Analytical SFC-MS Waters UPC2 Injection: 5μL Mobile phase: A: 0.1% NH3 in 20% IPA, B: 80% scCO2 (isocratic) Flow rate: 3mL / min Column: Chiralpak AD (4.6mm×100mm 5μm) Detection UV:DAD Oven temperature: 40℃ Pressure: 1800psi

[0413] Method SFC-5: Preparative Chiral HPLC Equipment: Waters Prep SFC100 MS Column: Chiralpak AD, 250mm x 30mm 5μm Eluent: A: 0.05% NH3 in 18% IPA, B: 82% scCO2 (isocratic) Flow rate: 80.0mL / min Detection: DAD Injection volume: 2.0mL Oven temperature: 40℃ Pressure: 120bar

[0414] Analytical Chiral HPLC Instrument: Analytical SFC-MS Waters UPC2 Injection: 5μL Mobile phase: A: 0.1% NH3 in 18% IPA, B: 82% scCO2 (isocratic) Flow rate: 3mL / min Column: Chiralpak AD (4.6mm×100mm 5μm) Detection UV: DAD Oven temperature: 40℃ Pressure: 1800psi

[0415] Method SFC-6: Preparative Chiral HPLC Equipment: Waters Prep SFC100 MS Column: Chiralpak IG, 250mm x 30mm 5μm Eluent: A: 0.05% NH3 in 50% MeOH, B: 50% scCO2 (isocratic) Flow rate: 80.0mL / min Detection: DAD Injection volume: 3.5mL Oven temperature: 40℃ Pressure: 120bar

[0416] Analytical Chiral HPLC Instrument: Analytical SFC-MS Waters UPC2 Injection: 5μL Mobile phase: A: 0.05% NH3 in 50% MeOH, B: 50% scCO2 (isocratic) Flow rate: 3mL / min Column: Chiralpak IG (4.6mm×100mm 5μm) Detection UV: DAD Oven temperature: 40℃ Pressure: 1800psi

[0417] Method SFC-7: Preparative Chiral HPLC Equipment: Sepiatec prep SFC-100 Column: Chiralpak IC, 250mm x 30mm 5μm Elution medium: A: 0.05% NH3 in 30% IPA, B: 70% scCO2 (isocratic) Flow rate: 80.0mL / min Detection: UV 237nm Injection volume: 0.8mL Oven temperature: 36°C Pressure: 130bar

[0418] Analytical Chiral HPLC Instrument: Analytical SFC-MS Waters UPC2 Injection: 5μL Mobile phase: A: 0.05% NH3 in 30% IPA, B: 70% scCO2 (isocratic) Flow rate: 3mL / min Column: Chiralpak IC (4.6mm x 100mm 5μm) Detection UV: DAD Oven temperature: 40℃ Pressure: 1800psi

[0419] Method SFC-8: Preparative Chiral HPLC Equipment: Waters Prep SFC100 MS Column: Amylose-1 250×30mm 5μm Eluent: A: 0.05% NH3B in 22% MeOH: 78% scCO2 (isocratic) Flow rate: 80.0mL / min Detection: DAD Injection volume: 2.0mL Oven temperature: 40℃ Pressure: 120bar

[0420] Analytical Chiral HPLC Instrument: Analytical SFC-MS Waters UPC2 Injection: 5μL Mobile phase: A: 20% 0.05% NH3 in MeOH, B: 80% scCO2 (isocratic) Flow rate: 3mL / min Column: Chiralpak AD (4.6mm×100mm 5μm) Detection UV:DAD Oven temperature: 40℃ Pressure: 1800psi

[0421] Method SFC-9: Preparative Chiral HPLC Equipment: Sepiatec SFC 100 Column: Chiralpak AD, 250mm x 30mm 5μm Eluent: A: 0.05% NH3 in 18% MeOH, B: 82% scCO2 (isocratic) Flow rate: 80.0mL / min Detection: UV 220nm Injection volume: 2.4mL Oven temperature: 40℃ Pressure: 130bar

[0422] Analytical Chiral HPLC Instrument: Analytical SFC-MS Waters UPC2 Injection: 5μL Mobile phase: A: 0.05% NH3 in 18% MeOH, B: 82% scCO2 (isocratic) Flow rate: 3mL / min Column: Chiralpak AD (4.6mm×100mm 5μm) Detection UV:DAD Oven temperature: 40℃ Pressure: 1800psi

[0423] Method SFC-10: Preparative Chiral HPLC Equipment: Sepiatec SFC100 Column: Chiralpak IG, 250mm x 30mm 5μm Eluent: A: 0.05% NH3 in 40% MeOH, B: 60% scCO2 (isocratic) Flow rate: 80.0mL / min Detection: UV 220nm Injection volume: 2.2mL Oven temperature: 40℃ Pressure: 130bar

[0424] Analytical Chiral HPLC Instrument: Analytical SFC-MS Waters UPC2 Injection: 5μL Mobile phase: A: 0.05% NH3 in 40% MeOH, B: 60% scCO2 (isocratic) Flow rate: 3mL / min Column: Chiralpak IG (4.6mm×100mm 5μm) Detection UV: DAD Oven temperature: 40℃ Pressure: 1800psi

[0425] Method SFC-11: Preparative Chiral HPLC Equipment: Sepiatec SFC100 Column: Chiralpak AD, 250mm x 30mm 5μm Eluent: A: 0.05% NH3 in 35% MeOH, B: 65% scCO2 (isocratic) Flow rate: 80.0mL / min Detection: DAD Injection volume: 2.8mL Oven temperature: 40℃ Pressure: 130bar

[0426] Analytical Chiral HPLC Instrument: Analytical SFC-MS Waters UPC2 Injection: 5μL Mobile phase: A: 0.05% NH3 in 30% MeOH, B: 70% scCO2 (isocratic) Flow rate: 3mL / min Column: Chiralpak AD (4.6mm×100mm 5μm) Detection UV:DAD Oven temperature: 40℃ Pressure: 1800psi

[0427] Method SFC-12: Preparative Chiral HPLC Equipment: Waters Prep SFC100 MS Column: Chiralpak IG, 250mm x 30mm 5μm Elution medium: A: 0.05% NH3 in 20% IPA, B: 80% scCO2 (isocratic) Flow rate: 80.0mL / min Detection: DAD Injection volume: 4.0mL Oven temperature: 40℃ Pressure: 120bar

[0428] Analytical Chiral HPLC Instrument: Analytical SFC-MS Waters UPC2 Injection: 5μL Mobile phase: A: 0.05% NH3 in 20% IPA, B: 80% scCO2 (isocratic) Flow rate: 3mL / min Column: Chiralpak IG (4.6mm×100mm 5μm) Detection UV: DAD Oven temperature: 40℃ Pressure: 1800psi

[0429] Method SFC-13: Preparative Chiral HPLC Equipment: Waters Prep SFC100 MS Column: Chiralpak IG, 250mm x 30mm 5μm Elution medium: A: 0.05% NH3 in 30% IPA, B: 70% scCO2 (isocratic) Flow rate: 80.0mL / min Detection: DAD Injection volume: 4mL Oven temperature: 40℃ Pressure: 120bar

[0430] Analytical Chiral HPLC Instrument: Analytical SFC-MS Waters UPC2 Injection: 5μL Mobile phase: A: 0.05% NH3 in 30% IPA, B: 70% scCO2 (isocratic) Flow rate: 3mL / min Column: Chiralpak IG (4.6mm×100mm 5μm) Detection UV: DAD Oven temperature: 40℃ Pressure 1800psi

[0431] Method SFC-14: Preparative Chiral HPLC Equipment: Sepiatec SFC100 Column: Chiralpak AD-H, 250mm x 30mm 5μm Eluent: A: 0.05% NH3 in 23% MeOH, B: 77% scCO2 (isocratic) Flow rate: 90.0mL / min; Detection: UV 234nm Injection volume: 2.30mL Oven temperature: 36°C Pressure: 130bar

[0432] Analytical Chiral HPLC Instrument: Analytical SFC-MS Waters UPC2 Injection: 5μL Mobile phase: A: 0.05% NH3 in 20% IPA, B: 80% scCO2 (isocratic) Flow rate: 3mL / min Column: Chiralpak AD (4.6mm×100mm 5μm) Detection UV: DAD Oven temperature: 40℃ Pressure: 1800psi

[0433] Method SFC-15: Preparative Chiral HPLC Equipment: Sepiatec SFC100 Column: Chiralpak AD, 250mm x 30mm 5μm Eluent: A: 0.05% NH3 in 22% IPA, B: 78% scCO2 (isocratic) Flow rate: 85.0mL / min Detection: UV 234nm Injection volume: 9mL Oven temperature: 40℃ Pressure: 120bar

[0434] Analytical Chiral HPLC Instrument: Analytical SFC-MS Waters UPC2 Injection: 5μL Mobile phase: A: 0.05% NH3 in 20% IPA, B: 80% scCO2 (isocratic) Flow rate: 3mL / min Column: Chiralpak AD (4.6mm×100mm 5μm) Detection UV: DAD Oven temperature: 40℃ Pressure: 1800psi

[0435] Method SFC-16: Instrument: Agilent 1260 infinity II Column: Chiralpak IJ (5μm×4.6mm×150mm) Column temperature: 25℃ Eluent: A: 80% hexane, B: 20% EtOH / MeOH (1:1) (isocratic) Flow rate: 1mL / min Detection UV: DAD

[0436] Method SFC-17: Instrument: Agilent 1260 infinity II Column: Chiralpak IG (5μm×4.6mm×150mm) Column temperature: 25℃ Eluent: A: 70% hexane, B: 30% EtOH / MeOH (1:1) (isocratic) Flow rate: 1mL / min Detection UV: DAD

[0437] Method SFC-18: Preparative Chiral HPLC Equipment: Waters Prep SFC100 MS Column: Chiralpak AD, 250mm x 30mm 5μm Eluent: A: 0.05% NH3 in 19% IPA, B: 81% scCO2 (isocratic) Flow rate: 80.0mL / min Detection: DAD Injection volume: 3mL Oven temperature: 40℃ Pressure: 120bar

[0438] Analytical Chiral HPLC Instrument: Analytical SFC-MS Waters UPC2 Injection: 5μL Mobile phase: A: 0.05% NH3 in 20% IPA, B: 80% scCO2 (isocratic) Flow rate: 3mL / min Column: Chiralpak AD (4.6mm×100mm 5μm) Detection UV: DAD Oven temperature: 40℃ Pressure 1800psi

[0439] Method SFC-19: Preparative Chiral HPLC Equipment: Sepiatec prep SFC 100 Column: Lux Cellulose 2,250mm x 30mm 5μm (OZ) Elution medium: A: 0.05% NH3 in 25% IPA, B: 75% scCO2 (isocratic) Flow rate: 110.0mL / min Detection: UV 217nm Injection volume: 27×3mL Oven temperature: 40℃ Pressure: 130bar

[0440] Analytical Chiral HPLC Instrument: Analytical SFC-MS Waters UPC2 Injection: 5μL Mobile phase: A: 30% 0.05% NH3 in IPA, B: 70% scCO2 (isocratic) Flow rate: 3mL / min Column: Chiralcel OZ (4.6mm x 100mm 5μm) Detection UV: DAD Oven temperature: 40℃ Pressure 1800psi

[0441] Method SFC-20: Preparative Chiral HPLC Equipment: Sepiatec prep SFC 100 Column: Chiralpak AD-H, 250mm x 30mm 5μm Elution medium: A: 0.05% NH3 in 15% IPA, B: 85% scCO2 (isocratic) Flow rate: 80mL / min Detection: UV 220nm Injection volume: 7×1.60mL Oven temperature: 40℃ Pressure: 90bar

[0442] Analytical Chiral HPLC Instrument: Analytical SFC-MS Waters UPC2 Injection: 5μL Mobile phase: A: 0.05% NH3 in 18% IPA, B: 82% scCO2 (isocratic) Flow rate: 3mL / min Column: Chiralpak AD (4.6mm×100mm 5μm) Detection UV: DAD Oven temperature: 40℃ Pressure 1800psi

[0443] Method SFC-21: Preparative Chiral HPLC Equipment: Sepiatec prep SFC 100 Column: Chiralpak IG, 250mm x 30mm 5μm Elution medium: A: 0.05% NH3 in 30% IPA, B: 70% scCO2 (isocratic) Flow rate: 80mL / min Detection: UV 220nm Injection volume: 21×0.60mL Oven temperature: 40℃ Pressure: 130bar

[0444] Analytical Chiral HPLC Instrument: Analytical SFC-MS Waters UPC2 Injection: 5μL Mobile phase: A: 30% 0.05% NH3 in IPA, B: 70% scCO2 (isocratic) Flow rate: 3mL / min Column: Chiralpak IG (4.6mm×100mm 5μm) Detection UV:DAD Oven temperature: 40℃ Pressure 1800psi

[0445] Method SFC-22: Preparative Chiral HPLC Equipment: Sepiatec prep SFC 100 Column: Chiralpak IG, 250mm x 30mm 5μm Eluent: A: 0.05% NH3 in 18% IPA, B: 82% scCO2 (isocratic) Flow rate: 80mL / min Detection: UV 235nm Injection volume: 16×0.80mL Oven temperature: 40℃ Pressure: 140bar

[0446] Analytical Chiral HPLC Instrument: Analytical SFC-MS Waters UPC2 Injection: 5μL Mobile phase: A: 0.05% NH3 in 20% IPA, B: 80% scCO2 (isocratic) Flow rate: 3mL / min Column: Chiralpak IG (4.6mm×100mm 5μm) Detection UV: DAD Oven temperature: 40℃ Pressure 1800psi

[0447] Method SFC-23: Preparative Chiral HPLC Equipment: Sepiatec prep SFC 100 Column: Chiralpak IG, 250mm x 30mm 5μm Elution medium: A: 0.05% NH3 in 40% IPA, B: 60% scCO2 (isocratic) Flow rate: 130mL / min Detection: UV 245nm Injection volume: 15×3.00mL Oven temperature: 40℃ Pressure: 130bar

[0448] Analytical Chiral HPLC Instrument: Analytical SFC-MS Waters UPC2 Injection: 5μL Mobile phase: A: 0.05% NH3 in 35% IPA, B: 65% scCO2 (isocratic) Flow rate: 3mL / min Column: Chiralpak IG (4.6mm×100mm 5μm) Detection UV: DAD Oven temperature: 40℃ Pressure 1800psi

[0449] Method SFC-24: Preparative Chiral HPLC Equipment: Sepiatec prep SFC 100 Column: Chiralpak AD-H, 250mm x 30mm 5μm Elution medium: A: 0.05% NH3 in 35% IPA, B: 65% scCO2 (isocratic) Flow rate: 80mL / min Detection: UV 220nm Injection volume: 9×1.50mL Oven temperature: 40℃ Pressure: 130bar

[0450] Analytical Chiral HPLC Instrument: Analytical SFC-MS Waters UPC2 Injection: 5μL Mobile phase: A: 0.05% NH3 in 35% IPA, B: 65% scCO2 (isocratic) Flow rate: 3mL / min Column: Chiralpak AD (4.6mm×100mm 5μm) Detection UV: DAD Oven temperature: 40℃ Pressure 1800psi

[0451] Method SFC-25: Preparative Chiral HPLC Equipment: Sepiatec prep SFC 100 Column: Chiralpak AD-H, 250mm x 30mm 5μm Eluent: A: 0.05% NH3 in 38% IPA, B: 62% scCO2 (isocratic) Flow rate: 80mL / min Detection: UV 220nm Injection volume: 10×2.00mL Oven temperature: 40℃ Pressure: 130bar

[0452] Analytical Chiral HPLC Instrument: Analytical SFC-MS Waters UPC2 Injection: 5μL Mobile phase: A: 30% 0.05% NH3 in IPA, B: 70% scCO2 (isocratic) Flow rate: 3mL / min Column: Chiralpak AD (4.6mm×100mm 5μm) Detection UV: DAD Oven temperature: 40℃ Pressure 1800psi

[0453] Method SFC-26: Preparative Chiral HPLC Equipment: Waters Prep SFC100 MS Column: Chiralpak IC, 250mm x 30mm 5μm Eluent: A: 0.1% NH3 in 28% MeOH, B: 72% scCO2 (isocratic) Flow rate: 80mL / min Detection: DAD Injection volume: 1.0mL Oven temperature: 40℃ Pressure: 120bar

[0454] Analytical Chiral HPLC Instrument: Analytical SFC-MS Waters UPC2 Injection: 5μL Mobile phase: A: 0.05% NH3 in 20% IPA, B: 80% scCO2 (isocratic) Flow rate: 3mL / min Column: Chiralpak AD (4.6mm×100mm 5μm) Detection UV: DAD Oven temperature: 40℃ Pressure 1800psi

[0455] Method SFC-27: Preparative Chiral HPLC Equipment: Sepiatec prep SFC 100 Column: Chiralpak IG, 250mm x 30mm 5μm Elution medium: A: 0.05% NH3 in 27% IPA, B: 73% scCO2 (isocratic) Flow rate: 80mL / min Detection: UV 235nm Injection volume: 7×1.00mL Oven temperature: 40℃ Pressure: 110bar

[0456] Analytical Chiral HPLC Instrument: Analytical SFC-MS Waters UPC2 Injection: 5μL Mobile phase: A: 0.05% NH3 in 25% IPA, B: 75% scCO2 (isocratic) Flow rate: 3mL / min Column: Chiralpak IG (4.6mm×100mm 5μm) Detection UV: DAD Oven temperature: 40℃ Pressure 1800psi

[0457] Method SFC-28: Preparative Chiral HPLC Equipment: Sepiatec prep SFC 100 Column: Chiralpak IG, 250mm x 30mm 5μm Elution medium: A: 0.05% NH3 in 25% IPA, B: 75% scCO2 (isocratic) Flow rate: 80mL / min Detection: UV 230nm Injection volume: 13×1.00mL Oven temperature: 40℃ Pressure: 130bar

[0458] Analytical Chiral HPLC Instrument: Analytical SFC-MS Waters UPC2 Injection: 5μL Mobile phase: A: 0.05% NH3 in 25% IPA, B: 75% scCO2 (isocratic) Flow rate: 3mL / min Column: Chiralpak IG (4.6mm×100mm 5μm) Detection UV: DAD Oven temperature: 40℃ Pressure 1800psi

[0459] biological analysis 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 3 nm concentration was incubated with various concentrations of test compound for 1 h at RT in PBS pH 7.4 containing 10 mM MgCl2 and 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.

[0460] 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.

[0461] 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 assays of Biological Example 2.6 and Biological Example 1) as a function of test compound concentration. 50 values ​​were calculated.

[0462] 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.

[0463] [Table 25]

[0464] [Table 26]

[0465] [Table 27]

[0466] 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.

[0467] 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, X is O or CR Ｘ１ R Ｘ２ and R １ is H, C １ ~C ６ Alkoxyl, C ３ ~C ５ Cycloalkoxyl, C １ ~C ６ Alkyl, and C ３ ~C ５ cycloalkyl, wherein C １ ~C ６ Alkoxyl, C １ ~C ６ Alkyl, and C ３ ~C ５ The cycloalkyl is unsubstituted or substituted with 1 or 2 halogen substituents; R ２ is C １ ~C ３ Alkyl or C ３ cycloalkyl, １ ~C ３ Alkyl or C ３ The cycloalkyl is unsubstituted or substituted with 1 or 2 halogen substituents; R Ｘ１ is hydrogen, fluoro, C １ ~C ６ Alkyl, and C ３ ~C ５ cycloalkyl; R Ｘ２ is hydroxyl, fluoro, C １ ~C ６ Alkyl, and C ３ ~C ５ cycloalkyl; However, R Ｘ２ is hydroxyl, R Ｘ１ Isn't it fluoro? Or, R Ｘ１ and R Ｘ２ combine with the carbon atom to which they are attached to form a spirocyclic carbocycle having 3 to 5 ring atoms; A is a phenyl ring or a 5- or 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from N, O, and S; Each R ５ is H, -CO ２ R ５ｂ , C １ ~C ６ Alkyl, CH ２ CO ２ R ５ｂ , C １ ~C ６ Hydroxyalkyl, 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; １ ~C ６ Hydroxyalkyl, C １ ~C ６ Alkyl, 5- to 6-membered heteroaryl and 4- to 6-membered heterocyclyl are unsubstituted or have one or two R ５ａ is substituted with; Each R ５ａ is fluoro, hydroxyl and C １ ~C ６ alkyl, wherein C １ ~C ６ alkyl is unsubstituted or substituted with 1, 2 or 3 fluoro; R ５ When R is a 4- to 6-membered heterocyclyl, two R ５ａ is not fluoro and hydroxyl substituted at the same position; and R ５ｂ is H or C １ ~C ５ alkyl; m is 0 or 1; n is 0, 1 or 2; Both m and n are not 0; however, When X is O, m is 1 and n is 1 or 2. or a pharmaceutically acceptable salt thereof.

2. Formula (IA) or (IB) 【Chemistry 2】 2. A compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof.

3. 3. The compound IA of claim 2, or a pharmaceutically acceptable salt thereof.

4. R ２ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein is selected from methyl, ethyl, and cyclopropyl.

5. R ２ 5. The compound of claim 4, or a pharmaceutically acceptable salt thereof, wherein is methyl.

6. 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein A is a phenyl ring.

7. R ５ 7. The compound of claim 6, or a pharmaceutically acceptable salt thereof, wherein is substituted at the para position of the phenyl ring.

8. 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein A is selected from furanyl, thiophenyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, pyrazolyl, imidazolyl, pyridyl, triazolyl, tetrazolyl, oxadiazolyl, isoxadiazolyl, pyrimidinyl, pyrazinyl, and pyridazinyl.

9. A is the following: 【Transformation 3】 9. The compound of claim 8, selected from:

10. R ５ But -CO ２ H, C １ ~C ６ hydroxyalkyl, 5-6 membered heteroaryl having 1-4 heteroatoms independently selected from N, O and S, and 4-6 membered heterocyclyl having 1 O heteroatom, wherein said 4-6 membered heterocyclyl is selected from 0-1 R ５ａ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, substituted with:

11. R ５ CO ２ R ５ｂ , C １ ~C ６ hydroxyalkyl, 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 and R ５ａ is hydroxyl, and R ５ｂ 2. The compound of claim 1, wherein is H, or a pharmaceutically acceptable salt thereof.

12. R ５ But -CO ２ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, selected from H, tetrazole, and hydroxyl-substituted oxetane.

13. R ５ Ga-CO ２ 2. The compound of claim 1, wherein R is H; or a pharmaceutically acceptable salt thereof.

14. R ５ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein is tetrazole.

15. R １ is C １ ~C ４ Alkoxyl, C １ ~C ４ Alkyl, and C ３ ~C ６ cycloalkyl, wherein C ３ ~C ６ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein cycloalkyl is unsubstituted or substituted with one or two fluoro substituents.

16. R １ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein is selected from methoxyl, methyl, and cyclopropyl, and said cyclopropyl is unsubstituted or substituted with one or two fluoro substituents.

17. R １ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein is selected from methoxyl and cyclopropyl, and said cyclopropyl is unsubstituted or substituted with one or two fluoro substituents.

18. R Ｘ１ and R Ｘ２ are both fluoro or fluoro and C １ ~C ６ alkyl, hydrogen and fluoro, or C １ ~C ６ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein: R is alkyl and hydroxyl; or R is hydrogen and hydroxyl.

19. R Ｘ１ and R Ｘ２ are both fluoro or fluoro and C １ ~C ６ 19. The compound of claim 18, wherein R is alkyl, or fluoro and H; or a pharmaceutically acceptable salt thereof.

20. 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein n is 1 or 2.

21. 2. The compound of claim 1, wherein X is O, or a pharmaceutically acceptable salt thereof.

22. X is CR Ｘ１ R Ｘ２ 2. The compound of claim 1, wherein:

23. R Ｘ１ is fluoro and R Ｘ２ is fluoro and C １ ~C ６ 23. The compound of claim 22, or a pharmaceutically acceptable salt thereof, wherein:

24. R ５ａ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein is hydroxyl.

25. Select from: 【Chemistry 4】 【Transformation 5】 【Transformation 6】 【Transformation 7】 【Transformation 8】 【Chemistry 9】 【Chemistry 10】 【Chemistry 11】 【Chemistry 12】 The compound or a pharmaceutically acceptable salt thereof.

26. 10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, present in at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess.

27. 10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, present in at least 90% diastereomeric excess, at least 95% diastereomeric excess, or at least 99% diastereomeric excess.

28. The compound of claim 25, or a pharmaceutically acceptable salt thereof, present in at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess.

29. The compound of claim 25, or a pharmaceutically acceptable salt thereof, present in at least 90% diastereomeric excess, at least 95% diastereomeric excess, or at least 99% diastereomeric excess.

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

31. 1. A pharmaceutical composition for use in a method for treating or preventing a disease or disorder in a subject in need thereof, comprising: The pharmaceutical composition comprises a compound of any one of claims 1 to 29 or a pharmaceutically acceptable salt thereof, and the method comprises administering to the subject a therapeutically effective amount of a compound of any one of claims 1 to 29 or a pharmaceutically acceptable salt thereof.

32. 1. A pharmaceutical composition for use in a method of modulating alternative complement pathway activity in a subject, comprising: The pharmaceutical composition comprises a compound of any one of claims 1 to 29 or a pharmaceutically acceptable salt thereof, and the method comprises administering to the subject a therapeutically effective amount of a compound of any one of claims 1 to 29 or a pharmaceutically acceptable salt thereof.

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

34. 1. A pharmaceutical composition for use in a method of treating a disease or disorder affected by modulation of the alternative complement pathway, comprising: The pharmaceutical composition comprises a compound of any one of claims 1 to 29 or a pharmaceutically acceptable salt thereof, and the method comprises administering to a subject a therapeutically effective amount of a compound of any one of claims 1 to 29 or a pharmaceutically acceptable salt thereof.

35. 1. A pharmaceutical composition for use in a method of treating a disease or disorder associated with dysregulation of the alternative complement pathway, comprising: The pharmaceutical composition comprises a compound of any one of claims 1 to 29 or a pharmaceutically acceptable salt thereof, and the method comprises administering to a subject a therapeutically effective amount of a compound of any one of claims 1 to 29 or a pharmaceutically acceptable salt thereof.

36. 1. A pharmaceutical composition for use in a method for inhibiting expression or activity of complement factor B, comprising: The pharmaceutical composition comprises a compound according to any one of claims 1 to 29 or a pharmaceutically acceptable salt thereof, and the method comprises administering to a subject a compound according to any one of claims 1 to 29 or a pharmaceutically acceptable salt thereof.

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 retinochoroiditis, 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 inflammatory disease, 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 unwanted 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 C 3 glomerulonephritis), IgA nephropathy, membranous nephropathy including idiopathic membranous nephropathy, diabetic nephropathy, atypical hemolytic uremic syndrome, hemolytic uremic syndrome, STEC-HUS (Shiga toxin-producing E. coli hemolytic uremic syndrome), peritonitis, CD55 deficiency with complement hyperactivation, vasculopathy thrombosis, protein-losing enteropathy (CHAPLE syndrome), inflammatory or autoimmune diseases such as Crohn's disease, adult respiratory distress syndrome, myocarditis, post-ischemic reperfusion state, myocardial infarction, balloon angioplasty, post-pump syndrome in cardiopulmonary bypass 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, spondyloarthropathies including rheumatoid arthritis, osteoarthritis, psoriatic arthritis, systemic lupus erythematosus (SLE), lupus nephritis, SLE nephritis, proliferative nephritis, 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 32. The pharmaceutical composition of claim 31, wherein the therapeutic agent is selected from the group consisting of pulmonary vasculitis, pauciimmune vasculitis including antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, other vasculitides such as Henoch-Schnerein vasculitis, Buerger's vasculitis, cryoglobulinemia, Kawasaki disease, Takayasu's arteritis, 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. 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 retinochoroiditis, 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, and North Neurological disorders such as carolina macular dystrophy, Stargardt's disease, corneal inflammatory disease, 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 unwanted 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 C 3 glomerulonephritis), IgA nephropathy, membranous nephropathy including idiopathic membranous nephropathy, diabetic nephropathy, atypical hemolytic uremic syndrome, hemolytic uremic syndrome, STEC-HUS (Shiga toxin-producing E. coli hemolytic uremic syndrome), peritonitis, CD55 deficiency with complement hyperactivation, vasculopathy thrombosis, protein-losing enteropathy (CHAPLE syndrome), inflammatory or autoimmune diseases such as Crohn's disease, adult respiratory distress syndrome, myocarditis, post-ischemic reperfusion state, myocardial infarction, balloon angioplasty, post-pump syndrome in cardiopulmonary bypass 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, spondyloarthropathies including rheumatoid arthritis, osteoarthritis, psoriatic arthritis, systemic lupus erythematosus (SLE), lupus nephritis, SLE nephritis, proliferative nephritis, 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 34. The pharmaceutical composition of claim 33, wherein the therapeutic agent is selected from the group consisting of pulmonary vasculitis, pauciimmune vasculitis including antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, other vasculitides such as Henoch-Schnerein vasculitis, Bürger's vasculitis, cryoglobulinemia, Kawasaki disease, Takayasu's arteritis, 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.

39. 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 retinochoroiditis, 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, and North Neurological disorders such as carolina macular dystrophy, Stargardt's disease, corneal inflammatory disease, 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 unwanted 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 C 3 glomerulonephritis), IgA nephropathy, membranous nephropathy including idiopathic membranous nephropathy, diabetic nephropathy, atypical hemolytic uremic syndrome, hemolytic uremic syndrome, STEC-HUS (Shiga toxin-producing E. coli hemolytic uremic syndrome), peritonitis, CD55 deficiency with complement hyperactivation, vasculopathy thrombosis, protein-losing enteropathy (CHAPLE syndrome), inflammatory or autoimmune diseases such as Crohn's disease, adult respiratory distress syndrome, myocarditis, post-ischemic reperfusion state, myocardial infarction, balloon angioplasty, post-pump syndrome in cardiopulmonary bypass 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, spondyloarthropathies including rheumatoid arthritis, osteoarthritis, psoriatic arthritis, systemic lupus erythematosus (SLE), lupus nephritis, SLE nephritis, proliferative nephritis, 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 35. The pharmaceutical composition of claim 34, wherein the therapeutic agent is selected from the group consisting of pulmonary vasculitis, pauciimmune vasculitis including antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, other vasculitides such as Henoch-Schnerein vasculitis, Bürger's vasculitis, cryoglobulinemia, Kawasaki disease, Takayasu's arteritis, 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.

40. 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 retinochoroiditis, 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, and North Neurological disorders such as carolina macular dystrophy, Stargardt's disease, corneal inflammatory disease, 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 unwanted 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 C 3 glomerulonephritis), IgA nephropathy, membranous nephropathy including idiopathic membranous nephropathy, diabetic nephropathy, atypical hemolytic uremic syndrome, hemolytic uremic syndrome, STEC-HUS (Shiga toxin-producing E. coli hemolytic uremic syndrome), peritonitis, CD55 deficiency with complement hyperactivation, vasculopathy thrombosis, protein-losing enteropathy (CHAPLE syndrome), inflammatory or autoimmune diseases such as Crohn's disease, adult respiratory distress syndrome, myocarditis, post-ischemic reperfusion state, myocardial infarction, balloon angioplasty, post-pump syndrome in cardiopulmonary bypass 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, spondyloarthropathies including rheumatoid arthritis, osteoarthritis, psoriatic arthritis, systemic lupus erythematosus (SLE), lupus nephritis, SLE nephritis, proliferative nephritis, 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 36. The pharmaceutical composition of claim 35, wherein the therapeutic agent is selected from the group consisting of pulmonary vasculitis, pauciimmune vasculitis including antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, other vasculitides such as Henoch-Schnerein vasculitis, Buerger's vasculitis, cryoglobulinemia, Kawasaki disease, Takayasu's arteritis, 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.

41. 1. A pharmaceutical composition for use in a method for treating age-related macular degeneration, comprising: The pharmaceutical composition comprises a compound according to any one of claims 1 to 29 or a pharmaceutically acceptable salt thereof, and the method comprises administering to a subject in need thereof an effective amount of a composition comprising a compound according to any one of claims 1 to 29 or a pharmaceutically acceptable salt thereof.

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

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

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

45. 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 retinochoroiditis, 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 inflammatory disease, 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 unwanted 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 C 3 glomerulonephritis), IgA nephropathy, membranous nephropathy including idiopathic membranous nephropathy, diabetic nephropathy, atypical hemolytic uremic syndrome, hemolytic uremic syndrome, STEC-HUS (Shiga toxin-producing E. coli hemolytic uremic syndrome), peritonitis, CD55 deficiency with complement hyperactivation, vasculopathy thrombosis, protein-losing enteropathy (CHAPLE syndrome), inflammatory or autoimmune diseases such as Crohn's disease, adult respiratory distress syndrome, myocarditis, post-ischemic reperfusion state, myocardial infarction, balloon angioplasty, post-pump syndrome in cardiopulmonary bypass 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, spondyloarthropathies including rheumatoid arthritis, osteoarthritis, psoriatic arthritis, systemic lupus erythematosus (SLE), lupus nephritis, SLE nephritis, proliferative nephritis, 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, pulmonary vasculitis, antihistamines ...

45. The compound or pharmaceutically acceptable salt thereof for use according to claim 44, selected from pauciimmune vasculitis, including neutrophil cytoplasmic antibody (ANCA)-associated vasculitis, other vasculitides such as Henoch-Schnerein vasculitis, Buerger's vasculitis, cryoglobulinemia, Kawasaki disease, Takayasu's arteritis, 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.

46. 30. Use of a compound according to any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a disease or disorder mediated by complement activation or activation 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, birdshot retinochoroiditis, 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 inflammatory disease, 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 unwanted 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 C 3 glomerulonephritis), IgA nephropathy, membranous nephropathy including idiopathic membranous nephropathy, diabetic nephropathy, atypical hemolytic uremic syndrome, hemolytic uremic syndrome, STEC-HUS (Shiga toxin-producing E. coli hemolytic uremic syndrome), peritonitis, CD55 deficiency with complement hyperactivation, vasculopathy thrombosis, protein-losing enteropathy (CHAPLE syndrome), inflammatory or autoimmune diseases such as Crohn's disease, adult respiratory distress syndrome, myocarditis, post-ischemic reperfusion state, myocardial infarction, balloon angioplasty, post-pump syndrome in cardiopulmonary bypass 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, spondyloarthropathies including psoriatic arthritis, systemic lupus erythematosus (SLE), lupus nephritis, SLE nephritis, proliferative nephritis, 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, pulmonary vasculitis, antineutrophil cytoplasmic antibody (ANCA)-related diseases Use of a compound according to any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a disease or disorder selected from: pauciimmune vasculitis, including vasculitis, other vasculitides such as Henoch-Schnerein vasculitis, Buerger's vasculitis, cryoglobulinemia, Kawasaki disease, Takayasu's arteritis, 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. A pharmaceutical combination comprising a compound according to any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof, and one or more further therapeutic agents.

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