WO2025054361A1 - Complement inhibition - Google Patents

Abstract

Among other things, the present disclosure provides technologies for modulating complement activation. In some embodiments, the present disclosure provides compounds that inhibit C3 convertase activity. In some embodiments, the present disclosure provides methods for treating complement-mediated conditions, disorders or diseases. In some embodiments, the present disclosure provides methods for treating conditions, disorders or diseases mediated by C3 convertase.

Description

COMPLEMENT INHIBITION

CROSS-REFERENCE TO RELATED APPLICATIONS

[00001] This application claims priority to United States Provisional Application Nos. 63/580,696, filed September 5, 2023, and 63/622,472, filed January 18, 2024, the entirety of each of which is incorporated herein by reference.

BACKGROUND

[00002] Complement is a system consisting of more than 30 plasma and cell-bound proteins that plays a significant role in both innate and adaptive immunity. The proteins of the complement system act in a series of enzymatic cascades through a variety of protein interactions and cleavage events. Complement activation occurs via three main pathways: the antibody-dependent classical pathway, the alternative pathway, and the mannose-binding lectin (MBL) pathway. Inappropriate or excessive complement activation is an underlying cause or contributing factor to a number of serious diseases and conditions, and considerable effort has been devoted over the past several decades to exploring various complement inhibitors as therapeutic agents.

SUMMARY

[00003] Among other things, the present disclosure provides technologies (e.g., compounds, compositions, methods, etc.) useful for treating various conditions, disorders or diseases. In some embodiments, the present disclosure provides technologies for preventing or treating conditions, disorders or diseases associated with complement activation. In some embodiments, a condition, disorder or disease is associated with alternative complement activation. In some embodiments, a condition, disorder or disease is associated with C3 convertase. In some embodiments, a condition, disorder or disease is associated with factor B.

[00004] The present disclosure encompasses, among other things, the recognition that increases ocular exposure can provide various benefits and advantages for preventing or treating various eye conditions, disorders or diseases. In some embodiments, the present disclosure provides technologies for increasing ocular- exposure of various compounds. In some embodiments, the present disclosure provides compounds with increased ocular exposure and compositions and methods thereof. In some embodiments, the present disclosure provides technologies for increasing melanin binding by various compounds. In some embodiments, melanin binding is increased such that when melanin is precipitated from a solution or suspension, a compound has an decreased concentration or percentage in the solution (e.g., of or below about 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, or 10% of a reference compound, and/or of or below about 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, or 10% of total amount) (see, e.g., as assessed by assays described in the Examples). In some embodiments, the present disclosure provides compounds with increased melanin binding and compositions and methods thereof. In some embodiments, present disclosure provides an ocular compound reservoir. In some embodiments, the present disclosure provides delivery to eye or a portion (e.g., a portion comprising melanin) thereof, e.g., choroid, BrM, RPE, iris, retina and/or ciliary body, with high concentrations, e.g., about or at least about 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, 90 or 100 fold of plasma concentration. In some embodiments, it is about or at least about 5 fold. In some embodiments, it is about or at least about 10 fold. In some embodiments, it is about or at least about 15 fold. In some embodiments, it is about or at least about 20 fold. In some embodiments, it is about or at least about 30 fold. In some embodiments, it is about or at least about 50 fold. In some embodiments, the present disclosure provides delivery to eye or a portion thereof, e.g., choroid, BrM, RPE, iris and/or ciliary body, with high concentration ratios over plasma concentration relative to a reference compound, e.g., about or at least about 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, 90 or 100 fold of the ratio of a reference compound. As those skilled in the art, concentrations may be assessed at various useful time points; at least at one time points and in some embodiments at multiple time points, high concentrations and/or ratios are observed. In some embodiments, the present disclosure provides prolonged exposure compared to a reference compound, e.g., about or at least about 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, 90 or 100 fold of that of a reference compound about a reference level (e.g., a therapeutically relevant or effective level). In some embodiments, a fold is independently about or at least about 5 fold. In some embodiments, it is independently about or at least about 10 fold. In some embodiments, it is independently about or at least about 15 fold. In some embodiments, it is independently about or at least about 20 fold. In some embodiments, it is independently about or at least about 30 fold. In some embodiments, it is independently about or at least about 50 fold. In some embodiments, a reference compound is an otherwise identical compound but without the amino group, e.g., without R^d or R^e or both. In some embodiments, a reference compound is an otherwise identical compound but whose Ring C comprises no basic nitrogen atom. In some embodiments, a provided compound is a compound having the structure of formula I or a salt thereof, wherein d is not 0, and a reference compound is a compound having the structure of formula I or a salt thereof, wherein d is 0. In some embodiments, a provided compound is a compound having the structure of formula I or a salt thereof, wherein e is not 0, and a reference compound is a compound having the structure of formula I or a salt thereof, wherein e is 0. In some embodiments, a provided compound is a compound having the structure of formula I or a salt thereof, wherein neither of d and e is 0, and a reference compound is a compound having the structure of formula I or a salt thereof, wherein both d and e are 0. In some embodiments, the present disclosure provides compounds that can achieve ocular compound reservoir, increased concentrations at an eye or a portion thereof, and/or prolonged exposure, and compositions and methods thereof. In some embodiments, with improvements, benefits, advantages, etc. as described herein, provided technologies can provide lower toxicity, improved dosage regimen (e.g., reduced unit doses, dose frequency, and/or total doses to achieve the same or comparable results, and/or improved results with the same or comparable unit doses, dose frequency and/or total doses), better patient compliance, higher efficacy, etc. [00005] In some embodiments, provided technologies comprise incorporating N-containing moieties into compounds. In some embodiments, provided technologies comprise incorporating basic moieties into compounds. In some embodiments, a N-containing or basic moiety is or comprises an amino group. In some embodiments, a N-containing or basic moiety is or comprises an optionally substituted 3-10 (e.g., 3-7, 4-7, 3, 4, 5, 6, 7, 8, 9, 10, etc.) membered ring having one or more (e.g., 1-5, 1, 2, 3, 4, 5, etc.) heteroatoms, wherein one or more (e.g., 1-5, 1, 2, 3, 4, 5, etc.) heteroatoms is nitrogen. In some embodiments, an optionally substituted N-containing or basic moiety is or comprises a 3-10 (e.g., 3-7, 4-7, 3, 4, 5, 6, 7, 8, 9, 10, etc.) membered heterocyclic ring having one or more (e.g., 1-5, 1, 2, 3, 4, 5, etc.) heteroatoms, wherein one or more (e.g., 1-5, 1, 2, 3, 4, 5, etc.) heteroatoms is nitrogen. In some embodiments, an optionally substituted N- containing or basic moiety is or comprises a 5-10 (e.g., 5-9, 5, 6, 7, 8, 9, 10, etc.) membered heteroaryl ring having one or more (e.g., 1-5, 1, 2, 3, 4, 5, etc.) heteroatoms, wherein one or more (e.g., 1-5, 1, 2, 3, 4, 5, etc.) heteroatoms is nitrogen. In some embodiments, each heteroatom is independently nitrogen, oxygen and sulfur.

[00006] For example, in various embodiments described herein, a N-containing or basic moiety is incorporated at Ring C, which is often bonded to an acidic moiety (e.g., — COOH) or a bioisostere thereof, or a moiety that can be converted (e.g., through metabolism) to such a moiety. See, e.g., various compounds of formula I or a salt thereof (e.g., see Table C-l). With such moieties, provided compounds can provide various benefits, e.g., increased melanin binding, increased ocular delivery/enrichment, increased ocular exposure, etc., compared to reference compounds (e.g., compounds without such N-containing or basic moieties at the relevant positions but otherwise identical). Many compounds, e.g., those described generically or specifically in WO 2015/009616, US 9682968, US 10093663, WO 2018/005552, WO 2019/043609, WO 2020/016749, WO 2022/028507, WO 2022/028527, WO 2022/143845, WO 2022/218429, WO 2022/234541, WO 2022/256586, WO 2023/020566, WO 2023/037218, WO 2023/072197, WO 2023/139534, and WO 2023/143293, the entirety of each of which is independently incorporated by reference, can be modified using technologies as described herein (e.g., introducing a N-containing or basic moiety, such as -N(R)z, at a ring moiety corresponding to Ring C, which is often bonded to an acidic moiety (e.g., -COOH) or a bioisostere thereof, or a moiety that can be converted (e.g., through metabolism) to such a moiety) to provide compounds that can deliver various benefits and advantages as described herein.

[00007] In some embodiments, the present disclosure provides a compound, wherein the compound has the structure of formula I:

I or a salt thereof, wherein:

Ring A is an optionally substituted 5-10 membered aromatic ring having 0-5 heteroatoms independently selected from nitrogen, oxygen and sulfur; each R^a is independently selected from halogen, — CN, R^al , -OR^al , and -NR^al R^a2, wherein each of R^al and R^a2 is independently R’ ; a is 0, 1, 2, 3, 4 or 5;

L¹ is optionally substituted -CH₂-;

Ring B is an optionally substituted 5-10 membered monocyclic, bicyclic or polycyclic, saturated or partially unsaturated ring having, in additional to the nitrogen atom, 0-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; each R^b is independently selected from halogen, -CN, -L^b-C(O)OR^bl , -L^b-C(O)NR^blR^b2, -L^b-R^bl, -L^b-OR^bl, -L^b-NR^blR^b2, -L^b-C(O)R^bl, -L^b-C(O)N(R^bl)S(O)₂R^b2, -L^b-S(O)₂N(R^bl)C(O)R^b2, -L^b-S(O)₂NR^blR^b2, -L^b-S(O)(NR^bl)R^b2, or -L^b-S(O)₂R^bl , wherein each of R^bl and R^b2 is independently R’, and L^b is a covalent bond or optionally substituted -CH₂— ; b is 0, l, 2, 3, 4 or 5;

Ring C is an optionally substituted 5-10 membered monocyclic, bicyclic or polycyclic, saturated or partially unsaturated or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen

R^c is -L^C-C(O)OH or a bioisostere thereof, -L^c-C(O)OR^cl, -L^c-C(O)NR^clR^c2, -L^c-R^cl, -L^c-OR^cl, -L^c-NR^clR^c2, -L^c-C(O)R^cl, -L^c-C(O)N(R^cl)S(O)₂R^c2, -L^c-S(O)₂N(R^cl)C(O)R^c2, -L^c-S(O)₂NR^clR^c2, -L^c-S(O)(NR^cl)R^c2, -L^C-S(O)₂R^CI, halogen, -CN, -L^c-P(O)(OR^cl)(OR^c2), -L^c-OP(O)(OR^cl)(OR^c2), or -L^c-BR^clR^c2, wherein each of R^cl and R^c2 is independently R’ or -N(R’)₂, and L^c is a covalent bond or optionally substituted -CH₂-; each R^d is independently selected from halogen, -CN, R^dl, -OR^dl, and -NR^dlR^d2, wherein each of R^dl and R^d2 is independently R’; d is 0, 1, or 2; each R^e is independently selected from halogen, -CN, R^el, -OR^el, and -NR^elR^e2, wherein each of R^el and R^e2 is independently R’ ; e is 0, 1, or 2; each R’ is independently R, -OR, -C(O)R, -C(O)OR, or -S(O)2R; each R is independently hydrogen or an optionally substituted group selected from C1-C10 aliphatic, C1-C₆ heteroaliphatic having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, 3-10 membered cycloaliphatic, 3-10 membered hctcrocyclyl having 1-4 hctcroatoms independently selected from nitrogen, oxygen and sulfur, 6-10 membered aryl, 5-10 membered heteroaryl having 1-6 heteroatoms independently selected from nitrogen, oxygen and sulfur, 6-10 membered aryl-C1-C6 aliphatic, and 5-10 membered heteroaryl having 1-6 heteroatoms-C1-C6 aliphatic wherein each heteroatom is independently selected nitrogen, oxygen and sulfur; or two R groups on the same atom are optionally and independently taken together with the atom to form an optionally substituted 3-10 membered ring having, in addition to the atom, 0-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; or two R groups on two atoms are optionally and independently taken together with their intervening atoms to form an optionally substituted 3-10 membered ring having, in addition to the intervening atoms, 0-4 heteroatoms.

[00008] In some embodiments, as described in the Examples, an occurrence of R^d or an occurrence R^e is an amino group. In some embodiments, an occurrence of R^d is -NR^dlR^d2 or an occurrence R^e is — NR^elR^e2, wherein each of each of

[00009] In some embodiments, wherein Ring B is an optionally substituted 6-10 membered monocyclic, bicyclic or polycyclic, saturated or partially unsaturated ring having, in addition to the nitrogen atom, 0-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein no monocyclic ring comprising the nitrogen atom is a saturated 5-8 membered ring having, in addition to the nitrogen atom, one nitrogen atom.

[00010] Among other things, provided compounds, e.g., those of formula I or a pharmaceutically acceptable salt thereof, are particularly useful for modulating C3 convertase activity. In some embodiments, provided compounds are useful for modulating complement activation. In some embodiments, the present disclosure provides a method for modulating a C3 convertase activity, comprising contacting a C3 convertase with a provided compound. In some embodiments, the present disclosure provides a method for modulating a C3 convertase activity, comprising administering to a system comprising a C3 convertase a provided compound. In some embodiments, the present disclosure provides a method for modulating a C3 convertase activity, comprising administering to a subject expressing or comprising a C3 convertase a provided compound. In some embodiments, an activity of a C3 convertase is inhibited. In some embodiments, a provided compound is useful as a C3 convertase inhibitor. In some embodiments, a C3 convertase is or comprises factor B. In some embodiments, a C3 convertase is factor B. In some embodiments, a C3 convertase forms a complex with one or more polypeptides.

[00011] In some embodiments, the present disclosure provides methods for preventing a condition, disorder or disease, comprising administering to a subject susceptible thereto an effective amount of a provided compound (e.g., a compound of formula I or a pharmaceutically acceptable salt thereof).

[00012] In some embodiments, the present disclosure provides methods for treating a condition, disorder or disease, comprising administering to a subject suffering therefrom an effective amount of a provided compound (e.g., a compound of formula I or a pharmaceutically acceptable salt thereof).

[00013] Various conditions, disorders or diseases associated with complement activation can prevented or treated utilizing provided technologies in accordance with the present disclosure. In some embodiments, a condition, disorder or disease is associated with complement activation. In some embodiments, a condition, disorder or disease is associated with alternative complement activation. In some embodiments, a condition, disorder or disease is associated with C3 convertase. In some embodiments, a subject who is suffering from a condition, disorder or disease can benefit from inhibition of a C3 convertase.

[00014] In some embodiments, a condition, disorder or disease is selected from age-related macular degeneration (e.g., intermediate age-related macular degeneration), geographic atrophy, Stargardt’s disease, diabetic retinopathy, uveitis, glaucoma, retinitis pigmentosa, macular edema, Behcet's uveitis, multifocal choroiditis, Vogt-Koyangi-Harada syndrome, intermediate uveitis, birdshot retino-chorioditis, sympathetic ophthalmia, ocular dicatricial pemphigoid, ocular pemphigus, nonartertic ischemic optic neuropathy, postoperative inflammation, retinal vein occlusion, neurological disorders, multiple sclerosis, stroke, Creutzfeld- Jacob disease, Guillain Barre Syndrome, spinal cord injury, traumatic brain injury, Alzheimer’s disease, Parkinson's disease, progressive supranuclear palsy, corticobasal syndrome, Pick’s disease, mild cognitive impairment, Huntington’s disease, diabetic neuropathy, neuropathic pain syndromes, fibromyalgia, frontotemporal dementia, dementia with Lewy bodies, multiple system atrophy, leptomeningeal metastasis, amyotrophic lateral sclerosis (ALS), chronic inflammatory demyelinating polyneuropathy (CIDP), neuromyelitis optica (NMO), disorders of inappropriate or undesirable complement activation, hemodialysis complications, graft rejection (e.g., hyperacute allograft rejection, xenograft rejection, interleukin-2 induced toxicity during IL-2 therapy, inflammatory disorders, inflammation of autoimmune diseases, Crohn's disease, acute respiratory distress syndrome (ARDS), myocarditis, postischemic reperfusion conditions, myocardial infarction, balloon angioplasty, post-pump syndrome in cardiopulmonary bypass or renal bypass, atherosclerosis, hemodialysis, renal ischemia, mesenteric artery reperfusion after aortic reconstruction, infectious disease or sepsis, immune complex disorders and autoimmune diseases, rheumatoid arthritis, systemic lupus erythematosus (SLE), SLE nephritis, proliferative nephritis, liver fibrosis, hemolytic anemia, myasthenia gravis, tissue regeneration, neural regeneration, dyspnea, hemoptysis, asthma, chronic obstructive pulmonary disease (COPD), emphysema, pulmonary embolisms and infarcts, pneumonia, fibrogenic dust diseases, pulmonary fibrosis, rhinosinusitis, nasal polyposis, allergy, bronchoconstriction, hypersensitivity pneumonitis, parasitic diseases, Goodpasture's Syndrome, pulmonary vasculitis, pauci-immune vasculitis, thrombotic microangiopathy (TMA), immune complex-associated inflammation, antiphospholipid syndrome, glomerulonephritis, C3 glomerulopathy, IgA nephropathy, cancer, periodontitis, gingivitis, and obesity. 1000151 In some embodiments a subject with hemolytic anemia suffers from paroxysmal nocturnal hemoglobinuria. In some embodiments a subject with hemolytic anemia suffers from autoimmune hemolytic anemia (e.g., cold agglutinin disease or warm autoimmune hemolytic anemia). In some embodiments a subject suffers from TMA secondary to atypical hemolytic uremic syndrome.

[00016] In some embodiments, a condition, disorder or disease, e.g., a complement-mediated disorder, is complement activation secondary to administration of another agent, e.g., a therapeutic or diagnostic agent. For example, in some embodiments, a complement-mediated disorder is complement activation secondary to gene therapy (e.g., gene therapy with a viral vector such as an adeno-associated virus (AAV), adenovirus, or lentivirus vector) or complement activation secondary to cell therapy. In some embodiments, a subject suffers from TMA secondary to hematopoietic stem cell transplant (HSCT-TMA). In some embodiments, a subject suffers from drug-induced TMA. In some embodiments, administration of a compound described herein prior to and/or following administration of another therapeutic agent may increase the efficacy and/or safety of said therapeutic agent. In some embodiments, the present disclosure provides methods for improving efficacy and/or safety of a therapeutic agent, comprising administering to a subject an effective amount of a provided compound (e.g., a compound of formula I or a pharmaceutically acceptable salt thereof) prior to, concurrently with (either in the same or different composition) or subsequently to administration of the therapeutic agent to the subject. In some embodiments, the present disclosure provides improved administration (e.g., dosage regimen, unit doses, total doses, improved intervals, durations of treatment, etc.) of a therapeutic agent, comprising administering to a subject a provided compound (e.g., a compound of formula I or a pharmaceutically acceptable salt thereof) prior to, concurrently with (either in the same or different composition) or subsequently to administration of the therapeutic agent to the subject, wherein the administration of the therapeutic agent provides improved efficacy and/or safety compared to a reference administration (e.g., administration of the therapeutic agent without administration of a provided compound (e.g., a compound of formula I or a pharmaceutically acceptable salt thereof)).

[00017] In some embodiments, a subject has a defect in complement regulation, optionally wherein the defect comprises abnormally low expression of one or more complement regulatory proteins by at least some of the subject’s cells.

[00018] In some embodiments, a complement-mediated disorder is a chronic disorder. In some embodiments, a complement-mediated disorder involves complement-mediated damage to red blood cells, optionally wherein the disorder is paroxysmal nocturnal hemoglobinuria or atypical hemolytic uremic syndrome. In some embodiments, a complement-mediated disorder is an autoimmune disease, optionally wherein the disorder is multiple sclerosis. In some embodiments, a complement-mediated disorder involves kidney, optionally wherein the disorder is membranoproliferative glomerulonephritis, lupus nephritis, IgA nephropathy (IgAN), primary membranous nephropathy (primary MN), C3 glomerulopathy (C3G), or acute kidney injury. In some embodiments, a complement-mediated disorder involves the central or peripheral nervous system or neuromuscular junction, optionally wherein a disorder is neuromyelitis optica, Guillain- Barre syndrome, multifocal motor neuropathy, or myasthenia gravis. In some embodiments, a complement- mediated disorder involves the respiratory system, optionally wherein the disorder is characterized by pulmonary fibrosis. Tn some embodiments, a complement-mediated disorder involves the vascular system, optionally wherein the disorder is characterized by vasculitis.

[00019] Certain conditions, disorders or diseases that can be prevented or treated by provided technologies, e.g., conditions, disorders or diseases mediated by complement activation (in some embodiments, alternative complement activation), conditions, disorders or diseases mediated by C3 convertase, conditions, disorders or diseases mediated by factor B, etc. are reported in, e.g., WO 2015/009616, US 9682968, US 10093663, WO 2018/005552, WO 2019/043609, WO 2020/016749, WO 2022/028507, WO 2022/028527, WO 2022/143845, WO 2022/218429, WO 2022/234541, WO 2022/256586, WO 2023/020566, WO 2023/037218, WO 2023/072197, WO 2023/139534, and WO 2023/143293. In some embodiments, a condition, disorder or disease is a renal condition, disorder or disease. In some embodiments, a condition, disorder or disease is an ocular condition, disorder or disease.

[00020] In some embodiments, a condition, disorder or disease is complement-driven renal disease C3G (C3 glomerulopathy). In some embodiments, a condition, disorder or disease is c IgAN (immunoglobuline A nephropathy). In some embodiments, a condition, disorder or disease is a nephropathy. In some embodiments, a condition, disorder or disease is a nephropathy with evidence of glomerular' C3 deposition. In some embodiments, a condition, disorder or disease is membranous nephropathy. In some embodiments, a condition, disorder or disease is HUS (E.coli induced hemolytic uremic syndrome).

[00021] In some embodiments, a compound (e.g., a compound of formula I or a pharmaceutically acceptable salt thereof) is provided in a pharmaceutical composition. In some embodiments, the present disclosure provides a pharmaceutical composition comprising a provided compound and a pharmaceutically acceptable earner. In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. In some embodiments, a composition may comprise two or more pharmaceutically acceptable salt forms of a compound. In some embodiments, a composition comprises two or more pharmaceutically acceptable salts of a compound of formula I. In some embodiments, the present disclosure provides a pharmaceutical composition which delivers a provided compound (e.g., a compound of formula I or a pharmaceutically acceptable salt thereof) and comprises a pharmaceutically acceptable carrier. In some embodiments, the present disclosure provides a pharmaceutical composition comprises a compound of formula I or a pharmaceutically acceptable salt dissolved in a pharmaceutically acceptable liquid, e.g., water or a pharmaceutically acceptable buffer.

[00022] Various technologies for administering compounds or compositions can be utilized in accordance with the present disclosure. For example, in some embodiments, provided compounds or compositions are administered orally. In some embodiments, provided compounds or compositions are administered intravenously.

1000231 In some embodiments, the composition is administered intravenously to the subject. In some embodiments, the composition is administered to a hepatocyte of the subject. In some embodiments, the composition is administered to the hepatocyte ex vivo. In some embodiments, the composition is administered to the hepatocyte in vivo.

DEFINITIONS

[00024] As used herein, the following definitions shall apply unless otherwise indicated. For purposes of this disclosure, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed. Additionally, general principles of organic chemistry are described in, e.g., “Organic Chemistry”, Thomas Sorrell, University Science Books, Sausalito: 1999, and “March's Advanced Organic Chemistry”, 5th Ed., Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001.

[00025] As used herein in the present disclosure, unless otherwise clear from context, (i) the term “a” or “an” may be understood to mean “at least one”; (ii) the term “or” may be understood to mean “and/or”; (iii) the terms “comprising”, “comprise”, “including” (whether used with “not limited to” or not), and “include” (whether used with “not limited to” or not) may be understood to encompass itemized components or steps whether presented by themselves or together with one or more additional components or steps; (iv) the term “another” may be understood to mean at least an additional/second one or more; (v) the terms “about” and “approximately” may be understood to permit standard variation as would be understood by those of ordinary skill in the art; and (vi) where ranges are provided, endpoints are included.

[00026] Aliphatic: As used herein, “aliphatic” means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation (but not aromatic), or a substituted or unsubstituted monocyclic, bicyclic, or polycyclic hydrocarbon ring that is completely saturated or that contains one or more units of unsaturation (but not aromatic), or combinations thereof. In some embodiments, aliphatic groups contain 1-50 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-20 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-10 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-9 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-8 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-7 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-6 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms, and in yet other embodiments, aliphatic groups contain 1, 2, 3, or 4 aliphatic carbon atoms. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.

[00027] Alkenyl: As used herein, the term “alkenyl” refers to an aliphatic group, as defined herein, having one or more double bonds.

[00028] Alkyl: As used herein, the term “alkyl” is given its ordinary meaning in the art and may include saturated aliphatic groups, including straight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups. In some embodiments, alkyl has 1 -100 carbon atoms. In certain embodiments, a straight chain or branched chain alkyl has about 1-20 carbon atoms in its backbone (e.g., C1-C20 for straight chain, C2-C20 for branched chain), and alternatively, about 1-10. In some embodiments, cycloalkyl rings have from about 3-10 carbon atoms in their ring structure where such rings are monocyclic, bicyclic, or polycyclic, and alternatively about 5, 6 or 7 carbons in the ring structure. In some embodiments, an alkyl group may be a lower alkyl group, wherein a lower alkyl group comprises 1-4 carbon atoms (e.g., C1-C4 for straight chain lower alkyls).

[00029] Alkynyl: As used herein, the term “alkynyl” refers to an aliphatic group, as defined herein, having one or more triple bonds.

[00030] Animal: As used herein, the term “animal” refers to any member of the animal kingdom. In some embodiments, “animal” refers to humans, at any stage of development. In some embodiments, “animal” refers to non-human animals, at any stage of development. In certain embodiments, the non-human animal is a mammal (e.g., a rodent, a mouse, a rat, a rabbit, a monkey, a dog, a cat, a sheep, cattle, a primate, and/or a pig). In some embodiments, animals include, but are not limited to, mammals, birds, reptiles, amphibians, fish, and/or worms. In some embodiments, an animal may be a transgenic animal, a genetically- engineered animal, and/or a clone.

[00031] Aryl: The term “aryl", as used herein, used alone or as part of a larger moiety as in “aralkyl,” “aralkoxy,” or “aryloxyalkyl,” refers to monocyclic, bicyclic or polycyclic ring systems having a total of five to thirty ring members, wherein at least one ring in the system is aromatic. In some embodiments, an aryl group is a monocyclic, bicyclic or polycyclic ring system having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic, and wherein each ring in the system contains 3 to 7 ring members. In some embodiments, each monocyclic ring unit is aromatic. In some embodiments, an aryl group is a biaryl group. The term “aryl” may be used interchangeably with the term “aryl ring.” In certain embodiments of the present disclosure, “aryl” refers to an aromatic ring system which includes, but is not limited to, phenyl, biphenyl, naphthyl, binaphthyl, anthracyl and the like, which may bear one or more substituents. Also included within the scope of the term “aryl,” as it is used herein, is a group in which an aromatic ring is fused to one or more non-aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl, and the like.

[00032] Approximately: As used herein, the terms “approximately” or “about” in reference to a number are generally taken to include numbers that fall within a range of 5%, 10%, 15%, or 20% in either direction (greater than or less than) of the number unless otherwise stated or otherwise evident from the context (except where such number would be less than 0% or exceed 100% of a possible value).

[00033] Complement component: As used herein, the terms "complement component" or "complement protein" is a molecule that is involved in activation of the complement system or par ticipates in one or more complement-mediated activities. Components of the classical complement pathway include, e.g., Clq, Clr, Cis, C2, C3, C4, C5, C6, C7, C8, C9, and the C5b-9 complex, also referred to as the membrane attack complex (MAC) and active fragments or enzymatic cleavage products of any of the foregoing (e.g., C3a, C3b, C4a, C4h, C5a, etc.). Components of the alternative pathway include, e.g., factors B, D, H, and T, and properdin, with factor H being a negative regulator of the pathway. Components of the lectin pathway include, e.g., MBL2, MASP-1, and MASP-2. Complement components also include cell-bound receptors for soluble complement components. Such receptors include, e.g., C5a receptor (C5aR), C3a receptor (C3aR), Complement Receptor 1 (CR1), Complement Receptor 2 (CR2), Complement Receptor 3 (CR3), etc. It will be appreciated that the term “complement component” is not intended to include those molecules and molecular structures that serve as “triggers” for complement activation, e.g., antigen-antibody complexes, foreign structures found on microbial or artificial surfaces, etc.

[00034] Concurrent administration: As used herein, the term “concurrent administration” with respect to two or more agents, e.g., therapeutic agents, is administration performed using doses and time intervals such that the administered agents are present together within the body, e.g., at one or more sites of action in the body, over a time interval in non-negligible quantities. The time interval can be minutes (e.g., at least 1 minute, 1-30 minutes, 30-60 minutes), hours (e.g., at least 1 hour, 1-2 hours, 2-6 hours, 6-12 hours, 12-24 hours), days (e.g., at least 1 day, 1-2 days, 2-4 days, 4-7 days, etc.), weeks (e.g., at least 1, 2, or 3 weeks, etc.). Accordingly, the agents may, but need not be, administered together as part of a single composition. In addition, the agents may, but need not be, administered essentially simultaneously (e.g., within less than 5 minutes, or within less than 1 minute apart) or within a short time of one another (e.g., less than 1 hour, less than 30 minutes, less than 10 minutes, approximately 5 minutes apart). According to various embodiments of the disclosure, agents administered within such time intervals may be considered to be administered at substantially the same time. In certain embodiments of the disclosure, concurrently administered agents are present at effective concentrations within the body (e.g., in the blood and/or at a site of local complement activation) over the time interval. When administered concurrently, the effective concentration of each of the agents needed to elicit a particular biological response may be less than the effective concentration of each agent when administered alone, thereby allowing a reduction in the dose of one or more of the agents relative to the dose that would be needed if the agent was administered as a single agent. The effects of multiple agents may, but need not be, additive or synergistic. The agents may be administered multiple times. The non-negligible concentration of an agent may be, for example, less than approximately 5% of the concentration that would be required to elicit a particular biological response, e.g., a desired biological response.

[00035] Cycloaliphatic: The term “cycloaliphatic,” “carbocycle,” “carbocyclyl,” “carbocyclic radical,” and “carbocyclic ring,” are used interchangeably, and as used herein, refer to saturated or partially unsaturated, but non-aromatic, cyclic aliphatic monocyclic, bicyclic, or polycyclic ring systems, as described herein, having, unless otherwise specified, from 3 to 30 ring members. Cycloaliphatic groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, cyclooctyl, cyclooctenyl, norbornyl, adamantyl, and cyclooctadienyl. In some embodiments, a cycloaliphatic group has 3-6 carbons. In some embodiments, a cycloaliphatic group is saturated and is cycloalkyl. The term “cycloaliphatic” may also include aliphatic rings that are fused to one or more aromatic or nonaromatic rings, such as decahydronaphthyl or tetrahydronaphthyl. In some embodiments, a cycloaliphatic group is bicyclic. In some embodiments, a cycloaliphatic group is tricyclic. In some embodiments, a cycloaliphatic group is polycyclic. In some embodiments, “cycloaliphatic” refers to C3- Cf> monocyclic hydrocarbon, or Cg-Cio bicyclic or polycyclic hydrocarbon, that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule, or a C9-C16 polycyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule.

[00036] Heteroaliphatic: The term “heteroaliphatic”, as used herein, is given its ordinary meaning in the art and refers to aliphatic groups as described herein in which one or more carbon atoms are independently replaced with one or more heteroatoms (e.g., oxygen, nitrogen, sulfur, silicon, phosphorus, and the like). In some embodiments, one or more units selected from C, CH, CHi, and CHj are independently replaced by one or more heteroatoms (including oxidized and/or substituted forms thereof). In some embodiments, a heteroaliphatic group is heteroalkyl. In some embodiments, a heteroaliphatic group is heteroalkenyl.

[00037] Heteroalkyl: The term “heteroalkyl”, as used herein, is given its ordinary meaning in the art and refers to alkyl groups as described herein in which one or more carbon atoms are independently replaced with one or more heteroatoms (e.g., oxygen, nitrogen, sulfur, silicon, phosphorus, and the like). Examples of heteroalkyl groups include, but are not limited to, alkoxy, poly(ethylene glycol)-, alkyl-substituted amino, tetrahydrofuranyl, piperidinyl, morpholinyl, etc.

[00038] Heteroaryl: The terms “heteroaryl” and “heteroar-”, as used herein, used alone or as part of a larger moiety, e.g., “heteroaralkyl,” or “heteroaralkoxy,” refer to monocyclic, bicyclic or polycyclic ring systems having a total of five to thirty ring members, wherein at least one ring in the system is aromatic and at least one aromatic ring atom is a heteroatom. In some embodiments, a heteroaryl group is a group having 5 to 10 ring atoms (i.e., monocyclic, bicyclic or polycyclic), in some embodiments 5, 6, 9, or 10 ring atoms. In some embodiments, each monocyclic ring unit is aromatic. In some embodiments, a heteroaryl group has 6, 10, or 14 n electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms. Heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. In some embodiments, a heteroaryl is a heterobiaryl group, such as bipyridyl and the like. The terms “heteroaryl” and “heteroar-”, as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where the radical or point of attachment is on the heteroaromatic ring. Non-limiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H- quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-l ,4-oxazin-3(4H)-one. A heteroaryl group may be monocyclic, bicyclic or polycyclic. The term “heteroaryl” may be used interchangeably with the terms “heteroaryl ring,” “hctcroaryl group,” or “hctcroaromatic,” any of which terms include rings that arc optionally substituted. The term “heteroaralkyl” refers to an alkyl group substituted by a heteroaryl group, wherein the alkyl and heteroaryl portions independently are optionally substituted.

[00039] Heteroatom: The term “heteroatom", as used herein, means an atom that is not carbon or hydrogen. In some embodiments, a heteroatom is boron, oxygen, sulfur, nitrogen, phosphorus, or silicon (including oxidized forms of nitrogen, sulfur, phosphorus, or silicon; charged forms of nitrogen (e.g., quaternized forms, forms as in iminium groups, etc.), phosphorus, sulfur, oxygen; etc.). In some embodiments, a heteroatom is silicon, phosphorus, oxygen, sulfur or nitrogen. In some embodiments, a heteroatom is silicon, oxygen, sulfur or nitrogen.In some embodiments, a heteroatom is oxygen, sulfur or nitrogen.

[00040] Heterocycle: As used herein, the terms “heterocycle,” “heterocyclyl,” “heterocyclic radical,” and “heterocyclic ring", as used herein, are used interchangeably and refer to a monocyclic, bicyclic or polycyclic ring moiety (e.g., 3-30 membered) that is saturated or partially unsaturated and has one or more heteroatom ring atoms. In some embodiments, a heterocyclyl group is a stable 5- to 7-membered monocyclic or 7- to 10-membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, preferably one to four, heteroatoms, as defined above. When used in reference to a ring atom of a heterocycle, the term "nitrogen" includes substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 0-3 heteroatoms selected from oxygen, sulfur and nitrogen, the nitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or ⁺NR (as in N-substituted pyrrolidinyl). A heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure and any of the ring atoms can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl. The terms “heterocycle,” “heterocyclyl,” “heterocyclyl ring,” “heterocyclic group,” “heterocyclic moiety,” and “heterocyclic radical,” are used interchangeably herein, and also include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings, such as indolinyl, 3H-indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl. A heterocyclyl group may be monocyclic, bicyclic or polycyclic. The term “heterocyclylalkyl” refers to an alkyl group substituted by a heterocyclyl, wherein the alkyl and heterocyclyl portions independently are optionally substituted.

[00041] Local administration: As used herein, the term “local administration” or “local delivery”, in reference to delivery of a composition or agent, refers to delivery that does not rely upon transport of the composition or agent to its intended target tissue or site via the vascular system. The composition or agent may be delivered directly to its intended target tissue or site, or in the vicinity thereof, e.g., in close proximity to the intended target tissue or site. For example, the composition may be delivered by injection or implantation of the composition or agent or by injection or implantation of a device containing the composition or agent. Following local administration in the vicinity of a target tissue or site, the composition or agent, or one or more components thereof, may diffuse to the intended target tissue or site. It will be understood that once having been locally delivered a fraction of a therapeutic agent (typically only a minor fraction of the administered dose) may enter the vascular system and be transported to another location, including back to its intended target tissue or site.

[00042] Local complement activation: As used herein, the term “local complement activation” refers to complement activation that occurs outside the vascular system.

[00043] Partially unsatur ated: As used herein, the term “partially unsaturated” refers to a ring moiety that includes at least one double or triple bond. The term “partially unsaturated” is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties, as herein defined.

[00044] Pharmaceutical composition: As used herein, the term “pharmaceutical composition” refers to an active agent, formulated together with one or more pharmaceutically acceptable carriers. In some embodiments, an active agent is present in unit dose amount appropriate for administration in a therapeutic regimen that shows a statistically significant probability of achieving a predetermined therapeutic effect when administered to a relevant population. In some embodiments, pharmaceutical compositions may be specially formulated for administration in solid or liquid form, including those adapted for the following: oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, e.g., those targeted for buccal, sublingual, and systemic absorption, boluses, powders, granules, pastes for application to the tongue; parenteral administration, for example, by subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution or suspension, or sustained-release formulation; topical application, for example, as a cream, ointment, or a controlled-release patch or spray applied to the skin, lungs, or oral cavity; intravaginally or intrarectally, for example, as a pessary, cream, or foam; sublingually; ocularly; transdermally; or nasally, pulmonary, and to other mucosal surfaces.

[00045] Pharmaceutically acceptable: As used herein, the phrase “pharmaceutically acceptable” refers to those compounds, materials, compositions and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

[00046] Pharmaceutically acceptable carrier: As used herein, the term “pharmaceutically acceptable earner” means a pharmaceutically-acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, or solvent encapsulating material, involved in carrying or transporting the subject compound from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials which can serve as pharmaceutically-acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer’s solution; ethyl alcohol; pH buffered solutions; polyesters, polycarbonates and/or poly anhydrides; and other non-toxic compatible substances employed in pharmaceutical formulations.

[00047] Pharmaceutically acceptable salt: The term “pharmaceutically acceptable salt”, as used herein, refers to salts of such compounds that are appropriate for use in pharmaceutical contexts, i.e., salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the ai t. For example, S. M. Berge, et al. describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19 (1977). In some embodiments, pharmaceutically acceptable salt include, but are not limited to, nontoxic acid addition salts, which are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. In some embodiments, pharmaceutically acceptable salts include, but are not limited to, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2- hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. In some embodiments, a provided compound comprises one or more acidic groups, and a pharmaceutically acceptable salt is an alkali, alkaline earth metal, or ammonium (e.g., an ammonium salt of N(R)s, wherein each R is optionally substituted C1-C6 alkyl) salt. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. In some embodiments, a pharmaceutically acceptable salt is a sodium salt. In some embodiments, a pharmaceutically acceptable salt is a potassium salt. In some embodiments, a pharmaceutically acceptable salt is a calcium salt. In some embodiments, pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, alkyl having from 1 to 6 carbon atoms, sulfonate and aryl sulfonate. In some embodiments, a provided compound comprises more than one acid groups. In some embodiments, a pharmaceutically acceptable salt, or generally a salt, of such a compound comprises two or more cations, which can be the same or different. In some embodiments, in a pharmaceutically acceptable salt (or generally, a salt), all ionizable hydrogen (e.g., in an aqueous solution with a pKa no more than about 11, 10, 9, 8, 7, 6, 5, 4, 3, or 2; in some embodiments, no more than about 7; in some embodiments, no more than about 6; in some embodiments, no more than about 5; in some embodiments, no more than about 4; in some embodiments, no more than about 3) in the acidic groups are replaced with cations.

[00048] Protecting group: The term “protecting group,” as used herein, is well known in the art and includes those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3^rd edition, John Wiley & Sons, 1999, the entirety of which is incorporated herein by reference. Also included are those protecting groups specially adapted for nucleoside and nucleotide chemistry described in Current Protocols in Nucleic Acid Chemistry, edited by Serge L. Beaucage et al. 06/2012, the entirety of Chapter 2 is incorporated herein by reference. Suitable amino-protecting groups include methyl carbamate, ethyl carbamante, 9-fluorenylmethyl carbamate (Fmoc), 9-(2-sulfo)fluorenylmethyl carbamate, 9-(2,7- dibromo)fluoroenyhnethyl carbamate, 2,7-di-t-butyl-[9-( 10, 10-dioxo-l 0, 10,10,10- tetrahydrothioxanthyl)] methyl carbamate (DBD-Tmoc), 4-methoxyphenacyl carbamate (Phenoc), 2,2,2- trichloroethyl carbamate (Troc), 2-trimethylsilylethyl carbamate (Teoc), 2-phenylethyl carbamate (hZ), 1- (l-adamantyl)-l -methylethyl carbamate (Adpoc), l,l-dimethyl-2-haloethyl carbamate, l,l-dimethyl-2,2- dibromoethyl carbamate (DB-t-BOC), l,l-dimethyl-2,2,2-trichloroethyl carbamate (TCBOC), 1-methyl-l- (4— biphenylyl) ethyl carbamate (Bpoc), l-(3,5-di-t-butylphenyl)-l-methylethyl carbamate (t-Bumeoc), 2- (2’- and 4’-pyridyl)ethyl carbamate (Pyoc), 2-(N,N-dicyclohexylcarboxamido)ethyl carbamate, t-butyl carbamate (BOC), 1-adamantyl carbamate (Adoc), vinyl carbamate (Voc), allyl carbamate (Alloc), 1- isopropylallyl carbamate (Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate (Noc), 8-quinolyl carbamate, N-hydroxypiperidinyl carbamate, alkyldithio carbamate, benzyl carbamate (Cbz), p- methoxybenzyl carbamate (Moz), p-nitobenzyl carbamate, p-bromobenzyl carbamate, p-chlorobenzyl carbamate, 2,4-dichlorobenzyl carbamate, 4-methylsulfinylbenzyl carbamate (Msz), 9-anthrylmethyl carbamate, diphenylmethyl carbamate, 2-methylthioethyl carbamate, 2-methylsulfonylethyl carbamate, 2- (p-toluenesulfonyl)ethyl carbamate, [2-( 1 ,3-dithianyl)Jmethyl carbamate (Dmoc), 4-methylthiophenyl carbamate (Mtpc), 2,4-dimethylthiophenyl carbamate (Bmpc), 2-phosphonioethyl carbamate (Peoc), 2- triphenylphosphonioisopropyl carbamate (Ppoc), 1,1 -dime thy 1-2-cy anoethyl carbamate, m-chloro-p- acyloxybenzyl carbamate, p-(dihydroxyboryl)benzyl carbamate, 5-benzisoxazolylmethyl carbamate, 2- (trifluoromethyl)-6-chromonylmethyl carbamate (Tcroc), m-nitrophenyl carbamate, 3,5-dimethoxybenzyl carbamate, o-nitrobenzyl carbamate, 3,4-dimethoxy-6-nitrobenzyl carbamate, phenyl(o-nitrophenyl)methyl carbamate, phenothiazinyl-(10)-carbonyl derivative, N’-p-toluenesulfonylaminocarbonyl derivative, N’- phenylaminothiocarbonyl derivative, t-amyl carbamate, S-benzyl thiocarbamate, p-cyanobenzyl carbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentyl carbamate, cyclopropyl methyl carbamate, p- decyloxybenzyl carbamate, 2,2-dimethoxycarbonylvinyl carbamate, o-(N,N-dimethylcarboxamido)benzyl carbamate, l,l-dimcthyl-3-(N,N-dimcthylcarboxamido)propyl carbamate, 1,1 -dime thy Ipropynyl carbamate, di(2-pyridyl)methyl carbamate, 2-furanylmethyl carbamate, 2-iodoethyl carbamate, isoborynl carbamate, isobutyl carbamate, isonicotinyl carbamate, p-(p’-methoxyphenylazo)benzyl carbamate, 1 -methylcyclobutyl carbamate, 1 -methylcyclohexyl carbamate, 1 -methyl- 1 -cyclopropylmethyl carbamate, 1 -methyl- 1 -(3, 5- dimethoxyphenyl)ethyl carbamate, l-methyl-l-(p-phenylazophenyl)ethyl carbamate, 1-methyl-l- phenylethyl carbamate, 1 -methyl- l-(4-pyridyl)ethyl carbamate, phenyl carbamate, p-(phenylazo)benzyl carbamate, 2,4,6-tri-t-butylphenyl carbamate, 4-(trimethylammonium)benzyl carbamate, 2,4,6- trimethylbenzyl carbamate, formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenylpropanamide, picolinamide, 3-pyridylcarboxamide, N-benzoylphenylalanyl derivative, benzamide, p-phenylbenzamide, o-nitophenylacetamide, o-nitrophenoxyacetamide, acetoacetamide, (N’-dithiobenzyloxycarbonylamino)acetamide, 3-(p-hydroxyphenyl)propanamide, 3-(o- nitrophenyl)propanamide, 2-methyl-2-(o-nitrophenoxy)propanamide, 2-methyl-2-(o- phenylazophenoxy)propanamide, 4-chlorobutanamide, 3-methyl-3-nitrobutanamide, o-nitrocinnamide, N- acetylmethionine derivative, o-nitrobenzamide, o-(benzoyloxymethyl)benzamide, 4,5-diphenyl-3-oxazolin- 2-one, N-phthalimide, N-dithiasuccinimide (Dts), N-2,3-diphenylmaleimide, N-2,5-dimethylpyrrole, N- 1,1,4,4-tetramethyldisilylazacyclopentane adduct (STABASE), 5-substituted l,3-dimethyl-l,3,5- triazacyclohexan-2-one, 5-substituted l,3-dibenzyl-l,3,5-triazacyclohexan-2-one, 1-substituted 3,5- dinitro-4-pyridone, N-methylamine, N-allylamine, N-[2-(trimethylsilyl)ethoxy]methylamine (SEM), N-3- acetoxypropylamine, N-(l-isopropyl-4-nitro-2-oxo-3-pyroolin-3-yl)amine, quaternary ammonium salts, N-benzylamine, N-di(4-methoxyphenyl)methylamine, N-5-dibenzosuberylamine, N-triphenylmethylamine (Tr), N-[(4-methoxyphenyl)diphenylmethyl] amine (MMTr), N-9-phenylfluorenylamine (PhF), N-2,7- dichloro-9-fluorenylmethyleneamine, N-ferrocenylmethylamino (Fem), N-2-picolylamino N’-oxide, N- 1,1 -dimethylthiomethyleneamine, N-benzylideneamine, N-p-methoxybenzylideneamine, N- diphenylmethyleneamine, N-[(2-pyridyl)mesityl]methyleneamine, N-(N’ ,N’- dimethylaminomethylene)amine, N,N’-isopropylidenediamine, N-p-nitrobenzylideneamine, N- salicylideneamine, N-5-chlorosalicylideneamine, N-(5-chloro-2-hydroxyphenyl)phenylmethyleneamine, N-cyclohexylideneamine, N-(5,5-dimethyl-3-oxo-l-cyclohexenyl)amine, N-borane derivative, N- diphenylborinic acid derivative, N-[phenyl(pentacarbonylchromium- or tungsten)carbonyl]amine, N-copper chelate, N-zinc chelate, N-nitroamine, N-nitrosoamine, amine N-oxide, diphenylphosphinamide (Dpp), dime thy Ithiophosphinamide (Mpt), diphenyl thiophosphinamide (Ppt), dialkyl phosphoramidates, dibenzyl phosphoramidate, diphenyl phosphoramidate, benzenesulfenamide, o-nitrobenzenesulfenamide (Nps), 2,4- dinitrobenzenesulfenamide, pentachlorobenzenesulfenamide, 2-nitro-4— methoxybenzenesulfenamide, triphenylmethylsulfenamide, 3-nitropyridinesulfenamide (Npys), p-toluenesulfonamide (Ts), benzenesulfonamide, 2,3,6,-trimethyl-4-methoxybenzenesulfonamide (Mtr), 2,4,6- trimethoxybenzenesulfonamide (Mtb), 2,6-dimethyl-4-methoxybenzenesulfonamide (Pme), 2, 3,5,6- tetramethyl-4-methoxybenzenesulfonamide (Mte), 4-methoxybenzenesulfonamide (Mbs), 2,4,6- trimcthylbcnzcncsulfonamidc (Mts), 2,6-dimcthoxy-4-mcthylbcnzcncsulfonamidc (iMds), 2, 2, 5,7,8- pentamethylchroman-6-sulfonamide (Pmc), methanesulfonamide (Ms), [3-trimethylsilylethanesulfonamide (SES), 9-anthracenesulfonamide, 4-(4’,8’-dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS), benzylsulfonamide, trifluoromethylsulfonamide, and phenacylsulfonamide.

[00049] Suitably protected carboxylic acids further include, but are not limited to, silyl-, alkyl-, alkenyl-, aryl-, and arylalkyl-protected carboxylic acids. Examples of suitable silyl groups include trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, triisopropylsilyl, and the like. Examples of suitable alkyl groups include methyl, benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, trityl, t-butyl, tetrahydropyran-2-yl. Examples of suitable alkenyl groups include allyl. Examples of suitable aryl groups include optionally substituted phenyl, biphenyl, or naphthyl. Examples of suitable arylalkyl groups include optionally substituted benzyl (e.g., p-methoxybenzyl (MPM), 3,4-dimethoxybenzyl, O-nitrobenzyl, p- nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl), and 2- and 4-picolyl.

[00050] Suitable hydroxyl protecting groups include methyl, methoxylmethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM), p- methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM), guaiacolmethyl (GUM), t- butoxymethyl, 4-pentenyloxymethyl (POM), siloxymethyl, 2-methoxyethoxymethyl (MEM), 2,2,2- trichloroethoxymethyl, bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl (SEMOR), tetrahydropyranyl (THP), 3-bromotetrahydropyranyl, tetrahydrothiopyranyl, 1-methoxycyclohexyl, 4- methoxytetrahydropyranyl (MTHP), 4-methoxytetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranyl S,S- dioxide, l-[(2-chloro-4-methyl)phenyl]-4-methoxypiperidin^l- yl (CTMP), 1 ,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl, 2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7- methanobenzofuran-2-yl, 1 -ethoxy ethyl, l-(2-chloroethoxy)ethyl, 1 -methyl- 1 -methoxy ethyl, 1-methyl-l- benzyloxyethyl, l-methyl-l-benzyloxy-2-fluoroethyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2- (phenylselenyl)ethyl, t-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl, benzyl, p- methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p- cyanobenzyl, p-phenylbenzyl, 2-picolyl, 4-picolyl, 3-methyl-2-picolyl N-oxido, diphenylmethyl, p,p’- dinitrobenzhydryl, 5-dibenzosuberyl, triphenylmethyl, a-naphthyldiphenylmethyl, p- methoxyphenyldiphenylmethyl, di(p-methoxyphenyl)phenylmethyl, tri(p-methoxyphenyl)methyl, 4-(4’- bromophenacyloxyphenyl)diphenylmethyl, 4,4’ ,4’ ’-tris(4,5-dichlorophthalimidophenyl)methyl, 4,4’ ,4’ ’- tris(levulinoyloxyphenyl)methyl, 4,4’ ,4’ ’-tris(benzoyloxyphenyl)methyl, 3-(imidazol-l-yl)bis(4’ ,4’ ’- dimethoxyphenyl)methyl, 1 ,l-bis(4-methoxyphenyl)-l ’-pyrenylmethyl, 9-anthryl, 9-(9-phenyl)xanthenyl, 9-(9-phenyl-10-oxo)anthryl, 1 ,3-benzodithiolan-2-yl, benzisothiazolyl S,S-dioxido, trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DEIPS), dimethylthexylsilyl, t-butyldimethylsilyl (TBDMS), t-butyldiphenylsilyl (TBDPS), tribenzylsilyl, tri-p- xylylsilyl, triphenylsilyl, diphenylmethylsilyl (DPMS), t-butylmethoxyphenylsilyl (TBMPS), formate, benzoylformate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxy acetate, triphcnylmcthoxyacctatc, phcnoxyacctatc, p-chlorophcnoxyacctatc, 3-phcnylpropionatc, 4-oxopcntanoatc (levulinate), 4,4-(ethylenedithio)pentanoate (levulinoyldi thioacetal), pivaloate, adamantoate, crotonate, 4— methoxycrotonate, benzoate, p-phenylbenzoate, 2,4,6-trimethylbenzoate (mesitoate), alkyl methyl carbonate, 9-fluorenylmethyl carbonate (Fmoc), alkyl ethyl carbonate, alkyl 2,2,2-trichloroethyl carbonate (Troc), 2- (trimethylsilyl)ethyl carbonate (TMSEC), 2-(phenylsulfonyl) ethyl carbonate (Psec), 2- (triphenylphosphonio) ethyl carbonate (Peoc), alkyl isobutyl carbonate, alkyl vinyl carbonate alkyl allyl carbonate, alkyl p-nitrophenyl carbonate, alkyl benzyl carbonate, alkyl p-methoxybenzyl carbonate, alkyl 3,4-dimethoxybenzyl carbonate, alkyl o-nitrobenzyl carbonate, alkyl p-nitrobenzyl carbonate, alkyl S- benzyl thiocarbonate, 4-ethoxy-l-napththyl carbonate, methyl dithiocarbonate, 2-iodobenzoate, 4- azidobutyrate, 4— nitro-4-methylpentanoate, o-(dibromomethyl)benzoate, 2-formylbenzenesulfonate, 2- (methylthiomethoxy)ethyl, 4-(methylthiomethoxy)butyrate, 2-(methylthiomethoxymethyl)benzoate, 2,6- dichloro-4-methylphenoxyacetate, 2,6-dichloro-4-( 1 , 1 ,3,3-tetramethylbutyl)phenoxyacetate, 2 ,4— bis( 1 , 1 — dimethylpropyl)phenoxyacetate, chlorodiphenylacetate, isobutyrate, monosuccinoate, (E)-2-methyl-2- butenoate, o-(methoxycarbonyl)benzoate, a-naphthoate, nitrate, alkyl N,N,N',N’- tetramethylphosphorodiamidate, alkyl N-phenylcarbamate, borate, dimethylphosphinothioyl, alkyl 2,4- dinitrophenylsulfenate, sulfate, methanesulfonate (mesylate), benzylsulfonate, and tosylate (Ts). For protecting 1,2- or 1,3-diols, the protecting groups include methylene acetal, ethylidene acetal, 1-t- butylethylidene ketal, 1-phenylethylidene ketal, (4-methoxyphenyl)ethylidene acetal, 2,2,2- trichloroethylidene acetal, acetonide, cyclopentylidene ketal, cyclohexylidene ketal, cycloheptylidene ketal, benzylidene acetal, p-methoxybenzylidene acetal, 2,4-dimethoxybenzylidene ketal, 3,4- dimethoxybenzylidene acetal, 2-nitrobenzylidene acetal, methoxymethylene acetal, ethoxymethylene acetal, dimethoxymethylene ortho ester, 1-methoxyethylidene ortho ester, 1-ethoxyethylidine ortho ester, 1,2- dimethoxyethylidene ortho ester, a-methoxybenzylidene ortho ester, l-(N,N-dimethylamino)ethylidene derivative, a-(N,N’ -dimethylamino (benzylidene derivative, 2-oxacyclopentylidene ortho ester, di— t— butylsilylene group (DTBS), l,3-(l,l,3,3-tetraisopropyldisiloxanylidene) derivative (TIPDS), tetra-t- butoxydisiloxane-l,3-diylidene derivative (TBDS), cyclic carbonates, cyclic boronates, ethyl boronate, and phenyl boronate.

[00051] In some embodiments, a hydroxyl protecting group is acetyl, t-butyl, tbutoxymethyl, methoxymethyl, tetrahydropyranyl, 1 -ethoxyethyl, 1 -(2-chloroethoxy)ethyl, 2- trimethylsilylethyl, p- chlorophenyl, 2,4-dinitrophenyl, benzyl, benzoyl, p-phenylbenzoyl, 2,6- dichlorobenzyl, diphenylmethyl, p- nitrobenzyl, triphenylmethyl (trityl), 4, 4'-dimethoxy trityl, trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, t- butyldiphenylsilyl, triphenylsilyl, triisopropylsilyl, benzoylformate, chloroacetyl, trichloroacetyl, trifiuoroacetyl, pivaloyl, 9- fluorenylmethyl carbonate, mesylate, tosylate, triflate, trityl, monomethoxytrityl (MMTr), 4,4'-dimethoxytrityl, (DMTr) and 4,4',4”-trimethoxytrityl (TMTr), 2-cyanoethyl (CE or Cne), 2- (trimethylsilyl)ethyl (TSE), 2-(2-nitrophenyl)ethyl, 2-(4-cyanophenyl)ethyl 2-(4-nitrophenyl)ethyl (NPE), 2- (4-nitrophenylsulfonyl)ethyl, 3,5-dichlorophenyl, 2,4-dimethylphenyl, 2-nitrophenyl, 4-nitrophenyl, 2,4,6- trimcthylphcnyl, 2-(2-nitrophcnyl)cthyl, butylthiocarbonyl, 4,4',4"-tris(bcnzoyloxy)trityl, diphcnylcarbamoyl, levulinyl, 2-(dibromomethyl)benzoyl (Dbmb), 2-(isopropylthiomethoxymethyl)benzoyl (Ptmt), 9- phenylxanthen-9-yl (pixyl) or 9-(p-methoxyphenyl)xanthine-9-yl (MOX). In some embodiments, each of the hydroxyl protecting groups is, independently selected from acetyl, benzyl, t- butyldimethylsilyl, t- butyldiphenylsilyl and 4,4'-dimethoxytrityl. In some embodiments a protecting group is 2-cyanoethyl (CE or Cne), 2-trimethylsilylethyl, 2-nitroethyl, 2-sulfonylethyl, methyl, benzyl, o-nitrobenzyl, 2-(p- nitrophenyl) ethyl (NPE or Npe), 2-phenylethyl, 3-(N-tert-butylcarboxamido)-l -propyl, 4-oxopentyl, 4- methylthio-l-butyl, 2-cy ano- 1,1 -dimethylethyl, 4-N-methylaminobutyl, 3-(2-pyridyl)-l-propyl, 2-[N-methyl- N-(2-pyridyl)]aminoethyl, 2-(N-formyl,N-methyl)aminoethyl, or 4-[N-methyl-N-(2,2,2- trifluoroacetyl) amino] butyl.

[00052] Sequential administration: As used herein, the term “Sequential administration” of two or more agents refers to administration of two or more agents to a subject such that the agents are not present together in the subject’s body, or at a relevant site of activity in the body, at greater than non-negligible concentrations. Administration of the agents may, but need not, alternate. Each agent may be administered multiple times. [00053] Subject: As used herein, the term “subject” or “test subject” refers to any organism to which a provided compound or composition is administered in accordance with the present disclosure, e.g., for experimental, diagnostic, prophylactic, and/or therapeutic purposes. Typical subjects include animals (e.g., mammals such as mice, rats, rabbits, non-human primates, and humans; insects; worms; etc.) and plants. In some embodiments, a subject may be suffering from, and/or susceptible to a disease, disorder, and/or condition. In many instances, provided compounds or compositions are administered or delivered to human subjects.

[00054] Substantially: As used herein, the term “substantially” refers to the qualitative condition of exhibiting total or near-total extent or degree of a characteristic or property of interest. One of ordinary skill in the biological arts will understand that biological and chemical phenomena rarely, if ever, go to completion and/or proceed to completeness or achieve or avoid an absolute result. The term “substantially” is therefore used herein to capture the potential lack of completeness inherent in many biological and/or chemical phenomena.

[00055] Substitution: As described herein, compounds of the disclosure may contain optionally substituted and/or substituted moieties. In general, the term “substituted,” whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. Unless otherwise indicated, an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. In some embodiments, an optionally substituted group is unsubstituted. In some embodiments, an optionally substituted group is substituted. Various substituents are described below.

[00056] Suitable monovalent substituents are halogen; -iCkbhi 4R⁰; -(CH₂)(MOR⁰; -0(CH2)o4R°, -O- (CH₂)(MC(0)0R°; -(CH2)(MCH(OR°)2; -(CH₂)o-4Ph, which may be substituted with R°; -(CH₂)(MO(CH₂)O- iPh which may be substituted with R°; -CH=CHPh, which may be substituted with R°; -(CH2)(MO(CH₂)o-j- pyridyl which may be substituted with R°; -NO2; -CN; -N₃; -(CH₂)(MN(R⁰)₂; -(CH₂)MN(R°)C(0)R⁰; - N(R°)C(S)R°; -(CH₂)(MN(R^O)C(O)N(R^O)₂; -N(R^O)C(S)N(R°)₂; -(CH₂)O^N(R⁰)C(0)OR°; - N(R°)N(R°)C(O)R°; -N(R°)N(R°)C(O)N(R^O)₂; -N(R°)N(R°)C(O)OR°; -(CH₂)(MC(0)R⁰; -C(S)R°; - (CH₂)CMC(O)OR⁰; -(CH₂)(MC(O)SR⁰; -(CH₂)o^C(0)OSi(R⁰)₃; -(CH₂)MOC(O)R°; -OC(O)(CH₂)O ₄SR^O, -SC(S)SR°; -(CH₂)(MSC(O)R°; -(CH₂)O 4C(O)N(R^O)₂; -C(S)N(R^O)₂; -C(S)SR°; -SC(S)SR°, -(CH₂)^ ₄OC(O)N(R^O)₂; -C(O)N(OR°)R°; -C(O)C(O)R°; -C(O)CH₂C(O)R^O; -C(NOR°)R°; -(CH₂)(MSSR⁰; -(CH₂)O- ₄S(O)₂R^O; -(CH₂)(MS(O)₂OR⁰; -(CH₂)O ^OS(O)₂R^O; -S(O)₂N(R°)2; -(CH₂)(MS(O)R⁰; -N(R^O)S(O)₂N(R°)₂; - N(R°)S(O)₂R°; -N(OR^O)R°; -C(NH)N(R^O)₂; -Si(R°)₃; -OSi(R°)₃; -P(R°)₂; -P(OR°)₂; -OP(R°)₂;

-OP(OR°)₂; -N(R°)P(R^O)₂; -B(R^O)₂; -OB(R^O)₂; -P(O)(R^O)₂; -OP(O)(R^O)₂; -N(R^O)P(O)(R°)₂; -(CM straight or branched alkylene)O-N(R°)₂; or -(Ci 4 straight or branched alkylene)C(O)O-N(R°)₂; wherein each R° may be substituted as defined below and is independently hydrogen, C1-10 (e.g., CM, CM, etc.) aliphatic, C1-10 (e.g., CM, CM, etc.) heteroaliphatic having 1-5 heteroatoms independently selected from nitrogen, oxygen, sulfur-, silicon and phosphorus, CMO (e.g., Ce, C10, etc.) aryl, 5-10 (e.g., 5-9, 5-6, 5, 6, 9, 10, etc.) membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, -CH₂-(C6 10 (e.g., Ce, C10. etc.) aryl), -0(CH₂)o i(Ce 10 (e.g., Ce, C10, etc.) aryl), -CH₂-(5-10 (e.g., 5-9, 5-6, 5, 6, 9, 10, etc.) membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur), -0(CH₂)o i(5-10 (e.g., 5-9, 5-6, 5, 6, 9, 10, etc.) membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur), a 3-10 (e.g., 3-6, 5-6, 3, 4, 5, 6, 7, 8, 9, 10, etc.) membered, monocyclic, bicyclic, or polycyclic, saturated, or partially unsaturated ring having 0-5 heteroatoms independently selected from nitrogen, oxygen, sulfur, silicon and phosphorus, or, notwithstanding the definition above, two independent occurrences of R°, taken together with then- intervening atom(s), form a 3- 10 (e.g., 3-6, 5-6, 3, 4, 5, 6, 7, 8, 9, 10, etc.) membered, monocyclic, bicyclic, or polycyclic, saturated, partially unsaturated or aromatic ring (for aromatic ring, 5-10 (e.g., 5-9, 5-6, 5, 6, 9, 10, etc.) membered) having, in addition to the intervening atom(s), 0-5 heteroatoms independently selected from nitrogen, oxygen, sulfur, silicon and phosphorus, which may be substituted as defined below.

[00057] Suitable monovalent substituents on R° (or the ring formed by taking two independent occurrences of R° together with their intervening atoms), arc independently halogen, -(CH₂)o-₂R*, -(haloR*), -(CH₂)o-₂OH, -(CH₂)O-₂OR", -(CH2)O-2CH(OR*)2; -O(haloR’), -CN, -N₃, -(CH2)o-2C(0)R*, -(CH₂)^ ₂C(O)OH, -(CH₂)O-2C(0)OR*, -(CH₂)O-₂SR*, -(CH₂)O -2SH, -(CH₂)O-2NH2, -(CH₂)O-2NHR*, -(CH₂)O-2NR*2, - N0₂, -SiR*3, -0SiR*3, -C(O)SR* - (Ci^t straight or branched alkylene)C(O)OR*, or -SSR* wherein each R* is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently selected from Ci^ aliphatic, -CH₂Ph, -0(CH₂)o-jPh, or a 3-6 (e.g., 3-5, 5-6, etc.)-membered saturated, partially unsaturated, or aromatic ring (for aromatic ring, 5- or 6-mcmbcrcd) having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. Suitable divalent substituents on a saturated carbon atom of R° are =0 and =S.

[00058] Suitable divalent substituents are the following: =0, =S, =NNR*₂, =NNHC(O)R*, =NNHC(0)0R*, =NNHS(O)₂R*, =NR*, =N0R*, -O(C(R*₂))_2-3O-, or -S(C(R*₂))_2-3S-, wherein each independent occurrence of R* is selected from hydrogen, C1-6 aliphatic which may be substituted as defined below, or an unsubstituted 3-6 (e.g., 3-5, 5-6, etc.)-membered saturated, partially unsaturated, or aromatic ring (for aromatic ring, 5- or 6-membered) having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. Suitable divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group are: -O(CR*₂)_2-3O-, wherein each independent occurrence of R* is selected from hydrogen, Cue aliphatic which may be substituted as defined below, or an unsubstituted 3-6 (e.g., 3-5, 5-

6, ctc.)-mcmbcrcd saturated, partially unsaturated, or aromatic ring (for aromatic ring, 5- or 6-mcmbcrcd) having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[00059] Suitable substituents on the aliphatic group of R* are halogen, -R*, -(haloR*), -OH, -OR*, - O(haloR*), -CN, -C(O)OH, -C(O)OR®, -NH₂, -NHR*, -NR*₂, or -NO₂, wherein each R* is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently Ci 4 aliphatic, -CH₂Ph, -0(CH₂)o-iPh, or a 3-6 (e.g., 3-5, 5-6, etc.)-membered saturated, partially unsaturated, or aromatic ring (for aromatic ring, 5- or 6-membered) having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[00060] Suitable substituents on a substitutable nitrogen arc -R^f, -NR^f ₂, -C(O)R^f, -C(O)OR^f, - C(O)C(O)R^t, -C(O)CH₂C(O)R^t, -S(O)₂R^f, -S(O)₂NR^f ₂, -C(S)NR%, -QNWNR^, or -N(R^t)S(O)₂R^t; wherein each R is independently hydrogen, C1-6 aliphatic which may be substituted as defined below, unsubstituted -OPh, or an unsubstituted 3-6 (e.g., 3-5, 5-6, etc.)-membered saturated, partially unsaturated, or aromatic ring (for aromatic ring, 5- or 6-membered) having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or, notwithstanding the definition above, two independent occurrences of R^:, taken together with their intervening atom(s) form an unsubstituted 3-12 (e.g., 3-10, 3-6, 5-10, 5-6, 3, 4, 5, 6,

7, 8, 9, 10, etc.) membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[00061] Suitable substituents on the aliphatic group of R^: are independently halogen, -R’, -(haloR*), -OH, -OR*, -O(haloR*), -CN, -C(O)OH, -C(O)OR*, -NH₂, -NHR*, -NR*₂, or -NO₂, wherein each R* is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently Ci^ aliphatic, -CH₂Ph, -0(CH₂)o-iPh, or a 3-6 (e.g., 3-5, 5-6, etc.)-membered saturated, partially unsaturated, or aromatic ring (for aromatic ring, 5- or 6-membered) having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[00062] Suffering from: An individual who is “suffering from” a disease, disorder, and/or condition has been diagnosed with and/or displays one or more symptoms of a disease, disorder, and/or condition.

[00063] Susceptible to: An individual who is “susceptible to” a disease, disorder and/or condition is one who has a higher risk of developing the disease, disorder and/or condition than does a member of the general public. In some embodiments, an individual who is susceptible to a disease, disorder and/or condition is predisposed to have that disease, disorder and/or condition. In some embodiments, an individual who is susceptible to a disease, disorder and/or condition may not have been diagnosed with the disease, disorder and/or condition. In some embodiments, an individual who is susceptible to a disease, disorder and/or condition may exhibit symptoms of the disease, disorder and/or condition. In some embodiments, an individual who is susceptible to a disease, disorder and/or condition may not exhibit symptoms of the disease, disorder and/or condition. In some embodiments, an individual who is susceptible to a disease, disorder, and/or condition will develop the disease, disorder, and/or condition. In some embodiments, an individual who is susceptible to a disease, disorder, and/or condition will not develop the disease, disorder, and/or condition.

[00064] Systemic: As used herein, the term “systemic” in reference to complement components, refers to complement proteins that are synthesized by liver hepatocytes and enter the bloodstream, or are synthesized by circulating macrophages or monocytes and secreted into the bloodstream.

[00065] Systemic complement activation: As used herein, the term “systemic complement activation” is complement activation that occurs in the blood, plasma, or serum and/or involves activation of systemic complement proteins at many locations throughout the body, affecting many body tissues, systems, or organs. [00066] Systemic administration: As used herein, the term “systemic administration” and like terms are used herein consistently with their usage in the art to refer to administration of an agent such that the agent becomes widely distributed in the body in significant amounts and has a biological effect, e.g., its desired effect, in the blood and/or reaches its desired site of action via the vascular system. Typical systemic routes of administration include administration by (i) introducing the agent directly into the vascular system or (ii) subcutaneous, oral, pulmonary, or intramuscular' administration wherein the agent is absorbed, enters the vascular- system, and is carried to one or more desired site(s) of action via the blood.

[00067] Therapeutic agent: As used herein, the phrase “therapeutic agent” refers to any agent that, when administered to a subject, has a therapeutic effect and/or elicits a desired biological and/or pharmacological effect. In some embodiments, a therapeutic agent is any substance that can be used to alleviate, ameliorate, relieve, inhibit, prevent, delay onset of, reduce severity of, and/or reduce incidence of one or more symptoms or features of a disease, disorder, and/or condition.

[00068] Therapeutically effective amount: As used herein, the term “therapeutically effective amount” means an amount of a substance (e.g., a therapeutic agent, composition, and/or formulation) that elicits a desired biological response when administered as part of a therapeutic regimen. In some embodiments, a therapeutically effective amount of a substance is an amount that is sufficient, when administered to a subject suffering from or susceptible to a disease, disorder, and/or condition, to treat, diagnose, prevent, and/or delay the onset of the disease, disorder, and/or condition. As will be appreciated by those of ordinary skill in this art, the effective amount of a substance may vary depending on such factors as the desired biological endpoint, the substance to be delivered, the target cell or tissue, etc. For example, the effective amount of compound in a formulation to treat a disease, disorder, and/or condition is the amount that alleviates, ameliorates, relieves, inhibits, prevents, delays onset of, reduces severity of and/or reduces incidence of one or more symptoms or signs of the disease, disorder, and/or condition. In some embodiments, a therapeutically effective amount is administered in a single dose; in some embodiments, multiple unit doses are required to deliver a therapeutically effective amount.

[00069] Treating: As used herein, the term “treating” refers to providing treatment, i.e, providing any type of medical or surgical management of a subject. The treatment can be provided in order to reverse, alleviate, inhibit the progression of, prevent or reduce the likelihood of a disease, disorder, or condition, or in order to reverse, alleviate, inhibit or prevent the progression of, prevent or reduce the likelihood of one or more symptoms or manifestations of a disease, disorder or condition. “Prevent” refers to causing a disease, disorder, condition, or symptom or manifestation of such not to occur for at least a period of time in at least some individuals. Treating can include administering an agent to the subject following the development of one or more symptoms or manifestations indicative of a complement-mediated condition, e.g., in order to reverse, alleviate, reduce the severity of, and/or inhibit or prevent the progression of the condition and/or to reverse, alleviate, reduce the severity of, and/or inhibit or one or more symptoms or manifestations of the condition. A composition of the disclosure can be administered to a subject who has developed a complement-mediated disorder or is at increased risk of developing such a disorder relative to a member of the general population. A composition of the disclosure can be administered prophylactically, i.e., before development of any symptom or manifestation of the condition. Typically in this case the subject will be at risk of developing the condition.

[00070] As those skilled in the art will appreciate, methods and compositions described herein relating to provided compounds generally also apply to pharmaceutically acceptable salts of such compounds. Unless specified otherwise, solvates, stereoisomers, tautomers, salts of provided compounds are included.

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS

[00071] Technologies of the present disclosure may be understood more readily by reference to the following detailed description of certain embodiments.

I. Complement System

[00072] To facilitate understanding of the disclosure, and without intending to limit the provided technologies in any way, this section provides an overview of complement and its pathways of activation. Further details are found, e.g., in Kuby Immunology, 6th ed., 2006; Paul, W.E., Fundamental Immunology, Lippincott Williams & Wilkins; 6th ed., 2008; and Walport MJ., Complement. First of two parts. N Engl J Med., 344(14):! 058-66, 2001.

[00073] Complement is an arm of the innate immune system that plays an important role in defending the body against infectious agents. The complement system comprises more than 30 scrum and cellular proteins that are involved in three major pathways, known as the classical, alternative, and lectin pathways. The classical pathway is usually triggered by binding of a complex of antigen and IgM or IgG antibody to Cl (though certain other activators can also initiate the pathway). Activated Cl cleaves C4 and C2 to produce C4a and C4b, in addition to C2a and C2b. C4b and C2a combine to form C3 convertase, which cleaves C3 to form C3a and C3b. Binding of C3b to C3 convertase produces C5 convertase, which cleaves C5 into C5a and C5b. C3a, C4a, and C5a are anaphylotoxins and mediate multiple reactions in the acute inflammatory response. C3a and C5a are also chemotactic factors that attract immune system cells such as neutrophils. It will be understood that the names “C2a” and “C2b” used initially were subsequently reversed in the scientific literature.

[00074] The alternative pathway is initiated by and amplified at, e.g., microbial surfaces and various complex polysaccharides. In this pathway, hydrolysis of C3 to C3(H2O), which occurs spontaneously at a low level, leads to binding of factor B, which is cleaved by factor D, generating a fluid phase C3 convertase that activates complement by cleaving C3 into C3a and C3b. C3b binds to targets such as cell surfaces and forms a complex with factor B, which is later cleaved by factor D, resulting in a C3 convertase. Surfacebound C3 convertases cleave and activate additional C3 molecules, resulting in rapid C3b deposition in close proximity to the site of activation and leading to formation of additional C3 convertase, which in turn generates additional C3b. This process results in a cycle of C3 cleavage and C3 convertase formation that significantly amplifies the response. Cleavage of C3 and binding of another molecule of C3b to the C3 convertase gives rise to a C5 convertase. C3 and C5 convertases of this pathway are regulated by cellular molecules CR1, DAF, MCP, CD59, and fH. The mode of action of these proteins involves either decay accelerating activity (i.e., ability to dissociate convertases), ability to serve as cofactors in the degradation of C3b or C4b by factor I, or both. Normally the presence of complement regulatory proteins on cell surfaces prevents significant complement activation from occurring thereon.

[00075] The C5 convertases produced in both pathways cleave C5 to produce C5a and C5b. C5b then binds to C6, C7, and C8 to form C5b-8, which catalyzes polymerization of C9 to form the C5b-9 membrane attack complex (MAC). The MAC inserts itself into target cell membranes and causes cell lysis. Small amounts of MAC on the membrane of cells may have a variety of consequences other than cell death.

[00076] The lectin complement pathway is initiated by binding of mannose-binding lectin (MBL) and MBL-associated serine protease (MASP) to carbohydrates. The MB 1-1 gene (known as LMAN-1 in humans) encodes a type I integral membrane protein localized in the intermediate region between the endoplasmic reticulum and the Golgi. The MBL-2 gene encodes the soluble mannose-binding protein found in serum. In the human lectin pathway, MASP-1 and MAS P-2 are involved in the proteolysis of C4 and C2, leading to a C3 convertase described above.

[00077] Complement activity is regulated by various mammalian proteins referred to as complement control proteins (CCPs) or regulators of complement activation (RCA) proteins (U.S. Pat. No. 6,897,290). These proteins differ with respect to ligand specificity and mcchanism(s) of complement inhibition. They may accelerate the normal decay of convertases and/or function as cofactors for factor I, to enzymatically cleave C3b and/or C4b into smaller fragments. CCPs are characterized by the presence of multiple (typically 4-56) homologous motifs known as short consensus repeats (SCR), complement control protein (CCP) modules, or SUSHI domains, about 50-70 amino acids in length that contain a conserved motif including four disulfide- bonded cysteines (two disulfide bonds), proline, tryptophan, and many hydrophobic residues. The CCP family includes complement receptor type 1 (CR1; C3b:C4b receptor), complement receptor type 2 (CR2), membrane cofactor protein (MCP; CD46), decay-accelerating factor (DAF), complement factor H (fH), and C4b-binding protein (C4bp). CD59 is a membrane-bound complement regulatory protein unrelated structurally to the CCPs. Complement regulatory proteins normally serve to limit complement activation that might otherwise occur on cells and tissues of the mammalian, e.g., human host. Thus, “self’ cells are normally protected from the deleterious effects that would otherwise ensue were complement activation to proceed on these cells. Deficiencies or defects in complement regulatory protein(s) are involved in the pathogenesis of a variety of complement-mediated disorders, e.g., as discussed herein.

II. Certain Provided Compounds and Composition

[00078] Among other things, the present disclosure demonstrates, surprisingly, that incorporation of N- containing moieties or basic moieties, into various compounds can unexpected increase binding to melanin, increase delivery to eyes or portions thereof, increase concentrations in eyes or portions thereof (e.g., those comprising melanin), and/or prolong ocular exposure. In some embodiments, a N-containing or basic moiety is or comprises an amino group, e.g., -N(R)z as described herein. In some embodiments, a N-containing or basic moiety is bonded to a ring, e.g., an aromatic ring, which is bonded to an acidic moiety (e.g., -COOH) or a bioisostere thereof, or a moiety that can be converted (e.g., through metabolism) to such a moiety. In some embodiments, a N-containing or basic moiety is an optionally substituted ring comprising a basic nitrogen and optionally one or more, e.g., 1-5, heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, a provided compound is a compound of formula I or a salt thereof. Those skilled in the art reading the present disclosure appreciate that many reported relevant factor B inhibitors or complement activation inhibitors can be modified and improved in accordance with the present disclosure. In some embodiments, relevant compounds, e.g., those reported in WO 2015/009616, US 9682968, US 10093663, WO 2018/005552, WO 2019/043609, WO 2020/016749, WO 2022/028507, WO 2022/028527, WO 2022/143845, WO 2022/218429, WO 2022/234541, WO 2022/256586, WO 2023/020566, WO 2023/037218, WO 2023/072197, WO 2023/139534, and WO 2023/143293, etc., can be modified and improved in accordance with the present disclosure. In some embodiments, such compounds are modified and improved by adding an amino group, e.g., -N(R)? as described herein, to a ring, e.g., an aromatic ring, that is bonded to an acidic moiety (e.g., — COOH) or a bioisostere thereof, or a moiety that can be converted (e.g., through metabolism) to such a moiety. In some embodiments, such an amino group is added to position 2 or 3 relevant to the acidic moiety (e.g., —COOH) or a bioisostere thereof, or a moiety that can be converted (e.g., through metabolism) to such a moiety (e.g., on a phenyl ring, o or m to the acidic moiety (e.g., -COOH) or a bioisostere thereof, or a moiety that can be converted (e.g., through metabolism) to such a moiety). In some embodiments, a provided compound is a compound generically or specifically described in WO 2015/009616, US 9682968, US 10093663, WO 2018/005552, WO 2019/043609, WO 2020/016749, WO 2022/028507, WO 2022/028527, WO 2022/143845, WO 2022/218429, WO 2022/234541, WO 2022/256586, WO 2023/020566, WO 2023/037218, WO 2023/072197, WO 2023/139534, or WO 2023/143293, wherein the compound comprises three optionally substituted rings optionally connected through linkers, Ring 1 (e.g., Ring A as described herein such as an optionally substituted heteroaromatic ring)-L¹² (e.g., L¹ as described herein)-Ring 2 (e.g., an optionally substituted nitrogen-containing optionally substituted non-aromatic ring which is bonded to L¹² through the nitrogen atom, Ring B as described herein, etc.)-L²³ (e.g., a covalent bond or optionally substituted — CH2— )— Ring 3 (e.g., an optionally substituted aromatic ring having 0-4 heteroatoms, Ring C as described herein), wherein Ring 3 is bonded to an acidic moiety (e.g., —COOH) or a bioisostere thereof, or a moiety that can be converted (e.g., through metabolism) to such a moiety, and an amino group (e.g., -N(R)2 as described herein) substitution is added to Ring C. In some embodiments, Ring C is replaced with an optionally substituted N-containing or basic moiety is or comprises a 3-10 (e.g., 3-7, 4- 7, 3, 4, 5, 6, 7, 8, 9, 10, etc.) membered ring having one or more (e.g., 1-5, 1, 2, 3, 4, 5, etc.) heteroatoms. In some embodiments, a first compound is a compound generically or specifically described in WO 2015/009616, US 9682968, US 10093663, WO 2018/005552, WO 2019/043609, WO 2020/016749, WO 2022/028507, WO 2022/028527, WO 2022/143845, WO 2022/218429, WO 2022/234541, WO 2022/256586, WO 2023/020566, WO 2023/037218, WO 2023/072197, WO 2023/139534, or WO 2023/143293. In some embodiments, a first compound is a factor B or complement activation inhibitor.

[00079] In some embodiments, the present disclosure provides a compound, wherein the compound has an identical structure as a fir st compound, wherein the first compound comprises an acidic moiety or a bioisostere thereof, or a moiety that can be converted to an acidic moiety or a bioisostere thereof, wherein the moiety is bonded to a ring, except that an additional amino group is bonded to the ring and/or except that the ring is replaced with a basic nitrogen-containing 5-10 membered ring. In some embodiments, a basic nitrogen-containing 5-10 membered ring is Ring C as described herein, wherein Ring C is an optionally substituted 5-10 membered ring having a nitrogen atom.

[00080] In some embodiments, an amino group is — N(R)2 wherein each R is independently as described herein. In some embodiments, each R is independently -H or an optionally substituted C1-6 aliphatic. In some embodiments, each R is independently -H or optionally substituted C1-6 alkyl. In some embodiments, each R is independently -H or C1-6 alkyl optionally substituted with halogen. In some embodiments, an amino group is -NHR wherein R is as described herein. In some embodiments, R is optionally substituted Ci 6 aliphatic. In some embodiments, R is C1-6 aliphatic. In some embodiments, R is optionally substituted C1-6 alkyl. In some embodiments, R is C1-6 alkyl. In some embodiments, R is methyl. In some embodiments, R is ethyl. Certain useful amino groups arc those described for R^d or R^e.

[00081] In some embodiments, a N-containing or basic moiety is or comprises an optionally substituted 3- 20 (e.g., 3-15, 3-10, 3-7, 4-7, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, etc.) membered ring having one or more (e.g., 1-5, 1, 2, 3, 4, 5, etc.) heteroatoms, wherein one or more (e.g., 1-5, 1, 2, 3, 4, 5, etc.) heteroatoms is nitrogen. In some embodiments, it is an optionally substituted monocyclic ring. In some embodiments, it is an optionally substituted bicyclic ring. In some embodiments, it is an optionally substituted tricyclic ring. In some embodiments, it is saturated. In some embodiments, it is partially unsaturated. In some embodiments, it is aromatic. In some embodiments, each monocyclic ring unit is independently an optionally substituted 3-10 (e.g., 3-7, 4-7, 3-6, 3, 4, 5, 6, 7, 8, 9, 10, etc.) membered saturated or partially unsaturated ring having 0-5 heteroatoms, or an optionally substituted 5-6 membered aromatic ring having 0-4 heteroatoms, wherein at least one monocyclic ring has a nitrogen atom. In some embodiments, a N-containing or basic moiety is or comprises an optionally substituted 3-10 (e.g., 3-7, 4-7, 3, 4, 5, 6, 7, 8, 9, 10, etc.) membered heterocyclic ring having one or more (e.g., 1-5, 1, 2, 3, 4, 5, etc.) heteroatoms, wherein one or more (e.g., 1-5, 1, 2, 3, 4, 5, etc.) heteroatoms is nitrogen. In some embodiments, a N-containing or basic moiety is or comprises an optionally substituted 5-10 (e.g., 5-9, 5, 6, 7, 8, 9, 10, etc.) membered heteroaryl ring having one or more (e.g., 1-5, 1, 2, 3, 4, 5, etc.) heteroatoms, wherein one or more (e.g., 1-5, 1, 2, 3, 4, 5, etc.) heteroatoms is nitrogen. In some embodiments, each heteroatom is independently nitrogen, oxygen and sulfur. In some embodiments, a N-containing or basic moiety is Ring C as described herein, wherein Ring C comprises a ring which has a nitrogen atom.

[00082] In some embodiments, a provided compound is a compound of formula I or a salt thereof, wherein each variable is independently as described herein.

[00083] Certain useful embodiments for various variables, and various compounds, are described below as examples.

Ring A

[00084] As those skilled in the art reading the present disclosure will appreciate, various rings and substituents may be utilized for Ring A or Ring 1. In some embodiments, a ring and/or its substituent(s) are described in WO 2015/009616, US 9682968, US 10093663, WO 2018/005552, WO 2019/043609, WO 2020/016749, WO 2022/028507, WO 2022/028527, WO 2022/143845, WO 2022/218429, WO 2022/234541, WO 2022/256586, WO 2023/020566, WO 2023/037218, WO 2023/072197, WO 2023/139534, or WO 2023/143293.

[00085] In some embodiments, Ring A is unsubstituted. In some embodiments, Ring A is substituted. In some embodiments, Ring A is an optionally substituted 5 -membered aromatic ring having 0-5 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, Ring A is an optionally substituted 6-membered aromatic ring having 0-5 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments. Ring A is an optionally substituted 9-membered bicyclic aromatic ring having 0-5 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, Ring A is an optionally substituted 10-mcmbcrcd bicyclic aromatic ring having 0-5 hctcroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, Ring A has at least one heteroatom. In some embodiments, Ring A has one heteroatom. In some embodiments, Ring A has a nitrogen atom. In some embodiments, Ring A is optionally substituted indolyl. In some embodiments, Ring

A is optionally substituted H a

[00086] In some embodiments, a is 0. In some embodiments, a is 1. In some embodiments, a is 2. In some embodiments, a is 3. In some embodiments, a is 4. In some embodiments, a is 5.

R^a

[00087] In some embodiments, each R^a is independently selected from halogen, — CN, R^al , -OR^al , and -NR^alR^a2, wherein each of R^al and R^a2 is independently R as described herein. In some embodiments, R^a is -H. In some embodiments, R^a is not -H. In some embodiments, R^a is halogen. In some embodiments, R^a is -CN. In some embodiments, R^a is R^al. In some embodiments, R^a is -OR^al. In some embodiments, R^a is -NR^alR^a2. In some embodiments, R^a is -NHR^al. In some embodiments, each R^a is independently R^al or -OR^al, wherein R^al is as described herein.

[00088] In some embodiments, R^al is R as described herein. In some embodiments, R^al is — H. In some embodiments, R^al is not hydrogen. In some embodiments, R^al is optionally substituted C1-6 aliphatic. In some embodiments, R^al is optionally substituted C1-6 alkyl. In some embodiments, R^al is optionally substituted -CH2-C1-6 aliphatic. In some embodiments, R^al is optionally substituted -CH2-C36 cycloalkyl. In some embodiments, R^al is optionally substituted -CH2-C36 cyclopropyl. In some embodiments, R^al is optionally substituted C3-10 cycloaliphatic. In some embodiments, R^al is optionally substituted C3-7 cycloaliphatic. In some embodiments, R^al is optionally substituted C3-6 cycloaliphatic. In some embodiments, R^al is optionally substituted C3-10 cycloalkyl. In some embodiments, R^al is optionally substituted C3-7 cycloalkyl. In some embodiments, R^al is optionally substituted C3-6 cycloalkyl. In some embodiments, R^al is optionally substituted cyclopropyl. In some embodiments, R^al is optionally substituted cyclobutyl. In some embodiments, R^al is optionally substituted cyclopentyl. In some embodiments, R^al is optionally substituted cyclohexyl. In some embodiments, R^al is substituted. In some embodiments, R^al is unsubstituted.

[00089] In some embodiments, R^a2 is R as described herein. In some embodiments, R^a2 is — H. In some embodiments, R^a2 is not hydrogen. In some embodiments, R^a2 is optionally substituted C1-6 aliphatic. In some embodiments, R^a2 is optionally substituted C1-6 alkyl. In some embodiments, R^a2 is optionally substituted -CH2-C1-6 aliphatic. In some embodiments, R^a2 is optionally substituted -CH2-C3-6 cycloalkyl.

In some embodiments, R^a2 is optionally substituted -CH2-C36 cyclopropyl. In some embodiments, R^al and R^a2 arc R and arc taken together to form a ring as described herein.

[00090] In some embodiments, R^a is R¹ as described herein. In some embodiments, R^a is R² as described herein. In some embodiments, R^a is R³ as described herein. For example, in some embodiments, R^a is -OMe. In some embodiments, R^a is methyl. In some embodiments, R^a is -H.

[00091] In some embodiments,

wherein each of R¹, R² and R³ is independently R^a. Certain embodiments of each of R¹, R² and R³ are independently described below.

L¹

[00092] In some embodiments, L¹ is optionally substituted -CH2-. In some embodiments, L¹ is -Chhin some embodiments, L¹ is substituted -CH2-. In some embodiments, L¹ is -CDi— . In some embodiments, L¹² is L¹ as described herein.

[00093]

Ring B

[00094] As those skilled in the art reading the present disclosure will appreciate, various rings and substituents may be utilized for Ring B or Ring 2. In some embodiments, a ring and/or its substituent(s) are described in WO 2015/009616, US 9682968, US 10093663, WO 2018/005552, WO 2019/043609, WO 2020/016749, WO 2022/028507, WO 2022/028527, WO 2022/143845, WO 2022/218429, WO 2022/234541, WO 2022/256586, WO 2023/020566, WO 2023/037218, WO 2023/072197, WO 2023/139534, or WO 2023/143293.

1000951 In some embodiments, Ring B is an optionally substituted 5-10 membered monocyclic, bicyclic or polycyclic, saturated or partially unsaturated ring having, in addition to the nitrogen atom, 0-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein no monocyclic ring comprising the nitrogen atom is a 5-8 membered ring having, in addition to the nitrogen atom, one nitrogen atom. In some embodiments, Ring B is an optionally substituted 5-10 membered monocyclic, bicyclic or polycyclic, saturated or partially unsaturated ring having, in additional to the nitrogen atom, 0-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein no monocyclic ring comprising the nitrogen atom is a saturated 5-8 membered ring having, in addition to the nitrogen atom, one nitrogen atom. [00096] In some embodiments, Ring B is saturated. In some embodiments, Ring B is partially unsaturated.

[00097] In some embodiments, Ring B is monocyclic. In some embodiments, Ring B is an optionally substituted 4-10 (e.g., 5-10, 4-8, 4, 5, 6, 7, 8, 9, 10, etc.) membered ring having, in additional to the nitrogen atom, 0-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, Ring B is an optionally substituted 5-membered ring having, in additional to the nitrogen atom, 0-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, Ring B is an optionally substituted 6-mcmbcrcd ring having, in additional to the nitrogen atom, 0-4 hctcroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, Ring B is monocyclic. In some embodiments, Ring B is an optionally substituted 7-membered ring having, in additional to the nitrogen atom, 0-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, Ring B is monocyclic. In some embodiments, Ring B is an optionally substituted 8-membered ring having, in additional to the nitrogen atom, 0-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, such a Ring B is saturated. In some embodiments, such a Ring B is partially unsaturated. In some embodiments, such a Ring B has 0 heteroatoms in addition to the nitrogen atom. In some embodiments, such a Ring B is saturated and has 0 heteroatoms in addition to the nitrogen atom. In some embodiments,

is optionally substituted

. In some embodiments,

is optionally substituted

. In some embodiments,

is optionally substituted

. In some embodiments,

is optionally substituted

[00098] In some embodiments, Ring B is bicyclic. In some embodiments, Ring B is polycyclic. In some embodiments, each monocyclic ring unit is independently an optionally substituted 3-8 (e.g., 3-7, 4-7, 3-6, 3, 4, 5, 6, 7, 8, etc.) membered saturated or partially unsaturated ring having 0-5 heteroatoms, or an optionally substituted 5-6 membered aromatic ring having 0-4 heteroatoms. In some embodiments, each monocyclic ring unit is independently an optionally substituted 3-8 (e.g., 3-7, 4-7, 3-6, 3, 4, 5, 6, 7, 8, etc.) membered saturated or partially unsaturated ring having 0-5 heteroatoms. In some embodiments, each monocyclic ring unit is independently an optionally substituted 3-8 (e.g., 3-7, 4-7, 3-6, 3, 4, 5, 6, 7, 8, etc.) membered saturated ring having 0-5 heteroatoms. In some embodiments, a monocyclic unit comprises the nitrogen atom, and is a

4-8 membered (e.g., 4-7, 4-6, 3, 4, 5, 6, 7, 8, etc.) membered saturated or partially unsaturated ring having 0-5 additional heteroatoms. In some embodiments, a monocyclic unit comprises the nitrogen atom, and is a 4- membered saturated or partially unsaturated ring having 0-2 additional heteroatoms. In some embodiments, a monocyclic unit comprises the nitrogen atom, and is a 5-membered saturated or partially unsaturated ring having 0-3 additional heteroatoms. In some embodiments, a monocyclic unit comprises the nitrogen atom, and is a 6-membered saturated or partially unsaturated ring having 0-3 additional heteroatoms. In some embodiments, a monocyclic unit comprises the nitrogen atom, and is a 7-membered saturated or partially unsaturated ring having 0-3 additional heteroatoms. In some embodiments, a monocyclic unit comprises the nitrogen atom, and is a 4-membered saturated or partially unsaturated ring having no additional heteroatoms. In some embodiments, a monocyclic unit comprises the nitrogen atom, and is a 5-membered saturated or partially unsaturated ring having no additional heteroatoms. In some embodiments, a monocyclic unit comprises the nitrogen atom, and is a 6-mcmbcrcd saturated or partially unsaturated ring having no additional heteroatoms. In some embodiments, a monocyclic unit comprises the nitrogen atom, and is a 7-membered saturated or partially unsaturated ring having no additional heteroatoms.

[00099] In some embodiments, Ring B is bicyclic, wherein one monocyclic ring unit comprises the nitrogen atom, is 6-membered and saturated, and has no additional heteroatom. In some embodiments, Ring B is spiro-bicyclic, wherein one monocyclic ring unit comprises the nitrogen atom, is 6-membered and saturated, and has no additional heteroatom. In some embodiments, the other ring is connected at position 4 (if the nitrogen is position 1). In some embodiments, Ring B is fused-bicyclic, wherein one monocyclic ring unit comprises the nitrogen atom, is 6-membered and saturated, and has no additional heteroatom. In some embodiments, the other monocyclic ring unit is 3-6 membered, saturated and has 0-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, the other monocyclic ring unit is 3-6 membered, saturated and has 0-2 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, the other ring is 3-membered. In some embodiments, the other ring is 4- membered. In some embodiments, the other ring is 5 -membered. In some embodiments, the other ring is 6- membered. In some embodiments, the other ring has no heteroatom. In some embodiments, the other ring has one heteroatom. In some embodiments, the other ring has two heteroatoms. For example, in some embodiments, Ring B is optionally substituted

In some embodiments, Ring B is optionally

In some embodiments. Ring B is optionally substituted

embodiments, Ring B is optionally substituted

. In some embodiments, Ring B is optionally substituted

. In some embodiments, Ring B is optionally substituted

. In some embodiments, Ring B is optionally substituted

some embodiments, Ring B is optionally substituted

[00100] In some embodiments,

wherein each variable is independently as described herein. In some embodiments.

wherein each variable is independently as described herein. In some embodiments,

wherein each variable is independently as described herein. In some embodiments,

ome

wherein each variable is independently as described herein.

independently as described herein. In some embodiments,

wherein each vaiiable is independently as described herein. In some embodiments,

wherein each variable is independently as described herein. In some embodiments,

[00102] In some embodiments,

is optionally substituted

. In some embodiments, it is optionally substituted

. In some embodiments, it is optionally substituted

. , . In some embodiments, it is

. In some embodiments,

some embodiments, it is

some embodiments,

some embodiments,

embodiments, i

[00103] In some embodiments, b is 0. In some embodiments, b is 1. In some embodiments, b is 2. In some embodiments, b is 3. In some embodiments, b is 4. In some embodiments, b is 5. In some embodiments, b is t as described herein.

R^b

[00104] In some embodiments, R^b is hydrogen. In some embodiments, R^b is not hydrogen. In some embodiments, R^b is R⁶ as described herein. In some embodiments, R^b is R⁶ as described herein. In some embodiments, an occurrence of R^b is R⁶ as described herein, and an occurrence of R^b is R⁶ as described herein. In some embodiments, R^b is R⁴ as described herein.

[00105] In some embodiments, R^b is halogen. In some embodiments, R^b is -F. In some embodiments, R^b is -Cl. In some embodiments, R^b is -Br. In some embodiments, R^b is -I. In some embodiments, each R^b is independently halogen. In some embodiments, each R^b is -F.

[00106] In some embodiments, R^b is -CN.

[00107] In some embodiments, R^b is -L^b— C(O)OR^bl , wherein R^bl is as described herein.

[00108] In some embodiments, R^b is -L^b-C(O)NR^blR^b2, wherein each of R^bl and R^b2 is independently as described herein. In some embodiments, R^b is -L^b— C(O)NHR^bl wherein R^bl is as described herein.

[00109] In some embodiments, R^b is -L^b-R^bl. In some embodiments, R^b is -R^bl wherein R^bl is R. In some embodiments, R^b is -R^bl wherein R^bl is optionally substituted C1-6 aliphatic. In some embodiments, R^b is optionally substituted C1-6 alkyl. In some embodiments, R^b is C1-6 alkyl. In some embodiments, R^b is Ci e haloalkyl. In some embodiments, R^b is -CF3. In some embodiments, R^b is -H. In some embodiments, R^b is optionally substituted C3-10 cycloaliphatic. In some embodiments, R^b is optionally substituted C3-6 cycloalkyl. In some embodiments, R^b is optionally substituted cyclopropyl. In some embodiments, R^b is cyclopropyl. In some embodiments, R^b is optionally substituted 3-7 membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, R^b is optionally substituted 3-7 membered heterocyclyl having one heteroatom independently selected from nitrogen, oxygen and sulfur. In some embodiments, R^b is optionally substituted 4-membered heterocyclyl having one heteroatom independently selected from nitrogen, oxygen and sulfur. In some embodiments, R^b is optionally substituted

, [00110] In some embodiments, R^b is -L^b-OR^bl. In some embodiments, R^b is -L^b-OR^bl, wherein R^bl is R as described herein. In some embodiments, R^b is -L^b-OR^bl, wherein R^bl is optionally substituted C1-6 aliphatic. In some embodiments, R^b is -L^b-OR^bl, wherein R^bl is optionally substituted Cue alkyl. In some embodiments, R^bl is methyl. In some embodiments, R^bl is ethyl. In some embodiments, R^bl is -CH2-C3 e cycloalkyl. In some embodiments, R^bl is -CH2-cyclopropyl. In some embodiments, L^b is a covalent bond. In some embodiments, R^b is -OCH3. In some embodiments, R^b is -O-CH2-cyclopropyl. In some embodiments, R^b is -OEt.

[00111] In some embodiments, R^b is -L^b-NR^blR^b2 wherein each of R^bl and R^b2 is independently as described herein. In some embodiments, R^b is -L^b— NHR^bl wherein R^bl is as described herein. [00112] In some embodiments, R^b is -L^b— C(O)R^bl wherein R^bl is as described herein.

[00113] In some embodiments, R^b is -L^b-C(O)N(R^bl)S(O)₂R^b2 wherein each of R^bl and R^b2 is independently as described herein. In some embodiments, R^b is -L^b-C(O)NHS(O)2R^b2 wherein R^b2 is as described herein.

[00114] In some embodiments, R^b is -L^b-S(O)2N(R^bl)C(O)R^b2 wherein each of R^bl and R^b2 is independently as described herein. In some embodiments, R^b is — L^h— S(O)2NHC(O)R^b2 wherein R^b2 is as described herein.

[00115] In some embodiments, R^b is -L^b-S(O)2NR^blR^b2 wherein each of R^bl and R^b2 is independently as described herein. In some embodiments, R^b is -L^b-S(O)2NHR^bl wherein R^bl is as described herein.

[00116] In some embodiments, R^b is -L^b-S(O)(NR^bl)R^b2 wherein each of R^bl and R^b2 is independently as described herein. In some embodiments, R^b is -L^b— S(O)(NH)R^b2 wherein and R^b2 is as described herein.

[00117] In some embodiments, R^b is -L^b— S(O)2R^bl , wherein R^bl is as described herein. In some embodiments, R^b is -S(O)2R^bl, wherein R^bl is as described herein. For example, in some embodiments, R^bl is -R wherein R is as described herein. In some embodiments, R^bl is -R wherein R is not -H. In some embodiments, R^bl is optionally substituted C1-6 aliphatic. In some embodiments, R^bl is ethyl.

[00118] In some embodiments, an occurrence of R^b is trans relative to Ring C. In some embodiments, an occurrence of R^b is cis relative to Ring C.

[00119] In some embodiments, R^bl is R as described herein. In some embodiments, R^bl is — H. In some embodiments, R^bl is not hydrogen. In some embodiments, R^bl is optionally substituted C1-6 aliphatic. In some embodiments, R^bl is optionally substituted C1-6 alkyl. In some embodiments, R^bl is optionally substituted -CH2-C1-6 aliphatic. In some embodiments, R^bl is optionally substituted -CH2-C36 cycloalkyl. In some embodiments, R^bl is optionally substituted -CH2-C36 cyclopropyl.

[00120] In some embodiments, R^b2 is R as described herein. In some embodiments, R^b2 is — H. In some embodiments, R^b2 is not hydrogen. In some embodiments, R^b2 is optionally substituted C1-6 aliphatic. In some embodiments, R^b2 is optionally substituted C1-6 alkyl. In some embodiments, R^b2 is optionally substituted -CH2-C1-6 aliphatic. In some embodiments, R^b2 is optionally substituted -CH2-C36 cycloalkyl. In some embodiments, R^b2 is optionally substituted -CH2-C36 cyclopropyl. In some embodiments, R^bl and R^b2 are R and are taken together to form a ring as described herein.

[00121 ] As described herein, two groups that are R or can be R, e.g., two R^b groups, may be taken together to form an optionally substituted ring as described herein. In some embodiments, two R^b groups are taken together with the carbon atom to which they arc attached to form an optionally substituted 3-10 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 3-8, 3-7, 3-6, 4-6, 5-6, 5-8, etc.) membered saturated ring having no heteroatoms. In some embodiments, a ring is 3-10 membered and has, in addition to the atom, 0-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, a ring has no heteroatoms. In some embodiments, a ring has 1-4, e.g., 1, 2, 3 or 4, heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, a ring is 3-membered. In some embodiments, a ring is 4-membered. In some embodiments, a ring is 5 -membered. In some embodiments, a ring is 6-membered. In some embodiments, a ring is 7-membered. In some embodiments, a ring is 8-membered. In some embodiments, a ring is 9- membered. In some embodiments, a ring is 10-membered. In some embodiments, a ring is saturated. In some embodiments, a ring is partially unsaturated. In some embodiments, a ring is aromatic. In some embodiments, a ring is monocyclic. In some embodiments, a ring is bicyclic. In some embodiments, a ring is polycyclic. In some embodiments, each monocyclic ring unit is independently an optionally substituted 3-8 (e.g., 3-7, 4-7, 3-6, 3, 4, 5, 6, 7, 8, etc.) membered saturated or partially unsaturated ring having 0-5 heteroatoms, or an optionally substituted 5-6 membered aromatic ring having 0-4 heteroatoms. In some embodiments, each monocyclic ring unit is independently an optionally substituted 3-8 (e.g., 3-7, 4-7, 3-6, 3, 4, 5, 6, 7, 8, etc.) membered saturated or partially unsaturated ring having 0-5 heteroatoms. In some embodiments, each monocyclic ring unit is independently an optionally substituted 3-8 (e.g., 3-7, 4-7, 3-6, 3, 4, 5, 6, 7, 8, etc.) membered saturated ring having 0-5 heteroatoms. In some embodiments, a monocyclic ring unit is an optionally substituted saturated 3-8 (e.g., 3-7, 4-7, 3-6, 3, 4, 5, 6, 7, 8, etc.) membered ring having no heteroatoms. In some embodiments, a monocyclic ring unit is an optionally substituted saturated 3-8 (e.g., 3-7, 4-7, 3-6, 3, 4, 5, 6, 7, 8, etc.) membered ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, a monocyclic ring unit is an optionally substituted 6- membered aromatic ring having no heteroatoms. In some embodiments, a monocyclic ring unit is an optionally substituted 10-membered aromatic ring having no heteroatoms. In some embodiments, a monocyclic ring unit is an optionally substituted 5-membered heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, a monocyclic ring unit is an optionally substituted 6-membered heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[00122] For example, in some embodiments, two R^b groups are taken together with the carbon atom to which they are attached to form an optionally substituted 4-membered monocyclic saturated ring having 0-4 heteroatoms independently selected from nitrogen, oxygen and sulfur-. In some embodiments, a ring has no heteroatoms. In some embodiments, a ring has one heteroatom. In some embodiments, there is one heteroatom in a ring which is oxygen. In some embodiments, there is one heteroatom in a ring which is nitrogen. In some embodiments, a ring is unsubstituted. In some embodiments, a ring is substituted with one or more halogen. In some embodiments, a ring is substituted with one or more -F. In some embodiments, a ring is substituted with one or more -SOilCH;). In some embodiments, a ring is substituted with one or more - CO(CH3). In some embodiments, two R^b groups arc taken together with the carbon atom to which they arc attached to form optionally substituted

. In some embodiments, two R^b groups are taken together with the carbon atom to which they are attached to form

. In some embodiments, two R^b groups are taken together with the carbon atom to which they are attached to form

. In some embodiments, two R^b groups are taken together with the carbon atom to which they are attached to form optionally substituted

. j_n some embodiments, two R^b groups are taken together with the carbon atom to which they are attached to form

. In some embodiments, two R^b groups are taken together with the carbon atom to which they ar e attached to form

. In some embodiments, two R^b groups are taken together with the carbon atom to which they are attached to form

L^b

[00123] In some embodiments, L^b is a covalent bond. In some embodiments, L^b is optionally substituted -CHi-. In some embodiments, L^b is -CH2-.

Ring C

[00124] As those skilled in the art reading the present disclosure will appreciate, various rings and substituents may be utilized for Ring C or Ring 3. In some embodiments, a ring and/or its substituent(s) are described in WO 2015/009616, US 9682968, US 10093663, WO 2018/005552, WO 2019/043609, WO 2020/016749, WO 2022/028507, WO 2022/028527, WO 2022/143845, WO 2022/218429, WO 2022/234541, WO 2022/256586, WO 2023/020566, WO 2023/037218, WO 2023/072197, WO 2023/139534, or WO 2023/143293.

[00125] In some embodiments, Ring C is substituted. In some embodiments, Ring C is unsubstituted.

[00126] In some embodiments, Ring C is 5-membered. In some embodiments, Ring C is 6-membered. In some embodiments, Ring C is 7 -membered. In some embodiments, Ring C is 8 -membered. In some embodiments, Ring C is 9-membered. In some embodiments, Ring C is 10-membered.

[00127] In some embodiments. Ring C is monocyclic. In some embodiments, Ring C is bicyclic. In some embodiments, Ring C is polycyclic. In some embodiments, each monocyclic ring unit is independently an optionally substituted 3-8 (e.g., 3-7, 4-7, 3-6, 3, 4, 5, 6, 7, 8, etc.) membered saturated or partially unsaturated ring having 0-5 heteroatoms, or an optionally substituted 5-6 membered aromatic ring having 0-4 hctcroatoms. In some embodiments, each monocyclic ring unit is independently an optionally substituted 3-8 (e.g., 3-7, 4-7, 3-6, 3, 4, 5, 6, 7, 8, etc.) membered saturated or partially unsaturated ring having 0-5 heteroatoms. In some embodiments, each monocyclic ring unit is independently an optionally substituted 3-8 (e.g., 3-7, 4-7, 3-6, 3, 4, 5, 6, 7, 8, etc.) membered saturated ring having 0-5 heteroatoms. In some embodiments, a monocyclic ring unit is an optionally substituted saturated 3-8 (e.g., 3-7, 4-7, 3-6, 3, 4, 5, 6, 7, 8, etc.) membered ring having no heteroatoms. In some embodiments, a monocyclic ring unit is an optionally substituted saturated 3-8 (e.g., 3-7, 4-7, 3-6, 3, 4, 5, 6, 7, 8, etc.) membered ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, a monocyclic ring unit is an optionally substituted 6-membered aromatic ring having no heteroatoms. In some embodiments, a monocyclic ring unit is an optionally substituted 10-membered aromatic ring having no heteroatoms. In some embodiments, a monocyclic ring unit is an optionally substituted 5-membered heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, a monocyclic ring unit is an optionally substituted 6-membered heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, at least one monocyclic ring unit is aromatic. In some embodiments, at least one monocyclic ring unit is aromatic and is bonded to Ring B and R^c.

[00128] In some embodiments. Ring C is saturated. In some embodiments, Ring C is partially unsaturated. In some embodiments, Ring C is aromatic.

[00129] In some embodiments, Ring C is an optionally substituted phenyl ring. In some embodiments, Ring C is an optionally substituted 10-membered aromatic ring having no heteroatoms. In some embodiments, Ring C is an optionally substituted 5-membered aromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, Ring C is an optionally substituted 6-membered aromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, Ring C is an optionally substituted 9-membered bicyclic aromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, Ring C is an optionally substituted 10-membered bicyclic aromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, at least one heteroatom is nitrogen. In some embodiments, each heteroatom is nitrogen.

[00130] In some embodiments, Ring C is optionally substituted

. In some embodiments, Ring C is optionally substituted

In some embodiments, Ring C is optionally substituted

. In some embodiments, Ring C is optionally substituted

In some embodiments, Ring C is optionally substituted

In some embodiments, Ring C is optionally substituted

embodiments, Ring C is optionally substituted

In some embodiments, Ring C is optionally

O substituted

. In some embodiments, Ring C is optionally substituted

.In some embodiments,

Ring C is optionally substituted

. In some embodiments, Ring C is optionally substituted

In some embodiments, Ring C is optionally substituted

In some embodiments,

Ring C is optionally substituted

embodiments, it is

In some embodiments, it is

In some embodiments, it is

. In some embodiments, it is

In some embodiments, it is

In some embodiments,

^Rk<“>^(R^d)d ^RC\x^N\x^Rd

[00132] In some embodiments, (^R e XSJk is X ^Xx.^zXr'- . I n some embodiments, R^d comprises a H-bond donor, e.g., -NH₂, -OH, etc., which can form a H-bond with the ring nitrogen atom.

[00133] In some embodiments,

is R⁴ as described herein. In some embodiments, R⁴ is substituted with R⁵ and one or two R⁵ . In some embodiments, at least one R⁵ is -N(R⁵¹)₂ as described herein. In some embodiments, R^e is R⁵ as described herein, wherein R⁵ is -N(R^5I)₂ as described herein. In some embodiments, R^d is R⁵ as described herein, wherein R⁵ is -N(R⁵¹)₂ as described herein.

R^c

[00134] As those skilled in the art reading the present disclosure will appreciate, various groups may be utilized for R^c. In some embodiments, a suitable group, e.g., -COOH or a bioisostere thereof, is described in WO 2015/009616, US 9682968, US 10093663, WO 2018/005552, WO 2019/043609, WO 2020/016749, WO 2022/028507, WO 2022/028527, WO 2022/143845, WO 2022/218429, WO 2022/234541, WO 2022/256586, WO 2023/020566, WO 2023/037218, WO 2023/072197, WO 2023/139534, or WO 2023/143293.

[00135] In some embodiments, R^c is or comprises an acidic group or a bioisostere thereof. In some embodiments, R^c is or comprises an acidic group. In some embodiments, R^c is or comprises a group that can be converted (e.g., through metabolism) to an acidic group or a bioisostere thereof. In some embodiments, R^c is R⁵ as described herein, hi some embodiments, R^c is -L^c— C(O)OH or a bioisostere thereof, -L^c-C(O)OR^cl , -L^c-C(O)NR^clR^c2, -L^c-C(O)N(R^cl)S(O)₂R^c2, -L^C-S(O)₂N(R^C1)C(O)R^C2, -L^C-S(O)₂NR^C1R^C2, -L^c-S(O)(NR^cl)R^c2, -L^C-S(O)₂R^CI, -CN, -L^C-P(O)(OR^C1)(OR^C2), -L^C-OP(O)(OR^C1)(OR^C2), or -L^c-BR^clR^c2. In some embodiments, R^c is -L^C-C(O)OH or a bioisostere thereof, -L^c-C(O)OR^cl, -L^c-C(O)NR^clR^c2, -L^C-C(O)N(R^C1)S(O)₂R^C2, -L^C-S(O)₂N(R^C1)C(O)R^C2, -L^C-S(O)₂NR^C1R^C2, -L^C-S(O)(NR^C1)R^C2, -L^C-S(O)₂R^C1, -CN, -L^c-P(O)(OR^cl)(OR^c2), or -L^c-OP(O)(OR^cl)(OR^c2). In some embodiments, R^c is -L^C-C(O)OH or a bioisostere thereof, -L^c-C(O)OR^cl, -L^c-C(O)NR^clR^c2, -L^c-C(O)N(R^cl)S(O)₂R^c2, -L^c-S(O)₂N(R^cl)C(O)R^c2, -L^c-S(O)₂NR^clR^c2, -L^C-S(O)(NR^C1 )R^C2, -L^C-S(O)₂R^C1, -L^C-P(O)(OR^C1)(OR^C2), or -L^c-0P(0)(0R^cl)(0R^c2). [00136] In some embodiments, R^c is — L^c— C(O)OH or a bioisostere thereof. In some embodiments, R^c is -C(O)OH or a bioisostere thereof. In some embodiments, R^c is — C(O)OH.

[00137] In some embodiments, R^c is — L^c— C(O)OR^cl wherein R^cl is independently as described herein.

[00138] In some embodiments, R^c is — L^c— C(O)NR^clR^c2 wherein each of R^cl and R^c2 is independently as described herein. In some embodiments, R^c is -L^c-C(O)NHR^cl wherein R^cl is independently as described herein.

[00139] In some embodiments, R^c is — L^c— R^cl wherein R^cl is independently as described herein. In some embodiments, R^c is R^cl as described herein. In some embodiments, R^cl is R’ as described herein. In some embodiments, R^cl is — N(R’)₂ wherein each R’ is independently as described herein. In some embodiments, R^cl is -N(R)₂ wherein each R is independently as described herein. In some embodiments, R^c is 5-6 membered heteroaryl having 1-4 ring nitrogen atoms and 0 or 1 ring oxygen or sulfur atom. In some embodiments, R^c is optionally substituted tetrazolyl. In some embodiments, R^c is tetrazolyl.

[00140] In some embodiments, R^c is — L^c— OR^cl wherein R^cl is independently as described herein.

[00141] In some embodiments, R^c is — L^c— NR^clR^c2 wherein each of R^cl and R^c2 is independently as described herein. In some embodiments, R^c is -L^c— NHR^cl wherein R^cl is independently as described herein. [00142] In some embodiments, R^c is -L^c-C(O)R^cl wherein R^cl is independently as described herein.

[00143] In some embodiments, R^c is -L^c-C(O)N(R^cl)S(O)₂R^c2 wherein each of R^cl and R^c2 is independently as described herein. In some embodiments, R^c is -L^c-C(O)NHS(O)₂R^c2 wherein R^c2 is independently as described herein.

[00144] In some embodiments, R^c is -L^c-S(O)₂N(R^cl)C(O)R^c2 wherein each of R^cl and R^c2 is independently as described herein. In some embodiments, R^c is — L^c— S(O)₂NHC(O)R^c2 wherein R^c2 is independently as described herein.

[00145] In some embodiments, R^c is -L^c-S(O)₂NR^clR^c2 wherein each of R^cl and R^c2 is independently as described herein. In some embodiments, R^c is -L^c-S(O)₂NHR^cl wherein R^cl is independently as described herein.

[00146] In some embodiments, R^c is -L^c-S(O)(NR^cl)R^c2 wherein each of R^cl and R^c2 is independently as described herein. In some embodiments, R^c is -L^c— S(O)(NH)R^c2 wherein R^c2 is independently as described herein.

[00147] In some embodiments, R^c is -L^L-S(O)₂R^cl wherein R^cl is independently as described herein.

[00148] In some embodiments, R^c is halogen. In some embodiments, R^c is -F. In some embodiments, R^c is -Cl. In some embodiments, R^c is — Br. In some embodiments, R^c is -I.

[00149] In some embodiments, R^c is — CN.

[00150] In some embodiments, R^c is — L^c— P(O)(OR^cl)(OR^c2) wherein each of R^cl and R^c2 is independently as described herein. In some embodiments, each of R^cl and R^c2 is -H.

|00151 | In some embodiments, R^c is -L^c-OP(O)(OR^cl)(OR^c2) wherein each of R^cl and R^c2 is independently as described herein. In some embodiments, each of R^cl and R^c2 is -H.

[00152] In some embodiments, R^c is — L^c— BR^clR^c2 wherein each of R^cl and R^c2 is independently as described herein.

[00153] In some embodiments, R^cl is R’ as described herein. In some embodiments, R^cl is -N(R’)2 wherein each R' is independently as described herein. In some embodiments, R^cl is R as described herein. In some embodiments, R^cl is -H. In some embodiments, R^cl is not hydrogen. In some embodiments, R^cl is optionally substituted C1-6 aliphatic. In some embodiments, R^cl is optionally substituted C1-6 alkyl. In some embodiments, R^cl is optionally substituted -CH 2— Ci 6 aliphatic. In some embodiments, R^cl is optionally substituted -CH2-C36 cycloalkyl. In some embodiments, R^cl is optionally substituted -CH2-C36 cyclopropyl.

[00154] In some embodiments, R^c2 is R' as described herein. In some embodiments, R^c2 is -N(R')2 wherein each R’ is independently as described herein. In some embodiments, R^c2 is R as described herein. In some embodiments, R^c2 is -H. In some embodiments, R^c2 is not hydrogen. In some embodiments, R^c2 is optionally substituted Ci 6 aliphatic. In some embodiments, R^c2 is optionally substituted Ci 6 alkyl. In some embodiments, R^c2 is optionally substituted -CH 2— CM aliphatic. In some embodiments, R^c2 is optionally substituted -CH2-C36 cycloalkyl. In some embodiments, R^c2 is optionally substituted -CH2-C36 cyclopropyl. In some embodiments, R^cl and R^c2 are R and arc taken together to form a ring as described herein.

L^c

[00155] In some embodiments, L^c is a covalent bond. In some embodiments, L^c is optionally substituted -CH2-. In some embodiments, L^c is -CH2-. d

[00156] In some embodiments, d is 0. In some embodiments, d is 1. In some embodiments, d is 2. In some embodiments, d is 0 and e is 0. In some embodiments, at least one of d and e is not 0.

R^d

[00157] In some embodiments, R^d is halogen. In some embodiments, it is —F. In some embodiments, it is -Cl. In some embodiments, it is -Br. In some embodiments, it is —I.

[00158] In some embodiments, R^d is -CN.

[00159] In some embodiments, R^d is R^dl as described herein.

[00160] In some embodiments, R^d is -OR^dl wherein R^dl is as described herein. In some embodiments, R^d is R as described herein.

[00161] In some embodiments, R^d is -NR^dlR^d2 wherein each of R^dl and R^d2 is independently as described herein. In some embodiments, R^d is — NHR^dl wherein R^dl is as described herein. In some embodiments, R^dl is -H. In some embodiments, R^dl is not — H. In some embodiments, R^dl is optionally substituted C1-6 aliphatic. In some embodiments, R^dl is optionally substituted C1-6 alkyl. In some embodiments, R^dl is optionally substituted CM aliphatic. In some embodiments, R^dl is optionally substituted CM alkyl. In some embodiments, R^dl is optionally substituted C1-3 aliphatic. In some embodiments, R^dl is optionally substituted C1-3 alkyl. In some embodiments, R^dl is optionally substituted Cm aliphatic. In some embodiments, R^dl is optionally substituted C1-2 alkyl. In some embodiments, R^dl is optionally substituted methyl. In some embodiments, R^dl is unsubstituted aliphatic or alkyl as described herein. In some embodiments, R^dl is substituted aliphatic or alkyl, wherein each substituent is independently halogen. In some embodiments, R^dl is substituted aliphatic or alkyl, wherein each substituent is -F. For example, in some embodiments, R^dl is methyl. In some embodiments, R^dl is ethyl. In some embodiments, R^d being a secondary amine provides various benefits as described herein (e.g., permeability, melanin binding, PK, etc.). In some embodiments, d is not 0 and R^d is -NR^dlR^d2, or e is not 0 and R^e is — NR^elR^e2. In some embodiments, R^d is -NH2. In some embodiments, R^d is -NHMe. In some embodiments, R^d is -NHEt. In some embodiments, R^d is at a position next to R^c. In some embodiments, R^d is at a position next to a position that is next to R^c (e.g., R^c— C-C-R^d). In some embodiments, R^dl is -CD3. In some embodiments, R^d is -NHCD3.

[00162] In some embodiments, R^dl is R’ as described herein. In some embodiments, R^dl is R. In some embodiments, R^dl is — C(O)R. In some embodiments, R^dl is -C(O)CHj. In some embodiments, R^dl is -S(O)?R. In some embodiments, R^dl is -S(O)2 CH3. In some embodiments, R^d is — NHAc. In some embodiments, R^d is -NHSlOhCH;.

[00163] In some embodiments, R^dl comprises a H-bond donor group. In some embodiments, R^dl comprises -NH2. In some embodiments, R^dl comprises -C(O)NH2. In some embodiments, R^dl comprises -OH. In some embodiments, the ring atom next to the carbon atom to which R^d is attached is -N=, and the H-bond donor in R^dl can form a H-bond with the -N=.

[00164] In some embodiments, R^dl is R as described herein. In some embodiments, R^dl is — H. In some embodiments, R^dl is not hydrogen. In some embodiments, R^dl is optionally substituted C1-6 aliphatic. In some embodiments, R^dl is optionally substituted C1-6 alkyl. In some embodiments, R^dl is optionally substituted -CH2-C1-6 aliphatic. In some embodiments, R^dl is optionally substituted -CH2-C36 cycloalkyl. In some embodiments, R^dl is optionally substituted -CH2-C36 cyclopropyl. In some embodiments, R^dl is optionally substituted 3-10 membered cycloaliphatic. In some embodiments, R^dl is optionally substituted cyclobutyl. In some embodiments, R^dl is optionally substituted cyclopropyl. In some embodiments, R^dl is optionally substituted 3-10 membered heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, R^dl is optionally substituted oxetane. In some embodiments, R^dl is optionally substituted 5-10 membered heteroaryl having 1-6 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[00165] In some embodiments, R^d2 is R as described herein. In some embodiments, R^d2 is — H. In some embodiments, R^d2 is not hydrogen. In some embodiments, R^d2 is optionally substituted C1-6 aliphatic. In some embodiments, R^d2 is optionally substituted C1-6 alkyl. In some embodiments, R^d2 is optionally substituted -CH2-C1-6 aliphatic. In some embodiments, R^d2 is optionally substituted -CH2-C36 cycloalkyl. In some embodiments, R^d2 is optionally substituted -CH2-C36 cyclopropyl. In some embodiments, R^d2is optionally substituted 3-10 membered cycloaliphatic. In some embodiments, R^d2is optionally substituted cyclobutyl. In some embodiments, R^d2is optionally substituted cyclopropyl. In some embodiments, R^d2is optionally substituted 3-10 membered heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, R^d2 is optionally substituted oxctanc. In some embodiments, R^d2 is optionally substituted 5-10 membered heteroaryl having 1-6 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, R^d2 is -CDj.

[00166] In some embodiments, R^dl and R^d2 are R and are taken together to form a ring as described herein. For example, in some embodiments, R^dl and R^d2 are taken together with the nitrogen atom to which they are attached to form an optionally substituted 3-10 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 3-8, 3-7, 3-6, 4-6, 5-6, 5-8, etc.) membered ring having, in addition to the nitrogen atom 0-5 (e.g., 1, 2, 3, 4, 5, 1-5, 1-4, 1-2, etc.) heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, a ring has no additional heteroatoms. In some embodiments, a ring is 3 -membered. In some embodiments, a ring is 4- membered. In some embodiments, a ring is 5 -membered. In some embodiments, a ring is 6-membered. In some embodiments, a ring is saturated. In some embodiments, a ring is partially unsaturated. In some embodiments, a ring is aromatic. In some embodiments, a ring is substituted. In some embodiments, a ring is unsubstituted. For example, in some embodiments, a formed ring is optionally substituted

. In some embodiments, a formed ring i

> . In some embodiments, a formed ring is optionally substituted

. In some embodiments, a formed ring is

. e

[00167] In some embodiments, e is 0. In some embodiments, e is 1. In some embodiments, e is 2.

R^e

[00168] In some embodiments, R^e is halogen. In some embodiments, it is -F. In some embodiments, it is -Cl. In some embodiments, it is -Br. In some embodiments, it is —I.

[00169] In some embodiments, R^e is R^el as described herein. In some embodiments, R^e is R as described herein.

[00170] In some embodiments, R^c is -CN.

[00171] In some embodiments, R^e is -OR^cl wherein R^el is as described herein.

[00172] In some embodiments, R^e is — NR^elR^e2 wherein each of R^el and R^e2 is independently as described herein. In some embodiments, R^e is — NHR^el wherein R^el is as described herein. In some embodiments, R^el is -H. In some embodiments, R^el is not — H. In some embodiments, R^el is optionally substituted C1-6 aliphatic. In some embodiments, R^el is optionally substituted C1-6 alkyl. In some embodiments, R^el is optionally substituted C1-4 aliphatic. In some embodiments, R^cl is optionally substituted CM alkyl. In some embodiments, R^el is optionally substituted C1-3 aliphatic. In some embodiments, R^el is optionally substituted C1-3 alkyl. In some embodiments, R^el is optionally substituted C1-2 aliphatic. In some embodiments, R^el is optionally substituted C1 2 alkyl. In some embodiments, R^el is optionally substituted methyl. In some embodiments, R^el is unsubstituted aliphatic or alkyl as described herein. In some embodiments, R^el is substituted aliphatic or alkyl, wherein each substituent is independently halogen. In some embodiments, R^el is substituted aliphatic or alkyl, wherein each substituent is -F. For example, in some embodiments, R^el is methyl. In some embodiments, R^{L I} is ethyl. In some embodiments, R^e being a secondary amine provides various benefits as described herein (e.g., permeability, melanin binding, PK, etc.). In some embodiments, R^e is -NH2. In some embodiments, R^e is — NHMe. In some embodiments, R^e is -NHEt. In some embodiments, R^e is at a position next to R^c. In some embodiments, R^e is at a position next to a position that is next to R^c (e.g., R^c-C-C-R^e).

[00173] In some embodiments, R^el is R' as described herein. In some embodiments, R^el is R. In some embodiments, R^el is -C(O)R. In some embodiments, R^el is -C(O)CH ;. In some embodiments, R^el is -S(O)2R. In some embodiments, R^el is -SlOhCH,. In some embodiments, R^el is -CD3.

[00174] In some embodiments, R^el is R as described herein. In some embodiments, R^el is — H. In some embodiments, R^el is not hydrogen. In some embodiments, R^el is optionally substituted Cre aliphatic. In some embodiments, R^el is optionally substituted C1-6 alkyl. In some embodiments, R^el is optionally substituted -CH2-C1-6 aliphatic. In some embodiments, R^el is optionally substituted -CH2-C36 cycloalkyl. In some embodiments, R^el is optionally substituted -CH2-C3-6 cyclopropyl. In some embodiments, R^{L I} is optionally substituted 3-10 membered cycloaliphatic. In some embodiments, R^el is optionally substituted cyclobutyl. In some embodiments, R^el is optionally substituted cyclopropyl. In some embodiments, R^el is optionally substituted 3-10 membered heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, R^el is optionally substituted oxetane. In some embodiments, R^el is optionally substituted 5-10 membered heteroaryl having 1-6 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, R^e is -NHAc. In some embodiments, R^e is -NHS(O)₂CH3.

[00175] In some embodiments, R^e2 is R as described herein. In some embodiments, R^e2 is — H. In some embodiments, R^e2 is not hydrogen. In some embodiments, R^e2 is optionally substituted C1-6 aliphatic. In some embodiments, R^e2 is optionally substituted C1-6 alkyl. In some embodiments, R^e2 is optionally substituted -CH2-C1-6 aliphatic. In some embodiments, R^e2 is optionally substituted -CH2-C36 cycloalkyl. In some embodiments, R^e2 is optionally substituted -CH2-C36 cyclopropyl. In some embodiments, R^el and R^e2 are R and are taken together to form a ring as described herein. In some embodiments, R^e2 is optionally substituted 3-10 membered cycloaliphatic. In some embodiments, R^e2 is optionally substituted cyclobutyl. In some embodiments, R^e2 is optionally substituted cyclopropyl. In some embodiments, R^e2 is optionally substituted 3-10 membered heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, R^e2 is optionally substituted oxetane. In some embodiments, R^e2 is optionally substituted 5-10 membered heteroaryl having 1-6 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, R^e2 is -CD3.

[00176] In some embodiments, R^d and R^e are R and are taken together with their intervening atom(s) to form a ring as described herein. In some embodiments, one of R^dl and R^d2 and one of R^el and R^e2 are R and arc taken together with then' intervening atom(s) to form a ring as described herein. In some embodiments, R^dl and R^el are R and are taken together with their intervening atom(s) to form a ring as described herein. In some embodiments, R^d2 and R^e2 are R and are taken together with their intervening atom(s) to form a ring as described herein. In some embodiments, R^el and R^e2 are R and are taken together to form a ring as described herein. For example, in some embodiments, R^el and R^e2 are taken together with the nitrogen atom to which they are attached to form an optionally substituted 3-10 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 3-8, 3-7, 3-6, 4-6, 5-6, 5-8, etc.) membered ring having, in addition to the nitrogen atom 0-5 (e.g., 1, 2, 3, 4, 5, 1-5, 1-4, 1-2, etc.) heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, a ring has no additional heteroatoms. In some embodiments, a ring 3-membered. In some embodiments, a ring is 4- membered. In some embodiments, a ring is 5 -membered. In some embodiments, a ring is 6-membered. In some embodiments, a ring is saturated. In some embodiments, a ring is partially unsaturated. In some embodiments, a ring is aromatic. In some embodiments, a ring is substituted. In some embodiments, a ring is unsubstituted. For example, in some embodiments, a formed ring is optionally substituted

. In some embodiments, a formed ring i

> . In some embodiments, a formed ring is optionally substituted

. In some embodiments, a formed ring is

.

R'

[00177] As described herein, various groups can independently be R’. In some embodiments, R’ is R as described herein. In some embodiments, R’ is -OR wherein R is as described herein. In some embodiments, R’ is -C(O)R wherein R is as described herein. In some embodiments, R’ is -C(O)OR wherein R is as described herein. In some embodiments, R’ is -S(O)2R wherein R is as described herein. In some embodiments, R’ is -H. In some embodiments, R’ is not -H. In some embodiments, two R’ are R and are taken together to form a ring as described herein. In some embodiments, R is methyl. In some embodiments, R is -CD3.

R

[00178] In some embodiments, R is -H. In some embodiments, R is not -H. In some embodiments, R is optionally substituted C1-10 aliphatic. In some embodiments, R is optionally substituted CMO alkyl. In some embodiments, R is optionally substituted C1-6 aliphatic. In some embodiments, R is optionally substituted C1-6 alkyl. In some embodiments, R is optionally substituted -CH2-C36 cycloaliphatic. In some embodiments, R is optionally substituted -CH2-C36 cycloaliphatic. In some embodiments, R is optionally substituted -CH2-C36 cycloalkyl. In some embodiments, R is methyl. In some embodiments, R is ethyl. In some embodiments, R is isopropyl. In some embodiments, R is -CF3. In some embodiments, R is -CH2CF3. In some embodiments, R is butyl. In some embodiments, R is t-butyl. In some embodiments, R is optionally substituted C3 10 cycloaliphatic. In some embodiments, R is optionally substituted C3 10 cycloalkyl. In some embodiments, R is optionally substituted cyclopropyl. In some embodiments, R is optionally substituted cyclobutyl. In some embodiments, R is optionally substituted cyclopentyl. In some embodiments, R is optionally substituted cyclohexyl. In some embodiments, R is optionally substitutedC1-C6 heteroaliphatic having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur C1-C6 heteroaliphatic having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, R is optionally substituted C1-C6 heteroaliphatic having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur C1-C6 heteroaliphatic having 1 heteroatom independently selected from nitrogen, oxygen and sulfur. In some embodiments, R is optionally substituted 3-10 membered heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, R is optionally substituted 3-membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, R is optionally substituted 3-membered heterocyclyl having one heteroatom independently selected from nitrogen, oxygen and sulfur. In some embodiments, R is optionally substituted 4-membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, R is optionally substituted 5-membered heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, R is optionally substituted 6-membered heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, R is optionally substituted 7-membered heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, R is optionally substituted phenyl. In some embodiments, R is phenyl. In some embodiments, R is optionally substituted naphthyl. In some embodiments, R is optionally substituted 5-10 membered heteroaryl having 1-6 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, R is optionally substituted 5-10 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, R is optionally substituted 5-membered heteroaryl having 1-4 heteroatoms. In some embodiments, R is optionally substituted 5 -membered heteroaryl having 1 heteroatom. In some embodiments, R is optionally substituted 6-membered heteroaryl having 1-4 heteroatoms. In some embodiments, R is optionally substituted 6-membered heteroaryl having 1 heteroatom. In some embodiments, R is optionally substituted bicyclic 8-10 membered aromatic ring having 1-6 heteroatoms. In some embodiments, R is optionally substituted bicyclic 9-membered aromatic ring having 1-6 heteroatoms. In some embodiments, R is optionally substituted bicyclic 10-membered aromatic ring having 1-6 heteroatoms. In some embodiments, R is optionally substituted bicyclic 9-membered aromatic ring having 1 heteroatom. In some embodiments, R is optionally substituted bicyclic 10-membered aromatic ring having 1 heteroatom. In some embodiments, each heteroatom is independently selected from nitrogen, oxygen and sulfur. In some embodiments, at least one heteroatom is nitrogen. In some embodiments, at least one heteroatom is oxygen. In some embodiments, at least one heteroatom is sulfur. In some embodiments, R is optionally substituted 6-10 membered aryl-C1-C6 aliphatic. In some embodiments, R is optionally substituted 6-10 membered aryl-C1-C6 alkyl. In some embodiments, R is optionally substituted 5-10 membered hctcroaryl having 1-6 hctcroatoms-C1-C6 aliphatic wherein each hctcroatom is independently selected nitrogen, oxygen and sulfur, hi some embodiments, R is optionally substituted 5-10 membered heteroaryl having 1-6 heteroatoms-C1-C6 alkyl wherein each heteroatom is independently selected nitrogen, oxygen and sulfur. In some embodiments, R is methyl. In some embodiments, R is -CD<

[00179] In some embodiments, two groups that are R or can be R (e.g., R^a, R^al, R^a2, R^b, R^bl, R^b2, R^c, R^cl, R^c2, R^d, R^dl, R^d2, R^e, R^el, R^e2, R’, etc.) are taken together with their intervening atom(s) to form an optionally substituted 3-10 membered, monocyclic, bicyclic or polycyclic ring having, in addition to the intervening atom(s), 0-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, a formed ring is substituted. In some embodiments, a formed ring is unsubstituted. In some embodiments, a formed ring is 3-9, 3-8, 3-7, 3-6, 4-10, 4-9, 4-8, 4-7, 4-6, 5-10, 5-9, 5-8, 5-7, 5-6, or 3, 4, 5, 6, 7, 8, 9, or 10- membered. In some embodiments, a formed ring is 3-9 membered. In some embodiments, a formed ring is 3-7 membered. In some embodiments, a formed ring is 4-10 membered. In some embodiments, a formed ring is 4-7 membered. In some embodiments, a formed ring is 5-10 membered. In some embodiments, a formed ring is 5-7 membered. In some embodiments, a formed ring is 3 -membered. In some embodiments, a formed ring is 4-membered, In some embodiments, a formed ring is 5-membered. In some embodiments, a formed ring is 6-membered, In some embodiments, a formed ring is 7-membered. In some embodiments. a formed ring is 8-membered. In some embodiments, a formed ring is 9-membered. In some embodiments. a formed ring is 10-membered. In some embodiments, a formed ring is monocyclic. In some embodiments, a formed ring is bicyclic. In some embodiments, a formed ring is polycyclic. In some embodiments, a formed ring has no heteroatoms in addition to the intervening atom(s). In some embodiments, a formed ring has 1-6, e.g., 1-5, 1-3, or 1, 2, 3, 4, 5, or 6 heteroatoms in addition to the intervening atom(s). In some embodiments, a formed ring is saturated. In some embodiments, a formed ring is partially unsaturated. In some embodiments, a formed ring comprises one or more aromatic ring. In some embodiments, a formed ring is bicyclic or polycyclic, and each monocyclic ring unit is independently 3-10 (e.g., 3-9, 3-8, 3-7, 3-6, 4-10, 4-9, 4-8, 4-7, 4-6, 5-10, 5-9, 5-8, 5-7, 5-6, or 3, 4, 5, 6, 7, 8, 9, or 10) membered, saturated, partially unsaturated or aromatic and having 0-5 heteroatoms. In some embodiments, each heteroatom is independently selected from nitrogen, oxygen and sulfur. In some embodiments, a monocyclic ring unit is saturated. In some embodiments, a monocyclic ring unit is partially unsaturated. In some embodiments, a monocyclic ring unit is aromatic. In some embodiments, a monocyclic ring unit is heteroaromatic. Those skilled in the art appreciate that intervening atom(s), e.g., of groups taken together to form a ring, are typically atoms on the shortest path connecting such groups if multiple paths exist.

[00180] In some embodiments, a group that can be R, e.g., R^a, R^al, R^a2, R^b, R^bl, R^b2, R\ R^cl, R^c2, R^d, R^dl, R^d2, R^c, R^el, R^e2, R’, etc., is R as described herein. Those skilled in the art appreciate that embodiments described for one group that can be R may also be utilized for another group that can be R to the extent that such embodiments fall within the definition of R.

[00181] As described herein, various groups may be optionally substituted. Substituents arc routinely utilized in chemistry including in development of various therapeutics. Many substituents can be utilized in accordance with the present disclosure. In some embodiments, an optionally substituted group is unsubstituted. In some embodiments, an optionally substituted group is substituted. Combinations of substituents envisioned by this disclosure are preferably those that result in the formation of stable or chemically feasible compounds. The term “stable,” as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein. In some embodiments, a substituent is a hydrocarbon group. In some embodiments, a substituent comprises a heteroatom. In some embodiments, a substituent comprises multiple heteroatoms. In some embodiments, each atom in a substituent is independently selected from hydrogen, carbon, halogen, nitrogen, oxygen, sulfur, phosphorus and silicon. In some embodiments, each atom in a substituent is independently selected from hydrogen, carbon, halogen, nitrogen, oxygen, and sulfur-. In some embodiments, each atom in a substituent is independently selected from hydrogen, carbon, fluorine, chlorine, bromine, iodine, nitrogen, oxygen, and sulfur. In some embodiments, the total number of carbon and non-halogen heteroatom(s) in a substituent is about or no more than about 1; in some embodiments, it is no more than about 2; in some embodiments, it is no more than about 3; in some embodiments, it is no more than about 4; in some embodiments, it is no more than about 5; in some embodiments, it is no more than about 6; in some embodiments, it is no more than about 7; in some embodiments, it is no more than about 8; in some embodiments, it is no more than about 9; in some embodiments, it is no more than about 10; in some embodiments, it is no more than about 11; in some embodiments, it is no more than about 12; in some embodiments, it is no more than about 13; in some embodiments, it is no more than about 14; in some embodiments, it is no more than about 15; in some embodiments, it is no more than about 20. In some embodiments, the total number of carbon and nonhalogen heteroatom(s) in each substituent is independently no more than about 20. In some embodiments, the total number of carbon and non-halogen heteroatom(s) in each substituent is independently no more than about 15. In some embodiments, the total number of carbon and non-halogen heteroatom(s) in each substituent is independently no more than about 10. In some embodiments, the total number of carbon and non-halogen heteroatom(s) in each substituent is independently no more than about 6.

[00182] In some embodiments, the present disclosure provides a compound, wherein the compound has the structure of formula I-Sl :

or a salt thereof, wherein each variable is independently described herein.

[00183] In some embodiments, the present disclosure provides a compound, wherein the compound has the structure of formula I-S2:

or a salt thereof, wherein each variable is independently described herein.

[00184] In some embodiments, a provided compounds has the structure of formula I-a:

or a salt thereof, wherein each variable is independently described herein.

[00185] In some embodiments, a provided compounds has the structure of formula I-a-1:

I-a-1 or a salt thereof, wherein each variable is independently described herein.

[00186] In some embodiments, a provided compounds has the structure of formula I-a-2:

or a salt thereof, wherein each variable is independently described herein.

[00187] In some embodiments, a provided compounds has the structure of formula I-b:

or a salt thereof, wherein each variable is independently described herein.

[00188] In some embodiments, a provided compounds has the structure of formula I-b- 1 :

I-b-1 or a salt thereof, wherein each variable is independently described herein.

[00189] In some embodiments, a provided compounds has the structure of formula I-b-2:

or a salt thereof, wherein each variable is independently described herein.

[00190] In some embodiments, a provided compounds has the structure of formula I-c:

or a salt thereof, wherein each variable is independently described herein.

[00191] In some embodiments, a provided compounds has the structure of formula I-c-1:

or a salt thereof, wherein each variable is independently described herein.

[00192] In some embodiments, a provided compounds has the structure of formula I-c-2:

I-c-2 or a salt thereof, wherein each variable is independently described herein.

[00193] In some embodiments, a provided compounds has the structure of formula I-d:

or a salt thereof, wherein each variable is independently described herein.

[00194] In some embodiments, a provided compounds has the structure of formula I-d- 1 :

I-d-1 or a salt thereof, wherein each variable is independently described herein.

[00195] In some embodiments, a provided compounds has the structure of formula I-d-2:

or a salt thereof, wherein each variable is independently described herein.

[00196] In some embodiments, a provided compounds has the structure of formula I-d-3:

or a salt thereof, wherein each variable is independently described herein.

[00197] In some embodiments, a provided compounds has the structure of formula I-e:

or a salt thereof, wherein each variable is independently described herein.

[00198] In some embodiments, a provided compounds has the structure of formula I-e-1:

or a salt thereof, wherein each variable is independently described herein.

[00199] In some embodiments, a provided compounds has the structure of formula I-e-2:

I-e-2 or a salt thereof, wherein each variable is independently described herein.

[00200] In some embodiments, a provided compounds has the structure of formula I-f:

I-f or a salt thereof, wherein each variable is independently described herein.

[00201] In some embodiments, a provided compounds has the structure of formula I-f-1 :

or a salt thereof, wherein each variable is independently described herein.

[00202] In some embodiments, a provided compounds has the structure of formula I-f-2:

or a salt thereof, wherein each variable is independently described herein.

[00203] In some embodiments, a provided compounds has the structure of formula I-f-3:

or a salt thereof, wherein each variable is independently described herein.

[00204] In some embodiments, a provided compounds has the structure of formula I-g:

or a salt thereof, wherein each variable is independently described herein.

[00205] In some embodiments, a provided compounds has the structure of formula I-g- 1 :

or a salt thereof, wherein each variable is independently described herein.

[00206] In some embodiments, a provided compounds has the structure of formula I-g-2:

or a salt thereof, wherein each variable is independently described herein.

[00207] In some embodiments, a provided compound is a compound of formula I-g, I-g-1 or I-g-2, or a salt thereof, wherein the two R^b groups are taken together with the carbon atom to which they are attached to form an optionally substituted 3-10 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 3-8, 3-7, 3-6, 4-6, 5-6, 5-8, etc.) monocyclic ring having 0-2 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, the ring is monocyclic. In some embodiments, the ring is satur ated. In some embodiments, m is 1. In some embodiments, n is 1. In some embodiments, R^c is -NR^clR^c2 wherein each of R^cl and R^c2 is independently as described herein. In some embodiments, R^e is -NHR^cl wherein R^el is as described herein. In some embodiments, R^el is optionally substituted CM aliphatic. In some embodiments, R^el is optionally substituted Ci 4 aliphatic. In some embodiments, R^el is optionally substituted C1-2 aliphatic. In some embodiments, R^el is optionally substituted C1-6 alkyl. In some embodiments, R^el is optionally substituted CM alkyl. In some embodiments, R^el is optionally substituted C1-2 alkyl. In some embodiments, R^el is not substituted. In some embodiments, R¹ is substituted and each substituent is independently halogen. In some embodiments, R^el is methyl. In some embodiments, R^cl is ethyl. In some embodiments, R^e is -NH(CH

In some embodiments, R^el and R^e2 are R and are taken together to form a ring as described herein. For example, in some embodiments, R^el and R^e2 are taken together with the nitrogen atom to which they are attached to form an optionally substituted 3-10 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 3-8, 3-7, 3-6, 4-6, 5-6, 5-8, etc.) membered ring having, in addition to the nitrogen atom 0-5 (e.g., 1, 2, 3, 4, 5, 1-5, 1-4, 1-2, etc.) heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, a ring has no additional heteroatoms. In some embodiments, a ring 3-membered. In some embodiments, a ring is 4-membered. In some embodiments, a ring is 5-membered. In some embodiments, a ring is 6-membered. In some embodiments, a ring is saturated. In some embodiments, a ring is partially unsaturated. In some embodiments, a ring is aromatic. In some embodiments, a ring is substituted. In some embodiments, a ring is unsubstituted. For example, in some embodiments, R^e is optionally substituted

. In some embodiments, R^e is

[00208] In some embodiments, a provided compounds has the structure of formula I-h:

or a salt thereof, wherein each variable is independently described herein.

[00209] In some embodiments, a provided compounds has the structure of formula I-h- 1 :

I-h-1 or a salt thereof, wherein each variable is independently described herein.

[00210] In some embodiments, a provided compounds has the structure of formula I-h-2:

I-h-2 or a salt thereof, wherein each variable is independently described herein.

[0021 1 ] In some embodiments, a provided compounds has the structure of formula I-h-3:

I-h-3 or a salt thereof, wherein each variable is independently described herein.

[00212] In some embodiments, m is 1 and n is 1. In some embodiments, R^c is -COOH. In some embodiments, R^d is -NR^d1R^d2 wherein each of R^dl and R^d2 is independently as described herein. In some embodiments, R^e is -NR^d1R^d2 wherein each of R^el and R^e2 is independently as described herein.

[00213] In some embodiments, a provided compounds has the structure of formula II:

II or a salt thereof, wherein: m is 1, or 2; n is 1, or 2;

R¹ is hydrogen, halogen, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C3-C6 cycloalkyl, C1-C6 alkoxy, halo C1-C6 alkyl, hydroxyC1-C6 alkyl, amino C1-C6 alkyl,C1-C6 alkoxyC1-C6 alkyl,C1-C6 alkoxy C1-C6 alkoxy, C3-C6 cycloalkylC1-C6 alkoxy, haloC1-C6 alkoxy, -S(O)_p C1-C6 alkyl, -CH2NHC(O)C1-C4 alkyl or -OCH₂C(O)R⁷; p is 0, 1, or 2;

R² is hydrogen, C1-C6 alkyl, C1-C6 alkoxy, hydroxy C1-C6 alkyl, or halogen;

R³ is hydrogen, halogen, cyano, C1-C4 alkyl, halo C1-C4 alkyl, -CH₂C(O)R⁷;

R⁴ is phenyl, naphthyl, 1,2,3,4-tetrahydronaphthalenyl and 5-10 membered heteroaryl having 1, 2 or 3 ring heteroatoms independently selected from nitrogen, oxygen and sulfur, and wherein the phenyl, naphthyl, 1,2,3,4-tetrahydronaphthalenyl, or heteroaryl is optionally substituted with R⁵ and further optionally substituted with one or two R⁵’ ; each R⁵’ is independently selected from halogen, C1-C4 alkyl, C1-C4 alkoxy, hydroxy C1-C4 alkyl, hydroxyl, R¹⁰, —OR⁶ , -N(R⁵¹)₂, halo alkyl, cyaCn1o-C, a6nd cyanomethyl; or two R⁵ are taken together with their intervening atoms to form a 4-8 membered monocyclic partially unsaturated or aromatic ring having 1-3 ring atoms independently selected from nitrogen, sulfur and oxygen, wherein the ring is optionally substituted with one or more substituents independently selected from halogen, C1-C4 alkyl, halo C1-C4 alkyl, C1-C4 alkoxy, hydroxyl, and oxo; each R⁵¹ is independently R⁶’ ;

R⁴ is hydrogen, C1-C4 alkyl, or hydroxy C1-C4 alkyl;

R⁵ is -C(O)R⁸, -CH₂C(O)R⁸, R⁹, -C(O)NHSO₂C1-C4alkyl, -SO₂NHC(O)C1-C4alkyl, -SO₂N(H)_P(C,- C4alkyl)_{2 p}, -SO(NH)C1-C4alkyl, -SO₂C1-C4alkyl, cyano, halogen, hydroxy C1-C4 alkyl, -B(R⁸)₂ or 5- membered heteroaryl having 1-4 ring nitrogen atoms and 0 or 1 ring oxygen or sulfur atom; each R⁶ is independently hydrogen, halogen, hydroxyl, amino, mono- and di- C1-C6 alkylamino, C1-C6 alkyl, halo C1-Cfi alkyl, hydroxy C1-C6 alkyl, cyano C1-C6 alkyl or CI-CA alkoxy, or: two R⁶ on a carbon atom are taken together to form =0, or two R⁶ on a carbon atom are taken together with the carbon atom to form a 3-membered monocyclic saturated ring having 0-1 ring atoms independently selected from nitrogen, sulfur and oxygen; or two R⁶ are taken together with their intervening atoms to form a 3-8 membered monocyclic saturated or partially unsaturated ring having 0-3 ring atoms independently selected from nitrogen, sulfur and oxygen, wherein the ring is optionally substituted with one or more substituents independently selected from halogen, C1-C4 alkyl, halo C1-C4 alkyl, C1-C4 alkoxy, hydroxyl, and oxo; or

R⁴ and one R⁶ are taken together to form C2-C4 alkylene; t is 0, 1, 2, 3 or 4;

R⁶ is hydrogen, halogen, aliCph1-aCti6c, R¹⁰, -CH₂-C3-Ce cycloaliphatic, -CH₂-R¹⁰, -CH₂-(hydroxy C1-C4 alkyl), phenyl, -C(O)-C1-C6 aliphatic, -SO₂-C1-C6 aliphatic, -CH₂-phenyl, -CH₂-(amino C1-C4 alkyl), or -CH₂-(mono- and di-C1-C4 alkylamino C1-C4 alkyl) wherein each of the C1-C6 aliphatic and phenyl is optionally substituted with one or more substituents independently selected from halogen, C1-C4 alkyl, C1-C4 alkoxy, G-G> cycloalkyl or 3-6 membered heterocyclyl having 1-4 ring atoms independently selected from nitrogen, oxygen and sulfur, wherein each of the alkyl, alkoxy, cycloalkyl and heterocyclyl is optionally and independently substituted with one or more substituents independently selected from halogen, C1-C4 alkyl, halo C1-C4 alkyl, C1-C4 alkoxy, hydroxyl, and oxo, and wherein each nitrogen ring atom of the heterocyclyl is optionally and independently substituted with C1-3 acyl, cyano C1-C4 alkyl, C3-C6 cycloalkyl, or 3-6 membered heterocyclyl having 1-4 ring atoms independently selected from nitrogen, oxygen and sulfur wherein each ring nitrogen is optionally and independently substituted with C1-3 acyl; or:

R⁶ and R⁶ are taken together with their' intervening atoms to form a 3-8 membered monocyclic or bicyclic saturated, partially unsaturated or aromatic ring having 1-3 ring atoms independently selected from nitrogen, sulfur and oxygen, wherein the ring is optionally substituted with one or more substituents independently selected from halogen, C1-C4 alkyl, halo C1-C4 alkyl, C1-C4 alkoxy, hydroxyl, and oxo;

R⁷ is hydroxyl, Ci-C4 alkoxy, amino, or mono- or di-Ci-C4 alkylamino; each R⁸ is independently hydroxyl, Cj-C4 alkoxy, amino or a 5-7 membered saturated heterocyclyl having 1 , 2, or 3 ring hctcroatoms independently selected from nitrogen, oxygen and sulfur; or mono- and di- C1-C4 alkylamino which is optionally substituted with one or more substituents independently selected from halogen, hydroxy and C1-C4 alkyl;

R⁹ is a 5-membered hetcroaryl having 1 to 4 ring nitrogen atoms and 0 or 1 ring oxygen or sulfur atom, which heteroaryl is optionally substituted with 0 to 2 Ci-C4 alkyl groups; and

R¹⁰ is 3-6 membered heterocyclyl or 5-6 membered heteroaryl having 1-3 ring atoms independently selected from nitrogen, oxygen and sulfur, wherein the heterocyclyl or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, C1-C4 alkyl, halo C1-C4 alkyl, C1-C4 alkoxy, hydroxyl, and oxo, and wherein each nitrogen ring atom of the heterocyclyl or heteroaryl is optionally and independently substituted with C1-3 acyl, cyano C1-C4 alkyl, Ci -Ct, cycloalkyl, or 3-6 membered heterocyclyl having 1-4 ring atoms independently selected from nitrogen, oxygen and sulfur.

[00214] In some embodiments, R⁴ is substituted with R⁵ and one or two R⁵’. In some embodiments, R⁴ is substituted with R⁵ and one or two R⁵', wherein R⁵ is -C(O)R⁸, -CH2C(O)R⁸, R⁹, — C(O)NHSC>2Ci-C4alkyl, -SO2NHC(O)Ci-C₄alkyl, -SO2N(H)_p(Ci-C₄alkyl)2-_P, -SO(NH)Ci-C₄alkyl, -SO₂Ci-C₄alkyl, -B(R⁸)₂ or 5- membered heteroaryl having 1-4 ring nitrogen atoms and 0 or 1 ring oxygen or sulfur atom, and at least one R⁵’ is -N(R^5I)₂, wherein each R⁵¹ is independently as described herein.

[00215] In some embodiments, a compound of formula I is a compound of formula I-Sl, I-S2, 1-a, I-a-1, I-a-2, 1-b, I-b-1, 1-b-2, 1-c, I-c-1, 1-c-2, 1-d, I-d-1, 1-d-2, 1-d-3, 1-e, I-e-1, 1-e-2, 1-f, I-f-1, 1-f-2, 1-f-3, 1-g, I-g-1, I-g-2, 1-h, I-h-1, 1-h-2, 1-h-3 or II.

[00216] In some embodiments, R¹ is hydrogen, halogen, hydroxyl, Ci-Cg alkyl, C2-C6 alkenyl, C3-C6 cycloalkyl, Ci-Ce alkoxy, halo Ci-Ce alkyl, hydroxy Ci-Ce alkyl, amino Ci-Ce alkyl, Ci-Ce alkoxy Ci-Q> alkyl, Ci-Ce alkoxy Ci-Ce alkoxy, C3-C6 cycloalkyl Ci-Ce alkoxy, halo Ci-Ce alkoxy, -S(O)_PCi-Ce alkyl, -CH2NHC(O)CI-C4 alkyl or -OCH2C(O)R⁷. In some embodiments, R¹ is halogen, hydroxyl, Ci-Ce alkyl, C2- G> alkenyl, C3-C6 cycloalkyl, Ci-Ce alkoxy, halo Ci-Ce alkyl, hydroxy Ci-Ce alkyl, amino Ci-C& alkyl, Ci-Ce alkoxy G-G> alkyl, Ci-Ce alkoxy Ci-Ce alkoxy, C3-C6 cycloalkyl Ci-Ce alkoxy, halo C1-C6 alkoxy, -S(O)_pCi- G> alkyl, -CH2NHC(O)CI-C4 alkyl or -OCH2C(O)R⁷. In some embodiments, R¹ is hydrogen, hydroxy Ci-G, alkyl, amino Ci-Ce alkyl, Ci-Ce alkoxy Ci-Ce alkyl, Ci-Ce alkoxy Ci-Ce alkoxy, C3-C6 cycloalkyl Ci-Ce alkoxy, halo Ci-Ce alkoxy, -S(O)_PCi-Ce alkyl, -CH2NHC(O)CI-C4 alkyl or -OCH2C(O)R⁷. In some embodiments, R¹ is hydroxy G-G, alkyl, amino Ci-Ct alkyl, Ci-Ce alkoxy Ci-Ce alkyl, Cj-Ce alkoxy Ci-Ce alkoxy, C3-C6 cycloalkyl Ci-Ce alkoxy, halo Ci-Ce alkoxy, -S(O)_pCi-C& alkyl, -CH2NHC(O)CI-C4 alkyl or -OCH2C(O)R⁷. In some embodiments, R¹ is hydrogen, hydroxy Ci-Ce alkyl, amino G-G, alkyl, Ci-Ce alkoxy Ci-Cg alkyl, Ci-Ce alkoxy Ci-Ce alkoxy, C3-C6 cycloalkyl Ci-Ce alkoxy, halo Ci-Ce alkoxy, -S(O)_pCi- C₆ alkyl, -CH₂NHC(O)CI-C₄ alkyl or -OCH₂C(O)R⁷. [00217] In some embodiments, R¹ is hydrogen. In some embodiments, R¹ is halogen. In some embodiments, R¹ is hydroxy. In some embodiments, R¹ is C₁-C₆ alkyl. In some embodiments, R¹ is C₂-C₆ alkenyl. In some embodiments, R¹ is C₃-C₆ cycloalkyl. In some embodiments, R¹ is C₃-C₅ cycloalkyl. In some embodiments, R¹ is cyclopropyl. [00218] In some embodiments, R¹ is halo C1-C6 alkyl. [00219] In some embodiments, R¹ is hydroxy C₁-C₆ alkyl. In some embodiments, R¹ is amino C₁-C₆ alkyl. In some embodiments, R¹ is C₁-C₆ alkoxy C₁-C₆ alkyl. In some embodiments, R¹ is C₁-C₆ alkoxy C₁- C6 alkoxy. In some embodiments, R¹ is C3-C6 cycloalkyl C1-C6 alkoxy. [00220] In some embodiments, R¹ is halo C1-C6 alkoxy. In some embodiments, R¹ is halo C1-C4 alkoxy. In some embodiments, R¹ is halo C1-C2 alkoxy. In some embodiments, R¹ is halo C1-C2 alkoxy. In some embodiments, R¹ is –OCHF2. [00221] In some embodiments, R¹ is −S(O)pC1-C6 alkyl. In some embodiments, R¹ is −SC1-C6 alkyl. In some embodiments, R¹ is −S(O)C1-C6 alkyl. In some embodiments, R¹ is −CH2NHC(O)C1-C4 alkyl. In some embodiments, R¹ is −OCH2C(O)R⁷. [00222] In some embodiments, R¹ is C1-C6 alkoxy. [00223] As those skilled in the art appreciate, a C1 to C6 (e.g., C1-C2, C1-C3, C1-C4, C1-C5, C1-C6, etc.) alkyl group, either independently or as part of another group (e.g., as in C1-C6 alkoxy, C1-C6 alkoxy C1-C6 alkyl, etc.), can independently be a C1, C2, C3, C4, C5, or C6 alkyl group. For example, in some embodiments, C1-C6 alkyl is methyl. In some embodiments, it is ethyl. In some embodiments, it is propyl. In some embodiments, it is n-propyl. In some embodiments, it is isopropyl. In some embodiments, it is butyl. In some embodiments, it is pentyl. In some embodiments, it is hexyl. In some embodiments, R¹ is C1-C6 alkoxy. In some embodiments, R¹ is −O−CH3. [00224] In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. [00225] In some embodiments, R¹ is −SC1-C6 alkyl. In some embodiments, R¹ is −S(O)C1-C6 alkyl. In some embodiments, R¹ is −S(O)2C1-C6 alkyl. [00226] In some embodiments, R² is hydrogen, C1-C6 alkyl, C1-C6 alkoxy, hydroxy C1-C6 alkyl, or halogen. [00227] In some embodiments, R² is hydrogen. [00228] In some embodiments, R² is C₁-C₆ alkyl. In some embodiments, R² is methyl. In some embodiments, R² is ethyl. [00229] In some embodiments, R² is C₁-C₆ alkoxy. In some embodiments, R² is hydroxy C₁-C₆ alkyl. In some embodiments, R² is halogen. In some embodiments, R² is −F. In some embodiments, R² is −Cl. In some embodiments, R² is −Br. In some embodiments, R² is −I. [00230] In some embodiments, R³ is hydrogen, halogen, cyano, C₁-C₄ alkyl, halo C₁-C₄ alkyl, −CH₂C(O)R⁷, phenyl or 5- or 6-membered heteroaryl having 1, 2 or 3 ring heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the phenyl or heteroaryl is optionally substituted with 1, or 2 C1-C4 alkyl groups, and wherein alkyl and haloalkyl are optionally substituted with 1 hydroxy group. [00231 ] In some embodiments, R³ is hydrogen.

[00232] In some embodiments, R³ is halogen. In some embodiments, R³ is -F. In some embodiments, R³ is -Cl. In some embodiments, R³ is — Br. In some embodiments, R³ is -I. In some embodiments, R³ is cyano.

[00233] In some embodiments, R³ is C1-C4 alkyl. In some embodiments, R³ is C1-C4 alkyl optionally substituted with one hydroxy group. In some embodiments, R³ is C1-C4 alkyl substituted with one hydroxy group.

[00234] In some embodiments, R³ is halo C1-C4 alkyl. In some embodiments, R³ is halo C1-C4 alkyl optionally substituted with one hydroxy group. In some embodiments, R³ is halo Cj-C4 alkyl substituted with one hydroxy group. In some embodiments, R³ is -CH2C(O)R⁷.

[00235] In some embodiments, R⁴ is phenyl, naphthyl, 1,2,3,4-tetrahydronaphthalenyl and 5-10 membered heteroaryl having 1 , 2 or 3 ring heteroatoms independently selected from nitrogen, oxygen and sulfur, and wherein the phenyl, naphthyl, 1,2,3,4-tetrahydronaphthalenyl, or heteroaryl is optionally substituted with R⁵ and further optionally substituted with one or two R⁵’. In some embodiments, R⁴ is phenyl, naphthyl, 1,2,3,4-tetrahydronaphthalenyl or 5- or 6-membered heteroaryl having 1, 2 or 3 ring heteroatoms independently selected from nitrogen, oxygen and sulfur, and where the phenyl, naphthyl, 1,2,3,4-tetrahydronaphthalenyl, or heteroaryl is optionally substituted with R⁵ and further substituted with 0 or 1 substituent selected from halogen, C1-C4 alkyl, C1-C4 alkoxy, hydroxy C1-C4 alkyl, hydroxyl, and cyanomethyl.

[00236] In some embodiments, R⁴ is optionally substituted phenyl. In some embodiments, R⁴ is optionally substituted naphthyl. In some embodiments, R⁴ is optionally substituted 1,2,3,4- tetrahydronaphthalenyl. In some embodiments, R⁴ is optionally substituted 5-10 membered heteroaryl. In some embodiments, R⁴ is optionally substituted 5-6 membered heteroaryl. In some embodiments, R⁴ is optionally substituted 9-membered bicyclic heteroaryl. In some embodiments, R⁴ is optionally substituted 10- membered bicyclic heteroaryl. In some embodiments, R⁴ is not substituted with R⁵. In some embodiments, R⁴ is not substituted with R⁵ . In some embodiments, R⁴ is not substituted with R⁵ or R⁵’. In some embodiments, R⁴ is substituted with R⁵. In some embodiments, R⁴ is substituted with R⁵ but no R⁵’. In some embodiments, R⁴ is substituted with R⁵ . In some embodiments, R⁴ is substituted with one R⁵ . In some embodiments, R⁴ is substituted with two R⁵ . In some embodiments, R⁴ is substituted with R⁵ and R⁵’. In some embodiments, R⁴ is substituted with one R⁵ and one R⁵’. In some embodiments, R⁴ is substituted with one R⁵ and two R⁵’.

[00237] In some embodiments, R⁴ is phenyl, naphthyl, 1,2,3,4-tetrahydronaphthalenyl or 5- or 6- membered heteroaryl having 1 , 2 or 3 ring heteroatoms independently selected from nitrogen, oxygen and sulfur, and where the phenyl, naphthyl, 1,2,3,4-tetrahydronaphthalenyl, or heteroaryl is substituted with R⁵ and further substituted with 0 or 1 substituent selected from halogen, C1-C4 alkyl, C1-C4 alkoxy, hydroxy C1- C4 alkyl, hydroxyl, sulfonyl, and cyanomethyl.

[00238] In some embodiments, R⁴ is phenyl, naphthyl, 1 ,2,3,4-tetrahydronaphthalenyl or 5- or 6- membered heteroaryl having 1 , 2 or 3 ring heteroatoms independently selected from nitrogen, oxygen and sulfur, and where the phenyl, naphthyl, 1,2,3,4-tctrahydronaphthalcnyl, or hctcroaryl is substituted with -C(O)R⁸ and further substituted with 0 or 1 substituent selected from halogen, C1-C4 alkyl, C1-C4 alkoxy, hydroxy C1-C4 alkyl, hydroxyl, sulfonyl, and cyanomethyl.

[00239] In some embodiments, R⁴ is phenyl, naphthyl, 1,2,3,4-tetrahydronaphthalenyl or 5- or 6- membered heteroaryl having 1 , 2 or 3 ring heteroatoms independently selected from nitrogen, oxygen and sulfur, and where the phenyl, naphthyl, 1,2,3,4-tetrahydronaphthalenyl, or heteroaryl is substituted with -C(O)OH and further substituted with 0 or 1 substituent selected from halogen, C1-C4 alkyl, C1-C4 alkoxy, hydroxy C1-C4 alkyl, hydroxyl, sulfonyl, and cyanomethyl.

[00240] In some embodiments, R⁴ is phenyl. In some embodiments, R⁴ is phenyl substituted with R⁵ and further substituted with 0 or 1 substituent selected from halogen, C1-C4 alkyl, C1-C4 alkoxy, hydroxy C1-C4 alkyl, hydroxyl, and cyanomethyl. In some embodiments, R⁴ is phenyl substituted with R⁵ only. In some embodiments, R⁴ is phenyl substituted with R⁵ and further substituted with one substituent selected from halogen, C1-C4 alkyl, C1-C4 alkoxy, hydroxy C1-C4 alkyl, hydroxyl, and cyanomethyl. In some embodiments, R⁴ is phenyl substituted with -C(O)R⁸ and further substituted with 0 or 1 substituent selected from halogen, C1-C4 alkyl, C1-C4 alkoxy, hydroxy C1-C4 alkyl, hydroxyl, and cyanomethyl. In some embodiments, R⁴ is phenyl substituted with -C(O)R⁸ only. In some embodiments, R⁴ is phenyl substituted with -C(O)R⁸ and further substituted with one substituent selected from halogen, C1-C4 alkyl, C1-C4 alkoxy, hydroxy C1-C4 alkyl, hydroxyl, and cyanomethyl. In some embodiments, R⁴ is phenyl substituted with — COOH and further substituted with 0 or 1 substituent selected from halogen, C1-C4 alkyl, C1-C4 alkoxy, hydroxy C1-C4 alkyl, hydroxyl, and cyanomethyl. In some embodiments, R⁴ is phenyl substituted with -COOH only. In some embodiments, R⁴ is phenyl substituted with -COOH and further substituted with one substituent selected from halogen, C1-C4 alkyl, C1-C4 alkoxy, hydroxy C1-C4 alkyl, hydroxyl, and cyanomethyl.

[00241] In some embodiments, R⁴ is naphthyl. In some embodiments, R⁴ is naphthyl substituted with R⁵ and further substituted with 0 or 1 substituent selected from halogen, C1-C4 alkyl, C1-C4 alkoxy, hydroxy C1- C4 alkyl, hydroxyl, and cyanomethyl. In some embodiments, R⁴ is naphthyl substituted with R⁵ only. In some embodiments, R⁴ is naphthyl substituted with R⁵ and further substituted with one substituent selected from halogen, C1-C4 alkyl, C1-C4 alkoxy, hydroxy C1-C4 alkyl, hydroxyl, and cyanomethyl. In some embodiments, R⁴ is naphthyl substituted with -C(O)R⁸ and further substituted with 0 or 1 substituent selected from halogen, C1-C4 alkyl, C1-C4 alkoxy, hydroxy C1-C4 alkyl, hydroxyl, and cyanomethyl. In some embodiments, R⁴ is naphthyl substituted with -C(O)R⁸ only. In some embodiments, R⁴ is naphthyl substituted with — C(O)R⁸ and further substituted with one substituent selected from halogen, C1-C4 alkyl, C1- C4 alkoxy, hydroxy C1-C4 alkyl, hydroxyl, and cyanomethyl. In some embodiments, R⁴ is naphthyl substituted with -COOH and further substituted with 0 or 1 substituent selected from halogen, C1-C4 alkyl, C1-C4 alkoxy, hydroxy C1-C4 alkyl, hydroxyl, and cyanomethyl. In some embodiments, R⁴ is naphthyl substituted with — COOH only. In some embodiments, R⁴ is naphthyl substituted with — COOH and further substituted with one substituent selected from halogen, C1-C4 alkyl, C1-C4 alkoxy, hydroxy C1-C4 alkyl, hydroxyl, and cyanomcthyl.

[00242] In some embodiments, R⁴ is tetrahydronaphthalenyl. In some embodiments, R⁴ is tetrahydronaphthalenyl substituted with R⁵ and further substituted with 0 or 1 substituent selected from halogen, C1-C4 alkyl, C1-C4 alkoxy, hydroxy C1-C4 alkyl, hydroxyl, and cyanomethyl. In some embodiments, R⁴ is tetrahydronaphthalenyl substituted with R⁵ only. In some embodiments, R⁴ is tetrahydronaphthalenyl substituted with R⁵ and further substituted with one substituent selected from halogen, C1-C4 alkyl, Cj-C4 alkoxy, hydroxy C1-C4 alkyl, hydroxyl, and cyanomethyl. In some embodiments, R⁴ is tetrahydronaphthalenyl substituted with — C(O)R⁸ and further substituted with 0 or 1 substituent selected from halogen, C1-C4 alkyl, C1-C4 alkoxy, hydroxy C1-C4 alkyl, hydroxyl, and cyanomethyl. In some embodiments, R⁴ is tetrahydronaphthalenyl substituted with -C(O)R⁸ only. In some embodiments, R⁴ is tetrahydronaphthalenyl substituted with — C(O)R⁸ and further substituted with one substituent selected from halogen, C1-C4 alkyl, C1-C4 alkoxy, hydroxy C1-C4 alkyl, hydroxyl, and cyanomethyl. In some embodiments, R⁴ is tetrahydronaphthalenyl substituted with -COOH and further substituted with 0 or 1 substituent selected from halogen, C1-C4 alkyl, C1-C4 alkoxy, hydroxy C1-C4 alkyl, hydroxyl, and cyanomethyl. In some embodiments, R⁴ is tetrahydronaphthalenyl substituted with -COOH only. In some embodiments, R⁴ is tetrahydronaphthalenyl substituted with -COOH and further substituted with one substituent selected from halogen, C1-C4 alkyl, C1-C4 alkoxy, hydroxy C1-C4 alkyl, hydroxyl, and cyanomethyl.

[00243] In some embodiments, R⁴ is 5- or 6-membered heteroaryl having 1, 2 or 3 ring heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, R⁴ is 5- or 6-membered heteroaryl having 1 , 2 or 3 ring heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the heteroaryl is substituted with R⁵ and further substituted with 0 or 1 substituent selected from halogen, C1-C4 alkyl, C1-C4 alkoxy, hydroxy C1-C4 alkyl, hydroxyl, and cyanomethyl. In some embodiments, the heteroaryl is substituted with R⁵ only. In some embodiments, the heteroaryl is substituted with R⁵ and further substituted with one substituent selected from halogen, C1-C4 alkyl, C1-C4 alkoxy, hydroxy C1-C4 alkyl, hydroxyl, and cyanomethyl. In some embodiments, R⁴ is 5- or 6-membered heteroaryl having 1, 2 or 3 ring heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the heteroaryl substituted with -C(O)R⁸ and further substituted with 0 or 1 substituent selected from halogen, C1-C4 alkyl, C1-C4 alkoxy, hydroxy C1-C4 alkyl, hydroxyl, and cyanomethyl. In some embodiments, the heteroaryl is substituted with — C(O)R⁸ only. In some embodiments, the heteroaryl substituted with -C(O)R⁸ and further substituted with one substituent selected from halogen, C1-C4 alkyl, C1-C4 alkoxy, hydroxy C1-C4 alkyl, hydroxyl, and cyanomethyl. In some embodiments, R⁴ is 5- or 6-membered heteroaryl having 1, 2 or 3 ring heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the heteroaryl substituted with -COOH and further substituted with 0 or 1 substituent selected from halogen, C1-C4 alkyl, C1-C4 alkoxy, hydroxy C1-C4 At alkyl, hydroxyl, and cyanomethyl. In some embodiments, the heteroaryl is substituted with − COOH only. In some embodiments, the heteroaryl substituted with −COOH and further substituted with one substituent selected from halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, hydroxy C₁-C₄ alkyl, hydroxyl, and cyanomethyl. In some embodiments, the heteroaryl of R⁴ is 5-membered. In some embodiments, it is 6-membered. In some embodiments, it has 1 heteroatom. In some embodiments, it has 1 heteroatom which is nitrogen. In some embodiments, it has 1 heteroatom which is oxygen. In some embodiments, it has 1 heteroatom which is sulfur. In some embodiments, it has 2 or 3 ring heteroatoms. In some embodiments, it has 2 or 3 ring heteroatoms at least one of which is nitrogen. In some embodiments, it . In some embodiments, it is bonded to R⁵, e.g., −COOH, at the o-positive relative gen atom.

[00244] In some embodiments, the further substituent on R⁴ in addition to R⁵ is halogen. In some embodiments, it is −F. In some embodiments, it is −Cl. In some embodiments, it is −Br. In some embodiments, it is −I. In some embodiments, it is C₁-C₄ alkyl. In some embodiments, it is C₁-C₄ alkoxy. In some embodiments, it is hydroxy C₁-C₄ alkyl. In some embodiments, it is hydroxy. In some embodiments, it is cyanomethyl. [00245] In some embodiments, wherein R⁴ is phenyl, naphthyl, 1,2,3,4-tetrahydronaphthalenyl and 5-10 membered heteroaryl having 1, 2 or 3 ring heteroatoms independently selected from nitrogen, oxygen and sulfur, and wherein the phenyl, naphthyl, 1,2,3,4-tetrahydronaphthalenyl, or heteroaryl is substituted with R⁵ and further optionally substituted with one or two R⁵’. In some embodiments, R⁴ is phenyl substituted with R⁵ and further optionally substituted with one or two R⁵’. In some embodiments, wherein R⁴ is phenyl para- substituted (unless otherwise indicated, relative to the atom at which R⁴ is attached to the rest of the compound) with R⁵ and further optionally substituted with one or two R⁵’. In some embodiments, R⁴ is phenyl meta-substituted with R⁵ and further optionally substituted with one or two R⁵’. In some embodiments, R⁴ is naphthyl substituted with R⁵ and further optionally substituted with one or two R⁵’. In some embodiments, R⁴ is 1,2,3,4-tetrahydronaphthalenyl substituted with R⁵ and further optionally substituted with one or two R⁵’. In some embodiments, R⁴ is 5-membered heteroaryl substituted with R⁵ and further optionally substituted with one or two R⁵’. In some embodiments, R⁴ is 6-membered heteroaryl substituted with R⁵ and further optionally substituted with one or two R⁵’. In some embodiments, R⁴ is 6-membered heteroaryl para-substituted with R⁵ and further optionally substituted with one or two R⁵’. In some embodiments, R⁴ is 6-membered heteroaryl meta-substituted with R⁵ and further optionally substituted with one or two R⁵’. In some embodiments, a 6-membered heteroaryl is pyridyl. In some embodiments, R⁴ is 9- membered bicyclic heteroaryl substituted with R⁵ and further optionally substituted with one or two R⁵’. In some embodiments, R⁴ is 10-membered bicyclic heteroaryl substituted with R⁵ and further optionally substituted with one or two R⁵’. [00246] In some embodiments, R⁴ is substituted with one R⁵. In some embodiments, R⁴ is substituted with two R⁵. In some embodiments, a R⁵ is attached to an atom that is boned to an atom to which R⁵ bonds. In some embodiments, a R⁵ is attached to a carbon atom that is boned to an atom to which R⁵ bonds. In some embodiments, a R⁵ is attached to a carbon atom that is boned to a carbon atom to which R⁵ bonds. In some embodiments, R⁴ is or comprises an aromatic ring to which both R⁵ and a R⁵’ are bonded. In some embodiments, R⁵ and a R⁵’ are ortho. [00247] In some embodiments, R⁵’ is halogen. In some embodiments, it is −F. In some embodiments, it is −Cl. In some embodiments, it is −Br. In some embodiments, it is −I. [00248] In some embodiments, R⁵’ is C1-C4 alkyl as described herein. In some embodiments, R⁵’ is methyl. In some embodiments, it is ethyl. In some embodiments, R⁵’ is cyclopropyl. [00249] In some embodiments, R⁵’ is C1-C4 alkoxy as described herein. In some embodiments, it is methoxy. In some embodiments, it is ethoxy. [00250] In some embodiments, R⁵’ is hydroxy C1-C4 alkyl as described herein. In some embodiments, it is −CH2OH. In some embodiments, it is −CH2CH2OH. [00251] In some embodiments, R^5’ is hydroxyl. [00252] In some embodiments, R⁵’ is R¹⁰ as described herein. In some embodiments, R¹⁰ comprises a nitrogen ring atom. In some embodiments, R¹⁰ is bonded to R⁴ at a nitrogen ring atom. [00253] In some embodiments, R⁵’ is −OR^6’ wherein R⁶’ is as described herein. In some embodiments, it is −OR¹⁰ wherein R¹⁰ is as described herein. [00254] In some embodiments, R⁵’ is halo C1-C6 alkyl. In some embodiments, R⁵’ is C1-C6 alkyl substituted with one or more −F. [00255] In some embodiments, R⁵’ is cyano. In some embodiments, R⁵’ is cyanomethyl. [00256] In some embodiments, two R^5’ are taken together to form an optionally substituted ring as described herein. In some embodiments, two R^5’ are taken together to form an optionally substituted 4-8 membered partially unsaturated ring as described herein. In some embodiments, a ring is 4-membered. In some embodiments, a ring is 5-membered. In some embodiments, a ring is 6-membered. In some embodiments, a ring is 7-membered. In some embodiments, a ring is 8-membered. In some embodiments, two R^5’ are taken together to form an optionally substituted 5-6 membered aromatic ring as described herein. In some embodiments, two R^5’ are taken together to form an optionally substituted 5-membered aromatic ring as described herein. In some embodiments, two R^5’ are taken together to form an optionally substituted 6- membered aromatic ring as described herein. In some embodiments, a formed ring in unsubstituted. In some embodiments, a formed ring is substituted. In some embodiments, a formed ring is substituted with oxo. In some embodiments, a formed ring has a nitrogen ring atom. In some embodiments, a formed ring has an oxygen ring atom. In some embodiments, a formed ring has a nitrogen ring atom and an oxygen ring atom. In some embodiments, a formed ring has two oxygen ring atoms. [00257] In some embodiments, R⁵’ is an amino group or a derivative thereof. In some embodiments, such R⁵’ provide improved activities and/or properties. In some embodiments, R⁵’ is −N(R⁵¹)₂ wherein each R⁵¹ is independently as described herein. In some embodiments, R⁵’ is −NHR⁵¹ wherein R⁵¹ is as described herein. In some embodiments, R⁵’ is −N(CH₃)R⁵¹ wherein R⁵¹ is as described herein. [00258] In some embodiments, R⁵’ is −NHC(O)CH₃. In some embodiments, R⁵’ is −NHC(O)CH₂CH₃. In some embodiments, R⁵¹ is −SO₂−C₁-C₆ aliphatic, wherein the C₁-C₆ aliphatic is optionally substituted. In some embodiments, R⁵¹ is −SO2−C1-C6 aliphatic. In some embodiments, R⁵¹ is −SO2−C1-C6 alkyl. In some embodiments, R⁵’ is −NHS(O)₂CH₃. In some embodiments, R⁵’ is −NH₂. In some embodiments, R⁵’ is −NH(CH₃). In some embodiments, R⁵’ is −NH(CH₂CH₃). [00259] As described herein, each R⁵¹ is independently R⁶’ as described herein. [00260] In some embodiments, each R⁵¹ is independently hydrogen, C1-C6 aliphatic, R¹⁰, −CH2−C3-C6 cycloaliphatic, −CH2−R¹⁰, −CH2−(hydroxy C1-C4 alkyl), phenyl, −C(O)−C1-C6 aliphatic, −SO2−C1-C6 aliphatic, −CH2−phenyl, −CH2−(amino C1-C4 alkyl), or −CH2−(mono- and di-C1-C4 alkylamino C1-C4 alkyl) wherein each of the C1-C6 aliphatic and phenyl is optionally substituted with one or more substituents independently selected from halogen, C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl or 3-6 membered heterocyclyl having 1-4 ring atoms independently selected from nitrogen, oxygen and sulfur, wherein each of the alkyl, alkoxy, cycloalkyl and heterocyclyl is optionally and independently substituted with one or more substituents independently selected from halogen, C1-C4 alkyl, halo C1-C4 alkyl, C1-C4 alkoxy, hydroxyl, and oxo, and wherein each nitrogen ring atom of the heterocyclyl is optionally and independently substituted with C1-3 acyl, cyano C1-C4 alkyl, C3-C6 cycloalkyl, or 3-6 membered heterocyclyl having 1-4 ring atoms independently selected from nitrogen, oxygen and sulfur wherein each ring nitrogen is optionally and independently substituted with C1-3 acyl. [00261] In some embodiments, R⁵¹ is hydrogen. In some embodiments, R⁵¹ is optionally substituted C1- C6 aliphatic. In some embodiments, R⁵¹ is C1-C6 aliphatic. In some embodiments, R⁵¹ is C1-C6 alkyl. In some embodiments, R⁵¹ is cyclopropyl. In some embodiments, R⁵¹ is methyl. In some embodiments, R⁵¹ is ethyl. In some embodiments, R⁵¹ is cyclobutyl. In some embodiments, R⁵¹ is −CH2−cyclopropyl. In some embodiments, R⁵¹ is substituted C1-C6 aliphatic. In some embodiments, R⁵¹ is −CH2(CO2H). In some embodiments, R⁵¹ is substituted C1-C6 alkyl. In some embodiments, R⁵¹ is (S)−CH(CH3)(CF3). In some embodiments, R⁵¹ is −CH2CF3. In some embodiments, R⁵¹ is substituted C3-C6 cycloalkyl. In some embodiments, R⁵¹ is 3,3-difluorocyclobutyl. In some embodiments, R⁵¹ is R¹⁰ as described herein. In some embodiments, R⁵¹ is −CH₂−R¹⁰ wherein R¹⁰ is as described herein. In some embodiments, R⁵¹ is −CH₂−CHF₂. [00262] In some embodiments, R⁵¹ is −C(O)−C₁-C₆ aliphatic, wherein the C₁-C₆ aliphatic is optionally substituted. In some embodiments, R⁵¹ is −C(O)−C₁-C₆ aliphatic. In some embodiments, R⁵¹ is −C(O)−C₁-C₆ alkyl. In some embodiments, R⁵¹ is −C(O)−CH₃. [00263] In some embodiments, R⁵¹ is −SO₂−C₁-C₆ aliphatic. In some embodiments, R⁵¹ is −SO₂−CH₃. [00264] In some embodiments, R^4’ is hydrogen. In some embodiments, R^4’ is C₁-C₄ alkyl. In some embodiments, R^4’ is hydroxy C₁-C₄ alkyl. In some embodiments, R^4’ and one R⁶ are taken together to form C2-C4 alkylene. In some embodiments, the carbon to which R⁴' is attached has a configuration .

In some embodiments, the carbon to which R⁴' is attached has a configurati In some

embodiments, the carbon to which R⁴' is attached has a structure o . In some embodiments, the

carbon to which R⁴' is attached has a structure o . [00265] In some embodiments, R⁵ is −C(O) (O)R⁸, R⁹, −C(O)NHSO2C1-C4

alkyl, −SO2NHC(O)C1-C4alkyl, −SO2N(H)p(C1-C4alkyl)2-p, −SO(NH)C1-C4alkyl, −SO2C1-C4alkyl, cyano, halogen, hydroxy C1-C4 alkyl, −B(R⁸)2 or 5-membered heteroaryl having 1-4 ring nitrogen atoms and 0 or 1 ring oxygen or sulfur atom. [00266] In some embodiments, R⁵ is −COOH or a bioisostere thereof. [00267] In some embodiments, R⁵ is −C(O)R⁸. In some embodiments, R⁵ is −C(O)OH. In some embodiments, R⁵ is −C(O)R⁸, wherein R⁸ is C1-C4 alkoxy. [00268] In some embodiments, R⁵ is −CH2C(O)R⁸. In some embodiments, R⁵ is −CH2C(O)OH. In some embodiments, R⁵ is −CH2C(O)R⁸, wherein R⁸ is C1-C4 alkoxy. [00269] In some embodiments, R⁵ is R⁹. In some embodiments, R⁵ is −C(O)NHSO₂C₁-C₄alkyl. In some embodiments, R⁵ is −C(O)NHSO₂CH₃. In some embodiments, R⁵ is −C(O)NHSO₂(cyclopropyl). In some embodiments, R⁵ is −SO₂NHC(O)C₁-C₄alkyl. In some embodiments, R⁵ is −SO₂N(H)_p(C₁-C₄alkyl)_2-p. In some embodiments, R⁵ is −SO₂N(C₁-C₄alkyl)₂. In some embodiments, R⁵ is −SO₂NH(C₁-C₄alkyl). In some embodiments, R⁵ is −SO₂NH₂. In some embodiments, R⁵ is −SO(NH)C₁-C₄alkyl. In some embodiments, R⁵ is −SO₂C₁-C₄alkyl. In some embodiments, R⁵ is cyano. In some embodiments, R⁵ is halogen. In some embodiments, R⁵ is −F. In some embodiments, R⁵ is −Cl. In some embodiments, R⁵ is −Br. In some embodiments, R⁵ is −I. In some embodiments, R⁵ is hydroxy C₁-C₄ alkyl. [00270] In some embodiments, R⁵ is −B(R⁸)₂. In some embodiments, R⁵ is −B(R⁸)₂, wherein each R⁸ is independently hydroxy or C₁-C₄ alkoxy. In some embodiments, R⁵ is −B(OH)₂. In some embodiments, R⁵ is −B(R⁸)₂, wherein each R⁸ is independently C₁-C₄ alkoxy. [00271] In some embodiments, R⁵ is 5-membered heteroaryl having 1-4 ring nitrogen atoms and 0 or 1 ring oxygen or sulfur atom. In some embodiments, R⁵ is 5-membered heteroaryl having 1-4 ring nitrogen atoms. In some embodiments, R⁵ is tetrazolyl. [00272] In some embodiments, each R⁶ is independently hydrogen, halogen, hydroxyl, amino, mono- and di-C₁-C₆ alkylamino, C₁-C₆ alkyl, halo C₁-C₆ alkyl, hydroxy C₁-C₆ alkyl, cyano C₁-C₆ alkyl or C₁-C₆ alkoxy. [00273] In some embodiments, R⁶ is hydrogen. In some embodiments, R⁶ is not hydrogen. In some embodiments, R⁶ is halogen. In some embodiments, R⁶ is −F. In some embodiments, R⁶ is −Cl. In some embodiments, R⁶ is −Br. In some embodiments, R⁶ is −I. In some embodiments, R⁶ is hydroxy. In some embodiments, R⁶ is amino. In some embodiments, R⁶ is mono- and di-C₁-C₆ alkylamino. In some embodiments, R⁶ is C₁-C₆ alkyl. [00274] In some embodiments, R⁶ is halo C1-C6 alkyl. In some embodiments, R⁶ is halo C1-C4 alkyl. In some embodiments, R⁶ is −CF3. In some embodiments, R⁶ is −CHF2. In some embodiments, R⁶ is −CH2F. [00275] In some embodiments, R⁶ is hydroxy C1-C6 alkyl. In some embodiments, R⁶ is hydroxy C1-C4 alkyl. In some embodiments, R⁶ is −CH2OH. [00276] In some embodiments, R⁶ is cyano C1-C6 alkyl. In some embodiments, R⁶ is cyano C1-C4 alkyl. In some embodiments, R⁶ is C1-C6 alkoxy. In some embodiments, R⁶ is C1-C4 alkoxy. [00277] In some embodiments, two R⁶ on a carbon atom are taken together to form =O. In some embodiments, =O is on a carbon at the o-position relative to the carbon to which R⁴ and R^4’ are attached. In some embodiments, =O is on a carbon at the p-position relative to the carbon to which R⁴ and R^4’ are attached. In some embodiments, two R⁶ on a carbon atom are taken together with the carbon atom to form a 3-membered monocyclic saturated ring having 0-1 ring atoms independently selected from nitrogen, sulfur and oxygen. In some embodiments, a formed ring is . In some embodiments, a formed ring is . In some embodiments, two R⁶ on a carbon atom ar

n together with the carbon atom to form

membered monocyclic saturated ring having a nitrogen ring atom. In some embodiments, two R⁶ on a carbon atom are taken together with the carbon atom to form a 3-membered monocyclic saturated ring having a sulfur ring atom. [00278] In some embodiments, two R⁶ are taken together with their intervening atoms to form a 3-8 membered monocyclic saturated or partially unsaturated ring having 0-3 ring atoms independently selected from nitrogen, sulfur and oxygen, wherein the ring is optionally substituted with one or more substituents independently selected from halogen, C1-C4 alkyl, halo C1-C4 alkyl, C1-C4 alkoxy, hydroxyl, and oxo. In some embodiments, a formed ring is 3-membered. In some embodiments, a formed ring is 4-membered. In some embodiments, a formed ring is 5-membered. In some embodiments, a formed ring is 6-membered. In some embodiments, a formed ring is 7-membered. In some embodiments, a formed ring is 8-membered. In some embodiments, a formed ring is saturated. In some embodiments, a formed ring is partially unsaturated. In some embodiments, a formed ring has no heteroatom ring atom. In some embodiments, a formed ring has 1-3 ring atoms independently selected from nitrogen, sulfur and oxygen. In some embodiments, one ring atom is a heteroatom. In some embodiments, two ring atoms are independently a heteroatom. In some embodiments, three ring atoms are independently a heteroatom. In some embodiments, a ring atom is nitrogen. In some embodiments, a ring atom is sulfur. In some embodiments, a ring atom is oxygen. In some embodiments, a formed ring is substituted. In some embodiments, a formed ring is unsubstituted. In some embodiments, a substituent is halogen. In some embodiments, a substituent is C₁-C₄ alkyl. In some embodiments, a substituent is halo C₁-C₄ alkyl. In some embodiments, a substituent is C₁-C₄ alkoxy. In some embodiments, a substituent is hydroxy. In some embodiments, a substituent is oxo. [00279] In some embodiments, t is 0. In some embodiments, t is 1. In some embodiments, t is 3. In some embodiments, t is 4. In some embodiments, t is 1, 2, 3 or 4, and each R⁶ is not hydrogen. In some embodiments, t is 1, 2, 3, or 4, and each R⁶ is independently halogen, hydroxyl, amino, mono- and di-C1-C6 alkylamino, C1-C6 alkyl, halo C1-C6 alkyl, hydroxy C1-C6 alkyl, cyano C1-C6 alkyl or C1-C6 alkoxy. [00280] In some embodiments, R^6’ is hydrogen, C1-C6 aliphatic, R¹⁰, −CH2−C3-C6 cycloaliphatic, −CH2−R¹⁰, −CH2−(hydroxy C1-C4 alkyl), phenyl, −C(O)−C1-C6 aliphatic, −SO2−C1-C6 aliphatic, −CH2−phenyl, −CH2−(amino C1-C4 alkyl), or −CH2−(mono- and di-C1-C4 alkylamino C1-C4 alkyl) wherein each of the C1-C6 aliphatic, C3-C6 cycloaliphatic and phenyl is optionally substituted with one or more substituents independently selected from halogen, C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl or 3-6 membered heterocyclyl having 1-4 ring atoms independently selected from nitrogen, oxygen and sulfur, wherein each of the alkyl, alkoxy, cycloalkyl and heterocyclyl is optionally and independently substituted with one or more substituents independently selected from halogen, C1-C4 alkyl, halo C1-C4 alkyl, C1-C4 alkoxy, hydroxyl, and oxo, and wherein each nitrogen ring atom of the heterocyclyl is optionally and independently substituted with C1-3 acyl, cyano C1-C4 alkyl, C3-C6 cycloalkyl, or 3-6 membered heterocyclyl having 1-4 ring atoms independently selected from nitrogen, oxygen and sulfur wherein each ring nitrogen is optionally and independently substituted with C1-3 acyl. [00281] In some embodiments, R^6’ is hydrogen. In some embodiments, R^6’ is not hydrogen. [00282] In some embodiments, R^6’ is halogen. In some embodiments, R^6’ is −F. In some embodiments, R^6’ is −Cl. In some embodiments, R^6’ is −Br. In some embodiments, R^6’ is −I. [00283] In some embodiments, R⁶’ is C1-C6 aliphatic optionally substituted with one or more substituents independently selected from halogen, C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl or 3-6 membered heterocyclyl having 1-4 ring atoms independently selected from nitrogen, oxygen and sulfur, , wherein each of the alkyl, alkoxy, cycloalkyl and heterocyclyl is optionally and independently substituted with one or more substituents independently selected from halogen, C₁-C₄ alkyl, halo C₁-C₄ alkyl, C₁-C₄ alkoxy, hydroxyl, and oxo, and wherein each nitrogen ring atom of the heterocyclyl is optionally and independently substituted with C_1-3 acyl, cyano C₁-C₄ alkyl, C₃-C₆ cycloalkyl, or 3-6 membered heterocyclyl having 1-4 ring atoms independently selected from nitrogen, oxygen and sulfur wherein each ring nitrogen is optionally and independently substituted with C_1-3 acyl. [00284] In some embodiments, R⁶’ is optionally substituted C_1-6 aliphatic. In some embodiments, R⁶’ is C_1-6 aliphatic. In some embodiments, R⁶’ is C₁-C₆ alkyl optionally substituted as described herein. In some embodiments, R⁶’ is C₁-C₆ alkyl. In some embodiments, R⁶’ is C₁. In some embodiments, R⁶’ is C₂. In some embodiments, R⁶’ is C₃. In some embodiments, R⁶’ is C₄. In some embodiments, R⁶’ is C₅. In some embodiments, R⁶’ is C₆. In some embodiments, R⁶’ is C₁-C₅. In some embodiments, R⁶’ is C₁-C₄. In some embodiments, R⁶’ is C₁-C₃. In some embodiments, R⁶’ is C₁-C₂. In some embodiments, R⁶’ is C₂-C₆. In some embodiments, R⁶’ is C₂-C₅. In some embodiments, R⁶’ is C₂-C₄. In some embodiments, R⁶’ is C₂-C₃. In some embodiments, R⁶’ is C3-C6. In some embodiments, R⁶’ is methyl. In some embodiments, R^6’ is - CD₃. In some embodiments, R⁶’ is ethyl. In some embodiments, R⁶’ is n-propyl. In some embodiments, R⁶’ is isopropyl. In some embodiments, R⁶’ is optionally substituted cyclopropyl. In some embodiments, R⁶’ is optionally substituted cyclobutyl. In some embodiments, R⁶’ is −CH2−cyclopropyl. In some embodiments, R⁶’ is −CH2−cyclobutyl. In some embodiments, R⁶’ is −CH2−cyclopentyl. In some embodiments, R⁶’ is 2- methylpropyl. In some embodiments, R⁶’ is 1-methylpropyl. In some embodiments, R⁶’ is n-butyl. In some embodiments, R⁶’ is −CH2CH(CH3)CH2CH3. In some embodiments, R⁶’ is −CH2CH2CH(CH3)2. In some embodiments, R⁶’ is −CH2−CHF2. In some embodiments, R⁶’ is C1-6 aliphatic optionally substituted with cyano. In some embodiments, R⁶’ is C1-C6 aliphatic optionally substituted with a 3-6 membered heterocyclyl having 1-4 ring atoms independently selected from nitrogen, oxygen and sulfur, In some embodiments, R⁶’ is C1-C6 aliphatic optionally substituted with tetrahydropyranyl. In some embodiments, R⁶’ is C1-C6 aliphatic optionally substituted with oxetanyl. In some embodiments, R⁶’ is C1-C6 aliphatic optionally substituted with sulfonyl. In some embodiments, R⁶’ is –(CH2)2SO2(CH3). In some embodiments, R⁵¹ is −CH2(CO2H). [00285] In some embodiments, R⁶’ is C3-6 (C3, C4, C5 or C6) cycloaliphatic optionally substituted as described herein. In some embodiments, R⁶’ is C3-C6 (C3, C4, C5 or C6) cycloalkyl optionally substituted as described herein. In some embodiments, R⁶’ is C3-6 (C3, C4, C5 or C6) cycloaliphatic. In some embodiments, R⁶’ is C3-C6 (C3, C4, C5 or C6) cycloalkyl. In some embodiments, cycloalkyl is cyclopropyl. In some embodiments, it is cyclobutyl. In some embodiments, it is cyclopentyl. In some embodiments, it is cyclohexyl. [00286] In some embodiments, R⁶’ is C2-C6 alkenyl optionally substituted as described herein. In some embodiments, R⁶’ is C2-C6 alkenyl. In some embodiments, an alkenyl is a terminal alkenyl group. In some embodiments, R^6’ is −CH2CH=CH2. [00287] In some embodiments, R⁶’ is C2-C6 alkynyl optionally substituted as described herein. In some embodiments, R⁶’ is C₂-C₆ alkynyl. In some embodiments, an alkynyl is a terminal alkynyl group. In some embodiments, R^6’ is −CH₂C≡CH. [00288] In some embodiments, R^6’ is −CH₂−(hydroxy C₁-C₄ alkyl). In some embodiments, R^6’ is −CH₂CH₂OH. [00289] In some embodiments, R^6’ is −C(O) −C₁-C₆ aliphatic. In some embodiments, R^6’ is −C(O)−CH₃. [00290] In some embodiments, R^6’ is −SO₂−C₁-C₆ aliphatic. In some embodiments, R^6’ is −SO₂−CH₃. [00291] In some embodiments, a group (e.g., C_1-6 aliphatic, C₃-C₆ cycloaliphatic, phenyl, etc.) of R^6’ is substituted as described herein. In some embodiments, it is substituted with halogen (e.g., −F, −Cl, −Br or −I). In some embodiments, it is substituted with −F. For example, in some embodiments, R^6’ is C_1-6 aliphatic substituted with one or more −F. In some embodiments, R^6’ is C_1-6 alkyl substituted with one or more −F. In some embodiments, R^6’ is −(CH₂)₂−F. In some embodiments, R^6’ is −(CH₂)₃−F. In some embodiments, R^6’ is −CH₂−CHF₂. In some embodiments, R^6’ is −CH(CH₃)−CHF₂. In some embodiments, R^6’ is −CH₂−CF₃. In some embodiments, R^6’ is −CH₂−CH₂−CHF₂. In some embodiments, R^6’ is −CH₂−CH₂−CF₃. In some embodiments, R^6’ is −CH2−CF2−CH3. In some embodiments, R^6’ is −CH(CH3)−CH2−CF3. In some embodiments, R^6’ is C₃-C₆ substituted one or more −F. In some embodiments, R^6’ is cyclopropyl substituted with −F. [00292] In some embodiments, a group (e.g., C1-6 aliphatic, C3-C6 cycloaliphatic, phenyl, etc.) of R^6’ is substituted as described herein. In some embodiments, it is substituted with C1-C4 (e.g., C1, C2, C3 or C4) alkoxy. In some embodiments, it is substituted with CH3O−. In some embodiments, R^6’ is −CH2CH2OCH3. [00293] In some embodiments, R⁶’ is R¹⁰. In some embodiments, R^6’ is 3-6 membered heterocyclyl optionally substituted as described herein. In some embodiments, R^6’ is 3-membered heterocyclyl optionally substituted as described herein. In some embodiments, R^6’ is 4-membered heterocyclyl optionally substituted as described herein. In some embodiments, R^6’ is 5-membered heterocyclyl optionally substituted as described herein. In some embodiments, R^6’ is 6-membered heterocyclyl optionally substituted as described herein. In some embodiments, a heterocyclyl group is substituted. In some embodiments, it is unsubstituted. In some embodiments, a heterocyclyl group has a ring oxygen atom. In some embodiments, R^6’ is . [00294] In some embodiments, R^6’ is 5-6 membered heteroaryl optionally substituted as described herein. In some embodiments, R^6’ is 5-membered heteroaryl optionally substituted as described herein. In some embodiments, R^6’ is 6-membered heteroaryl optionally substituted as described herein. In some embodiments, a heteroaryl group is substituted. In some embodiments, a heteroaryl group is unsubstituted. In some embodiments, R⁶’ i . In some embodiments, R⁶’ . In some embodiments, R⁶’ is

. In some embodiments, In some

embodiments, . [00295] In

ments, the atom of R¹⁰ that forms a bond with the nitrogen to which R¹⁰ is attached is a carbon atom. [00296] In some embodiments, R⁶’ is −CH₂−C₃-C₆ cycloaliphatic wherein the cycloaliphatic group is optionally substituted as described herein. In some embodiments, a cycloaliphatic group is a cycloalkyl group. In some embodiments, R⁶’ is −CH₂−C₃-C₆ cycloalkyl wherein the cycloaliphatic group is optionally substituted as described herein. In some embodiments, R⁶’ is −CH₂−C₃-C₆ cycloaliphatic. In some embodiments, R⁶’ is −CH2−C3-C6 cycloalkyl. In some embodiments, a cycloalkyl is cyclopropyl. In some embodiments, a cycloalkyl is cyclobutyl. In some embodiments, a cycloalkyl is cyclopentyl. In some embodiments, a cycloalkyl is cyclohexyl. [00297] In some embodiments, R⁶’ is −CH₂−R¹⁰, wherein R¹⁰ is as described herein. [00298] In some embodiments, R⁶’ is −CH₂−(hydroxy C₁-C₄ alkyl). In some embodiments, R^6’ is −CH2CH2OH. [00299] In some embodiments, R⁶’ is phenyl optionally substituted as described herein. In some embodiments, a phenyl group is substituted. In some embodiments, a phenyl group is substituted with one or more halogen. In some embodiments, a phenyl group is unsubstituted. In some embodiments, R⁶’ is phenyl. [00300] In some embodiments, R^6’is −C(O)−C1-C6 aliphatic, wherein the C1-C6 aliphatic is as described herein. In some embodiments, R^6’is −C(O)−C1-C6 aliphatic, wherein the C1-C6 aliphatic is optionally substituted as described herein. In some embodiments, R^6’is −C(O)−C1-C6 alkyl. In some embodiments, R^6’is −C(O)−CH3. [00301] In some embodiments, R^6’is −SO2−C1-C6 aliphatic, wherein the C1-C6 aliphatic is as described herein. In some embodiments, R^6’is −SO2−C1-C6 aliphatic, wherein the C1-C6 aliphatic is optionally substituted as described herein. In some embodiments, R^6’is −SO2−C1-C6 alkyl. In some embodiments, R^6’is −SO2−CH3. [00302] In some embodiments, R⁶’ is −CH2−phenyl, wherein the phenyl group is optionally substituted as described herein. In some embodiments, a phenyl group is substituted. In some embodiments, a phenyl group is substituted with one or more halogen. In some embodiments, a phenyl group is unsubstituted. In some embodiments, R⁶’ is −CH2−phenyl. [00303] In some embodiments, R⁶’ is −CH2−(amino C1-C4 alkyl). In some embodiments, R⁶’ is −CH2−(amino C1-C4 alkyl), wherein the alkyl group is optionally substituted with oxo. In some embodiments, R⁶’ is −CH2−C(O)−NH2. In some embodiments, R⁶’ is −CH2−(amino C1-C4 alkyl), wherein the alkyl is optionally substituted with oxo and C1-C4 alkyl. In some embodiments, R⁶’ is −CH(CH3)−C(O)−NH2. [00304] In some embodiments, R⁶’ is −CH2−(mono- and di-C1-C4 alkylamino C1-C4 alkyl). [00305] In some embodiments, R⁶ and R^6’ are taken together with their intervening atoms to form a 3-8 membered monocyclic or bicyclic saturated, partially unsaturated or aromatic ring having 1-3 ring atoms independently selected from nitrogen, sulfur and oxygen, wherein the ring is optionally substituted with one or more substituents independently selected from halogen, C₁-C₄ alkyl, halo C₁-C₄ alkyl, C₁-C₄ alkoxy, hydroxyl, and oxo. [00306] In some embodiments, R⁶ and R^6’ are taken together with their intervening atoms to form a 3-8 membered monocyclic saturated or partially unsaturated ring having 0-3 ring atoms independently selected from nitrogen, sulfur and oxygen, wherein the ring is optionally substituted with one or more substituents independently selected from halogen, C₁-C₄ alkyl, halo C₁-C₄ alkyl, C₁-C₄ alkoxy, hydroxyl, and oxo. In some embodiments, a formed ring is 3-membered. In some embodiments, a formed ring is 4-membered. In some embodiments, a formed ring is 5-membered. In some embodiments, a formed ring is 6-membered. In some embodiments, a formed ring is 7-membered. In some embodiments, a formed ring is 8-membered. [00307] In some embodiments, a formed ring is 3-membered. In some embodiments, a formed ring is 4- membered. In some embodiments, a formed ring is 5-membered. In some embodiments, a formed ring is 6- membered. In some embodiments, a formed ring is 7-membered. In some embodiments, a formed ring is 8- membered. In some embodiments, a formed ring is monocyclic. In some embodiments, a formed ring a bicyclic. In some embodiments, a formed ring is saturated. In some embodiments, a formed ring is partially saturated. In some embodiments, a formed ring is aromatic. In some embodiments, a formed ring is 5- membered and is aromatic. In some embodiments, a formed ring is 6-membered and is aromatic. In some embodiments, a formed ring has no additional ring heteroatom in addition to the nitrogen atom to which R⁶’ is attached. In some embodiments, a formed ring has 1 or 2 additional ring heteroatoms in addition to the nitrogen atom to which R⁶’ is attached. In some embodiments, an additional ring heteroatom is nitrogen. In some embodiments, an additional ring heteroatom is oxygen. [00308] In some embodiments, R⁶ and R^6’ are taken together with their intervening atoms to form a 3-8 membered monocyclic or bicyclic saturated, partially unsaturated or aromatic ring having 0-3 ring atoms independently selected from nitrogen, sulfur and oxygen, wherein the ring is optionally substituted with one or more substituents independently selected from halogen, C1-C4 alkyl, halo C1-C4 alkyl, C1-C4 alkoxy, hydroxyl, and oxo. In some embodiments, R⁶ and R^6’ are taken together with their intervening atoms to form a 3-8 membered monocyclic or bicyclic saturated, partially unsaturated or aromatic ring having 0-3 ring atoms independently selected from nitrogen, sulfur and oxygen, wherein the ring is optionally substituted with sulfonyl. In some embodiments, R⁶ and R^6’ are taken together with their intervening atoms to form a 3-8 membered monocyclic or bicyclic saturated, partially unsaturated or aromatic ring having 0-3 ring atoms independently selected from nitrogen, sulfur and oxygen, wherein the ring is optionally substituted with one or more substituents independently selected from halogen, C1-C4 alkyl, halo C1-C4 alkyl, C1-C4 alkoxy, hydroxyl, sulfonyl and oxo. In some embodiments, R⁶ and R^6’ are taken together with their intervening atoms to form a 3-8 membered monocyclic or bicyclic saturated, or partially unsaturated ring having 0-3 ring atoms independently selected from nitrogen, sulfur and oxygen, wherein the ring is optionally substituted with one or more substituents independently selected from halogen, C1-C4 alkyl, halo C1-C4 alkyl, C1-C4 alkoxy, hydroxyl, and oxo. In some embodiments, R⁶ and R^6’ are taken together with their intervening atoms to form a 3-8 membered monocyclic or bicyclic saturated ring having 0-3 ring atoms independently selected from nitrogen, sulfur and oxygen, wherein the ring is optionally substituted with one or more substituents independently selected from halogen, C₁-C₄ alkyl, halo C₁-C₄ alkyl, C₁-C₄ alkoxy, hydroxyl, and oxo. In some embodiments, R⁶ and R^6’ are taken together with their intervening atoms to form a 3-8 membered monocyclic or bicyclic partially unsaturated ring having 0-3 ring atoms independently selected from nitrogen, sulfur and oxygen, wherein the ring is optionally substituted with one or more substituents independently selected from halogen, C₁-C₄ alkyl, halo C₁-C₄ alkyl, C₁-C₄ alkoxy, hydroxyl, and oxo. In some embodiments, R⁶ and R^6’ are taken together with their intervening atoms to form a 5-6 membered monocyclic or bicyclic aromatic ring having 0-3 ring atoms independently selected from nitrogen, sulfur and oxygen, wherein the ring is optionally substituted with one or more substituents independently selected from halogen, C₁-C₄ alkyl, halo C₁-C₄ alkyl, C₁-C₄ alkoxy, hydroxyl, and oxo. In some embodiments, R⁶ and R^6’ are taken together with their intervening atoms to form a 5-8 membered monocyclic saturated or partially unsaturated ring having 0-3 ring atoms independently selected from nitrogen, sulfur and oxygen, wherein the ring is optionally substituted with one or more substituents independently selected from halogen, C₁-C₄ alkyl, halo C₁-C₄ alkyl, C₁-C₄ alkoxy, hydroxyl, and oxo. In some embodiments, R⁶ and R^6’ are taken together with their intervening atoms to form a 5-8 membered monocyclic saturated or partially unsaturated ring having 1 ring nitrogen atom. In some embodiments, R⁶ and R^6’ are taken together with their intervening atoms to form a 5- 8 membered monocyclic saturated ring having 1 ring nitrogen atom. In some embodiments, R⁶ and R^6’ are taken together with their intervening atoms to form an optionally substituted 5-membered monocyclic saturated ring having 1 ring nitrogen atom. In some embodiments, R⁶ and R^6’ are taken together with their intervening atoms to form a 5-membered monocyclic saturated ring having 1 ring nitrogen atom, wherein the ring is substituted with one or more substituents each of which is independently halogen. In some embodiments, R⁶ and R^6’ are taken together with their intervening atoms to form an optionally substituted 4- membered monocyclic saturated ring having 1 ring nitrogen atom. In some embodiments, R⁶ and R^6’ are taken together with their intervening atoms to form an optionally substituted 6-membered monocyclic saturated ring having 1 ring nitrogen atom. In some embodiments, R⁶ and R^6’ are taken together with their intervening atoms to form an optionally substituted 6-membered monocyclic saturated ring having 1 ring nitrogen atom and 1 ring oxygen atom. In some embodiments, R⁶ and R^6’ are taken together with their intervening atoms to form a 6-8 membered bicyclic saturated or partially unsaturated ring having 1-3 ring atoms independently selected from nitrogen, sulfur and oxygen, wherein the ring is optionally substituted with one or more substituents independently selected from halogen, C1-C4 alkyl, halo C1-C4 alkyl, C1-C4 alkoxy, hydroxyl, and oxo. In some embodiments, R⁶ and R^6’ are taken together with their intervening atoms to form a 6-membered bicyclic saturated or partially unsaturated ring having 1-3 ring atoms independently selected from nitrogen, sulfur and oxygen, wherein the ring is optionally substituted with one or more substituents independently selected from halogen, C1-C4 alkyl, halo C1-C4 alkyl, C1-C4 alkoxy, hydroxyl, and oxo. [00309] In some embodiments, R⁷ is hydroxy. In some embodiments, R⁷ is C₁-C₄ alkoxy. In some embodiments, R⁷ is amino. In some embodiments, R⁷ is mono-C₁-C₄ alkylamino. In some embodiments, R⁷ is di-C₁-C₄ alkylamino. [00310] In some embodiments, each R⁸ is independently hydroxyl, C₁-C₄ alkoxy, amino or a 5-7 membered saturated heterocyclyl having 1, 2, or 3 ring heteroatoms independently selected from nitrogen, oxygen and sulfur; or R⁸ is mono- and di-C₁-C₄ alkylamino which is optionally substituted with one or more substituents independently selected from halogen, hydroxy and C₁-C₄ alkyl. [00311] In some embodiments, R⁸ −OH. In some embodiments, R⁸ is C_1-4 alkoxy. In some embodiments, R⁸ is methoxy. In some embodiments, R⁸ is ethoxy. In some embodiments, R⁸ is amino. In some embodiments, R⁸ is 5-, 6- or 7-membered saturated heterocyclyl having 1, 2, or 3 ring heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, R⁸ is mono-C1-C4 alkylamino which is optionally substituted with one or more substituents independently selected from halogen, hydroxy and C1-C4 alkyl. In some embodiments, R⁸ is mono-C1-C4 alkylamino. In some embodiments, R⁸ is di-C1-C4 alkylamino which is optionally substituted with one or more substituents independently selected from halogen, hydroxy and C1-C4 alkyl. In some embodiments, R⁸ is di-C1-C4 alkylamino.

[00312] In some embodiments, R⁸ is 5-7 membered saturated heterocyclyl having 1, 2, or 3 ring heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, R⁸ is mono- and di-C1-C4 alkylamino which is optionally substituted with one or more substituents independently selected from halogen, hydroxy and C1-C4 alkyl.

[00313] In some embodiments, R⁹ is a 5-membered heteroaryl having 1 to 4 ring nitrogen atoms and 0 or 1 ring oxygen or sulfur atom, which heteroaryl is optionally substituted with 0 to 2 C1-C4 alkyl groups. In some embodiments, R⁹ is a 5 -membered heteroaryl having 1 to 4 ring nitrogen atoms and 0 ring oxygen or sulfur atom, which heteroaryl is optionally substituted with 0 to 2 C1-C4 alkyl groups. In some embodiments, a heteroaryl group is substituted. In some embodiments, a heteroaryl group is unsubstituted.

[00314] In some embodiments, R¹⁰ is optionally substituted 3-6 membered heterocyclyl. In some embodiments, R¹⁰ is optionally substituted 3-membered heterocyclyl. In some embodiments, R¹⁰ is optionally substituted 4-membered heterocyclyl. In some embodiments, R¹⁰ is optionally substituted 5-membered heterocyclyl. In some embodiments, R¹⁰ is optionally substituted 6-membered heterocyclyl. In some embodiments, R¹⁰ is optionally substituted 5-membered heteroaryl. In some embodiments, R¹⁰ is optionally substituted 6-membered heteroaryl. In some embodiments, R¹⁰ is substituted. In some embodiments, R¹⁰ is unsubstituted. In some embodiments, R¹⁰ has one and only one ring heteroatom. In some embodiments, a ring heteroatom is nitrogen. In some embodiments, a ring heteroatom is oxygen.

[00315] In some embodiments, R¹⁰ is 3-6 membered heterocyclyl or 5-6 membered heteroaryl having 1-3 ring atoms independently selected from nitrogen, oxygen and sulfur, wherein the heterocyclyl or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, C1-C4 alkyl, halo C1-C4 alkyl, C1-C4 alkoxy, hydroxyl, and oxo, and wherein each nitrogen ring atom of the heterocyclyl or heteroaryl is optionally and independently substituted with C1-3 acyl, cyano C1-C4 alkyl, C3-C6 cycloalkyl, or 3-6 membered heterocyclyl having 1-4 ring atoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, R¹⁰ is 3-, 4-, 5- or 6-membered heterocyclyl optionally substituted as described herein. In some embodiments, R¹⁰ is 5- or 6-membered heteroaryl optionally substituted as described herein. In some embodiments, a heterocyclyl group is substituted. In some embodiments, a heterocyclyl group is unsubstituted. In some embodiments, a heteroaryl group is substituted. In some embodiments, a heteroaryl group is unsubstituted. In some embodiments, at least one ring atom of heterocyclyl is nitrogen. In some embodiments, at least one ring atom of heteroaryl is nitrogen. In some embodiments, each heteroatom ring atom of heterocyclyl is nitrogen. In some embodiments, each heteroatom ring atom of heteroaryl is nitrogen. [00316] In some embodiments, R¹⁰ is optionally substituted 5-6 membered heteroaryl having 1 -3 ring atoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, R¹⁰ is 5-membered hctcroaryl having 1-3 ring nitrogen atoms substituted with C1-C4 alkyl. In some embodiments, R¹⁰ is

. In some embodiments, R¹⁰ is optionally substituted 3-6 membered heterocyclyl. In some embodiments, R¹⁰ is optionally substituted 6-membered heterocyclyl. In some embodiments, R¹⁰ is

. , . In some embodiments, R¹⁰ is

.

[00317] In some embodiments, provided compounds or compositions comprise enriched levels of one or more isotopes. For example, in some embodiments, provided compounds or compositions comprise enriched levels of deuterium (D). Various technologies are available for incorporating enriched levels of various isotopes and can be utilized in accordance with the present disclosure. In some embodiments, one or more isotopes at one or more positions in a compound are independently enriched, e.g., relative to natural abundances. In some embodiments, an enrichment is about or at least about 2, 5, 10, 20, 50, 100, 200, 500, 1000, 2000, 5000 or 10000 fold. In some embodiments, an enrichment is such that about or at least about 1%, 2%, 5%, 10%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, or 95% of the molecules of the compound has a particular- isotope at a particular position, wherein the percentage is higher than a reference (e.g., the percentage in an un-enriched preparation of the compound, natural abundance, etc.). In some embodiments, a compound has an isotopic purity of about 5%-100% (e.g., about 5%, 10%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or more, or about 5%-100%, 10%-100%, 20%-100%, 30%-100%, 50%-100%, 80%-100%, 90-100%, 95%-100%, 96%- 100%, 97%-100%, 98%-100%, 99%-100%, 95-99%, 95%-99.5%, 95%-99.9%, etc.). In some embodiments, an isotopic purity is about 5%-100% (e.g., about 5%, 10%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or more, or about 5%-100%, 10%-100%, 20%- 100%, 30%-100%, 50%-100%, 80%-100%, 90-100%, 95%-100%, 96%-100%, 97%-100%, 98%-100%, 99%-100%, 95-99%, 95%-99.5%, 95%-99.9%, etc.) with respect to an isotope at a position. For example, in some embodiments, a compound comprises one or more D at one or more positions, and for each D at a particular position, its isotopic purity is independently about 5%-100% (e.g., about 5%, 10%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or more, or about 5%-100%. 10%-100%, 20%-100%, 30%-100%, 50%-100%, 80%-100%, 90-100%, 95%-100%, 96%- 100%, 97%-100%, 98%-100%, 99%-100%, 95-99%, 95%-99.5%, 95%-99.9%, etc.). In some embodiments, an isotopic purity is about 5% or more. In some embodiments, an isotopic purity is about 10% or more. In some embodiments, an isotopic purity is about 20% or more. In some embodiments, an isotopic purity is about 30% or more. In some embodiments, an isotopic purity is about 40% or more. In some embodiments, an isotopic purity is about 50% or more. In some embodiments, an isotopic purity is about 60% or more. In some embodiments, an isotopic purity is about 70% or more. In some embodiments, an isotopic purity is about 80% or more. In some embodiments, an isotopic purity is about 90% or more. For example, in some embodiments, R^d is -NHCDj, and a compound or composition has an isotopic purity for each D independently as described herein. In some embodiments, L¹ is -CD2-, and a compound or composition has an isotopic purity for each D independently as described herein.

[00318] In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, m is 1 and n is 1. In some embodiments, t is 0. In some embodiments, t is 1. In some embodiments, t is 2. In some embodiments, t is 3. In some embodiments, t is 4. In some embodiments, a provided compound has the structure of:

or a pharmaceutically acceptable salt thereof, wherein each variable is independently as described herein. In some embodiments, a provided compound has the structure of:

or a pharmaceutically acceptable salt thereof, wherein each variable is independently as described herein. In some embodiments, a provided compound has the structure of:

or a pharmaceutically acceptable salt thereof, wherein each variable is independently as described herein. In some embodiments, a provided compound has the structure of:

or a pharmaceutically acceptable salt thereof, wherein each variable is independently as described herein. In some embodiments, a provided compound has the structure of:

or a pharmaceutically acceptable salt thereof, wherein each variable is independently as described herein. In some embodiments, R⁶ and R⁶ are taken together with their intervening atoms to form a ring as described herein. In some embodiments, a provided compound has the structure of:

or a pharmaceutically acceptable salt thereof, wherein each variable is independently as described herein. [00319] In some embodiments, a compound is selected from Table C-l below, or a pharmaceutically acceptable salt thereof. In some embodiments, a composition comprises or delivers a compound selected from C-l below, or a pharmaceutically acceptable salt thereof. In some embodiments, a compound is selected from Table E-l, or a pharmaceutically acceptable salt thereof. In some embodiments, a composition comprises or delivers a compound selected from E-l, or a pharmaceutically acceptable salt thereof. In some embodiments, a compound is selected from Table E-lb, or a pharmaceutically acceptable salt thereof. In some embodiments, a composition comprises or delivers a compound selected from E-lb, or a pharmaceutically acceptable salt thereof. In some embodiments, a compound is selected from Table E-lc, or a pharmaceutically acceptable salt thereof. In some embodiments, a composition comprises or delivers a compound selected from E-lc, or a pharmaceutically acceptable salt thereof. In some embodiments, a compound is selected from Table E-ld, or a pharmaceutically acceptable salt thereof. In some embodiments, a composition comprises or delivers a compound selected from E-ld, or a pharmaceutically acceptable salt thereof. In some embodiments, a compound is selected from Table E-2, or a pharmaceutically acceptable salt thereof. In some embodiments, a composition comprises or delivers a compound selected from E-2, or a pharmaceutically acceptable salt thereof.

Table C-l. Certain compounds.

[00320] In some embodiments, compounds of the present disclosure comprise one or more chiral elements, e.g., chiral centers. In some embodiments, compounds are utilized as a mixture of two or more stereoisomers. In some embodiments, compounds are utilized as a mixture of enantiomers. In some embodiments, certain stereoisomer(s) may provide better activities, properties (e.g., lower toxicities), etc. compared to others. In some embodiments, an enantiomer may provide better activities, properties (e.g., lower toxicities), etc. than the other. In some embodiments, single stereoisomers are utilized. In some embodiments, a single enantiomer is utilized. In some embodiments, a provide compound is of the .S' configuration at a chiral center. In some embodiments, a provide compound is of the R configuration at a chiral center. In some embodiments, a provide compound is of the .S’ configuration the carbon atom of Ring B to which Ring C is attached. In some embodiments, a provide compound is of the R configuration the carbon atom of Ring B to which Ring C is attached. In some embodiments, an occurrence of R^b is trans relative to Ring C. In some embodiments, an occurrence of R^b is cis relative to Ring C. In some embodiments, a stereoisomer is more active than another. In some embodiments, a diastereomer is more active than another. In some embodiments, an enantiomer is more active than another.

[00321] In some embodiments, compounds of the present disclosure can provide superior permeability, PK, etc. compared to a reference compound. For example, in some embodiments, various compounds has better permeability, e.g., higher apparent permeability coefficient, lower efflux ration, etc. Certain technologies for assessing permeability properties are described in the Examples. Those skilled in the art appreciate that other technologies may be utilized in accordance with the present disclosure. In some embodiments, apparent permeability coefficient of a compound is about or at least about 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25 or more. In some embodiments, apparent permeability coefficient of a compound is about 4 or greater. In some embodiments, apparent permeability coefficient of a compound is about 5 or greater. In some embodiments, apparent permeability coefficient of a compound is about 10 or greater. In some embodiments, apparent permeability coefficient of a compound is about 15 or greater. In some embodiments, apparent permeability coefficient of a compound is about 20 or greater. In some embodiments, apparent permeability coefficient of a compound is about 25 or greater. In some embodiments, efflux ratio of a compound is about or no more than about 3, 2.9, 2.8, 2.7, 2.6, 2.5, 2.4, 2.3, 2.2, 2.1, 2, 1.9, 1.8, 1.7, 1.6, 1.5, 1.4, 1.3, 1.2, 1.1 or 1.0. In some embodiments, it is about or less than about 2.5. In some embodiments, it is about or less than about 2. In some embodiments, it is about or less than about 1.5. In some embodiments, it is about or less than about 1.2. In some embodiments, it is about or less than about 1.1. In some embodiments, it is about or less than about 1. In some embodiments, a reference compound has each of R^d and R^e being -H. In some embodiments, a reference compound is otherwise identical but has each of R^d and R^e being -H.

[00322] For example, as demonstrated herein, compounds comprising secondary amino groups (e.g., R^d or R^e) can provide better apparent permeability coefficients and/or efflux ratios compared to reference compounds (e.g., compounds with certain primary or tertiary amino groups instead of secondary amino groups, compounds with R^d and R^e being groups other than amino groups, etc.).

[00323] In some embodiments, a compound has a purity of about 95%-100% (e.g., about 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or more, or about 96%-100%, 97%-100%, 98%-100%, 99%-100%, 95-99%, 95%- 99.5%, 95%-99.9%, etc.), hr some embodiments, a compound has a diastereomeric purity of about 95%- 100% (e.g., about 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or more, or about 96%-100%, 97%-100%, 98%-100%, 99%-100%, 95-99%, 95%-99.5%, 95%-99.9%, etc.). In some embodiments, a compound has an enantiomeric purity of about 95%-100% (e.g., about 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or more, or about 96%-100%, 97%-100%, 98%-100%, 99%-100%, 95-99%, 95%-99.5%, 95%-99.9%, etc.). In some embodiments, a percentage is weight percentage. In some embodiments, a percentage is about or at least about 95%. In some embodiments, a percentage is about or at least about 96%. In some embodiments, a percentage is about or at least about 97%. In some embodiments, a percentage is about or at least about 98%. In some embodiments, a percentage is about or at least about 99%. In some embodiments, a percentage is about or at least about 99.5%. In some embodiments, a percentage is about or at least about 99.9%. In some embodiments, a percentage is about 100%. III. Compositions and Administration

[00324] In some embodiments, compounds are administered as pharmaceutical compositions. In some embodiments, the present disclosure provides a pharmaceutical composition comprising a provided compound, e.g., a compound of formula I or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. In some embodiments, a composition, e.g. a pharmaceutical composition, delivers a provided compound, e.g., a compound of formula I or a pharmaceutically acceptable salt thereof. In some embodiments, agents, e.g., compounds of formula I or pharmaceutically acceptable salts thereof and compositions are useful for treating various conditions, disorders or diseases, e.g., complement- mediated conditions, disorders or diseases, C3 convertase-mediated conditions, disorders or diseases, etc. In some embodiments, a salt is a pharmaceutically acceptable salt.

[00325] Various technologies, e.g., routes, modes, dosage regimens, etc. may be utilized to administer and/or deliver provided compounds and compositions in accordance with the present disclosure. In some embodiments, a route and/or mode of administration can vary depending upon desired result(s). One with skill in the art, i.e., a physician, is aware that dosage regimens can be adjusted to provide a desired response, e.g., a therapeutic response. Methods of administration include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, oral, sublingual, intracerebral, intrathecal, intravaginal, transdermal, rectal, by inhalation, or topical, particularly to the ears, nose, eyes, or skin. In some embodiments, a mode of administration is left to the discretion of a practitioner.

[00326] In some embodiments, compounds can be incorporated into pharmaceutical compositions. Such pharmaceutical compositions are useful for, among other things, administration and delivery to a subject in vivo or ex vivo. In some embodiments, pharmaceutical compositions also contain a pharmaceutically acceptable earner or excipient. Such carriers or excipients include any pharmaceutical agent, e.g., a pharmaceutical agent that does not itself induce an immune response harmful to the individual receiving a composition, and which may be administered without undue toxicity. Pharmaceutically acceptable carriers or excipients include, but are not limited to, liquids such as water, saline, glycerol, sugars and ethanol. Pharmaceutically acceptable salts can also be included therein, for example, mineral acid salts such as hydrochlorides, hydrobromides, phosphates, sulfates, and the like; and the salts of organic acids such as acetates, propionates, malonates, benzoates, and the like. Additionally, auxiliary substances, such as wetting or emulsifying agents, pH buffering substances, and the like, may be present in such vehicles.

[00327] Compounds in pharmaceutical compositions may be provided as pharmaceutically acceptable salts. In some embodiments, salts can be formed with many acids, including but not limited to, hydrochloric, sulfuric, acetic, lactic, tartaric, malic, succinic, benzenesulfonic, etc. In some embodiments, salts can be formed with bases. In some embodiments, salts are alkali, alkaline earth metal, or ammonium salts, e.g., sodium, calcium, trialkylamine salts, etc.

[00328] In some embodiments, salts are more soluble in aqueous or other protonic solvents than corresponding, free acid or base forms. In some embodiments, a pharmaceutical composition may be a lyophilized powder. In some embodiments, a pharmaceutical composition comprises a provided compound, e.g., a compound of formula T or a pharmaceutically acceptable salt thereof dissolved in a pharmaceutically acceptable buffer. In some embodiments, a buffer is a saline buffer. In some embodiments, a buffer has a pH around 7.4.

[00329] Pharmaceutical compositions can include solvents (aqueous or non-aqueous), solutions (aqueous or non-aqueous), emulsions (e.g., oil-in-water or water-in-oil), suspensions, syrups, elixirs, dispersion and suspension media, coatings, isotonic and absorption promoting or delaying agents, compatible with pharmaceutical administration or in vivo contact or delivery. Aqueous and non-aqueous solvents, solutions and suspensions may include suspending agents and thickening agents. Such pharmaceutically acceptable carriers include tablets (coated or uncoated), capsules (hard or soft), microbeads, powder, gr anules and crystals. Supplementary active compounds (e.g., preservatives, antibacterial, antiviral and antifungal agents) can also be incorporated into the compositions.

[00330] Pharmaceutical compositions can be formulated to be compatible with a particular route of administration or delivery, as set forth herein or known to one of skill in the art. In some embodiments, pharmaceutical compositions comprise carriers, diluents, or excipients suitable for administration by various routes.

[00331] In some embodiments, provided compositions are suitable for parenteral administration. In some embodiments, such compositions comprise aqueous and non-aqueous solutions, suspensions or emulsions of active compounds, which preparations are typically sterile and can be isotonic with blood of intended recipients. Non-limiting illustrative examples include water, buffered saline, Hanks' solution, Ringer's solution, dextrose, fructose, ethanol, animal, vegetable or synthetic oils. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxy methyl cellulose, sorbitol, or dextran. Additionally, suspensions of active compounds may be prepared as appropriate oil injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Optionally, a suspension may also contain suitable stabilizers or agents which increase solubility to allow for the preparation of highly concentrated solutions.

[00332] Cosolvents and adjuvants may be added to compositions and formulations. Non-limiting examples of cosolvents contain hydroxyl groups or other polar groups, for example, alcohols, such as isopropyl alcohol; glycols, such as propylene glycol, polyethyleneglycol, polypropylene glycol, glycol ether; glycerol; polyoxyethylene alcohols and polyoxyethylene fatty acid esters. Adjuvants include, for example, surfactants such as, soya lecithin and oleic acid; sorbitan esters such as sorbitan trioleate; and polyvinylpyrrolidone .

[00333] After pharmaceutical compositions have been prepared, they may be placed in an appropriate container and labeled for treatment. Such labeling can include amount, frequency, and method of administration. [00334] Various pharmaceutical compositions and delivery systems appropriate for compositions, methods and uses of the present disclosure are known in the art (see, e.g., Remington: The Science and Practice of Pharmacy. 21st Edition. Philadelphia, PA. Lippincott Williams & Wilkins, 2005) and can be utilized in accordance with the present disclosure.

[00335] In some embodiments, the present disclosure provides methods for introducing provided compounds and compositions into cells, animals or subjects. In some embodiments, such methods include contacting a subject (e.g., a cell or tissue of a subject) with, or administering to a subject (e.g., a subject such as a mammal or human) a provided compound, e.g., a compound of formula I or a salt thereof, or a composition thereof.

[00336] A compound or composition described herein can be administered in a sufficient or effective amount to a subject (or a cell, tissue or organ thereof) in need thereof. Doses can vary and may depend upon the type, onset, progression, severity, frequency, duration, or probability of a condition, disorder or disease to which treatment is directed, a clinical endpoint desired, previous or simultaneous treatments, general health, age, gender, race or immunological competency of a subject and other factors that will be appreciated by a skilled artisan. Dose amount, number, frequency or duration may be proportionally increased or reduced, as indicated by efficacy, any adverse side effects, complications or other risk factors of a treatment or therapy and the status of a subject. A skilled artisan will appreciate factors that may influence dosage and timing required to provide an amount sufficient for providing a therapeutic or prophylactic benefit.

[00337] A dose to achieve a therapeutic effect will vary based on several factors including, but not limited to: route of administration, amount to achieve a therapeutic effect, the specific condition, disorder or disease treated, any host immune response to administered compound or composition, or stability of administered compound or composition.

[00338] An effective amount or a sufficient amount can (but need not) be provided in a single administration, may require multiple administrations, and, can (but need not) be, administered alone or in combination with another composition (e.g., comprising or delivering another therapeutic agent). For example, an amount may be proportionally increased as indicated by the need of a subject, type, status and severity of a condition, disorder or disease treated and/or side effects (if any) of treatment. Amounts considered effective also include amounts that result in a reduction of the use of another treatment, therapeutic regimen or protocol, such as administration of another complement inhibitor described herein. [00339] In some embodiments, pharmaceutical compositions comprise or deliver active ingredients, e.g., compounds of formula I or pharmaceutically acceptable salts thereof, in effective amounts to achieve intended purposes e.g., therapeutic purposes. Various technologies may be utilized to determine therapeutically effective amounts in accordance with the present disclosure. Therapeutic doses can depend on, among other factors, ages and general conditions of subjects, severity of conditions, disorders or diseases (e.g., complement-mediated conditions, disorders or diseases, C3 convertase-mediated conditions, disorders or diseases, etc. ), etc. Thus, therapeutically effective amounts in humans may fall in a relatively broad range that may be determined by medical practitioners based on responses of individual patients.

[00340] In some embodiments, methods and uses of the present disclosure include delivery and administration systemically, regionally or locally, or by any route, for example, by injection or infusion. In some embodiments, delivery of a pharmaceutical composition in vivo may generally be accomplished via injection using a conventional syringe, although other delivery methods such as convection-enhanced delivery can also be used (see, e.g., U.S. Pat. No. 5,720,720). In some embodiments, compounds and compositions may be delivered subcutaneously, epidermally, intradermally, intrathecally, intraorbitally, intramucosally, intraperitoneally, intravenously, intra-pleurally, intraarterially, orally, intrahepatically, via the portal vein, or intramuscularly. In some embodiments, modes of administration include oral and pulmonary administration, suppositories, and transdermal applications. Clinicians specializing in treating patients with complement-mediated conditions, disorders or diseases may determine optimal routes for administration of compounds and compositions as described herein.

[00341] In some embodiments, a compound or composition may be administered to a subject four times a day, three times a day, twice a day, once daily, every 2, 3, 4, 5, or 6 days, weekly, or every 2, 3, or 4 weeks, or even at longer intervals. In some embodiments, a compound or composition is administered to a subject once, e.g., as a single injection or as a single infusion over time (e.g., over 5, 10, 15, 20, 30, 40, 50, 60, 90, 120 minutes, or longer). In some embodiments, a compound or composition is administered to a subject twice, e.g., as two injections (e.g., 2, 4, 6, 8, 10, or 12 hours apart) or as two infusions (e.g., 2, 4, 6, 8, 10, or 12 hours apart). In some embodiments, a subject is monitored before and/or following an administration or treatment for level of C3 expression and/or activity, a complement activity, etc., e.g., as measured using an alternative pathway assay, a classical pathway assay, or both. Suitable assays are known in the art and include, e.g., a hemolysis assay and those described in the Examples.

IV. Diseases, Disorders, and Conditions

[00342] Provided technologies are useful for preventing or treating various conditions, disorders or diseases. In some embodiments, the present disclosure provides methods for preventing a condition, disorder or disease, comprising administering or a delivering to a subject susceptible thereto an effective amount of a compound, e.g., a compound of formula I or a pharmaceutically acceptable salt. In some embodiments, the present disclosure provides methods for treating a condition, disorder or disease, comprising administering to a subject suffering therefrom a therapeutically effective amount of a compound, e.g., a compound of formula I or a pharmaceutically acceptable salt. In some embodiments, the present disclosure provides a method for reducing C3 convertase activity, comprising contacting a C3 convertase with a provided compound, e.g., a compound of formula I or a pharmaceutically acceptable salt thereof, or a composition thereof. In some embodiments, the present disclosure provides a method for reducing factor B activity, comprising contacting a factor B with a provided compound, e.g., a compound of formula I or a pharmaceutically acceptable salt thereof, or a composition thereof. In some embodiments, the present disclosure provides a method for reducing complement activation in a system, comprising administering to the system a provided compound, e.g., a compound of formula T or a pharmaceutically acceptable salt thereof, or a composition thereof. In some embodiments, the present disclosure provides a method for reducing C3 convertase activity in a system, comprising administering to the system a provided compound, c.g., a compound of formula I or a pharmaceutically acceptable salt thereof, or a composition thereof. In some embodiments, the present disclosure provides a method for reducing factor B activity in a system, comprising administering to the system a provided compound, e.g., a compound of formula I or a pharmaceutically acceptable salt thereof, or a composition thereof. In some embodiments, a system is a plurality of cells, a tissue, organ or organism. In some embodiments, a system is or comprises blood. In some embodiments, a system is an animal. In some embodiments, a system is a human. In some embodiments, a subject is a human.

[00343] In some embodiments, a condition, disorder or disease is a complement-mediated condition, disorder or disease. In some embodiments, a condition, disorder or disease is a C3 convertase-mediated condition, disorder or disease. In some embodiments, a condition, disorder or disease is a factor B-mediated condition, disorder or disease. In some embodiments, a condition, disorder or disease is or comprises complement-mediated damage to an organ, tissue, or cells. In some embodiments, a compound or composition is administered in combination with another therapeutic agent, e.g., a complement inhibitor. [00344] In some embodiments, a condition, disorder or disease is described in WO 2015/009616, US 9682968, US 10093663, WO 2018/005552, WO 2019/043609, WO 2020/016749, WO 2022/028507, WO 2022/028527, WO 2022/143845, WO 2022/218429, WO 2022/234541, WO 2022/256586, WO 2023/020566, WO 2023/037218, WO 2023/072197, WO 2023/139534, or WO 2023/143293.

Blood-related disorders

[00345] In some embodiments, a compound is administered to a subject suffering from, or at risk of, a complement-mediated blood-related disorder, such as paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (aHUS), autoimmune hemolytic anemia, chronic cold agglutinin disease, HELLP syndrome, and/or warm autoimmune hemolytic anemia. In some embodiments, a compound is administered to a subject suffering from, or at risk of, a complement-mediated disorder that affects the circulatory system. For example, in some embodiments, the disorder is thrombotic microangiopathy (TMA) or a vasculitis (e.g., IgA vasculitis) or other disorder associated with vessel inflammation, e.g., blood vessel and/or lymph vessel inflammation. In some embodiments, a vasculitis is polyarteritis nodosa, hypocomplementemic urticarial vasculitis, pulmonary vasculitis, Wegener’s granulomatosis, giant cell arteritis, Churg-Strauss syndrome, microscopic polyangiitis, pauci-immune vasculitis, Henoch-Schonlein purpura, Takayasu’s arteritis, Kawasaki disease, or Behcet’s disease. In some embodiments, a disorder is TMA secondary to atypical hemolytic uremic syndrome. In some embodiments, a subject is positive for antineutrophil cytoplasmic antibody (ANCA). Eye Disorders

[00346] In some embodiments, a compound is administered to a subject for treatment of a complement- mediated eye disorder, such as macular degeneration (e.g., age-related macular degeneration (AMD) and Stargardt macular dystrophy), diabetic retinopathy, glaucoma, or uveitis (e.g., posterior uveitis or anterior uveitis). In some embodiments, a subject suffers from or is at risk of AMD. In some embodiments the AMD is neovascular (wet) AMD. In some embodiments the AMD is dry AMD. As will be appreciated by those of ordinary skill in the art, dry AMD encompasses geographic atrophy (GA), intermediate AMD, and early AMD. In some embodiments, a subject with GA is treated in order to slow or halt progression of the disease. For example, in some embodiments, treatment of a subject with GA reduces the rate of retinal cell death. A reduction in the rate of retinal cell death may be evidenced by a reduction in the rate of GA lesion growth in patients treated with a compound, as compared with control (e.g., patients given a sham administration). In some embodiments, a subject has intermediate AMD. In some embodiments, a subject has early AMD. In some embodiments, a subject with intermediate or early AMD is treated in order to slow or halt progression of the disease. For example, in some embodiments, treatment of a subject with intermediate AMD may slow or prevent progression to an advanced form of AMD (neovascular AMD or GA). In some embodiments, treatment of a subject with early AMD may slow or prevent progression to intermediate AMD. In some embodiments an eye has both GA and neovascular AMD. In some embodiments an eye has GA but not wet AMD.

[00347] In some embodiments, a subject has an eye disorder characterized by macular degeneration, choroidal neovascularization (CNV), retinal neovascularization (RNV), ocular inflammation, or any combination of the foregoing. Macular degeneration, CNV, RNV, and/or ocular inflammation may be a defining and/or diagnostic feature of the disorder. Exemplary disorders that are characterized by one or more of these features include, but are not limited to, macular degeneration related conditions, diabetic retinopathy, retinopathy of prematurity, proliferative vitreoretinopathy, uveitis, keratitis, conjunctivitis, and scleritis. In some embodiments, a subject is in need of treatment for ocular inflammation. Ocular inflammation can affect a large number of eye structures such as the conjunctiva (conjunctivitis), cornea (keratitis), episclera, sclera (scleritis), uveal tract, retina, vasculature, and/or optic nerve. Evidence of ocular inflammation can include the presence of inflammation-associated cells such as white blood cells (e.g., neutrophils, macrophages) in the eye, the presence of endogenous inflammatory mediator(s), one or more symptoms such as eye pain, redness, light sensitivity, blurred vision and floaters, etc. Uveitis is a general term that refers to inflammation in the uvea of the eye, e.g., in any of the structures of the uvea, including the iris, ciliary body or choroid. Specific types of uveitis include iritis, iridocyclitis, cyclitis, pars planitis and choroiditis. In some embodiments, the eye disorder is Behcet’s disease. In some embodiments, the eye disorder is an eye disorder characterized by optic nerve damage (e.g., optic nerve degeneration), such as glaucoma. Additional eye disorders include, e.g., retinitis pigmentosa, macular edema, Vogt-Koyangi-Harada syndrome, birdshot retino-chorioditis, sympathetic ophthalmia, ocular dicatricial pemphigoid, ocular pemphigus, nonartertic ischemic optic neuropathy, post-operative inflammation, and retinal vein occlusion.

Nervous System Disorders

[00348] In some embodiments, a compound is used to treat a subject suffering from or at risk of a complement-mediated disorder that affects the nervous system, e.g., the central nervous system (CNS) and/or peripheral nervous system (PNS). Examples of such disorders include, e.g., a neurodegenerative disorder such as multiple sclerosis, other demyelinating diseases (e.g., neuromyelits optica or chronic inflammatory demyelinating polyneuropathy (CIDP)), amyotrophic lateral sclerosis, chronic pain, fibromyalgia, stroke, intracerebral hemorrhage, allergic neuritis, diabetic neuropathy, Huntington’s disease, schizophrenia, Alzheimer’s disease, Parkinson’s disease, progressive supranuclear palsy, Lewy body dementia (i.e., dementia with Lewy bodies or Parkinson’s disease dementia), frontotemporal dementia, progressive supranuclear palsy, corticobasal syndrome, Pick’ s disease, mild cognitive impairment, traumatic brain injury, traumatic spinal cord injury, multisystem atrophy, chronic traumatic encephalopathy, Creutzfeldt-Jakob disease, Guillain Barre Syndrome, and leptomeningeal metastasis. In some embodiments, a subject suffers from neuropathic pain, e.g., arising from lesions that involve the somatosensory pathways with damage to small fibres in peripheral nerves and/or to the spino-thalamocortical system in the CNS.

Kidney Disorders

[00349] In some embodiments, a compound is used to treat a subject suffering from, or at risk of. a complement-mediated kidney disorder. Such disorders include, e.g., nephritis, e.g., glomerulonephritis, e.g., membranoproliferative glomerulonephritis (MPGN) (e.g., MPGN type I, MPGN type II, or MPGN type III), e.g., immune complex membranoproliferative glomerulonephritis (IC-MPGN). In some embodiments the disorder is IgA nephropathy (IgAN), primary membranous nephropathy, or diabetic nephropathy. In some embodiments, the disorder is polycystic kidney disease (PKD). In some embodiments, the disorder is C3 glomerulopathy. In some embodiments the disorder is characterized by glomerular deposits containing one or more complement activation products, e.g., C3b, in the kidney. In some embodiments treatment as described herein reduces the level of such deposits. In some embodiments a subject suffering from a complement- mediated kidney disorder suffers from proteinuria (an abnormally high level of protein in the urine) and/or an abnormally low glomerular filtration rate (GFR). In some embodiments treatment as described herein results in decreased proteinuria and/or an increased or stabilized GFR.

Respiratory Disorders

[00350] In some embodiments, a compound is used to treat a subject suffering from or at risk of a complement-mediated disorder respiratory disorder. In some embodiments, a subject is suffering from or at risk of acute respiratory distress syndrome. In some embodiments, a respiratory disease is, e.g., asthma (e.g., allergic asthma), emphysema, chronic inflammation, chronic obstructive pulmonary disease (COPD), pulmonary fibrosis (e.g., idiopathic pulmonary fibrosis), radiation-induced lung injury, allergic bronchopulmonary aspergillosis, hypersensitivity pneumonitis (also known as allergic alveolitis), eosinophilic pneumonia, interstitial pneumonia, sarcoid, Wegener’s granulomatosis, pulmonary embolisms and infarcts, dyspnea, hemoptysis, bronchoconstriction, or bronchiolitis obliterans.

Musculoskeletal Disorders

[00351] In some embodiments, a compound is used to treat a subject suffering from, or at risk of, a complement-mediated disorder that affects the musculoskeletal system. Examples of such disorders include inflammatory joint conditions (e.g., arthritis such as rheumatoid arthritis or psoriatic arthritis, juvenile chronic arthritis, spondyloarthropathies Reiter’s syndrome, gout). In some embodiments, a musculoskeletal system disorder results in symptoms such as pain, stiffness and/or limitation of motion of the affected body part(s). Inflammatory myopathies include dermatomyositis, polymyositis, and various others are disorders of chronic muscle inflammation of unknown etiology that result in muscle weakness. In some embodiments, a complement-mediated musculoskeletal disorder is myasthenia gravis.

Transplantation

[00352] In some embodiments, a compound is used to protect a graft from complement-mediated damage. A graft can be contacted with a compound prior to, during, and/or after being transplanted, in various embodiments of the disclosure. In another embodiment, a compound is administered to a donor prior to removal of the graft. In some embodiments, a compound is administered to a recipient during and/or after the introduction of the graft. In some embodiments, a compound is administered to a recipient prior to the introduction of the graft. In some embodiments, a subject receives a compound after receiving the graft.

[00353] In some embodiments, a graft is or comprises a solid organ such as a kidney, liver, lung, pancreas, or heart. In some embodiments, a graft is or comprises bone, cartilage, fascia, tendon, ligament, cornea, sclera, pericardium, skin, heart valve, blood vessel, amniotic membrane, or dura mater. In some embodiments, a graft comprises multiple organs such as a heart-lung or pancreas-kidney graft. In some embodiments, a graft comprises less than a complete organ or tissue. For example, a graft may contain a portion of an organ or tissue, e.g., a liver lobe, section of blood vessel, skin flap, or heart valve. In some embodiments, a graft comprises a preparation comprising isolated cells or tissue fragments that have been isolated from their tissue of origin but retain at least some tissue architecture, e.g., pancreatic islets. In some embodiments, a preparation comprises isolated cells that are not attached to each other via connective tissue, e.g., hematopoietic stem cells or progenitor cells derived from peripheral and/or cord blood, or whole blood or any cell-containing blood product such as red blood cells (RBCs) or platelets.

[00354] In some embodiments, a graft is a xenograft (i.e., the donor and recipient are of different species), an autograft (i.e., a graft from one part of the body to another part of the body in the same individual), an isograft (i.e., the donor and recipient are genetically identical), or an allograft (i.e., the donor and recipient are genetically non-identical members of the same species).

Ischemia/Reperfusion Injury

[00355] Ischcmia-rcpcrfusion (I/R) injury is an important cause of tissue damage following trauma and in other conditions associated with temporary disruption of blood flow such as myocardial infarction, stroke, severe infection, vascular disease, aneurysm repair, cardiopulmonary bypass, and transplantation. In the setting of trauma, systemic hypoxemia, hypotension, and local interruption of the blood supply resulting from contusions, compartment syndrome, and vascular injuries cause ischemia that damages metabolically active tissues. Restoration of the blood supply triggers an intense systemic inflammatory reaction. After reperfusion, all three major complement pathways are activated and, acting cooperatively or independently, are involved in I/R related adverse events affecting numerous organ systems.

[00356] In some embodiments a compound is administered to a subject who has recently (e.g., within the preceding 2, 4, 8, 12, 24, or 48 hours) experienced trauma, e.g., trauma that puts the subject at risk of I/R injury, e.g., due to systemic hypoxemia, hypotension, and/or local interruption of the blood supply. In some embodiments, a compound may be administered intravascularly, optionally into a blood vessel that supplies an injured body part or directly to the body part. In some embodiments, the subject suffers from spinal cord injury, traumatic brain injury, burn, and/or hemorrhagic shock.

[00357] In some embodiments, a compound is administered to a subject prior to, during, or after a surgical procedure, e.g., a surgical procedure that is expected to temporarily disrupt blood flow to a tissue, organ, or portion of the body. Examples of such procedures include cardiopulmonary bypass, angioplasty, heart valve repair/replacement, aneurysm repair, or other vascular surgeries. A compound may be administered prior to, after, and/or during an overlapping time period with the surgical procedure.

[00358] In some embodiments, a compound is administered to a subject who has suffered an MI, thromboembolic stroke, deep vein thrombosis, or pulmonary embolism. A compound may be administered in combination with a thrombolytic agent such as tissue plasminogen activator (tPA) (e.g., alteplase (Activase), reteplase (Retavase), tenecteplase (TNKase)), anistreplase (Eminase), streptokinase (Kabikinase, Streptase), or urokinase (Abbokinase). In some embodiments, a compound may be administered prior to, after, and/or during an overlapping time period with the thrombolytic agent.

Other Disorders

[00359] In some embodiments, a compound is used to treat a subject suffering from, or at risk of, a complement-mediated disorder that affects the integumentary system. Examples of such disorders include, e.g., atopic dermatitis, psoriasis, pemphigoid, pemphigus, systemic lupus erythematosus, dermatomyositis, scleroderma, sclerodermatomyositis, Sjogren syndrome, and chronic urticaria.

[00360] In some embodiments, a compound is used to treat a subject suffering from, or at risk of, a complement-mediated disorder that affects the gastrointestinal system, e.g., inflammatory bowel disease, e.g., Crohn’s disease or ulcerative colitis.

[00361 ] In some embodiments, a compound is used to treat a subject suffering from, or at risk of, a complement-mediated inflammatory disorder, such as rhinosinusitis or myocarditis.

[00362] In some embodiments, a compound is used to treat a subject suffering from, or at risk of, thyroiditis (e.g., Hashimoto's thyroiditis, Graves’ disease, post-partum thyroiditis), hepatitis (e.g., hepatitis C), pancreatitis, panniculitis, or MYH9-related disorders.

[00363] In some embodiments, a compound is used to treat interleukin-2 induced toxicity during IL-2 therapy, myocardial infarction, post-pump syndrome in cardiopulmonary bypass or renal bypass, atherosclerosis, hemodialysis, renal ischemia, mesenteric artery reperfusion after aortic reconstruction, infectious disease or sepsis, immune complex disorders and autoimmune diseases, liver fibrosis, fibrogenic dust diseases, nasal polyposis, parasitic diseases, Goodpasture’s Syndrome, immune complex-associated inflammation, antiphospholipid syndrome, cancer, periodontitis, gingivitis, or obesity.

[00364] In some embodiments, a complement-mediated condition, disorder or disease is complement activation secondary to administration of another therapeutic or diagnostic agent. For example, in some embodiments, a complement-mediated condition, disorder or disease is complement activation secondary to gene therapy (e.g., gene therapy with a viral vector such as an adeno-associated virus (AAV), adenovirus, or lentivirus vector) or complement activation secondary to cell therapy). In some embodiments, a subject suffers from TMA secondary to hematopoietic stem cell transplant (HSCT-TMA). In some embodiments, a subject suffers from drug-induced TMA. In some embodiments, administration of a compound described herein prior to and/or following administration of another therapeutic agent may increase efficacy and/or safety of said therapeutic agent.

V. Manufacturing

[00365] Various technologies, e.g., synthetic chemistry technologies, formulation technologies, assays, etc. can be utilized to prepare, characterization, and assess compounds, compositions and methods described herein in accordance with the present disclosure. Certain technologies are described below and in the Examples. Certain useful technologies are described in WO 2015/009616, US 9682968, US 10093663, WO 2018/005552, WO 2019/043609, WO 2020/016749, WO 2022/028507, WO 2022/028527, WO 2022/143845, WO 2022/218429, WO 2022/234541, WO 2022/256586, WO 2023/020566, WO 2023/037218, WO 2023/072197, WO 2023/139534, and WO 2023/143293, and can be utilized in accordance with the present disclosure.

[00366] In some embodiments, the present disclosure provides technologies for manufacturing compounds and compositions described herein, comprising incorporating R^d, R^c, and/or Ring C as described herein. In some embodiments, a provided technology comprises incorporation of R^d as described herein. In some embodiments, a provided technology comprises incorporation of R^e as described herein. In some embodiments, a provided technology comprises incorporation of Ring C as described herein. [00367] In various embodiments, reactions are performed in solvent systems, e.g., those exemplified in the samples. In some embodiments, a solvent system is or comprises a polar solvent. In some embodiments, a solvent system is or comprises a non-polar solvent. In some embodiments, a solvent system is or comprises a hydrocarbon solvent. In some embodiments, a solvent system is or comprises a protic solvent. In some embodiments, a solvent system is or comprises water. In some embodiments, a solvent system is anhydrous. In some embodiments, a solvent system is or comprises an alcohol.

[00368] In some embodiments, certain reactions may be performed at room temperature. In some embodiments, certain reactions are performed at about 23 °C. In some embodiments, certain reactions are performed at lowered temperatures, e.g., 0 °C, -10 °C, -20 °C, etc. In some embodiments, certain reactions are performed at increased temperatures, e.g., about 30-200, 40-150, or about 30, 40, 50, 60, 70, 80, 90, 100, 110, or 150 °C. In some embodiments, temperatures may change during reactions, e.g., increasing from a lowered temperature, decreasing from an increased temperature, or combinations thereof. In some embodiments, certain reactions may be performed at increased or decreased pressure.

[00369] Many technologies are available for isolating, purifying or characterizing chemical compounds and can be utilized in accordance with the present disclosure. For example, in some embodiments, one or more of extraction, filtration, crystallization, and distillation are utilized to isolate desired products and/or remove undesired byproducts or impurities. In some embodiments, chromatography, e.g., column chromatography, GC, HPLC, SFC, etc. is utilized for separation and/or characterization.

[00370] In some embodiments, compounds comprise chiral elements, e.g., carbon chiral centers and two or more stereoisomers (e.g., enantiomers, diastereomers, etc.) may be formed. In some embodiments, stereoselective technologies are utilized so desired stereoisomers are formed. In some embodiments, separation technologies, e.g., crystallization in an asymmetric environment (e.g., with a chirally pure reagent), chiral chromatography, etc., are utilized to isolated, purify or characterize stereoisomers. In some embodiments, a stereoisomer is an enantiomer. In some embodiments, a provided compound is enriched for a particular stereoisomer. In some embodiments, a provided compound is enriched for a particular diastereomer. In some embodiments, a provided compound is enriched for a particular enantiomer. In some embodiments, an enrichment level is a stereopurity, e.g., a diastereomeric purity, an enantiomeric purity, etc. as described herein. In some embodiments, an enrichment level is about 80%-100% (e.g., about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or more, or about 85%-100%, 90%- 100%, 9I%-I00%, 92%-100%, 93%-100%, 94%-100%, 95%-100%, 96%-100%, 97%-100%, 98%-100%, 99%-100%, 95-99%, 95%-99.5%, 95%-99.9%, etc.) as described herein.

[00371] Those skilled in the ait appreciate that in addition to the compounds specified in provided methods, other reagents and/or conditions may be utilized in accordance with the present disclosure. For example, in some de-protecting reactions, an acid or base may be utilized. In some embodiments, in oxidation reactions, oxidation reagents are utilized. In some embodiments, in reduction reactions, reduction reagents are utilized. Many suitable reagents and conditions are reported and can be utilized in accordance with the present disclosure.

[00372] Properties and activities of provided compounds and compositions may be assessed using a variety of technologies in accordance with the present disclosure. In some embodiments, modulation of C3 convcrtasc activity is assessed. In some embodiments, inhibition of C3 convcrtasc is assessed. In some embodiments, modulation of complement activation is assessed. In some embodiments, inhibition of complement activation is assessed. Certain useful technologies are described in the Examples.

[00373] Among other things, the present disclosure provides the following Embodiments:

1. A compound, wherein the compound has the structure of formula I:

or a salt thereof, wherein:

Ring A is an optionally substituted 5-10 membered aromatic ring having 0-5 heteroatoms independently selected from nitrogen, oxygen and sulfur; each R^a is independently selected from halogen, — CN, R^al, -OR^al, and -NR^alR^a2, wherein each of R^al and R^a2 is independently R’ ; a is 0, 1, 2, 3, 4 or 5;

L¹ is optionally substituted -CH₂-;

Ring B is an optionally substituted 5-10 membered monocyclic, bicyclic or polycyclic, saturated or partially unsaturated ring having, in additional to the nitrogen atom, 0-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; each R^b is independently selected from halogen, -CN, -L^b-C(O)OR^bl , -L^b-C(O)NR^blR^b2, -L^b-R^bl, -L^b-OR^bl, -L^b-NR^blR^b2, -L^b-C(O)R^bl, -L^b-C(O)N(R^bl)S(O)₂R^b2, -L^b-S(O)₂N(R^bl)C(O)R^b2, -L^b-S(O)₂NR^blR^b2, -L^b-S(O)(NR^bl)R^b2, or -L^b-S(O)₂R^bl, wherein each of R^bl and R^b2 is independently R’, and L^b is a covalent bond or optionally substituted -CH₂-; b is 0, 1, 2, 3, 4 or 5;

Ring C is an optionally substituted 5-10 membered monocyclic, bicyclic or polycyclic, saturated or partially unsaturated or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or Ring

-L^c-BR^clR^c2, wherein each of R^cl and R^c2 is independently R' or -N(R')₂, and L^c is a covalent bond or optionally substituted -CH₂-; each R^d is independently selected from halogen, -CN, R^dl, -0R^dl, and -NR^dlR^d2, wherein each of R^dl and R^d2 is independently R’; d is 0, 1, or 2; each R^e is independently selected from halogen, — CN, R^el , -OR^el , and -NR^el R^e2, wherein each of R^el and R^e2 is independently R’ ; e is 0, 1, or 2; each R’ is independently R, -OR, -C(O)R, -C(O)OR, or -S(O)₂R; each R is independently hydrogen or an optionally substituted group selected from C1-Cio aliphatic, C1-C6 heteroaliphatic having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, 3-10 membered cycloaliphatic, 3-10 membered heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, 6-10 membered aryl, 5-10 membered heteroaryl having 1-6 heteroatoms independently selected from nitrogen, oxygen and sulfur, 6-10 membered aryl-C1-C6 aliphatic, and 5-10 membered heteroaryl having 1-6 heteroatoms-C1-C6 aliphatic wherein each heteroatom is independently selected nitrogen, oxygen and sulfur; or two R groups on the same atom are optionally and independently taken together with the atom to form an optionally substituted 3-10 membered ring having, in addition to the atom, 0-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; or two R groups on two atoms are optionally and independently taken together with their intervening atoms to form an optionally substituted 3-10 membered ring having, in addition to the intervening atoms, 0-4 heteroatoms.

2. The compound of Embodiment 1 , wherein the compound is a compound having the structure of formula I-Sl or a salt thereof.

3. The compound of Embodiment 1, wherein the compound is a compound having the structure of formula I-S2 or a salt thereof.

4. The compound of any one of the preceding Embodiments, wherein Ring B is an optionally substituted 6-10 membered monocyclic, bicyclic or polycyclic, saturated or partially unsaturated ring having, in additional to the nitrogen atom, 0-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein no monocyclic ring comprising the nitrogen atom is a saturated 5-8 membered ring having, in addition to the nitrogen atom, one nitrogen atom.

The compound of any one of the preceding Embodiments, wherein Ring A is optionally substituted 9-

10 membered aromatic ring having 1-5 hctcroatoms independently selected from nitrogen, oxygen and sulfur.

6. The compound of any one of the preceding Embodiments, wherein Ring A is optionally substituted 5-

6 membered aromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

7. The compound of any one of Embodiments 5-6, wherein at least one heteroatom is nitrogen.

8. The compound of any one of Embodiments 1-5, wherein Ring A is optionally substituted indolyl.

9. The compound of any one of Embodiments 1-5, wherein Ring A is optionally substituted H

10. The compound of any one of the preceding Embodiments, wherein a is 0.

11. The compound of any one of Embodiments 1-9, wherein a is 1, 2, 3, 4, or 5.

12. The compound of any one of the preceding Embodiments, wherein each R^a is independently not -H.

13.

wherein each of R¹, R² and R³ is independently R^a.

14. The compound of Embodiment 13, wherein R¹ is -OR.

15. The compound of Embodiment 13, wherein R¹ is -OR, wherein R is optionally substituted C1-io aliphatic.

16. The compound of Embodiment 13, wherein R¹ is -OR, wherein R is optionally substituted C1-6 alkyl.

17. The compound of Embodiment 13, wherein R¹ is -OR, wherein R is C1-6 alkyl.

18. The compound of any one of Embodiments 13-17, wherein R¹ is -OMe.

19. The compound of any one of Embodiments 13-17, wherein R¹ is -OEt.

20. The compound of any one of Embodiments 13-15, wherein R¹ is -OR, wherein R is optionally substituted -CH2-C36 cycloaliphatic.

21. The compound of any one of Embodiments 13-15, wherein R¹ is -OR, wherein R is optionally substituted -CH2-C3-6 cycloalkyl.

22. The compound of any one of Embodiments 13-15, wherein R¹ is -OR, wherein R is -CH2-cyclopropyl.

23. The compound of Embodiment 13, wherein R¹ is -R.

24. The compound of Embodiment 23, wherein R¹ is optionally substituted C1-6 aliphatic.

25. The compound of Embodiment 23, wherein R¹ is optionally substituted C1-6 alkyl. 26. The compound of Embodiment 23, wherein R¹ is optionally substituted C3-6 cycloalkyl.

27. The compound of Embodiment 23, wherein R¹ is optionally substituted C3-6 cyclopropyl.

28. The compound of any one of Embodiments 13-27, wherein R² is R.

29. The compound of Embodiment 28, wherein R² is optionally substituted C1-6 aliphatic.

30. The compound of Embodiment 28, wherein R² is optionally substituted C1-6 alkyl.

31. The compound of Embodiment 28, wherein R² is methyl.

32. The compound of any one of Embodiments 13-31, wherein R ’ is R.

33. The compound of Embodiment 32, wherein R³ is -H.

34. The compound of any one of the preceding Embodiments, wherein L¹ is -CH2-.

35. The compound of any one of Embodiments 1-33, wherein L¹ is substituted -CH2-.

36. The compound of any one of the preceding Embodiments, wherein L^b is a covalent bond.

37. The compound of any one of Embodiments 1-35, wherein L^b is optionally substituted -CH2-.

38. The compound of any one of the preceding Embodiments, wherein Ring B is 5 -membered.

39. The compound of any one of Embodiments 1-37, wherein Ring B is 6-membered.

40. The compound of any one of Embodiments 1-37, wherein Ring B is 7-membered.

41. The compound of any one of Embodiments 1-37, wherein Ring B is 8-membered.

42. The compound of any one of Embodiments 1-37, wherein Ring B is 9-membered.

43. The compound of any one of Embodiments 1-37, wherein Ring B is 10-membered.

44. The compound of any one of the preceding Embodiments, wherein Ring B is monocyclic.

45. The compound of any one of Embodiments 1-43, wherein Ring B is bicyclic.

46. The compound of any one of the preceding Embodiments, wherein Ring B is saturated.

47. The compound of any one of Embodiments 1-45, wherein Ring B is partially unsaturated.

48. The compound of any one of the preceding Embodiments, wherein Ring B has no heteroatoms in addition to the nitrogen atom.

49. The compound of any one of Embodiments 1-47, wherein Ring B has 1-4 heteroatoms in addition to the nitrogen atom independently selected from nitrogen, oxygen and sulfur.

50. The compound of any one of Embodiments 1-37, wherein Ring B is an optionally substituted 5-7 membered monocyclic saturated or partially unsaturated ring having 0 heteroatoms in addition to the nitrogen atom.

51. The compound of any one of Embodiments 1-37, wherein Ring B is an optionally substituted 5-7 membered monocyclic saturated ring having 0 heteroatoms in addition to the nitrogen atom.

52. The compound of any one of Embodiments 1-37, wherein Ring B is optionally substituted

53. The compound of any one of Embodiments 1-37, wherein Ring B is optionally substituted

54. The compound of any one of Embodiments 1-37, wherein Ring B is optionally substituted

55. The compound of any one of Embodiments 1-37, wherein Ring B is optionally substituted

56. The compound of any one of Embodiments 1-37, wherein Ring B is optionally substituted

57. The compound of any one of Embodiments 1-37, wherein Ring B is optionally substituted

58. The compound of any one of Embodiments 1-37, wherein Ring B is optionally substituted

59. The compound of any one of Embodiments 1-37, wherein Ring B is optionally substituted

60. The compound of any one of Embodiments 1-37, wherein Ring B is optionally substituted

61. The compound of any one of the preceding Embodiments, wherein b is 1, 2, 3, 4, or 5.

62. The compound of any one of Embodiments 1-37, wherein

wherein t is 0, 1, 2, 3, or 4, and each of m and n is independently 1 or 2. The compound of any one of Embodiments 1-37, wherein

wherein t is 0, 1, 2, 3, or 4, and each of m and n is independently 1 or 2.

64. The compound of any one of Embodiments 1-37, wherein

s , and each of m and n is independently 1 or 2.

65. The compound of any one of Embodiments 1-37, wherein

of m and n is independently 1 or 2.

66. The compound of any one of Embodiments 1-37, wherein

67. The compound of any one of Embodiments 1-37, wherein

and each of m and n is independently 1 or 2.

68. The compound of any one of Embodiments 1-37, wherein

69. The compound of any one of Embodiments 1-68, wherein an occurrence of R^b is R.

70. The compound of any one of Embodiments 1-68, wherein an occurrence of R^b is optionally substituted C1-6 aliphatic.

71. The compound of any one of Embodiments 1-68, wherein an occurrence of R^b is optionally substituted C1-6 alkyl.

72. The compound of any one of Embodiments 1-68, wherein an occurrence of R^b is C1-6 alkyl.

73. The compound of any one of Embodiments 1-68, wherein an occurrence of R^b is C1-6 haloalkyl.

74. The compound of any one of Embodiments 1-68, wherein an occurrence of R^b is -CF3.

75. The compound of any one of Embodiments 1-68, wherein an occurrence of R^b is -H.

76. The compound of any one of Embodiments 1-68, wherein an occurrence of R^b is optionally substituted C3-10 cycloaliphatic.

77. The compound of any one of Embodiments 1-68, wherein an occurrence of R^b is optionally substituted C36 cycloalkyl. 78. The compound of any one of Embodiments 1-68, wherein an occurrence of R^b is optionally substituted cyclopropyl.

79. The compound of any one of Embodiments 1-68, wherein an occurrence of R^b is cyclopropyl.

80. The compound of any one of Embodiments 1-68, wherein an occurrence of R^b is optionally substituted 3-7 membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur.

81. The compound of any one of Embodiments 1-68, wherein an occurrence of R^b is optionally substituted 3-7 membered heterocyclyl having one heteroatom independently selected from nitrogen, oxygen and sulfur.

82. The compound of any one of Embodiments 1-68, wherein an occurrence of R^b is optionally substituted 4-membered heterocyclyl having one heteroatom independently selected from nitrogen, oxygen and sulfur.

83. The compound of any one of Embodiments 1-68, wherein an occurrence of R^b is

>

84. The compound of any one of Embodiments 1-68, wherein an occurrence of R^b is -OR.

85. The compound of any one of Embodiments 1-68, wherein an occurrence of R^b is -OR, wherein R is optionally substituted CMO aliphatic.

86. The compound of any one of Embodiments 1-68, wherein an occurrence of R^b is -OR, wherein R is optionally substituted CMO aliphatic.

87. The compound of any one of Embodiments 1-68, wherein an occurrence of R^b is -OR, wherein R is optionally substituted C1-6 alkyl.

88. The compound of any one of Embodiments 1-68, wherein an occurrence of R^b is -OR, wherein R is Cj 6 alkyl.

89. The compound of any one of Embodiments 1-68, wherein an occurrence of R^b is -OMe.

90. The compound of any one of Embodiments 1-68, wherein an occurrence of R^b is -OEt.

91. The compound of any one of Embodiments 1-68, wherein an occurrence of R^b is -OR, wherein R is optionally substituted -CH2-C36 cycloaliphatic.

92. The compound of any one of Embodiments 1-68, wherein an occurrence of R^b is -OR, wherein R is optionally substituted -CH2-C36 cycloalkyl.

93. The compound of any one of Embodiments 1-68, wherein an occurrence of R^b is -OR, wherein R is -CEE-cyclopropyl.

94. The compound of any one of Embodiments 1-68, wherein an occurrence of R^b is -S(O)2R^bl.

95. The compound of Embodiment 94, wherein R^bl is R.

96. The compound of Embodiment 94, wherein R^bl is R and is not -H.

97. The compound of Embodiment 94, wherein R^bl is optionally substituted C1-6 aliphatic.

98. The compound of Embodiment 94, wherein R^bl is optionally substituted C1-6 alkyl. 99. The compound of Embodiment 94, wherein R^bl is optionally substituted ethyl.

100. The compound of any one of Embodiments 1 -68, wherein an occurrence of R^b is -halogen.

101. The compound of any one of Embodiments 1-68, wherein an occurrence of R^b is -F.

102. The compound of any one of Embodiments 1-68, wherein each occurrence of R^b is independently halogen.

103. The compound of any one of Embodiments 1-68, wherein each occurrence of R^b is -F.

104. The compound of any one of Embodiments 1-103, wherein two occurrences of R^b are attached to the same atom.

105. The compound of any one of Embodiments 1-103, wherein all occurrences of R^b are attached to the same atom.

106. The compound of any one of Embodiments 65-66, wherein the two R^b are taken together with the carbon atom to which they are attached to form an optionally substituted 3-7 membered ring having 0-3 nitrogen, oxygen and sulfur.

107. The compound of any one of Embodiments 65-66, wherein the two R^b are taken together with the carbon atom to which they are attached to form an optionally substituted 4-7 membered ring having 0-2 nitrogen, oxygen and sulfur.

108. The compound of any one of Embodiments 106-107, wherein the formed ring is 4-membered.

109. The compound of any one of Embodiments 106-108, wherein the formed ring is saturated.

110. The compound of any one of Embodiments 106-109, wherein the formed ring has no heteroatom.

111. The compound of any one of Embodiments 106-109, wherein the formed ring has one heteroatom.

112. The compound of Embodiment 111, wherein the heteroatom is nitrogen.

113. The compound of Embodiment 111, wherein the heteroatom is oxygen.

114. The compound of Embodiment 111, wherein the heteroatom is sulfur.

115. The compound of any one of Embodiments 106-114, wherein the formed ring is substituted.

116. The compound of Embodiment 115, wherein the formed ring is substituted with -CF3.

117. The compound of Embodiment 115, wherein the formed ring is substituted with halogen.

118. The compound of Embodiment 115, wherein the formed ring is substituted with -F.

119. The compound of Embodiment 115, wherein the formed ring is substituted with two -F.

120. The compound of Embodiment 115, wherein the formed ring is substituted with two -F on one carbon atom.

121. The compound of Embodiment 115, wherein the formed ring is substituted with oxo.

122. The compound of any one of Embodiments 65-66, wherein the two R^b are taken together with the carbon atom to which they are attached to form optionally substituted

123. The compound of any one of Embodiments 65-66, wherein the two R^b are taken together with the carbon atom to which they are attached to form

124. The compound of any one of Embodiments 65-66, wherein the two R^b are taken together with the carbon atom to which they are attached to form optionally substituted 5 ' *'\■ /° .

125. The compound of any one of Embodiments 65-66, wherein the two R^b are taken together with the ixQo carbon atom to which they are attached to form t .

126. The compound of any one of Embodiments 67-68, wherein R^b is R.

127. The compound of any one of Embodiments 67-68, wherein R^b is optionally substituted Cue aliphatic.

128. The compound of any one of Embodiments 67-68, wherein R^b is optionally substituted C1-6 alkyl.

129. The compound of any one of Embodiments 67-68, wherein R^b is C1-6 alkyl.

130. The compound of any one of Embodiments 67-68, wherein R^b is C1-6 haloalkyl.

131. The compound of any one of Embodiments 67-68, wherein R^b is -CF3.

132. The compound of any one of Embodiments 67-68, wherein R^b is -H.

133. The compound of any one of Embodiments 67-68, wherein R^b is optionally substituted C3-10 cycloaliphatic.

134. The compound of any one of Embodiments 67-68, wherein R^b is optionally substituted C3-6 cycloalkyl.

135. The compound of any one of Embodiments 67-68, wherein R^b is optionally substituted cyclopropyl.

136. The compound of any one of Embodiments 67-68, wherein R^b is cyclopropyl.

137. The compound of any one of Embodiments 67-68, wherein R^b is optionally substituted 3-7 membered hctcrocyclyl having 1-2 hctcroatoms independently selected from nitrogen, oxygen and sulfur.

138. The compound of any one of Embodiments 67-68, wherein R^b is optionally substituted 3-7 membered heterocyclyl having one heteroatom independently selected from nitrogen, oxygen and sulfur.

139. The compound of any one of Embodiments 67-68, wherein R^b is optionally substituted 4-membered heterocyclyl having one heteroatom independently selected from nitrogen, oxygen and sulfur.

140. The compound of any one of Embodiments 67-68, wherein R^b is

141. The compound of any one of Embodiments 67-68, wherein R^b is -OR.

142. The compound of any one of Embodiments 67-68, wherein R^b is -OR, wherein R is optionally substituted C1-10 aliphatic.

143. The compound of any one of Embodiments 67-68, wherein R^b is -OR, wherein R is optionally substituted C1- 10 aliphatic.

144. The compound of any one of Embodiments 67-68, wherein R^b is -OR, wherein R is optionally substituted C1-6 alkyl. 145. The compound of any one of Embodiments 67-68, wherein R^b is -OR, wherein R is C1-6 alkyl.

146. The compound of any one of Embodiments 67-68, wherein R^b is -OMe.

147. The compound of any one of Embodiments 67-68, wherein R^b is -OEt.

148. The compound of any one of Embodiments 67-68, wherein R^b is -OR, wherein R is optionally substituted -CH2-C36 cycloaliphatic.

149. The compound of any one of Embodiments 67-68, wherein R^b is -OR, wherein R is optionally substituted -CH2-C3 6 cycloalkyl.

150. The compound of any one of Embodiments 67-68, wherein R^b is -OR, wherein R is -CH2-cyclopropyl.

151. The compound of any one of Embodiments 67-68, wherein R^b is -S(O)2R^bl.

152. The compound of Embodiment 151, wherein R^bl is R.

153. The compound of Embodiment 151, wherein R^bl is R and is not -H.

154. The compound of Embodiment 151, wherein R^bl is optionally substituted C1-6 aliphatic.

155. The compound of Embodiment 151, wherein R^bl is optionally substituted Ci 6 alkyl.

156. The compound of Embodiment 151, wherein R^bl is optionally substituted ethyl.

157. The compound of any one of Embodiments 67-68, wherein R^b is -halogen.

158. The compound of any one of Embodiments 67-68, wherein R^b is -F.

159. The compound of any one of the preceding Embodiments, wherein an occurrence of R^b is trans relative to Ring C.

160. The compound of any one of the preceding Embodiments, wherein Ring C is 5-membered.

161. The compound of any one of Embodiments 1-159, wherein Ring C is 6-membered.

162. The compound of any one of Embodiments 1-159, wherein Ring C is 7-membered.

163. The compound of any one of Embodiments 1-159, wherein Ring C is 8-membered.

164. The compound of any one of Embodiments 1-159, wherein Ring C is 9-membered.

165. The compound of any one of Embodiments 1-159, wherein Ring C is 10-membered.

166. The compound of any one of the preceding Embodiments, wherein Ring C is monocyclic.

167. The compound of any one of Embodiments 1-165, wherein Ring C is bicyclic.

168. The compound of any one of the preceding Embodiments, wherein Ring C is saturated.

169. The compound of any one of Embodiments 1-167, wherein Ring C is partially unsaturated.

170. The compound of any one of Embodiments 1-167, wherein Ring C is partially unsaturated.

171. The compound of any one of Embodiments 1-167, wherein Ring C is aromatic.

172. The compound of any one of Embodiments 1-167, wherein at least one monocyclic unit of Ring C is aromatic.

173. The compound of any one of Embodiments 1-159, wherein Ring C is an optionally substituted phenyl ring.

174. The compound of any one of Embodiments 1-159, wherein Ring C is an unsubstituted phenyl ring. 175. The compound of any one of Embodiments 1-159, wherein Ring C is an optionally substituted 5- membered heteroaromatic ring having 1 -4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

176. The compound of any one of Embodiments 1-159, wherein Ring C is an optionally substituted pyridyl ring.

177. The compound of any one of Embodiments 1-159, wherein Ring C is an unsubstituted pyridyl ring.

178. The compound of any one of Embodiments 176-177, wherein the pyridyl is 2-pyridyl.

179. The compound of any one of Embodiments 176-177, wherein the pyridyl is 3-pyridyl.

180. The compound of any one of Embodiments 176-177, wherein the pyridyl is 4-pyridyl.

HN-,

N 3

181. The compound of any one of Embodiments 1-159, wherein Ring C is optionally substituted .

182. The compound of any one of Embodiments 1-159, wherein Ring C is optionally substituted

183. The compound of any one of Embodiments 1 -159, wherein Ring C is optionally substituted

184. The compound of any one of Embodiments 1-159, wherein Ring C is optionally substituted

185. The compound of any one of Embodiments 1-159, wherein Ring C is optionally substituted

186. The compound of any one of Embodiments 1-159, wherein Ring C is optionally substituted

187. The compound of any one of Embodiments 1-159, wherein Ring C is optionally substituted

188. The compound of any one of Embodiments 1-159, wherein Ring C is optionally substituted

189. The compound of any one of the preceding Embodiments, wherein d is 1 or 2. 190. The compound of any one of the preceding Embodiments, wherein e is 1 or 2.

191. The compound of any one of Embodiments 1-159, wherein

192. The compound of any one of Embodiments 1-159. wherein

193. The compound of any one of Embodiments 1-159. wherein

194. The compound of any one of Embodiments 1-159, wherein

195. The compound of any one of Embodiments -159, wherein

196. The compound of any one of Embodiments -159, wherein

197. The compound of any one of Embodiments -159, wherein

198. The compound of any one of Embodiments

199. The compound of any one of Embodiments 1-198, wherein R^c is -L^C-C(O)OH or a bioisostere thereof, -L^c-C(O)OR^cl, -L^c-C(O)NR^clR^c2, -L^c-C(O)N(R^cl)S(O)₂R^c2, -L^c-S(O)₂N(R^cl)C(O)R^c2,

-L^c-S(O)₂NR^clR^c2, -L^C-S(O)(NR^C1)R^C2, -L^C-S(O)₂R^CI, -CN, -L^c-P(O)(OR^cl)(OR^c2), -L^c-OP(O)(OR^cl)(OR^c2), or -L^c-BR^clR^c2.

200. The compound of any one of Embodiments 1-198, wherein R^c is -L^C-C(O)OH or a bioisostere thereof, -L^c-C(O)OR^cl, -L^c-C(O)NR^clR^c2, -L^c-C(O)N(R^cl)S(O)₂R^c2, -L^c-S(O)₂N(R^cl)C(O)R^c2, -L^c-S(O)₂NR^clR^c2, -L^C-S(O)(NR^C1)R^C2, -L^C-S(O)₂R^C1, -CN, -L^C-P(O)(OR^C1)(OR^C2), or -L^c-OP(O)(OR^cl)(OR^c2).

201. The compound of any one of Embodiments 1-198, wherein R^c is -L^C-C(O)OH or a bioisostere thereof, -L^c-C(O)OR^cl, -L^c-C(O)NR^clR^c2, -L^c-C(O)N(R^cl)S(O)₂R^c2, -L^c-S(O)₂N(R^cl)C(O)R^c2, -L^C-S(O)₂NR^C1R^C2, -L^C-S(O)(NR^C1)R^C2, -L^C-S(O)₂R^C1, -L^C-P(O)(OR^C1)(OR^C2), or -L^c-OP(O)(OR^cl)(OR^c2).

202. The compound of any one of Embodiments 1-198, wherein R^c is -L^C-C(O)OH or a bioisostere thereof.

203. The compound of any one of Embodiments 1-202, wherein L^c is a covalent bond.

204. The compound of any one of Embodiments 1-202, wherein L^c is optionally substituted -CH₂-

205. The compound of any one of Embodiments 1-198, wherein R^c is -C(O)OH or a bioisostere thereof.

206. The compound of any one of Embodiments 1-198, wherein R^c is -C(O)OH.

207. The compound of any one of Embodiments 1-198, wherein R^c is -L^c-C(O)OR^cl.

208. The compound of any one of Embodiments 1-198, wherein R^c is -CH₂-C(O)OR^cl.

209. The compound of any one of Embodiments 1-198, wherein R^c is -C(O)OR^cl.

210. The compound of any one of Embodiments 207-209, wherein R^cl is R.

211. The compound of any one of Embodiments 207-209, wherein R^cl is optionally substituted C1-6 aliphatic.

212. The compound of any one of Embodiments 1-198, wherein R^c is 5-6 membered heteroaryl having 1-4 ring nitrogen atoms and 0 or 1 ring oxygen or sulfur atom.

213. The compound of any one of Embodiments 1-198, wherein R^c is optionally substituted tetrazolyl.

214. The compound of any one of Embodiments 1-198, wherein R^c is tetrazolyl.

215. The compound of any one of the preceding Embodiments, wherein R^d is -NR^dlR^d2.

216. The compound of any one of the preceding Embodiments, wherein R^dl is R.

217. The compound of any one of the preceding Embodiments, wherein R^dl is -H.

218. The compound of any one of Embodiments 1-216, wherein R^dl is optionally substituted C1-6 aliphatic.

219. The compound of any one of Embodiments 1-216, wherein R^dl is optionally substituted C1-6 alkyl.

220. The compound of any one of Embodiments 1-216, wherein R^dl is optionally substituted C1-4 aliphatic.

221. The compound of any one of Embodiments 1-216, wherein R^dl is optionally substituted C1-4 alkyl.

222. The compound of any one of Embodiments 1-216, wherein R^dl is optionally substituted Cm aliphatic.

223. The compound of any one of Embodiments 1-216, wherein R^dl is optionally substituted Cm alkyl.

224. The compound of any one of Embodiments 1-216, wherein R^dl is optionally substituted Cm aliphatic.

225. The compound of any one of Embodiments 1-216, wherein R^dl is optionally substituted Cm alkyl.

226. The compound of any one of Embodiments 1-216, wherein R^dl is optionally substituted methyl.

227. The compound of any one of Embodiments 218-226, wherein R^dl is unsubstituted.

228. The compound of any one of Embodiments 218-226, wherein R^dl is substituted.

229. The compound of any one of Embodiments 218-226, wherein R^dl is substituted wherein each substituent is independently halogen.

230. The compound of any one of Embodiments 218-226, wherein R^dl is substituted wherein each substituent is -F. 231. The compound of any one of Embodiments 1-216, wherein R^dl is C1-6 alkyl.

232. The compound of any one of Embodiments 1 -216, wherein R^dl is methyl.

233. The compound of any one of Embodiments 1-216, wherein R^dl is ethyl.

234. The compound of any one of Embodiments 1-233, wherein R^d is -NHR^dl .

235. The compound of any one of the preceding Embodiments, wherein R^d2 is R.

236. The compound of any one of the preceding Embodiments, wherein R^d2 is -H.

237. The compound of any one of Embodiments 1-233, wherein R^d2 is optionally substituted C1-6 aliphatic.

238. The compound of any one of Embodiments 1-233, wherein R^d2 is optionally substituted Ci 6 alkyl.

239. The compound of any one of Embodiments 1-233, wherein R^d2 is C1-6 alkyl.

240. The compound of any one of Embodiments 1-233, wherein R^d2 is CM alkyl.

241. The compound of any one of Embodiments 1-233, wherein R^d2 is methyl.

242. The compound of any one of Embodiments 1-233, wherein R^d2 is ethyl.

243. The compound of any one of Embodiments 1-214, wherein R^d is -NH2.

244. The compound of any one of Embodiments 1-214, wherein R^d is -NHMe.

245. The compound of any one of Embodiments 1-214, wherein R^d is -NHEt.

246. The compound of any one of Embodiments 1-214, wherein R^d is -NR^dlR^d2, and R^dl and R^d2 are taken together with the nitrogen atom to which they are attached to form an optionally substituted 3-10 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 3-8, 3-7, 3-6, 4-6, 5-6, 5-8, etc.) membered ring having, in addition to the nitrogen atom 0-5 (e.g., 1, 2, 3, 4, 5. 1-5, 1-4, 1-2, etc.) heteroatoms independently selected from nitrogen, oxygen and sulfur.

247. The compound of Embodiment 246, wherein the formed ring is 4-membered.

248. The compound of Embodiment 246, wherein the formed ring is 5-membered.

249. The compound of Embodiment 246, wherein the formed ring is 6-membered.

250. The compound of any one of Embodiments 246-249, wherein the formed ring monocyclic.

251. The compound of any one of Embodiments 246-250, wherein the formed ring is is saturated.

252. The compound of any one of Embodiments 246-250, wherein the formed ring is partially unsaturated.

253. The compound of any one of Embodiments 246-250, wherein the formed ring is aromatic.

254. The compound of any one of Embodiments 246-253, wherein the formed ring has no additional heteroatoms.

255. The compound of any one of Embodiments 246-253, wherein the formed ring has 1-2 additional heteroatoms.

256. The compound of any one of Embodiments 246-253, wherein the formed ring has an additional heteroatom which is nitrogen.

257. The compound of any one of Embodiments 1-214, wherein R^d is optionally substituted

.

258. The compound of any one of Embodiments 1-214, wherein R^d is

. 259. The compound of any one of Embodiments 1-214, wherein R^d is -H.

260. The compound of any one of Embodiments 1 -190 and 198-259, wherein R^e is -NR^elR^e2.

261. The compound of any one of the preceding Embodiments, wherein R^el is R.

262. The compound of any one of the preceding Embodiments, wherein R^el is -H.

263. The compound of any one of Embodiments 1-190 and 198-261, wherein R^el is optionally substituted

Ci -6 aliphatic.

264. The compound of any one of Embodiments 1-190 and 198-261, wherein R^el is optionally substituted Cj 6 alkyl.

265. The compound of any one of Embodiments 1-190 and 198-261, wherein R^el is optionally substituted Ci 4 aliphatic.

266. The compound of any one of Embodiments 1-190 and 198-261, wherein R^el is optionally substituted CM alkyl.

267. The compound of any one of Embodiments 1-190 and 198-261, wherein R^el is optionally substituted Ci 3 aliphatic.

268. The compound of any one of Embodiments 1-190 and 198-261, wherein R^el is optionally substituted CM alkyl.

269. The compound of any one of Embodiments 1-190 and 198-261, wherein R^el is optionally substituted Ci -2 aliphatic.

270. The compound of any one of Embodiments 1-190 and 198-261, wherein R^el is optionally substituted C1-2 alkyl.

271. The compound of any one of Embodiments 1-190 and 198-261, wherein R^el is optionally substituted methyl.

272. The compound of any one of Embodiments 263-271 , wherein R^el is unsubstituted.

273. The compound of any one of Embodiments 263-271, wherein R^el is substituted.

274. The compound of any one of Embodiments 263-271, wherein R^el is substituted wherein each substituent is independently halogen.

275. The compound of any one of Embodiments 263-271, wherein R^el is substituted wherein each substituent is -F.

276. The compound of any one of Embodiments 1-190 and 198-261, wherein R^el is C1-6 alkyl.

277. The compound of any one of Embodiments 1-190 and 198-261, wherein R^el is methyl.

278. The compound of any one of Embodiments 1-190 and 198-261, wherein R^el is ethyl.

279. The compound of any one of Embodiments 1-190 and 198-278, wherein R^e is -NHR^el.

280. The compound of any one of the preceding Embodiments, wherein R^e2 is R.

281. The compound of any one of the preceding Embodiments, wherein R^e2 is -H.

282. The compound of any one of Embodiments 1-190 and 198-280, wherein R^e2 is optionally substituted

Ci -6 aliphatic. 283. The compound of any one of Embodiments 1-190 and 198-280, wherein R^c2 is optionally substituted C1-6 alkyl.

284. The compound of any one of Embodiments 1-190 and 198-280, wherein R^e2 is C1-6 alkyl.

285. The compound of any one of Embodiments 1-190 and 198-280, wherein R^e2 is methyl.

286. The compound of any one of Embodiments 1-190 and 198-280, wherein R^e2 is ethyl.

287. The compound of any one of Embodiments 1-190 and 198-259, wherein R^e is -NFfc.

288. The compound of any one of Embodiments 1-190 and 198-259, wherein R^e is -NHMe.

289. The compound of any one of Embodiments 1-190 and 198-259, wherein R^e is -NHEt.

290. The compound of any one of Embodiments 1-190 and 198-259, wherein R^e is — H.

291. The compound of any one of Embodiments 1-190 and 198-259, wherein R^e is — NR^clR^e2, and R^el and

R^e2 are taken together with the nitrogen atom to which they are attached to form an optionally substituted 3-10 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 3-8, 3-7, 3-6, 4-6, 5-6, 5-8, etc.) membered ring having, in addition to the nitrogen atom 0-5 (e.g., 1, 2, 3, 4, 5, 1-5, 1-4, 1-2, etc.) heteroatoms independently selected from nitrogen, oxygen and sulfur.

292. The compound of Embodiment 291, wherein the formed ring is 4-membered.

293. The compound of Embodiment 291, wherein the formed ring is 5 -membered.

294. The compound of Embodiment 291, wherein the formed ring is 6-membered.

295. The compound of any one of Embodiments 291-294, wherein the formed ring is monocyclic.

296. The compound of any one of Embodiments 291-295, wherein the formed ring is saturated.

297. The compound of any one of Embodiments 291-295, wherein the formed ring is partially unsaturated.

298. The compound of any one of Embodiments 291-295, wherein the formed ring is aromatic.

299. The compound of any one of Embodiments 291-298, wherein the formed ring has no additional heteroatoms.

300. The compound of any one of Embodiments 291-298, wherein the formed ring has 1-2 additional heteroatoms.

301. The compound of any one of Embodiments 291-298, wherein the formed ring has an additional heteroatom which is nitrogen.

302. The compound of any one of Embodiments 1-190 and 198-259, wherein R^e is optionally substituted

303. The compound of any one of Embodiments 1-190 and 198-259, wherein R^e is

.

304. The compound of any one of Embodiments 1-190 and 198, wherein R^d and R^e are taken together with their intervening atom(s) to form an optionally substituted 3-10 membered ring having, in addition to the intervening atom(s), 0-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

305. The compound of Embodiment 304, wherein the formed ring is 4-membered. 306. The compound of Embodiment 304, wherein the formed ring is 5-membered.

307. The compound of Embodiment 304, wherein the formed ring is 6-membered.

308. The compound of any one of Embodiments 304-307, wherein the formed ring is partially unsaturated.

309. The compound of any one of Embodiments 304-307, wherein the formed ring is aromatic.

310. The compound of any one of Embodiments 304-309, wherein the formed ring has no additional heteroatoms.

311. The compound of any one of Embodiments 304-309, wherein the formed ring has 1-2 additional heteroatoms.

312. The compound of any one of Embodiments 304-309, wherein the formed ring has an additional heteroatom which is nitrogen.

313. The compound of any one of Embodiments 1-190 and 198, wherein R^d is NR^dlR^d2 and R^e is -NR^elR^c2, and R^dl and R^d2 are taken together with their intervening atoms to form an optionally substituted 3- 10 membered ring having, in addition to the intervening atoms, 0-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

314. The compound of Embodiment 313, wherein the formed ring is 4-membered.

315. The compound of Embodiment 313, wherein the formed ring is 5 -membered.

316. The compound of Embodiment 313, wherein the formed ring is 6-membered.

317. The compound of any one of Embodiments 313-316, wherein the formed ring is partially unsaturated.

318. The compound of any one of Embodiments 313-316, wherein the formed ring is aromatic.

319. The compound of any one of Embodiments 313-318, wherein the formed ring has no additional heteroatoms.

320. The compound of any one of Embodiments 313-318, wherein the formed ring has 1-2 additional heteroatoms.

321. The compound of any one of Embodiments 313-318, wherein the formed ring has an additional heteroatom which is nitrogen.

322. The compound of any one of Embodiments 313-321, wherein R^el is — R.

323. The compound of any one of Embodiments 313-321, wherein R^el is — H.

324. The compound of any one of Embodiments 313-323, wherein R^e2 is — R.

325. The compound of any one of Embodiments 313-323, wherein R^e2 is -H.

326. The compound of any one of Embodiments 1-159, wherein

327. The compound of any one of Embodiments 1-159,

328. The compound of any one of Embodiments 1-159, wherein

329. The compound of any one of Embodiment 326-328, wherein R^c is -OR.

330. The compound of any one of Embodiment 326-328, wherein R^c is -OH.

331. The compound of any one of Embodiment 326-328, wherein R^c is -L^c— C(O)OH or a bioisostere thereof, -L^c-C(O)OR^cl, -L -L^C-S(O)₂NR^C1R^C2, -L^C-S( -L^c-OP(O)(OR^cl)(OR^c2), o

332. The compound of any one of Embodiment 326-328, wherein R^c is -L^c— C(O)OH or a bioisostere thereof, -L^c-C(O)OR^cl, -L^c-C(O)NR^clR^c2, -L^c-C(O)N(R^cl)S(O)₂R^c2, -L^c-S(O)₂N(R^cl)C(O)R^c2, -L^C-S(O)₂NR^C1R^C2, -L^C-S(O)(NR^C1)R^C2, -L^C-S(O)₂R^C1, -CN, -L^c-P(O)(OR^cl)(OR^c2), or -L^c-OP(O)(OR^cl)(OR^c2).

333. The compound of any one of Embodiment 326-328, wherein R^c is -L^C-C(O)OH or a bioisostere thereof, -L^c-C(O)OR^cl, -L^c-C(O)NR^clR^c2, -L^c-C(O)N(R^cl)S(O)₂R^c2, -L^c-S(O)₂N(R^cl)C(O)R^c2, -L^C-S(O)₂NR^C1R^C2, -L^C-S(O)(NR^C1)R^C2, -L^C-S(O)₂R^C1, -L^C-P(O)(OR^C1)(OR^C2), or -L^c-OP(O)(OR^cl)(OR^c2).

334. The compound of any one of Embodiment 326-328, wherein R^c is -L^c— C(O)OH or a bioisostere thereof.

335. The compound of Embodiment 334, wherein L^c is a covalent bond.

336. The compound of Embodiment 334, wherein L^c is optionally substituted -CH₂-.

337. The compound of any one of Embodiment 326-328, wherein R^c is -C(O)OH or a bioisostere thereof.

338. The compound of any one of Embodiment 326-328, wherein R^c is -C(O)OH.

339. The compound of any one of Embodiment 326-328, wherein R^c is -L^c— C(O)OR^cl.

340. The compound of any one of Embodiment 326-328, wherein R^c is -CH₂-C(O)OR^cl.

341. The compound of any one of Embodiment 326-328, wherein R^c is -C(O)OR^cl.

342. The compound of any one of Embodiments 339-341, wherein R^cl is R.

343. The compound of any one of Embodiments 339-341, wherein R^cl is optionally substituted Crs aliphatic.

344. The compound of any one of Embodiment 326-328, wherein R^c is 5-6 membered heteroaryl having 1- 4 ring nitrogen atoms and 0 or 1 ring oxygen or sulfur atom.

345. The compound of any one of Embodiment 326-328, wherein R^c is optionally substituted tetrazolyl.

346. The compound of any one of Embodiment 326-328, wherein R^c is tetrazolyl.

347. The compound of any one of Embodiment 326-328, wherein R^c is -N(R’)₂.

348. The compound of any one of Embodiment 326-328, wherein R^c is -N(R)₂.

349. The compound of any one of Embodiment 326-328, wherein R^c is -NHR'. 350. The compound of any one of Embodiment 326-328, wherein R^c is −NHR. 351. The compound of any one of Embodiment 326-328, wherein R^c is −NH₂. 352. The compound of any one of the preceding Embodiments, wherein the compound has the structure of formula I-a, I-a-1, I-a-2, I-b, I-b-1, I-b-2, I-c, I-c-1, I-c-2, I-d, I-d-1, I-d-2, I-d-3, I-e, I-e-1, I-e-2, I-f, I-f-1, I-f- 2, I-f-3, I-g, I-g-1, I-g-2, I-h, I-h-1, I-h-2, I-h-3 or II, or a salt thereof. 353. A compound, wherein the compound has the structure of formula I-a or a salt thereof, wherein each variable is described in any one of Embodiments 1-352, individually or in combination. 354. A compound, wherein the compound has the structure of formula I-b or a salt thereof, wherein each variable is described in any one of Embodiments 1-352, individually or in combination. 355. A compound, wherein the compound has the structure of formula I-c or a salt thereof, wherein each variable is described in any one of Embodiments 1-352, individually or in combination. 356. A compound, wherein the compound has the structure of formula I-d or a salt thereof, wherein each variable is described in any one of Embodiments 1-352, individually or in combination. 357. A compound, wherein the compound has the structure of formula I-e or a salt thereof, wherein each variable is described in any one of Embodiments 1-352, individually or in combination. 358. A compound, wherein the compound has the structure of formula I-f or a salt thereof, wherein each variable is described in any one of Embodiments 1-352, individually or in combination. 359. A compound, wherein the compound has the structure of formula I-g or a salt thereof, wherein each variable is described in any one of Embodiments 1-352, individually or in combination. 360. A compound, wherein the compound has the structure of formula I-h or a salt thereof, wherein each variable is described in any one of Embodiments 1-352, individually or in combination. 361. A compound, wherein the compound has the structure of formula II: , or a salt thereof, wherein:

m is 1, or 2; n is 1, or 2; R¹ is hydrogen, halogen, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C3-C6 cycloalkyl, C1-C6 alkoxy, halo C1-C6 alkyl, hydroxy C1-C6 alkyl, amino C1-C6 alkyl, C1-C6 alkoxy C1-C6 alkyl, C1-C6 alkoxy C1-C6 alkoxy, C3-C6 cycloalkyl C1-C6 alkoxy, halo C1-C6 alkoxy, −S(O)pC1-C6 alkyl, −CH2NHC(O)C1-C4 alkyl or −OCH2C(O)R⁷; p is 0, 1, or 2; R² is hydrogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, hydroxy C₁-C₆ alkyl, or halogen; R³ is hydrogen, halogen, cyano, C₁-C₄ alkyl, halo C₁-C₄ alkyl, −CH₂C(O)R⁷; R⁴ is phenyl, naphthyl, 1,2,3,4-tetrahydronaphthalenyl and 5-10 membered heteroaryl having 1, 2 or 3 ring heteroatoms independently selected from nitrogen, oxygen and sulfur, and wherein the phenyl, naphthyl, 1,2,3,4-tetrahydronaphthalenyl, or heteroaryl is optionally substituted with R⁵ and further optionally substituted with one or two R⁵’; each R⁵’ is independently selected from halogen, C1-C4 alkyl, C1-C4 alkoxy, hydroxy C1-C4 alkyl, hydroxyl, R¹⁰, −OR^6’, −N(R⁵¹)2, halo C1-C6 alkyl, cyano, and cyanomethyl; or two R^5’ are taken together with their intervening atoms to form a 4-8 membered monocyclic partially unsaturated or aromatic ring having 1-3 ring atoms independently selected from nitrogen, sulfur and oxygen, wherein the ring is optionally substituted with one or more substituents independently selected from halogen, C1-C4 alkyl, halo C1-C4 alkyl, C1-C4 alkoxy, hydroxyl, and oxo; each R⁵¹ is independently R⁶’; R^4’ is hydrogen, C1-C4 alkyl, or hydroxy C1-C4 alkyl; R⁵ is −C(O)R⁸, −CH2C(O)R⁸, R⁹, −C(O)NHSO2C1-C4alkyl, −SO2NHC(O)C1-C4alkyl, −SO2N(H)p(C1- C4alkyl)2-p, −SO(NH)C1-C4alkyl, −SO2C1-C4alkyl, cyano, halogen, hydroxy C1-C4 alkyl, −B(R⁸)2 or 5- membered heteroaryl having 1-4 ring nitrogen atoms and 0 or 1 ring oxygen or sulfur atom; each R⁶ is independently hydrogen, halogen, hydroxyl, amino, mono- and di-C1-C6 alkylamino, C1-C6 alkyl, halo C1-C6 alkyl, hydroxy C1-C6 alkyl, cyano C1-C6 alkyl or C1-C6 alkoxy, or: two R⁶ on a carbon atom are taken together to form =O, or two R⁶ on a carbon atom are taken together with the carbon atom to form a 3-membered monocyclic saturated ring having 0-1 ring atoms independently selected from nitrogen, sulfur and oxygen; or two R⁶ are taken together with their intervening atoms to form a 3-8 membered monocyclic saturated or partially unsaturated ring having 0-3 ring atoms independently selected from nitrogen, sulfur and oxygen, wherein the ring is optionally substituted with one or more substituents independently selected from halogen, C1-C4 alkyl, halo C1-C4 alkyl, C1-C4 alkoxy, hydroxyl, and oxo; or R^4’ and one R⁶ are taken together to form C₂-C₄ alkylene; t is 0, 1, 2, 3 or 4; R^6’ is hydrogen, halogen, C₁-C₆ aliphatic, R¹⁰, −CH₂−C₃-C₆ cycloaliphatic, −CH₂−R¹⁰, −CH₂−(hydroxy C₁-C₄ alkyl), phenyl, −C(O)−C₁-C₆ aliphatic, −SO₂−C₁-C₆ aliphatic, −CH₂−phenyl, −CH₂−(amino C₁-C₄ alkyl), or −CH₂−(mono- and di-C₁-C₄ alkylamino C₁-C₄ alkyl) wherein each of the C₁-C₆ aliphatic and phenyl is optionally substituted with one or more substituents independently selected from halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, C₃-C₆ cycloalkyl or 3-6 membered heterocyclyl having 1-4 ring atoms independently selected from nitrogen, oxygen and sulfur, wherein each of the alkyl, alkoxy, cycloalkyl and heterocyclyl is optionally and independently substituted with one or more substituents independently selected from halogen, C₁-C₄ alkyl, halo C₁-C₄ alkyl, C₁-C₄ alkoxy, hydroxyl, and oxo, and wherein each nitrogen ring atom of the heterocyclyl is optionally and independently substituted with C_1-3 acyl, cyano C₁-C₄ alkyl, C₃-C₆ cycloalkyl, or 3-6 membered heterocyclyl having 1-4 ring atoms independently selected from nitrogen, oxygen and sulfur wherein each ring nitrogen is optionally and independently substituted with C_1-3 acyl; or: R⁶ and R^6’ are taken together with their intervening atoms to form a 3-8 membered monocyclic or bicyclic saturated, partially unsaturated or aromatic ring having 1-3 ring atoms independently selected from nitrogen, sulfur and oxygen, wherein the ring is optionally substituted with one or more substituents independently selected from halogen, C1-C4 alkyl, halo C1-C4 alkyl, C1-C4 alkoxy, hydroxyl, and oxo; R⁷ is hydroxyl, C1-C4 alkoxy, amino, or mono- or di-C1-C4 alkylamino; each R⁸ is independently hydroxyl, C1-C4 alkoxy, amino or a 5-7 membered saturated heterocyclyl having 1, 2, or 3 ring heteroatoms independently selected from nitrogen, oxygen and sulfur; or mono- and di- C1-C4 alkylamino which is optionally substituted with one or more substituents independently selected from halogen, hydroxy and C1-C4 alkyl; R⁹ is a 5-membered heteroaryl having 1 to 4 ring nitrogen atoms and 0 or 1 ring oxygen or sulfur atom, which heteroaryl is optionally substituted with 0 to 2 C1-C4 alkyl groups; and R¹⁰ is 3-6 membered heterocyclyl or 5-6 membered heteroaryl having 1-3 ring atoms independently selected from nitrogen, oxygen and sulfur, wherein the heterocyclyl or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, C1-C4 alkyl, halo C1-C4 alkyl, C1-C4 alkoxy, hydroxyl, and oxo, and wherein each nitrogen ring atom of the heterocyclyl or heteroaryl is optionally and independently substituted with C1-3 acyl, cyano C1-C4 alkyl, C3-C6 cycloalkyl, or 3-6 membered heterocyclyl having 1-4 ring atoms independently selected from nitrogen, oxygen and sulfur. 362. The compound of Embodiment 361, wherein R¹ is selected from C1-C6 alkoxy, C1-C6 alkoxy C1-C6 alkyl, C1-C6 alkoxy C1-C6 alkoxy, C3-C6 cycloalkyl C1-C6 alkoxy, and halo C1-C6 alkoxy. 363. The compound of any one of Embodiments 361-362, wherein R¹ is C1-C6 alkoxy. 364. The compound of any one of Embodiments 361-362, wherein R¹ is C1-C4 alkoxy. 365. The compound of any one of Embodiments 361-362, wherein R¹ is C1-C2 alkoxy. 366. The compound of any one of Embodiments 361-362, wherein R¹ is methoxy. 367. The compound of any one of Embodiments 361-362, wherein R¹ is halo C₁-C₆ alkoxy. 368. The compound of any one of Embodiments 361-362 and 367, wherein R¹ is halo C₁-C₄ alkoxy. 369. The compound of any one of Embodiments 361-362 and 368, wherein R¹ is halo C₁-C₂ alkoxy. 370. The compound of any one of Embodiments 361-362 and 370, wherein R¹ is halo C₁-C₂ alkoxy. 371. The compound of any one of Embodiments 361-362 and 370, wherein R¹ is –OCHF₂. 372. The compound of Embodiment 361, wherein R¹ is C₁-C₆ alkyl. 373. The compound of Embodiment 361, wherein R¹ is C₁-C₄ alkyl. 374. The compound of Embodiment 361, wherein R¹ is C₁-C₂ alkyl. 375. The compound of Embodiment 361, wherein R¹ is C₃-C₆ cycloalkyl. 376. The compound of Embodiment 361, wherein R¹ is C₃-C₅ cycloalkyl. 377. The compound of Embodiment 376, wherein R¹ is cyclopropyl. 378. The compound of any one of the preceding Embodiments, wherein R² is selected from C₁-C₆ alkyl and halogen. 379. The compound of any one of the preceding Embodiments, wherein R² is C1-C6 alkyl. 380. The compound of any one of the preceding Embodiments, wherein R² is C₁-C₄ alkyl. 381. The compound of any one of the preceding Embodiments, wherein R² is C₁-C₂ alkyl. 382. The compound of any one of the preceding Embodiments, wherein R² is methyl. 383. The compound of any one of Embodiments 361-378, wherein R² is halogen. 384. The compound of any one of Embodiments 361-378 and 383, wherein R² is selected from chloro and fluoro. 385. The compound of Embodiment 383, wherein R² is chloro. 386. The compound of Embodiment 383, wherein R² is fluoro. 387. The compound of any one of Embodiments 361-378 and 383, wherein R² is selected from bromo and iodo. 388. The compound of Embodiment 383, wherein R² is bromo. 389. The compound of Embodiment 383, wherein R² is iodo. 390. The compound of any one of Embodiments 361-377, wherein R² is selected from hydrogen, C1-C6 alkoxy, and hydroxy C1-C6 alkyl. 391. The compound of any one of the preceding Embodiments, wherein R² is hydrogen. 392. The compound of any one of Embodiments 361-377 and 390, wherein R² is C1-C6 alkoxy. 393. The compound of any one of Embodiments 361-377 and 390, wherein R² is C1-C4 alkoxy. 394. The compound of any one of Embodiments 361-377 and 390, wherein R² is methoxy. 395. The compound of any one of Embodiments 361-377 and 390, wherein R² is hydroxy C1-C6 alkyl. 396. The compound of any one of Embodiments 361-377 and 390, wherein R² is hydroxy C1-C4 alkyl. 397. The compound of any one of the preceding Embodiments, wherein R³ is selected from hydrogen, halogen, and cyano. 398. The compound of any one of the preceding Embodiments, wherein R³ is hydrogen. 399. The compound of any one of Embodiments 361-397, wherein R³ is halogen. 400. The compound of Embodiment 399, wherein R³ is selected from fluoro and chloro. 401. The compound of Embodiment 400, wherein R³ is fluoro. 402. The compound of Embodiment 400, wherein R³ is chloro. 403. The compound of Embodiment 399, wherein R³ is selected from bromo and iodo. 404. The compound of Embodiment 403, wherein R³ is bromo. 405. The compound of Embodiment 403, wherein R³ is iodo. 406. The compound of any one of Embodiments 361-397, wherein R³ is selected from C₁-C₄ alkyl, halo C₁-C₄ alkyl, and −CH₂C(O)R⁷. 407. The compound of Embodiment 406, wherein R³ is C₁-C₆ alkyl. 408. The compound of Embodiment 406, wherein R³ is C₁-C₄ alkyl. 409. The compound of Embodiment 408, wherein R³ is methyl. 410. The compound of Embodiment 406, wherein R³ is halo C1-C4 alkyl. 411. The compound of Embodiment 410, wherein R³ is halo C₁-C₂ alkyl. 412. The compound of Embodiment 406, wherein R³ is −CH₂C(O)R⁷. 413. The compound of any one of the preceding Embodiments, wherein R⁴ is phenyl, naphthyl, 1,2,3,4- tetrahydronaphthalenyl and 5-10 membered heteroaryl having 1, 2 or 3 ring heteroatoms independently selected from nitrogen, oxygen and sulfur, and wherein the phenyl, naphthyl, 1,2,3,4-tetrahydronaphthalenyl, or heteroaryl is substituted with R⁵ and further optionally substituted with one or two R⁵’. 414. The compound of any one of the preceding Embodiments, wherein R⁴ is phenyl substituted with R⁵ and further optionally substituted with one or two R⁵’. 415. The compound of any one of the preceding Embodiments, wherein R⁴ is phenyl para-substituted (unless otherwise indicated, relative to the atom at which R⁴ is attached to the rest of the compound) with R⁵ and further optionally substituted with one or two R⁵’. 416. The compound of any one of the preceding Embodiments, wherein R⁴ is phenyl meta-substituted with R⁵ and further optionally substituted with one or two R⁵’. 417. The compound of any one of Embodiments 361-412, wherein R⁴ is naphthyl substituted with R⁵ and further optionally substituted with one or two R⁵’. 418. The compound of any one of Embodiments 361-412, wherein R⁴ is 1,2,3,4-tetrahydronaphthalenyl substituted with R⁵ and further optionally substituted with one or two R⁵’. 419. The compound of any one of Embodiments 361-412, wherein R⁴ is 5-membered heteroaryl substituted with R⁵ and further optionally substituted with one or two R⁵’. 420. The compound of any one of Embodiments 361-412, wherein R⁴ is 6-membered heteroaryl substituted with R⁵ and further optionally substituted with one or two R⁵’. 421. The compound of any one of Embodiments 361-412, wherein R⁴ is 6-membered heteroaryl para- substituted with R⁵ and further optionally substituted with one or two R⁵’. 422. The compound of any one of Embodiments 361-412, wherein R⁴ is 6-membered heteroaryl meta- substituted with R⁵ and further optionally substituted with one or two R⁵’. 423. The compound of any one of Embodiments 420-422, wherein the 6-membered heteroaryl is pyridyl. 424. The compound of any one of Embodiments 361-412, wherein R⁴ is 9-membered bicyclic heteroaryl substituted with R⁵ and further optionally substituted with one or two R⁵’. 425. The compound of any one of Embodiments 361-412, wherein R⁴ is 10-membered bicyclic heteroaryl substituted with R⁵ and further optionally substituted with one or two R⁵’. 426. The compound of any one of the preceding Embodiments, wherein R⁵ is −C(O)R⁸. 427. The compound of any one of the preceding Embodiments, wherein R⁵ is −CH₂C(O)R⁸. 428. The compound of any one of the preceding Embodiments, wherein R⁸ is hydroxy. 429. The compound of any one of the preceding Embodiments, wherein R⁸ is C₁-C₄ alkoxy. 430. The compound of any one of the preceding Embodiments, wherein R⁸ is −NH₂. 431. The compound of any one of the preceding Embodiments, wherein R⁸ is 5-7 membered saturated heterocyclyl having 1, 2, or 3 ring heteroatoms independently selected from nitrogen, oxygen and sulfur. 432. The compound of any one of the preceding Embodiments, wherein R⁸ is mono- and di-C₁-C₄ alkylamino which is optionally substituted with one or more substituents independently selected from halogen, hydroxy and C1-C4 alkyl. 433. The compound of any one of Embodiments 361-425, wherein R⁵ is −C(O)NHSO2C1-C4alkyl. 434. The compound of any one of Embodiments 361-425, wherein R⁵ is −SO2NHC(O)C1-C4alkyl. 435. The compound of any one of Embodiments 361-425, wherein R⁵ is −SO2N(H)p(C1-C4alkyl)2-p. 436. The compound of any one of Embodiments 361-425, wherein R⁵ is −SO2NH2. 437. The compound of any one of Embodiments 361-425, wherein R⁵ is −SO(NH)C1-C4alkyl. 438. The compound of any one of Embodiments 361-425, wherein R⁵ is −SO(NH)CH3. 439. The compound of any one of Embodiments 361-425, wherein R⁵ is −SO2C1-C4alkyl. 440. The compound of any one of Embodiments 361-425, wherein R⁵ is cyano. 441. The compound of any one of Embodiments 361-425, wherein R⁵ is halogen. 442. The compound of any one of Embodiments 361-425, wherein R⁵ is hydroxy C1-C4 alkyl. 443. The compound of any one of Embodiments 361-425, wherein R⁵ is −B(R⁸)2. 444. The compound of Embodiment 443, wherein each R⁸ is independently hydroxy or C1-C4 alkoxy. 445. The compound of Embodiment 443, wherein each R⁸ is independently hydroxy. 446. The compound of Embodiment 443, wherein each R⁸ is independently C1-C4 alkoxy. 447. The compound of any one of Embodiments 361-425, wherein R⁵ is 5-membered heteroaryl having 1- 4 ring nitrogen atoms and 0 or 1 ring oxygen or sulfur atom. 448. The compound of Embodiment 447, wherein R⁵ is tetrazolyl. 449. The compound of any one of the preceding Embodiments, wherein R⁴ is substituted with one R⁵’. 450. The compound of any one of the preceding Embodiments, wherein R⁴ is substituted with two R⁵’. 451. The compound of any one of the preceding Embodiments, wherein R⁵’ is ortho relative to R⁵. 452. The compound of any one of the preceding Embodiments, wherein R⁵’ is halogen. 453. The compound of any one of the preceding Embodiments, wherein R⁵’ is −F. 454. The compound of any one of the preceding Embodiments, wherein R⁵’ is −Cl. 455. The compound of any one of Embodiments 361-451, wherein R⁵’ is C₁-C₄ alkyl. 456. The compound of any one of Embodiments 361-451, wherein R⁵’ is methyl. 457. The compound of any one of Embodiments 361-451, wherein R⁵’ is ethyl. 458. The compound of any one of Embodiments 361-451, wherein R⁵’ is cyclopropyl. 459. The compound of any one of Embodiments 361-451, wherein R⁵’ is C₁-C₄ alkoxy. 460. The compound of any one of Embodiments 361-451, wherein R⁵’ is −OCH₃. 461. The compound of any one of Embodiments 361-451, wherein R⁵’ is hydroxy C₁-C₄ alkyl. 462. The compound of any one of Embodiments 361-451, wherein R⁵’ is −CH₂OH. 463. The compound of any one of Embodiments 361-451, wherein R⁵’ is hydroxy. 464. The compound of any one of Embodiments 361-451, wherein R⁵’ is cyanomethyl. 465. The compound of any one of Embodiments 361-448, wherein R⁴ is not substituted with R⁵’. 466. The compound of any one of Embodiments 361-451, wherein R⁵’ is −OR^6’. 467. The compound of any one of Embodiments 361-451, wherein R⁵’ is −OR¹⁰. 468. The compound of any one of Embodiments 361-451, wherein R⁵’ is R¹⁰. 469. The compound of Embodiment 466, wherein R¹⁰ is bonded to R⁴ at a nitrogen atom. 470. The compound of any one of Embodiments 467-469, wherein R¹⁰ is optionally substituted 3-6 membered heterocyclyl. 471. The compound of any one of Embodiments 467-469, wherein R¹⁰ is optionally substituted 5-6 membered heteroaryl. 472. The compound of any one of Embodiments 467-471, wherein R¹⁰ has an oxygen ring atom. 473. The compound of Embodiment 451, wherein two R^5’ are taken together with their intervening atoms to form a 4-8 membered monocyclic partially unsaturated or aromatic ring. 474. The compound of Embodiment 451, wherein two R^5’ are taken together with their intervening atoms to form a 4-8 membered monocyclic partially unsaturated ring. 475. The compound of Embodiment 451, wherein two R^5’ are taken together with their intervening atoms to form a 5-6 membered monocyclic heteroaryl ring. 476. The compound of any one of Embodiments 361-451, wherein R⁵’ is −N(R⁵¹)2. 477. The compound of any one of Embodiments 361-451, wherein R⁵’ is −NHR⁵¹. 478. The compound of any one of Embodiments 476-477, wherein each R⁵¹ is independently hydrogen, C1-C6 aliphatic, R¹⁰, −CH2−C3-C6 cycloaliphatic, −CH2−R¹⁰, −CH2−(hydroxy C1-C4 alkyl), phenyl, −C(O)−C1-C6 aliphatic, −SO2−C1-C6 aliphatic, −CH2−phenyl, −CH2−(amino C1-C4 alkyl), or −CH2−(mono- and di-C₁-C₄ alkylamino C₁-C₄ alkyl) wherein each of the C₁-C₆ aliphatic and phenyl is optionally substituted with one or more substituents independently selected from halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, C₃-C₆ cycloalkyl or 3-6 membered heterocyclyl having 1-4 ring atoms independently selected from nitrogen, oxygen and sulfur, wherein each of the alkyl, alkoxy, cycloalkyl and heterocyclyl is optionally and independently substituted with one or more substituents independently selected from halogen, C₁-C₄ alkyl, halo C₁-C₄ alkyl, C₁-C₄ alkoxy, hydroxyl, and oxo, and wherein each nitrogen ring atom of the heterocyclyl is optionally and independently substituted with C_1-3 acyl, cyano C₁-C₄ alkyl, C₃-C₆ cycloalkyl, or 3-6 membered heterocyclyl having 1-4 ring atoms independently selected from nitrogen, oxygen and sulfur wherein each ring nitrogen is optionally and independently substituted with C_1-3 acyl. 479. The compound of any one of Embodiments 476-477, wherein an occurrence of R⁵¹ is hydrogen. 480. The compound of any one of Embodiments 476-477, wherein an occurrence of R⁵¹ is optionally substituted C₁-C₆ aliphatic. 481. The compound of any one of Embodiments 476-477, wherein an occurrence of R⁵¹ is C₁-C₆ aliphatic. 482. The compound of any one of Embodiments 476-477, wherein an occurrence of R⁵¹ is C1-C6 alkyl. 483. The compound of any one of Embodiments 476-477, wherein an occurrence of R⁵¹ is cyclopropyl. 484. The compound of any one of Embodiments 476-477, wherein an occurrence of R⁵¹ is methyl. 485. The compound of any one of Embodiments 476-477, wherein an occurrence of R⁵¹ is ethyl. 486. The compound of any one of Embodiments 476-477, wherein an occurrence of R⁵¹ is cyclobutyl. 487. The compound of any one of Embodiments 476-477, wherein an occurrence of R⁵¹ is −CH2−cyclopropyl. 488. The compound of any one of Embodiments 476-477, wherein an occurrence of R⁵¹ is substituted C1- C6 aliphatic. 489. The compound of any one of Embodiments 476-477, wherein an occurrence of R⁵¹ is substituted C1- C6 alkyl. 490. The compound of any one of Embodiments 476-477, wherein an occurrence of R⁵¹ is (S)−CH(CH3)(CF3). 491. The compound of any one of Embodiments 476-477, wherein an occurrence of R⁵¹ is −CH2CF3. 492. The compound of any one of Embodiments 476-477, wherein an occurrence of R⁵¹ is substituted C3- C6 cycloalkyl. 493. The compound of any one of Embodiments 476-477, wherein an occurrence of R⁵¹ is 3,3- difluorocyclobutyl. 494. The compound of any one of Embodiments 476-477, wherein an occurrence of R⁵¹ is R¹⁰. 495. The compound of any one of Embodiments 476-477, wherein an occurrence of R⁵¹ is −CH2−R¹⁰. 496. The compound of any one of Embodiments 494-495, wherein R¹⁰ is optionally substituted 5-6 membered heteroaryl having 1-3 ring atoms independently selected from nitrogen, oxygen and sulfur. 497. The compound of any one of Embodiments 494-495, wherein R¹⁰ is 5-membered heteroaryl having 1- 3 ring nitrogen atoms substituted with C₁-C₄ alkyl. 498. The compound of any one of Embodiments 494-495, wherein R¹⁰ . 499. The compound of any one of Embodiments 494-495, wherein R¹⁰

s op onally substituted 3-6 membered heterocyclyl. 500. The compound of any one of Embodiments 494-495, wherein R¹⁰ is optionally substituted 6- membered heterocyclyl. 501. The compound of Embodiment 499, wherein R¹⁰ is . 502. The compound of Embodiment 499, wherein R¹⁰

. 503. The compound of any one of Embodiments 476-4 ein an occurrence of R⁵¹ is −C(O)−C1-C6

aliphatic, wherein the C1-C6 aliphatic is optionally substituted. 504. The compound of any one of Embodiments 476-477, wherein an occurrence of R⁵¹ is −C(O)−C1-C6 aliphatic. 505. The compound of any one of Embodiments 476-477, wherein an occurrence of R⁵¹ is −C(O)−C1-C6 alkyl. 506. The compound of any one of Embodiments 476-477, wherein R⁵’ is −NHC(O)CH₃. 507. The compound of any one of Embodiments 476-477, wherein R⁵’ is −NHC(O)CH₂CH₃. 508. The compound of any one of Embodiments 476-477, wherein an occurrence of R⁵¹ is −SO₂−C₁-C₆ aliphatic, wherein the C₁-C₆ aliphatic is optionally substituted. 509. The compound of any one of Embodiments 476-477, wherein an occurrence of R⁵¹ is −SO₂−C₁-C₆ aliphatic. 510. The compound of any one of Embodiments 476-477, wherein an occurrence of R⁵¹ is −SO₂−C₁-C₆ alkyl. 511. The compound of any one of Embodiments 476-477, wherein R⁵’ is −NHS(O)₂CH₃. 512. The compound of Embodiment 476, wherein R⁵’ is −NH₂. 513. The compound of Embodiment 476, wherein R⁵’ is −NH(CH₃). 514. The compound of Embodiment 476, wherein R⁵’ is −NH(CH₂CH₃). 515. The compound of any one of the preceding Embodiments, wherein the carbon to which R⁴ is attached has a configuration . 516. The comp

ne of Embodiments 361-514, wherein the carbon to which R⁴ is attached has a configuration . 517. The c

any one of the preceding Embodiments, wherein R^4’ is hydrogen. 518. The compound of any one of the preceding Embodiments, wherein t is 1, 2, 3 or 4. 519. The compound of any one of the preceding Embodiments, wherein an occurrence of R⁶ is hydroxy. 520. The compound of any one of the preceding Embodiments, wherein an occurrence of R⁶ is amino. 521. The compound of any one of the preceding Embodiments, wherein an occurrence of R⁶ is mono- and di-C₁-C₄ alkylamino. 522. The compound of any one of the preceding Embodiments, wherein an occurrence of R⁶ is C₁-C₆ alkyl. 523. The compound of any one of the preceding Embodiments, wherein an occurrence of R⁶ is C₁-C₄ alkyl. 524. The compound of any one of the preceding Embodiments, wherein an occurrence of R⁶ is methyl. 525. The compound of any one of the preceding Embodiments, wherein an occurrence of R⁶ is halo C1-C6 alkyl. 526. The compound of any one of the preceding Embodiments, wherein an occurrence of R⁶ is halo C₁-C₄ alkyl. 527. The compound of any one of the preceding Embodiments, wherein an occurrence of R⁶ is −CF3. 528. The compound of any one of the preceding Embodiments, wherein an occurrence of R⁶ is −CHF2. 529. The compound of any one of the preceding Embodiments, wherein an occurrence of R⁶ is −CH2F. 530. The compound of any one of the preceding Embodiments, wherein an occurrence of R⁶ is hydroxy C1-C6 alkyl. 531. The compound of any one of the preceding Embodiments, wherein an occurrence of R⁶ is hydroxy C1-C4 alkyl. 532. The compound of any one of the preceding Embodiments, wherein an occurrence of R⁶ is −CH2OH. 533. The compound of any one of the preceding Embodiments, wherein an occurrence of R⁶ is cyano C1- C6 alkyl. 534. The compound of any one of the preceding Embodiments, wherein an occurrence of R⁶ is cyano C1- C4 alkyl. 535. The compound of any one of the preceding Embodiments, wherein an occurrence of R⁶ is C1-C6 alkoxy. 536. The compound of any one of the preceding Embodiments, wherein an occurrence of R⁶ is C1-C4 alkoxy. 537. The compound of any one of the preceding Embodiments, wherein two R⁶ on a carbon atom are taken together to form =O. 538. The compound of any one of the preceding Embodiments, wherein two R⁶ on a carbon atom are taken together to form a 3-8 membered monocyclic saturated or partially unsaturated ring having 0-3 ring atoms independently selected from nitrogen, sulfur and oxygen, wherein the ring is optionally substituted with one or more substituents independently selected from halogen, C₁-C₄ alkyl, halo C₁-C₄ alkyl, C₁-C₄ alkoxy, hydroxyl, and oxo. 539. The compound of any one of the preceding Embodiments, wherein two R⁶ on a carbon atom are taken together to form a cyclopropyl ring. 540. The compound of any one of the preceding Embodiments, wherein two R⁶ are taken together with their intervening atoms to form a 3-8 membered monocyclic saturated or partially unsaturated ring having 0-3 ring atoms independently selected from nitrogen, sulfur and oxygen, wherein the ring is optionally substituted with one or more substituents independently selected from halogen, C₁-C₄ alkyl, halo C₁-C₄ alkyl, C₁-C₄ alkoxy, hydroxyl, and oxo. 541. The compound of any one of the preceding Embodiments, wherein two R⁶ are taken together with their intervening atoms to form a 5-7 membered cycloalkyl ring, wherein the ring is optionally substituted with one or more substituents independently selected from halogen, C1-C4 alkyl, halo C1-C4 alkyl, C1-C4 alkoxy, hydroxyl, and oxo. 542. The Embodiment of any one of the preceding Embodiments, wherein m is 1. 543. The compound of any one of Embodiments 361-541, wherein m is 2. 544. The Embodiment of any one of the preceding Embodiments, wherein n is 1. 545. The compound of any one of Embodiments 361-543, wherein n is 2. 546. The compound of any one of Embodiments 361-541, wherein the compound has the structure of: or a salt thereof.

547. The compound of Embodiment 546, wherein an occurrence of R⁶ is hydrogen. 548. The compound of any one of Embodiments 546-547, wherein each R⁶ is independently selected from −H, −CH2OH, −CH2F, −CHF2 and −CF3. 549. The compound of any one of Embodiments 361-541, wherein the compound has the structure of: or a salt thereof.

550. The compound of any one of Embodiments 361-541, wherein the compound has the structure of:

or a salt thereof. 551. The compound of any one of Embodiments 361-541, wherein the compound has the structure of: or a salt thereof.

552. The compound of any one of Embodiments 361-541, wherein the compound has the structure of: or a salt thereof.

553. The compound of any one of Embodiments 361-541, wherein the compound has the structure of: or a salt thereof.

554. The compound of any one of Embodiments 552-553, wherein an occurrence of R⁶ is hydrogen. 555. The compound of any one of Embodiments 552-554, wherein an occurrence of R⁶ is −OH. 556. The compound of any one of Embodiments 552-554, wherein an occurrence of R⁶ is halogen. 557. The compound of any one of Embodiments 552-554, wherein an occurrence of R⁶ is −F. 558. The compound of any one of Embodiments 552-554, wherein an occurrence of R⁶ is C_1-6 alkyl. 559. The compound of any one of Embodiments 552-554, wherein an occurrence of R⁶ is methyl. 560. The compound of any one of Embodiments 552-553, wherein each R⁶ is independently halogen. 561. The compound of any one of Embodiments 552-553, wherein each R⁶ is independently −F. 562. The compound of any one of Embodiments 361-541, wherein t is 2, 3 or 4. 563. The compound of any one of Embodiments 361-541, wherein t is 2. 564. The compound of any one of the preceding Embodiments, wherein at least one occurrence of R⁶ is bonded to a carbon atom that is bonded to the nitrogen atom to which R⁶’ is bonded to.

565. The compound of Embodiment 564, wherein the carbon atom is not bonded to the carbon atom to which R⁴ is bonded to.

566. The compound of Embodiment 564, wherein the carbon atom is bonded to the carbon atom to which R⁴ is bonded to.

567. The compound of any one of Embodiments 361-517, wherein t is 0.

568. The compound of any one of Embodiments 361-536, wherein t is 1.

569. The compound of any one of Embodiments 361-536, wherein t is 2.

570. The compound of any one of the preceding Embodiments, wherein R⁶ is hydrogen.

571. The compound of any one of Embodiments 361-569, wherein R⁶ is halogen.

572. The compound of any one of Embodiments 361-569, wherein R⁶ is -F.

573. The compound of any one of Embodiments 361-569, wherein R⁶ is -CH2-(hydroxy C1-C4 alkyl).

574. The compound of any one of Embodiments 361-569, wherein R⁶ is — CH2— CH2OH.

575. The compound of any one of Embodiments 361-569, wherein R⁶ is — CH2— ( amino C1-C4 alkyl).

576. The compound of any one of Embodiments 361-569, wherein R⁶ is — CH2— (mono- and di-C1-C4 alkylamino C1-C4 alkyl).

577. The compound of any one of Embodiments 361-569, wherein R⁶ is optionally substituted C1-C6 aliphatic.

578. The compound of any one of Embodiments 361-569, wherein R⁶ is optionally substituted C1-C6 linear aliphatic.

579. The compound of any one of Embodiments 361-578, wherein R⁶ is optionally substituted C1-C<, alkyl.

580. The compound of any one of Embodiments 361-578, wherein R⁶ is optionally substituted C1-C4 alkyl.

581. The compound of any one of Embodiments 577-580, wherein the C1-C6 aliphatic is substituted with one C1-C4 alkoxy substituent.

582. The compound of any one of Embodiments 577-580, wherein R⁶’ is -CH2CH2OCH3.

583. The compound of any one of Embodiments 361-569, wherein R⁶ is aliphatic. C1-C6

584. The compound of any one of Embodiments 361-569, wherein R⁶ is linear aliphatic. C1-C6

585. The compound of any one of Embodiments 361-584, wherein R⁶ is alkyl. C1-C6

586. The compound of any one of Embodiments 361-584, wherein R⁶ is C1-C4 alkyl.

587. The compound of any one of Embodiments 361-569, wherein R⁶ is methyl.

588. The compound of any one of Embodiments 361-569, wherein R⁶ is ethyl.

589. The compound of any one of Embodiments 361-569, wherein R⁶ is n-propyl.

590. The compound of any one of Embodiments 361-569, wherein R⁶ is isopropyl. 591. The compound of any one of Embodiments 361-569, wherein R⁶ is n-butyl.

592. The compound of any one of Embodiments 361 -569, wherein R⁶ is 2-butyl.

593. The compound of any one of Embodiments 361-569, wherein R⁶ is — CFECH^CI-b.

594. The compound of any one of Embodiments 361-569, wherein R⁶ is — CtTCH^CH?.

595. The compound of any one of Embodiments 361-569, wherein R⁶ is C1-C4 alkoxy.

596. The compound of any one of Embodiments 361-569, wherein R⁶ is C3-C6 cycloalkyl.

597. The compound of any one of Embodiments 361-569, wherein R⁶ is -CHiCHj-C1-C4 aliphatic.

598. The compound of Embodiment 597, wherein the C1-C4 aliphatic is linear.

599. The compound of Embodiment 597, wherein the C1-C4 aliphatic is C1-C4 alkyl.

600. The compound of Embodiment 597, wherein the C1-C4 aliphatic is linear C1-C4 alkyl.

601. The compound of Embodiment 597, wherein the C1-C4 aliphatic is methyl.

602. The compound of Embodiment 597, wherein the C1-C4 aliphatic is ethyl.

603. The compound of Embodiment 597, wherein the C1-C4 aliphatic is n-propyl.

604. The compound of any one of Embodiments 361-569, wherein R⁶ is C3-C6 cycloaliphatic.

605. The compound of any one of Embodiments 361-569, wherein R⁶ is C3-C6 cycloalkyl.

606. The compound of any one of Embodiments 361-569, wherein R⁶ is cyclopropyl.

607. The compound of any one of Embodiments 361-569, wherein R⁶ is cyclobutyl.

608. The compound of any one of Embodiments 361-569, wherein R⁶ is cyclopentyl.

609. The compound of any one of Embodiments 361-569, wherein R⁶ is -CH2-C3-C5 cycloaliphatic.

610. The compound of Embodiment 609, wherein the C3-C5 cycloaliphatic is C3-C5 cycloalkyl.

611. The compound of Embodiment 609, wherein the C3-C5 cycloaliphatic is C3-C5 cyclopropyl.

612. The compound of Embodiment 609, wherein the C3-C5 cycloaliphatic is C3-C5 cyclobutyl.

613. The compound of Embodiment 609, wherein the C3-C5 cycloaliphatic is C3-C5 cyclopentyl.

614. The compound of any one of Embodiments 361-569, wherein R⁶ is aliphatic substituteCd 1 w-Cit6h one or more substituents independently selected from halogen, C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl or 3-6 membered heterocyclyl having 1-4 ring atoms independently selected from nitrogen, oxygen and sulfur, wherein each of the alkyl, alkoxy, cycloalkyl and heterocyclyl is optionally and independently substituted with one or more substituents independently selected from halogen, C1-C4 alkyl, halo C1-C4 alkyl, C1-C4 alkoxy, hydroxyl, and oxo, and wherein each nitrogen ring atom of the heterocyclyl is optionally and independently substituted with C1-3 acyl, cyano C1-C4 alkyl, C3-C6 cycloalkyl, or 3-6 membered heterocyclyl having 1-4 ring atoms independently selected from nitrogen, oxygen and sulfur wherein each ring nitrogen is optionally and independently substituted with C1-3 acyl.

615. The compound of any one of Embodiments 361-569, wherein R⁶ is alkyl substituted wCith1-C on6e or more substituents independently selected from halogen, C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl or 3-6 membered heterocyclyl having 1-4 ring atoms independently selected from nitrogen, oxygen and sulfur, wherein each of the alkyl, alkoxy, cycloalkyl and heterocyclyl is optionally and independently substituted with one or more substituents independently selected from halogen, C₁-C₄ alkyl, halo C₁-C₄ alkyl, C₁-C₄ alkoxy, hydroxyl, and oxo, and wherein each nitrogen ring atom of the heterocyclyl is optionally and independently substituted with C_1-3 acyl, cyano C₁-C₄ alkyl, C₃-C₆ cycloalkyl, or 3-6 membered heterocyclyl having 1-4 ring atoms independently selected from nitrogen, oxygen and sulfur wherein each ring nitrogen is optionally and independently substituted with C1-3 acyl. 616. The compound of any one of Embodiments 614-615, wherein R⁶’ is C₁-C₆ aliphatic substituted with one or more halogen. 617. The compound of any one of Embodiments 614-616, wherein R⁶’ is C1-C6 alkyl substituted with one or more −F. 618. The compound of any one of Embodiments 614-616, wherein R⁶’ is C1-C6 linear alkyl substituted with one or more −F. 619. The compound of any one of Embodiments 614-618, wherein R⁶’ is −CH2CH2F. 620. The compound of any one of Embodiments 614-618, wherein R⁶’ is −CH2CH2CH2F. 621. The compound of any one of Embodiments 614-618, wherein R⁶’ is −CH2CHF2. 622. The compound of any one of Embodiments 614-618, wherein R⁶’ is −CH2CH2CHF2. 623. The compound of any one of Embodiments 614-618, wherein R⁶’ is −CH2CF3. 624. The compound of any one of Embodiments 614-618, wherein R⁶’ is −CH2CH2CF3. 625. The compound of any one of Embodiments 614-616, wherein R⁶’ is −CH2CF=CH2. 626. The compound of any one of Embodiments 614-615, wherein R⁶’ is C1-C6 aliphatic substituted with one or more C1-C4 alkyl wherein the alkyl is optionally and independently substituted with one or more substituents independently selected from halogen, C1-C4 alkyl, halo C1-C4 alkyl, C1-C4 alkoxy, hydroxyl, and oxo. 627. The compound of any one of Embodiments 614-615, wherein R⁶’ is C1-C6 aliphatic substituted with one or more C1-C4 alkyl. 628. The compound of any one of Embodiments 614-616, wherein R⁶’ is C1-C6 aliphatic substituted with one or more C1-C4 alkoxy wherein the alkoxy is optionally and independently substituted with one or more substituents independently selected from halogen, C1-C4 alkyl, halo C1-C4 alkyl, C1-C4 alkoxy, hydroxyl, and oxo. 629. The compound of any one of Embodiments 614-616, wherein R⁶’ is C₁-C₆ aliphatic substituted with one or more C₁-C₄ alkoxy. 630. The compound of any one of Embodiments 628-629, wherein an occurrence of C₁-C₄ alkoxy is methoxy. 631. The compound of any one of Embodiments 614-616, wherein R⁶’ is C₁-C₆ aliphatic substituted with one or more C₃-C₆ cycloalkyl wherein the cycloalkyl is optionally and independently substituted with one or more substituents independently selected from halogen, C₁-C₄ alkyl, halo C₁-C₄ alkyl, C₁-C₄ alkoxy, hydroxyl, and oxo. 632. The compound of any one of Embodiments 614-616, wherein R⁶’ is C₁-C₆ aliphatic substituted with one or more C₃-C₆ cycloalkyl. 633. The compound of any one of Embodiments 614-616, wherein R⁶’ is C₁-C₆ aliphatic substituted with one or more 3-6 membered heterocyclyl having 1-4 ring atoms independently selected from nitrogen, oxygen and sulfur, wherein the heterocyclyl is optionally and independently substituted with one or more substituents independently selected from halogen, C₁-C₄ alkyl, halo C₁-C₄ alkyl, C₁-C₄ alkoxy, hydroxyl, and oxo, and wherein each nitrogen ring atom of the heterocyclyl is optionally and independently substituted with C_1-3 acyl, cyano C1-C4 alkyl, C3-C6 cycloalkyl, or 3-6 membered heterocyclyl having 1-4 ring atoms independently selected from nitrogen, oxygen and sulfur wherein each ring nitrogen is optionally and independently substituted with C1-3 acyl. 634. The compound of any one of Embodiments 614-616, wherein R⁶’ is C1-C6 aliphatic substituted with one or more 3-6 membered heterocyclyl having 1-4 ring atoms independently selected from nitrogen, oxygen and sulfur, wherein each nitrogen ring atom of the heterocyclyl is optionally and independently substituted with C1-3 acyl, cyano C1-C4 alkyl, C3-C6 cycloalkyl, or 3-6 membered heterocyclyl having 1-4 ring atoms independently selected from nitrogen, oxygen and sulfur wherein each ring nitrogen is optionally and independently substituted with C1-3 acyl. 635. The compound of any one of Embodiments 633-634, wherein an occurrence of 3-6 membered heterocyclyl having 1-4 ring atoms independently selected from nitrogen, oxygen and sulfur is . 636. The compound of any one of Embodiments 626-635, wherein the C1-C6 aliphatic is

637. The compound of any one of Embodiments 626-636, wherein the C1-C6 aliphatic is C1-C6 alkyl. 638. The compound of any one of Embodiments 626-637, wherein the C1-C6 aliphatic is ethyl. 639. The compound of Embodiment 638, wherein R^6’ is −CH2CH2OCH3. 640. The compound of any one of Embodiments 626-637, wherein the C1-C6 aliphatic is methyl. 641. The compound of Embodiment 640, wherein R^6’ i . 642. The compound of any one of Embodiments 361

ein R^6’ is R¹⁰. 643. The compound of Embodiment 642, wherein R¹⁰ is 5-6 membered heteroaryl having a nitrogen ring atom, wherein the heteroaryl is optionally substituted with one or more substituents independently selected from halogen, C₁-C₄ alkyl, halo C₁-C₄ alkyl, C₁-C₄ alkoxy, hydroxyl, and oxo, and wherein the nitrogen ring atom of the heteroaryl is optionally and independently substituted with C_1-3 acyl, cyano C₁-C₄ alkyl, C₃-C₆ cycloalkyl, or 3-6 membered heterocyclyl having 1-4 ring atoms independently selected from nitrogen, oxygen and sulfur. 644. The compound of Embodiment 642, wherein R¹⁰ is 5-6 membered heteroaryl having a nitrogen ring atom, wherein the nitrogen ring atom of the heteroaryl is substituted with C_1-3 acyl, cyano C₁-C₄ alkyl, C₃-C₆ cycloalkyl, or 3-6 membered heterocyclyl having 1-4 ring atoms independently selected from nitrogen, oxygen and sulfur. 645. The compound of Embodiment 642, wherein R¹⁰ is 3-6 membered heterocyclyl having a nitrogen ring atom, wherein the heterocyclyl is optionally substituted with one or more substituents independently selected from halogen, C₁-C₄ alkyl, halo C₁-C₄ alkyl, C₁-C₄ alkoxy, hydroxyl, and oxo, and wherein the nitrogen ring atom of the heterocyclyl is optionally and independently substituted with C1-3 acyl, cyano C1-C4 alkyl, C3-C6 cycloalkyl, or 3-6 membered heterocyclyl having 1-4 ring atoms independently selected from nitrogen, oxygen and sulfur. 646. The compound of Embodiment 642, wherein R¹⁰ is 3-6 membered heterocyclyl having a nitrogen ring atom, wherein the nitrogen ring atom of the heterocyclyl is substituted with C1-3 acyl, cyano C1-C4 alkyl, C3- C6 cycloalkyl, or 3-6 membered heterocyclyl having 1-4 ring atoms independently selected from nitrogen, oxygen and sulfur. 647. The compound of Embodiment 642, wherein R¹⁰ is 3-6 membered heterocyclyl having a nitrogen ring atom substituted with C1-3 acyl. 648. The compound of Embodiment 642, wherein R¹⁰ i . 649. The compound of any one of Embodiments 476-4

n occurrence of R^6’ is −SO2−C1-C6 aliphatic, wherein the C₁-C₆ aliphatic is optionally substituted. 650. The compound of any one of Embodiments 476-477, wherein an occurrence of R^6’ is −SO2−C1-C6 aliphatic. 651. The compound of any one of Embodiments 476-477, wherein an occurrence of R^6’ is −SO2−C1-C6 alkyl. 652. The compound of any one of Embodiments 476-477, wherein R⁶’ is −S(O)2CH3. 653. The compound of any one of Embodiments 476-477, wherein an occurrence of R^6’ is −C(O)−C1-C6 aliphatic, wherein the C1-C6 aliphatic is optionally substituted. 654. The compound of any one of Embodiments 476-477, wherein an occurrence of R^6’ is −C(O)−C1-C6 aliphatic. 655. The compound of any one of Embodiments 476-477, wherein an occurrence of R^6’ is −C(O)−C1-C6 alkyl. 656. The compound of any one of Embodiments 476-477, wherein R⁶’ is −C(O)CH3. 657. The compound of any one of Embodiments 361-566, wherein R⁶ and R^6’ are taken together with their intervening atoms to form a 3-8 membered monocyclic or bicyclic saturated, partially unsaturated or aromatic ring having 0-3 ring atoms independently selected from nitrogen, sulfur and oxygen, wherein the ring is optionally substituted with one or more substituents independently selected from halogen, C1-C4 alkyl, halo C1-C4 alkyl, C1-C4 alkoxy, hydroxyl, and oxo. 658. The compound of any one of Embodiments 361-566, wherein R⁶ and R^6’ are taken together with their intervening atoms to form a 3-8 membered monocyclic or bicyclic saturated, or partially unsaturated ring having 0-3 ring atoms independently selected from nitrogen, sulfur and oxygen, wherein the ring is optionally substituted with one or more substituents independently selected from halogen, C₁-C₄ alkyl, halo C₁-C₄ alkyl, C₁-C₄ alkoxy, hydroxyl, and oxo. 659. The compound of any one of Embodiments 361-566, wherein R⁶ and R^6’ are taken together with their intervening atoms to form a 3-8 membered monocyclic or bicyclic saturated ring having 0-3 ring atoms independently selected from nitrogen, sulfur and oxygen, wherein the ring is optionally substituted with one or more substituents independently selected from halogen, C₁-C₄ alkyl, halo C₁-C₄ alkyl, C₁-C₄ alkoxy, hydroxyl, and oxo. 660. The compound of any one of Embodiments 361-566, wherein R⁶ and R^6’ are taken together with their intervening atoms to form a 3-8 membered monocyclic or bicyclic partially unsaturated ring having 1-3 ring atoms independently selected from nitrogen, sulfur and oxygen, wherein the ring is optionally substituted with one or more substituents independently selected from halogen, C1-C4 alkyl, halo C1-C4 alkyl, C1-C4 alkoxy, hydroxyl, and oxo. 661. The compound of any one of Embodiments 361-566, wherein R⁶ and R^6’ are taken together with their intervening atoms to form an optionally substituted 3-5-membered monocyclic saturated ring having 0-2 heteroatom independently selected from nitrogen, oxygen and sulfur. 662. The compound of any one of Embodiments 361-566, wherein R⁶ and R^6’ are taken together with their intervening atoms to form an optionally substituted 3-5-membered monocyclic saturated ring having 1-2 heteroatom independently selected from nitrogen, oxygen and sulfur. 663. The compound of any one of Embodiments 361-566, wherein R⁶ and R^6’ are taken together with their intervening atoms to form an optionally substituted 4-5-membered monocyclic saturated ring having 0-2 heteroatom independently selected from nitrogen, oxygen and sulfur. 664. The compound of Embodiment 648, wherein R⁶ and R^6’ are taken together with their intervening atoms to form . 665. The c

nd of Embodiment 648, wherein R⁶ and R^6’ are taken together with their intervening atoms to form . 666. The compound of Embodiment 648, wherein R⁶ and R^6’ are taken together with their intervening atoms to form . 667. The c

ompound of Embodiment 648, wherein R⁶ and R^6’ are taken together with their intervening atoms to form . 668. The c

ompound of Embodiment 648, wherein R⁶ and R^6’ are taken together with their intervening atoms to form . 669. The c d of Embodiment 648, wherein R⁶ and R^6’ are taken together with their intervening

atoms to form . 670. The c mbodiment 648, wherein R⁶ and R^6’ are taken together with their intervening

atoms to form . 671. The c d of Embodiment 648, wherein R⁶ and R^6’ are taken together with their intervening

t t f . f Embodiment 648, wherein R⁶ and R^6’ are taken together with their intervening

atoms to form . 673. The c

d of Embodiment 648, wherein R⁶ and R^6’ are taken together with their intervening atoms to form . 674. A co

d selected from Table C-1, E-1, E-1b, E-1c, or E-1d, or a salt thereof. 675. A compound, wherein the compound has an identical structure as a first compound, wherein the first compound comprises an acidic moiety or a bioisostere thereof, or a moiety that can be converted to an acidic moiety or a bioisostere thereof, wherein the moiety is bonded to a ring, except that an additional amino group is bonded to the ring. 676. The compound of Embodiment 675, wherein the additional amino group is R^d as described in one of the preceding Embodiments. 677. The compound of Embodiment 675, wherein the additional amino group is R^e as described in any one of the any one of the preceding Embodiments. 678. A compound, wherein the compound has an identical structure as a first compound, wherein the first compound comprises an acidic moiety or a bioisostere thereof, or a moiety that can be converted to an acidic moiety or a bioisostere thereof, wherein the moiety is bonded to a ring, except that the ring is replaced with a basic nitrogen-containing 5-10 membered ring. 679. The compound of Embodiment 678, wherein the basic nitrogen-containing 5-10 membered ring is Ring C as described in one of the preceding Embodiments. 680. The compound of any one of Embodiments 675-679, wherein the first compound has the structure of Ring 1 (e.g., Ring A as described herein such as an optionally substituted heteroaromatic ring)−L¹² (e.g., L¹ as described herein)−Ring 2 (e.g., an optionally substituted nitrogen-containing optionally substituted non- aromatic ring which is bonded to L¹² through the nitrogen atom, Ring B as described herein, etc.)−L²³ (e.g., a covalent bond or optionally substituted −CH₂−)−Ring 3 (e.g., an optionally substituted aromatic ring having 0-4 heteroatoms, Ring C as described herein), wherein Ring 3 is bonded to an acidic moiety (e.g., −COOH) or a bioisostere thereof, or a moiety that can be converted (e.g., through metabolism) to an acidic moiety or a bioisostere thereof. 681. The compound of any one of Embodiments 675-680, wherein the first compound is a factor B or complement activation inhibitor. 682. The compound of any one of Embodiments 675-681, wherein the first compound is a compound described generically or specifically in WO 2015/009616, US 9682968, US 10093663, WO 2018/005552, WO 2019/043609, WO 2020/016749, WO 2022/028507, WO 2022/028527, WO 2022/143845, WO 2022/218429, WO 2022/234541, WO 2022/256586, WO 2023/020566, WO 2023/037218, WO 2023/072197, WO 2023/139534, or WO 2023/143293. 683. The compound of any one of the preceding Embodiments, wherein the compound has an IC50 of about or no more than about 1000, 900, 800, 700, 600, 500, 400, 300, 200, 100, 90, 80, 70, 60, 50, 40, 30, 20, or 10 nM as measured in an assay in the Examples. 684. The compound of any one of the preceding Embodiments, wherein the compound has a diastereomeric purity of about or no less than about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%. 685. The compound of any one of the preceding Embodiments, wherein the compound has an enantiomeric purity of about or no less than about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%. 686. The compound of any one of the preceding Embodiments, wherein the compound comprises one or more isotopes each of which is not the most abundant isotope. 687. The compound of any one of the preceding Embodiments, wherein the compound comprises one or more D. 688. The compound of any one of the preceding Embodiments, wherein R^d is −NHCD3. 689. The compound of any one of the preceding Embodiments, wherein L¹ is −CD2. 690. The compound of any one of Embodiments 686-689, wherein for each D at a particular position, the isotopic purity is independently about 5%-100% (e.g., about 5%, 10%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or more, or about 5%-100%, 10%- 100%, 20%-100%, 30%-100%, 50%-100%, 80%-100%, 90-100%, 95%-100%, 96%-100%, 97%-100%, 98%- 100%, 99%-100%, 95-99%, 95%-99.5%, 95%-99.9%, etc.) 691. The compound of any one of the preceding Embodiments, wherein the compound has a purity of about or no less than about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%. 692. The compound of any one of the preceding Embodiments, wherein when administered or delivered to a subject, its concentration at an eye or a portion thereof is about or at least about 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, 90 or 100 fold of plasma concentration. 693. The compound of any one of the preceding Embodiments, wherein when administered or delivered to a subject, its concentration at an eye or a portion thereof is about or at least about 10 fold of plasma concentration. 694. The compound of any one of the preceding Embodiments, wherein when administered or delivered to a subject, its concentration at an eye or a portion thereof is about or at least about 20 fold of plasma concentration. 695. The compound of any one of the preceding Embodiments, wherein when administered or delivered to a subject, its concentration at an eye or a portion thereof is about or at least about 50 fold of plasma concentration. 696. The compound of any one of Embodiments 692-695, wherein the eye or a portion thereof comprises melanin. 697. The compound of any one of Embodiments 692-696, wherein the eye or a portion thereof is or comprise choroid, BrM, RPE, iris, retina and/or ciliary body. 698. The compound of any one of the preceding Embodiments, wherein the compound provides higher concentration ratios at an eye or a portion thereof over plasma concentration relative to a reference compound. 699. The compound of Embodiment 698, wherein the ratio of the compound is about or at least about 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, 90 or 100 fold of the ratio of a reference compound. 700. The compound of Embodiment 698, wherein the ratio of the compound is about or at least about 2 fold of the ratio of a reference compound. 701. The compound of Embodiment 698, wherein the ratio of the compound is about or at least about 5 fold of the ratio of a reference compound. 702. The compound of Embodiment 698, wherein the ratio of the compound is about or at least about 10 fold of the ratio of a reference compound. 703. The compound of Embodiment 698, wherein the ratio of the compound is about or at least about 20 fold of the ratio of a reference compound. 704. The compound of any one of Embodiments 698-703, wherein the eye or a portion thereof comprises melanin. 705. The compound of any one of Embodiments 698-704, wherein the eye or a portion thereof is or comprise choroid, BrM, RPE, iris, retina and/or ciliary body. 706. The compound of any one of the preceding Embodiments, wherein the compound provides prolonged ocular exposure compared to a reference compound. 707. The compound of any one of the preceding Embodiments, wherein ocular exposure of the compound is about or at least about 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, 90 or 100 fold of that of a reference compound. 708. The compound of any one of the preceding Embodiments, wherein the compound provides increased melanin binding compared to a reference compound. 709. The compound of any one of the preceding Embodiments, when assessed as in the Examples, % Bound (as in Table E-2) is about or at least about 80%, 85%, 90% or 95%. 710. The compound of any one of the preceding Embodiments, when assessed as in the Examples, % Bound (as in Table E-2) is about or at least about 90%. 711. The compound of any one of the preceding Embodiments, when assessed as in the Examples, % Recovery (as in Table E-2) is about or no more than about 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, or 10%. 712. The compound of any one of the preceding Embodiments, when assessed as in the Examples, % Recovery (as in Table E-2) is about or no more than about 20%, 15%, or 10%. 713. The compound of any one of the preceding Embodiments, when assessed as in the Examples, % Unbound Compound at 6 hours (as in Table E-2) is about or no more than about 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, or 10%. 714. The compound of any one of the preceding Embodiments, when assessed as in the Examples, % Unbound Compound at 6 hours (as in Table E-2) is about or no more than about 20%, 15%, or 10%. 715. The compound of any one of Embodiments 698-707, wherein the reference compound is an otherwise identical compound but without the amino group, e.g., without R^d or R^e or both, and/or but whose Ring C comprises no basic nitrogen atom. 716. The compound of any one of the preceding Embodiments, wherein the compound is a pharmaceutically acceptable salt. 717. A pharmaceutical composition comprising a compound of any one of the preceding Embodiments or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient or diluent. 718. A pharmaceutical composition which delivers a compound of any one of the preceding Embodiments or a pharmaceutically acceptable salt thereof. 719. A method for preparing a compound or composition of any one of the preceding Embodiments. 720. A method for assessing a compound, comprising utilizing an assay described in the Examples. 721. A method of inhibiting a C3 convertase, comprising contacting a C3 convertase with a compound or composition of any one of the preceding Embodiments. 722. A method of modulating complement alternative pathway activity in a subject, wherein the method comprises administering to the subject a therapeutically effective amount of a compound or composition of any one of the preceding Embodiments. 723. A method of treating a disorder or a disease in a subject mediated by complement activation, wherein the method comprises administering to the subject a therapeutically effective amount of a compound or composition of any one of the preceding Embodiments. 724. A method of treating a disorder or a disease in a subject mediated by activation of the complement alternative pathway, wherein the method comprises administering to the subject a therapeutically effective amount of a compound or composition of any one of the preceding Embodiments. 725. The method of any one of Embodiments 721-724, wherein the subject is suffering from a disease or disorder selected from age-related macular degeneration, geographic atrophy, Stargardt’s disease, diabetic retinopathy, uveitis, glaucoma, retinitis pigmentosa, macular edema, Behcet's uveitis, multifocal choroiditis, Vogt-Koyangi-Harada syndrome, intermediate uveitis, birdshot retino-chorioditis, sympathetic ophthalmia, ocular dicatricial pemphigoid, ocular pemphigus, nonartertic ischemic optic neuropathy, post-operative inflammation, retinal vein occlusion, neurological disorders, multiple sclerosis, stroke, Creutzfeld-Jacob disease, Guillain Barre Syndrome, spinal cord injury, traumatic brain injury, Alzheimer’s disease, Parkinson's disease, progressive supranuclear palsy, corticobasal syndrome, Pick’s disease, mild cognitive impairment, Huntington’s disease, diabetic neuropathy, neuropathic pain syndromes, fibromyalgia, frontotemporal dementia, dementia with Lewy bodies, multiple system atrophy, leptomeningeal metastasis, amyotrophic lateral sclerosis (ALS), chronic inflammatory demyelinating polyneuropathy (CIDP), neuromyelitis optica (NMO), disorders of inappropriate or undesirable complement activation, hemodialysis complications, graft rejection (e.g., hyperacute allograft rejection, xenograft rejection, interleukin-2 induced toxicity during IL-2 therapy, inflammatory disorders, inflammation of autoimmune diseases, Crohn's disease, acute respiratory distress syndrome (ARDS), myocarditis, postischemic reperfusion conditions, myocardial infarction, balloon angioplasty, post-pump syndrome in cardiopulmonary bypass or renal bypass, atherosclerosis, hemodialysis, renal ischemia, mesenteric artery reperfusion after aortic reconstruction, infectious disease or sepsis, immune complex disorders and autoimmune diseases, rheumatoid arthritis, systemic lupus erythematosus (SLE), SLE nephritis, proliferative nephritis, liver fibrosis, hemolytic anemia, myasthenia gravis, tissue regeneration, neural regeneration, dyspnea, hemoptysis, asthma, chronic obstructive pulmonary disease (COPD), emphysema, pulmonary embolisms and infarcts, pneumonia, fibrogenic dust diseases, pulmonary fibrosis, rhinosinusitis, nasal polyposis, allergy, bronchoconstriction, hypersensitivity pneumonitis, parasitic diseases, Goodpasture's Syndrome, pulmonary vasculitis, pauci-immune vasculitis, thrombotic microangiopathy (TMA), immune complex-associated inflammation, antiphospholipid syndrome, glomerulonephritis, C3 glomerulopathy, IgA nephropathy, cancer, periodontitis, gingivitis, and obesity. 726. The method of Embodiment 725, wherein the condition, disorder or disease is hemolytic anemia, and the subject is suffering from paroxysmal nocturnal hemoglobinuria. 727. The method of Embodiment 725, wherein the condition, disorder or disease is hemolytic anemia, and the subject is suffering from autoimmune hemolytic anemia (e.g., cold agglutinin disease or warm autoimmune hemolytic anemia). 728. The method of any one of Embodiments 721-724, wherein the subject suffers from TMA secondary to atypical hemolytic uremic syndrome. 729. The method of any one of Embodiments 721-724, wherein the subject suffers from TMA secondary to hematopoietic stem cell transplant (HSCT-TMA). 730. The method of any one of Embodiments 721-724, wherein the subject suffers from drug-induced TMA. 731. The method of any one of Embodiments 721-724, wherein the subject suffers from complement activation secondary to administration of another therapeutic or diagnostic agent. 732. The method of any one of Embodiments 721-724, wherein the subject suffers from complement- mediated disorder is complement activation secondary to gene therapy (e.g., gene therapy with a viral vector such as an adeno-associated virus (AAV), adenovirus, or lentivirus vector). 733. The method of any one of Embodiments 721-724, wherein the subject suffers from complement- mediated disorder is complement activation secondary to cell therapy. 734. A method of treating age related macular degeneration, comprising administering to a subject suffering therefrom a therapeutically effective amount of a compound or composition of any one of the preceding Embodiments. 735. The method of Embodiment 734, wherein the age related macular degeneration is intermediate age- related macular degeneration. 736. The method of any one of Embodiments 721-735, wherein another therapeutic agent is administered such that a subject is exposed to the effects of both the compound and the another therapeutic agent. 737. The method of any one of Embodiments 721-736, wherein another therapeutic agent is administered prior to, concurrently with or subsequently to the administration of the compound. 738. The improvement in any one of the preceding Embodiments compared to a reference compound. 739. A compound or composition of any one of Embodiments 1-718 for use in the treatment or prevention of a condition, disease or disorder. 740. A compound or composition of any one of Embodiments 1-718 for use in the method of any one of the preceding Embodiments. 741. Use of a compound or composition of any one of Embodiments 1-718 for the manufacture of a medicament for treating a condition, disease or disorder. 742. Use of a compound or composition of any one of Embodiments 1-718 for the manufacture of a medicament for a method of any one of the preceding Embodiments. EXEMPLIFICATION [00374] Technologies of the present disclosure may be understood more readily by reference to the following detailed description of certain examples. [00375] Those skilled in the art appreciate that various technologies are available for preparing provided compounds and compositions in accordance with the present disclosure. For example, in some embodiments, technologies described below can be utilized to prepare or assess activity or property of provided technologies (e.g., compounds, compositions, methods, etc.). Certain useful technologies, e.g., for preparing or assessing certain activity or property of provided technologies, are described in WO 2015/009616, US 9682968, US 10093663, WO 2018/005552, WO 2019/043609, WO 2020/016749, WO 2022/028507, WO 2022/028527, WO 2022/218429, WO 2022/234541, WO 2022/256586, WO 2023/020566, WO 2023/037218, WO 2023/072197, WO 2023/139534, and WO 2023/143293, the entirety of each of which is independently incorporated by reference. [00376] Example 1. (S)-4-(1-((5-Methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl)-2- (methylamino)benzoic acid & (R)-4-(1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl)-2- (methylamino)benzoic acid & 4-(1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl)-2- (methylamino)benzoic acid.

[003

[00378] A mixture of methyl 4-bromo

5 g, 21.64 mmol), 4,4,5,5-tetramethyl-2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (8.2 g, 32.46 mmol), Pd(dppf)Cl2 (1.6 g, 2.16 mmol) and KOAc (5.3 g, 54.10 mmol) in 1,4-dioxane (50 mL) was stirred for 1h at 90 ºC under nitrogen atmosphere. The solvent was removed under vacuum. The crude product was used in the next step directly without further purification. A mixture of the above residue, 2-bromopyridine (8.5 g, 53.94 mmol), sodium carbonate (9.5 g, 89.90 mmol), CuCl (3.6 g, 35.96 mmol) and Pd(dppf)Cl₂ (2.6 g, 3.60 mmol) in 1,4-dioxane (80 mL) and water (20 mL) was stirred for overnight at 90ºC under nitrogen atmosphere. The reaction was quenched with water and extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford methyl 2-hydroxy-4-(pyridin-2-yl)benzoate (9 g, 98.27% yield) as a yellow solid. LCMS (ESI, m/z): [M+H]⁺ = 230.0. [00379] Step 2: Methyl 2-hydroxy-4-(piperidin-2-yl)benzoate. [00380] A mixture of methyl 2-hydrox zoate (5 g, 21.81 mmol) and PtO₂ (0.5 g, 2.18

mmol) in EtOH (20 mL) and HOAc (10 mL) was stirred for overnight at 60°C under 20 atm hydrogen atmosphere. The solids were filter out. The filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (10mmol/L NH₄HCO₃), 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in methyl 2-hydroxy-4-(piperidin-2-yl)benzoate (2.6 g, 49.14% yield) as a yellow oil. LCMS (ESI, m/z): [M+H]⁺ = 235.9. [00381] Step 3: tert-Butyl 4-((2-(3-hydroxy-4-(methoxycarbonyl)phenyl)piperidin-1-yl)methyl)-5- methoxy-7-methylindole-1-carboxylate. [00382] A solution of methyl 2-hydro

enzoate (600 mg, 2.55 mmol), tert-butyl 4- formyl-5-methoxy-7-methylindole-1-carboxylate (885.4 mg, 3.06 mmol) and Titanium tetraisopropanolate (7247.8 mg, 25.50 mmol) in 1,2-dichloroethane (10 mL) was stirred for 0.5 h at room temperature under nitrogen atmosphere. Then Sodium triacetoxyborohydride (1621.4 mg, 7.65 mmol) was added and stirred for additional 1 h. The resulting mixture was quenched with water and extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% TFA), 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in tert-butyl 4-((2-(3-hydroxy-4- (methoxycarbonyl)phenyl)piperidin-1-yl)methyl)-5-methoxy-7-methylindole-1-carboxylate (350 mg, 25.64% yield) as a yellow solid. LCMS (ESI, m/z): [M+H]⁺ = 509.3. [00383] Step 4: tert-Butyl 5-methoxy-4-((2-(4-(methoxycarbonyl)-3- (trifluoromethanesulfonyloxy)phenyl)piperidin-1-yl)methyl)-7-methylindole-1-carboxylate. [00384] A solution of tert-butyl 4-((2- ycarbonyl)phenyl)piperidin-1-yl)methyl)-5-

methoxy-7-methylindole-1-carboxylate (300 mg, 0.59 mmol) and 1,1,1-trifluoro-N-phenyl-N- (trifluoromethane)sulfonylmethanesulfonamide (421.4 mg, 1.18 mmol) and DIEA (152.5 mg, 1.18 mmol) in ACN (5 mL) was stirred for overnight at 80ºC. The reaction was quenched with water and extracted with Dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford tert-butyl 5-methoxy-4-((2-(4- (methoxycarbonyl)-3-(trifluoromethanesulfonyloxy)phenyl)piperidin-1-yl)methyl)-7-methylindole-1- carboxylate (120 mg, 31.12% yield) as a white solid. LCMS (ESI, m/z): [M+H]⁺ = 641.4. [00385] Step 5: tert-Butyl 5-methoxy-4-((2-(4-(methoxycarbonyl)-3-(methylamino)phenyl)piperidin-1- yl)methyl)-7-methylindole-1-carboxylate. [00386] A solution of tert-butyl 5-met

y ycarbonyl)-3- (trifluoromethanesulfonyloxy)phenyl)piperidin-1-yl)methyl)-7-methylindole-1-carboxylate (240 mg, 0.38 mmol), methylamine hydrochloride (252.9 mg, 3.75 mmol), Cesium carbonate (313.7 mg, 4.13 mmol) and Pd-PEPPSI-IPentCl 2-methylpyridine (o-picoline) (22.1 mg, 0.03 mmol) in 1,4-dioxane (2 mL) was stirred for 1 h at 100ºC under nitrogen atmosphere. The reaction was quenched with water and extracted with Dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (10mmol/L NH4HCO3), 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in tert-butyl 5-methoxy-4-((2-(4-(methoxycarbonyl)-3-(methylamino)phenyl)piperidin-1-yl)methyl)-7- methylindole-1-carboxylate (100 mg, 47.59% yield) as a yellow solid. LCMS (ESI, m/z): [M+H]⁺ = 522.4. [00387] Step 6: 4-(1-((5-Methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl)-2- (methylamino)benzoic acid I-1.. [00388] A solution of tert-butyl 5-met ycarbonyl)-3-

(methylamino)phenyl)piperidin-1-yl)methyl)-7-methylindole-1-carboxylate (60 mg, 0.12 mmol) and KOH (13 mg, 0.23 mmol) in EtOH (0.3 mL) and H2O (0.3 mL) was stirred for 2 h at 80ºC. The mixture was acidified to pH = 6 with sat. citric acid. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (10mmol/L NH4HCO3), 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in 4-(1-((5-methoxy-7- methyl-1H-indol-4-yl)methyl)piperidin-2-yl)-2-(methylamino)benzoic acid (17.3 mg, 36.47%) as a white solid. LCMS (ESI, m/z): [M+H]⁺ = 408.2.¹H NMR (300 MHz, Methanol-d4) δ 8.02 (d, J = 8.0 Hz, 1H), 7.29 (d, J = 3.1 Hz, 1H), 6.82 (d, J = 1.7 Hz, 1H), 6.74 (d, J = 7.5 Hz, 2H), 6.30 (s, 1H), 4.47 – 4.04 (m, 3H), 3.77 (s, 3H), 3.48 (d, J = 13.2 Hz, 1H), 3.18 (s, 1H), 2.95 (s, 3H), 2.50 (s, 3H), 2.08 (brs, 2H), 1.91 – 1.72 (m, 4H). [00389] Step 7: tert-Butyl 5-methoxy-4-(((2S)-2-(4-(methoxycarbonyl)-3-(methylamino)phenyl)piperidin- 1-yl)methyl)-7-methylindole-1-carboxylate & tert-butyl 5-methoxy-4-(((2R)-2-(4-(methoxycarbonyl)-3- (methylamino)phenyl)piperidin-1-yl)methyl)-7-methylindole-1-carboxylate. [00390] tert-butyl 5-metho no)phenyl)piperidin-1-

yl)methyl)-7-methylindole-1-carboxylate (100 mg) was applied for further separation by Chiral HPLC with the following condition: Column: CHIRALPAK IG, 5*25 cm, 5 μm; Mobile Phase A: Hex(0.5% 2M NH3- MeOH)--HPLC, Mobile Phase B: EtOH--HPLC; Gradient: isocratic ; Wave Length: 220/254 nm; RT1(min): 7.55; RT2(min): 9.874; Sample Solvent: EtOH-HPLC. [00391] The faster peak was assigned as Isomer ester I-1-1 and the slower peak was assigned as Isomer ester I-1-2. [00392] Isomer ester I-1-1: 37 mg, 37% yield, LCMS (ESI, m/z): [M+H]⁺ = 522.4. [00393] Isomer ester I-1-2: 36 mg, 36% yield, LCMS (ESI, m/z): [M+H]⁺ = 522.4. [00394] Step 8: (S)-4-(1-((5-Methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl)-2- (methylamino)benzoic acid & (R)-4-(1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl)-2- (methylamino)benzoic acid. [00395] A solution of

g, . . mg, 0.40 mmol) in EtOH (0.3 mL) and H₂O (0.3 mL) was stirred for 2h at 80 ºC. The mixture was acidified to pH = 6 with sat. citric acid. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (10 mmol/L NH₄HCO₃), 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in Isomer I-1-1 (10 mg, 34.45% yield) as a white solid. LCMS (ESI, m/z): [M+H]⁺ = 408.3.¹H NMR (300 MHz, Methanol-d4) δ 8.01 (d, J = 7.9 Hz, 1H), 7.29 (d, J = 3.1 Hz, 1H), 6.83 – 6.69 (m, 3H), 6.30 (s, 1H), 4.42 (d, J = 12.7 Hz, 1H), 4.20 (s, 1H), 4.08 (s, 1H), 3.77 (s, 3H), 3.46 (s, 1H), 3.16 (s, 1H), 2.95 (s, 3H), 2.50 (s, 3H), 2.06 (s, 2H), 1.90 – 1.60 (m, 4H). [00396] A solution of Isomer ester I-1-2 and KOH (23.2 mg, 0.41 mmol) in EtOH (0.3 mL) and H₂O (0.3 mL) was stirred for 2h at 80 ºC under air atmosphere. The mixture was acidified to pH = 6 with sat. citric acid. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (10 mmol/L NH₄HCO₃), 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in Isomer I-1-2 (13.7 mg, 47.98% yield) as a white solid. LCMS (ESI, m/z): [M+H]+ = 408.3.¹H NMR (300 MHz, Methanol-d4) δ 8.01 (d, J = 7.9 Hz, 1H), 7.29 (d, J = 3.1 Hz, 1H), 6.83 – 6.69 (m, 3H), 6.30 (s, 1H), 4.42 (d, J = 12.7 Hz, 1H), 4.20 (s, 1H), 4.08 (s, 1H), 3.77 (s, 3H), 3.46 (s, 1H), 3.16 (s, 1H), 2.95 (s, 3H), 2.50 (s, 3H), 2.06 (s, 2H), 1.90 – 1.60 (m, 4H). [00397] One of Isomer I-1-1 and Isomer I-1-2 is I-2 and the other is I-3. [00398] Example 2.6-(4,4-Difluoro-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl)-2- (methylamino)nicotinic acid

[00399] Step 1: Methyl 2-acetamido-6-bromonicotinate. [00400] To a stirred solution of methyl yridine-3-carboxylate (2 g, 8.76 mmol) and pyridine (1.37 g, 17.31 mmol) in dichlorome

thane (30 mL) was added acetyl chloride (1.36 g, 17.31 mmol) dropwise at 0 ºC. The resulting mixture was stirred for 2 h at room temperature. After completion, the reaction mixture was diluted with water and extracted with dichloromethane. Then the organic layers were combined and washed with brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with PE / EA (3:1) to afford the title compound (2.22 g, 88.3% yield) as a white solid. LCMS (ESI): [M+H] ⁺ =273.0 and 275.0. [00401] Step 2: Methyl 2-acetamido-6-(1-(tert-butoxycarbonyl)-4,4-difluoropiperidin-2-yl)nicotinate. [00402] A solution of methyl 6-bro

carboxylate (100 mg, 0.366 mmol), [Ir(dF(Me)ppy)2(dtbbpy)]PF6 (18.57 mg, 0.018 mmol), nickel(ii) chloride ethylene glycol dimethyl ether complex (8.05 mg, 0.037 mmol), 4,4-di-tert-butyl bipyridine (9.83 mg, 0.037 mmol) and Cesium carbonate (360.32 mg, 1.11 mmol) in DMF (0.5 mL) was stirred for 12 h under nitrogen atmosphere under blue light. After completion, the reaction mixture was diluted with water and extracted with dichloromethane. Then the organic layers were combined and washed with brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with PE / EA (5:1) to afford the title compound (50 mg, 33.0% yield) as a yellow solid. LCMS (ESI): [M+H]⁺ = 414.2. [00403] Step 3: Methyl 2-amino-6-(4,4-difluoropiperidin-2-yl)nicotinate. [00404] A solution of methyl 6-[1-(t

e - u o yca o y - , - ifluoropiperidin-2-yl]-2-acetamidopyridine- 3-carboxylate (750 mg, 1.81 mmol) in dichloromethane (10 mL) and trifluoroacetic acid (5 mL) was stirred for 1h at room temperature. The solvent was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (3:1) to afford the title compound (620 mg) as a yellow solid and as crude. LCMS (ESI): [M+H] ⁺ =272.1. [00405] Step 4: tert-Butyl 4-((2-(6-amino-5-(methoxycarbonyl)pyridin-2-yl)-4,4-difluoropiperidin-1- yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate. [00406] A solution of methyl 2-ami -2-yl)pyridine-3-carboxylate (310 mg, 1.14

mmol), tert-butyl 4-formyl-5-methoxy-7-methylindole-1-carboxylate (662 mg, 2.29 mmol) in 1,2- Dichloroethane (5 mL) was added titanium(IV) ethoxide (522 mg, 2.29 mmol) and stirred for 40 mins at 70ºC. Then sodium triacetoxyborohydride (727 mg, 3.43 mmol) was added at room temperature. The resulting mixture was stirred for 40 mins at 70ºC. After completion, the reaction mixture was diluted with water and extracted with dichloromethane. Then the organic layers were combined and washed with brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with PE / EA (5:1) to afford the title compound (135 mg, 21.69%) as a yellow solid. LCMS (ESI): [M+H] ⁺ =545.2. [00407] Step 5: tert-Butyl 4-((4,4-difluoro-2-(5-(methoxycarbonyl)-6-(methylamino)pyridin-2- yl)piperidin-1-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate. [00408] A solution of tert-Butyl 4-(

y rbonyl)pyridin-2-yl)-4,4-difluoropiperidin- 1-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (60 mg, 0.110 mmol) and titanium tetraisopropanolate (63 mg, 0.22 mmol) in MeOH (0.5 mL) was added paraformaldehyde (3 mg, 0.100 mmol) and stirred for 40 min at 70 ºC. Then sodium triacetoxyborohydride (70 mg, 0.33 mmol) was added and stirred for 40 mins at 70 ºC. After completion, the reaction mixture was diluted with water and extracted with dichloromethane. Then the organic layers were combined and washed with brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (10mmol/L NH₄HCO₃), 5% to 95% gradient in 50 mins; detector, UV 254 nm. This resulted in the title compound (20 mg, 32.5% yield) as a white solid. LCMS (ESI): [M+H] ⁺ =589.3. [00409] Step 6: 6-(4,4-Difluoro-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl)-2- (methylamino)nicotinic acid. [00410] A solution of tert-butyl 4-((4 xycarbonyl)-6-(methylamino)pyridin-2-

yl)piperidin-1-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (20 mg, 0.036 mmol) in ethanol (0.2 mL) was added potassium hydroxide (40 mg, 0.713 mmol) in water (0.2 mL) and stirred for 2h at 70 ºC. The reaction was adjusted to pH = 7 with sat. citric acid. The solvent was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (10mmol/L NH₄HCO₃), 5% to 50% gradient in 20 min; detector, UV 254 nm. This resulted in the title compound (8.8 mg, 53.9% yield) as a white solid. LCMS (ESI): [M+H] ⁺ =445.2, ¹H NMR (400 MHz, Methanol-d₄) δ 8.07 (d, J = 7.6 Hz, 1H), 7.22 – 7.15 (m, 1H), 6.74 (s, 1H), 6.58 (d, J = 3.1 Hz, 1H), 6.53 (d, J = 7.6 Hz, 1H), 5.00 (d, J = 13.4 Hz, 1H), 4.93 – 4.90 (m, 1H), 3.88 (s, 3H), 3.32 – 3.25 (m, 1H), 3.10 (d, J = 12.4 Hz, 1H), 2.58 – 2.50 (m, 1H), 2.49 (s, 3H), 2.41 – 2.22 (m, 2H), 2.19 (s, 3H), 2.17 – 2.12 (m, 3H). [00411] Example 3. 2-Amino-6-(4,4-difluoro-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2- yl)nicotinic acid.

O NH₂ O NH₂ O N HO N F F [00412] ropiperidin-

1-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (50 mg, 0.092 mmol) in ethanol (0.5 mL) was added Potassium hydroxide (103 mg, 1.84 mmol) in water (0.5 mL) and stirred for 2 h at 70 ºC. Desired product could be detected by LCMS. The reaction was adjusted to pH = 7 with sat. citric acid. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (10mmol/L NH4HCO3), 5% to 50% gradient in 20 min; detector, UV 254 nm. This resulted in the title compound (27.3 mg, 68.7% yield) as a white solid. LCMS (ESI): [M+H] ⁺ =431.2, ¹H NMR (300 MHz, Methanol-d4) δ 8.24 (d, J = 7.7 Hz, 1H), 7.29 (d, J = 3.1 Hz, 1H), 6.85 (d, J = 7.7 Hz, 1H), 6.74 (s, 1H), 6.42 (d, J = 3.2 Hz, 1H), 4.26 – 4.03 (m, 2H), 3.94 (d, J = 12.1 Hz, 1H), 3.83 (s, 3H), 3.11 – 2.91 (m, 1H), 2.59 – 2.46 (m, 4H), 2.42 – 2.01 (m, 4H). [00413] Example 4. 2-Amino-4-((2R,4R)-4-ethoxy-1-((5-methoxy-7-methyl-1H-indol-4- yl)methyl)piperidin-2-yl)benzoic acid, 2-Amino-4-((2S,4S)-4-ethoxy-1-((5-methoxy-7-methyl-1H-indol-4- yl)methyl)piperidin-2-yl)benzoic acid, 2-Amino-4-((2R,4S)-4-ethoxy-1-((5-methoxy-7-methyl-1H-indol-4- yl)methyl)piperidin-2-yl)benzoic acid, and 2-amino-4-((2S,4R)-4-ethoxy-1-((5-methoxy-7-methyl-1H-indol- 4-yl)methyl)piperidin-2-yl)benzoic acid.

[

[00415] A solution of 4-bromo-2-chl 6.2 mmol) in THF was added 2 M isopropylmagnesium chloride in THF (6 m

L, 120.0 mmol) and stirred for 2 h at 0 ºC under nitrogen atmosphere. Then 4-methoxypyridine (7.6 g, 69.3 mmol) and Benzyl chloroformate (11.8 g, 69.3 mmol) was added by dropwise at -5ºC. And the mixture was stirred for 16 h at room temperature under nitrogen atmosphere. The mixture was adjusted to pH 2 with 2 M HCl. The resulting mixture was extracted with Ethyl acetate and washed with brine, dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (1:1) to afford the title compound (7 g, 41% yield) as a yellow oil. LCMS (ESI): [M+H] ⁺ = 367.1. [00416] Step 2: Benzyl 2-(3-chloro-4-cyanophenyl)-4-oxopiperidine-1-carboxylate. [00417] A mixture of benzyl 2-(3-chl

xo-2,3-dihydropyridine-1-carboxylate (3 g, 8.17 mmol) and Zn (5.34 g, 81.70 mmol) in HOAc (30 mL) was stirred for 2 h at 100 ºC. The solids were filtered out. The filtrate was concentrated to afford the title compound (3 g) as crude. LCMS (ESI): [M+H] ⁺ = 369.1. [00418] Step 3: Benzyl 2-(3-chloro-4-cyanophenyl)-4-hydroxypiperidine-1-carboxylate. [00419] A solution of benzyl 2-(3-ch

xopiperidine-1-carboxylate (3 g, 8.13mmol) in THF (10 mL) was added Sodium borohydride (1495 mg, 39.53 mmol) and stirred for 1 h at room temperature. The reaction was quenched with sat. Ammonium chloride at 0 ºC and extracted with ethyl acetate. The solvent was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (1:1) to afford the title compound (2.5 g, 83% yield) as a yellow oil. LCMS (ESI, m/z): [M+H] ⁺ = 371.1. [00420] Step 4: Benzyl 2-(3-chloro-4-cyanophenyl)-4-ethoxypiperidine-1-carboxylate. [00421] Under nitrogen, a solution nophenyl)-4-hydroxypiperidine-1- carboxylate (15 g, 40.45 mmol) in THF

(500 mL) was added ethyl trifluoromethanesulfonate (14.41 g, 80.90 mmol) and 1 M NaHMDS in THF (121 mL, 121.35 mmol) at -78ºC and stirred for 1h at the same temperature. The reaction was quenched with sat. NH₄Cl at 0ºC. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layers were combined. The organic layer was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with PE/EA (3/1) to afford the title compound (6.5 g, 34.6% yield) as a white oil. LCMS (ESI): [M+H] ⁺ = 399.1. [00422] Step 5: 4-(1-((Benzyloxy)carbonyl)-4-ethoxypiperidin-2-yl)-2-chlorobenzoic acid. [00423] A solution of benzyl 2-(3

xypiperidine-1-carboxylate (6.5 g, 17.54 mmol) in isopropyl alcohol (80 mL) was added Barium hydroxide (30.07 g, 175.49 mmol) in water (40 mL) and stirred for overnight at 100ºC. The resulting mixture was filtered, the filter cake was washed with methanol. The filtrate was neutralized to pH =7 with 2 M HCl. The solvent was concentrated under vacuum. The crude product was used in the next step directly without further purification. LCMS (ESI): [M+H]⁺ = 418.1. [00424] Step 6: Benzyl 2-(3-chloro-4-(methoxycarbonyl)phenyl)-4-ethoxypiperidine-1-carboxylate. [00425] A solution of 4-(1-((Benz

ridin-2-yl)-2-chlorobenzoic acid (6.5 g, 15.55 mmol) in methanol (8 mL) and dichloromethane (60 mL) was added 2 M (trimethylsilyl)diazomethane in hexane (31 mL, 62.21 mmol) and stirred for 1h at room temperature. The solvent was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with PE/EA (4/1) to afford the title compound (5 g, 59.2% yield) as a yellow oil. LCMS (ESI): [M+H]⁺ = 432.1. [00426] Step 7: Benzyl 2-(3-((tert-butoxycarbonyl)amino)-4-(methoxycarbonyl)phenyl)-4- ethoxypiperidine-1-carboxylate.

[00427] Under nitrogen, a solution of Benzyl 2-(3-chloro-4-(methoxycarbonyl)phenyl)-4- ethoxypiperidine-1 -carboxylate (5 g, 11.57mmol), tert-butyl carbamate (6.78 g, 57.88 mmol), Tris(dibenzylideneacetone)dipalladium (1.59 g, 1.73mmol), XantPhos (1004.78 mg, 1.73 mmol), Cesium carbonate (11.32 g, 34.72 mmol) in dioxane (55 mL) was stirred for overnight at 100°C. The solvent was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with PE/EA (4/1) to afford the title compound (6 g, 28.2% yield) as a yellow oil. LCMS (ESI): [M+H] ⁺= 513.3. [00428] Step 8: Methyl 2-((tert-butoxycarbonyl)amino)-4-(4-ethoxypiperidin-2-yl)benzoate.

[00429] Under hydrogen, a mixture of Benzyl 2-(3-((tert-butoxycarbonyl)amino)-4- (methoxycarbonyl)phenyl)-4-ethoxypiperidine-l -carboxylate (6 g, 11.70 mmol) and 10% Pd/C (6 g, 56.41 mmol) in ethyl acetate (80 mL) was stirred for Ih at room temperature. The solids were filtered out. The filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, Cl 8 silica gel; mobile phase, MeCN in Water (lOmmol/L NH4HCO3), 10% to 58% gradient in 30 min; detector, UV 254 nm. This resulted in the title compound (1.5 g, 32.4% yield) as a yellow oil. LCMS (ESI,): [M+H] ⁺= 379.2.

[00430] Step 9: tert- Butyl 4-((2-(3-((tert-butoxycarbonyl)amino)-4-(methoxycarbonyl)phenyl)-4- ethoxypiperidin- 1 -yl)methyl)-5-methoxy-7 -methyl- 1 H-indole- 1 -carboxylate.

[00431] A solution of Methyl 2-((tert-butoxycarbonyl)amino)-4-(4-ethoxypiperidin-2-yl)benzoate (1.5 g.

3.96 mmol) in 1 ,2-Dichloroethane (30 mL) was added tert-butyl 4-formyl-5-methoxy-7-methylindole-l- carboxylate (2.29 g, 7.92 mmol), Sodium triacetoxyborohydride (2.52 g, 11.88 mmol), HOAc (0.71 g, 11.88 mmol) and stirred for overnight at 70ºC. The reaction mixture was quenched with water and extracted with ethyl acetate and the organic layers were combined. The solvent was removed under vacuum. The residue was purified by silica gel column chromatography, eluted with PE/EA (0-37%) to afford the title compound (900 mg, 29.96% yield) as a yellow oil. LCMS (ESI): [M+H]⁺ = 651.4. [00432] Step 10: tert-Butyl 4-(((2R,4R)-2-(3-amino-4-(methoxycarbonyl)phenyl)-4-ethoxypiperidin-1- yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate, tert-Butyl 4-(((2S,4S)-2-(3-amino-4- (methoxycarbonyl)phenyl)-4-ethoxypiperidin-1-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate, tert-Butyl 4-(((2R,4S)-2-(3-amino-4-(methoxycarbonyl)phenyl)-4-ethoxypiperidin-1-yl)methyl)-5-methoxy- 7-methyl-1H-indole-1-carboxylate, and tert-Butyl 4-(((2S,4R)-2-(3-amino-4-(methoxycarbonyl)phenyl)-4- ethoxypiperidin-1-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate. [ ridin-

1-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (900 mg) was applied for 2 rounds Chiral separation with the following conditions to afford 4 isomers: [00434] Column: CHIRALPAK IF, 2*25 cm, 5 μm; Mobile Phase A: HEX(0.5% 2M NH3-MeOH), Mobile Phase B: IPA; Flow rate: 20 mL/min; Gradient: isocratic 5; Wave Length: 220/254 nm; RT1(min): 4.876; RT2(min): 6.878; Sample Solvent: EtOH; Injection Volume: 0.6 mL; Number Of Runs: 14. [00435] Column: CHIRALPAK IF, 2*25 cm, 5 μm; Mobile Phase A: HEX(0.5% 2M NH3-MeOH), Mobile Phase B: IPA; Flow rate: 20 mL/min; Gradient: isocratic 5; Wave Length: 220/254 nm; RT1(min): 3.994; RT2(min): 4.973; Sample Solvent: EtOH; Injection Volume: 0.5 mL; Number Of Runs: 32. [00436] Certain data for the four isomers: [00437] A: 70 mg, 7.8% yield; tR = 1.02 min (CHIRALPAK IF-3 (4.6*50 mm, 3 µm), Hex(0.1%DEA):IPA=93:7, 1.0 mL/min, 254 nm). [00438] B: 85 mg, 9.4% yield; tR = 1.40 min (CHIRALPAK IF-3 (4.6*50 mm, 3 µm), Hex(0.1%DEA):IPA=93:7, 1.0 mL/min, 254 nm). [00439] C: 120 mg, 13.3% yield; tR = 0.99 min (CHIRALPAK IF-3 (4.6*50 mm, 3 µm), Hex(0.1%DEA):IPA=97:3, 1.0 mL/min, 254 nm). [00440] D: 130 mg, 14.4% yield; tR = 1.39 min (CHIRALPAK IF-3 (4.6*50 mm, 3 µm), Hex(0.1%DEA):IPA=97:3, 1.0 mL/min, 254 nm). [00441] Step 11: 2-Amino-4-((2R,4R)-4-ethoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin- 2-yl)benzoic acid, 2-Amino-4-((2S,4S)-4-ethoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2- yl)benzoic acid, 2-Amino-4-((2R,4S)-4-ethoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2- yl)benzoic acid, and 2-amino-4-((2S,4R)-4-ethoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin- 2-yl)benzoic acid. [

hydroxide (43.04 mg, 0.77 mmol) in water (0.5 mL). After stirring for 48 h at 100ºC, the mixture was allowed to cool down to room temperature. The residue was adjusted to pH = 7 with sat. citric acid. The solvent was removed. The residue was purified by reverse phase flash with the following conditions (ACN, 5-20% / 10 mM NH4HCO3 in water) to afford the acid (11.5 mg, 33.5% yield) as a light brown solid. LCMS (ESI): [M+H] ⁺ = 438.2.¹H NMR (400 MHz, DMSO-d6) δ 10.80 (t, J = 2.3 Hz, 1H), 8.77 – 8.08 (brs, 1H), 7.71 (d, J = 8.2 Hz, 1H), 7.23 (t, J = 2.8 Hz, 1H), 6.85 (s, 1H), 6.75 – 6.59 (m, 2H), 6.53 – 6.38 (m, 1H), 3.70 (s, 3H), 3.59 (d, J = 11.8 Hz, 1H), 3.47 – 3.36 (m, 2H), 3.36 – 3.26 (m, 1H), 3.19 – 3.11 (m, 1H), 3.03 – 2.94 (m, 1H), 2.76 – 2.67 (m, 1H), 2.41 (s, 3H), 2.03 – 1.88 (m, 2H), 1.80 (d, J = 12.0 Hz, 1H), 1.48 – 1.34 (m, 1H), 1.26 – 1.09 (m, 1H), 1.05 (t, J = 7.0 Hz, 3H). [00443] To a solution of isomer B (50 mg, 0.07 mmol) in ethanol (0.5 mL) was added Potassium hydroxide (43.04 mg, 0.77 mmol) in water (0.5 mL). After stirring for 48 h at 100ºC, the mixture was allowed to cool down to room temperature. The residue was adjusted to pH = 7 with sat. citric acid. The solvent was removed. The residue was purified by reverse phase flash with the following conditions (ACN, 5-20% / 10 mM NH4HCO3 in water) to afford the acid (6.7 mg, 19.1% yield) as a light brown solid. LCMS (ESI): [M+H] + = 438.2.¹H NMR (400 MHz, DMSO-d6) δ 10.80 (t, J = 2.3 Hz, 1H), 8.77 – 8.08 (brs, 1H), 7.71 (d, J = 8.2 Hz, 1H), 7.23 (t, J = 2.8 Hz, 1H), 6.85 (s, 1H), 6.75 – 6.59 (m, 2H), 6.53 – 6.38 (m, 1H), 3.70 (s, 3H), 3.59 (d, J = 11.8 Hz, 1H), 3.47 – 3.36 (m, 2H), 3.36 – 3.26 (m, 1H), 3.19 – 3.11 (m, 1H), 3.03 – 2.94 (m, 1H), 2.76 – 2.67 (m, 1H), 2.41 (s, 3H), 2.03 – 1.88 (m, 2H), 1.80 (d, J = 12.0 Hz, 1H), 1.48 – 1.34 (m, 1H), 1.26 – 1.09 (m, 1H), 1.05 (t, J = 7.0 Hz, 3H). [00444] To a solution of isomer C (100 mg, 0.15 mmol) in ethanol (1 mL) was added Potassium hydroxide (86.08 mg, 1.53 mmol) in water (1 mL). After stirring for 48 h at 100ºC, the mixture was allowed to cool down to room temperature. The residue was adjusted to pH = 7 with sat. citric acid. The solvent was removed. The residue was purified by reverse phase flash with the following conditions (ACN, 5-20% / 10 mM NH₄HCO₃ in water) to afford the acid (13.0 mg, 18.5% yield) as a light brown solid. LCMS (ESI): [M+H] ⁺ = 438.2.¹H NMR (400 MHz, DMSO-d₆) δ 10.79 (s, 1H), 7.71 (d, J = 8.2 Hz, 1H), 7.23 (t, J = 2.8 Hz, 1H), 6.86 (s, 1H), 6.74 (d, J = 8.3 Hz, 1H), 6.65 (s, 1H), 6.51 (dd, J = 3.1, 1.9 Hz, 1H), 3.72 (s, 3H), 3.64 – 3.53 (m, 2H), 3.49 – 3.38 (m, 2H), 3.30 – 3.14 (m, 2H), 2.48 – 2.35 (m, 4H), 2.24 (t, J = 12.0 Hz, 1H), 1.88 – 1.74 (m, 1H), 1.68 (t, J = 13.1 Hz, 2H), 1.48 – 1.37 (m, 1H), 1.16 (t, J = 7.0 Hz, 3H). [00445] To a solution of isomer D (100 mg, 0.15 mmol) in ethanol (1 mL) was added Potassium hydroxide (86.08 mg, 1.53 mmol) in water (1 mL). After stirring for 48 h at 100ºC, the mixture was allowed to cool down to room temperature. The residue was adjusted to pH = 7 with sat. citric acid. The solvent was removed. The residue was purified by reverse phase flash with the following conditions (ACN, 5-20% / 10 mM NH₄HCO₃ in water) to afford the acid (24.9 mg, 35.3%yield) as a light brown solid. LCMS (ESI): [M+H] ⁺ = 438.2.¹H NMR (400 MHz, DMSO-d6) δ 10.79 (s, 1H), 7.71 (d, J = 8.2 Hz, 1H), 7.23 (t, J = 2.8 Hz, 1H), 6.86 (s, 1H), 6.74 (d, J = 8.3 Hz, 1H), 6.65 (s, 1H), 6.51 (dd, J = 3.1, 1.9 Hz, 1H), 3.72 (s, 3H), 3.64 – 3.53 (m, 2H), 3.49 – 3.38 (m, 2H), 3.30 – 3.14 (m, 2H), 2.48 – 2.35 (m, 4H), 2.24 (t, J = 12.0 Hz, 1H), 1.88 – 1.74 (m, 1H), 1.68 (t, J = 13.1 Hz, 2H), 1.48 – 1.37 (m, 1H), 1.16 (t, J = 7.0 Hz, 3H). [00446] Example 5. Provided compounds can inhibit complement activation. [00447] Among other things, provided compounds can modulate complement activation. In some embodiments, provided technologies inhibit complement activation. In some embodiments, provided technologies inhibit C3 convertase. Various technologies are available for assessing provided compounds, compositions and methods. In some embodiments, a useful assay is an assay described below. In some embodiments, IC50 of a provided compound measured in an assay is about or no more than about 1000, 900, 800, 700, 600, 500, 400, 300, 200, 100, 90, 80, 70, 60, 50, 40, 30, 20, or 10 nM. In some embodiments, a useful assay is a biochemical assay assessing inhibition of C3 convertase activity by a provided compound. In some embodiments, a purified, isolated or enriched C3 convertase is utilized. In some embodiments, CVF:Bb (e.g., assembled from three components Cobra Venom Factor (CVF), Complement Factor B (FB) and Complement Factor D (FD)) was utilized, sometimes using different concentrations of CVF (certain results are presented as “A” or “B” in the Table below). In some embodiments, a compound was first contacted with CVF:Bb, followed by addition of C3 substrates. As those skilled in the art will appreciate, products C3a and/or C3b could be detected through a number of technologies (e.g., antibodies specific for a product) and reduction of levels of one or both of them could be utilized to assess inhibition. In some embodiments, a useful assay is Wieslab® assay (certain results are presented as “C” in the Table below). [00448] In some embodiments, classical and alternative pathway activity are assessed using Wieslab® technologies. In some embodiments, Wieslab® assay was performed with a commercially available kit, using a protocol adapted for measurement of complement inhibitory activity of compounds. In some embodiments, human serum was utilized as a positive control. In some embodiments, human serum serves as a source of complement proteins, and inhibition of complement activity of a serum by various compounds were assessed. In some embodiments, a kit is COMPL AP330, Complement Alternative Pathway ELISA, Eagle Biosciences. In some embodiments, a kit is COMPL CP310, Complement Classical Pathway ELISA, Eagle Biosciences. In some embodiments, kits are available from VWR (102994-104, Complement Alternative pathway ELISA, Eagle Biosciences, Inc.; 102994-106, Complement Classical pathway ELISA, Eagle Biosciences, Inc.). [00449] In some embodiments, a useful procedure described below is utilized: 1. Make fresh test compound stock at 1 mM. 2. Test compound serial dilution: dilute the stock to working stock concentrations. Add DMSO to dilution buffer using same dilution factor for the working stock so the composition of all the serial diluted stock is the same. In some embodiments, stock was serial diluted from the working stock 1: 4 (for classical pathway) or 1:2 (for alternative pathway) using new diluted dilution buffers. 3. Dilute positive controls using the dilution buffer provided with the assay kit to 2X of the final conc., for classical pathway, 50.5X. Positive control is human serum, which contains complement proteins. 4. Add 125 μL of test compound solution and 125 μL of diluted positive control to a 96 well polypropylene plate, mix gently and cover the plate and incubate at 4 °C for 30 min. 5. Add 100 μL/well to the assay plate and incubate at 37 °C for 1h. Typically, controls in the assay plate, for example, buffer alone for negative control, positive control alone to verify the complement activity of the reagent. 6. Wash plate and add 100 μL/well conjugate, incubate at room temperature for 30 min. 7. Wash plate and add 100 μL/well substrate, then incubate at room temperature for approximately 30 minutes. Periodically monitor the absorbance at 405 nm (OD405) in the positive control alone well. 8. Once the OD405 is > 1, read the whole plate immediately. Or stop the reaction by adding 100 μL of 5 mM EDTA to each well and read within 60 minutes. [00450] Certain results are provided below using technologies described above or similar technologies. A: C3 Convertase Assay (2nM CVF) IC50 (nM). B. C3 Convertase Assay (0.5nM CVF) IC50 (nM). C: Wieslab AP IC50 (nM) (alternative pathway). NA: IC50 greater than 10 uM. As demonstrated herein, various compounds can inhibit C3 convertase activity and/or complement activation. Table E-1. Certain compounds and data. Compound A C

[00451] Results from additional assessments are provided below as additional examples, confirming activities, benefits, advantages, etc. of provided technologies. Table E-1b. Certain compounds and data. A & C: See Table E-1. Compound A C

[00452] Results from additional assessments are provided below as additional examples, confirming activities, benefits, advantages, etc. of provided technologies. Table E-1c. Certain compounds and data. B & C: See Table E-1 and E-1b. For each I-X, I-X-1, I-X-2, I-X-3, and I-X-4 are its isomers. Compound B C

[00453] Results from additional assessments are provided below as additional examples, confirming activities, benefits, advantages, etc. of provided technologies.

Table E-ld. Certain compounds and data. A : See Table E-l, E-lb, and E-lc.

[00454] Example 6. Provided compounds can bind to melanin.

[00455] Among other things, the present disclosure provides technologies for improving binding to melanin, for improving delivery to eyes (e.g., choroid/BrM/RPE, Iris-ciliary body, etc.), for increasing choroid/BrM/RPE concentrations (absolute or relative to, e.g., plasma), for increasing iris-ciliary body concentrations (absolute or relative to, e.g., plasma), for increasing exposure at eyes, etc. In some embodiments, the present disclosure provides technologies, e.g., compounds, compositions, methods, etc., with such improvements and advantages. Various technologies are available for assessing provided technologies in accordance with the present disclosure. In some embodiments, provided technologies are assessed in biochemical assays. In some embodiments, provided technologies are assessed using animal models, e.g., pigmented/less or non-pigmented animals. In some embodiments, useful animals include Dutch-belted rabbits, New Zealand white rabbits, pigmented (e.g., BN) rats, albino (e.g., SD) rats, etc.

[00456] For example, in some embodiments, various compounds are assessed following protocols below (or protocols similar thereto) for melanin binding.

[00457] 1. Preparation of melanin suspension. Melanin is stored in a -20°C freezer. Prior to use, melanin was suspended into PBS (pH 7.4) at 10 mg/mL and sonicated for 5 min at 37 °C

[00458] 2. Preparation of Working Solutions. The working solutions of test compounds and control compound were prepared in DMSO at the concentration of 200 pM, and then the working solutions were spiked into melanin suspension. The final concentration of compounds was 1 LIM. The final concentration of DMSO was 0.5%. Propranolol was used as positive control in the assay.

[00459] 3. Preparation of Dialysis Membranes. The dialysis membranes were soaked in ultrapure water for 60 minutes to separate strips, then in 20% ethanol for 20 minutes, finally in dialysis buffer for 20 minutes. [00460] 4. Procedure for Equilibrium Dialysis. The dialysis set up was assembled according to the manufacturer’s instruction. Each Cell was with 150 pL of melanin suspension sample and dialyzed against equal volume of dialysis buffer (PBS). The assay was performed in duplicate. The dialysis plate was sealed and incubated in an incubator at 37°C with 5% CO2 at 100 rpm for 6 hours. At the end of incubation, 50 pL of samples from both buffer and melanin chambers were transferred to wells of a 96-well plate.

[00461] 5. Procedure for Sample Analysis. 50 pL of melanin suspension was added to each buffer samples and an equal volume of PBS was supplemented to the collected melanin sample. 400 pL of cold acetonitrile containing internal standards (IS, 100 nM alprazolam, 200 nM labetalol, 200 nM imipramine and 2 pM ketoprofen) was added to precipitate protein and release compounds. Samples were vortexed for 2 minutes and centrifuged for 30 minutes at 3,220 g. Aliquot of 100 pL of the supernatant was diluted by 100 pL ultra-pure H2O, and the mixture was used for LC-MS/MS analysis.

[00462] 6. Stability Determination in Melanin Suspension. 50 pL of spiked melanin suspension sample was transfered to new plate, respectively. Incubate samples at 37°C, 5% CO2 for 0 and 6 hrs. At designated time points, add 50 pL of PBS. Mix thoroughly and then add 400 pL of room temperature quench solution (acetonitrile containing internal standards (IS, 200 nM labetalol, 100 nM tolbutamide and 100 nM ketoprofen)) to precipitate protein and release compounds. Samples were vortexed for 2 minutes and centrifuged for 30 minutes at 3,220 g. Aliquot of 100 pL of the supernatant was diluted by ultra-pure H2O, and the mixture was used for LC-MS/MS analysis.

[00463] 7. Data analysis. All calculations were carried out using Microsoft Excel. The concentrations of test compounds in the buffer and melanin suspension chambers were determined from peak area ratios. The percentages of bound compound were calculated as follows:

% Free — (Peak Area Ratio buffer chamber I Peak Area Ratio melanin suspension chamber) *100%

% Bound = 100% - % Free

Certain results are presented below as examples. As demonstrated, provided technologies can provide, among other things, dramatically increased binding to melanin.

Table E-2. Certain compounds and data.

[00464] Various other compounds with various structural elements, including various combinations of Ring A, Ring B and Ring C moieties, that comprise structural features as described herein, e.g., amino groups at Ring C (e.g., various compounds in Table E-l, E-lb, E-lc or E-ld), also demonstrated greatly improved melanin binding, including % Recovery and/or % Remaining at 6 hours at or below about 80%, 75%, 70%, 65%, 60%, 55%. 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, or 10% of % Recovery and/or % Remaining at 6 hours, respectively, of the corresponding compounds without such structural features (e.g., amino groups at Ring C), and/or % Recovery and/or % Remaining at 6 hours at or below about 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, or 10%, respectively. In some embodiments, increased binding to melanin and/or concentrations at eyes or portions thereof (e.g., choroid, BrM, RPE, iris, and/or ciliary body, retina, etc.) (absolute or relative to a reference, e.g., plasma) are achieved in animals. In some embodiments, ratio of a concentration at an eye or a portion thereof (e.g.. retina) over plasma concentration is increased to about or more than about 2, 3, 4, 5, 6, 7, 8, 9, or 10 fold that of a reference compound (e.g., an otherwise identical compound without an amino group at Ring C).

[00465] Example 7. Provided compounds can provide high permeability.

[00466] Among other things, provided compounds have various beneficial properties and/or activities. For example, as demonstrated in the present Example, various compounds demonstrate high permeability. [00467] Various technologies can be utilized to assess permeability in accordance with the present disclosure. A useful protocol is described below as an example [00468] Caco-2 permeability assay.

[00469] 1. Prepar ation of Caco-2 Cells. 1) 50 uL and 25 mL of cell culture medium were added to each well of the Transwell insert and reservoir, respectively. Then the HTS transwell plates were incubated at 37 °C, 5% CO2 for 1 hour before cell seeding. 2) Caco-2 cell cells were diluted to 6.86xl0⁵ cells/mL with culture medium and 50 uL of cell suspension were dispensed into the filter well of the 96-well HTS Transwell plate. Cells were cultivated for 14-18 days in a cell culture incubator at 37 °C, 5% COr, 95% relative humidity. Cell culture medium was replaced every other day, beginning no later than 24 hours after initial plating.

[00470] 2. Preparation of Stock Solutions. 10 mM stock solutions of test compounds were prepared in

DMSO. The stock solutions of positive controls were prepared in DMSO at the concentration of 10 mM. Digoxin, prazosin and metoprolol were used as control compounds in this assay.

[00471 ] 3. Assessment of Cell Monolayer Integrity. 1 ) Medium was removed from the reservoir and each

Transwell insert and replaced with prewarmed fresh culture medium. 2) Transepithelial electrical resistance (TEER) across the monolayer was measured using Milliccll Epithelial Volt-Ohm measuring system (Millipore, USA). 3) The Plate was returned to the incubator once the measurement was done.

The TEER value was calucated according to the following equation:

TEER measurement (ohms) x Area of membrane (cm²) = TEER value (ohm*cm²)

TEER value should be greater than 230 ohm«cnr, which indicates the well-qualified Caco-2 monolayer. [00472] 4. Assay Procedures. 1) The Caco-2 plate was removed from the incubator and washed twice with pre-warmed HBSS (10 mM HEPES, pH 7.4), and then incubated at 37 °C for 30 minutes. 2) The stock solutions of control compounds were diluted in DMSO to get 1 mM solutions and then diluted with HBSS (10 mM HEPES, pH 7.4) to get 5 LIM working solutions. The stock solutions of the test compounds were diluted in DMSO to get 1 mM solutions and then diluted with HBSS (10 mM HEPES , pH 7.4) to get 5 pM working solutions. The final concentration of DMSO in the incubation system was 0.5%. 3) To assess the rate of compound transport in the apical to basolateral direction. 75 pL of 5 pM working solutions of test compounds were added to the Transwell insert (apical compartment) and the wells in the receiver plate (basolateral compartment) were filled with 235 pL of HBSS (10 mM HEPES , pH 7.4). 4) To assess the rate of compound transport in the basolateral to apical direction. 235 pL of 5 pM working solutions of test compounds were to the receiver plate wells (basolateral compartment) and then the Transwell inserts (apical compartment) were filled with 75 pL of HBSS (10 mM HEPES , pH 7.4). Time 0 samples were prepared by transferring 50 pL of 5 pM working solution to wells of the 96-deepwell plate, followed by the addition of 200 pL cold methanol containing appropriate internal standards (IS). 5) The plates were incuabted at 37 °C for 2 hours. 6) At the end of the incubation, 50 pL samples from donor sides (apical compartment for Ap— >-Bl flux, and basolateral compartment for Bl— >Ap) and receiver sides (basolateral compartment for Ap^Bl flux, and apical compartment for Bl— >Ap) were transferred to wells of a new 96-well plate, followed by the addition of 4 volume of cold acetonitrile or methanol containing appropriate internal standards (IS). Samples were vortexed for 5 minutes and then centrifuged at 3,220 g for 40 minutes. An aliquot of 100 pL of the supernatant was mixed with an appropriate volume of ultra-pure water before LC-MS/MS analysis. 7) To assess the Lucifer Yellow leakage after 2 hour transport period, stock solution of Lucifer yellow was prepared in ultra-pure water and diluted with HBSS (10 mM HEPES, pH 7.4) to reach the final concentration of 100 pM. 100 pL of the Lucifer yellow solution was added to each Trans well insert (apical compartment), followed by filling the wells in the receiver plate (basolateral compartment) with 300 pL of HBSS (10 mM HEPES, pH 7.4). The plates were incubated at 37 °C for 30 minutes. 80 pL samples were removed directly from the apical and basolateral wells (using the basolateral access holes) and transferred to wells of new 96 wells plates. The Lucifer Yellow fluorescence (to monitor monolayer integrity) signal was measured in a fluorescence plate reader at 485 nM excitation and 530 nM emission. [00473] 5. Data Analysis. The apparent permeability coefficient (Papp), in units of centimeter per second, can be calculated for Caco-2 compound transport assays using the following equation:

Papp = (VAx[compound]acceptor)/(AreaxTimex[compound]initial, donor), wherein VAis the volume (in mL) in the acceptor well, Area is the surface area of the membrane (0.143 cm² for Transwell-96 Well Permeable Supports), and time is the total transport time in seconds. [00474] The efflux ratio will be calculated using the following equation:

Efflux Ratio=Papp(B-A)/Papp(A-B) wherein Papp (B-A) indicates the apparent permeability coefficient in basolateral to apical direction, and Papp (A-B) indicates the apparent permeability coefficient in apical to basolateral direction. [00475] The recovery can be calculated using the following equation:

Recovery%=(VAx[compound]acceptor + VDx [compound] donor)/(VDx [compound] initial, donor) wherein VA is the volume (in mL) in the acceptor well (0.235 mL for Ap— >-Bl flux, and 0.075 mL for Bl— >Ap), VD is the volume (in mL) in the donor well (0.075 mL for Ap^Bl flux, and 0.235 mL for Bl— >-Ap) [00476] The leakage of Lucifer Yellow, in unit of percentage (%), can be calculated using the following equation:

%LY leakage = 100x[0.3xLY]acceptor/([0.1xLY]donor+[0.3xLY]acceptor)

LY leakage of < 1 % is acceptable to indicate the well-qualified Caco-2 monolayer. [00477] Certain results are presented in Table E-3 below as examples.

Table E-3. Certain permeability data. A: Caco-2 Papp (A-B) (10⁶, cm/s). B: Caco-2 Efflux Ratio.

[00478] In some embodiments, permeability properties of various compounds are superior to reference compounds. For example, as demonstrated herein, compounds comprising secondary amino groups (e.g., R^d or R^e) demonstrated better apparent permeability coefficients and/or efflux ratios compared to reference compounds (e.g., compounds with certain primary or tertiary amino groups instead of secondary amino groups, compounds with R^d and/or R^e being — H, etc.).

[00479] Among other things, various compounds demonstrated superior PK profiles, e.g., AUC, Tic, etc. compared to a reference compound in various assessments.

[00480] Example 8. 4-(6-((5-Methoxy-7-methyl-lH-indol-4-yl)methyl)-6-azaspiro[2.5]octan-5-yl)-3- (methylamino)benzoic acid.

[00481] Step 1: tert- Butyl 6-azaspiro[2.5]octane-6-carboxylate. A solution of 6-azaspiro[2.5]octane (5 g, 44.97 mmol) in DCM (50 mL) was added with Triethylamine (6.8 g, 67.20 mmol) and Di-tert-butyl dicarbonate (10 g, 45.820 mmol) 0 °C. The resulting mixture was stirred for 3 h at room temperature under air atmosphere. The resulting mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to afford the title compound (7 g crude) as a white solid. LCMS (ESI, m/z): [M+H]⁺ = 212.2.

[00482] Step 2: tert- Butyl 5-oxo-6-azaspiro[2.5]octane-6-carboxylate. A mixture of tert-butyl 6- azaspiro[2.5]octane-6-carboxylate (6 g, 28.395 mmol) and Ruodium (III) chloride hydrate (1.2 g, 5.32 mmol) and sodium periodate (12 g, 56.10 mmol) in water (30 mL) and Ethyl acetate (30 mL) was stirred for 1 h at 0 °C under air atmosphere. The resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with water and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by reverse phase flash with the following conditions (column, Cl 8 silica gel; mobile phase, MeCN in water (0.1% NH3. water), 40% to 60% gradient in 10 min; detector, UV 254 nm) to afford the title compound (4.9 g, 76.60% yield) as a white oil. LCMS (ESI, m/z): [M+H]⁺ = 226.3.

[00483] Step 3: ft? ;7- Butyl 5-(trifhioromethanesulfonyloxy)-6-azaspiro[2.5]oct-4-ene-6-carboxylate. A solution of tert-butyl 5-oxo-6-azaspiro[2.5]octane-6-carboxylate (4.3 g, 19.08 mmol) in THF (40 mL) was added with 1 M Potassium bis(trimethylsilyl)amide in THF (20 mL, 20 mmol) in 30 min at -78 °C under nitrogen atmosphere followed by the addition of LLl-trifluoro-A-phenyl-A- (trifluoromethane)sulfonylmethanesulfonamide (10.30 g, 28.83 mmol) in portions at -78 °C. The reaction was quenched with sat. ammonium chloride (aq.) at room temperature. The resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with water and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with petroleum ether / ethyl acetate (7: 1) to afford the title compound (12 g crude) as a white solid. LCMS (ESI, m/z): [M+H]⁺= 358.08.

[00484] Step 4: tert- Butyl 5-(4-(methoxycarbonyl)-2-nitrophenyl)-6-azaspiro[2.5]oct-4-ene-6- carboxylate. A mixture of tert-butyl 5-(trifluoromethanesulfonyloxy)-6-azaspiro[2.5]oct-4-ene-6-carboxylate (2 g, 5.60 mmol), 4-(methoxycarbonyl)-2-nitrophenylboronic acid (2.53 g, 11.25 mmol), Tris(dibenzylideneacetone)dipalladium (512 mg, 0.56 mmol), tri-tert-butylphosphine tetrafluoroborate (324 mg, 1.12 mmol) and Potassium fluoride (972 mg, 16.73 mmol) in THF (5 mL) and water (0.5 mL) was stirred for 1 h at 60 °C under nitrogen atmosphere. The resulting mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, Cl 8 silica gel; mobile phase, MeCN in water (0.1% NH4HCO3), 40% to 60% gradient in 10 min; detector, UV 254 nm to afford the title compound (1.12 g, 51.52%) as a yellow solid. LCMS (ESI, m/z): [M+H]⁺ =389.1.

[00485] Step 5: tert-Butyl 5-(2-amino-4-(methoxycarbonyl)phenyl)-6-azaspiro[2.5]oct-4-ene-6- carboxylate. A mixture of tert-butyl 5-(4-(methoxycarbonyl)-2-nitrophenyl)-6-azaspiro[2.5]oct-4-ene-6- carboxylatc (1.2 g, 3.08 mmol), Iron (560 mg, 0.072 mmol), and ammonium chloride (1.00 g, 18.63 mmol) in ethanol (5 mL) and water (5 inL) was stirred for Ih at 80 °C under air atmosphere. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with petroleum ether / ethyl acetate (12:1) to afford the title compound (500 mg, 38.38%) as a yellow solid. LCMS (ESI, m/z): [M+H]⁺ = 359.4.

[00486] Step 6: tert- Butyl 5-(4-(methoxycarbonyl)-2-(methylamino)phenyl)-6-azaspiro[2.5]oct-4-ene-6- carboxylate. A mixture of tert-butyl 5-(2-amino-4-(methoxycarbonyl)phenyl)-6-azaspiro[2.5]oct-4-ene-6- carboxylate (600 mg, 1.67 mmol), Paraformaldehyde (50 mg, 1.67 mmol) and sodium cyanoborohydride (316 mg, 5.03 mmol) in methanol (9 mL) was stirred for 1 h at 70 °C under air atmosphere. The solvent was removed under vacuum. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% NH4HCO3), 10% to 50% gradient in 10 min; detector, UV 254 nm.to afford the title compound (300 mg, 32.08%) as a yellow solid. LCMS (ESI, m/z): [M+H]⁺ = 373.4.

[00487] Step 7: Methyl 3-(methylamino)-4-(6-azaspiro[2.5]octan-5-yl)benzoate. A mixture of tert-butyl 5-(4-(methoxycarbonyl)-2-(methylamino)phenyl)-6-azaspiro[2.5]oct-4-ene-6-carboxylate (250 mg, 0.67 mmol) and sodium cyanoborohydride (423 mg, 6.73 mmol) in TFA (2 mL) and DCM (2 mL) was stirred for 1 h at room temperature under air atmosphere. The solvent was removed under vacuum. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% NH4HCO3), 50% to 60% gradient in 10 min; detector, UV 254 nm. This resulted in the title compound (100 mg, 54.30%) as a yellow oil. LCMS (ESI, m/z): [M+H]⁺ = 275.4.

[00488] Step 8: tc/t- Butyl 5-methoxy-4-((5-(4-(methoxycarbonyl)-2-(methylamino)phenyl)-6- azaspiro[2.5]octan-6-yl)methyl)-7-methyl-lH-indole-l-carboxylate. A solution of tert-butyl 4-formyl-5- methoxy-7-methyl-lH-indole-l -carboxylate (100 mg, 0.33 mol). Methyl 3-(methylamino)-4-(6- azaspiro[2.5]octan-5-yl)benzoate (90 mg, 0.33 mmol) in 1 ,2-dichloroethane (2 mL) was added acetic acid (25 mg, 0. 42 mmol) and stirred for 2 h at 70 °C under air atmosphere, followed by the addition of sodium triacetoxyborohydride (208 mg, 9.82 mmol) in portions at room temperature. The resulting mixture was stirred for 12 h at 70 °C under air atmosphere. To the above mixture was added sodium borohydride (37 mg, 9.90 mmol) in portions over 1 min at room temperature. The resulting mixture was stirred for additional 1 h at 70 °C. The resulting mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (lOmmol/L NH4HCO3), 10% to 50% gradient in 10 min; detector, UV 254 nm to afford the title compound (60 mg, 16.70%) as a white solid. LCMS (ESI, m/z): [M+H]⁺ = 548.3.

[00489] Step 9: 4-(6-((5-Methoxy-7-methyl-lH-indol-4-yl)methyl)-6-azaspiro[2.5]octan-5-yl)-3- (methylamino)benzoic acid. A mixture of tert-butyl 5-methoxy-4-((5-(4-(methoxycarbonyl)-2- (mcthylamino)phcnyl)-6-azaspiro[2.5]octan-6-yl)mcthyl)-7-mcthyl-lH-indolc-l -carboxylate (55 mg, 0.10 mmol) and potassium hydroxide (55 mg, 0.98 mmol) in methanol (0.9 mL) and water (0.3 mL) was stirred for 1 h at 75 °C under air atmosphere. The mixture was acidified to pH 6 with citric acid. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (lOmmol/L NH4HCO3), 10% to 50% gradient in 10 min; detector, UV 254 nm to afford the title compound (10.5 mg, 24.00%) as a white solid. LCMS (ESI, m/z): [M+H]⁺= 434.1. 'H NMR (400 MHz, Methanol-d₄) 87.71 - 7.31 (m, 3H), 7.31 - 7.23 (m, 1H), 6.74 (s, 1H), 6.22 (s, IH), 4.78 - 4.03 (m, 3H), 3.76 (s, 3H), 3.58 (s, IH), 2.93 (s, 3H), 2.67 (s, IH), 2.50 (s, 3H), 2.35 - 2.21 (m, IH), 1.32 - 0.81 (m, 3H), 0.79 - 0.30 (m, 4H).

[00490] Example 9. (R)-3-(Azetidin-l-yl)-4-( l-((5-methoxy-7-methyl-l H-indol-4-yl)methyl)piperidin-2- yl)benzoic acid & (S)-3-(azetidin-l-yl)-4-(l-((5-methoxy-7-methyl-lH-indol-4-yl)methyl)piperidin-2- yl)benzoic acid.

[00491] Step 1: tert-Butyl 6-(2-chloro-4-(methoxycarbonyl)phenyl)-3,4-dihydropyridine-l(2H)- carboxylate. A solution of 2-chloro-4-(methoxycarbonyl)phenylboronic acid (5.5 g, 25.65 mmol), tert-butyl 2-(trifluoromethanesulfonyloxy)-5,6-dihydro-4//-pyridine-l-carboxylate (25.50 g, 76.96 mmol), 1,T- Bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (2.09 g, 2.56 mmol) and sodium carbonate (8.16 g, 76.96 mmol) in 1 ,4-dioxane (100 mL) and water (20 mL) was stirred for 1 h at 90 °C under nitrogen. The resulting mixture was quenched with water and extracted with ethyl acetate. The organic layer washed with brine, dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with petroleum ether / ethyl acetate (9:1) to afford the title compound (3 g, 33.24%) as a yellow oil. LC-MS: (ES, m/z): 295.90 [M-(t-Bu)]⁺.

[00492] Step 2: Methyl 3-chloro-4-(piperidin-2-yl)benzoate. A solution of tert-butyl 6-(2-chloro-4- (methoxycarbonyl)phenyl)-3,4-dihydropyridine-l(2H)-carboxylate (1 g, 2.84 mmol) in DCM (8 mL) was treated with sodium cyanoborohydride (1.79 g, 28.42 mmol). Then TFA (8 mL) was added at 0 °C and was stirred for 1 h at room temperature. The resulting mixture was concentrated under vacuum. The residue was purified by C18 silica gel column chromatography, eluted with CFLCNAvatcr (1:4) to afford methyl 3-chloro- 4-(piperidin-2-yl)benzoate (600 mg, 83.20%) as a yellow oil. LC-MS: (ES, m/z): 253.85 [M+H]⁺.

[00493] Step 3: tert- Butyl 4-((2-(2-chloro-4-(methoxycarbonyl)phenyl)piperidin-l-yl)methyl)-5-methoxy- 7-methyl-lH-indole-l -carboxylate. A solution of methyl 3-chloro-4-(piperidin-2-yl)benzoate (700 mg, 2.76 mmol), tert-butyl 4-formyl-5-methoxy-7-methylindole-l-carboxylate (1.20 g, 4.14 mmol) in EtOH (15 mL) was added (3Z)-4-(iridiooxy)pent-3-en-2-one; bis(methanidylidyneoxidanium) (140 mg, 0.40 mmol) and stirred for overnight at 70 °C under hydrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with acetonitrile. The filtrate was concentrated under reduced pressure. The residue was purified by Cl 8 silica gel column chromatography, eluted with CLLCN/waterlNfLHCOj) (10:1) to afford the title compound (180 mg, 12.38%) as a yellow oil. LC-MS: (ES, m/z)'- 527.2 [M+H]⁺.

[00494] Step 4: tert-Butyl 4-((2-(2-(azetidin-l-yl)-4-(methoxycarbonyl)phenyl)piperidin-l-yl)methyl)-5- methoxy-7-methyl-lH-indole-l -carboxylate. A solution of tert-butyl 4-((2-(2-chloro-4- (methoxycarbonyl)phenyl Jpiperidin- 1 -yl)methyl)-5-methoxy-7 -methyl- 1 H-indole- 1 -carboxylate (160 mg, 0.30 mmol), azetidine (69.33 mg, 1.22 mmol) , Pd-PEPPSLIPentCl 2-methylpyridine (o-picoline) (25.54 mg, 0.030 mmol) in 1,4-dioxane (3 mL) was added Cesium carbonate (296.73 mg, 0.91 mmol) and stirred for overnight at 110 °C under nitrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with acetonitrile. The filtrate was concentrated under reduced pressure. The residue was purified by Cl 8 silica gel column chromatography, eluted with CFLCNAvatcr (NH4HCO3) (10: 1) to afford the title compound (80 mg, 48.12%) as a yellow oil. LC-MS: (ES, m/z)'- 548.2 [M+H]⁺.

[00495] Step 5: tert-Butyl (7?)-4-((2-(2-(azetidin-l-yl)-4-(methoxycarbonyl)phenyl)piperidin-l- yl)methyl)-5-methoxy-7-methyl-l H-indole- 1 -carboxylate & tert-Butyl (S)-4-((2-(2-(azetidin-l-yl)-4- (methoxycarbonyl)phenyl)piperidin-l-yl)methyl)-5-methoxy-7-methyl-lH-indole-l-carboxylate. tert-Butyl 4-((2-(2-(azetidin-l-yl)-4-(methoxycarbonyl)phenyl)piperidin-l-yl)methyl)-5-methoxy-7-methyl-lH-indole- 1 -carboxylate was applied for further separation by Chiral HPLC with the following condition: CHIRALPAK IE, 2*25 cm, 5 pm; Mobile Phase A: HEX(0.5% 2M NH3-MeOH), Mobile Phase B: 1PA; Plow rate: 20 mL/min; Gradient: isocratic 5; Wave Length: 220/254 nm; RT1(min): 7.657; RT2(min): 9.847; Sample Solvent: EtOH. The faster peak was assigned as isomer 1 and the slower peak was assigned as isomer 2. Isomer 1: faster peak, 50 mg, 38% yield. LC-MS: (ES, m/z): 548.30 [M+H]⁺. t_R = 1.50 min (CHIRALPAK IF-34.6*50 mm 3 μm), HEX(0.1%DEA):IPA=95:5, 1.0 mL/min, 254 nm. Isomer 2: slower peak, 55 mg, 42% yield. LC-MS: (ES, m/z): 548.30 [M+H]⁺. tR = 1.71 min (CHIRALPAK IF-34.6*50 mm 3 μm), HEX(0.1%DEA):IPA=95:5, 1.0 mL/min, 254 nm). [00496] Step 6: (R)-3-(Azetidin-1-yl)-4-(1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2- yl)benzoic acid & (S)-3-(azetidin-1-yl)-4-(1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2- yl)benzoic acid. A solution of isomer 1 (faster peak) from the step above (50 mg, 0.12 mmol) in ethanol (2 mL) and water (0.7 mL) was added potassium hydroxide (102.44 mg, 1.83 mmol) and stirred for 2 h at 70 ºC. The mixture was acidified to pH 6 with citric acid. Then the crude product was purified by Prep-HPLC to afford the compounds.27.4 mg, 33.68%, white solid. LC-MS: (ES, m/z): 434.20 [M+H]⁺.¹H NMR (500 MHz, Methanol-d4) δ 7.73 (d, J = 8.1, 1H), 7.52 (d, J = 8.0 Hz, 1H), 7.49 (s, 1H), 7.32 (d, J = 3.2 Hz, 1H), 6.76 (s, 1H), 6.34 (d, J = 3.2 Hz, 1H), 4.54 (d, J = 11.4 Hz, 1H), 4.30 – 4.11 (m, 3H), 4.03 (d, J = 12.7 Hz, 1H), 3.94 – 3.83 (m, 2H), 3.78 (s, 3H), 3.51 – 3.42 (m, 1H), 3.35 (s, 1H), 2.51 (s, 3H), 2.45 – 2.32 (m, 2H), 2.19 – 2.01 (m, 2H), 2.01 – 1.91 (m, 1H), 1.91 – 1.69 (m, 3H). A solution of isomer 2 (slower peak) from the step above (55 mg, 0.12 mmol) in ethanol (2 mL) and water (0.7 mL) was added potassium hydroxide (102.44 mg, 1.83 mmol) and stirred for 2 h at 70 ºC. The mixture was acidified to pH 6 with citric acid. Then the crude product was purified by Prep-HPLC to afford the title compounds. 30.2 mg, 37.24%, white solid. LC-MS: (ES, m/z): 434.20 [M+H]⁺.¹H NMR (500 MHz, Methanol-d4) δ 7.73 (d, J = 8.1, 1H), 7.52 (d, J = 8.0 Hz, 1H), 7.49 (s, 1H), 7.32 (d, J = 3.2 Hz, 1H), 6.76 (s, 1H), 6.34 (d, J = 3.2 Hz, 1H), 4.54 (d, J = 11.4 Hz, 1H), 4.30 – 4.11 (m, 3H), 4.03 (d, J = 12.7 Hz, 1H), 3.94 – 3.83 (m, 2H), 3.78 (s, 3H), 3.51 – 3.42 (m, 1H), 3.35 (s, 1H), 2.51 (s, 3H), 2.45 – 2.32 (m, 2H), 2.19 – 2.01 (m, 2H), 2.01 – 1.91 (m, 1H), 1.91 – 1.69 (m, 3H). [00497] Example 10. (S)-4-(1-((5-Methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl)-3- (methylamino)benzoic acid & (R)-4-(1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl)-3- (methylamino)benzoic acid. [00498] Step 1: tert-Butyl 6-(((trifluoromethyl)sulfonyl)oxy)-3,4-dihydropyridine-1(2H)-carboxylate . A solution of tert-butyl 2-oxopiperidine-1-carboxylate (20 g, 100.38 mmol) in THF (200 mL)

1 M LiHMDS in THF (120 mL, 120 mmol) at -78 ºC and stirred for 1 h at -78 ºC under nitrogen atmosphere. To the above mixture was added N-Phenyl-bis(trifluoromethanesulfonimide) (53.8 g, 150.57 mmol) in THF (530 mL) dropwise over 10 min at -78 ºC. The resulting mixture was stirred at -78 ºC for additional 1h. The reaction was quenched by the addition of sat. ammonium chloride. The resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with water and dried over anhydrous sodium sulfate. The residue was purified by silica gel column chromatography, eluted with Petroleum ether/CH₂Cl₂ (10:1) to afford the title compound (15 g, 40.59% yield) as a yellow oil. LCMS (ESI, m/z): [M+H-56]⁺ = 276.0. [00499] Step 2: tert-Butyl 6-(4-(methoxycarbonyl)-2-nitrophenyl)-3,4-dihydropyridine-1(2H)-carboxylate . A solution of tert-butyl 2-(trifluoromethanesulfonyloxy)-5,6-dihydro-4H-pyridine-1- 27 mmol), 4-(methoxycarbonyl)-2-nitrophenylboronic acid (20.37 g, 90.55 mmol),

Pd2(dba)3 (4.14 g, 4.53 mmol), tri-tert-butylphosphine tetrafluoroborate (2.62 g, 9.05 mmol) and KF (5.27 g, 90.55 mmol) in THF (113 mL) and water (38 mL) was stirred for 2 h at 60 ºC under nitrogen atmosphere. The resulting mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with petroleum ether / ethyl acetate (9:1) to afford the title compound (9 g, 54.7% yield) as a yellow solid. LCMS (ESI, m/z): [M+H-100]⁺ = 263.0. [00500] Step 3: Methyl 3-nitro-4-(piperidin-2-yl)benzoa . A solution of tert- butyl 2-[4-(methoxycarbonyl)-2-nitrophenyl]-5,6-dihydro-4

ate (9 g, 24.84 mmol) and sodium cyanoborohydride (15.61 g, 248.36mmol) in DCM (90 mL) was stirred for 5 min at 0 ºC. To the above mixture was added TFA (90 mL) dropwise at 0 ºC. The resulting mixture was stirred for additional 1 h at 0 ºC. The reaction was quenched with sat. ammonium chloride (aq.) at 0 ºC. The resulting mixture was extracted with CH₂Cl₂. The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography, eluted with CH₃CN/water (1:1) to afford the title compound (5 g, 76.18% yield) as a yellow oil. LCMS (ESI, m/z): [M+H]⁺ = 265.15. [00501] Step 4: tert-Butyl 5-methoxy-4-((2-(4-(methoxycarbonyl)-2-nitrophenyl)piperidin-1-yl)methyl)- 7-methyl-1H-indole-1-carboxylat . A solution of methyl 3-nitro-4-(piperidin-2-

yl)benzoate (5 g, 18.92 mmol), HOAc (568.07 mg, 9.46 mmol) and tert-butyl 4-formyl-5-methoxy-7- methylindole-1-carboxylate (10.95 g, 37.84 mmol) in 1,2-dichloroethane (70 mL) was stirred for 2 h at 70 ºC. To the above mixture was added sodium triacetoxyborohydride (12.03 g, 56.76 mmol) at room temperature. The resulting mixture was stirred for additional 12 h at 70 ºC. The resulting mixture was filtered, the filter cake was washed with ethyl acetate. The filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10mmol/L NH₄HCO₃), 75% to 80% gradient in 10 min; detector, UV 254 nm.to afford the title compound (1.5 g, 14.75% yield) as a yellow solid. LCMS (ESI, m/z): [M+H]⁺ =538.2. [00502] Step 5: tert-Butyl 4-((2-(2-amino-4-(methoxycarbonyl)phenyl)piperidin-1-yl)methyl)-5-methoxy- 7-methyl-1H-indole-1-carboxylat . A solution of tert-butyl 5-methoxy-4-((2-(4- (methoxycarbonyl)-2-nitrophenyl

l)-7-methylindole-1-carboxylate (1.5 g, 2.79 mmol) and 10% Pd/C (3 g) in ethyl acetate (20 mL) was stirred for 3 h at room temperature under hydrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with ethyl acetate. The filtrate was concentrated under reduced pressure to afford the title compound (1.2 g, 84.73% yield) as a yellow solid. LCMS (ESI, m/z): [M+H]⁺ =508.4. [00503] Step 6: tert-Butyl (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)-2-(methylamino)phenyl)piperidin- 1-yl)methyl)-7-methyl-1H-indole-1-carboxylate & tert-Butyl (R)-5-methoxy-4-((2-(4-(methoxycarbonyl)-2- (methylamino)phenyl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylate . A solution of tert-butyl 4-((2-(2-amino-4-

me oxycar ony p eny p per n- -y me y -5-methoxy-7-methylindole-1-carboxylate (900 mg, 1.77 mmol), sodium cyanoborohydride (445.65 mg, 7.09 mmol) and paraformalclehyde (390.5 mg, 8.87 mmol) in MeOH (10 mL) was stirred for 4 h at 50 ºC. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10mmol/L NH₄HCO₃), 75% to 80% gradient in 5 min; detector, UV 254 nm to afford the crude product (480 mg). The crude product was further separated by Chiral HPLC with the following conditions: (Column: CHIRALPAK IA, 2*25 cm, 5 μm; Mobile Phase A: Hex (0.5% 2M NH3-MeOH)-HPLC, Mobile Phase B: IPA-HPLC; Flow rate: 20 mL/min; Gradient: isocratic 10; Wave Length: 220/254 nm; RT1(min): 6.272; RT2(min): 8.858; Sample Solvent: EtOH-HPLC; Injection Volume: 0.5 mL; Number Of Runs: 24). Isomer 1: 170 mg, 18.3% yield as a colorless solid. LCMS (ESI, m/z): [M+H]⁺ = 522. t_R = 2.23 min (CHIRALPAK IG-3, 4.6*50 mm, 3.0 µm, Hex (0.1%DEA):IPA=90:10, 1.0 mL/min, 254 nm). Isomer 2: 172 mg, 18.6% yield as a colorless solid. LCMS (ESI, m/z): [M+H]⁺ = 522.4. tR = 3.41 min (CHIRALPAK IG-3, 4.6*50 mm, 3.0 µm, Hex (0.1%DEA):IPA=90:10, 1.0 mL/min, 254 nm). [00504] Step 7: (S)-4-(1-((5-Methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl)-3- (methylamino)benzoic acid & (R)-4-(1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl)-3- (methylamino)benzoic aci A solution of isomer 1 from the step above (150 mg, 0.

.5 mL) and water (0.5 mL) was stirred for 2 h at 80 ºC. The mixture was acidified to pH< 7 with sat. citric acid. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10mmol/L NH₄HCO₃), 30% to 40% gradient in 10 min; detector, UV 254 nm to afford a title compound (114.8 mg, 87.12% yield) as a white solid. LCMS (ESI, m/z): [M+H]⁺ = 408.05.¹H NMR (500 MHz, Methanol-d4) δ 7.51 (d, J = 7.8 Hz, 1H), 7.46 – 7.36 (m, 2H), 7.28 (d, J = 3.1 Hz, 1H), 6.73 (s, 1H), 6.22 (d, J = 3.1 Hz, 1H), 4.69 – 3.87 (m, 3H), 3.76 (s, 3H), 3.50 – 3.39 (m, 1H), 3.25 – 3.01 (m, 1H), 2.92 (s, 3H), 2.50 (s, 3H), 2.21 – 1.45 (m, 6H). A solution of isomer 2 from the step above (155 mg, 0.29 mmol) and KOH (180 mg, 3.21 mmol) in EtOH (1.5 mL) and water (0.5 mL) was stirred for 2 h at 80 ºC. The mixture was acidified to pH< 7 with sat. citric acid. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10mmol/L NH4HCO3), 30% to 40% gradient in 10 min; detector, UV 254 nm to afford the other title compound (107.7 mg, 85.6% yield) as a white solid. LCMS (ESI, m/z): [M+H]⁺ = 408.05.¹H NMR (500 MHz, Methanol-d4) δ 7.51 (d, J = 7.8 Hz, 1H), 7.46 – 7.36 (m, 2H), 7.28 (d, J = 3.1 Hz, 1H), 6.73 (s, 1H), 6.22 (d, J = 3.1 Hz, 1H), 4.69 – 3.87 (m, 3H), 3.76 (s, 3H), 3.50 – 3.39 (m, 1H), 3.25 – 3.01 (m, 1H), 2.92 (s, 3H), 2.50 (s, 3H), 2.21 – 1.45 (m, 6H). [00505] Example 11. 3-(Ethylamino)-4-(1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2- yl)benzoic acid. [0 -5-

methoxy-7-methyl-1H-indole-1-carboxylate. tert-butyl 4-((2-(2-amino-4- (methoxycarbonyl)phenyl)piperidin-1-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (300 mg, 0.59 mmol), acetaldehyde (131 mg, 2.97mmol) and sodium cyanoborohydride (148 mg, 2.35 mmol) in MeOH (5 mL) was stirred at 70 ºC for 2h. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10mmol/L NH₄HCO₃), 50% to 60% gradient in 5 min; detector, UV 254 nm to afford tert-butyl 4-((2-(2-(ethylamino)-4-(methoxycarbonyl)phenyl)piperidin-1- yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (90 mg, 28.43% yield) as a yellow oil. LCMS (ESI): [M+H]⁺ = 536.4. [00507] Step 2: 3-(Ethylamino)-4-(1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl)benzoic acid. A mixture of tert-butyl 4-((2-(2-(ethylamino)-4-(methoxycarbonyl)phenyl)piperidin-1-yl)methyl)-5- methoxy-7-methyl-1H-indole-1-carboxylate (70 mg, 0.13 mmol) and KOH (146 mg, 2.62 mmol) in water (0.6 mL) and EtOH (1.8 mL) was stirred for 1h at 80 ºC under air atmosphere. The mixture was acidified to pH= 6 with citric acid. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10mmol/L NH₄HCO₃), 10% to 50% gradient in 20 min; detector, UV 254 nm to afford 3-(ethylamino)-4-(1-((5-methoxy-7-methyl-1H-indol-4- yl)methyl)piperidin-2-yl)benzoic acid (33.8 mg, 61.18% yield) as a white solid. LCMS (ESI): [M+H]⁺ = 422.2.¹H NMR (300 MHz, Methanol-d₄) δ 7.44 (d, J = 11.9 Hz, 3H), 7.27 (d, J = 3.1 Hz, 1H), 6.73 (s, 1H), 6.19 (d, J = 3.2 Hz, 1H), 4.59 (s, 1H), 4.32 (s, 1H), 4.01 (d, J = 12.4 Hz, 1H), 3.75 (s, 3H), 3.56 – 3.39 (m, 1H), 3.26 (d, J = 7.2 Hz, 2H), 2.52 – 2.47 (m, 3H), 1.96 (d, J = 88.7 Hz, 7H), 1.37 – 1.22 (m, 3H). [00508] Example 12. (R)-3-Amino-4-(1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2- yl)benzoic acid & (S)-3-amino-4-(1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl)benzoic acid.

[005

(methoxycarbonyl)phenyl)piperidin-1-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (100 mg, 0.20 mmol) was applied for further separation by Chiral HPLC with the following condition: Column: CHIRALPAK IF 2*25 cm, 5 μm; Mobile Phase A: HEX(0.5% 2M NH3-MeOH), Mobile Phase B: EtOH; Flow rate: 20 mL/min; Gradient: isocratic 50; Wave Length: 220/254 nm; RT1(min): 7.905; RT2(min): 11.418; Sample Solvent: ETOH; Injection Volume: 1.0 mL; Number Of Runs: 4. Isomer 1: faster peak, 33 mg, 33.0% yield. LCMS (ESI): [M+H]⁺ = 508.4. tR = 1.67 min (CHIRALPAK IF-3 (0.46*5cm,3um), Hex (0.1%DEA): EtOH =50:50, 0.7 mL/min, 254 nm). Isomer 2, slower peak, 30 mg, 30 % yield. LCMS (ESI): [M+H]⁺ = 508.4. tR = 2.31 min (CHIRALPAK IF‐3 (0.46*5cm,3um), Hex (0.1%DEa): EtOH =50:50, 0.7 mL/min, 254 nm). [00510] Step 2: (R)-3-Amino-4-(1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl)benzoic acid & (S)-3-amino-4-(1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl)benzoic acid. A solution of isomer 1 (faster peak) from the step above (33 mg, 0.06 mmol) and KOH (36 mg, 0.64 mmol) in EtOH (1 mL) and water (0.3 mL) was stirred for 2h at 80 ºC. The mixture was acidified to pH< 7 with sat. citric acid. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10mmol/L NH4HCO3), 20% to 30% gradient in 5 min; detector, UV 254 nm to afford an enantiomer of 3-amino-4-(1-((5-methoxy-7-methyl-1H-indol-4- yl)methyl)piperidin-2-yl)benzoic acid (19.3 mg, 76.6% yield) as a white solid. LCMS (ESI): [M+H]⁺ = 394.3. ¹H NMR (500 MHz, Methanol-d4) δ 7.52 – 7.45 (m, 2H), 7.39 (d, J = 8.1 Hz, 1H), 7.27 (d, J = 3.1 Hz, 1H), 6.72 (s, 1H), 6.24 (d, J = 3.1 Hz, 1H), 4.62 – 4.29 (m, 2H), 4.05 (d, J = 12.9 Hz, 1H), 3.74 (s, 3H), 3.51 – 3.36 (m, 1H), 3.14 (d, J = 22.3 Hz, 1H), 2.48 (s, 3H), 2.19 – 2.03 (m, 1H), 2.03 – 1.87 (m, 2H), 1.77 (d, J = 39.2 Hz, 3H). A solution of isomer 2 (slower peak) from the step above (30 mg, 0.06 mmol) and KOH (35 mg, 0.62 mmol) in EtOH (1 mL) and water (0.3 mL) was stirred for 2 h at 80 ºC. The mixture was acidified to pH< 7 with sat. citric acid. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10mmol/L NH₄HCO₃), 20% to 30% gradient in 5 min; detector, UV 254 nm to afford the other enantiomer of 3-amino-4-(1-((5-methoxy-7- methyl-1H-indol-4-yl)methyl)piperidin-2-yl)benzoic acid (18.4 mg, 76.6% yield) as a white solid. LCMS (ESI): [M+H]⁺ = 394.3. H NMR (300 MHz, Methanol-d₄) δ 7.53 – 7.46 (m, 2H), 7.40 (d, J = 8.1 Hz, 1H), 7.28 (d, J = 3.1 Hz, 1H), 6.74 (s, 1H), 6.24 (d, J = 3.2 Hz, 1H), 4.59 – 4.31 (m, 2H), 4.08 (d, J = 12.7 Hz, 1H), 3.76 (s, 3H), 3.44 (d, J = 12.4 Hz, 1H), 3.23 – 3.04 (m, 1H), 2.49 (d, J = 0.7 Hz, 3H), 2.21 – 1.89 (m, 3H), 1.82 (s, 3H). [00511] Example 13. (S)-4-(2,2-Difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)-3-(methylamino)benzoic acid & (R)-4-(2,2-Difluoro-7-((5-methoxy-7-methyl-1H- indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)-3-(methylamino)benzoic acid.

[00512] Ste ure of 2,2-difluoro-

7-azaspiro[3.5]nonane hydrochloride (30 g, 151.51 mmol) and triethylamine (30.7 g, 303.6 mmol) in DCM (400 mL) was added Boc2O (43 g, 197.3 mmol) and the reaction was stirred for 3 h at room temperature under air atmosphere. The reaction was quenched with water and extracted with CH2Cl2. The combined organic layers were washed with water, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 40% to 60% gradient over 30 min; detector, UV 200 nm.to afford the title compound (30 g, 75.6% yield) as a white solid. LCMS (ESI, m/z): [M+H-100]⁺ = 162.10. [00513] Step 2: tert-Butyl 2,2-difluoro-6-oxo-7-azaspiro[3.5]nonane-7-carboxylate. To a mixture of tert- butyl 2,2-difluoro-7-azaspiro[3.5]nonane-7-carboxylate (30 g, 114.8 mmol) in water (300 mL) and ethyl acetate (300 mL) was added RuCl₃.water (5.18 g, 22.96 mmol) and NaIO₄ (49.2 g, 229.6 mmol) at 0 ºC and the reaction was stirred for 3h at the same temperature. The solids were filtered out. The resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with water and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 50% to 60% gradient in 30 min; detector, UV 220 nm.to afford the title compound (25 g, 79.10% yield) as a white solid. LCMS (ESI, m/z): [M+H-56]⁺ = 219.85. [00514] Step 3: tert-Butyl 2,2-difluoro-6-(((trifluoromethyl)sulfonyl)oxy)-7-azaspiro[3.5]non-5-ene-7- carboxylate. To a mixture of tert-butyl 2,2-difluoro-6-oxo-7-azaspiro[3.5]nonane-7-carboxylate (15 g, 54.54 mmol) in THF (125 mL) was added 1 M KHMDS in THF (81.8 mL, 81.8 mmol) at -78 ºC and the reaction was stirred for 30 min at -78 ºC under nitrogen atmosphere. To the above mixture was added N-Phenyl- bis(trifluoromethanesulfonimide) (38.93 g, 108.98 mmol) in THF (390 mL) dropwise over 10 min at -78 ºC. The resulting mixture was stirred for additional 2 h at -78 ºC. The reaction was quenched by the addition of sat. ammonium chloride at room temperature. The resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with water and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 50% to 60% gradient in 30 min; detector, UV 220 nm to afford the title compound (12.5 g, 56.32% yield) as a yellow oil. LCMS (ESI, m/z): [M+H-56]⁺ =351.95. [00515] Step 4: tert-Butyl 2,2-difluoro-6-(4-(methoxycarbonyl)-2-nitrophenyl)-7-azaspiro[3.5]non-5-ene- 7-carboxylate. A solution of tert-butyl 2,2-difluoro-6-(trifluoromethanesulfonyloxy)-7-azaspiro[3.5]non-5-

ene-7-carboxylate (9 g, 22.09 mmol), 4-(methoxycarbonyl)-2-nitrophenylboronic acid (9.94 g, 44.19 mmol), Pd2(dba)3 (2.02 g, 2.21 mmol), tri-tert-butylphosphine tetrafluoroborate (1.28 g, 4.418 mmol) and KF (2.57 g, 44.19 mmol) in 1,4-dioxane (68 mL) and water (22 mL) was stirred for 1 h at 90 ºC under nitrogen atmosphere. The reaction was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with Petroleum ether/ethyl acetate (11:1) to afford the title compound (4.5 g, 46.5% yield) as a yellow solid. LCMS (ESI, m/z): [M+H-100]⁺ = 338.9. [00516] Step 5: Methyl 4-(2,2-difluoro-7-azaspiro[3.5]nonan-6-yl)-3-nitrobenzoate. To a solution of tert- butyl 2,2-difluoro-6-(4-(methoxycarbonyl)-2-nitrophenyl)-7-azaspiro[3.5]non-5-ene-7-carboxylate (4.5 g, 10.26 mmol) in DCM (45 mL) was added sodium cyanoborohydride (6.46 g, 102.85 mmol) and the reaction was stirred for 5 min at 0 ºC. To the above mixture was added TFA (45 mL) dropwise at 0 ºC. The resulting mixture was stirred for additional 1 hour at 0 ºC. The reaction was quenched with sat. ammonium chloride at 0 ºC. The resulting mixture was extracted with CH2Cl2. The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10mmol/L NH4HCO3), 30% to 40% gradient in 20 min; detector, UV 254 nm. to get the title compound (3.05 g, 74.2% yield) as a yellow solid. LCMS (ESI, m/z): [M+H]⁺ = 341.2. [00517] Step 6: tert-Butyl 4-((2,2-difluoro-6-(4-(methoxycarbonyl)-2-nitrophenyl)-7-azaspiro[3.5]nonan- 7-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate. A solution of methyl 4-(2,2-difluoro-7- azaspiro[3.5]nonan-6-yl)-3-nitrobenzoate (3.05 g, 8.96 mmol), tert-butyl 4-formyl-5-methoxy-7- methylindole-1-carboxylate (5.19 g, 17.92 mmol) and HOAc (269.1 mg, 4.48 mmol) in 1,2-dichloroethane (50 mL) was stirred for 2 h at 70 ºC. To the above mixture was added sodium triacetoxyborohydride (5.70 g, 26.87 mmol) at room temperature. The resulting mixture was stirred for additional 12 h at 70 ºC. The resulting mixture was filtered, the filter cake was washed with ethyl acetate. The filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10mmol/L NH₄HCO₃), 75% to 80% gradient in 10 min; detector, UV 254 nm to afford the title compound (1.34 g, 24.4% yield) as a yellow solid. LCMS (ESI, m/z): [M+H]⁺ =614.4. [00518] Step 7: tert-Butyl 4-((6-(2-amino-4-(methoxycarbonyl)phenyl)-2,2-difluoro-7- azaspiro[3.5]nonan-7-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate. A solution of tert-butyl 4- ((2,2-difluoro-6-(4-(methoxycarbonyl)-2-nitrophenyl)-7-azaspiro[3.5]nonan-7-yl)methyl)-5-methoxy-7- methyl-1H-indole-1-carboxylate (1.34 g, 2.18 mmol) and Pd/C (2 g) in ethyl acetate (20 mL) was stirred for 3 h at room temperature under hydrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with ethyl acetate. The filtrate was concentrated under reduced pressure to get the title compound (1.03 g, 80.8% yield) as a yellow solid. LCMS (ESI, m/z): [M+H]⁺ =584.3. [00519] Step 8: tert-Butyl (S)-4-((2,2-Difluoro-6-(4-(methoxycarbonyl)-2-(methylamino)phenyl)-7- azaspiro[3.5]nonan-7-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate & tert-Butyl (R)-4-((2,2- Difluoro-6-(4-(methoxycarbonyl)-2-(methylamino)phenyl)-7-azaspiro[3.5]nonan-7-yl)methyl)-5-methoxy-7- methyl-1H-indole-1-carboxylate. A solution of tert-butyl 4-((6-(2-amino-4-(methoxycarbonyl)phenyl)-2,2- difluoro-7-azaspiro[3.5]nonan-7-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (1.03 g, 1.77 mmol), paraformaldehyde (323 mg, 10.77 mmol) and sodium cyanoborohydride (448.0 mg, 7.13mmol) in MeOH (10 mL) was stirred for 3 h at 70 ºC. The solvent was removed. The residue was purified by reversed- phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10mmol/L NH4HCO3), 70% to 80% gradient in 5 min; detector, UV 254 nm. to get the crude product (530 mg). The crude product was further separated by Chiral HPLC with the following conditions: Column: CHIRALPAK IA, 2*25 cm, 5 μm; Mobile Phase A: Hex (0.5% 2M NH3-MeOH)-HPLC, Mobile Phase B: EtOH-HPLC; Flow rate: 20 mL/min; Gradient: isocratic 7; Wave Length: 220/254 nm; RT1(min): 6.115; RT2(min): 7.31; Sample Solvent: EtOH-HPLC; Injection Volume: 0.4 mL; Number of Runs: 45) to afford the title compound. Isomer 1: 185 mg, 17.4% yield as a white solid. LCMS (ESI, m/z): [M+H]⁺ = 598.3, tR = 1.16 min (CHIRALPAK IA-3, 4.6*50 mm, 3.0 µm, Hex (0.1%DEA):EtOH=93:7, 1.0 mL/min, 254 nm). Isomer 2: 181 mg, 17.1% yield as a white solid. LCMS (ESI, m/z): [M+H]⁺ = 598.3, tR = 1.427 min (CHIRALPAK IA-3, 4.6*50 mm, 3.0 µm, Hex (0.1%DEA):EtOH=93:7, 1.0 mL/min, 254 nm). [00520] Step 9: (S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan- 6-yl)-3-(methylamino)benzoic & (R)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)-3-(methylamino)benzoic acid. A solution of isomer 1 from the step above (180 mg, 0.30 mmol) and KOH (185 mg, 3.31 mmol) in EtOH (1.5 mL) and water (0.5 mL) was stirred for 2.5 h at 80 ºC. The mixture was acidified to pH = 6 with sat. citric acid. The solvent was removed. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10mmol/L NH₄HCO₃), 30% to 40% gradient in 5 min; detector, UV 254 nm to afford an enantiomer of 4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)-3-(methylamino)benzoic acid (129.6 mg, 88.8% yield) as a white solid. LCMS (ESI, m/z): [M+H]⁺ = 484.3.¹H NMR (500 MHz, DMSO-d₆) δ 12.63 (s, 1H), 10.87 (s, 1H), 7.24 (d, J = 34.4 Hz, 3H), 7.12 (d, J = 2.3 Hz, 1H), 6.94 (s, 1H), 6.67 (s, 1H), 6.23 (s, 1H), 3.71 – 3.66 (m, 4H), 3.23 (d, J = 12.2 Hz, 1H), 2.78 (d, J = 3.9 Hz, 3H), 2.67 (d, J = 12.4 Hz, 3H), 2.42 (s, 5H), 2.31 (t, J = 13.2 Hz, 2H), 1.94 (s, 1H), 1.52 (s, 3H). A solution of isomer 2 from the step above (181 mg, 0.30 mmol) and KOH (185 mg, 3.31 mmol) in EtOH (1.5 mL) and water (0.5 mL) was stirred for 2.5 h at 80 ºC. The mixture was acidified to pH = 6 with sat. citric acid. The solvent was removed. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10mmol/L NH4HCO3), 30% to 40% gradient in 5 min; detector, UV 254 nm to afford the other enantiomer of 4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)-3- (methylamino)benzoic acid (99 mg, 87.0% yield) as a white solid. LCMS (ESI, m/z): [M+H]⁺ = 484.3.¹H NMR (500 MHz, DMSO-d6) δ 12.63 (s, 1H), 10.87 (s, 1H), 7.24 (d, J = 34.4 Hz, 3H), 7.12 (d, J = 2.3 Hz, 1H), 6.94 (s, 1H), 6.67 (s, 1H), 6.23 (s, 1H), 3.71 – 3.66 (m, 4H), 3.23 (d, J = 12.2 Hz, 1H), 2.78 (d, J = 3.9 Hz, 3H), 2.67 (d, J = 12.4 Hz, 3H), 2.42 (s, 5H), 2.31 (t, J = 13.2 Hz, 2H), 1.94 (s, 1H), 1.52 (s, 3H). [00521] Example 14. (R)-5-(2,2-Difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)-6-(methylamino)picolinic acid & (S)-5-(2,2-difluoro-7-((5-methoxy-7-methyl-1H- indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)-6-(methylamino)picolinic acid.

[00522] St idin-3-yl)-7-

azaspiro[3.5]nonan-7-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate. A solution of tert-butyl 4- ((6-(2-amino-6-(methoxycarbonyl)pyridin-3-yl)-2,2-difluoro-7-azaspiro[3.5]nonan-7-yl)methyl)-5-methoxy- 7-methylindole-1-carboxylate (150 mg, 0.26 mmol) and paraformalclehyde (80 mg, 1.816 mmol) in MeOH (2 mL) was treated with sodium cyanoborohydride (70 mg, 1.11 mmol) at 50 ºC for 4 h. The resulting mixture was filtered, the filter cake was washed with MeCN. The filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10mmol/L NH₄HCO₃), 5% to 100% gradient in 30 min; detector, UV 220 nm. This resulted in the title compound (110 mg, 71.62%) as a yellow solid. LCMS (ESI): [M+H] ⁺ =599.3. [00523] Step 2: tert-Butyl (R)-4-((2,2-difluoro-6-(6-(methoxycarbonyl)-2-(methylamino)pyridin-3-yl)-7- azaspiro[3.5]nonan-7-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate & tert-butyl (S)-4-((2,2- difluoro-6-(6-(methoxycarbonyl)-2-(methylamino)pyridin-3-yl)-7-azaspiro[3.5]nonan-7-yl)methyl)-5- methoxy-7-methyl-1H-indole-1-carboxylate. tert-Butyl 4-((2,2-difluoro-6-(6-(methoxycarbonyl)-2- (methylamino)pyridin-3-yl)-7-azaspiro[3.5]nonan-7-yl)methyl)-5-methoxy-7-methyl-1H-indole-1- carboxylate (150 mg) was applied for further separation by Chiral HPLC with the following condition: Column: CHIRALPAK IG 2*25 cm, 5 μm; Mobile Phase A: HEX(0.5% 2M NH3-MeOH), Mobile Phase B: IPA; Flow rate: 20 mL/min; Gradient: isocratic 10; Wave Length: 220/254 nm; RT1(min): 12.206; RT2(min): 18.002; Sample Solvent: ETOH; Injection Volume: 1.3 mL; Number Of Runs: 7. Isomer 1: faster peak, 55 mg, 36.67% yield. LCMS (ESI, m/z): [M+H]⁺ = 599.3. tR = 2.00 min (CHIRALPAK IG-34.6*50mm 3um), Hex (0.1%DEA):IPA=90:10, 1.0 mL/min, 254 nm). Isomer 2: slower peak, 45 mg, 30% yield. LCMS (ESI, m/z): [M+H]⁺ = 599.3. tR = 3.19 min (CHIRALPAK IG-34.6*50mm 3um), Hex (0.1%DEA):IPA=90:10, 1.0 mL/min, 254 nm). [00524] Step 3: (R)-5-(2,2-Difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)-6-(methylamino)picolinic acid & (S)-5-(2,2-difluoro-7-((5-methoxy-7-methyl-1H- indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)-6-(methylamino)picolinic acid. A solution of isomer 1 (faster peak) from the step above (55 mg, 0.092 mmol) and KOH (68 mg, 1.212 mmol) in EtOH (4 mL) and water (1 mL) was stirred for 2h at 90 ºC. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10mmol/L NH4HCO3), 3% to 50% gradient in 25 min; detector, UV 220 nm. The resulting mixture was concentrated under reduced pressure. The resulting liquid was dried by lyophilization. This resulted in one enantiomer of 5-(2,2-Difluoro- 7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)-6-(methylamino)picolinic acid (35.2 mg, 78.9%) as a white solid. LCMS (ESI): [M+H]⁺ =485.3.¹H NMR (300 MHz, Methanol-d₄) δ 7.62 (d, J = 7.3 Hz, 1H), 7.34 – 7.28 (m, 1H), 7.26 (d, J = 7.3 Hz, 1H), 6.79 (s, 1H), 6.61 (d, J = 3.1 Hz, 1H), 4.95 (s, 2H), 3.98 (s, 3H), 3.23 – 3.12 (m, 1H), 3.00 – 2.88 (m, 1H), 2.51 (s, 3H), 2.47 – 2.09 (m, 5H), 1.94 (s, 3H), 1.89 – 1.66 (m, 3H), 1.46 (d, J = 13.4 Hz, 1H). A solution of isomer 2 (slower peak) from the step above (45 mg, 0.075 mmol) and KOH (55 mg, 0.98 mmol) in EtOH (4 mL) and water (1 mL) was stirred for 2 h at 90 ºC. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10mmol/L NH4HCO3), 3% to 50% gradient in 25 min; detector, UV 220 nm. The resulting mixture was concentrated under reduced pressure. The resulting liquid was dried by lyophilization. This resulted in the other enantiomer of 5-(2,2-Difluoro-7-((5-methoxy-7- methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)-6-(methylamino)picolinic acid (36.2 mg, 99%) as a white solid. LCMS (ESI): [M+H]⁺ =485.3.¹H NMR (400 MHz, Methanol-d4) δ 7.60 (d, J = 7.2 Hz, 1H), 7.29 (d, J = 3.0 Hz, 1H), 7.25 (d, J = 7.3 Hz, 1H), 6.78 (s, 1H), 6.59 (d, J = 3.1 Hz, 1H), 4.94 (s, 2H), 3.97 (s, 3H), 3.15 (d, J = 11.1 Hz, 1H), 2.92 (d, J = 11.9 Hz, 1H), 2.50 (s, 3H), 2.47 – 2.32 (m, 2H), 2.31 – 2.06 (m, 3H), 1.92 (s, 3H), 1.90 – 1.73 (m, 2H), 1.68 (d, J = 13.4 Hz, 1H), 1.44 (d, J = 13.4 Hz, 1H). [00525] Example 15. (R)-6-Amino-5-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)picolinic acid & (S)-6-Amino-5-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4- yl)methyl)-7-azaspiro[3.5]nonan-6-yl)picolinic acid.

O O O O O N NH₂ F F [0 mino-

5-bromopyridine-2-carboxylate (1 g, 4.33 mmol), KOAc (849 mg, 8.65 mmol), Pd(dppf)Cl2 (317 mg, 0.43 mmol) in 1,4-dioxane (10 mL) was treated with bis(pinacolato)diboron (1.43 g, 5.63 mmol) for 1h at 90 ºC under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with water. The resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The precipitated solids were collected by filtration and washed with Petroleum ether. The resulting solid was dried under infrared light. This resulted in the title compound (970 mg, 80.58%) as a black solid. The crude product was used in the next step directly without further purification. LCMS (ESI): [M+H] ⁺ =197.1. [00527] Step 2: tert-Butyl 6-(2-amino-6-(methoxycarbonyl)pyridin-3-yl)-2,2-difluoro-7-azaspiro[3.5]non- 5-ene-7-carboxylate. A solution of methyl 6-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine- 2-carboxylate (1.05 g, 3.77 mmol), tert-butyl 2,2-difluoro-6-(trifluoromethanesulfonyloxy)-7- azaspiro[3.5]non-5-ene-7-carboxylate (1.05 g, 2.578 mmol), Pd(dppf)Cl2 (188 mg, 0.26 mmol) and sodium carbonate (560 mg, 5.28 mmol) in 1,4-dioxane (10 mL) and water (2 mL) was stirred for 1h at 90 ºC under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with water. The resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. This resulted in the title compound (800 mg, 75.80%) as a brown solid. LCMS (ESI): [M+H] ⁺ =410.2. [00528] Step 3: Methyl 6-amino-5-(2,2-difluoro-7-azaspiro[3.5]nonan-6-yl)picolinate. To a stirred solution of tert-butyl 6-(2-amino-6-(methoxycarbonyl)pyridin-3-yl)-2,2-difluoro-7-azaspiro[3.5]non-5-ene-7- carboxylate (3.1 g, 7.57 mmol) and NaBH4 (0.44 g, 11.51 mmol) in DCM (15 mL) was added TFA (15 mL) dropwise at room temperature. The resulting mixture was stirred for 1h at room temperature. The solvent was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (10:1) to afford the title compound (2.5 g, 95.45%) as a yellow solid. LCMS (ESI): [M+H] ⁺ =312.1. [00529] Step 4: tert-Butyl 4-((6-(2-amino-6-(methoxycarbonyl)pyridin-3-yl)-2,2-difluoro-7- azaspiro[3.5]nonan-7-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate. A solution of methyl 6- amino-5-(2,2-difluoro-7-azaspiro[3.5]nonan-6-yl)pyridine-2-carboxylate (300 mg, 0.96 mmol), IR(CO)2(acac) (60 mg, 0.17 mmol,) and tert-butyl 4-formyl-5-methoxy-7-methylindole-1-carboxylate (500 mg, 1.73 mmol) in EtOH (10 mL) was stirred for 30nmin at 70 ºC under hydrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with MeCN. The filtrate was concentrated under reduced pressure. A solution of the crude product (350 mg, 0.60 mmol) and sodium cyanoborohydride (650 mg, 10.34 mmol) in 1,2-dichloroethane (5 mL) was stirred for 1h at room temperature. The reaction was quenched with ice at room temperature. The resulting mixture was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10mmol/L NH4HCO3), 5% to 100% gradient in 30 min; detector, UV 220 nm. This resulted in the title compound (110 mg, 27.87%) as a white solid. LCMS (ESI): [M+H] ⁺ =585.3. [00530] Step 5: tert-Butyl (R)-4-((6-(2-amino-6-(methoxycarbonyl)pyridin-3-yl)-2,2-difluoro-7- azaspiro[3.5]nonan-7-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate & tert-butyl (S)-4-((6-(2- amino-6-(methoxycarbonyl)pyridin-3-yl)-2,2-difluoro-7-azaspiro[3.5]nonan-7-yl)methyl)-5-methoxy-7- methyl-1H-indole-1-carboxylate. tert-Butyl 4-((6-(2-amino-6-(methoxycarbonyl)pyridin-3-yl)-2,2-difluoro-7- azaspiro[3.5]nonan-7-yl)methyl)-5-methoxy-7-methylindole-1-carboxylate (140 mg, 0.24 mmol) was applied for further separation by Chiral HPLC with the following condition: Column: CHIRALPAK SB 2*25 cm, 5 μm; Mobile Phase A: HEX(0.5% 2M NH3-MeOH), Mobile Phase B: EtOH; Flow rate: 20 mL/min; Gradient: isocratic 50; Wave Length: 220/254 nm; RT1(min): 6.855; RT2(min): 10.502; Sample Solvent: ETOH; Injection Volume: 1.0 mL; Number Of Runs: 5. Isomer 1: faster peak, 55 mg, 39.29% yield. LCMS (ESI): [M+H]⁺ = 585.3. t_R = 2.12 min (CHIRALCellulose SB 4.6*100mm,3um), Hex (0.1%DEA):EtOH=30:70, 1.0 mL/min, 254 nm). Isomer 2: slower peak, 45 mg, 32.14% yield. LCMS (ESI): [M+H]⁺ = 585.3. t_R = 3.23 min (CHIRALCellulose SB 4.6*100mm,3um), Hex (0.1%DEA):EtOH=30:70, 1.0 mL/min, 254 nm). [00531] Step 6: (R)-6-Amino-5-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)picolinic acid & (S)-6-amino-5-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4- yl)methyl)-7-azaspiro[3.5]nonan-6-yl)picolinic acid. A solution isomer 1 (faster peak) from the step above (55 mg, 0.094 mmol) and KOH (55 mg, 0.98 mmol) in EtOH (2 mL) and water (1 mL) was stirred for 1h at 100 ºC. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10mmol/L NH₄HCO₃), 5% to 50% gradient in 20 min; detector, UV 220 nm. The resulting mixture was concentrated under reduced pressure. The resulting liquid was dried by lyophilization. This resulted in one enantiomer of 6-Amino-5-(2,2-difluoro-7-((5-methoxy-7- methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)picolinic acid (24.6 mg, 53.41%) as a white solid. LCMS (ESI): [M+H] ⁺ =471.2.¹H NMR (300 MHz, Methanol-d4) δ 7.62 (s, 1H), 7.29 (d, J = 2.9 Hz, 1H), 7.22 (s, 1H), 6.77 (s, 1H), 6.60 (d, J = 3.3 Hz, 1H), 4.92 (s, 2H), 4.01 – 3.94 (m, 3H), 3.86 – 3.74 (m, 1H), 3.13 – 3.03 (m, 1H), 2.75 – 2.64 (m, 1H), 2.51 – 2.44 (m, 3H), 2.42 – 2.09 (m, 4H), 1.84 – 1.73 (m, 1H), 1.71 – 1.53 (m, 3H). [00532] A solution of isomer 2 (slower peak) from the step above (45 mg, 0.077 mmol) and KOH (45 mg, 0.82 mmol) in EtOH (2 mL) and water (1 mL) was stirred for 1h at 100 ºC. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10mmol/L NH4HCO3), 5% to 50% gradient in 20 min; detector, UV 220 nm. The resulting mixture was concentrated under reduced pressure. The resulting liquid was dried by lyophilization. This resulted in the other enantiomer of 6-Amino-5-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)- 7-azaspiro[3.5]nonan-6-yl)picolinic acid (31.8 mg, 85.44%) as a white solid. LCMS (ESI): [M+H] ⁺ =471.2. LCMS (ESI): [M+H] ⁺ =471.2.¹H NMR (300 MHz, Methanol-d4) δ 7.63 (d, J = 7.4 Hz, 1H), 7.37 – 7.29 (m, 1H), 7.25 (d, J = 7.3 Hz, 1H), 6.79 (s, 1H), 6.68 – 6.58 (m, 1H), 4.94 (d, J = 3.4 Hz, 2H), 3.98 (s, 3H), 3.86 – 3.75 (m, 1H), 3.14 – 3.03 (m, 1H), 2.79 – 2.63 (m, 1H), 2.51 (s, 3H), 2.49 – 2.38 (m, 2H), 2.36 – 2.15 (m, 2H), 1.87 – 1.73 (m, 1H), 1.73 – 1.65 (m, 2H), 1.65 – 1.54 (m, 1H). [00533] Example 16. (R)-3-Amino-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)benzoic acid & (S)-3-amino-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4- yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzoic acid.

[00534] Step 1: Is (6-(2-amino-4-

(methoxycarbonyl)phenyl)-2,2-difluoro-7-azaspiro[3.5]nonan-7-yl)methyl)-5-methoxy-7-methyl-1H-indole- 1-carboxylate. tert-butyl 4-((6-(2-Amino-4-(methoxycarbonyl)phenyl)-2,2-difluoro-7-azaspiro[3.5]nonan-7- yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (90 mg, 0.15 mmol) was applied for further separation by Chiral HPLC with the following condition: Column: CHIRALPAK IF, 2*25 cm, 5 μm; Mobile Phase A: HEX(0.5% 2M NH3-MeOH), Mobile Phase B: ETOH; Flow rate: 20 mL/min; Gradient: isocratic 50; Wave Length: 220/254 nm; RT1(min): 5.544; RT2(min): 9.002; Sample Solvent: EtOH; Injection Volume: 0.7 mL; Number Of Runs: 9. Isomer 1: faster peak, 36 mg, 40.0% yield. LCMS (ESI): [M+H]⁺ = 584.3. t_R = 1.25 min (CHIRALPAK IF-3 (0.46*5cm,3um), Hex (0.1%DEA): EtOH =50:50, 1.0 mL/min, 254 nm). Isomer 2: slower peak, 37 mg, 41.1 % yield. LCMS (ESI): [M+H]⁺ = 584.3. t_R = 2.02 min (CHIRALPAK IF‐3 (0.46*5cm,3um), Hex (0.1%DEA): EtOH =50:50, 1.0 mL/min, 254 nm). [00535] Step 2: (R)-3-amino-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)benzoic acid & (S)-3-amino-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4- yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzoic acid. A solution of isomer 1 (faster peak) from the step above (36 mg, 0.06 mmol) and KOH (71 mg, 1.26 mmol) in EtOH (1.6 mL) and water (0.4 mL) was stirred for 1.5 h at 80 ºC. The mixture was acidified to pH<7 with sat. citric acid. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10mmol/L NH₄HCO₃), 25% to 30% gradient in 5 min; detector, UV 254 nm to afford one enantiomer of 3- amino-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzoic acid (20.4 mg, 70.41% yield) as a white solid. LCMS (ESI): [M+H]⁺ = 470.2.¹H NMR (400 MHz, Methanol- d4) δ 7.80 – 7.20 (m, 4H), 6.72 (s, 1H), 6.23 (s, 1H), 4.55 – 4.20 (m, 1H), 4.10 (s, 1H), 3.80 – 3.67 (m, 3H), 3.55 – 3.39 (m, 1H), 3.27 – 3.04 (m, 1H), 2.80 – 2.60 (m, 2H), 2.55– 2.30 (m, 7H), 2.12 – 1.48 (m, 3H). A solution of isomer 2 (slower peak) from the step above (37 mg, 0.06 mmol) and KOH (71 mg, 1.26 mmol) in EtOH (1.6 mL) and water (0.4 mL) was stirred for 1.5 h at 80 ºC. The mixture was acidified to pH<7 with sat. citric acid. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10mmol/L NH4HCO3), 25% to 30% gradient in 5 min; detector, UV 254 nm to afford the other enantiomer of 3-amino-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H- indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzoic acid (21.9 mg, 73.5% yield) as a white solid. LCMS (ESI): [M+H]⁺ = 470.2.¹H NMR (400 MHz, Methanol-d4) δ 7.80 – 7.20 (m, 4H), 6.72 (s, 1H), 6.23 (s, 1H), 4.55 – 4.20 (m, 1H), 4.10 (s, 1H), 3.80 – 3.67 (m, 3H), 3.55 – 3.39 (m, 1H), 3.27 – 3.04 (m, 1H), 2.80 – 2.60 (m, 2H), 2.55– 2.30 (m, 7H), 2.12 – 1.48 (m, 3H). [00536] Example 17. (S)-2-Amino-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)benzoic acid & (R)-2-Amino-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4- yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzoic acid.

[0

amino-4-bromobenzoate (10 g, 43.47 mmol) and CbzCl (14.8 g, 86.93 mmol), sodium carbonate (13.8 g, 130.40 mmol) in DCM (50 mL) and water (50 mL) was stirred for 2 h at room temperature under air atmosphere. The resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with water and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with petroleum ether / ethyl acetate (6:1) to afford the title compound (15 g, 90.02% yield) as a white solid. LCMS (ESI, m/z): [M+H]+ = 363.0. [00538] Step 2: Methyl 2-(((benzyloxy)carbonyl)amino)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzoate. A mixture of methyl methyl 2-(((benzyloxy)carbonyl)amino)-4-bromobenzoate (9 g, 24.71 mmol) and bis(pinacolato)diboron (16.2 g, 63.80 mmol) and Pd(dppf)Cl2 (1.8 g, 2.48 mmol) and KOAc (7.2 g, 73.36 mmol) in 1,4-dioxane (90 mL) was stirred for 1h at 110 ºC under nitrogen atmosphere. The resulting mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with water and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with Petroleum ether/ethyl acetate (5:1) to afford the title compound (13 g, 91.3% yield) as a white solid. LCMS (ESI, m/z): [M+H]+ = 411.2. [00539] Step 3: tert-Butyl 6-(3-(((benzyloxy)carbonyl)amino)-4-(methoxycarbonyl)phenyl)-2,2-difluoro- 7-azaspiro[3.5]non-5-ene-7-carboxylate. A solution of methyl 2-(((benzyloxy)carbonyl)amino)-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (360 mg, 0.88 mmol), tert-butyl 2,2-difluoro-6- (trifluoromethanesulfonyloxy)-7-azaspiro[3.5]non-5-ene-7-carboxylate (300 mg, 0.74 mmol), bis(diphenylphosphino)ferrocene dichloropalladium(II) (215.55 mg, 0.295 mmol) and sodium carbonate (232 mg, 2.19 mmol) in 1,4-dioxane (8 mL) and water (2 mL) was stirred for 1h at 90 ºC under nitrogen atmosphere. The resulting mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with water and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10mmol/L NH4HCO3), 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in the title compound (300 mg, 68.22% yield) as a brown oil. LCMS (ESI, m/z): [M+H]+ = 542.2. [00540] Step 4: Methyl 2-(((benzyloxy)carbonyl)amino)-4-(2,2-difluoro-7-azaspiro[3.5]nonan-6- yl)benzoate. A solution of tert-butyl 6-(3-(((benzyloxy)carbonyl)amino)-4-(methoxycarbonyl)phenyl)-2,2- difluoro-7-azaspiro[3.5]non-5-ene-7-carboxylate (250 mg, 0.46 mmol) and NaBH4 (30.2 mg, 0.80 mmol) in TFA (1.5 mL) and DCM (1.5 mL) was stirred for 1h at room temperature under air atmosphere. The resulting mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with water and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10mmol/L NH4HCO3), 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in the title compound (150 mg, 80.20% yield) as a yellow solid. LCMS (ESI, m/z): [M+H]+ = 444.2. [00541] Step 5: tert-Butyl 4-((6-(3-(((benzyloxy)carbonyl)amino)-4-(methoxycarbonyl)phenyl)-2,2- difluoro-7-azaspiro[3.5]nonan-7-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate. A solution of methyl 2-(((benzyloxy)carbonyl)amino)-4-(2,2-difluoro-7-azaspiro[3.5]nonan-6-yl)benzoate (100 mg, 0.23 mmol) and tert-butyl 4-formyl-5-methoxy-7-methylindole-1-carboxylate (78.1 mg, 0.27 mmol), tetrakis(propan-2-yloxy)titanium (639.43 mg, 2.25 mmol), sodium triacetoxyborohydride (143.1 mg, 0.68 mmol) in 1,2-dichloroethane (1 mL) was stirred for 1h at room temperature under air atmosphere. The resulting mixture was quenched with water and extracted with DCM. The combined organic layers were washed with water and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10mmol/L NH4HCO3), 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in the title compound (60 mg, 36.78% yield) as a colorless oil. LCMS (ESI, m/z): [M+H]+ = 717.3. [00542] Step 6: tert-Butyl 4-((6-(3-amino-4-(methoxycarbonyl)phenyl)-2,2-difluoro-7- azaspiro[3.5]nonan-7-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate. A solution of tert-butyl 4- ((6-(3-(((benzyloxy)carbonyl)amino)-4-(methoxycarbonyl)phenyl)-2,2-difluoro-7-azaspiro[3.5]nonan-7- yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (100 mg, 0.14 mmol) and 10% Pd/C (20 mg) in ethyl acetate (1mL) was stirred for 1h at room temperature under hydrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with ethyl acetate (3x10 mL). The filtrate was concentrated under reduced pressure. This resulted in the title compound (80 mg, 96.42% yield) as a colorless solid. LCMS (ESI, m/z): [M+H]+ = 583.3. [00543] Step 7: Isomer 1 (faster peak) & isomer 2 (slower peak) of tert-butyl-4-((6-(3-amino-4- (methoxycarbonyl)phenyl)-2,2-difluoro-7-azaspiro[3.5]nonan-7-yl)methyl)-5-methoxy-7-methyl-1H-indole- 1-carboxylate. tert-Butyl 4-((6-(3-amino-4-(methoxycarbonyl)phenyl)-2,2-difluoro-7-azaspiro[3.5]nonan-7- yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (100 mg) was applied for further separation by Chiral HPLC with the following condition: Column: CHIRALPAK IG, 2*25 cm, 5 μm; Mobile Phase A: Hex (0.5% 2M NH3-MeOH)-HPLC, Mobile Phase B: EtOH-HPLC; Flow rate: 20 mL/min; Gradient: isocratic 10; Wave Length: 220/254 nm; RT1(min): 9.948; RT2(min): 15.703; Sample Solvent: EtOH-HPLC. Isomer 1: faster peak, 20.8 mg, 21.33% yield. LCMS (ESI, m/z): [M+H]⁺ = 469.2. t_R = 2.01 min (CHIRALPAK IG-3 4.6*50 mm 3 μm (HEX0.1%DEA):EtOH=90:10), HEX0.1%DEA):EtOH=90:10, 1.0 mL/min, 254 nm. Isomer 2: slower peak, 24.8 mg, 25.49% yield. LCMS (ESI, m/z): [M+H]+ = 469.2. tR = 3.29 min (CHIRALPAK IG-34.6*50 mm 3 μm (HEX0.1%DEA):EtOH=90:10), HEX0.1%DEA):EtOH=90:10, 1.0 mL/min, 254 nm). [00544] Step 8: (S)-2-Amino-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)benzoic acid & (R)-2-Amino-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4- yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzoic acid. A solution of isomer 1 from the step above (120 mg, 0.21 mmol) and KOH (115.35 mg, 2.06 mmol) in EtOH (0.7 mL) and water (0.3 mL) was stirred for 1h at 90 ºC under air atmosphere. The pH was adjusted to 6 with Citric acid. The residue was purified by reversed- phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10mmol/L NH4HCO3), 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in one enantiomer of 2-Amino-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)benzoic acid (20.8 mg, 21.33%) as a white solid. LCMS (ESI, m/z): [M+H]⁺ = 469.2. ¹H NMR (400 MHz, Methanol-d4) δ 7.99 (d, J = 8.1 Hz, 1H), 7.34 – 7.29 (m, 1H), 6.88 (s, 1H), 6.82 – 6.73 (m, 2H), 6.33 (d, J = 3.1 Hz, 1H), 4.37 (s, 1H), 4.07 (d, J = 12.4 Hz, 1H), 3.96 (d, J = 11.0 Hz, 1H), 3.83 – 3.78 (m, 3H), 3.38 (d, J = 12.9 Hz, 1H), 3.12 – 3.03 (m, 1H), 2.74 – 2.58 (m, 2H), 2.51 (d, J = 3.2 Hz, 3H), 2.42 (d, J = 14.2 Hz, 2H), 2.19 (d, J = 51.6 Hz, 1H), 2.02 (d, J = 14.6 Hz, 2H), 1.85 (d, J = 14.8 Hz, 1H). A solution of isomer 2 from the step above (120 mg, 0.21 mmol) and KOH (115.35 mg, 2.06 mmol) in EtOH (0.7 mL) and water (0.3 mL) was stirred for 1 h at 90 ºC under air atmosphere. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10mmol/L NH4HCO3), 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in the other enantiomer of 2-Amino-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)benzoic acid (24.8 mg, 25.49%) as a white solid. LCMS (ESI, m/z): [M+H]+ = 408.3.¹H NMR (400 MHz, Methanol-d4) δ 7.99 (d, J = 8.1 Hz, 1H), 7.33 – 7.29 (m, 1H), 6.88 (s, 1H), 6.82 – 6.73 (m, 2H), 6.34 (s, 1H), 4.34 (d, J = 12.3 Hz, 1H), 4.05 (d, J = 11.9 Hz, 1H), 3.94 (d, J = 13.5 Hz, 1H), 3.83 – 3.78 (m, 3H), 3.37 (d, J = 13.7 Hz, 1H), 3.07 (d, J = 13.5 Hz, 1H), 2.72 – 2.59 (m, 2H), 2.52 (d, J = 1.9 Hz, 3H), 2.43 (s, 2H), 2.23 (s, 1H), 2.02 (d, J = 15.0 Hz, 2H), 1.84 (d, J = 14.8 Hz, 1H). [00545] Example 18. (S)-4-(7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-2-oxa-7-azaspiro[3.5]nonan- 6-yl)-2-(methylamino)benzoic acid & (R)-4-(7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-2-oxa-7- azaspiro[3.5]nonan-6-yl)-2-(methylamino)benzoic acid & 4-(7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)- 2-oxa-7-azaspiro[3.5]nonan-6-yl)-2-(methylamino)benzoic acid.

[00546] step 1: tert-Butyl 2-oxa-7-azaspiro[3.5]nonane-7-carboxylate. A solution of 2-oxa-7- azaspiro[3.5]nonane (3 g, 23.59 mmol) and Boc₂O (6.69 g, 30.66 mmol) in DCM (40 mL) was added with TEAS (4.77 g, 47.17 mmol) and stirred for 1 h at room temperature. The resulting mixture was concentrated under vacuum. The residue was purified by C18 silica gel column chromatography, eluted with CH₃CN/water (1:1) to afford tert-butyl 2-oxa-7-azaspiro[3.5]nonane-7-carboxylate (2 g, 37.30%) as a yellow oil. LC-MS: (ES, m/z): 212.90 [M-(t-Bu)+CH₃CN]⁺. [00547] Step 2: tert-Butyl 6-oxo-2-oxa-7-azaspiro[3.5]nonane-7-carboxylate. A solution of tert-butyl 2- oxa-7-azaspiro[3.5]nonane-7-carboxylate (1 g, 4.40 mmol) and RuCl3.water (0.10 g, 0.44 mmol) in ethyl acetate (6 mL) and water (6 mL) was added NaIO4 (1.88 g, 8.80 mmol) and stirred for 1 h at 0 ºC. The resulting mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by C18 silica gel column chromatography, eluted with CH3CN/water (1:1) to afford the title compound (600 mg, 56.52%) as a yellow oil. LC-MS: (ES, m/z): 226.95 [M-(t-Bu)+CH3CN]⁺. [00548] Step 3: tert-Butyl 6-(trifluoromethanesulfonyloxy)-2-oxa-7-azaspiro[3.5]non-5-ene-7- carboxylate. A solution of tert-butyl 6-oxo-2-oxa-7-azaspiro[3.5]nonane-7-carboxylate (1.2 g, 4.97 mmol) in THF (15 mL) was added KHMDS (7.46 mL, 7.46 mmol) (1M in THF) for 40 min at -78 ºC under nitrogen atmosphere. Then 1,1,1-trifluoro-N-phenyl-N-(trifluoromethane)sulfonylmethanesulfonamide (3.55 g, 9.94 mmol) was added and stirred for 1h at -78 ºC. The reaction was quenched with sat. ammonium chloride (aq.) at 0 ºC. The resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by C18 silica gel column chromatography, eluted with CH3CN/water (1:1) to afford tert-butyl 6-(trifluoromethanesulfonyloxy)-2-oxa-7-azaspiro[3.5]non-5-ene-7- carboxylate (900 mg, 48.47%) as a yellow oil. LC-MS: (ES, m/z): 359.10 [M-(t-Bu)+CH3CN]⁺. [00549] Step 4: tert-Butyl 6-(3-(((benzyloxy)carbonyl)(methyl)amino)-4-(methoxycarbonyl)phenyl)-2- oxa-7-azaspiro[3.5]non-5-ene-7-carboxylate. A solution of tert-butyl 6-(trifluoromethanesulfonyloxy)-2-oxa- 7-azaspiro[3.5]non-5-ene-7-carboxylate (920 mg, 2.46 mmol), methyl 2- (((benzyloxy)carbonyl)(methyl)amino)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (1.26 g, 2.96 mmol), Pd(dppf)Cl₂CH₂Cl₂ (0.20 g, 0.25 mmol), sodium carbonate (0.52 g, 4.93 mmol) in 1,4-dioxane (8 mL) and water (2 mL) was stirred for 1 h at 90 ºC under nitrogen atmosphere. The resulting mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by C18 silica gel column chromatography, eluted with CH₃CN/water (1:1) to afford the title compound (650 mg, 50.47%) as a yellow oil. LC-MS: (ES, m/z): 467.05 [M-(t-Bu)]⁺. [00550] Step 5: tert-Butyl 6-(4-(methoxycarbonyl)-3-(methylamino)phenyl)-2-oxa-7- azaspiro[3.5]nonane-7-carboxylate. A solution of tert-butyl 6-(3-(((benzyloxy)carbonyl)(methyl)amino)-4- (methoxycarbonyl)phenyl)-2-oxa-7-azaspiro[3.5]non-5-ene-7-carboxylate (640 mg, 1.22 mmol) in IPA (15 mL) was added 10% Pd/C (1.3 g) and stirred for 5 h at 60 ºC under hydrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with acetonitrile. The filtrate was concentrated under reduced pressure to afford the title compound (420 mg, 89%) as a light yellow oil. LC-MS: (ES, m/z): 391.30 [M+H]⁺. [00551] Step 6: tert-Butyl 6-(4-(methoxycarbonyl)-3-(methylamino)phenyl)-2-oxa-7- azaspiro[3.5]nonane-7-carboxylate. A solution of tert-butyl 6-(4-(methoxycarbonyl)-3- (methylamino)phenyl)-2-oxa-7-azaspiro[3.5]nonane-7-carboxylate (510 mg, 1.31 mmol) in TFA (3 mL) and DCM (3 mL) was stirred for 30 min at room temperature. The resulting mixture was concentrated under vacuum. The mixture was basified to pH 7 with DIEA. The residue was purified by C18 silica gel column chromatography, eluted with CH3CN/water (1:8) to afford the title compound (350 mg, 92.29%) as a light yellow oil. LC-MS: (ES, m/z): 291.10 [M+H]⁺. [00552] Step 7: tert-Butyl 5-methoxy-4-((6-(4-(methoxycarbonyl)-3-(methylamino)phenyl)-2-oxa-7- azaspiro[3.5]nonan-7-yl)methyl)-7-methyl-1H-indole-1-carboxylate. A solution of methyl 2-(methylamino)- 4-(2-oxa-7-azaspiro[3.5]nonan-6-yl)benzoate (340 mg, 1.17 mmol), tert-butyl 4-formyl-5-methoxy-7- methylindole-1-carboxylate (677.58 mg, 2.34 mmol) in 1,2-dichloroethane (5 mL) was added titanium(IV) ethoxide (534.21 mg, 2.34 mmol) and stirred for 50 min at 70 ºC. Then the sodium triacetoxyborohydride (744.51 mg, 3.51 mmol) was added and stirred for 1 h at 70 ºC. The reaction was quenched with sat. ammonium chloride (aq.) at room temperature. The resulting mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by C18 silica gel column chromatography, eluted with CH3CN/water (8:1) to afford the title compound (170 mg, 25.76%) as a light yellow solid. LC-MS: (ES, m/z): 564.30 [M+H]⁺. [00553] Step 8: 4-(7-((5-Methoxy-7-methyl-1H-indol-4-yl)methyl)-2-oxa-7-azaspiro[3.5]nonan-6-yl)-2- (methylamino)benzoic acid. A solution of tert-butyl 5-methoxy-4-((6-[4-(methoxycarbonyl)-3- (methylamino)phenyl]-2-oxa-7-azaspiro[3.5]nonan-7-yl)methyl)-7-methylindole-1-carboxylate (30 mg, 0.053 mmol) and KOH (29.86 mg, 0.53 mmol)in EtOH (1 mL) and water (1 mL) was stirred with for 1.5 h at 80 ºC. The mixture was acidified to pH 6 with citric acid. The solvent was removed under vacuum. The residue was purified by C18 silica gel column chromatography, eluted with CH₃CN/water(NH₄HCO₃) (1:4) to afford the title compound (13.7 mg, 54.40%) as a white solid. LC-MS: (ESI, m/z): 450.20 [M+H]⁺.¹H NMR (500 MHz, Methanol-d₄) δ 8.02 (d, J = 7.9 Hz, 1H), 7.26 (d, J = 3.1 Hz, 1H), 6.85 (s, 1H), 6.75 (d, J = 16.2 Hz, 2H), 6.34 (d, J = 3.1 Hz, 1H), 4.69 (d, J = 40.3, 2H), 4.45 – 4.30 (m, 2H), 4.22 (d, J = 12.5 Hz, 1H), 3.77 (d, J = 1.8 Hz, 5H), 3.28 (s, 1H), 2.95 (s, 3H), 2.81 (s, 1H), 2.49 (s, 3H), 2.41 (d, J = 14.1 Hz, 1H), 2.25 – 2.20 (m, 1H), 2.15 – 2.02 (m 1H), 1.99 – 1.89 (m, 1H). [00554] Step 9: Isomer 1 (faster peak) and isomer 2 (slower peak) of tert-butyl 5-methoxy-4-((6-(4- (methoxycarbonyl)-3-(methylamino)phenyl)-2-oxa-7-azaspiro [3.5]nonan-7-yl)methyl)-7-methyl-1H-indole- 1-carboxylate. tert-butyl 5-methoxy-4-((6-(4-(methoxycarbonyl)-3-(methylamino)phenyl-2-oxa-7- azaspiro[3.5]nonan-7-yl)methyl)-7-methylindole-1-carboxylate (170 mg, 0.30 mmol) was applied for further separation by Chiral HPLC with the following condition: Column: CHIRALPAK IC 2*25 cm, 5 μm; Mobile Phase A: HEX(0.5% 2M NH3-MeOH), Mobile Phase B: EtOH; Flow rate: 20 mL/min; Gradient: isocratic 5; Wave Length: 220/254 nm; RT1(min): 15.676; RT2(min): 18.777. Isomer 1: faster peak, 60 mg, 35.3% yield. LC-MS: (ES, m/z): 563.70 [M+H]⁺, tR = 2.56 min CHIRALPAK IC-3 (4.6*50 mm 3 μm), HEX(0.1%DEA):EtOH=90:10, 1.0 mL/min, 254 nm). Isomer 2: slower peak, 65 mg, 38.2 % yield. LC-MS: (ES, m/z): 563.70 [M+H]⁺, t_R = 2.94 min CHIRALPAK IC-3 (4.6*50 mm 3 μm), HEX(0.1%DEA):EtOH=90:10, 1.0 mL/min, 254 nm). [00555] Step10: (S)-4-(7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-2-oxa-7-azaspiro[3.5]nonan-6-yl)- 2-(methylamino)benzoic acid & (R)-4-(7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-2-oxa-7- azaspiro[3.5]nonan-6-yl)-2-(methylamino)benzoic acid. A solution of isomer 1 (faster peak) from the step above (60 mg, 0.11 mmol) in EtOH (0.5 mL) and water (0.5 mL) was treated with KOH (59.54 mg, 1.06 mmol) for 2 h at 80 ºC. The mixture was acidified to pH 6 with citric acid. The solvent was removed under vacuum. The residue was purified by C18 silica gel column chromatography, eluted with CH3CN/water(NH4HCO3) (1:4) to afford one enantiomer of 4-(7-((5-methoxy-7-methyl-1H-indol-4- yl)methyl)-2-oxa-7-azaspiro[3.5]nonan-6-yl)-2-(methylamino)benzoic acid (29.2 mg, 61.0%) as white solid. LC-MS: (ES, m/z): 450.20 [M+H]⁺.¹H NMR (400 MHz, Methanol-d4) δ 8.04 (d, J = 8.0 Hz, 1H), 7.30 (d, J = 3.1 Hz, 1H), 6.86 (s, 1H), 6.77 (d, J = 4.8 Hz, 2H), 6.32 (d, J = 3.2 Hz, 1H), 4.80 – 4.73 (m, 1H), 4.68 (d, J = 6.2 Hz, 1H), 4.49 – 4.39 (m, 2H), 4.35 (d, J = 12.6 Hz, 1H), 4.10 (d, J = 12.4 Hz, 1H), 3.96 (d, J = 12.6 Hz, 1H), 3.79 (s, 3H), 3.41 (d, J = 13.1 Hz, 1H), 3.04 (s, 1H), 2.98 (s, 3H), 2.60 – 2.41 (m, 4H), 2.36 – 2.15 (m, 2H), 2.07 – 1.88 (m, 1H). A solution of isomer 2 (slower peak) from the step above (65 mg, 0.12 mmol) in EtOH (0.5 mL) and water (0.5 mL) was treated with KOH (64.50 mg, 1.15 mmol) for 2h at 80 ºC. The mixture was acidified to pH 6 with citric acid. The solvent was removed under vacuum. The residue was purified by C18 silica gel column chromatography, eluted with CH3CN/water(NH4HCO3) (1:4) to afford the other enantiomer of 4-(7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-2-oxa-7-azaspiro[3.5]nonan-6-yl)-2- (methylamino)benzoic acid (29.7 mg, 57.3%, white solid). LC-MS: (ES, m/z): 450.20 [M+H]⁺.¹H NMR (400 MHz, Methanol-d4) δ 8.04 (d, J = 8.0 Hz, 1H), 7.30 (d, J = 3.1 Hz, 1H), 6.86 (s, 1H), 6.77 (s, 2H), 6.32 (d, J = 3.1 Hz, 1H), 4.76 (d, J = 6.2 Hz, 1H), 4.68 (d, J = 6.2 Hz, 1H), 4.50 – 4.38 (m, 2H), 4.35 (d, J = 12.6 Hz, 1H), 4.09 (d, J = 12.3 Hz, 1H), 3.95 (d, J = 12.5 Hz, 1H), 3.79 (s, 3H), 3.40 (d, J = 13.3 Hz, 1H), 2.98 (s, 4H), 2.51 (s, 4H), 2.34 – 2.11 (m, 2H), 1.98 (s, 1H). [00556] Example 19. 4-(4-Methoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl)-2- (methylamino)benzoic acid.

[0

of benzyl 2-(3-chloro-4-cyanophenyl)-4-hydroxypiperidine-1-carboxylate (7.2 g, 19.42 mmol) in THF (80 mL) was added NaH (2.33 g, 58.25 mmol, 60%) and stirred for 50 min at room temperature. Then the CH₃I (7.17 g, 50.48 mmol) was added and stirred for 3 h at room temperature. The reaction was quenched with sat. ammonium chloride (aq.) at room temperature. The resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by C18 silica gel column chromatography, eluted with CH3CN/water (4:1) to afford the title compound (5.2 g, 69.59%) as a light yellow oil. LC-MS: (ES, m/z): 384.9 [M+H]⁺. [00558]

nzyloxy)carbonyl)-4-methoxypiperidin-2-yl)-2-chlorobenzoic acid. A solution of benzyl 2-(3-chloro-4-cyanophenyl)-4-methoxypiperidine-1-carboxylate (5.5 g, 14.29 mmol) in IPA (50 mL) and water (25 mL) was added Ba(OH)2 (24.49 g, 142.91 mmol) and stirred for overnight at 100 ºC. The mixture was acidified to pH 3 with conc. HCl. The resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to afford the title compound (4.5 g, 77.97%) as a yellow solid. LC-MS: (ES, m/z): 404.1 [M+H]⁺. [00559] Step 3: Benzyl 2-(3-chloro-4-(methoxycarbonyl)phenyl)-4-methoxypiperidine-1-carboxylate. A solution of 4-(1-((benzyloxy)carbonyl)-4-methoxypiperidin-2-yl)-2-chlorobenzoic acid (4.5 g, 11.14 mmol) in DCM (45 mL) and MeOH (5 mL) was added with 2M TMSCHN₂ in hexane (11.14 mL, 22.28 mmol) for 3h at room temperature. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with petroleum ether / ethyl acetate (3:1) to afford the title compound (4 g, 85.90%) as a yellow solid. LC-MS: (ES, m/z): 418.1 [M+H]⁺. [00560] Step 4: Benzyl 4-methoxy-2-[4-(methoxycarbonyl)-3-(methylamino)phenyl]piperidine-1- carboxylate. A solution of benzyl 2-(3-chloro-4-(methoxycarbonyl)phenyl)-4-methoxypiperidine-1- carboxylate (1.5 g, 3.59 mmol), methanamine hydrochloride (0.97 g, 14.36 mmol), Pd-PEPPSI-IPentCl 2- methylpyridine (o-picoline) (0.30 g, 0.36 mmol) and Cs2CO3 (5.85 g, 17.94 mmol) in 1,4-dioxane (25 mL) was stirred for 3h at 100 ºC under nitrogen atmosphere. The resulting mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with petroleum ether / ethyl acetate (4:1) to afford the title compound (800 mg, 54.03%) as a yellow solid. LC-MS: (ES, m/z): 413.1 [M+H]⁺. [00561] Step 5: Methyl 4-(4-methoxypiperidin-2-yl)-2-(methylamino)benzoate. A solution of benzyl 4- methoxy-2-(4-(methoxycarbonyl)-3-(methylamino)phenyl)piperidine-1-carboxylate (800 mg, 1.94 mmol) and 10% Pd/C (1.60 g) in ethyl acetate (15 mL) was stirred for 1h at room temperature under hydrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with ethyl acetate. The filtrate was concentrated under reduced pressure to afford the title compound (380 mg, 70.39%) as a light yellow solid. LC-MS: (ES, m/z): 280.1 [M+H]⁺. [00562] Step 6: tert-Butyl 5-methoxy-4-((4-methoxy-2-(4-(methoxycarbonyl)-3-(methylamino)phenyl) piperidin-1-yl)methyl)-7-methylindole-1-carboxylate. A solution of methyl 4-(4-methoxypiperidin-2-yl)-2- (methylamino)benzoate (600 mg, 2.16 mmol), tert-butyl 4-formyl-5-methoxy-7-methylindole-1-carboxylate (1247.33 mg, 4.31 mmol) and titanium(IV) ethoxide (983.40 mg, 4.31 mmol) in 1,2-dichloroethane (8 mL) was stirred for 40 min at 70 ºC. Then sodium triacetoxyborohydride (1370.54 mg, 6.47 mmol) was added at room temperature and was stirred for 40 min at 70 ºC. The resulting mixture was concentrated under vacuum. The residue was purified by C18 silica gel column chromatography, eluted with CH3CN/water (NH4HCO3) (8:1) to afford the title compound (250 mg, 20.39%) as a light yellow solid. LC-MS: (ES, m/z): 552.30 [M+H]⁺. [00563] Step 7: Fraction A and fraction B of tert-butyl 5-methoxy-4-((4-methoxy-2-(4- (methoxycarbonyl)-3-(methylamino)phenyl) piperidin-1-yl)methyl)-7-methylindole-1-carboxylate. tert-Butyl 5-methoxy-4-((4-methoxy-2-(4-(methoxycarbonyl)-3-(methylamino)phenyl)piperidin-1-yl) methyl)-7- methylindole-1-carboxylate (250 mg, 0.45 mmol) was applied for further separation by Chiral HPLC with the following condition: Column: Lux 5um Cellulose-22.12*25 cm, 5 μm; Mobile Phase A: HEX(0.1% DEA), Mobile Phase B: IPA; Flow rate: 20 mL/min; Gradient: isocratic 1; Wave Length: 220/254 nm; RT1(min): 10.518; RT2(min): 14.944. Fraction A: 85 mg, 34.0% yield. t_R = 1.705 min (Lux Cellulose‐24.6*50 mm,3 um), Hex (0.1%DEA):IPA=98:2, 1.0 mL/min, 254 nm). Fraction B: 90 mg, 36.0 % yield. t_R = 2.315 min (Lux Cellulose‐24.6*50 mm,3 um), Hex (0.1%DEA):IPA=98:2, 1.0 mL/min, 254 nm). [00564] Step 8: Fractions of 4-(4-Methoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2- yl)-2-(methylamino)benzoic acid & (S)-4-(4-methoxy-1-((5-methoxy-7-methyl-1H-indol-4- yl)methyl)piperidin-2-yl)-2-(methylamino)benzoic acid. A solution of Fraction A from the step above (85 mg, 0.15 mmol) in EtOH (0.5 mL) and water (0.5 mL) was added KOH (86.23 mg, 1.54 mmol) and stirred for 1.5 h at 80 ºC. The solvent was removed under vacuum. The residue was purified by C18 silica gel column chromatography, eluted with CH₃CN/water(NH₄HCO₃) (1:4) to afford one fraction of 4-(4-Methoxy- 1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl)-2-(methylamino)benzoic acid (52.6 mg, 78.16%, white solid). LC-MS: (ES, m/z): 438.20 [M+H]⁺.¹H NMR (500 MHz, Methanol-d4) δ 8.04 (d, J = 7.9 Hz, 1H), 7.31 (d, J = 3.1 Hz, 1H), 6.84 (s, 1H), 6.77 (d, J = 11.3 Hz, 2H), 6.40 – 6.27 (m, 1H), 4.51 (d, J = 11.3 Hz, 1H), 4.42 (d, J = 12.7 Hz, 1H), 4.15 (d, J = 12.8 Hz, 1H), 3.79 (s, 3H), 3.71 (s, 1H), 3.45 (s, 4H), 3.30 (s, 1H), 2.97 (s, 3H), 2.52 (s, 3H), 2.34 – 2.16 (m, 2H), 2.08 (d, J = 15.4 Hz, 1H), 1.97 (d, J = 14.8 Hz, 1H). A solution of fraction B (90 mg, 0.16 mmol) in EtOH (0.5 mL) and water (0.5 mL) was added KOH (91.25 mg, 1.63 mmol) and stirred for 1.5 h at 80 ºC. The solvent was removed under vacuum. The residue was purified by C18 silica gel column chromatography, eluted with CH3CN/water(NH4HCO3) (1:4) to afford the other fraction of 4-(4-Methoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl)-2- (methylamino)benzoic acid (56.1 mg, 78.57%, white solid). LC-MS: (ES, m/z): 438.20 [M+H]⁺.¹H NMR (300 MHz, Methanol-d4) δ 8.04 (d, J = 8.0 Hz, 1H), 7.31 (d, J = 3.2 Hz, 1H), 6.84 (d, J = 1.7 Hz, 1H), 6.76 (d, J = 7.1 Hz, 2H), 6.34 (s, 1H), 4.52 (s, 1H), 4.43 (d, J = 12.8 Hz, 1H), 4.15 (d, J = 12.7 Hz, 1H), 3.79 (s, 3H), 3.71 (s, 1H), 3.45 (s, 4H), 3.32 (s, 1H), 2.97 (s, 3H), 2.52 (d, J = 0.7 Hz, 3H), 2.27 (s, 2H), 2.16 – 1.79 (m, 2H). In some embodiments, a fraction, e.g., depending on separation conditions, substrate(s) utilized for prepare it, etc., may contain one or two or more stereoisomers such as diastereomers. [00565] Example 20. 4-(4-(Cyclopropylmethoxy)-1-((5-methoxy-7-methyl-1H-indol-4- yl)methyl)piperidin-2-yl)-2-(methylamino)benzoic acid.

[0 e. A

solution of benzyl 2-(3-chloro-4-cyanophenyl)-4-hydroxypiperidine-1-carboxylate (5 g, 13.48 mmol), (bromomethyl)cyclopropane (3.64 g, 26.96 mmol), TBAI (2.49 g, 6.74 mmol) and NaOH (30 g, 750.05 mmol) in water (30 mL) and toluene (50 mL) was stirred for overnight at 50 ºC. The resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with petroleum ether / ethyl acetate (8:1) to afford the title compound (3.2 g, 55.85% yield) as a yellow oil. LCMS (ESI, m/z): [M+H]⁺ = 425.2. [00567] Step 2: 4-(1-((Benzyloxy)carbonyl)-4-(cyclopropylmethoxy)piperidin-2-yl)-2-chlorobenzoic acid. A solution of benzyl 2-(3-chloro-4-cyanophenyl)-4-(cyclopropylmethoxy)piperidine-1-carboxylate (3.2 g, 7.53 mmol) and Ba(OH)2 (12.9 g, 75.31 mmol) in i-PrOH (40 mL) and water (15 mL) was stirred for 1 day at 100 ºC. The mixture was acidified to pH < 7 with conc. HCl. The resulting mixture was extracted with ethyl acetate (150 mL). The combined organic layers were washed with brine (3x100 mL), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to afford the title compound (3 g, 75.38% yield) as a yellow oil. LCMS (ESI, m/z): [M+H]⁺ = 444.1. [00568] Step 3: Benzyl 2-(3-chloro-4-(methoxycarbonyl)phenyl)-4-(cyclopropylmethoxy)piperidine-1- carboxylate. To a stirred solution of 4-(1-[(benzyloxy)carbonyl]-4-(cyclopropylmethoxy)piperidin-2-yl)-2- chlorobenzoic acid (3 g, 6.75 mmol) in DCM (27 mL) and MeOH (3 mL) was added TMSCHN2 (13.52 mL, 13.51 mmol)(1M in THF) dropwise at room temperature and stirred for 1h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with petroleum ether / ethyl acetate (8:1) to afford the title compound (1.8 g, 58.16% yield) as a yellow oil. LCMS (ESI, m/z): [M+H]⁺ =458.0. [00569] Step 4: Benzyl 4-(cyclopropylmethoxy)-2-(4-(methoxycarbonyl)-3- (methylamino)phenyl)piperidine-1-carboxylate. A solution of benzyl 2-(3-chloro-4- (methoxycarbonyl)phenyl)-4-(cyclopropylmethoxy)piperidine-1-carboxylate (1.2 g, 2.62 mmol), methylamine hydrochloride(488 mg, 15.72 mmol), Cs₂CO₃ (5.97 g, 18.34 mmol) and Pd-PEPPSI-IPentCl 2- methylpyridine (o-picoline (220 mg, 0.26 mmol) in 1,4-dioxane (20 mL) was stirred for 3 h at 100 ºC under nitrogen atmosphere. The solvent was removed. The residue was purified by silica gel column chromatography, eluted with petroleum ether / ethyl acetate (8:1) to afford the title compound (710 mg, 59.87% yield) as a yellow oil. LCMS (ESI, m/z): [M+H]⁺ =453.3. [00570] Step 5: Methyl 4-(4-(cyclopropylmethoxy)piperidin-2-yl)-2-(methylamino)benzoate. A solution of benzyl 4-(cyclopropylmethoxy)-2-(4-(methoxycarbonyl)-3-(methylamino)phenyl)piperidine-1-carboxylate (710 mg, 1.56 mmol) and 10% Pd/C (360 mg) in ethyl acetate (10 mL) was stirred for 1 h at room temperature. The resulting mixture was filtered, the filter cake was washed with ethyl acetate. The filtrate was concentrated under reduced pressure. The resulting mixture was concentrated under vacuum to afford the title compound (480 mg, 96.08% yield) as a yellow solid. LCMS (ESI, m/z): [M+H]⁺ = 319.2. [00571] Step 6: tert-Butyl 4-((4-(cyclopropylmethoxy)-2-(4-(methoxycarbonyl)-3- (methylamino)phenyl)piperidin-1-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate. A solution of methyl 4-(4-(cyclopropylmethoxy)piperidin-2-yl)-2-(methylamino)benzoate (470 mg, 1.47 mmol), titanium(IV) ethoxide (673 mg, 2.95 mmol) and tert-butyl 4-formyl-5-methoxy-7-methylindole-1-carboxylate (854 mg, 2.95 mmol) in 1,2-dichloroethane (10 mL) was stirred for 40 min at 70 ºC. Then sodium triacetoxyborohydride (938 mg, 4.42 mmol) was added to the solution and stirred for 30 min at 70 ºC. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10mmol/L NH4HCO3), 70% to 80% gradient in 15 min; detector, UV 254 nm to afford the title compound as a yellow solid(520 mg, 58.19% yield). LCMS (ESI, m/z): [M+H]⁺ = 592.3. [00572] Step 7: Fraction A and fraction B of tert-Butyl 4-((4-(cyclopropylmethoxy)-2-(4- (methoxycarbonyl)-3-(methylamino)phenyl)piperidin-1-yl)methyl)-5-methoxy-7-methyl-1H-indole-1- carboxylate. tert-Butyl 4-((4-(cyclopropylmethoxy)-2-(4-(methoxycarbonyl)-3- (methylamino)phenyl)piperidin-1-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate(210 mg, 0.354 mmol ) was applied for further separation by Chiral HPLC with the following condition: Column: Lux 5um Cellulose-4, 2.12*25 cm, 5 μm; Mobile Phase A: Hex (0.1% FA)-HPLC, Mobile Phase B: EtOH-HPLC; Flow rate: 20 mL/min; Gradient: isocratic 1; Wave Length: 220/254 nm; RT1(min): 6.412; RT2(min): 10.17; Sample Solvent: EtOH-HPLC; Injection Volume: 1.0 mL; Number Of Runs: 25. Fraction A: 70 mg, 33.3 % yield. LCMS (ESI, m/z): [M+H]⁺ = 592.3. t_R = 0.81 min (Lux Cellulose-4 (0.46*5cm,3um), Hex (0.1%DEA): EtOH =98: 2, 1 mL/min, 254 nm). Fraction B: 70 mg, 33.3 % yield. LCMS (ESI, m/z): [M+H]⁺ = 592.3. t_R = 1.351 min (Lux Cellulose-4 (0.46*5cm,3um), Hex (0.1%DEA): EtOH =98: 2, 1 mL/min, 254 nm). [00573] Step 8: Fractions of 4-(4-(Cyclopropylmethoxy)-1-((5-methoxy-7-methyl-1H-indol-4- yl)methyl)piperidin-2-yl)-2-(methylamino)benzoic acid. A solution of fraction B from the step above (60 mg, 0.1 mmol) and KOH (114 mg, 2.03 mmol) in ETOH (1.5 mL) and water (0.5 mL) was stirred for 2 h at 80 ºC. The mixture was acidified to pH <7 with sat. citric acid. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10mmol/L NH₄HCO₃), 20% to 30% gradient in 5 min; detector, UV 254 nm to afford a fraction of 4-(4- (cyclopropylmethoxy)-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl)-2- (methylamino)benzoic acid (17.6 mg, 35.76% yield) as a white solid. LCMS (ESI, m/z): [M+H]⁺ = 478.2.¹H NMR (300 MHz, Methanol-d₄) δ 8.02 (d, J = 7.9 Hz, 1H), 7.29 (d, J = 3.1 Hz, 1H), 6.82 (d, J = 1.7 Hz, 1H), 6.79 – 6.71 (m, 2H), 6.32 (s, 1H), 4.52 (s, 1H), 4.41 (d, J = 12.6 Hz, 1H), 4.15 (d, J = 12.7 Hz, 1H), 3.83 (s, 1H), 3.77 (s, 3H), 3.38 (d, J = 6.8 Hz, 3H), 2.94 (s, 3H), 2.50 (s, 3H), 2.23 (s, 2H), 1.97 (d, J = 22.7 Hz, 2H), 1.22 – 1.07 (m, 1H), 0.85- 0.74(m, 1H), 0.64 – 0.53 (m, 2H), 0.33 – 0.23 (m, 2H). Fraction A of the step above can be utilized to prepare other stereoisomer(s). [00574] Example 21. 4-(4-Ethoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl)-2- (methylamino)benzoic acid.

[0 To a

stirred solution of 4-bromo-2-chlorobenzonitrile (40 g, 184.79 mmol) in THF (240 mL) was added 1.3 M Isopropylmagnesium chloride - lithium chloride complex in THF (142.2 mL, 184.79 mmol) dropwise at -5ºC under nitrogen atmosphere. Then stirred at room temperature for 0.5 hour.4-Methoxypyridine (18.16 g, 166.31 mmol) was added dropwise at -78 ºC and stirred for 20 minutes. CbzCl (28.36 g, 166.31 mmol) was added dropwise at -78 ºC and stirred for 5 hour. The reaction was quenched by the addition of HCl (6M) at room temperature. The resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with petroleum ether / ethyl acetate (3:1) to afford the title compound (36 g, 53.11% yield) as a brown oil. LCMS (ESI, m/z): [M+H]⁺ = 367.0. [00576] Step 2: Benzyl 2-(3-chloro-4-cyanophenyl)-4-oxopiperidine-1-carboxylate. A solution of benzyl 2-(3-chloro-4-cyanophenyl)-4-oxo-2,3-dihydropyridine-1-carboxylate (20 g, 54.53 mmol) and Zn (35.65 g, 545.3 mmol) in HOAc (175 mL) was stirred for 2 h at 100 ºC. The resulting mixture was extracted with ethyl acetate (500 mL). The combined organic layers were washed with water (3x200 mL), dried over anhydrous sodium sulfate. The organic layers were washed with saturated sodium bicarbonate aqueous solution. After filtration, the filtrate was concentrated under reduced pressure to get the title compound (22 g, 73.30% yield) as a brown oil. LCMS (ESI, m/z): [M+H]⁺ = 369.0. [00577] Step 3: Benzyl 2-(3-chloro-4-cyanophenyl)-4-hydroxypiperidine-1-carboxylate. A solution of benzyl 2-(3-chloro-4-cyanophenyl)-4-oxopiperidine-1-carboxylate (20 g, 54.22 mmol) and NaBH4 (4.11 g, 108.45 mmol) in THF (100 mL) was stirred for 1 h at room temperature. The resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with petroleum ether / ethyl acetate (2:1) to afford the title compound (12.5 g, 62.16% yield) as a yellow oil. LCMS (ESI, m/z): [M+H]⁺ =371.0. [00578] Step 4: Benzyl 2-(3-chloro-4-cyanophenyl)-4-ethoxypiperidine-1-carboxylate. A solution of benzyl 2-(3-chloro-4-cyanophenyl)-4-hydroxypiperidine-1-carboxylate (8 g, 21.57 mmol) in THF (200 mL) was stirred for 5 mins at 0 ºC under nitrogen atmosphere followed by the addition of NaHMDS (38.83 mL, 38.83 mmol)(1M in THF) dropwise at 0 ºC, the solution was stirred for 30min. ethyl trifluoromethanesulfonate (7.68 g, 43.14mmol) as added to the solution and stirred at 0 °C for 30 min. The reaction was quenched with sat. ammonium chloride (aq.) at room temperature. The resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with petroleum ether / ethyl acetate (4:1) to afford the title compound (5.12 g, 51.17% yield) as a yellow oil. LCMS (ESI, m/z): [M+H]⁺ =399.0.

[00579] Step 5: 4-(l-((Benzyloxy)carbonyl)-4-ethoxypiperidin-2-yl)-2-chlorobenzoic acid. A solution of benzyl 2-(3-chloro-4-cyanophenyl)-4-ethoxypiperidine-l -carboxylate (5 g, 12.53 mmol) and Ba(OH)2 (21.48 g, 125.35 mmol) in water (20 mL) and i-PrOH (32 mL) was stirred for overnight at 100 °C. The mixture was acidified to pH< 7 with cone. HC1. The resulting mixture was extracted with ethyl acetate (50 mL). The combined organic layers were washed with brine (50mL), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to afford the title compound (5.17 g, 90.74% yield) as a yellow oil. LCMS (ESI, m/z): [M+H]⁺= 418.0.

[00580] Step 6: Benzyl 2-(3-chloro-4-(methoxycarbonyl)phenyl)-4-ethoxypiperidine-l -carboxylate. A solution of 4-(l-((benzyloxy)carbonyl)-4-ethoxypiperidin-2-yl)-2-chlorobenzoic acid (5.1 g, 12.2 mmol) and TMSCHNz (24.4 mL, 24.4 mmol) (IM in hexane) in DCM (45 mL) and MeOH (5 mL) was stirred for 1 h at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with petroleum ether / ethyl acetate (10:1) to afford the title compound (4.5 g. 81.1% yield) as a yellow oil. LCMS (ESI, m/z): [M+H]⁺= 432.2.

[00581] Step 7: Benzyl 4-ethoxy-2-(4-(methoxycarbonyl)-3-(methylamino)phenyl)piperidine-l- carboxylate. A solution of benzyl 2-(3-chloro-4-(methoxycarbonyl)phenyl)-4-ethoxypiperidine-l -carboxylate (1.2 g, 2.77 mmol), Methylamine hydrochloride (750. 93 mg, 11.11 mmol), Pd-PEPPSI-IPentCl 2- methylpyridine (o-picoline (234 mg, 0.28 mmol) and CszCCL (4.52 g, 4.63 mmol) in 1,4-dioxane (30 mL) was stirred for 3 h at 100 °C under nitrogen atmosphere. The solvent was removed. The residue was purified by silica gel column chromatography, eluted with petroleum ether I ethyl acetate (10:1) to afford the title compound (720 mg, 54.68% yield) as a yellow oil. LCMS (ESI, m/z): [M+H]⁺ = 427.2.

[00582] Step 8: Methyl 4-(4-ethoxypiperidin-2-yl)-2-(methylamino)benzoate. A solution of benzyl 4- ethoxy-2-[4-(methoxycarbonyl)-3-(methylamino)phenyl]piperidine-l-carboxylate (720 mg, 1.68 mmol) and 10% Pd/C (360 mg) in ethyl acetate (10 mL) was stirred for 1 h at room temperature under hydrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with ethyl acetate (50 mL). The filtrate was concentrated under reduced pressure to afford the title compound (410 mg, 83.07% yield) as a yellow oil. LCMS (ESI, m/z): [M+H]⁺= 293.1.

[00583] Step 9: tert-Butyl 4-((4-ethoxy-2-(4-(methoxycarbonyl)-3-(methylamino)phenyl)piperidin-l- yl)methyl)-5-methoxy-7-methyl-lH-indole-l-carboxylate. A solution of methyl 4-(4-ethoxypiperidin-2-yl)- 2-(methylamino)benzoate (440 mg, 1.5 mmol), tert-butyl 4-formyl-5-methoxy-7-methylindole-l-carboxylate (870 mg, 3.01 mmol) and titanium(lV) ethoxide (687 mg, 3.01 mmol) in 1 ,2-dichloroethane (10 mL) was stirred for 40 min at 70 ºC. Sodium triacetoxyborohydride (957 mg, 4.51 mmol) was added to the solution and stirred at 70 ºC for 30 min. The solvent was removed. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10mmol/L NH₄HCO₃), 75% to 80% gradient in 10 min; detector, UV 254 nm to afford the title compound (380 mg, 44.64% yield) as a yellow solid. LCMS (ESI, m/z): [M+H]⁺ = 566.30. [00584] Step 10: Fraction A and fraction B of tert-butyl 4-((4-ethoxy-2-(4-(methoxycarbonyl)-3- (methylamino)phenyl)piperidin-1-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate. tert-Butyl 4-((4- ethoxy-2-(4-(methoxycarbonyl)-3-(methylamino)phenyl)piperidin-1-yl)methyl)-5-methoxy-7-methyl-1H- indole-1-carboxylate (180 mg, 0.31 mmol) was applied for further separation by Chiral HPLC with the following condition: Column: Lux 5um Cellulose-4, 2.12*25 cm, 5 μm; Mobile Phase A: Hex (0.1% FA)- HPLC, Mobile Phase B: EtOH-HPLC; Flow rate: 20 mL/min; Gradient: isocratic 1; Wave Length: 220/254 nm; RT1(min): 5.404; RT2(min): 6.749; Sample Solvent: EtOH-HPLC; Injection Volume: 0.7 mL; Number Of Runs: 20. Fraction A: 60 mg, 33.2 % yield. LCMS (ESI, m/z): [M+H]⁺ = 566.3. tR = 1.06 min (LuxCellulose4, Hex (0.1%DEA): EtOH =100: 1, 1 mL/min, 254 nm). Fraction B: 62 mg, 34.4 % yield). LCMS (ESI, m/z): [M+H]⁺ = 566.3. tR = 2.00 min (LuxCellulose4, Hex (0.1%DEA): EtOH =100: 1, 1 mL/min, 254 nm). [00585] Step 11: (R)-4-(4-Ethoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl)-2- (methylamino)benzoic acid and (S)-4-(4-Ethoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2- yl)-2-(methylamino)benzoic acid. A solution of fraction B from the step above (60 mg, 0.1 mmol) and KOH (70 mg, 1.24 mmol) in EtOH (1.5 mL) and water (0.5 mL) was stirred for 1.5h at 80 ºC. The mixture was acidified to pH<7 with sat. citric acid. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10mmol/L NH4HCO3), 20% to 30% gradient in 5 min; detector, UV 254 nm to afford one enantiomer of 4-(4-Ethoxy-1-((5-methoxy-7- methyl-1H-indol-4-yl)methyl)piperidin-2-yl)-2-(methylamino)benzoic acid (33.2 mg, 69.32% yield) as a white solid. LCMS (ESI, m/z): [M+H]⁺ = 452.2.¹H NMR (300 MHz, Methanol-d4) δ 8.01 (d, J = 7.9 Hz, 1H), 7.29 (d, J = 3.1 Hz, 1H), 6.82 (d, J = 1.7 Hz, 1H), 6.74 (d, J = 7.0 Hz, 2H), 6.31 (s, 1H), 4.62 – 4.36 (m, 2H), 4.14 (d, J = 12.7 Hz, 1H), 3.77 (s, 4H), 3.65 – 3.54 (m, 2H), 3.50 – 3.37 (m, 1H), 3.29 (s, 1H), 2.94 (s, 3H), 2.52 – 2.48 (m, 3H), 2.23 (s, 2H), 2.07 – 1.92 (m, 2H), 1.33 – 1.27 (m, 3H). Fraction A from the step above can be utilized to prepare other stereoisomer(s). [00586] Example 22. 4-(1-((5-Methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl)-3- (methylamino)benzoic acid.

[0

amino-4-bromobenzoate (50 g, 217.33 mmol) and Boc2O (71.2 g, 326.00 mmol), DIEA (56.2 g, 434.67 mmol) and DMAP (13.3 g, 108.67 mmol) in THF (500 mL) was stirred for 4 h at room temperature under air atmosphere. The resulting mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with water and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with petroleum ether / ethyl acetate (1:1) to afford the title compound (10 g, 13.94%) as a yellow solid. LCMS (ESI, m/z): [M+H]⁺ = 330.0. [00588] Step 2: 4-Bromo-3-((tert-butoxycarbonyl)(methyl)amino)benzoic acid. A mixture of methyl 4- bromo-3-( (tert-butoxycarbonyl) amino)benzoate (10 g, 30.29 mmol) and NaH (2.2 g, 90.86 mmol) in THF (100 mL) was stirred for 30 min at room temperature under air atmosphere. To the above mixture was added CH₃I (12.9. g, 90.86 mmol) dropwise over 1 min at room temperature. The resulting mixture was stirred for additional 2h at room temperature. The reaction was quenched by the addition of water at 0 ºC. The resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with water and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with petroleum ether / ethyl acetate (1:1) to afford the title compound (6 g, 60.00%) as a yellow oil. LCMS (ESI, m/z): [M+H]⁺ = 330.0. [00589] Step 3: Methyl 4-bromo-3-((tert-butoxycarbonyl)(methyl)amino)benzoate. A mixture of 4- bromo-3-((tert-butoxycarbonyl)(methyl)amino)benzoic acid (6 g, 18.17 mmol) and 1M TMSCHN₂ in hexane (36 mL, 36 mmol) in MeOH (5 mL) and DCM (45 mL) was stirred for 1h at room temperature under air atmosphere. The resulting mixture was concentrated under reduced pressure. The crude product was used in the next step directly without further purification. LCMS (ESI, m/z): [M+H]⁺ = 345.0. [00590] Step 4: Methyl 3-((tert-butoxycarbonyl)(methyl)amino)-4-(pyridin-2-yl)benzoate. A mixture of methyl 4-bromo-3-((tert-butoxycarbonyl)(methyl)amino)benzoate (5 g, 14.53 mmol) and 2- (tributylstannyl)pyridine (10.7 g, 29.05 mmol)and Pd(PPh3)4 (1.68 g, 1.453 mmol) in 1,4-dioxane (30 mL) was stirred for 12 h at 110 ºC under nitrogen atmosphere. The reaction was quenched by the addition of KF aqueous solution at room temperature. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), 10% to 50% gradient in 10 min; detector, UV 254 nm to afford the title compound (1.5 g, 30.16%) as a yellow solid. LCMS (ESI, m/z): [M+H]⁺ = 343.2. [00591] Step 5: Methyl 3-((tert-butoxycarbonyl)(methyl)amino)-4-(piperidin-2-yl)benzoate. A mixture of methyl 3-((tert-butoxycarbonyl)(methyl)amino)-4-(pyridin-2-yl)benzoate (1500 mg, 4.38 mmol) and 10% Pd/C (2997.7 mg, 28.17 mmol) in IPA (20 mL) was stirred for 12 h at 60 ºC under hydrogen atmosphere. After filtration, the filtrate was concentrated to afford the title compound (1000 mg, 65.51%) as a yellow oil. LCMS (ESI, m/z): [M+H]+ = 349.2. [00592] Step 6: Methyl 3-(methylamino)-4-(piperidin-2-yl)benzoate. A mixture of methyl 3-((tert- butoxycarbonyl)(methyl)amino)-4-(piperidin-2-yl)benzoate (1000 mg, 2.87 mmol) in 4 M HCl(gas) in 1,4- dioxane (10.00 mL) was stirred for 1h at room temperature under air atmosphere. The solvent was removed. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% TFA), 5% to 30% gradient in 30 min; detector, UV 254 nm to afford the title compound (500 mg, 70.16%) as a yellow oil. LCMS (ESI, m/z): [M+H]+ = 249.2. [00593] Step 7: tert-Butyl 5-methoxy-4-((2-(4-(methoxycarbonyl)-2-(methylamino)phenyl)piperidin-1- yl)methyl)-7-methyl-1H-indole-1-carboxylate. A mixture of methyl 3-(methylamino)-4-(piperidin-2- yl)benzoate (500 mg, 2.01 mmol) and tert-butyl 4-formyl-5-methoxy-7-methylindole-1-carboxylate (699.1 mg, 2.42 mmol) and acetic acid (725.5 mg, 12.08 mmol) in 1,2-dichloroethane (1 mL) was stirred for 1h at 70 ºC under air atmosphere. To the above mixture was added sodium triacetoxyborohydride (1280.2 mg, 6.04 mmol) in portions over 10 mins at room temperature. The resulting mixture was stirred for additional 2h at 70 ºC. The solvent was removed under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10mmol/L NH₄HCO₃), 10% to 50% gradient in 10 min; detector, UV 254 nm to afford the title compound (140 mg, 13.33%) as a yellow oil. LCMS (ESI, m/z): [M+H]+ = 522.3. [00594] Step 8: 4-(1-((5-Methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl)-3- (methylamino)benzoic acid. A mixture of tert-butyl 5-methoxy-4-((2-[4-(methoxycarbonyl)-2- (methylamino)phenyl]piperidin-1-ylmethyl)-7-methylindole-1-carboxylate (140 mg, 0.27 mmol) and KOH (150.57 mg, 2.68 mmol) in EtOH (1 mL) and water (1 mL) was stirred for 2 h at 80 ºC under air atmosphere. The residue was acidified to pH 6 with citric acid. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10mmol/L NH₄HCO₃), 20% to 50% gradient in 30 min; detector, UV 254 nm. This resulted in the title compound (21.5 mg, 19.58%) as a white solid. LCMS (ESI, m/z): [M+H]⁺ = 408.2.¹H NMR (300 MHz, Methanol-d4) δ 7.47 (d, J = 10.1 Hz, 2H), 7.38 (d, J = 13.1 Hz, 1H), 7.26 (d, J = 3.1 Hz, 1H), 6.68 (s, 1H), 6.21 (d, J = 3.1 Hz, 1H), 4.51 – 3.84 (m, 3H), 3.73 (s, 4H), 3.39 – 3.33 (m, 1H), 2.93 (s, 3H), 2.47 (s, 3H), 2.13 (d, J = 12.4 Hz, 1H), 1.90 (d, J = 10.7 Hz, 2H), 1.87 – 1.70 (m, 2H) 1.77 (s, 1H). [00595] Example 23. (S)-4-(2,2-Difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)-2-(methylamino)benzoic acid & (R)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H- indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)-2-(methylamino)benzoic acid & 4-(2,2-difluoro-7-((5- methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)-2-(methylamino)benzoic acid.

[0

, . . , oro- 7-azaspiro[3.5]nonane hydrochloride (3 g, 15.15 mmol) and triethyl amine (3.1 g, 30.30 mmol) and Boc₂O (4.3 g, 19.69 mmol) in DCM (30 mL) was stirred for 2 h at room temperature under air atmosphere. The resulting mixture was quenched with water and extracted with CH₂Cl₂. The combined organic layers were washed with water and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% TFA), 10% to 100% gradient in 30 min; detector, UV 200 nm.to afford the title compound (2 g, 51% yield) as a yellow solid. LCMS (ESI, m/z): [M+H]⁺ = 262.2. [00597] Step 2: tert-Butyl 2,2-difluoro-6-oxo-7-azaspiro[3.5]nonane-7-carboxylate. A mixture of tert- butyl 2,2-difluoro-7-azaspiro[3.5]nonane-7-carboxylate (2 g, 7.65 mmol) and RuCl₃.water (172.5 mg, 0.77 mmol) and NaIO₄ (3.3 g, 15.31 mmol, 2 equiv) in water (10 mL) and Ethyl acetate (10 mL) was stirred for 3 h at 0 ºC under air atmosphere. The resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with water and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% TFA), 10% to 80% gradient in 30 min; detector, UV 220 nm.to afford the title compound (1.6 g, 75.94% yield) as a white solid. LCMS (ESI, m/z): [M+H]+ = 276.1. [00598] Step 3: tert-Butyl 2,2-difluoro-6-(trifluoromethanesulfonyloxy)-7-azaspiro[3.5]non-5-ene-7- carboxylate. A mixture of tert-butyl 2,2-difluoro-6-oxo-7-azaspiro[3.5]nonane-7-carboxylate (1.6 g, 5.81 mmol) and KHMDS (8.7 mL, 8.72 mmol, 1.5 equiv) (1M in THF) in THF (10 mL) was stirred for 30 mins at -78 ºC under nitrogen atmosphere. To the above mixture was added 1,1,1-trifluoro-N-phenyl-N- (trifluoromethane)sulfonylmethanesulfonamide (4.2 g, 11.63 mmol) dropwise over 10 mins at -78 ºC. The resulting mixture was stirred for additional 2 h at -78 ºC. The reaction was quenched by the addition of sat. ammonium chloride (aq.) at room temperature. The resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with water and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% TFA), 10% to 100% gradient in 30 min; detector, UV 220 nm to afford the title compound (1.2 g, 50.69% yield) as a yellow solid. LCMS (ESI, m/z): [M+H]+ = 408.1. [00599] Step 4: Methyl 2-(((benzyloxy)carbonyl)amino)-4-iodobenzoate. A solution of methyl 2-amino- 4-iodobenzoate (2 g, 4.47 mmol) in DCM (10 mL) and water (10 mL) was treated with sodium carbonate (2.70 g, 25.47 mmol, 5.70 equiv) for 5min at room temperature under nitrogen atmosphere followed by the addition of Cbz-Cl (2.4 g, 14.03 mmol) dropwise at room temperature. The resulting mixture was extracted with CH2Cl2. The combined organic layers were washed with water and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with petroleum ether / ethyl acetate (5:1) to afford the title compound (2 g, 68.9% yield) as a white solid. LCMS (ESI, m/z): [M+H]+ = 412.0. [00600] Step 5: Methyl 2-(((benzyloxy)carbonyl)(methyl)amino)-4-iodobenzoate. A solution of methyl 2-(((benzyloxy)carbonyl)amino-4-iodobenzoate (1 g, 2.43 mmol) in DMF (10 mL) was treated with NaH (116 mg, 4.83 mmol) and stirred for 30 mins at 0 ºC followed by the addition of CH₃I (689 mg, 4.85 mmol) in portions at 0 ºC. The resulting mixture was stirred for 40min at 0 ºC under air atmosphere. The reaction was quenched with sat. ammonium chloride (aq.) at room temperature. The resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with water and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with petroleum ether / ethyl acetate (6:1) to afford the title compound (800 mg, 77.36% yield) as a white solid. LCMS (ESI, m/z): [M+H]+ = 426.0. [00601] Step 6: Methyl 2-(((benzyloxy)carbonyl)(methyl)amino)-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzoate. A mixture of methyl 2-(((benzyloxy)carbonyl)(methyl)amino)-4-iodobenzoate (800 mg, 1.89 mmol), bis(pinacolato)diboron (1.20 g, 4.7 mmol), Pd(dppf)Cl₂ (137.6 mg, 0.19 mmol) and KOAc (553.9 mg, 5.64 mmol) in 1,4-dioxane (10 mL) was stirred for 1h at 110 ºC under nitrogen atmosphere. The resulting mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with water and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with petroleum ether / ethyl acetate (1:1) to afford the title compound (500 mg, 62.49% yield) as a yellow oil. LCMS (ESI, m/z): [M+H]+ = 426.2 [00602] Step 7: tert-Butyl 6-(3-(((benzyloxy)carbonyl)(methyl)amino)-4-(methoxycarbonyl)phenyl)-2,2- difluoro-7-azaspiro[3.5]non-5-ene-7-carboxylate. A mixture of tert-butyl 2,2-difluoro-6- (trifluoromethanesulfonyloxy)-7-azaspiro[3.5]non-5-ene-7-carboxylate (1.2 g, 2.95 mmol), methyl 2- (((benzyloxy)carbonyl)(methyl)amino)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (1.5 g, 3.54 mmol), Pd(dppf)Cl2 (215.6 mg, 0.30 mmol) and sodium carbonate (624.5 mg, 5.89 mmol) in 1,4-dioxane (8 mL) and water (2 mL) was stirred for 1h at 90 ºC under nitrogen atmosphere. The solvent was removed under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% TFA), 20% to 100% gradient in 30 min; detector, UV 254 nm to afford the title compound (600 mg, 36.59% yield) as a white solid. LCMS (ESI, m/z): [M+H]+ = 557.2. [00603] Step 8: tert-Butyl 2,2-difluoro-6-(4-(methoxycarbonyl)-3-(methylamino)phenyl)-7- azaspiro[3.5]nonane-7-carboxylate. A mixture of tert-butyl 6-(3-(((benzyloxy)carbonyl)(methyl)amino)-4- (methoxycarbonyl)phenyl)-2,2-difluoro-7-azaspiro[3.5]non-5-ene-7-carboxylate (600 mg, 1.02 mmol) and 10% Pd/C (1.2) in IPA (10 mL) was stirred for 2 h at room temperature under hydrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with MeOH. The filtrate was concentrated under reduced pressure. The crude product was used in the next step directly without further purification. LCMS (ESI, m/z): [M+H]⁺ = 425.2. [00604] Step 9: Methyl 4-(2,2-difluoro-7-azaspiro[3.5]nonan-6-yl)-2-(methylamino)benzoate. A mixture of tert-butyl 2,2-difluoro-6-(4-(methoxycarbonyl)-3-(methylamino)phenyl)-7-azaspiro[3.5]nonane-7- carboxylate (500 mg, 1.18 mmol) in 4 M HCl in 1,4-dioxane (10 mL) was stirred for 1h at room temperature under air atmosphere. The resulting mixture was concentrated under reduced pressure. The crude resulting mixture was used in the next step directly without further purification. LCMS (ESI, m/z): [M+H]⁺ =325.2. [00605] Step 10: tert-Butyl 4-((2,2-difluoro-6-(4-(methoxycarbonyl)-3-(methylamino)phenyl)-7- azaspiro[3.5]nonan-7-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate. A mixture of methyl 4-(2,2- difluoro-7-azaspiro[3.5]nonan-6-yl-2-(methylamino)benzoate (400 mg, 1.23 mmol), tert-butyl 4-formyl-5- methoxy-7-methylindole-1-carboxylate (713.6 mg, 2.47 mmol) and titanium(IV) ethoxide (562.6 mg, 2.47 mmol) in 1,2-dichloroethane (5 mL) was stirred for 30 mins at 70 ºC under air atmosphere. To the above mixture was added sodium triacetoxyborohydride (784.1 mg, 3.70 mmol) in batches over 10 mins at room temperature. The resulting mixture was stirred for additional 1 h at 70 ºC. The resulting mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with water and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10mmol/L NH₄HCO₃), 10% to 90% gradient in 30 min; detector, UV 254 nm. This resulted in the title compound (200 mg, 27.13% yield)as a yellow oil. LCMS (ESI, m/z): [M+H]⁺ =598.3. [00606] Step 11: 4-(2,2-Difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan- 6-yl)-2-(methylamino)benzoic acid. A mixture of tert-butyl 4-(2,2-difluoro-6-[4-(methoxycarbonyl)-3- (methylamino)phenyl]-7-azaspiro[3.5]nonan-7-yl)methyl-5-methoxy-7-methylindole-1-carboxylate (30 mg, 0.050 mmol) and KOH (28.2 mg, 0.50 mmol) in EtOH (1 mL) and water (1 mL) was stirred for 3 h at 80 ºC under air atmosphere. The residue was acidified to pH 6 with citric acid. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% NH4HCO3), 10% to 60% gradient in 20 min; detector, UV 254 nm.to afford the title compound (12.6 mg, 51.34% yield) as a white solid. LCMS (ESI, m/z): [M+H]⁺ = 484.3.¹H NMR (300 MHz, Methanol-d4) δ 8.02 (d, J = 8.0 Hz, 1H), 7.28 (d, J = 3.2 Hz, 1H), 6.85 (s, 1H), 6.75 (d, J = 7.0 Hz, 2H), 6.30 (d, J = 3.2 Hz, 1H), 4.63 (s, 1H), 4.37 (d, J = 12.6 Hz, 1H), 4.18 (d, J = 12.2 Hz, 1H), 4.01 (d, J = 12.6 Hz, 1H), 3.76 (s, 3H), 3.47 – 3.35 (m, 1H), 3.21 – 3.03 (m, 1H), 2.95 (s, 3H), 2.71 (d, J = 12.4 Hz, 1H), 2.63 (d, J = 12.3 Hz, 1H), 2.49 (s, 5H), 2.10 – 1.95 (m, 2H), 1.85 (d, J = 13.4 Hz, 1H). [00607] Step 12: Isomer 1 (faster peak) and isomer 2 (slower peak) of tert-butyl 4-((2,2-difluoro-6-(4- (methoxycarbonyl)-3-(methylamino)phenyl)-7-azaspiro[3.5]nonan-7-yl)methyl)-5-methoxy-7-methyl-1H- indole-1-carboxylate. tert-Butyl 4-((2,2-difluoro-6-(4-(methoxycarbonyl)-3-(methylamino)phenyl)-7- azaspiro[3.5]nonan-7-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (170 mg) was applied for further separation by Chiral HPLC with the following condition: Column: CHIRAL ART Cellulose-SB, 2*25 cm, 5 μm; Mobile Phase A: Hex (0.1% FA)-HPLC, Mobile Phase B: IPA-HPLC; Flow rate: 20 mL/min; Gradient: isocratic 1; Wave Length: 220/254 nm; RT1(min): 7.354; RT2(min): 8.792; Sample Solvent: EtOH- HPLC; Injection Volume: 0.5 mL; Number Of Runs: 22. Isomer 1: faster peak, 53 mg, 31% yield. LCMS (ESI, m/z): [M+H]⁺ = 598.3. t_R = 2.85 min CHIRALCellulose-SB(4.6*100mm3μm), Hex (0.1%DEA):IPA=90:10, 1.0 mL/min, 254 nm). Isomer 2: slower peak , 67 mg, 39% yield. LCMS (ESI, m/z): [M+H]⁺ = 598.3. t_R = 3.40 min CHIRALCellulose-SB(4.6*100mm3μm), Hex (0.1%DEA):IPA=90:10, 1.0 mL/min, 254 nm. [00608] Step 13: (S)-4-(2,2-Difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)-2-(methylamino)benzoic acid & (R)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H- indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)-2-(methylamino)benzoic acid. A solution of isomer 1 (faster peak) from the step above (53 mg, 0.09 mmol) and KOH (99.5 mg, 1.780 mmol) in water (1 mL) and ethanol (1 mL) was stirred for 2h at 80 ºC under air atmosphere. The residue was acidified to pH 6 with citric acid. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10mmol/L NH₄HCO₃), 20% to 70% gradient in 30 min; detector, UV 254 nm. This resulted in one enantiomer of 4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol- 4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)-2-(methylamino)benzoic acid (26.1 mg, 60.20% yield) as a white solid. LCMS (ESI, m/z): [M+H]⁺ = 484.3.¹H NMR (300 MHz, Methanol-d₄) δ 8.03 (d, J = 7.9 Hz, 1H), 7.30 (d, J = 3.1 Hz, 1H), 6.86 (s, 1H), 6.81 – 6.72 (m, 2H), 6.33 (d, J = 3.2 Hz, 1H), 4.37 (d, J = 12.5 Hz, 1H), 4.19 – 4.09 (m, 1H), 4.00 (d, J = 12.5 Hz, 1H), 3.79 (s, 3H), 3.46 – 3.36 (m, 1H), 3.16 – 3.01 (m, 1H), 2.97 (s, 3H), 2.84 – 2.59 (m, 2H), 2.51 (s, 5H), 2.36 – 2.21 (m, 1H), 2.11 – 1.96 (m, 2H), 1.86 (d, J = 14.1 Hz, 1H). A solution of isomer 2 (slower peak) from the step above (67 mg, 0.11 mmol, 1 equiv) and KOH (125.8 mg, 2.24 mmol) in water (1 mL) and EtOH (1 mL) was stirred for 2h at 80 ºC under nitrogen atmosphere. The residue was acidified to pH 6 with citric acid. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10mmol/L NH4HCO3), 20% to 70% gradient in 30 min; detector, UV 254 nm. This resulted in the other enantiomer of (R)-4-(2,2-Difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6- yl)-2-(methylamino)benzoic acid (30.6 mg, 55.83% yield) as a white solid. LCMS (ESI, m/z): [M+H]⁺ = 484.3.¹H NMR (300 MHz, Methanol-d4) δ 8.03 (d, J = 8.0 Hz, 1H), 7.30 (d, J = 3.1 Hz, 1H), 6.86 (s, 1H), 6.77 (d, J = 4.7 Hz, 2H), 6.33 (d, J = 3.2 Hz, 1H), 4.36 (d, J = 12.5 Hz, 1H), 4.13 (d, J = 12.2 Hz, 1H), 3.99 (d, J = 12.7 Hz, 1H), 3.78 (s, 3H), 3.40 (d, J = 12.9 Hz, 1H), 3.14 – 2.98 (m, 1H), 2.97 (s, 3H), 2.77 – 2.59 (m, 2H), 2.51 (s, 3H), 2.49 – 2.37 (m, 2H), 2.36 – 2.21 (m, 1H), 2.10 – 1.95 (m, 2H), 1.86 (d, J = 14.3 Hz, 1H). [00609] Example 24. (S)-4-(1-((5-Methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl)-2- (methylamino)benzoic acid & (R)-4-(1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl)-2- (methylamino)benzoic acid & 4-(1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl)-2- (methylamino)benzoic acid.

[00

hydroxybenzoate (5 g, 21.64 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 1,3,2-dioxaborolane (8.2 g, 32.46 mmol), Pd(dppf)Cl₂ (1.6 g, 2.16 mmol) and KOAc (5.3 g, 54.10 mmol) in 1,4-dioxane (50 mL) was stirred for 1h at 90 ºC under nitrogen atmosphere. The solvent was removed under vacuum. The crude product was used in the next step directly without further purification. A mixture of the above residue, 2-bromopyridine (8.5 g, 53.94 mmol), sodium carbonate (9.5 g, 89.90 mmol), CuCl (3.6 g, 35.96 mmol) and Pd(dppf)Cl₂ (2.6 g, 3.60 mmol) in 1,4-dioxane (80 mL) and water (20 mL) was stirred for overnight at 90 ºC under nitrogen atmosphere. The reaction was quenched with water and extracted with Dichloromethane. The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with petroleum ether / ethyl acetate (1:1) to afford the title compound (7 g, 75.20% yield) as a yellow solid. LCMS (ESI, m/z): [M+H]⁺ = 230.0. [00611] Step 2: Methyl 2-hydroxy-4-(piperidin-2-yl)benzoate. A mixture of methyl 2-hydroxy-4- (pyridin-2-yl)benzoate (5 g, 21.81 mmol) and PtO2 (0.5 g, 2.18 mmol) in EtOH (20 mL) and HOAc (10 mL) was stirred for overnight at 60 ºC under 20 atm hydrogen. The solids were filter out. The filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10mmol/L NH4HCO3), 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in the title compound (2.6 g, 49.14% yield) as a yellow oil. LCMS (ESI, m/z): [M+H]+ = 235.9. [00612] Step 3: tert-Butyl 4-((2-(3-hydroxy-4-(methoxycarbonyl)phenyl)piperidin-1-yl)methyl)-5- methoxy-7-methylindole-1-carboxylate. A solution of methyl 2-hydroxy-4-(piperidin-2-yl)benzoate (600 mg, 2.55 mmol), tert-butyl 4-formyl-5-methoxy-7-methylindole-1-carboxylate (885.4 mg, 3.06 mmol) and titanium tetraisopropanolate (7247.8 mg, 25.50 mmol) in 1,2-dichloroethane (10 mL) was stirred for 0.5 h at room temperature under nitrogen atmosphere. Then sodium triacetoxyborohydride (1621.4 mg, 7.65 mmol) was added and stirred for additional 1 h. The resulting mixture was quenched with water and extracted with dichloromethane. The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% TFA), 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in the title compound (350 mg, 25.64% yield) as a yellow solid. LCMS (ESI, m/z): [M+H]+ = 509.3. [00613] Step 4: tert-Butyl 5-methoxy-4-((2-(4-(methoxycarbonyl)-3- (trifluoromethanesulfonyloxy)phenyl)piperidin-1-yl)methyl)-7-methylindole-1-carboxylate. A solution of tert-butyl 4-((2-(3-hydroxy-4-(methoxycarbonyl)phenyl)piperidin-1-yl)methyl)-5-methoxy-7-methylindole-1- carboxylate (300 mg, 0.59 mmol) and 1,1,1-trifluoro-N-phenyl-N- (trifluoromethane)sulfonylmethanesulfonamide (421.4 mg, 1.18 mmol) and DIEA (152.5 mg, 1.18 mmol) in ACN (5 mL) was stirred for overnight at 80 ºC. The reaction was quenched with water and extracted with dichloromethane. The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with petroleum ether / ethyl acetate (1:1) to afford the title compound (120 mg, 31.12% yield) as a white solid. LCMS (ESI, m/z): [M+H]+ = 641.4. [00614] Step 5: tert-Butyl 5-methoxy-4-((2-(4-(methoxycarbonyl)-3-(methylamino)phenyl)piperidin-1- yl)methyl)-7-methylindole-1-carboxylate. A solution of tert-butyl 5-methoxy-4-((2-(4-(methoxycarbonyl)-3- (trifluoromethanesulfonyloxy)phenyl)piperidin-1-yl)methyl)-7-methylindole-1-carboxylate (240 mg, 0.38 mmol), methylamine hydrochloride (252.9 mg, 3.75 mmol), cesium carbonate (313.7 mg, 4.13 mmol) and Pd- PEPPSI-IPentCl 2-methylpyridine (o-picoline) (22.1 mg, 0.03 mmol) in 1,4-dioxane (2 mL) was stirred for 1 h at 100 ºC under nitrogen atmosphere. The reaction was quenched with water and extracted with dichloromethane. The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10mmol/L NH4HCO3), 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in the title compound (100 mg, 47.59% yield) as a yellow solid. LCMS (ESI, m/z): [M+H]⁺ = 522.4. [00615] Step 6: 4-(1-((5-Methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl)-2- (methylamino)benzoic acid. A solution of tert-butyl 5-methoxy-4-((2-(4-(methoxycarbonyl)-3- (methylamino)phenyl)piperidin-1-yl)methyl)-7-methylindole-1-carboxylate (60 mg, 0.12 mmol) and KOH (13 mg, 0.23 mmol) in EtOH (0.3 mL) and water (0.3 mL) was stirred for 2 h at 80 ºC. The mixture was acidified to pH = 6 with sat. citric acid. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10mmol/L NH4HCO3), 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in the title compound (17.3 mg, 36.47%) as a white solid. LCMS (ESI, m/z): [M+H]⁺ = 408.2.¹H NMR (300 MHz, Methanol-d4) δ 8.02 (d, J = 8.0 Hz, 1H), 7.29 (d, J = 3.1 Hz, 1H), 6.82 (d, J = 1.7 Hz, 1H), 6.74 (d, J = 7.5 Hz, 2H), 6.30 (s, 1H), 4.47 – 4.04 (m, 3H), 3.77 (s, 3H), 3.48 (d, J = 13.2 Hz, 1H), 3.18 (s, 1H), 2.95 (s, 3H), 2.50 (s, 3H), 2.08 (s, 2H), 1.91 – 1.72 (m, 4H). [00616] Step 7: tert-Butyl 5-methoxy-4-(((2S)-2-(4-(methoxycarbonyl)-3-(methylamino)phenyl)piperidin- 1-yl)methyl)-7-methylindole-1-carboxylate & tert-butyl 5-methoxy-4-(((2R)-2-(4-(methoxycarbonyl)-3- (methylamino)phenyl)piperidin-1-yl)methyl)-7-methylindole-1-carboxylate. tert-butyl 5-methoxy-4-((2-(4- (methoxycarbonyl)-3-(methylamino)phenyl)piperidin-1-yl)methyl)-7-methylindole-1-carboxylate (100 mg) was applied for further separation by Chiral HPLC with the following condition: Column: CHIRALPAK IG, 5*25 cm, 5 μm; Mobile Phase A: Hex (0.5% 2M NH3-MeOH)-HPLC, Mobile Phase B: EtOH-HPLC; Gradient: isocratic ; Wave Length: 220/254 nm; RT1(min): 7.55; RT2(min): 9.874; Sample Solvent: EtOH- HPLC. Isomer 1, faster peak, 37 mg, 37% yield. LCMS (ESI, m/z): [M+H]⁺ = 522.4. t_R = 2.06 min (CHIRALPAK IG-3 (4.6*50mm 3um), Hex (0.1%DEA):IPA=95:5, 1.0 mL/min, 254 nm). Isomer 2: slower peak, 36 mg, 36% yield. LCMS (ESI, m/z): [M+H]⁺ = 522.4. t_R = 3.06 min (CHIRALPAK IG-3 (4.6*50mm 3um), Hex (0.1%DEA):IPA=95:5, 1.0 mL/min, 254 nm). [00617] Step 8: (S)-4-(1-((5-Methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl)-2- (methylamino)benzoic acid & (R)-4-(1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl)-2- (methylamino)benzoic acid. A solution of isomer 1 (faster peak) from the step above (35 mg, 0.07 mmol) and KOH (22.6 mg, 0.40 mmol) in EtOH (0.3 mL) and water (0.3 mL) was stirred for 2h at 80 ºC. The mixture was acidified to pH = 6 with sat. citric acid. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10mmol/L NH₄HCO₃), 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in one enantiomer of 4-(1-((5-Methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl)-2-(methylamino)benzoic acid (10 mg, 34.45% yield) as a white solid. LCMS (ESI, m/z): [M+H]⁺ = 408.3.¹H NMR (300 MHz, Methanol-d4) δ 8.01 (d, J = 7.9 Hz, 1H), 7.29 (d, J = 3.1 Hz, 1H), 6.83 – 6.69 (m, 3H), 6.30 (s, 1H), 4.42 (d, J = 12.7 Hz, 1H), 4.20 (s, 1H), 4.08 (s, 1H), 3.77 (s, 3H), 3.46 (s, 1H), 3.16 (s, 1H), 2.95 (s, 3H), 2.50 (s, 3H), 2.06 (s, 2H), 1.90 – 1.60 (m, 4H). A solution of isomer 2 (slower peak) from the step above (36 mg, 0.07 mmol) and KOH (23.2 mg, 0.41 mmol) in EtOH (0.3 mL) and water (0.3 mL) was stirred for 2h at 80 ºC under air atmosphere. The mixture was acidified to pH = 6 with sat. citric acid. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10mmol/L NH4HCO3), 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in the other enantiomer of 4-(1-((5-Methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl)-2- (methylamino)benzoic acid (13.7 mg, 47.98% yield) as a white solid. LCMS (ESI, m/z): [M+H]⁺ = 408.3.¹H NMR (300 MHz, Methanol-d4) δ 8.01 (d, J = 7.9 Hz, 1H), 7.29 (d, J = 3.1 Hz, 1H), 6.83 – 6.69 (m, 3H), 6.30 (s, 1H), 4.42 (d, J = 12.7 Hz, 1H), 4.20 (s, 1H), 4.08 (s, 1H), 3.77 (s, 3H), 3.46 (s, 1H), 3.16 (s, 1H), 2.95 (s, 3H), 2.50 (s, 3H), 2.06 (s, 2H), 1.90 – 1.60 (m, 4H). [00618] Example 25. 2-Amino-4-((2R,4R)-4-ethoxy-1-((5-methoxy-7-methyl-1H-indol-4- yl)methyl)piperidin-2-yl)benzoic acid & 2-Amino-4-((2S,4R)-4-ethoxy-1-((5-methoxy-7-methyl-1H-indol-4- yl)methyl)piperidin-2-yl)benzoic acid & 2-Amino-4-((2R,4S)-4-ethoxy-1-((5-methoxy-7-methyl-1H-indol-4- yl)methyl)piperidin-2-yl)benzoic acid & 2-amino-4-((2S,4S)-4-ethoxy-1-((5-methoxy-7-methyl-1H-indol-4- yl)methyl)piperidin-2-yl)benzoic acid.

[0061 solution

of 4-bromo-2-chlorobenzonitrile (10 g, 46.2 mmol) in THF was added 2 M isopropylmagnesium chloride in THF (6 mL, 120.0 mmol) and stirred for 2 h at 0 ºC under nitrogen atmosphere. Then 4-methoxypyridine (7.6 g, 69.3 mmol) and Benzyl chloroformate (11.8 g, 69.3 mmol) was added by dropwise at -5 ºC. The mixture was stirred for 16 h at room temperature under nitrogen atmosphere. The mixture was adjusted to pH 2 with 2 M HCl. The resulting mixture was extracted with ethyl acetate and washed with brine, dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with Petroleum ether/ethyl acetate (1:1) to afford the title compound (7 g, 41% yield) as a yellow oil. LCMS (ESI): [M+H] ⁺ = 367.1. [00620] Step 2: Benzyl 2-(3-chloro-4-cyanophenyl)-4-oxopiperidine-1-carboxylate. A mixture of benzyl 2-(3-chloro-4-cyanophenyl)-4-oxo-2,3-dihydropyridine-1-carboxylate (3 g, 8.17 mmol) and Zn (5.34 g, 81.70 mmol) in HOAc (30 mL) was stirred for 2 h at 100 ºC. The solids were filtered out. The filtrate was concentrated to afford the title compound (3 g) as crude. LCMS (ESI): [M+H] ⁺ = 369.1. [00621] Step 3: Benzyl 2-(3-chloro-4-cyanophenyl)-4-hydroxypiperidine-1-carboxylate. A solution of benzyl 2-(3-chloro-4-cyanophenyl)-4-oxopiperidine-1-carboxylate (3 g, 8.13mmol) in THF (10 mL) was added sodium borohydride (1495 mg, 39.53 mmol) and stirred for 1 h at room temperature. The reaction was quenched with sat. ammonium chloride at 0 ºC and extracted with ethyl acetate. The solvent was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with Petroleum ether/ethyl acetate (1:1) to afford the title compound (2.5 g, 83% yield) as a yellow oil. LCMS (ESI, m/z): [M+H] ⁺ = 371.1. [00622] Step 4: Benzyl 2-(3-chloro-4-cyanophenyl)-4-ethoxypiperidine-1-carboxylate. Under nitrogen, a solution of benzyl 2-(3-chloro-4-cyanophenyl)-4-hydroxypiperidine-1-carboxylate (15 g, 40.45 mmol) in THF (500 mL) was added ethyl trifluoromethanesulfonate (14.41 g, 80.90 mmol) and 1 M NaHMDS in THF (121 mL, 121.35 mmol) at -78 ºC and stirred for 1h at the same temperature. The reaction was quenched with sat. ammonium chloride at 0 ºC. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layers were combined. The organic layer was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with petroleum ether/ethyl acetate (3/1) to afford the title compound (6.5 g, 34.6% yield) as a white oil. LCMS (ESI): [M+H] ⁺ = 399.1. [00623] Step 5: 4-(1-((Benzyloxy)carbonyl)-4-ethoxypiperidin-2-yl)-2-chlorobenzoic acid. A solution of benzyl 2-(3-chloro-4-cyanophenyl)-4-ethoxypiperidine-1-carboxylate (6.5 g, 17.54 mmol) in isopropyl alcohol (80 mL) was added Barium hydroxide (30.07 g, 175.49 mmol) in water (40 mL) and stirred for overnight at 100 ºC. The resulting mixture was filtered, the filter cake was washed with methanol. The filtrate was neutralized to pH =7 with 2 M HCl. The solvent was concentrated under vacuum. The crude product was used in the next step directly without further purification. LCMS (ESI): [M+H]⁺ = 418.1. [00624] Step 6: Benzyl 2-(3-chloro-4-(methoxycarbonyl)phenyl)-4-ethoxypiperidine-1-carboxylate. A solution of 4-(1-((benzyloxy)carbonyl)-4-ethoxypiperidin-2-yl)-2-chlorobenzoic acid (6.5 g, 15.55 mmol) in methanol (8 mL) and dichloromethane (60 mL) was added 2 M (trimethylsilyl)diazomethane in hexane (31 mL, 62.21 mmol) and stirred for 1h at room temperature. The solvent was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with Petroleum ether/ethyl acetate (4/1) to afford the title compound (5 g, 59.2% yield) as a yellow oil. LCMS (ESI): [M+H]⁺ = 432.1. [00625] Step 7: Benzyl 2-(3-((tert-butoxycarbonyl)amino)-4-(methoxycarbonyl)phenyl)-4- ethoxypiperidine-1-carboxylate. Under nitrogen, a solution of benzyl 2-(3-chloro-4- (methoxycarbonyl)phenyl)-4-ethoxypiperidine-1-carboxylate (5 g, 11.57mmol), tert-butyl carbamate (6.78 g, 57.88 mmol), tris(dibenzylideneacetone)dipalladium (1.59 g, 1.73mmol), XantPhos (1004.78 mg, 1.73 mmol), cesium carbonate (11.32 g, 34.72 mmol) in dioxane (55 mL) was stirred for overnight at 100 ºC. The solvent was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with petroleum ether/ethyl acetate (4/1) to afford the title compound (6 g, 28.2% yield) as a yellow oil. LCMS (ESI): [M+H] ⁺ = 513.3. [00626] Step 8: Methyl 2-((tert-butoxycarbonyl)amino)-4-(4-ethoxypiperidin-2-yl)benzoate. Under hydrogen, a mixture of benzyl 2-(3-((tert-butoxycarbonyl)amino)-4-(methoxycarbonyl)phenyl)-4- ethoxypiperidine-1-carboxylate (6 g, 11.70 mmol) and 10% Pd/C (6 g, 56.41 mmol) in ethyl acetate (80 mL) was stirred for 1h at room temperature. The solids were filtered out. The filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10mmol/L NH4HCO3), 10% to 58% gradient in 30 min; detector, UV 254 nm. This resulted in the title compound (1.5 g, 32.4% yield) as a yellow oil. LCMS (ESI,): [M+H] ⁺ = 379.2. [00627] Step 9: tert-Butyl 4-((2-(3-((tert-butoxycarbonyl)amino)-4-(methoxycarbonyl)phenyl)-4- ethoxypiperidin-1-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate. A solution of methyl 2-((tert- butoxycarbonyl)amino)-4-(4-ethoxypiperidin-2-yl)benzoate (1.5 g, 3.96 mmol) in 1,2-dichloroethane (30 mL) was added tert-butyl 4-formyl-5-methoxy-7-methylindole-1-carboxylate (2.29 g, 7.92 mmol), sodium triacetoxyborohydride (2.52 g, 11.88 mmol), HOAc (0.71 g, 11.88 mmol) and stirred for overnight at 70 ºC. The reaction mixture was quenched with water and extracted with ethyl acetate and the organic layers were combined. The solvent was removed under vacuum. The residue was purified by silica gel column chromatography, eluted with Petroleum ether/ethyl acetate (0-37%) to afford the title compound (900 mg, 29.96% yield) as a yellow oil. LCMS (ESI): [M+H]⁺ = 651.4. [00628] Step 10: tert-Butyl 4-(((2R,4R)-2-(3-amino-4-(methoxycarbonyl)phenyl)-4-ethoxypiperidin-1- yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate & tert-tutyl 4-(((2S,4R)-2-(3-amino-4- (methoxycarbonyl)phenyl)-4-ethoxypiperidin-1-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate & tert-butyl 4-(((2R,4S)-2-(3-amino-4-(methoxycarbonyl)phenyl)-4-ethoxypiperidin-1-yl)methyl)-5-methoxy-7- methyl-1H-indole-1-carboxylate & tert-butyl 4-(((2S,4S)-2-(3-amino-4-(methoxycarbonyl)phenyl)-4- ethoxypiperidin-1-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate. tert-Butyl 4-((2-(3-((tert- butoxycarbonyl)amino)-4-(methoxycarbonyl)phenyl)-4-ethoxypiperidin-1-yl)methyl)-5-methoxy-7-methyl- 1H-indole-1-carboxylate (900 mg) was applied for 2 rounds Chiral separation with the following conditions to afford 4 isomers: [00629] Column: CHIRALPAK IF, 2*25 cm, 5 μm; Mobile Phase A: HEX (0.5% 2M NH3-MeOH), Mobile Phase B: IPA; Flow rate: 20 mL/min; Gradient: isocratic 5; Wave Length: 220/254 nm; RT1(min): 4.876; RT2(min): 6.878; Sample Solvent: EtOH; Injection Volume: 0.6 mL; Number Of Runs: 14. [00630] Column: CHIRALPAK IF, 2*25 cm, 5 μm; Mobile Phase A: HEX (0.5% 2M NH3-MeOH), Mobile Phase B: IPA; Flow rate: 20 mL/min; Gradient: isocratic 5; Wave Length: 220/254 nm; RT1(min): 3.994; RT2(min): 4.973; Sample Solvent: EtOH; Injection Volume: 0.5 mL; Number Of Runs: 32. [00631] Isomer 1: 70 mg, 7.8% yield. tR = 1.02 min (CHIRALPAK IF-3 (4.6*50 mm, 3 µm), Hex (0.1%DEA):IPA=93:7, 1.0 mL/min, 254 nm). [00632] Isomer 2: 85 mg, 9.4% yield. tR = 1.40 min (CHIRALPAK IF-3 (4.6*50 mm, 3 µm), Hex (0.1%DEA):IPA=93:7, 1.0 mL/min, 254 nm). [00633] Isomer 3: 120 mg, 13.3% yield. tR = 0.99 min (CHIRALPAK IF-3 (4.6*50 mm, 3 µm), Hex (0.1%DEA):IPA=97:3, 1.0 mL/min, 254 nm). [00634] Isomer 4: 130 mg, 14.4% yield. tR = 1.39 min (CHIRALPAK IF-3 (4.6*50 mm, 3 µm), Hex (0.1%DEA):IPA=97:3, 1.0 mL/min, 254 nm). [00635] Step 11: 2-Amino-4-((2R,4R)-4-ethoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin- 2-yl)benzoic acid & 2-amino-4-((2S,4R)-4-ethoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin- 2-yl)benzoic acid & 2-amino-4-((2R,4S)-4-ethoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin- 2-yl)benzoic acid & 2-amino-4-((2S,4S)-4-ethoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2- yl)benzoic acid. To a solution of isomer 1 from the step above (50 mg, 0.07 mmol) in ethanol (0.5 mL) was added potassium hydroxide (43.04 mg, 0.77 mmol) in water (0.5 mL). After stirring for 5 h at 100 ºC, the mixture was allowed to cool down to room temperature. The residue was adjusted to pH = 7 with sat. citric acid. The solvent was removed. The residue was purified by reverse phase flash with the following conditions (ACN, 5-20% / 10 mM NH₄HCO₃ in water) to afford isomer 1 of 2-amino-4-(4-ethoxy-1-((5-methoxy-7- methyl-1H-indol-4-yl)methyl)piperidin-2-yl)benzoic acid (11.5 mg, 33.5% yield) as a light brown solid. LCMS (ESI): [M+H] ⁺ = 438.2.¹H NMR (400 MHz, DMSO-d6) δ 10.80 (t, J = 2.3 Hz, 1H), 8.77 – 8.08 (brs, 1H), 7.71 (d, J = 8.2 Hz, 1H), 7.23 (t, J = 2.8 Hz, 1H), 6.85 (s, 1H), 6.75 – 6.59 (m, 2H), 6.53 – 6.38 (m, 1H), 3.70 (s, 3H), 3.59 (d, J = 11.8 Hz, 1H), 3.47 – 3.36 (m, 2H), 3.36 – 3.26 (m, 1H), 3.19 – 3.11 (m, 1H), 3.03 – 2.94 (m, 1H), 2.76 – 2.67 (m, 1H), 2.41 (s, 3H), 2.03 – 1.88 (m, 2H), 1.80 (d, J = 12.0 Hz, 1H), 1.48 – 1.34 (m, 1H), 1.26 – 1.09 (m, 1H), 1.05 (t, J = 7.0 Hz, 3H). To a solution of isomer 2 from the step above (50 mg, 0.07 mmol) in ethanol (0.5 mL) was added Potassium hydroxide (43.04 mg, 0.77 mmol) in water (0.5 mL). After stirring for 5 h at 100 ºC, the mixture was allowed to cool down to room temperature. The residue was adjusted to pH = 7 with sat. citric acid. The solvent was removed. The residue was purified by reverse phase flash with the following conditions (ACN, 5-20% / 10 mM NH₄HCO₃ in water) to afford isomer 22-amino-4- (4-ethoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl)benzoic acid (6.7 mg, 19.1% yield) as a light brown solid. LCMS (ESI): [M+H] ⁺ = 438.2.¹H NMR (400 MHz, DMSO-d6) δ 10.80 (t, J = 2.3 Hz, 1H), 8.77 – 8.08 (brs, 1H), 7.71 (d, J = 8.2 Hz, 1H), 7.23 (t, J = 2.8 Hz, 1H), 6.85 (s, 1H), 6.75 – 6.59 (m, 2H), 6.53 – 6.38 (m, 1H), 3.70 (s, 3H), 3.59 (d, J = 11.8 Hz, 1H), 3.47 – 3.36 (m, 2H), 3.36 – 3.26 (m, 1H), 3.19 – 3.11 (m, 1H), 3.03 – 2.94 (m, 1H), 2.76 – 2.67 (m, 1H), 2.41 (s, 3H), 2.03 – 1.88 (m, 2H), 1.80 (d, J = 12.0 Hz, 1H), 1.48 – 1.34 (m, 1H), 1.26 – 1.09 (m, 1H), 1.05 (t, J = 7.0 Hz, 3H). To a solution of isomer 3 (100 mg, 0.15 mmol) in ethanol (1 mL) was added Potassium hydroxide (86.08 mg, 1.53 mmol) in water (1 mL). After stirring for 5 h at 100 ºC, the mixture was allowed to cool down to room temperature. The residue was adjusted to pH = 7 with sat. citric acid. The solvent was removed. The residue was purified by reverse phase flash with the following conditions (ACN, 5-20% / 10 mM NH4HCO3 in water) to afford isomer 3 of 2- amino-4-(4-ethoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl)benzoic acid (13.0 mg, 18.5% yield) as a light brown solid. LCMS (ESI): [M+H] ⁺ = 438.2.¹H NMR (400 MHz, DMSO-d6) δ 10.79 (s, 1H), 7.71 (d, J = 8.2 Hz, 1H), 7.23 (t, J = 2.8 Hz, 1H), 6.86 (s, 1H), 6.74 (d, J = 8.3 Hz, 1H), 6.65 (s, 1H), 6.51 (dd, J = 3.1, 1.9 Hz, 1H), 3.72 (s, 3H), 3.64 – 3.53 (m, 2H), 3.49 – 3.38 (m, 2H), 3.30 – 3.14 (m, 2H), 2.48 – 2.35 (m, 4H), 2.24 (t, J = 12.0 Hz, 1H), 1.88 – 1.74 (m, 1H), 1.68 (t, J = 13.1 Hz, 2H), 1.48 – 1.37 (m, 1H), 1.16 (t, J = 7.0 Hz, 3H). To a solution of isomer 4 from the step above (100 mg, 0.15 mmol) in ethanol (1 mL) was added potassium hydroxide (86.08 mg, 1.53 mmol) in water (1 mL). After stirring for 5 h at 100 ºC, the mixture was allowed to cool down to room temperature. The residue was adjusted to pH = 7 with sat. citric acid. The solvent was removed. The residue was purified by reverse phase flash with the following conditions (ACN, 5-20% / 10 mM NH4HCO3 in water) to afford isomer 4 of 2-amino-4-(4-ethoxy-1-((5- methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl)benzoic acid (24.9 mg, 35.3%yield) as a light brown solid. LCMS (ESI): [M+H] ⁺ = 438.2.¹H NMR (400 MHz, DMSO-d₆) δ 10.79 (s, 1H), 7.71 (d, J = 8.2 Hz, 1H), 7.23 (t, J = 2.8 Hz, 1H), 6.86 (s, 1H), 6.74 (d, J = 8.3 Hz, 1H), 6.65 (s, 1H), 6.51 (dd, J = 3.1, 1.9 Hz, 1H), 3.72 (s, 3H), 3.64 – 3.53 (m, 2H), 3.49 – 3.38 (m, 2H), 3.30 – 3.14 (m, 2H), 2.48 – 2.35 (m, 4H), 2.24 (t, J = 12.0 Hz, 1H), 1.88 – 1.74 (m, 1H), 1.68 (t, J = 13.1 Hz, 2H), 1.48 – 1.37 (m, 1H), 1.16 (t, J = 7.0 Hz, 3H). [00636] Example 26. (R)-4-(1-((5-Methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl)-3-((2- methoxyethyl)amino)benzoic acid & (S)-4-(1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl)-3- ((2-methoxyethyl)amino)benzoic acid.

methoxyethyl)amino)phenyl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylate [00639] A solution of 1,1 -2-trimeth

, mo1) in 1 M HCI (10 mL) was heated at 70 °C for 2 hours. The cooled mixture was extracted with Dichloromethane and the organic solution dried by 3Å molecular sieves. Tert-butyl 4-((2-(2-amino-4-(methoxycarbonyl)phenyl)piperidin-1-yl)methyl)-5-methoxy- 7-methyl-1H-indole-1-carboxylate (1.25 g, 2.5 mmol) was added and the resultant solution stirred under nitrogen for 20 minutes. Sodium triacetoxyborohydride (1.3 g, 7.5 mmol) was added and the reaction mixture stirred under nitrogen at room temperature for 2 hours. Saturated sodium bicarbonate aqueous solution was added in portions and the resulted mixture was stirred for 0.5 hour and extracted with Dichloromethane. The organic solution was dried over solium sulfate, and the solvent removed under vacuum. The residue was purified by reversed-phase flash chromatography to afford the title compound (300 mg, 20% yield) as a white solid. LCMS (ESI, m/z): [M+H]⁺ = 566.3. [00640] Step 2: tert-Butyl (R)-5-methoxy-4-((2-(4-(methoxycarbonyl)-2-((2- methoxyethyl)amino)phenyl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylate (isomer 1, faster peak) & tert-butyl (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)-2-((2-methoxyethyl)amino)phenyl)piperidin-1- yl)methyl)-7-methyl-1H-indole-1-carboxylate (isomer 2, slower peak) [00641] tert-Butyl 5- yl)amino)phenyl)piperidin-1-

yl)methyl)-7-methyl-1H-indole-1-carboxylate (200 mg, 0.35 mmol) was applied for further separation by Chiral HPLC with the following condition: [00642] Column: CHIRALPAK AY-H, 4.6*250mm, 5um; Mobile Phase A: HEX(0.5% 2M NH3- Methanol), Mobile Phase B: Ethanol; Flow rate: 20 mL/min; Gradient: isocratic 10; Wave Length: 220/254 nm; RT1(min): 9.591; RT2(min): 11.708; Sample Solvent: ETOH; Injection Volume: 1.0 mL; Number Of Runs: 12 [00643] tert-Butyl (R)-5-methoxy-4-((2-(4-(methoxycarbonyl)-2-((2- methoxyethyl)amino)phenyl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylate (isomer 1, faster peak) (50 mg, 25.0% yield) as a white solid. LCMS (ESI, m/z): [M+H]⁺ = 565.7.tR = 1.57 min (CHIRALPAK AY-3, 4.6*50mm,3um, Hex(0.1%DEA): Ethanol =90:10, 1 mL/min, 254 nm). [00644] tert-Butyl (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)-2-((2- methoxyethyl)amino)phenyl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylate (isomer 2, slower peak) (40 mg, 20 % yield) as a white solid. LCMS (ESI, m/z): [M+H]⁺ = 565.7. tR = 3.97 min (CHIRALPAK AY‐3 (4.6*50mm,3um), Hex(0.1%DEA): Ethanol =90:10, 1 mL/min, 254 nm). [00645] Step 2: (R)-4-(1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl)-3-((2- methoxyethyl)amino)benzoic acid & (S)-4-(1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl)-3- ((2-methoxyethyl)amino)benzoic acid

[00646] A solution ((2-

methoxyethyl)amino)phenyl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylate (isomer 1, faster peak) (50 mg, 0.08 mmol) and Potassium hydroxide (65 mg, 1.14 mmol) in Ethanol (1.6 mL) and water (0.2 mL) was stirred for 2 hours at 80 °C. The mixture was acidified to pH = 6 with citric acid saturated aqueous solution. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in Water (10mmol/L Ammonium bicarbonate), 20% to 30% gradient in 5 min; detector, UV 254 nm. to afford (R)-4-(1-((5-methoxy-7-methyl-1H-indol-4- yl)methyl)piperidin-2-yl)-3-((2-methoxyethyl)amino)benzoic acid (28.6 mg, 71.6% yield) as a white solid. LCMS (ESI, m/z): [M+H]⁺ = 452.3.¹H NMR (300 MHz, DMSO-d₆) δ 12.63 (s, 1H), 10.85 (s, 1H), 7.26 (t, J = 2.8 Hz, 1H), 7.18 (d, J = 7.1 Hz, 3H), 7.04 (s, 1H), 6.67 (s, 1H), 6.34 (dd, J = 3.0, 1.8 Hz, 1H), 3.70 (d, J = 12.2 Hz, 1H), 3.69 (s, 3H), 3.55 – 3.45 (m, 3H), 3.34 – 3.25 (m, 3H), 3.22 (s, 3H), 2.78 (d, J = 11.6 Hz, 1H), 2.43 (s, 3H), 2.18 – 2.03 (m, 1H), 1.98 – 1.84 (m, 1H), 1.78-1.63 (m, 1H), 1.51 (d, J = 10.9 Hz, 2H), 1.39 – 1.23 (m, 2H). [00647] A solution of tert-butyl (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)-2-((2- methoxyethyl)amino)phenyl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylate (40 mg, 0.07 mmol) and Potassium hydroxide (51.5 mg, 0.92 mmol) in Ethanol (1.6 mL) and water (0.2 mL) was stirred for 2 hours at 80 °C. The mixture was acidified to pH< 7 with citric acid. The residue was purified by reversed- phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in Water (10mmol/L Ammonium bicarbonate), 20% to 30% gradient in 5 min; detector, UV 254 nm. to afford (S)-4-(1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl)-3-((2-methoxyethyl)amino)benzoic acid (22.2 mg, 69.5% yield) as a white solid. LCMS (ESI, m/z): [M+H]⁺ = 452.4. H NMR (300 MHz, DMSO-d6) δ 12.63 (s, 1H), 10.85 (s, 1H), 7.27 (t, J = 2.8 Hz, 1H), 7.18 (d, J = 7.1 Hz, 3H), 7.04 (s, 1H), 6.68 (s, 1H), 6.34 (dd, J = 3.0, 1.8 Hz, 1H), 3.70 (d, J = 12.0 Hz, 1H), 3.69 (s, 3H), 3.55 – 3.44 (m, 3H), 3.34 – 3.25 (m, 3H), 3.23 (s, 3H), 2.78 (d, J = 11.7 Hz, 1H), 2.43 (s, 3H), 2.24 – 2.02 (m, 1H), 1.92 (t, J = 11.0 Hz, 1H), 1.75 – 1.65 (m, 1H), 1.51 (d, J = 10.9 Hz, 2H), 1.40 – 1.23 (m, 2H). [00648] Example 27. (R)-4-(1-((5-Methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl)-3- (methylsulfonamido)benzoic acid & (S)-4-(1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl)-3- (methylsulfonamido)benzoic acid. O O O O S O O S NH

(methylsulfonamido)phenyl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylate. [00651] A solution of tert-butyl 4-((2-

ycarbonyl)phenyl)piperidin-1-yl)methyl)-5- methoxy-7-methyl-1H-indole-1-carboxylate (500 mg, 0.98 mmol) in Dichloromethane (10 mL) was added pyridine (233.7 mg, 2.96 mmol) and methanesulfonic anhydride (204.0 mg, 1.17 mmol) at 0 °C. The resulting mixture was stirred for 1 h at room temperature. The resulting mixture was diluted with water and extracted with Dichloromethane. The combined organic layers were dried over anhydrous Sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with dichloromethane/methanol (13:1) to afford tert-butyl 5-methoxy-4-((2-(4- (methoxycarbonyl)-2-(methylsulfonamido)phenyl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylate (380.1 mg, 68.88% yield) as a white solid. LCMS (ESI, m/z): [M+H]⁺ = 586.3. [00652] Step 2: tert-Butyl (R)-5-methoxy-4-((2-(4-(methoxycarbonyl)-2- (methylsulfonamido)phenyl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylate (isomer 1, faster peak) & tert-butyl (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)-2-(methylsulfonamido)phenyl)piperidin-1- yl)methyl)-7-methyl-1H-indole-1-carboxylate (isomer 2, slower peak) [00653] tert-butyl 5-meth

namido)phenyl)piperidin-1- yl)methyl)-7-methyl-1H-indole-1-carboxylate (200 mg, 0.34 mmol) was applied for further separation by Chiral HPLC with the following condition: Column: Column: CHIRALPAK IK 2x25 cm, 5 μm; Mobile Phase A: Hex (0.5% 2M NH3-Methanol)--HPLC, Mobile Phase B: Ethanol--HPLC; Flow rate: 20 mL/min; Gradient: isocratic 30; Wave Length: 220/254 nm; RT1(min): 11.184; RT2 (min): 13.432; Sample Solvent: Ethanol--HPLC; Injection Volume: 0.5 mL; Number Of Runs: 12 [00654] tert-Butyl (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)-2-(methylsulfonamido)phenyl)piperidin-1- yl)methyl)-7-methyl-1H-indole-1-carboxylate (isomer 1, faster peak) (60 mg, 30.0% yield) . LCMS (ESI, m/z): [M+H]⁺ = 586.7. tR = 11.184 min (CHIRALPAK IK, 2x25 cm, 5 μm, Hex (0.5% 2M NH3-Methanol)-- HPLC, Mobile Phase B: Ethanol--HPLC; Flow rate: 20 mL/min; Gradient: isocratic 30; Wave Length: 220/254 nm). [00655] tert-Butyl (R)-5-methoxy-4-((2-(4-(methoxycarbonyl)-2-(methylsulfonamido)phenyl)piperidin-1- yl)methyl)-7-methyl-1H-indole-1-carboxylate (isomer 2, slower peak) (60 mg 30 % yield) as a white solid. LCMS (ESI, m/z): [M+H]⁺ = 586.7. tR = 13.432 min (CHIRALPAK IK, 2 × 25 cm, 5 μm, Hex (0.5% 2M NH3-Methanol)--HPLC, Mobile Phase B: Ethanol--HPLC; Flow rate: 20 mL/min; Gradient: isocratic 30; Wave Length: 220/254 nm). [00656] Step 3: (S)4-(1-((5-Methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl)-3- (methylsulfonamido)benzoic acid & (R)-4-(1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl)-3- (methylsulfonamido)benzoic acid [00657] A solution of tert yl)-2-

(methylsulfonamido)phenyl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylate (isomer 1, faster peak, 80 mg, 0.137 mmol) in ethanol (2 mL) and water (0.7 mL) was added Potassium hydroxide (102.44 mg, 1.83 mmol) and stirred for 2 h at 70 °C. The mixture was acidified to pH 6 with sat. citric acid. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in Water (10 mmol/L Ammonium bicarbonate), 10% to 10% gradient in 10 min; detector, UV 254 nm. This resulted in (S)-4-(1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl)- 3-(methylsulfonamido)benzoic acid (30.3 mg, 47.04% yield, white solid ). LCMS: (ESI, m/z): 472.3 [M+H]⁺. ¹H NMR (500 MHz, Methanol-d4) δ 13.72 – 12.52 (brs, 1H) 11.77 – 10.99 (brs, 1H), 10.91 (s, 1H), 7.98 (d, J = 1.6 Hz, 1H), 7.68 (d, J = 7.8 Hz, 1H), 7.51 (s, 1H), 7.29 (t, J = 2.8 Hz, 1H), 6.69 (s, 1H), 6.43 (dd, J = 3.1, 1.8 Hz, 1H), 3.71 (s, 4H), 3.70 – 3.50 (m, 1H),3.25 – 3.23 (m, 1H) 3.14 (s, 3H), 2.82 (d, J = 11.6 Hz, 1H), 2.44 (s, 3H), 2.04 (t, J = 11.5 Hz, 1H), 1.90 – 1.51 (m, 4H), 1.45 – 1.23 (s, 2H). [00658] A solution of tert-butyl (R)-5-methoxy-4-((2-(4-(methoxycarbonyl)-2- (methylsulfonamido)phenyl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylate (80 mg, 0.139 mmol) in ethanol (2 mL) and water (0.7 mL) was added Potassium hydroxide (102.44 mg, 1.83 mmol) and stirred for 2 h at 70 °C. The mixture was acidified to pH 6 with citric acid. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in Water (10 mmol/L Ammonium bicarbonate), 10% to 10% gradient in 10 min; detector, UV 254 nm. This resulted in (R)-4-(1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl)-3- (methylsulfonamido)benzoic acid (23.4 mg, 35.59% yield, white solid). LCMS: (ESI, m/z):472.0 [M+H]⁺.¹H NMR (500 MHz, Methanol-d₄) δ 13.52 – 12.72 (m, 1H) 11.77 – 10.99 (m, 1H), 10.91 (s, 1H), 7.98 (d, J = 1.7 Hz, 1H), 7.68 (s, 1H), 7.52 (s, 1H), 7.29 (t, J = 2.8 Hz, 1H), 6.69 (s, 1H), 6.46 – 6.39 (m, 1H), 3.71 (s, 3H), 3.70 – 3.50 (m, 1H),3.25 – 3.23 (m, 1H）,3.14 (s, 3H), 2.82 (d, J = 11.6 Hz, 1H), 2.44 (s, 3H), 2.12 – 2.00 (m, 1H), 1.98 – 1.45 (m, 4H), 1.42 – 1.20 (s, 2H). [00659] Example 28. (S)-3-Acetamido-4-(1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2- yl)benzoic acid & (R)-3-acetamido-4-(1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl)benzoic acid.

)-5- methoxy-7-methyl-1H-indole-1-carboxylate (isomer 1, faster peak) & tert-butyl (R)-4-((2-(2-acetamido-4- (methoxycarbonyl)phenyl)piperidin-1-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (isomer 2, slower peak) [00662] To a stirred m

y y yl)phenyl)piperidin-1- yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (500 mg, 0.99 mmol) and N,N- Diisopropylethylamine (381.91 mg, 2.96 mmol) in Dichloromethane (5 mL) was added acetyl acetate (201.11 mg, 1.97 mmol) dropwise at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2h under nitrogen atmosphere. The resulting mixture was quenched with water and extracted with Ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with Petroleum ether/Ethyl acetate (10:1). to afford the title product (200 mg, 36.7% yield) as a white solid. LCMS (ESI, m/z): [M+H]⁺ = 550.3. [00663] The crude product was further separated by Chiral HPLC with the following conditions: Column: CHIRALPAK IG, 2*25 cm, 5 μm; Mobile Phase A: HEX(0.5% 2M NH3-Methanol), Mobile Phase B: ETOH; Flow rate: 20 mL/min; Gradient: isocratic 50; Wave Length: 220/254 nm; RT1(min): 13.768; RT2(min): 18.472; Sample Solvent: Ethanol; Injection Volume: 0.5 mL; Number Of Runs: 10. [00664] tert-butyl (S)-4-((2-(2-acetamido-4-(methoxycarbonyl)phenyl)piperidin-1-yl)methyl)-5-methoxy- 7-methyl-1H-indole-1-carboxylate (isomer 1, faster peak) (60 mg, 30.0% yield) . LCMS (ESI, m/z): [M+H]⁺ = 550.1. tR = 3.626 min (CHIRALPAK IG-3, 4.6*50mm 3um, HEX(0.1%DEA):ETOH=70:30, Flow rate 2 mL/min). [00665] tert-butyl (R)-4-((2-(2-acetamido-4-(methoxycarbonyl)phenyl)piperidin-1-yl)methyl)-5-methoxy- 7-methyl-1H-indole-1-carboxylate (isomer 2, slower peak) (60 mg 30 % yield) as a white solid. LCMS (ESI, m/z): [M+H]⁺ = 550.1. tR = 4.99 min (CHIRALPAK IG-34.6*50mm 3um, HEX(0.1%DEA):ETOH=70:30, Flow rate 2 mL/min). [00666] Step 2: (S)-3-Acetamido-4-(1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2- yl)benzoic acid & (R)-3-acetamido-4-(1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl)benzoic acid [00667] To a stirred mixtu

hoxycarbonyl)phenyl)piperidin-1- yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (60 mg, 0.11 mmol) in ethanol (1.6 mL) and water (0.4 mL) was added Potassium hydroxide (61.24 mg, 1.09 mmol) in portions at room temperature. The resulting mixture was stirred at 80 °C for 2 h. The mixture was acidified to pH 7 with saturated citric acid aqueous solution. The residue was purified by reversed-phase flash chromatography. This resulted in (S)-3- acetamido-4-(1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl)benzoic acid (24.5 mg, 51.54% yield) as a white solid. LCMS (ESI, m/z): [M+H]⁺ = 436.3.¹H NMR (500 MHz, DMSO-d6) δ 11.38 (s, 1H), 10.91 (s, 1H), 8.78 (s, 1H), 7.65 – 7.60 (m, 1H), 7.41 (s, 1H), 7.32 – 7.27 (m, 1H), 6.68 (s, 1H), 6.39 – 6.34 (m, 1H), 3.75 – 3.69 (m, 1H), 3.65 (s, 3H), 3.46 – 3.41 (m, 1H), 3.24 – 3.18 (m, 1H), 2.82 – 2.76 (m, 1H), 2.43 (s, 3H), 1.98 (s, 4H), 1.77 (s, 1H), 1.75 – 1.69 (m, 1H), 1.67 – 1.61 (m, 1H), 1.60 – 1.54 (m, 1H), 1.41 – 1.21 (m, 2H). [00668] To a stirred mixture of tert-butyl (R)-4-((2-(2-acetamido-4-(methoxycarbonyl)phenyl)piperidin-1- yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (60 mg, 0.109 mmol) in Ethanol (1.6 mL) and water (0.4 mL) was added Potassium hydroxide (61.24 mg, 1.09 mmol) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 80 °C for 2h. The residue was acidified to pH 6 with sat. citric acid. The residue was purified by reversed-phase flash chromatography. This resulted in (R)-3- acetamido-4-(1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl)benzoic acid (29.5 mg, 62.05% yield) as a white solid. LCMS (ESI, m/z): [M+H]⁺ = 436.3, ¹H NMR (500 MHz, DMSO-d6) δ 12.88 (s, 1H), 11.39 (s, 1H), 10.91 (s, 1H), 8.79 (s, 1H), 7.65 – 7.60 (m, 1H), 7.42 (s, 1H), 7.32 – 7.27 (m, 1H), 6.68 (s, 1H), 6.39 – 6.34 (m, 1H), 3.75 – 3.69 (m, 1H), 3.65 (s, 3H), 3.48 – 3.41 (m, 1H), 3.24 – 3.18 (m, 1H), 2.83 – 2.77 (m, 1H), 2.43 (s, 3H), 1.98 (s, 4H), 1.78 (s, 1H), 1.75 – 1.69 (m, 1H), 1.67 – 1.61 (m, 1H), 1.60 – 1.54 (m, 1H), 1.41 – 1.21 (m, 2H). [00669] Example 29. (S)-4-(2,2-Difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)-3-(3-methoxyazetidin-1-yl)benzoic acid & (R)-4-(2,2-difluoro-7-((5-methoxy-7- methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)-3-(3-methoxyazetidin-1-yl)benzoic acid.

[ 5-

ene-7-carboxylate [00672] A solution of 2-chloro-4-

nic acid (0.95 g, 4.43 mmol), [1,1'- Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.27 g, 0.37 mmol), Sodium carbonate (0.78 g, 7.36 mmol) and tert-butyl 2,2-difluoro-6-(trifluoromethanesulfonyloxy)-7-azaspiro[3.5]non-5-ene-7-carboxylate (1.5 g, 3.68 mmol) in 1,4-dioxane (10 mL) and water (5 mL) was stirred for 1h at 90 °C under nitrogen atmosphere. The resulting mixture was quenched with water and extracted with Ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with Petroleum ether/Ethyl acetate (4:1) to afford the title compound (1 g, 47.60% yield) as a colorless solid. LCMS (ESI, m/z): [M+H] ⁺ = 428.1 [00673] Step 2: tert-Butyl 2,2-difluoro-6-(2-(3-methoxyazetidin-1-yl)-4-(methoxycarbonyl)phenyl)-7-

yl)phenyl)-2,2-difluoro-7- azaspiro[3.5]non-5-ene-7-carboxylate (50 mg, 0.096 mmol), 3-methoxyazetidine (600 mg, 6.89 mmol) and Cesium carbonate (950 mg, 2.92 mmol) in 1,4-dioxane (6 mL) was treated with (SP-4-1)-[1,3-BIs[2,6-bis(1- ethylpropyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazol-2-ylidene]dichloro(2-methylpyridine)palladium (120 mg, 0.14 mmol) at 110 °C for 12 h under nitrogen atmosphere. The resulting mixture was quenched with water and extracted with Ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Sodium sulfate. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with Petroleum ether/Ethyl acetate (5:1) to afford the title compound (600 mg, 89.41% yield) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ =479.2 [00675] Step 3: Methyl 4-(2,2-difluoro-7-azaspiro[3.5]nonan-6-yl)-3-(3-methoxyazetidin-1-yl)benzoate [00676] A solution of tert-butyl 2, etidin-1-yl)-4-(methoxycarbonyl)phenyl]-

7-azaspiro[3.5]non-5-ene-7-carboxylate (600 mg, 1.25 mmol) and Sodium cyanoborohydride (810 mg, 12.89 mmol) in Dichloromethane (6 mL) was stirred at 0 °C for 5min. To the above mixture was added trifluoroacetic acid (3 mL) in portions over 2 mins at 0 °C. The resulting mixture was stirred at room temperature for additional 1 h. The reaction was quenched by the addition of Water/Ice (10 mL) at 0 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with Dichloromethane/Methanol (10:1) to afford the title compound (300 mg, 62.89% yield) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 381.1 [00677] Step 4: tert-Butyl 4-((2,2-difluoro-6-(2-(3-methoxyazetidin-1-yl)-4-(methoxycarbonyl)phenyl)-7- azaspiro[3.5]nonan-7-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate [00678] A solution of methyl 4-(2,

p . an-6-yl)-3-(3-methoxyazetidin-1- yl)benzoate (0.9 g, 2.37 mmol), tert-butyl 4-(chloromethyl)-5-methoxy-7-methylindole-1-carboxylate (1.10 g, 3.55 mmol), Potassium iodide (0.63 g, 3.79 mmol) and Cesium carbonate (2.34 g, 7.19 mmol) in DMF (10 mL) was stirred at 50 °C for 1 h. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with water. The resulting mixture was extracted with Ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography to afford the title compound (200 mg, 12.93% yield) as a grey solid. LCMS (ESI, m/z): [M+H] ⁺ =654.3 [00679] Step 5: tert-Butyl (R)-4-((2,2-difluoro-6-(2-(3-methoxyazetidin-1-yl)-4- (methoxycarbonyl)phenyl)-7-azaspiro[3.5]nonan-7-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (isomer 1, faster peak) & tert-butyl (S)-4-((2,2-difluoro-6-(2-(3-methoxyazetidin-1-yl)-4- (methoxycarbonyl)phenyl)-7-azaspiro[3.5]nonan-7-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (isomer 2, slower peak) [00680] tert-butyl

rbonyl)phenyl)-7- azaspiro[3.5]nonan-7-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (200 mg, 0.31 mmol) was applied for further separation by Chiral HPLC with the following condition: Column: CHIRALPAK IA 2*25 cm, 5 μm; Mobile Phase A: HEX(0.5% 2M NH3-Methanol), Mobile Phase B: ETOH; Flow rate: 20 mL/min; Gradient: isocratic 40; Wave Length: 220/254 nm; RT1(min): 5.454; RT2(min): 7.238; Sample Solvent: ETOH; Injection Volume: 0.4 mL; Number Of Runs: 16. [00681] tert-butyl (R)-4-((2,2-difluoro-6-(4-(methoxycarbonyl)-2-((2-methoxyethyl)amino)phenyl)-7- azaspiro[3.5]nonan-7-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (isomer 1, faster peak) (60 mg, 30% yield) . LCMS (ESI, m/z): [M+H]⁺ =653.3. tR = 1.12 min (CHIRALPAK IA‐3, 4.6*50 mm,3 um, Hex(0.1%DEA):IPA=90:10, 1.0 mL/min, 254 nm). [00682] tert-butyl (S)-4-((2,2-difluoro-6-(2-(3-methoxyazetidin-1-yl)-4-(methoxycarbonyl)phenyl)-7- azaspiro[3.5]nonan-7-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (isomer 2, slower peak) (60 mg, 30%). LCMS (ESI, m/z): [M+H]⁺ = 653.3. tR = 1.56 min (CHIRALPAK IA‐3, 4.6*50 mm,3 um, Hex(0.1%DEA):IPA=90:10, 1.0 mL/min, 254 nm). [00683] Step 6: (R)-4-(2,2-Difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)-3-(3-methoxyazetidin-1-yl)benzoic acid & (S)-4-(2,2-difluoro-7-((5-methoxy-7- methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)-3-(3-methoxyazetidin-1-yl)benzoic acid [00684] A solutio l)-4-

(methoxycarbonyl)phenyl)-7-azaspiro[3.5]nonan-7-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (isomer 1, faster peak) (20 mg, 0.03 mmol) and Potassium hydroxide (26 mg, 0.46 mmol) in ethanol (2 mL) and water (2 mL) was stirred for 1h at 80 °C. The reaction mixture was acidified to pH = 6 with sat. citric acid solution. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in Water (10mmol/L Ammonium bicarbonate), 5% to 50% gradient in 20 min; detector, UV 220 nm. The resulting mixture was concentrated under reduced pressure. The resulting liquid was dried by lyophilization. This resulted in tert-butyl (R)-4-((2,2-difluoro-6- (2-(3-methoxyazetidin-1-yl)-4-(methoxycarbonyl)phenyl)-7-azaspiro[3.5]nonan-7-yl)methyl)-5-methoxy-7- methyl-1H-indole-1-carboxylate (10.2 mg, 61.79% yield) as a white solid. LCMS (ESI, m/z): [M+H] ⁺ =540.4.¹H NMR (300 MHz, DMSO- d6) δ 12.79 (s, 1H), 10.81 (s, 1H), 7.85 (d, J = 8.0 Hz, 1H), 7.56 – 7.47 (m, 1H), 7.29 – 7.21 (m, 1H), 7.13 (d, J = 1.6 Hz, 1H), 6.65 (s, 1H), 6.50 – 6.42 (m, 1H), 4.30 (d, J = 10.8 Hz, 2H), 4.20 (d, J = 7.0 Hz, 1H), 3.86 – 3.76 (m, 1H), 3.70 (s, 4H), 3.45 (d, J = 11.7 Hz, 1H), 3.29 (s, 4H), 3.13 (d, J = 11.8 Hz, 1H), 2.67 (d, J = 11.8 Hz, 1H), 2.41 (s, 4H), 2.31 (d, J = 6.7 Hz, 2H), 2.01 (s, 1H), 1.79 (d, J = 13.1 Hz, 1H), 1.74 – 1.62 (m, 1H), 1.52 (s, 2H). [00685] A solution of tert-butyl (S)-4-((2,2-difluoro-6-(4-(methoxycarbonyl)-2-((2- methoxyethyl)amino)phenyl)-7-azaspiro[3.5]nonan-7-yl)methyl)-5-methoxy-7-methyl-1H-indole-1- carboxylate (isomer 2, slower peak) (25 mg, 0.038 mmol) and Potassium hydroxide (30 mg, 0.58 mmol) in ethanol (2 mL) and water (2 mL) was stirred for 1h at 80 °C. The reaction mixture was acidified to pH = 6 with sat. citric acid solution. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in Water (10mmol/L Ammonium bicarbonate), 5% to 50% gradient in 20 min; detector, UV 220 nm. The resulting mixture was concentrated under reduced pressure. The resulting liquid was dried by lyophilization. This resulted in (S)-4-(2,2-difluoro- 7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)-3-(3-methoxyazetidin-1- yl)benzoic acid (7.2 mg, 34.89% yield) as a white solid. LCMS (ESI, m/z): [M+H] ⁺ =540.4.¹H NMR (400 MHz, DMSO-d6) δ 12.79 (s, 1H),10.81 (s, 1H), 7.77 (d, J = 8.0 Hz, 1H), 7.51 (d, J = 8.0 Hz, 1H), 7.26 – 7.21 (m, 1H), 7.16 (s, 1H), 6.63 (s, 1H), 6.48 – 6.43 (m, 1H), 4.29 (s, 2H), 4.15 (s, 1H), 3.82 – 3.75 (m, 1H), 3.69 (s, 4H), 3.43 (s, 2H), 3.27 (s, 3H), 3.11 (d, J = 11.8 Hz, 1H), 2.64 (s, 1H), 2.45 (d, J = 11.7 Hz, 1H), 2.40 (s, 3H), 2.36 – 2.23 (m, 2H), 2.00 (s, 1H), 1.89 (s, 1H), 1.80 – 1.63 (m, 2H), 1.51 (s, 2H). [00686] Example 30.5-((6S)-2,2-Difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)-6-(dimethylamino)pyridine-2-carboxylic acid & 5-((6R)-2,2-Difluoro-7-((5- methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)-6-(dimethylamino)pyridine-2- carboxylic acid.

p y ,,, y ,, y py y e [00689] A solution of methyl 6-amin rboxylate (1.00 g, 4.33 mmol,), bis(pinacolato)diboron (2.2 g, 8.66 mmol

), potassium acetate (1.27 g, 13.00 mmol) and 1,1'- Bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (355 mg, 0.43 mmol) in 1,4-dioxane (25 mL) was stirred at 80 °C for 2 hours under nitrogen atmosphere. The reaction was quenched with water. The resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The crude product was used in the next step directly without further purification. LCMS (ESI, m/z): [M+H] ⁺ =279.2. [00690] Step 2: tert-Butyl 6-(2-amino-6-(methoxycarbonyl)pyridin-3-yl)-2,2-difluoro-7-azaspiro[3.5]non- 5-ene-7-carboxylate [00691] A solution of methyl 6-a

3,2-dioxaborolan-2-yl)pyridine-2- carboxylate (1.00 g, 3.60 mmol), tert-butyl 2,2-difluoro-6-(trifluoromethanesulfonyloxy)-7-azaspiro[3.5]non- 5-ene-7-carboxylate (1.46 g, 3.60 mmol), 1,1’-Bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (355 mg, 0.43 mmol) and sodium carbonate (1.14 g, 10.80 mmol) in 1,4-dioxane (12 mL) and water (3 mL) was stirred at 90 °C for 3 hours under nitrogen atmosphere. The resulting mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with petroleum ether/ethyl acetate (55:45) to afford the title compound (1.22 g, 82.87% yield) as a light yellow solid. LCMS (ESI, m/z): [M+H] ⁺ =410.1. [00692] Step 3: tert-Butyl 6-(2-amino-6-(methoxycarbonyl)pyridin-3-yl)-2,2-difluoro-7- azaspiro[3.5]nonane-7-carboxylate [00693] A solution of tert-butyl 6-

-a o- - e o yca o yl)pyridin-3-yl)-2,2-difluoro-7- azaspiro[3.5]non-5-ene-7-carboxylate (1.00 g, 2.44 mmol) and 10% Pd/C (260 mg) in ethyl acetate (20 mL) was stirred at room temperature for 6 hours under hydrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with ethyl acetate. The filtrate was concentrated under reduced pressure. The crude product was used in the next step directly without further purification. LCMS (ESI, m/z): [M+H] ⁺ =412.1. [00694] Step 4: tert-Butyl 6-(2-(dimethylamino)-6-(methoxycarbonyl)pyridin-3-yl)-2,2-difluoro-7- azaspiro[3.5]nonane-7-carboxylate [00695] A solution of tert-butyl 6 l)pyridin-3-yl)-2,2-difluoro-7-

azaspiro[3.5]nonane-7-carboxylate (450 mg, 1.1 mmol), paraformaldehyde (660 mg, 22.00 mmol) and sodium cyanoborohydride (690 mg, 11.00 mmol) in tetrahydrofuran (5 mL) and acetic acid (5 mL) was stirred at 50 °C for 3 hours. The resulting mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with petroleum ether/ethyl acetate (70:30) to afford the title compound (450 mg, 93.62% yield) as a colorless oil. LCMS (ESI, m/z): [M+H] ⁺ =440.3 [00696] Step 5: Methyl 5-(2,2-difluoro-7-azaspiro[3.5]nonan-6-yl)-6-(dimethylamino) pyridine-2- carboxylate [00697] A solution of tert-butyl 6

xycarbonyl)pyridin-3-yl)-2,2-difluoro-7- azaspiro[3.5]nonane-7-carboxylate (450 mg, 1.33 mmol) in dichloromethane (10 mL) and trifluoroacetic acid (2 mL) was stirred at room temperature for 3 hours. The resulting mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The crude product was used in the next step directly without further purification. LCMS (ESI, m/z): [M+H] ⁺ =340.1 [00698] Step 6: tert-Butyl 4-((6-(2-(dimethylamino)-6-(methoxycarbonyl)pyridin-3-yl)-2,2-difluoro-7- azaspiro[3.5]nonan-7-yl)methyl)-5-methoxy-7-methylindole-1-carboxylate [00699] A solution of methyl 5-(2 an-6-yl)-6-(dimethylamino)pyridine-2-

carboxylate (300 mg, 0.88 mmol), tert-butyl 4-(chloromethyl)-5-methoxy-7-methylindole-1-carboxylate (550 mg, 1.77 mmol), cesium carbonate (865 mg, 2.65 mmol) and potassium iodide (220 mg, 1.32 mmol) in N,N- dimethylformamide (5 mL) was stirred at room temperature for 4 hours. The resulting mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with petroleum ether/ethyl acetate (85:15) to afford the title compound (310 mg, 57.24% yield) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ =613.3 [00700] Step 7: tert-Butyl 4-(((6S)-6-(2-(dimethylamino)-6-(methoxycarbonyl)pyridin-3-yl)-2,2-difluoro- 7-azaspiro[3.5]nonan-7-yl)methyl)-5-methoxy-7-methylindole-1-carboxylate (isomer 1, faster peak) & tert- Butyl 4-(((6R)-6-(2-(dimethylamino)-6-(methoxycarbonyl)pyridin-3-yl)-2,2-difluoro-7-azaspiro[3.5]nonan-7- yl)methyl)-5-methoxy-7-methylindole-1-carboxylate (isomer 2, slower peak) [00701] The crud

wing conditions: CHIRALPAK IA, 2*25 cm, 5 μm; Mobile Phase A: HEX(0.5% 2M NH₃-Methanol), Mobile Phase B: Ethanol; Flow rate: 20 mL/min; Gradient: isocratic 3; Wave Length: 220/254 nm; RT1(min): 6.125; RT2(min): 7.171; Sample Solvent: Ethanol. [00702] tert-Butyl 4-(((6S)-6-(2-(dimethylamino)-6-(methoxycarbonyl)pyridin-3-yl)-2,2-difluoro-7- azaspiro[3.5]nonan-7-yl)methyl)-5-methoxy-7-methylindole-1-carboxylate (isomer 1, faster peak) (65 mg, 12.01% yield) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ =613.3. tR = 1.12 min (CHIRALPAK IA‐3, 4.6*50 mm, 3 μm, Hex(0.1%DEA): Ethanol = 95:5, 1.0 mL/min, 254 nm). [00703] tert-Butyl 4-(((6R)-6-(2-(dimethylamino)-6-(methoxycarbonyl)pyridin-3-yl)-2,2-difluoro-7- azaspiro[3.5]nonan-7-yl)methyl)-5-methoxy-7-methylindole-1-carboxylate (isomer 2, slower peak) (83 mg, 15.32% yield) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ =613.3. t_R = 1.40 min (CHIRALPAK IA‐3, 4.6*50 mm, 3 μm, Hex(0.1%DEA): Ethanol = 95:5, 1.0 mL/min, 254 nm). [00704] Step 8: 5-((6S)-2,2-Difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)-6-(dimethylamino)pyridine-2-carboxylic acid & 5-((6R)-2,2-Difluoro-7-((5- methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)-6-(dimethylamino)pyridine-2- carboxylic acid [00705] A soluti nyl)pyridin-3-yl]-2,2-

difluoro-7-azaspiro[3.5]nonan-7-yl)methyl)-5-methoxy-7-methylindole-1-carboxylate (65 mg, 0.11 mmol) and potassium hydroxide (60 mg, 1.07 mmol) in ethanol (1 mL) and water (0.2 mL) was stirred at 80 °C for 3 hours. The mixture was neutralized to pH 7 with saturated citric acid aqueous solution. The residue was purified by reversed-phase flash chromatography to afford the title compound (34.1 mg, 64.47% yield) as an off-white solid. LCMS (ESI, m/z): [M+H] ⁺ =499.3.¹H NMR (500 MHz, DMSO-d6) δ 12.73 (s, 1H), 10.81 (s, 1H), 8.21 (d, J = 7.8 Hz, 1H), 7.79 (d, J = 7.7 Hz, 1H), 7.23 (t, J = 2.8 Hz, 1H), 6.63 (s, 1H), 6.33 (dd, J = 3.1, 1.9 Hz, 1H), 3.67 (s, 3H), 3.56 – 3.50 (m, 1H), 3.26 (d, J = 11.7 Hz, 1H), 3.11 (d, J = 11.7 Hz, 1H), 2.85 (s, 6H), 2.72 – 2.64 (m, 1H), 2.59 – 2.53 (m, 1H), 2.48 – 2.42 (m, 1H), 2.40 (s, 3H), 2.38 – 2.27 (m, 2H), 2.11 – 1.99 (m, 1H), 1.88 – 1.73 (m, 2H), 1.59 – 1.49 (m, 2H). [00706] A solution of tert-butyl 4-(((6R)-6-(2-(dimethylamino)-6-(methoxycarbonyl)pyridin-3-yl)-2,2- difluoro-7-azaspiro[3.5]nonan-7-yl)methyl)-5-methoxy-7-methylindole-1-carboxylate (83 mg, 0.14 mmol) and potassium hydroxide (80 mg, 1.42 mmol) in ethanol (1 mL) and water (0.2 mL) was stirred at 80 °C for 3 hours. The mixture was neutralized to pH 7 with saturated citric acid aqueous solution. The residue was purified by reversed-phase flash chromatography to afford the title compound (33.8 mg, 47.75% yield,) as an off-white solid. LCMS (ESI, m/z): [M+H] ⁺ =499.3.¹H NMR (500 MHz, DMSO-d6) δ 12.68 (s, 1H), 10.81 (s, 1H), 8.21 (d, J = 7.7 Hz, 1H), 7.79 (d, J = 7.8 Hz, 1H), 7.24 (t, J = 2.8 Hz, 1H), 6.63 (s, 1H), 6.34 (dd, J = 3.1, 2.0 Hz, 1H), 3.67 (s, 3H), 3.56 – 3.51 (m, 1H), 3.27 (d, J = 11.6 Hz, 1H), 3.11 (d, J = 11.7 Hz, 1H), 2.85 (s, 6H), 2.71 – 2.65 (m, 1H), 2.58 – 2.52 (m, 1H), 2.49 – 2.44 (m, 1H), 2.40 (s, 3H), 2.38 – 2.27 (m, 2H), 2.13 – 2.00 (m, 1H), 1.87 – 1.74 (m, 2H), 1.58 – 1.48 (m, 2H). [00707] Example 31.3-((Cyanomethyl)amino]-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4- yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzoic acid. [00708] Procedure:

[00709]

difluoro-7- azaspiro[3.5]nonan-7-yl)methyl]-5-methoxy-7-methylindole-1-carboxylate [00710] A solution of tert-butyl 4

onyl)phenyl)-2,2-difluoro-7- azaspiro[3.5]nonan-7-yl)methyl)-5-methoxy-7-methylindole-1-carboxylate (250 mg, 0.43 mmol), N,N- Diisopropylethylamine (166.01 mg, 1.30 mmol) and iodoacetonitrile (715 mg, 4.28 mmol) in DMF (2 mL) was stirred at 60 °C for 1h. The resulting mixture was quenched with water and extracted with ethyl acetate. The organic layer washed with brine, dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with Petroleum ether/Ethyl acetate (5:1) to afford the title compound (120 mg, 45.0 % yield) as a white solid. LCMS: (ESI, m/z): 623.3 [M+H]⁺. [00711] Step 2: Methyl 3-((cyanomethyl)amino]-4-(1-( (5-methoxy-7-methyl-1H-indol-4- yl)methyl)piperidin-2-yl)benzoate [00712] A solution of tert-butyl 4 4-(methoxycarbonyl)phenyl)-2,2-

difluoro-7-azaspiro[3.5]nonan-7-yl)methyl)-5-methoxy-7-methylindole-1-carboxylate (400 mg, 0.64 mmol) and 2,6-Lutidine (344 mg, 3.21 mmol), Trimethylsilyl trifluoromethanesulfonate (713 mg , 3.21 mmol) in Dichloromethane (4 mL) was stirred at 0 °C for 1h. The resulting mixture was quenched with water and extracted with ethyl acetate. The organic layer washed with brine, dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in Water (10 mmol/L Ammonium bicarbonate), 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in methyl 3-((cyanomethyl)amino)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)- 7-azaspiro[3.5]nonan-6-yl)benzoate (200 mg, 59.6% yield) as a white solid. LCMS: (ESI, m/z): 523.2 [M+H]⁺. [00713] Step 3: 3-((Cyanomethyl)amino)-4-(1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2- yl)benzoic acid. [00714] A solution of methyl 3-((c

, fluoro-7-[(5-methoxy-7-methyl-1H-indol- 4-yl)methyl-7-azaspiro[3.5]nonan-6-yl)benzoate (30 mg, 0.057 mmol, 1 equiv) and pig liver esterase (30 mg) in Phosphate Buffer solution (PH=7.2-7.4) (1 mL) was stirred at 35 °C for 5 days under air atmosphere. The resulting mixture was quenched with water and extracted with ethyl acetate. The organic layer washed with brine, dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in Water (10mmol/L Ammonium bicarbonate), 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in 3-[(cyanomethyl)amino]-4-{2,2-difluoro-7- [(5-methoxy-7-methyl-1H-indol-4-yl)methyl]-7-azaspiro[3.5]nonan-6-yl}benzoic acid (5.1 mg, 17.47% yield) as a white solid. LCMS: (ESI, m/z): 509.4 [M+H]⁺.¹H NMR (300 MHz, DMSO-d6) δ 10.86 (s, 1H), 7.53 – 7.17 (m, 5H), 6.66 (s, 1H), 6.32 – 6.25 (m, 1H), 4.40 – 4.32 (m, 2H), 3.69 (s, 4H), 3.20 (s, 3H), 2.74 – 2.61 (m, 2H), 2.41 (s, 4H), 2.35 – 2.25 (m, 2H), 1.92 (s, 1H), 1.66 – 1.48 (m, 3H). [00715] Example 32.3-[(Cyanomethyl)amino]-4-{1-[(5-methoxy-7-methyl-1H-indol-4- yl)methyl]piperidin-2-yl}benzoic acid. [00716] Procedure:

[00717

p y y y y y p y pp n-1- yl)methyl]-5-methoxy-7-methylindole-1-carboxylate [00718] To a stirred solution of tert-b (methoxycarbonyl)phenyl]piperidin-1-

yl}methyl)-5-methoxy-7-methylindole-1-carboxylate (0.8 g, 1.58 mmol) and N,N-Diisopropylethylamine (0.62 g, 4.80 mmol) in DMF (12 mL) was added iodoacetonitrile (1.32 g, 7.88 mmol) dropwise at room temperature. The resulting mixture was stirred at 80 °C for 2 h under nitrogen atmosphere. The resulting mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with Petroleum ether/Ethyl acetate = 90/10 to afford tert-butyl 4-[(2-{2-[(cyanomethyl)amino]-4-(methoxycarbonyl)phenyl}piperidin-1- yl)methyl]-5-methoxy-7-methylindole-1-carboxylate (540 mg, 62.68% yield) as an off-white solid. LCMS: (ESI, m/z): 547.3 [M+H]⁺. [00719] Step 2: Methyl 3-[(cyanomethyl)amino]-4-{1-[(5-methoxy-7-methyl-1H-indol-4- yl)methyl]piperidin-2-yl}benzoate [00720] A solution of tert-butyl 4-[(2-

no]-4-(methoxycarbonyl)phenyl}piperidin-1- yl)methyl]-5-methoxy-7-methylindole-1-carboxylate (500 mg, 0.99 mmol) and 2,6-Lutidine (527.73 mg, 4.93 mmol) trimethylsilyl trifluoromethanesulfonate (1094.55 mg, 4.93 mmol) in Dichloromethane (5 mL) was stirred at r.t for 1h. The resulting mixture was quenched with water and extracted with Ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in Water (10 mmol/L Ammonium bicarbonate), 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in methyl 3-[(cyanomethyl)amino]-4-{1-[(5-methoxy-7-methyl-1H-indol-4-yl)methyl]piperidin-2-yl}benzoate (320 mg, 72.75% yield) as a white solid. LCMS: (ESI, m/z): 447.2 [M+H]⁺. [00721] Step 3: 3-[(Cyanomethyl)amino]-4-{1-[(5-methoxy-7-methyl-1H-indol-4-yl)methyl]piperidin-2- yl}benzoic acid [00722] A solution of methyl 3-[(cya [(5-methoxy-7-methyl-1H-indol-4-

yl)methyl]piperidin-2-yl}benzoate (50 mg, 0.11 mmol) pig liver esterase (30 mg) in Phosphate Buffer solution (PH=7.2-7.4) (1 mL) was stirred at 35 °C for 5 days. The resulting mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in Water (10mmol/L Ammonium bicarbonate), 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in 3-[(cyanomethyl)amino]-4-{1-[(5-methoxy-7-methyl-1H-indol-4- yl)methyl]piperidin-2-yl}benzoic acid (5.6 mg, 11.56% yield) as a white solid. LCMS: (ESI, m/z): 433.3 [M+H]⁺.¹H NMR (300 MHz, DMSO-d6) δ 10.85 (s, 1H), 7.48 – 7.12 (m, 5H), 6.66 (s, 1H), 6.35 – 6.27 (m, 1H), 4.41 – 4.33 (m, 2H), 3.69 (s, 3H), 3.27 – 3.19 (m, 3H), 2.80 – 2.70 (m, 1H), 2.41 (s, 3H), 2.02 – 1.85 (m, 2H), 1.69 (s, 1H), 1.58 – 1.45 (m, 2H), 1.40 – 1.30 (m, 2H), 1.22 (s, 1H). [00723] Example 33.6-[(Cyanomethyl)amino]-5-[(6S)-2,2-difluoro-7-[(5-methoxy-7-methyl-1H-indol-4- yl)methyl]-7-azaspiro[3.5]nonan-6-yl]pyridine-2-carboxylic acid & 6-[(cyanomethyl)amino]-5-[(6R)-2,2- difluoro-7-[(5-methoxy-7-methyl-1H-indol-4-yl)methyl]-7-azaspiro[3.5]nonan-6-yl]pyridine-2-carboxylic acid.

[00725] Step 1: methyl 5-bromo-6-[(cyanomethyl)amino]pyridine-2-carboxylate. [00726] A mixture of methyl 5-brom rboxylate (3 g, 12.82 mmol, 1 equiv) and

aminoacetonitrile (3.6 g, 64.21 mmol, 5.01 equiv) and N,N-Diisopropylethylamine (5 g, 38.69 mmol, 3.02 equiv) in N-Methyl-2-pyrrolidone (30 mL) was stirred at 130 °C for 1h. The resulting mixture was quenched with water and extracted with ethyl acetate. The organic layer washed with brine, dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure. The residue was purified by reversed- phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in Water (10mmol/L Ammonium bicarbonate), 40% to 70% gradient in 10 min; detector, UV 254 nm. to afford methyl 5-bromo-6-[(cyanomethyl)amino]pyridine-2-carboxylate (410 mg, 55% yield) as a yellow oil. LCMS (ESI, m/z): [M+H]+ = 271.1. [00727] Step 2: Methyl 6-[(cyanomethyl)amino]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine- 2-carboxylate. [00728] A mixture of methyl 5-brom

o]pyridine-2-carboxylate (400 mg, 1.48 mmol, 1 equiv) and bis(pinacolato)diboron (564 mg, 2.22 mmol, 1.50 equiv) and [1,1'- Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (121 mg, 0.15 mmol, 0.10 equiv) and Potassium Acetate (290 mg, 2.96 mmol, 2.00 equiv) in 1,4-dioxane (4 mL) was stirred at 90 °C for overnight under nitrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with PE (2 × 10 mL). After filtration, the filtrate was concentrated under reduced pressure. The crude product was used in the next step directly without further purification. LCMS (ESI, m/z): [M+H]⁺ = 318.2. [00729] Step 3: tert-Butyl 6-{2-[(cyanomethyl)amino]-6-(methoxycarbonyl)pyridin-3-yl}-2,2-difluoro-7- azaspiro[3.5]non-5-ene-7-carboxylate [00730] A mixture of tert-butyl 2,

- uo o- - uo o e a esulfonyloxy)-7-azaspiro[3.5]non-5-ene- 7-carboxylate (300 mg, 0.74 mmol, 1 equiv) and methyl 6-[(cyanomethyl)amino]-5-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)pyridine-2-carboxylate (450 mg, 1.42 mmol, 1.93 equiv) and 1,1’- Bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (30 mg, 0.037 mmol, 0.05 equiv) and Sodium carbonate (230 mg, 2.17 mmol, 2.95 equiv) in 1,4-dioxane (3 mL) and water (0.6 mL) was stirred at 90 °C for 1h under nitrogen atmosphere. The resulting mixture was quenched with water and extracted with ethyl acetate. The organic layer washed with brine, dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with Petroleum ether/Ethyl acetate (5:1) to afford tert-Butyl 6-{2- [(cyanomethyl)amino]-6-(methoxycarbonyl)pyridin-3-yl}-2,2-difluoro-7-azaspiro[3.5]non-5-ene-7- carboxylate ( 600 mg) as a yellow solid. LCMS (ESI, m/z): [M+H]⁺ = 449.5. [00731] Step 4: methyl 6-[(Cyanomethyl)amino]-5-{2,2-difluoro-7-azaspiro[3.5]nonan-6-yl}pyridine-2- carboxylate [00732] A solution of tert-butyl 6

methoxycarbonyl)pyridin-3-yl}-2,2- difluoro-7-azaspiro[3.5]non-5-ene-7-carboxylate (270 mg, 0.60 mmol, 1 equiv) in Dichloromethane (1.5 mL) was treated with sodium cyanoborohydride (337 mg, 5.36 mmol, 8.91 equiv) at room temperature for 5 mins under nitrogen atmosphere followed by the addition of trifluoroacetic acid (1.5 mL) dropwise at 0 °C. The resulting mixture was stirred at room temperature for 2 h.The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in Water (10mmol/L Ammonium bicarbonate), 10% to 50% gradient in 10 min; detector, UV 254 nm to afford methyl 6-[(cyanomethyl)amino]-5-{2,2- difluoro-7-azaspiro[3.5]nonan-6-yl}pyridine-2-carboxylate (100 mg) as a red solid. LCMS (ESI, m/z): [M+H]⁺ =351.1. [00733] Step 5: tert-Butyl 4-[(6-{2-[(cyanomethyl)amino]-6-(methoxycarbonyl)pyridin-3-yl}-2,2- difluoro-7-azaspiro[3.5]nonan-7-yl)methyl]-5-methoxy-7-methylindole-1-carboxylate

[00734] A mixture of methyl 6-[(cyanomethyl)amino]-5-{2,2-difluoro-7-azaspiro[3.5]nonan-6- yl}pyridine-2-carboxylate (100 mg, 0.29 mmol, 1 equiv) and tert-butyl 4-(chloromethyl)-5-methoxy-7- methylindole-1-carboxylate (176 mg, 0.57 mmol, 1.99 equiv) and Cesium carbonate (277 mg, 0.85 mmol, 2.98 equiv) and Potassium iodide (48 mg, 0.29 mmol, 1.01 equiv) in DMF (2 mL) was stirred at 50 °C for 1h . The resulting mixture was quenched with water and extracted with ethyl acetate. The organic layer washed with brine, dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in Water (10mmol/L Ammonium bicarbonate), 10% to 50% gradient in 10 min; detector, UV 254 nm.to afford tert-butyl 4-[(6-{2-[(cyanomethyl)amino]-6- (methoxycarbonyl)pyridin-3-yl}-2,2-difluoro-7-azaspiro[3.5]nonan-7-yl)methyl]-5-methoxy-7-methylindole- 1-carboxylate (90 mg) as a yellow solid. LCMS (ESI, m/z): [M+H]⁺ =624.7. [00735] Step 6: tert-Butyl 4-{[(6S)-6-{2-[(cyanomethyl)amino]-6-(methoxycarbonyl)pyridin-3-yl}-2,2- difluoro-7-azaspiro[3.5]nonan-7-yl]methyl}-5-methoxy-7-methylindole-1-carboxylate (isomer 1, faster peak) & tert-Butyl 4-{[(6R)-6-{2-[(cyanomethyl)amino]-6-(methoxycarbonyl)pyridin-3-yl}-2,2-difluoro-7- azaspiro[3.5]nonan-7-yl]methyl}-5-methoxy-7-methylindole-1-carboxylate (isomer 2, slower peak) [00736] tert-butyl

3-yl}-2,2-difluoro-7- azaspiro[3.5]nonan-7-yl)methyl]-5-methoxy-7-methylindole-1-carboxylate (90 mg) for further separation by Chiral HPLC with the following condition: Column: CHIRALPAK ID, 2*25 cm, 5 μm; Mobile Phase A: HEX(0.5% 2M NH3-Methanol), Mobile Phase B: ETOH; Flow rate: 20 mL/min; Gradient: isocratic 30; Wave Length: 220/254 nm; RT1(min): 9.252; RT2(min): 12.935; Sample Solvent: Ethanol; Injection Volume: 1.0 mL; Number Of Runs: 7 [00737] tert-butyl 4-{[(6S)-6-{2-[(cyanomethyl)amino]-6-(methoxycarbonyl)pyridin-3-yl}-2,2-difluoro- 7-azaspiro[3.5]nonan-7-yl]methyl}-5-methoxy-7-methylindole-1-carboxylate (isomer 1, faster peak, 30 mg,33.3% yield) LCMS (ESI, m/z): [M+H]⁺ = 624.7. tR =1.72 min (Chiral PAK ID-3, Hex(0.1%DEA): Ethanol=70: 30, 1 mL/min). [00738] tert-butyl 4-{[(6R)-6-{2-[(cyanomethyl)amino]-6-(methoxycarbonyl)pyridin-3-yl}-2,2-difluoro- 7-azaspiro[3.5]nonan-7-yl]methyl}-5-methoxy-7-methylindole-1-carboxylate (isomer 2, slower peak, 20 mg, 22.2% yield) LCMS (ESI, m/z): [M+H]⁺ = 624.7. tR =2.44 min (Chiral PAK ID-3, Hex(0.1%DEA): Ethanol=70: 30, 1 mL/min). [00739] Step 7: 6-[(cyanomethyl)amino]-5-[(6S)-2,2-difluoro-7-[(5-methoxy-7-methyl-1H-indol-4- yl)methyl]-7-azaspiro[3.5]nonan-6-yl]pyridine-2-carboxylic acid & 6-[(cyanomethyl)amino]-5-[(6R)-2,2- difluoro-7-[(5-methoxy-7-methyl-1H-indol-4-yl)methyl]-7-azaspiro[3.5]nonan-6-yl]pyridine-2-carboxylic acid [00740] A mixtu carbonyl)pyridin-3-yl}-

2,2-difluoro-7-azaspiro[3.5]nonan-7-yl]methyl}-5-methoxy-7-methylindole-1-carboxylate (isomer 1, faster peak) (30 mg, 0.048 mmol, 1 equiv) and Potassium hydroxide (27 mg, 0.48 mmol, 10.01 equiv) in Ethanol (0.9 mL) and water (0.3 mL) was stirred at 80 °C for 1 h .The mixture was acidified to pH 6 with citric acid. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in Water (10mmol/L Ammonium bicarbonate), 10% to 50% gradient in 10 min; detector, UV 254 nm to afford 6-[(cyanomethyl)amino]-5-[(6S)-2,2-difluoro-7-[(5- methoxy-7-methyl-1H-indol-4-yl)methyl]-7-azaspiro[3.5]nonan-6-yl]pyridine-2-carboxylic acid (4.4 mg, 17.95% yield) as a yellow solid. LCMS (ESI, m/z): [M+H]⁺ = 510.6.¹H NMR (300 MHz, DMSO-d6) δ 11.01 (s, 1H), 7.56 – 7.15 (m, 3H), 6.99 (s, 1H), 6.69 (s, 1H), 6.45 (s, 1H), 4.41 – 3.61 (m, 9H), 3.09 – 2.87 (m, 2H), 2.72 – 2.58 (m, 2H), 2.48 – 2.31 (m, 6H), 2.00 – 1.84(m, 2H), 1.70 (s, 1H). [00741] A mixture of tert-butyl 4-{[(6R)-6-{2-[(cyanomethyl)amino]-6-(methoxycarbonyl)pyridin-3-yl}- 2,2-difluoro-7-azaspiro[3.5]nonan-7-yl]methyl}-5-methoxy-7-methylindole-1-carboxylate (isomer 2, slower peak)(20 mg, 0.032 mmol, 1 equiv) and Potassium hydroxide (18 mg, 0.32 mmol, 10.01 equiv) in Ethanol (0.9 mL) and water (0.3 mL) was stirred at 80 °C for 1h .The mixture was acidified to pH 6 with citric acid.The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in Water (10mmol/L Ammonium bicarbonate), 10% to 50% gradient in 10 min; detector, UV 254 nm.This resulted in 6-[(cyanomethyl)amino]-5-[(6R)-2,2-difluoro- 7-[(5-methoxy-7-methyl-1H-indol-4-yl)methyl]-7-azaspiro[3.5]nonan-6-yl]pyridine-2-carboxylic acid (5.7 mg, 34.88% yield) as a yellow oil. LCMS (ESI, m/z): [M+H]⁺ = 510.6.¹H NMR (400 MHz, DMSO-d6) δ 11.01 (s, 1H), 7.56 – 7.15 (m, 3H), 6.97 (s, 1H), 6.68 (s, 1H), 6.44 (s, 1H), 4.07 – 3.92 (m, 3H), 3.68 – 3.64 (m, 6H), 3.06 – 2.92(m, 2H), 2.72 – 2.58 (m, 2H), 2.47 – 2.43 (m, 3H), 2.41 – 2.31 (m, 3H), 1.99 – 1.84 (m, 2H), 1.69 (s, 1H). [00742] Example 34.4-[(6S)-2,2-Difluoro-7-[(5-methoxy-7-methyl-1H-indol-4-yl)methyl]-7- azaspiro[3.5]nonan-6-yl]-3-[(3,3-difluorocyclobutyl)amino]benzoic acid & 4-[(6R)-2,2-Difluoro-7-[(5- methoxy-7-methyl-1H-indol-4-yl)methyl]-7-azaspiro[3.5]nonan-6-yl]-3-[(3,3- difluorocyclobutyl)amino]benzoic acid. F F F F

, , [00745] A mixture of tert-butyl 8- l)phenyl]-2,2-difluoro-7-

azaspiro[3.5]non-5-ene-7-carboxylate (500 mg, 1.17 mmol, 1 equiv) and 3,3-difluorocyclobutan-1-amine (367 mg, 3.43 mmol, 2.93 equiv) and (SP-4-1)-[1,3-BIs[2,6-bis(1-ethylpropyl)phenyl]-4,5-dichloro-1,3- dihydro-2H-imidazol-2-ylidene]dichloro(2-methylpyridine)palladium (99 mg, 0.12 mmol, 0.10 equiv) in 1,4- dioxane (5 mL) was stirred at 110 °C for 12 h under nitrogen atmosphere. The resulting mixture was quenched with water and extracted with Ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in Water (10mmol/L Ammonium bicarbonate), 10% to 50% gradient in 10 min; detector, UV 254 nm.to afford tert-butyl 8-{2-[(3,3-difluorocyclobutyl)amino]-4- (methoxycarbonyl)phenyl}-2,2-difluoro-7-azaspiro[3.5]non-5-ene-7-carboxylate (350 mg) as a yellow oil. LCMS (ESI, m/z): [M+H]+ = 499.5 [00746] Step 2: tert-Butyl 6-{2-[(3,3-difluorocyclobutyl)amino]-4-(methoxycarbonyl)phenyl}-2,2- difluoro-7-azaspiro[3.5]nonane-7-carboxylate [00747] A mixture of tert-butyl 6-

mino]-4-(methoxycarbonyl)phenyl}-2,2- difluoro-7-azaspiro[3.5]non-5-ene-7-carboxylate (700 mg, 1.40 mmol, 1 equiv) and 10% Pd/C (300 mg) in methanol (10 mL) was stirred at room temperature for 1h under hydrogen atmosphere.The resulting mixture was filtered, the filter cake was washed with methanol (3 × 10 mL). The filtrate was concentrated under reduced pressure to afford tert-butyl 6-{2-[(3,3-difluorocyclobutyl)amino]-4-(methoxycarbonyl)phenyl}-2,2- difluoro-7-azaspiro[3.5]nonane-7-carboxylate (500 mg) as a yellow solid. The crude product mixture was used in the next step directly without further purification. LCMS (ESI, m/z): [M+H]⁺ = 501.5 [00748] Step 3: Methyl 4-{2,2-difluoro-7-azaspiro[3.5]nonan-6-yl}-3-[(3,3- difluorocyclobutyl)amino]benzoate [00749] A mixture of tert-butyl 6- mino]-4-(methoxycarbonyl)phenyl}-2,2- difluoro-7-azaspiro[3.5]nonane-7-carb

oxylate (500 mg, 0.99 mmol, 1 equiv) in trifluoroacetic acid (2.5 mL) and Dichloromethane (2.5 mL) was stirred at room temperature for 30 min . The resulting mixture was extracted with Dichloromethane. The combined organic layers were washed with water, dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in Water (10mmol/L Ammonium bicarbonate), 10% to 50% gradient in 10 min; detector, UV 254 nm.to afford methyl 4-{2,2-difluoro-7-azaspiro[3.5]nonan-6-yl}-3-[(3,3- difluorocyclobutyl)amino]benzoate as a brown yellow oil. LCMS (ESI, m/z): [M+H]⁺ = 401.4 [00750] Step 4: tert-Butyl 4-[(6-{2-[(3,3-difluorocyclobutyl)amino]-4-(methoxycarbonyl)phenyl}-2,2- difluoro-7-azaspiro[3.5]nonan-7-yl)methyl]-5-methoxy-7-methylindole-1-carboxylate [00751] A mixture of methyl 4-{2

an-6-yl}-3-[(3,3- difluorocyclobutyl)amino]benzoate (400 mg, 0.99 mmol, 1 equiv) and tert-butyl 4-(chloromethyl)-5- methoxy-7-methylindole-1-carboxylate (640 mg, 2.07 mmol, 2.07 equiv) in DMF (4 mL) was stirred at 50 °C for 1h. The resulting mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in Water (10mmol/L Ammonium bicarbonate), 10% to 50% gradient in 10 min; detector, UV 254 nm. to afford tert-butyl 4-[(6-{2-[(3,3- difluorocyclobutyl)amino]-4-(methoxycarbonyl)phenyl}-2,2-difluoro-7-azaspiro[3.5]nonan-7-yl)methyl]-5- methoxy-7-methylindole-1-carboxylate (300 mg) as a brown yellow solid. LCMS (ESI, m/z): [M+H]⁺ = 674.7 [00752] Step 5: tert-Butyl 4-{[(6S)-6-{2-[(3,3-difluorocyclobutyl)amino]-4-(methoxycarbonyl)phenyl}- 2,2-difluoro-7-azaspiro[3.5]nonan-7-yl]methyl}-5-methoxy-7-methylindole-1-carboxylate (isomer 1, faster peak) & tert-Butyl 4-{[(6R)-6-{2-[(3,3-difluorocyclobutyl)amino]-4-(methoxycarbonyl)phenyl}-2,2-difluoro- 7-azaspiro[3.5]nonan-7-yl]methyl}-5-methoxy-7-methylindole-1-carboxylate (isomer 2, slower peak) [00753] tert-Bu l)phenyl}-2,2-difluoro-

7-azaspiro[3.5]nonan-7-yl)methyl]-5-methoxy-7-methylindole-1-carboxylate was applied for further separation by Chiral HPLC with the following condition: Column: CHIRALPAK AY-H, 4.6*250mm, 5um; Mobile Phase A: HEX(0.5% 2M NH3-Methanol), Mobile Phase B: Ethanol; Flow rate: 20 mL/min; Gradient: isocratic 5; Wave Length: 220/254 nm; RT1(min): 5.612; RT2(min): 9.421; Sample Solvent: ETOH; Injection Volume: 0.7 mL; Number Of Runs: 21. [00754] tert-butyl 4-{[(6S)-6-{2-[(3,3-difluorocyclobutyl)amino]-4-(methoxycarbonyl)phenyl}-2,2- difluoro-7-azaspiro[3.5]nonan-7-yl]methyl}-5-methoxy-7-methylindole-1-carboxylate (isomer1, faster peak, 35 mg, 35% yield) as a white solid. LCMS (ESI, m/z): [M+H]+ = 674.7. tR = 1.24 min (CHIRALPAK AY- H, 4.6*250 mm, 5um; Hex(0.1%DEA): Ethanol=95: 5, 1 mL/min) [00755] tert-butyl 4-{[(6R)-6-{2-[(3,3-difluorocyclobutyl)amino]-4-(methoxycarbonyl)phenyl}-2,2- difluoro-7-azaspiro[3.5]nonan-7-yl]methyl}-5-methoxy-7-methylindole-1-carboxylate (isomer 2, slower peak, 40 mg, 40% yield) as a white solid. LCMS (ESI, m/z): [M+H]+ = 674.7. tR = 2.32 min (CHIRALPAK AY-H, 4.6*250 mm, 5um; Hex(0.1%DEA): Ethanol=95: 5, 1 mL/min). [00756] Step 6: 4-[(6R)-2,2-difluoro-7-[(5-methoxy-7-methyl-1H-indol-4-yl)methyl]-7- azaspiro[3.5]nonan-6-yl]-3-[(3,3-difluorocyclobutyl)amino]benzoic acid & 4-[(6R)-2,2-difluoro-7-[(5- methoxy-7-methyl-1H-indol-4-yl)methyl]-7-azaspiro[3.5]nonan-6-yl]-3-[(3,3- difluorocyclobutyl)amino]benzoic acid

[00757] A mixt

(methoxycarbonyl)phenyl}-2,2-difluoro-7-azaspiro[3.5]nonan-7-yl]methyl}-5-methoxy-7-methylindole-1- carboxylate (isomer 1, faster peak, 35 mg, 0.052 mmol, 1 equiv) and Potassium hydroxide (30 mg, 0.54 mmol, 10.29 equiv) in Ethanol (0.9 mL) and water (0.3 mL) was stirred at 80 °C for 2 h .The mixture was acidified to pH 6 with citric acid. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in Water (10mmol/L Ammonium bicarbonate), 10% to 50% gradient in 10 min; detector, UV 254 nm. to afford 4-[(6S)-2,2-difluoro-7-[(5- methoxy-7-methyl-1H-indol-4-yl)methyl]-7-azaspiro[3.5]nonan-6-yl]-3-[(3,3- difluorocyclobutyl)amino]benzoic acid (12.9 mg, 44.37% yield) as a white solid. LCMS (ESI, m/z): [M+H]⁺=560.6.¹H NMR (400 MHz, DMSO-d6) δ 10.88 (s, 1H), 7.36 (s, 1H), 7.31 – 7.21 (m, 3H), 6.99 (s, 1H), 6.66 (s, 1H), 6.27 (s, 1H), 3.86 (s, 1H), 3.72 – 3.64 (m, 4H), 3.28 – 3.2 (m,2H), 3.10 – 2.91 (m, 3H), 2.72 – 2.65 (m, 1H), 2.61 (s, 1H), 2.47 – 2.37 (m, 5H), 2.35 – 2.26 (m, 3H), 1.97 (s, 1H), 1.62 – 1.45 (m, 3H), 1.23 (s, 1H). [00758] A mixture of tert-butyl 4-{[(6R)-6-{2-[(3,3-difluorocyclobutyl)amino]-4- (methoxycarbonyl)phenyl}-2,2-difluoro-7-azaspiro[3.5]nonan-7-yl]methyl}-5-methoxy-7-methylindole-1- carboxylate (isomer 2, slower peak,40 mg, 0.059 mmol, 1 equiv) and Potassium hydroxide (33 mg, 0.59 mmol, 9.91 equiv) in Ethanol (0.9 mL) and water (0.3 mL) was stirred at 80 °C for 2 h .The mixture was acidified to pH 6 with citric acid. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in Water (10mmol/L Ammonium bicarbonate), 10% to 50% gradient in 10 min; detector, UV 254 nm.to afford 4-[(6R)-2,2-difluoro-7-[(5- methoxy-7-methyl-1H-indol-4-yl)methyl]-7-azaspiro[3.5]nonan-6-yl]-3-[(3,3- difluorocyclobutyl)amino]benzoic acid (12.4 mg, 37.32% yield,) as a white solid. LCMS (ESI, m/z): [M+H]⁺ = 560.6.¹H NMR (400 MHz, DMSO-d6) δ 10.88 (s, 1H), 7.36 (s, 1H), 7.31 – 7.20 (m, 3H), 6.99 (s, 1H), 6.66 (s, 1H), 6.27 (s, 1H), 3.86 (s, 1H), 3.72 – 3.64 (m, 4H), 3.28 – 3.22 (m, 2H), 3.09 – 2.94 (m, 3H), 2.73 – 2.65 (m, 1H), 2.61 (s, 1H), 2.47 – 2.37 (m, 5H), 2.36 – 2.25 (m, 3H), 2.02 – 1.90 (m, 1H), 1.60 – 1.47 (m, 3H). [00759] Example 35.4-Amino-5-{2,2-difluoro-7-[(5-methoxy-7-methyl-1H-indol-4-yl)methyl]-7- azaspiro[3.5]nonan-6-yl}pyridine-2-carboxylic acid.

[00762] A solution of methyl 4-aminop

te (5 g, 32.86 mmol, 1 equiv) and NBS (5.85 g, 32.86 mmol, 1 equiv) in 1,2-Dichloroethane (70 mL) was stirred at room temperature for 1h. The resulting mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to afford methyl 4-amino-5-bromopyridine-2-carboxylate (5.6 g, 73.76% yield,) as a light orange solid. LCMS: (ESI, m/z): 231.0 [M+H]⁺. [00763] Step 2: 4-Amino-6-(methoxycarbonyl)pyridin-3-ylboronic acid [00764] A solution of methyl 4-amin arboxylate (5 g, 21.64 mmol, 1 equiv),

bis(pinacolato)diboron (27.48 g, 108.20 mmol, 5 equiv), Potassium Acetate (4.25 g, 43.28 mmol, 2.00 equiv) and 1,1’-Bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (1.77 g, 2.16 mmol, 0.10 equiv) in 1,4-dioxane (60 mL) was stirred at 110 °C for 1 hour under nitrogen atmosphere. The resulting mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to afford the title compound (5 g crude) as a brown solid. LCMS: (ESI, m/z): 197.1 [M+H]⁺. [00765] Step 3: tert-Butyl 6-[4-amino-6-(methoxycarbonyl)pyridin-3-yl]-2,2-difluoro-7-azaspiro[3.5]non- 5-ene-7-carboxylate [00766] A solution of 4-amino-6-

lboronic acid (3.61 g, 18.41 mmol, 1.50 equiv), tert-butyl 2,2-difluoro-6-(trifluoromethanesulfonyloxy)-7-azaspiro[3.5]non-5-ene-7-carboxylate (5 g, 12.27 mmol, 1.00 equiv), 1,1’-Bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (1.00 g, 1.23 mmol, 0.1 equiv), Sodium carbonate (2.60 g, 24.55 mmol, 2 equiv) in 1,4-dioxane (60 mL) and water (12 mL) was treated at 90 °C for 1 h under nitrogen. The resulting mixture was quenched with water and extracted with ethyl acetate. The organic layer washed with brine, dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by C18 silica gel column chromatography, eluted with Acetonitrile/water (1:1) to afford tert-butyl 6-[4-amino-6- (methoxycarbonyl)pyridin-3-yl]-2,2-difluoro-7-azaspiro[3.5]non-5-ene-7-carboxylate (700 mg, 13.93% yield) as a yellow solid. LCMS: (ESI, m/z): 410.2 [M+H]⁺. [00767] Step 4: Methyl 4-amino-5-{2,2-difluoro-7-azaspiro[3.5]nonan-6-yl}pyridine-2-carboxylate [00768] A solution of tert-butyl 6-

y yl)pyridin-3-yl]-2,2-difluoro-7- azaspiro[3.5] non-5-ene-7-carboxylate (600 mg, 1.46 mmol, 1 equiv) in Dichloromethane (5 mL) and trifluoroacetic acid (5 mL) was treated with sodium cyanoborohydride (920.88 mg, 14.65 mmol, 10 equiv) at room temperature for 1h. The resulting mixture was concentrated under reduced pressure. The mixture was basified to pH 7 with citric acid. The resulting mixture was extracted with Ethyl acetate (3 × 10 mL). The combined organic layers were washed with brine (3 × 10 mL), dried over anhydrous Sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by C18 silica gel column chromatography, eluted with Acetonitrile/water (1:5) to afford methyl 4-amino-5-{2,2-difluoro-7- azaspiro[3.5]nonan-6-yl}pyridine-2-carboxylate (450 mg, 98.63% yield) as a light yellow solid. LCMS: (ESI, m/z): 312.2 [M+H]⁺. [00769] Step 5: tert-Butyl 4-({6-[4-amino-6-(methoxycarbonyl)pyridin-3-yl]-2,2-difluoro-7- azaspiro[3.5]nonan-7-yl}methyl)-5-methoxy-7-methylindole-1-carboxylate [00770] A solution of methyl 4-a

o[3.5]nonan-6-yl}pyridine-2-carboxylate (450 mg, 1.44 mmol, 1 equiv), tert-butyl 4-(chloromethyl)-5-methoxy-7-methylindole-1-carboxylate (1791.08 mg, 5.78 mmol, 4 equiv), Potassium iodide (359.91 mg, 2.17 mmol, 1.5 equiv) in DMF (7 mL) was treated with Cesium carbonate (1412.81 mg, 4.33 mmol, 3 equiv) at 50 °C for 1.5 h. The resulting mixture was quenched with saturated sodium chloride solution and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by C18 silica gel column chromatography, eluted with Acetonitrile/water (4:1) to afford tert-butyl 4-({6-[4-amino-6-(methoxycarbonyl)pyridin-3-yl]- 2,2-difluoro-7-azaspiro[3.5]nonan-7-yl}methyl)-5-methoxy-7-methylindole-1-carboxylate (230 mg, 27.22% yield) as a light yellow solid. LCMS: (ESI, m/z): 585.1 [M+H]⁺. [00771] Step 6: 4-Amino-5-{2,2-difluoro-7-[(5-methoxy-7-methyl-1H-indol-4-yl)methyl]-7- azaspiro[3.5]nonan-6-yl}pyridine-2-carboxylic acid [00772] A solution of tert-butyl 4

y onyl)pyridin-3-yl]-2,2-difluoro-7- azaspiro [3.5]nonan-7-yl}methyl)-5-methoxy-7-methylindole-1-carboxylate (13 mg, 0.022 mmol, 1 equiv) in Ethanol (1.2 mL) and water (0.4 mL) was treated with Potassium hydroxide (12.47 mg, 0.22 mmol, 10 equiv) at 70 °C for 3 h. The mixture was allowed to cool down to room temperature. The mixture was acidified to pH 6 with citric acid. The residue was purified by C18 silica gel column chromatography, eluted with Acetonitrile/water(Ammonium bicarbonate) (1:3) to afford 4-amino-5-{2,2-difluoro-7-[(5-methoxy-7-methyl- 1H-indol-4-yl)methyl]-7-azaspiro[3.5] nonan-6-yl}pyridine-2-carboxylic acid (7.5 mg, 71.69% yield) as an off-white solid. LCMS: (ESI, m/z): 471.3 [M+H]⁺.¹H NMR (300 MHz, DMSO-d₆) δ 10.91 (s, 1H), 8.11 (s, 2H), 7.28 (d, J = 2.8 Hz, 2H), 6.68 (s, 1H), 6.41 (s, 1H), 3.72 (s, 4H), 3.48 (d, J = 12.0 Hz, 1H), 3.25 (s, 1H), 2.88 – 2.73 (m, 1H), 2.66 (d, J = 11.3 Hz, 1H), 2.44 (s, 3H), 2.36 (d, J = 5.7 Hz, 1H), 2.33 – 2.23 (m, 2H), 2.18 – 1.74 (s, 2H), 1.71 – 1.37 (m, 3H). [00773] Example 36.5-((6R)-2,2-Difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)-6-(isopropylamino)pyridine-2-carboxylic acid & 5-((6S)-2,2-Difluoro-7-((5- methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)-6-(isopropylamino)pyridine-2- carboxylic acid. [00774] Procedu

[0

[00776] A solution of methyl 5-bromo-

arboxylate (1.00 g, 4.27 mmol), isopropylamine (760 mg, 12.86 mmol) and triethylamine (2.16 g, 21.35 mmol) in N, N-dimethylformamide (18 mL) was stirred at 60 °C for 8 hours. The reaction was quenched with water. The resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with petroleum ether/ethyl acetate (85:15) to afford the title compound (850 mg, 72.83% yield) as a colorless oil. LCMS (ESI, m/z): [M+H] ⁺ =273.0. [00777] Step 2: Methyl 6-(isopropylamino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridine-2- carboxylate [00778] A solution of methyl 5-brom ridine-2-carboxylate (850 mg, 3.11 mmol), bis(pinacolato)diboron (7.90 g, 31.11 mm

ol), 1,1 -Bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (254 mg, 0.31 mmol) and potassium acetate (916 mg, 9.33 mmol) in 1,4-dioxane (15 mL) was stirred at 80 °C for 3 hours under nitrogen atmosphere. The reaction was quenched with water. The resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The crude product was used in the next step directly without further purification. LCMS (ESI, m/z): [M+H] ⁺ =321.2. [00779] Step 3: tert-Butyl 2,2-difluoro-6-(2-(isopropylamino)-6-(methoxycarbonyl)pyridin-3-yl)-7- azaspiro[3.5]non-5-ene-7-carboxylate

amethyl-1,3,2-dioxaborolan-2- yl)pyridine-2-carboxylate (500 mg, 1.56 mmol), tert-butyl 2,2-difluoro-6-(trifluoromethanesulfonyloxy)-7- azaspiro[3.5]non-5-ene-7-carboxylate (700 mg, 1.72 mmol), 1,1’-Bis(diphenylphosphino)ferrocene- palladium(II)dichloride dichloromethane complex (130 mg, 0.16 mmol) and sodium carbonate (500 mg, 4.72 mmol) in 1,4-dioxane (6 mL) and water (1.5 mL) was stirred at 90 °C for 3 hours under nitrogen atmosphere. The reaction was quenched with water. The resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with petroleum ether/ethyl acetate (90:10) to afford the title compound (570 mg, 80.85% yield) as a colorless oil. LCMS (ESI, m/z): [M+H] ⁺ =452.1 [00781] Step 4: Methyl 5-(2,2-difluoro-7-azaspiro[3.5]nonan-6-yl)-6-(isopropylamino)pyridine-2- carboxylate

[00782] A solution of tert-butyl 2,2-difluoro-6-(2-(isopropylamino)-6-(methoxycarbonyl)pyridin-3-yl)-7- azaspiro[3.5]non-5-ene-7-carboxylate (550 mg, 1.22 mmol) and Sodium cyanoborohydride (765 mg, 12.17 mmol) in dichloromethane (5 mL) and trifluoroacetic acid (2 mL) was stirred at room temperature for 4 hours. The reaction mixture was quenched by water. The resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The crude product was used in the next step directly without further purification. LCMS (ESI, m/z): [M+H] ⁺ =354.1 [00783] Step 5: tert-Butyl 4-((2,2-difluoro-6-(2-(isopropylamino)-6-(methoxycarbonyl) pyridin-3-yl)-7- azaspiro[3.5]nonan-7-yl)methyl)-5-methoxy-7-methylindole-1-carboxylate [00784] A solution of methyl 5-(2

an-6-yl)-6-(isopropylamino)pyridine-2- carboxylate (500 mg, 1.41 mmol), tert-butyl 4-(chloromethyl)-5-methoxy-7-methylindole-1-carboxylate (880 mg, 2.84 mmol), cesium carbonate (1.38 mg, 4.24 mmol) and potassium iodide (352 mg, 2.12 mmol) in N,N- dimethylformamide (8 mL) was stirred at 50 °C for 3 hours. The reaction was quenched with water. The resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with petroleum ether/ethyl acetate (85:15) to afford the title compound (330 mg, 37.22% yield) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ =627.3. [00785] Step 6: tert-Butyl 4-(((6R)-2,2-difluoro-6-(2-(isopropylamino)-6-(methoxycarbonyl) pyridin-3- yl)-7-azaspiro[3.5]nonan-7-yl)methyl)-5-methoxy-7-methylindole-1-carboxylate & tert-Butyl 4-(((6S)-2,2- difluoro-6-(2-(isopropylamino)-6-(methoxycarbonyl) pyridin-3-yl)-7-azaspiro[3.5]nonan-7-yl)methyl)-5- methoxy-7-methylindole-1-carboxylate [00786] The crude product was further separated by Chiral HPLC with the following conditions: CHIRALPAK IF 2*25 cm, 5 μm; Mobile Phase A: HEX(0.5% 2M NH3-Methanol), Mobile Phase B: Ethanol; Flow rate: 20 mL/min; Gradient: isocratic 10; Wave Length: 220/254 nm; RT1(min): 5.911; RT2(min): 7.575; Sample Solvent: Ethanol. [00787] tert-Butyl 4-(((6R)-2,2-difluoro-6-(2-(isopropylamino)-6-(methoxycarbonyl) pyridin-3-yl)-7- azaspiro[3.5]nonan-7-yl)methyl)-5-methoxy-7-methylindole-1-carboxylate (140 mg, 15.79% yield) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ =627.3. tR = 1.41 min (CHIRALPAK IF‐3, 4.6*50 mm, 3 μm, Hex(0.1%DEA): Ethanol = 95:5, 1.0 mL/min, 254 nm). [00788] tert-Butyl 4-(((6S)-2,2-difluoro-6-(2-(isopropylamino)-6-(methoxycarbonyl) pyridin-3-yl)-7- azaspiro[3.5]nonan-7-yl)methyl)-5-methoxy-7-methylindole-1-carboxylate (130 mg, 14.66% yield) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ =627.3. tR = 1.98 min (CHIRALPAK IF‐3, 4.6*50 mm, 3 μm, Hex(0.1%DEA): Ethanol = 95:5, 1.0 mL/min, 254 nm). [00789] Step 7: 5-((6R)-2,2-Difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)-6-(isopropylamino)pyridine-2-carboxylic acid & 5-((6S)-2,2-Difluoro-7-((5- methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)-6-(isopropylamino)pyridine-2- carboxylic acid [00790] A soluti

(methoxycarbonyl)pyridin-3-yl)-7-azaspiro[3.5]nonan-7-yl)methyl)-5-methoxy-7-methylindole-1-carboxylate (140 mg, 0.22 mmol) and potassium hydroxide (125 mg, 2.23 mmol) in ethanol (1.6 mL) and water (0.4 mL) was stirred at 80 °C for 2 hours. The mixture was acidified to pH 7 with saturated citric acid aqueous solution. The residue was purified by reversed-phase flash chromatography to afford the title compound (87.0 mg, 75.98% yield) as a light yellow solid. LCMS (ESI, m/z): [M+H] ⁺ =513.2.¹H NMR (400 MHz, DMSO-d6) δ 12.43 (s, 1H), 10.88 (s, 1H), 7.57 (s, 1H), 7.40 (s, 1H), 7.27 (t, J = 2.8 Hz, 1H), 7.24 (d, J = 7.3 Hz, 1H), 6.68 (s, 1H), 6.40 (s, 1H), 4.21 (s, 1H), 3.71 – 3.62 (m, 4H), 3.35 – 3.28 (m, 2H), 2.76 (d, J = 12.3 Hz, 1H), 2.71 – 2.57 (m, 1H), 2.48 – 2.39 (m, 4H), 2.33 (t, J = 13.1 Hz, 2H), 2.28 – 2.09 (m, 1H), 1.99 (s, 1H), 1.55 (s, 3H), 1.22 (d, J = 6.3 Hz, 3H), 1.10 (d, J = 6.3 Hz, 3H). [00791] A solution of tert-butyl 4-(((6S)-2,2-difluoro-6-(2-(isopropylamino)-6-(methoxycarbonyl) pyridin-3-yl)-7-azaspiro[3.5]nonan-7-yl)methyl)-5-methoxy-7-methylindole-1-carboxylate (130 mg, 0.21 mmol) and potassium hydroxide (116 mg, 2.07 mmol) in ethanol (1.6 mL) and water (0.4 mL) was stirred at 80 °C for 2 hours. The mixture was acidified to pH 7 with saturated citric acid aqueous solution. The residue was purified by reversed-phase flash chromatography to afford the title compound (80.1 mg, 75.34% yield) as a light yellow solid. LCMS (ESI, m/z): [M+H] ⁺ =513.2.¹H NMR (500 MHz, DMSO-d6) δ 12.43 (s, 1H), 10.88 (s, 1H), 7.57 (s, 1H), 7.39 (s, 1H), 7.28 (t, J = 2.8 Hz, 1H), 7.26 – 7.18 (m, 1H), 6.68 (s, 1H), 6.41 (s, 1H), 4.22 (s, 1H), 3.71 – 3.65 (m, 4H), 3.37 – 3.28 (m, 2H), 2.80 – 2.73 (m, 1H), 2.68 – 2.57 (m, 1H), 2.47 – 2.40 (m, 4H), 2.33 (t, J = 13.1 Hz, 2H), 2.30 – 2.12 (m, 1H), 1.99 (s, 1H), 1.55 (s, 3H), 1.22 (d, J = 6.4 Hz, 3H), 1.10 (d, J = 6.4 Hz, 3H). [00792] Example 37.5-[(6S)-2,2-Difluoro-7-[(5-methoxy-7-methyl-1H-indol-4-yl)methyl]-7- azaspiro[3.5]nonan-6-yl]-6-(3-methoxyazetidin-1-yl)pyridine-2-carboxylic acid & 5-[(6R)-2,2-difluoro-7-[(5- methoxy-7-methyl-1H-indol-4-yl)methyl]-7-azaspiro[3.5]nonan-6-yl]-6-(3-methoxyazetidin-1-yl)pyridine-2- carboxylic acid.

[00795] A solution of methyl 5-bromopy ate (1 g, 4.63 mmol, 1 equiv) and Silver(II) fluoride (2.36 g, 16.20 mmol, 3.5 equiv) in A

cetonitrile (10 mL) was stirred at room temperature for 2h. The reaction mixture was quenched by water. The resulting mixture was extracted with Dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The crude product was used in the next step directly without further purification. LCMS (ESI, m/z): [M+H]⁺= 233.9 [00796] Step 2: Methyl 5-bromo-6-(3-methoxyazetidin-1-yl)pyridine-2-carboxylate [00797] A solution of methyl 5-brom boxylate (1 g, 4.27 mmol, 1 equiv), 3-

methoxyazetidine hydrochloride (1.06 g, 8.55 mmol, 2 equiv) and Triethylamine (1.08 g, 10.68 mmol, 2.5 equiv) in DMF (10 mL) was stirred at 60 °C for 1 hour. The reaction mixture was quenched by water. The resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with Petroleum ether/Ethyl acetate (5:1) to afford methyl 5-bromo-6-(3-methoxyazetidin-1-yl)pyridine-2-carboxylate (1.14 g, 88.59% yield) as a yellow solid. LCMS (ESI, m/z): [M+H]⁺ = 301.0 [00798] Step 3: Methyl 6-(3-methoxyazetidin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)pyridine-2-carboxylate [00799] A solution of methyl 5-brom

1-yl)pyridine-2-carboxylate (800 mg, 2.66 mmol, 1 equiv) and bis(pinacolato)diboron (3.38 g, 3.85mmol, 5 equiv) Potassium Acetate (521.44 mg, 5.314 mmol, 2 equiv), [1,1’-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (200 mg, 0.26 mmol) in 1,4- dioxane (8 mL) was stirred at 110 °C for 1h under nitrogen atmosphere. The resulting mixture was quenched with water and extracted with Ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The crude produc was used in the next step directly without further purification. LCMS (ESI, m/z): [M+H]⁺ = 348.9 [00800] Step 4: tert-Butyl 2,2-difluoro-6-[2-(3-methoxyazetidin-1-yl)-6-(methoxycarbonyl)pyridin-3-yl]- 7-azaspiro[3.5]non-5-ene-7-carboxylate [00801] A solutionof tert-butyl 2, sulfonyloxy)-7-azaspiro[3.5]non-5-ene-7-

carboxylate (200 mg, 0.49 mmol, 1 equiv) and methyl 6-(3-methoxyazetidin-1-yl)-5-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)pyridine-2-carboxylate (256.45 mg, 0.74 mmol, 1.5 equiv), [1,1’- Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (40.10 mg, 0.049 mmol, 0.1 equiv) and Sodium carbonate (104.08 mg, 0.98 mmol, 2 equiv) in 1,4-dioxane (2 mL) and water (0.4 mL) was stirred at 100 °C for 1h under nitrogen atmosphere. The resulting mixture was quenched with water and extracted with Ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with Petroleum ether/Ethyl acetate (5:1) to afford tert-butyl 2,2-difluoro-6-[2-(3- methoxyazetidin-1-yl)-6-(methoxycarbonyl)pyridin-3-yl]-7-azaspiro[3.5]non-5-ene-7-carboxylate (120 mg, 50.97% yield) as a brown oil. LCMS (ESI, m/z): [M+H]⁺ = 479.5 [00802] Step 5: Methyl 5-{2,2-difluoro-7-azaspiro[3.5]nonan-6-yl}-6-(3-methoxyazetidin-1-yl)pyridine- 2-carboxylate [00803] A solution of tert-butyl 2

etidin-1-yl)-6-(methoxycarbonyl)pyridin- 3-yl]-7-azaspiro[3.5]non-5-ene-7-carboxylate (150 mg, 0.31 mmol, 1 equiv) and sodium cyanoborohydride (196.57 mg, 3.13 mmol, 10 equiv) in trifluoroacetic acid (1 mL), Dichloromethane (1 mL) was stirred at 0 °C for 2 h. The reaction mixture was quenched by water. The resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in Water (10mmol/L Ammonium bicarbonate), 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in methyl 5-{2,2-difluoro-7-azaspiro[3.5]nonan-6-yl}-6-(3-methoxyazetidin-1-yl)pyridine-2-carboxylate as a brown oil. (100 mg, 83.81% yield) [00804] Step 6: tert-Butyl 4-({2,2-difluoro-6-[2-(3-methoxyazetidin-1-yl)-6-(methoxycarbonyl)pyridin-3- yl]-7-azaspiro[3.5]nonan-7-yl}methyl)-5-methoxy-7-methylindole-1-carboxylate [00805] A solution of methyl 5-{ an-6-yl}-6-(3-methoxyazetidin-1-

yl)pyridine-2-carboxylate (250 mg, 0.66 mmol, 1 equiv) and tert-butyl 4-(chloromethyl)-5-methoxy-7- methylindole-1-carboxylate (406.10 mg, 1.31 mmol, 2 equiv), Cesium carbonate (640.66 mg, 1.97 mmol, 3 equiv), Potassium iodide (163.21 mg, 0.98 mmol, 1.5 equiv) in DMF (3 mL) was stirred at 50 °C for 1 h. The reaction mixture was quenched by water. The resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in Water (10mmol/L Ammonium bicarbonate), 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in tert-butyl 4-({2,2-difluoro-6-[2-(3-methoxyazetidin-1-yl)-6-(methoxycarbonyl)pyridin-3-yl]-7- azaspiro[3.5]nonan-7-yl}methyl)-5-methoxy-7-methylindole-1-carboxylate as a brown solid.(110 mg, 25.63% yield) as a white solid. [00806] Step 7: tert-Butyl 4-{[(6S)-2,2-difluoro-6-[2-(3-methoxyazetidin-1-yl)-6- (methoxycarbonyl)pyridin-3-yl]-7-azaspiro[3.5]nonan-7-yl]methyl}-5-methoxy-7-methylindole-1- carboxylate & tert-butyl 4-{[(6R)-2,2-difluoro-6-[2-(3-methoxyazetidin-1-yl)-6-(methoxycarbonyl)pyridin-3- yl]-7-azaspiro[3.5]nonan-7-yl]methyl}-5-methoxy-7-methylindole-1-carboxylate [00807] The crud

p p y wing conditions: Column: CHIRALPAK IF, 2*25 cm, 5 μm; Mobile Phase A: Hex(0.5% 2M NH3-Methanol)--HPLC, Mobile Phase B: ETOH: Dichloromethane=1: 1--HPLC; Flow rate: 20 mL/min; Gradient: isocratic 10; Wave Length: 220/254 nm; RT1(min): 9.19; RT2(min): 14.344; Sample Solvent: Ethanol. [00808] tert-butyl 4-{[(6S)-2,2-difluoro-6-[2-(3-methoxyazetidin-1-yl)-6-(methoxycarbonyl)pyridin-3- yl]-7-azaspiro[3.5]nonan-7-yl]methyl}-5-methoxy-7-methylindole-1-carboxylate (isomer 1, faster peak, 80 mg, 40% yield) LCMS: (ESI, m/z): 654.8 [M+H]⁺. tR = 1.209 min (CHIRALPAK IF-3, 4.6*50 mm 3 μm), HeX(0.1%DEA):(Ethanol:Dichloromethane=1:1)=90:10, 1.0 mL/min, 254 nm). [00809] tert-butyl 4-{[(6R)-2,2-difluoro-6-[2-(3-methoxyazetidin-1-yl)-6-(methoxycarbonyl)pyridin-3- yl]-7-azaspiro[3.5]nonan-7-yl]methyl}-5-methoxy-7-methylindole-1-carboxylate (isomer 2, slower peak,80 mg, 40% yield) LCMS: (ESI, m/z): 654.8 [M+H]⁺. tR = 1.708 min (CHIRALPAK IF-3, 4.6*50 mm 3 μm), HeX(0.1%DEA):(Ethanol:Dichloromethane=1:1)=90:10, 1.0 mL/min, 254 nm). [00810] Step 8: 5-[(6S)-2,2-Difluoro-7-[(5-methoxy-7-methyl-1H-indol-4-yl)methyl]-7- azaspiro[3.5]nonan-6-yl]-6-(3-methoxyazetidin-1-yl)pyridine-2-carboxylic acid & 5-[(6R)-2,2-difluoro-7-[(5- methoxy-7-methyl-1H-indol-4-yl)methyl]-7-azaspiro[3.5]nonan-6-yl]-6-(3-methoxyazetidin-1-yl)pyridine-2- carboxylic acid [00811] A solutio

1-yl)-6- (methoxycarbonyl)pyridin-3-yl]-7-azaspiro[3.5]nonan-7-yl]methyl}-5-methoxy-7-methylindole-1- carboxylate (200 mg, 0.31 mmol, 1 equiv) and Potassium hydroxide (171.38 mg, 3.05 mmol, 10 equiv) in Ethanol (0.9 mL) and water (0.3 mL) was stirred at 80 °C for 2.5 h . The mixture was acidified to pH = 6 with sat. citric acid. The solvent was removed. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in Water (10mmol/L Ammonium bicarbonate), 10% to 50% gradient in 10 min; detector, UV 254 nm to afford 5-[(6S)-2,2- difluoro-7-[(5-methoxy-7-methyl-1H-indol-4-yl)methyl]-7-azaspiro[3.5]nonan-6-yl]-6-(3-methoxyazetidin-1- yl)pyridine-2-carboxylic acid (62.2 mg, 37.67% yield) as a white solid. LCMS (ESI, m/z): [M+H]⁺ =541.2. ¹H NMR (300 MHz, DMSO-d6) δ 10.84 (s, 1H), 8.16 – 8.08 (m, 1H), 7.59 – 7.50 (m, 1H), 7.30 – 7.22 (m, 1H), 6.65 (s, 1H), 6.45 – 6.37 (m, 1H), 4.52 – 4.41 (m, 1H), 4.33 – 4.25 (m, 2H), 4.15 – 4.06 (m, 1H), 3.96 – 3.86 (m, 1H), 3.69 (s, 3H), 3.51 – 3.44 (m, 1H), 3.34 (s, 3H), 3.24 (s, 1H), 3.17 – 3.07 (m, 1H), 2.74 – 2.64 (m, 1H), 2.54 (s, 1H), 2.49 – 2.44 (m, 1H), 2.42 (s, 3H), 2.38 – 2.23 (m, 2H), 2.09 – 2.03 (m, 1H), 1.88 – 1.78 (m, 1H), 1.71 – 1.57 (m, 1H), 1.52 (s, 2H). [00812] A solution of tert-butyl 4-{[(6R)-2,2-difluoro-6-[2-(3-methoxyazetidin-1-yl)-6- (methoxycarbonyl)pyridin-3-yl]-7-azaspiro[3.5]nonan-7-yl]methyl}-5-methoxy-7-methylindole-1- carboxylate (200 mg, 0.31 mmol, 1 equiv) and Potassium hydroxide (171.38 mg, 3.05 mmol, 10 equiv) in Ethanol (0.9 mL) and water (0.3 mL) was stirred at 80 °C for 2.5h. The mixture was acidified to pH = 6 with sat. citric acid. The solvent was removed. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in Water (10 mmol/L Ammonium bicarbonate), 10% to 50% gradient in 10 min; detector, UV 254 nm. to afford 5-[(6R)-2,2- difluoro-7-[(5-methoxy-7-methyl-1H-indol-4-yl)methyl]-7-azaspiro[3.5]nonan-6-yl]-6-(3-methoxyazetidin-1- yl)pyridine-2-carboxylic acid (55 mg, 33.31% yield) as a white solid. LCMS (ESI, m/z): [M+H]⁺ = 541.3.¹H NMR (300 MHz, DMSO-d6) δ 10.84 (s, 1H), 8.19 – 8.10 (m, 1H), 7.61 – 7.53 (m, 1H), 7.30 – 7.22 (m, 1H), 6.65 (s, 1H), 6.45 – 6.37 (m, 1H), 4.53 – 4.42 (m, 1H), 4.34 – 4.28 (m, 2H), 4.14 – 4.06 (m, 1H), 3.97 – 3.88 (m, 1H), 3.69 (s, 3H), 3.53 – 3.43 (m, 2H), 3.28 (s, 3H), 3.25 – 3.17 (m, 1H), 3.15 – 3.08 (m, 1H), 2.74 – 2.64 (m, 1H), 2.55 (s, 1H), 2.46 (s, 1H), 2.42 (s, 3H), 2.39 – 2.23 (m, 2H), 2.11 – 2.03 (m, 1H), 1.88 – 1.78 (m, 1H), 1.71 – 1.57 (m, 1H), 1.52 (s, 2H). [00813] Example 38.4-[(6R)-2-Acetyl-7-[(5-Methoxy-7-methyl-1H-indol-4-yl)methyl]-2,7- diazaspiro[3.5]nonan-6-yl]-3-(methylamino)benzoic acid & 4-[(6S)-2-acetyl-7-[(5-methoxy-7-methyl-1H- indol-4-yl)methyl]-2,7-diazaspiro[3.5]nonan-6-yl]-3-(methylamino)benzoic acid

[00816] A solution of tert-butyl 2,7-dia 7-carboxylate (15 g, 66.28 mmol), acetic

anhydride (10.15 g, 99.42 mmol) in Dichloromethane (200 mL) was treated with N,N-Diisopropylethylamine (25.70 g, 198.83 mmol) at room temperature for 1 h. The reaction mixture was quenched by water. The resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by C18 silica gel column chromatography, eluted with Acetonitrile/water (1:5) to afford tert-butyl 2-acetyl-2,7-diazaspiro[3.5]nonane-7-carboxylate (15 g, 84.32% yield) as a white solid. LCMS: (ESI, m/z): 269.2 [M+H]⁺. [00817] Step 2: tert-Butyl 2-acetyl-6-oxo-2,7-diazaspiro[3.5]nonane-7-carboxylate [00818] A solution of tert-butyl 2-acety

]nonane-7-carboxylate (15 g, 55.90 mmol), Sodium periodate (23.91 g, 111.79 mmol) in ethyl acetate (90 mL) and water (90 mL) was treated with Ruodium (III) chloride hydrate (1260.11 mg, 5.59 mmol) at room temperature for 1 h. The resulting mixture was filtered, the filter cake was washed with ethyl acetate (3 × 60 mL). The filtrate was concentrated under reduced pressure. The resulting mixture was extracted with Ethyl acetate (3 × 60 mL). The combined organic layers were washed with brine (3 × 60 mL), dried over anhydrous Sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by C18 silica gel column chromatography, eluted with Acetonitrile/water (1:4) to afford tert-butyl 2-acetyl-6-oxo-2,7- diazaspiro[3.5]nonane-7-carboxylate (5.1 g, 32.31% yield) as a white solid. LCMS: (ESI, m/z): 183.2 [M- Boc]⁺. [00819] Step 3: tert-Butyl 2-acetyl-6-(trifluoromethanesulfonyloxy)-2,7-diazaspiro[3.5]non-5-ene-7- carboxylate [00820] A solution of tert-butyl 2-acety ro[3.5]nonane-7-carboxylate (5.1 g, 18.06

mmol) and KHMDS (1M in Tetrahydrofuran) (27.09 mL, 27.09 mmol) in Tetrahydrofuran (60 mL) was stirred at -78 °C for 40 min under nitrogen. Then the 1,1,1-trifluoro-N-phenyl-N- (trifluoromethane)sulfonylmethanesulfonamide (12.91 g, 36.13 mmol) was added and stirred for 40 mins at r.t. The reaction was quenched with sat. Ammonium chloride (aq.). The combined organic layers were washed with brine (3 × 20 mL), dried over anhydrous Sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with Acetonitrile/water (1:4) to afford tert-butyl 2-acetyl-6-(trifluoromethanesulfonyloxy)-2,7- diazaspiro[3.5]non-5-ene-7-carboxylate (4.7 g, 62.77% yield) as a yellow solid. LCMS: (ESI, m/z): 415.2 [M+H]⁺. [00821] Step 4: tert-Butyl 2-acetyl-6-[4-(methoxycarbonyl)-2-nitrophenyl]-2,7-diazaspiro[3.5]non-5-ene- 7-carboxylate [00822] A solution of tert-butyl 2

onyloxy)-2,7-diazaspiro[3.5]non-5-ene- 7-carboxylate (4.7 g, 11.34 mmol), 4-(methoxycarbonyl)-2-nitrophenylboronic acid (3.83 g, 17.01 mmol), 1,1’-Bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (0.93 g, 1.13 mmol) and Sodium carbonate (2.40 g, 22.68 mmol) in 1,4-dioxane (70 mL) and water (14 mL) was stirred at 90 °C for 1 h under nitrogen. The resulting mixture was diluted with water. The resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with Dichloromethane/Methanol (1:10) to afford tert-butyl 2- acetyl-6-[4-(methoxycarbonyl)-2-nitrophenyl]-2,7-diazaspiro[3.5]non-5-ene-7-carboxylate (750 mg, 14.85% yield) as a yellow solid. LCMS: (ESI, m/z): 446.2 [M+H]⁺. [00823] Step 5: Methyl 4-{2-acetyl-2,7-diazaspiro[3.5]nonan-6-yl}-3-nitrobenzoate [00824] A solution of tert-butyl 2 )-2-nitrophenyl]-2,7-diazaspiro[3.5]non- 5-ene-7-carboxylate (800 mg, 1.80 mm

ol, 1 equiv) in Dichloromethane (10 mL) and trifluoroacetic acid (10 mL) was treated with Sodium cyanoborohydride (1.13 g, 17.96 mmol, 10 equiv) at room temperature for 1h. The resulting mixture was concentrated under vacuum. The mixture was basified to pH 7 with saturated Sodium bicarbonate (aq.). The resulting mixture was diluted with water. The resulting mixture was extracted with Ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by C18 silica gel column chromatography, eluted with Acetonitrile/water (Ammonium bicarbonate) (3:7) to afford methyl 4-{2-acetyl-2,7-diazaspiro[3.5]nonan-6-yl}-3-nitrobenzoate (400 mg, 64.12% yield) as a light yellow solid. LCMS (ESI, m/z): 348.9 [M+H]⁺. [00825] Step 6: tert-Butyl 4-({2-acetyl-6-[4-(methoxycarbonyl)-2-nitrophenyl]-2,7-diazaspiro[3.5]nonan- 7-yl}methyl)-5-methoxy-7-methylindole-1-carboxylate [00826] A solution of methyl 4-{

an-6-yl}-3-nitrobenzoate (800 mg, 2.30 mmol), tert-butyl 4-(chloromethyl)-5-methoxy-7-methylindole-1-carboxylate (1426.90 mg, 4.61 mmol), Potassium iodide (458.77 mg, 2.76 mmol) in DMF (10 mL) was treated with Cesium carbonate (2251.10 mg, 6.91 mmol) at 50 °C for 1 h. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with water. The resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by C18 silica gel column chromatography, eluted with Acetonitrile/water (7:3) to afford tert-butyl 4-({2-acetyl-6-[4-(methoxycarbonyl)-2-nitrophenyl]- 2,7-diazaspiro[3.5]nonan-7-yl}methyl)-5-methoxy-7-methylindole-1-carboxylate (600 mg, 41.97% yield) as a yellow solid. LCMS: (ESI, m/z): 621.4 [M+H]⁺. [00827] Step 7: tert-Butyl 4-({2-acetyl-6-[2-amino-4-(methoxycarbonyl)phenyl]-2,7- diazaspiro[3.5]nonan-7-yl}methyl)-5-methoxy-7-methylindole-1-carboxylate [00828] A solution of tert-butyl 4 nyl)-2-nitrophenyl]-2,7-diazaspiro[3.5]

nonan-7-yl}methyl)-5-methoxy-7-methylindole-1-carboxylate (400 mg, 0.64 mmol) in ethyl acetate (10 mL) was treated with 10% Pd/C (800 mg) at room temperature for overnight under hydrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with Methanol (3 × 30 mL). The filtrate was concentrated under reduced pressure to afford tert-butyl 4-({2-acetyl-6-[2-amino-4-(methoxycarbonyl) phenyl]-2,7-diazaspiro[3.5]nonan-7-yl}methyl)-5-methoxy-7-methylindole-1-carboxylate (320 mg, 84.06% yield) as a light yellow solid. LCMS: (ESI, m/z): 591.2 [M+H]⁺. [00829] Step 8: tert-butyl 4-{[(6S)-2-acetyl-6-[4-(methoxycarbonyl)-2-(methylamino)phenyl]-2,7- diazaspiro[3.5]nonan-7-yl]methyl}-5-methoxy-7-methylindole-1-carboxylate (isomer 1, faster peak) & tert- butyl 4-{[(6R)-2-acetyl-6-[4-(methoxycarbonyl)-2-(methylamino)phenyl]-2,7-diazaspiro[3.5]nonan-7- yl]methyl}-5-methoxy-7-methylindole-1-carboxylate (isomer 2, slower peak) [00830] A soluti

enyl]-2,7- diazaspiro[3.5]nonan-7-yl}methyl)-5-methoxy-7-methylindole-1-carboxylate (320 mg, 0.54 mmol), Paraformaldehyde (81.26 mg, 2.71 mmol) in methanol (5 mL) was treated with Sodium cyanoborohydride (102.12 mg, 1.63 mmol) at 70 °C for overnight. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with water. The resulting mixture was extracted with Ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in Water (10mmol/L Ammonium bicarbonate), 5% to 100% gradient in 30 min; detector, UV 220 nm. This resulted in the title compound (220 mg, 54%) as a white solid. LCMS (ESI, m/z): [M+H] ⁺ =605.3. The title was applied for further separation by Chiral HPLC with the following condition: Column: CHIRALPAK IA, 2*25 cm, 5 μm; Mobile Phase A: Hex(0.5% 2M NH3-Methanol)--HPLC, Mobile Phase B: Ethanol--HPLC; Flow rate: 20 mL/min; Gradient: isocratic 30; Wave Length: 220/254 nm; RT1(min): 6.594; RT2(min): 9.373; Sample Solvent: Ethanol--HPLC; Injection Volume: 0.5 mL; Number Of Runs: 16 [00831] tert-butyl 4-{[(6S)-2-acetyl-6-[4-(methoxycarbonyl)-2-(methylamino)phenyl]-2,7- diazaspiro[3.5]nonan-7-yl]methyl}-5-methoxy-7-methylindole-1-carboxylate (isomer 1, faster peak) (80 mg, 24.42% yield off-white solid). LCMS: (ESI, m/z): 605.3 [M+H]⁺. t_R = 1.06 min (CHIRALPAK IA, 2*25 cm, 5 μm, Hex(0.1%DEA): EtOH=50: 50, Wave Length: 254 nm). [00832] tert-butyl 4-{[(6R)-2-acetyl-6-[4-(methoxycarbonyl)-2-(methylamino)phenyl]-2,7- diazaspiro[3.5]nonan-7-yl]methyl}-5-methoxy-7-methylindole-1-carboxylate (isomer 2, slower peak) (90 mg, 27.47% yield, off-white solid). LCMS: (ESI, m/z): 605.3 [M+H]⁺. tR = 1.58 min (CHIRALPAK IA, 2*25 cm, 5 μm, Hex(0.1%DEA): EtOH=50: 50, Wave Length: 254 nm). [00833] Step 9: 4-[(6S)-2-Acetyl-7-[(5-methoxy-7-methyl-1H-indol-4-yl)methyl]-2,7- diazaspiro[3.5]nonan-6-yl]-3-(methylamino)benzoic acid & 4-[(6S)-2-acetyl-7-[(5-methoxy-7-methyl-1H- indol-4-yl)methyl]-2,7-diazaspiro[3.5]nonan-6-yl]-3-(methylamino)benzoic acid [00834] A sol

lamino)phenyl]-2,7- diazaspiro[3.5]nonan-7-yl]methyl}-5-methoxy-7-methylindole-1-carboxylate (isomer 1, faster peak, 50 mg, 0.083 mmol) in Phosphate Buffer solution (PH7.2-7.4) (2 mL) was treated with Pig liver enzyme (100 mg) at 35 °C for 5 days. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with water. The resulting mixture was extracted with Ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by C18 silica gel column chromatography, eluted with Acetonitrile/water(Ammonium bicarbonate) (1:4) to afford 4-[(6S)-2-acetyl-7-[(5-methoxy-7-methyl-1H- indol-4-yl)methyl]-2,7-diazaspiro[3.5]nonan-6-yl]-3-(methylamino)benzoic acid (19.9 mg, 49.06% yield) as an off-white solid. LCMS: (ESI, m/z): 491.2 [M+H]⁺.¹H NMR (300 MHz, DMSO-d6) δ 10.89 (s, 1H), 7.29 (s, 1H), 7.22 (s, 2H), 7.13 (s, 1H), 6.92 (s, 1H), 6.68 (s, 1H), 6.23 (d, J = 2.9 Hz, 1H), 4.19 – 3.84 (m, 1H), 3.84 – 3.63 (m, 6H), 3.60 (d, J = 9.4 Hz, 1H), 3.43 (s, 1H), 3.26 – 3.14 (m, 2H), 2.79 (d, J = 4.0 Hz, 3H), 2.68 (d, J = 6.0 Hz, 1H), 2.43 (s, 3H), 1.91 (s, 1H), 1.77 (s, 2H), 1.71 (s, 3H), 1.53 (s, 1H). [00835] A solution of tert-butyl 4-{[(6R)-2-acetyl-6-[4-(methoxycarbonyl)-2-(methylamino)phenyl]-2,7- diazaspiro[3.5]nonan-7-yl]methyl}-5-methoxy-7-methylindole-1-carboxylate (isomer 2, slower peak, 50 mg, 0.083 mmol, 1 equiv) in Phosphate Buffer solution (pH 7.2-7.4) (2 mL) was treated with Pig liver enzyme (100 mg) at 35 °C for 5 days. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with water. The resulting mixture was extracted with Ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by C18 silica gel column chromatography, eluted with Acetonitrile/water(Ammonium bicarbonate) (1:4) to afford 4-[(6R)-2-acetyl-7-[(5-methoxy-7- methyl-1H-indol-4-yl)methyl]-2,7-diazaspiro[3.5]nonan-6-yl]-3-(methylamino)benzoic acid (10.9 mg, 26.87% yield) as an off-white solid. LCMS: (ESI, m/z): 491.2 [M+H]⁺.¹H NMR (300 MHz, DMSO-d6) δ 10.89 (s, 1H), 7.36 – 7.17 (m, 3H), 7.13 (s, 1H), 6.93 (s, 1H), 6.68 (s, 1H), 6.23 (s, 1H), 4.14 – 3.86 (m, 1H), 3.85 – 3.53 (m, 6H), 3.44 (s, 1H), 3.25 – 3.12 (m, 1H), 2.79 (d, J = 4.2 Hz, 3H), 2.69 (d, J = 11.8 Hz, 1H), 2.43 (s, 4H), 1.91 (s, 1H), 1.77 (d, J = 4.2 Hz, 2H), 1.71 (s, 3H), 1.53 (s, 1H), 1.24 (s, 1H). [00836] Example 39.4-[(6S)-2,2-Difluoro-7-[(5-methoxy-7-methyl-1H-indol-4-yl)methyl]-7- azaspiro[3.5]nonan-6-yl]-3-(oxetan-3-ylamino)benzoic acid & 4-[(6R)-2,2-difluoro-7-[(5-methoxy-7-methyl- 1H-indol-4-yl)methyl]-7-azaspiro[3.5]nonan-6-yl]-3-(oxetan-3-ylamino)benzoic acid. [00837] Proced

[00838] henyl]-7-

azaspiro[3.5]nonan-7-yl}methyl)-5-methoxy-7-methylindole-1-carboxylate [00839] A mixture of tert-butyl 4-

onyl)phenyl]-2,2-difluoro-7- azaspiro[3.5]nonan-7-yl}methyl)-5-methoxy-7-methylindole-1-carboxylate (300 mg, 0.51 mmol, 1 equiv) and 3-oxetanone (740 mg, 10.27 mmol, 19.98 equiv) and Sodium cyanoborohydride (90 mg, 1.43 mmol, 2.79 equiv) in Tetrahydrofuran (1.5 mL) and Acetic acid (1.5 mL) was stirred at room temperature for 1h. The resulting mixture was diluted with water. The resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with Petroleum ether/Ethyl acetate (5:1) to afford tert-butyl 4-({2,2-difluoro-6-[4- (methoxycarbonyl)-2-(oxetan-3-ylamino)phenyl]-7-azaspiro[3.5]nonan-7-yl}methyl)-5-methoxy-7- methylindole-1-carboxylate (110 mg) as a yellow oil. LCMS (ESI, m/z): [M+H]⁺ = 640.7 [00840] Step 2: tert-Butyl 4-{[(6R)-2,2-difluoro-6-[4-(methoxycarbonyl)-2-(oxetan-3-ylamino)phenyl]-7- azaspiro[3.5]nonan-7-yl]methyl}-5-methoxy-7-methylindole-1-carboxylate (isomer 1, faster peak) & tert- Butyl 4-{[(6S)-2,2-difluoro-6-[4-(methoxycarbonyl)-2-(oxetan-3-ylamino)phenyl]-7-azaspiro[3.5]nonan-7- yl]methyl}-5-methoxy-7-methylindole-1-carboxylate (isomer 2, slower peak) [00841] tert-buty o)phenyl]-7-

azaspiro[3.5]nonan-7-yl}methyl)-5-methoxy-7-methylindole-1-carboxylate (80 mg 0.12 mmol) was applied for further separation by Chiral HPLC with the following condition: Column: CHIRALPAK IA, 2*25 cm, 5 μm; Mobile Phase A: HEX(0.5% 2M NH3-Methanol), Mobile Phase B: IPA; Flow rate: 20 mL/min; Gradient: isocratic 5; Wave Length: 220/254 nm; RT1(min): 9.415; RT2(min): 11.725; Sample Solvent: Ethanol; Injection Volume: 0.5 mL; Number Of Runs: 16. [00842] tert-butyl 4-{[(6S)-2,2-difluoro-6-[4-(methoxycarbonyl)-2-(oxetan-3-ylamino)phenyl]-7- azaspiro[3.5]nonan-7-yl]methyl}-5-methoxy-7-methylindole-1-carboxylate (isomer 1, faster peak,40 mg,36.3% yield) as a white solid. LCMS (ESI, m/z): [M+H]+ = 640.7. tR = 1.53 min (CHIRALPA KI, A-3, 4.6*50mm3um, HEX(0.1%DEA): IPA=90: 10, 1.0mL/min) [00843] tert-butyl 4-{[(6R)-2,2-difluoro-6-[4-(methoxycarbonyl)-2-(oxetan-3-ylamino)phenyl]-7- azaspiro[3.5]nonan-7-yl]methyl}-5-methoxy-7-methylindole-1-carboxylate (isomer 2, slower peak,40 mg,36.3% yield) as a white solid. LCMS (ESI, m/z): [M+H]+ = 640.7. tR = 1.93 min (CHIRALPA KI, A-3, 4.6*50mm3um, HEX(0.1%DEA): IPA=90: 10, 1.0mL/min). [00844] Step 3: 4-[(6S)-2,2-Difluoro-7-[(5-methoxy-7-methyl-1H-indol-4-yl)methyl]-7- azaspiro[3.5]nonan-6-yl]-3-(oxetan-3-ylamino)benzoic acid & 4-[(6R)-2,2-difluoro-7-[(5-methoxy-7-methyl- 1H-indol-4-yl)methyl]-7-azaspiro[3.5]nonan-6-yl]-3-(oxetan-3-ylamino)benzoic acid [00845] A mixtu

y , y y xetan-3- ylamino)phenyl]-7-azaspiro[3.5]nonan-7-yl]methyl}-5-methoxy-7-methylindole-1-carboxylate (40 mg, 0.063 mmol, 1 equiv) and Potassium hydroxide (35 mg, 0.624 mmol, 9.98 equiv) in Ethanol (0.9 mL) and water (0.3 mL) was stirred at 80 °C for 2 h. The mixture was acidified to pH = 6 with sat. citric acid. The solvent was removed .The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in Water (10mmol/L Ammonium bicarbonate), 10% to 50% gradient in 10 min; detector, UV 254 nm.to afford 4-[(6S)-2,2-difluoro-7-[(5-methoxy-7-methyl- 1H-indol-4-yl)methyl]-7-azaspiro[3.5]nonan-6-yl]-3-(oxetan-3-ylamino)benzoic acid (20.5 mg, 62.38% yield) as a white solid. LCMS (ESI, m/z): [M+H]⁺=526.2.¹H NMR (300 MHz, DMSO-d6) δ 12.69 (s, 1H), 10.89 (s, 1H), 7.52 (s, 1H), 7.37 – 7.19 (m, 3H), 6.75 (s, 1H), 6.67 (s, 1H), 6.25 (s, 1H), 4.96 – 4.80 (m, 2H), 4.56 (s, 1H), 4.48 – 4.25 (m, 2H), 3.74 – 3.65 (m, 4H), 3.30 (s, 1H), 3.26 (s, 1H), 2.70 (d, J = 12.7 Hz, 2H), 2.48 – 2.37 (m, 5H), 2.33 (d, J = 11.2 Hz, 2H), 1.99 (s, 1H), 1.66 – 1.49 (m, 3H). [00846] A mixture of tert-butyl 4-{[(6R)-2,2-difluoro-6-[4-(methoxycarbonyl)-2-(oxetan-3- ylamino)phenyl]-7-azaspiro[3.5]nonan-7-yl]methyl}-5-methoxy-7-methylindole-1-carboxylate (40 mg, 0.063 mmol, 1 equiv) and Potassium hydroxide (35 mg, 0.62 mmol, 9.98 equiv) in Ethanol (0.9 mL) and water (0.3 mL) was stirred at 80 °C for 2 h. The mixture was acidified to pH = 6 with sat. citric acid. The solvent was removed. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in Water (10mmol/L Ammonium bicarbonate), 10% to 50% gradient in 10 min; detector, UV 254 nm.to afford 4-[(6R)-2,2-difluoro-7-[(5-methoxy-7-methyl-1H- indol-4-yl)methyl]-7-azaspiro[3.5]nonan-6-yl]-3-(oxetan-3-ylamino)benzoic acid (18.3 mg, 55.7% yield) as a white solid. LCMS (ESI, m/z): [M+H]⁺ = 526.2.¹H NMR (300 MHz, DMSO-d6) δ 12.69 (s, 1H), 10.89 (s, 1H), 7.64 – 7.45 (m, 1H), 7.33 – 7.25 (m, 3H), 6.76 (s, 1H), 6.67 (s, 1H), 6.25 (s, 1H), 4.96 – 4.80 (m, 2H), 4.56 (s, 1H), 4.45 – 4.34 (m, 2H), 3.71 – 3.60 (m, 4H), 3.31 – 3.24 (m, 2H), 2.75 – 2.65 (m, 2H), 2.45 – 2.26 (m, 7H), 1.99 (s, 1H), 1.67 – 1.50 (m, 3H). [00847] Example 40.5-[(6R)-2,2-Difluoro-7-[(5-methoxy-7-methyl-1H-indol-4-yl)methyl]-7- azaspiro[3.5]nonan-6-yl]-4-(methylamino)pyrimidine-2-carboxylic acid & 5-[(6S)-2,2-difluoro-7-[(5- methoxy-7-methyl-1H-indol-4-yl)methyl]-7-azaspiro[3.5]nonan-6-yl]-4-(methylamino)pyrimidine-2- carboxylic acid. [00848] Procedur

[

[00850] A mixture of 5-bromo-2,4-dichlor

1000 mg, 4.39 mmol, 1 equiv) and methylamine hydrochloride (888.93 mg, 13.16 mmol, 3 equiv) and Potassium carbonate (2426.03 mg, 17.55 mmol, 4 equiv) in methanol (12 mL) was stirred at room temperature for 1 h. The resulting mixture was diluted with water. The resulting mixture was extracted with Ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with Petroleum ether/Ethyl acetate (5:1) to afford 5-bromo-2-chloro-N-methylpyrimidin-4-amine (700 mg, 71.70% yield) as a white solid. LCMS (ESI, m/z): [M+H]⁺ = 222.1 [00851] Step 2: 5-Bromo-4-(methylamino)pyrimidine-2-carbonitrile [00852] A mixture of 5-bromo-2-chloro- din-4-amine (500 mg, 2.25 mmol, 1 equiv) and tetraethylammonium cyanide (421.47 mg, 2.7

0 mmol, 1.2 equiv) and 1,4-diazabicyclo[2.2.2]octane hexahydrate (594.06 mg, 2.70 mmol, 1.2 equiv) in Acetonitrile (10 mL) was stirred at 50 °C for 12 h . The resulting mixture was diluted with water. The resulting mixture was extracted with Ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with Petroleum ether/Ethyl acetate (1:1) to afford 5-bromo-4- (methylamino)pyrimidine-2-carbonitrile (300 mg, 62.66% yield) as a white solid. LCMS (ESI, m/z): [M+H]⁺ = 213.1 [00853] Step 3: Methyl 5-bromo-4-(methylamino)pyrimidine-2-carboxylate [00854] Into a 20 mL vial were added 5

mino)pyrimidine-2-carbonitrile (400 mg, 1.88 mmol, 1 equiv) and hydrogen chloride(4.0 M in methanol) (4 mL) was stirred at 30 °C for 5 h. The resulting mixture was diluted with water. The resulting mixture was extracted with Ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The crude product was used in the next step directly without further purification. LCMS (ESI, m/z): [M+H]⁺ = 246.1 [00855] Step 4: Methyl 4-(methylamino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine-2- carboxylate [00856] A mixture of methyl 5-brom

idine-2-carboxylate (100 mg, 0.41 mmol, 1 equiv) and 4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (206.40 mg, 0.812 mmol, 2 equiv) and [1,1’-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (59.47 mg, 0.081 mmol, 0.2 equiv) and Potassium Acetate (79.77 mg, 0.81 mmol, 2 equiv) in 1,4-dioxane (5 mL) was stirred at 100 °C for 6 h . The resulting mixture was diluted with water. The resulting mixture was extracted with Ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The resulting mixture was used in the next step directly without further purification. LCMS (ESI, m/z): [M+H]⁺ = 293.2 [00857] Step 5: tert-Butyl 2,2-difluoro-6-[2-(methoxycarbonyl)-4-(methylamino)pyrimidin-5-yl]-7- azaspiro[3.5]non-5-ene-7-carboxylate [00858] A mixture of methyl 4-(m ethyl-1,3,2-dioxaborolan-2-

yl)pyrimidine-2-carboxylate (150 mg, 0.51 mmol, 2 equiv), tert-butyl 2,2-difluoro-6- (trifluoromethanesulfonyloxy)-7-azaspiro[3.5]non-5-ene-7-carboxylate (104.22 mg, 0.26 mmol, 1 equiv), Tris(dibenzylideneacetone)dipalladium (46.86 mg, 0.051 mmol, 0.2 equiv), KF (29.73 mg, 0.51 mmol, 2 equiv) and Tri-tert-butylphosphine tetrafluoroborate (7.42 mg, 0.026 mmol, 0.1 equiv) in 1,4-dioxane (0.8 mL) and water (0.2 mL) was stirred at 90 °C for 1h . The resulting mixture was diluted with water. The resulting mixture was extracted with Ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with Petroleum ether/Ethyl acetate (1:1) to afford tert-butyl 2,2-difluoro-6-[2-(methoxycarbonyl)-4-(methylamino)pyrimidin-5-yl]-7- azaspiro[3.5]non-5-ene-7-carboxylate (20 mg, 18.42% yield) as a yellow solid. LCMS (ESI, m/z): [M+H]⁺ = 424.2 [00859] Step 6: Methyl 5-{2,2-difluoro-7-azaspiro[3.5]nonan-6-yl}-4-(methylamino)pyrimidine-2- carboxylate [00860] A solution of tert-butyl 2,

onyl)-4-(methylamino)pyrimidin-5-yl]-7- azaspiro[3.5]non-5-ene-7-carboxylate (500 mg, 1.18 mmol, 1 equiv) and Sodium cyanoborohydride (740.25 mg, 11.78 mmol, 10 equiv) in Dichloromethane (3 mL) was stirred at 0 °C for 1 h. The resulting mixture was diluted with water. The resulting mixture was extracted with Ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in Water (10mmol/L Ammonium bicarbonate), 10% to 50% gradient in 10 min; detector, UV 254 nm.to afford methyl 5-{2,2-difluoro-7-azaspiro[3.5]nonan- 6-yl}-4-(methylamino)pyrimidine-2-carboxylate (330 mg, 85.84% yield) as a yellow solid. LCMS (ESI, m/z): [M+H]⁺ = 326.2 [00861] Step 7: tert-Butyl 4-({2,2-difluoro-6-[2-(methoxycarbonyl)-4-(methylamino)pyrimidin-5-yl]-7- azaspiro[3.5]nonan-7-yl}methyl)-5-methoxy-7-methylindole-1-carboxylate [00862] A solution of methyl 5-{2 nan-6-yl}-4-(methylamino)pyrimidine-2-

carboxylate (300 mg, 0.92 mmol, 1 equiv), tert-butyl 4-(chloromethyl)-5-methoxy-7-methylindole-1- carboxylate (569.56 mg, 1.84 mmol, 2 equiv), Cesium carbonate (898.54 mg, 2.76 mmol, 3 equiv), Potassium iodide (228.90 mg, 1.38 mmol, 1.5 equiv) in DMF (3 mL) was stirred at 50 °C for 2 h . The resulting mixture was diluted with water. The resulting mixture was extracted with Ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in Water (10 mmol/L Ammonium bicarbonate), 10% to 50% gradient in 10 min; detector, UV 254 nm.to afford tert-butyl 4-({2,2-difluoro-6-[2- (methoxycarbonyl)-4-(methylamino)pyrimidin-5-yl]-7-azaspiro[3.5]nonan-7-yl}methyl)-5-methoxy-7- methylindole-1-carboxylate (110 mg, 19.95% yield,) as a white solid. LCMS (ESI, m/z): [M+H]⁺ = 599.7. [00863] Step 8: tert-Butyl 4-{[(6R)-2,2-difluoro-6-[2-(methoxycarbonyl)-4-(methylamino)pyrimidin-5- yl]-7-azaspiro[3.5]nonan-7-yl]methyl}-5-methoxy-7-methylindole-1-carboxylate & tert-butyl 4-{[(6S)-2,2- difluoro-6-[2-(methoxycarbonyl)-4-(methylamino)pyrimidin-5-yl]-7-azaspiro[3.5]nonan-7-yl]methyl}-5- methoxy-7-methylindole-1-carboxylate [00864] tert-butyl 4

, yrimidin-5-yl]-7- azaspiro[3.5]nonan-7-yl}methyl)-5-methoxy-7-methylindole-1-carboxylate was applied for further separation by Chiral HPLC with the following condition: Column: Enantiocel C9, 3*25 cm, 10 μm; Mobile Phase A: HEX(0.5% 2M NH3-Methanol), Mobile Phase B: ETOH; Flow rate: 20 mL/min; Gradient: isocratic 40; Wave Length: 220/254 nm; RT1(min): 7.089; RT2(min): 21.67; Sample Solvent: Ethanol. [00865] tert-Butyl 4-{[(6R)-2,2-difluoro-6-[2-(methoxycarbonyl)-4-(methylamino)pyrimidin-5-yl]-7- azaspiro[3.5]nonan-7-yl]methyl}-5-methoxy-7-methylindole-1-carboxylate(isomer 1, faster peak, 40 mg, 40% yield) LCMS: (ESI, m/z): 599.7 [M+H]⁺. t_R = 1.357 min (Enantiocel C9‐3, 4.6*50 mm 3 μm, HEX(0.1%DEA):Ethanol=60:40, 1.0 mL/min, 254 nm). [00866] tert-Butyl 4-{[(6S)-2,2-difluoro-6-[2-(methoxycarbonyl)-4-(methylamino)pyrimidin-5-yl]-7- azaspiro[3.5]nonan-7-yl]methyl}-5-methoxy-7-methylindole-1-carboxylate (isomer 2, slower peak, 35 mg, 35% yield) LCMS: (ESI, m/z): 599.7 [M+H]⁺. tR = 4.177 min (Enantiocel C9‐3, 4.6*50 mm 3 μm, HEX(0.1%DEA):Ethanol=60:40, 1.0 mL/min, 254 nm). [00867] Step 9: 5-[(6R)-2,2-Difluoro-7-[(5-methoxy-7-methyl-1H-indol-4-yl)methyl]-7- azaspiro[3.5]nonan-6-yl]-4-(methylamino)pyrimidine-2-carboxylic acid & 5-[(6S)-2,2-difluoro-7-[(5- methoxy-7-methyl-1H-indol-4-yl)methyl]-7-azaspiro[3.5]nonan-6-yl]-4-(methylamino)pyrimidine-2- carboxylic acid [00868] A solutio

hylamino)pyrimidin-5- yl]-7-azaspiro[3.5]nonan-7-yl}methyl)-5-methoxy-7-methylindole-1-carboxylate (35 mg, 0.058 mmol, 1 equiv) and Potassium hydroxide (32.75 mg, 0.58 mmol, 10 equiv) in Ethanol (0.9 mL) and water (0.3 mL) was stirred at 80 °C for 2 h . The mixture was acidified to pH = 6 with sat. citric acid. The solvent was removed. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in Water (10mmol/L Ammonium bicarbonate), 10% to 50% gradient in 10 min; detector, UV 254 nm.This resulted in 5-[(6R)-2,2-difluoro-7-[(5-methoxy-7-methyl- 1H-indol-4-yl)methyl]-7-azaspiro[3.5]nonan-6-yl]-4-(methylamino)pyrimidine-2-carboxylic acid (22.8 mg, 80.46% yield) as a white solid. LCMS (ESI, m/z): [M+H]⁺ = 567.7.¹H NMR (500 MHz, DMSO-d6) δ 10.89 (s, 1H), 8.17 – 7.92 (m, 2H), 7.32 – 7.27 (m, 1H), 6.65 (s, 1H), 6.33 – 6.29 (m, 1H), 3.69 (s, 4H), 3.26 (s, 2H), 2.93 – 2.86 (m, 3H), 2.75 – 2.64 (m, 3H), 2.42 (s, 4H), 2.36 – 2.27 (m, 2H), 2.03 (s, 1H), 1.65 – 1.49 (m, 3H). [00869] A solution of tert-butyl 4-({2,2-difluoro-6-[2-(methoxycarbonyl)-4-(methylamino)pyrimidin-5- yl]-7-azaspiro[3.5]nonan-7-yl}methyl)-5-methoxy-7-methylindole-1-carboxylate (35 mg, 0.058 mmol, 1 equiv) and Potassium hydroxide (32.75 mg, 0.580 mmol, 10 equiv) in Ethanol (0.9 mL) and water (0.3 mL) was stirred at 80 °C for 2 h . The mixture was acidified to pH = 6 with sat. citric acid. The solvent was removed. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in Water (10mmol/L Ammonium bicarbonate), 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in 5-[(6S)-2,2-difluoro-7-[(5-methoxy-7-methyl- 1H-indol-4-yl)methyl]-7-azaspiro[3.5]nonan-6-yl]-4-(methylamino)pyrimidine-2-carboxylic acid (17.3 mg, 61.05% yield) as a white solid. LCMS (ESI, m/z): [M+H]⁺ = 567.7.¹H NMR (500 MHz, DMSO-d6) δ 10.89 (s, 1H), 8.18 – 7.91 (m, 2H), 7.32 – 7.27 (m, 1H), 6.65 (s, 1H), 6.33 – 6.29 (m, 1H), 3.69 (s, 4H), 3.28 (s, 2H), 2.93 – 2.88 (m, 3H), 2.76 – 2.64 (m, 2H), 2.42 (s, 4H), 2.36 – 2.27 (m, 2H), 2.03 (s, 2H), 1.68 – 1.49 (m, 3H). [00870] Example 41.7-{2,2-Difluoro-7-[(5-methoxy-7-methyl-1H-indol-4-yl)methyl]-7- azaspiro[3.5]nonan-6-yl}-1H-indazole-4-carboxylic acid.

ate

bis(pinacolato)diboron (3.11 g, 12.26 mmol, 3.00 equiv), [1,1’- Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.30 g, 0.41 mmol, 0.10 equiv) and Potassium Acetate (0.80 g, 8.18 mmol, 2.00 equiv) in 1,4-dioxane (15 mL) was stirred at 100 °C for 1h under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was filtered, the filter cake was washed with ethyl acetate (3 × 10 mL). The filtrate was concentrated under reduced pressure to afford ethyl 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole-4-carboxylate (5 g crude) as a brown solid. The crude product was used in the next step directly without further purification. LCMS: (ESI, m/z): 317.1 [M+H]⁺. [00874] Step 2: Ethyl 7-[7-(tert-butoxycarbonyl)-2,2-difluoro-7-azaspiro[3.5]non-5-en-6-yl]-1H-indazole- 4-carboxylate [00875] A solution of ethyl 7-(4,

, , , , olan-2-yl)-1H-indazole-4-carboxylate (1.3 g, 4.11 mmol, 1 equiv), tert-butyl 2,2-difluoro-6-(trifluoromethanesulfonyloxy)-7-azaspiro[3.5]non-5- ene-7-carboxylate (1.84 g, 4.52 mmol, 1.1 equiv), Tri-tert-butylphosphine tetrafluoroborate (0.24 g, 0.82 mmol, 0.2 equiv), Tris(dibenzylideneacetone)dipalladium (0.38 g, 0.41 mmol, 0.10 equiv) and Potassium Acetate (0.81 g, 8.22 mmol, 2.00 equiv) in 1,4-dioxane (22 mL)and water (4.4 mL) was stirred at 100 °C for 1h under nitrogen atmosphere. The resulting mixture was extracted with Ethyl acetate. The combined organic layers were washed with water, dried over anhydrous Sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by C18 silica gel column chromatography, eluted with Acetonitrile/water (1:1) to afford ethyl 7-[7-(tert-butoxycarbonyl)-2,2-difluoro-7- azaspiro[3.5]non-5-en-6-yl]-1H-indazole-4-carboxylate (900 mg, 43.56% yield) as a light brown solid. LCMS: (ESI, m/z): 448.3 [M+H]⁺. [00876] Step 3: Ethyl 7-[7-(tert-butoxycarbonyl)-2,2-difluoro-7-azaspiro[3.5]nonan-6-yl]-1H-indazole-4- carboxylate [00877] A solution of ethyl 7-[7- o-7-azaspiro[3.5]non-5-en-6-yl]-1H-

indazole-4-carboxylate (890 mg, 1.99 mmol, 1 equiv) and 10% Pd/C (800 mg) in Ethanol (20 mL) was stirred at room temperature for overnight under hydrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with Methanol (3 × 20 mL). The filtrate was concentrated under reduced pressure to afford ethyl 7-[7-(tert-butoxycarbonyl)-2,2-difluoro-7-azaspiro[3.5]nonan-6-yl]-1H-indazole-4-carboxylate (800 mg, 89.49% yield) as a light yellow solid. LCMS: (ESI, m/z): 450.3 [M+H]⁺. [00878] Step 4: Ethyl 7-[7-(tert-butoxycarbonyl)-2,2-difluoro-7-azaspiro[3.5]nonan-6-yl]-1-{[2- (trimethylsilyl) ethoxy]methyl}indazole-4-carboxylate [00879] A solution of ethyl 7-[7-

o-7-azaspiro[3.5]nonan-6-yl]-1H- indazole-4-carboxylate (320 mg, 0.71 mmol, 1 equiv) in Tetrahydrofuran (5 mL) was treated with NaH (34.17 mg, 1.42 mmol, 2 equiv) at 0 °C for 30 min. Then the [2-(chloromethoxy)ethyl]trimethylsilane (178.03 mg, 1.07 mmol, 1.5 equiv) was added and stirred at r.t. for 1 h. The reaction was quenched with sat. Ammonium chloride (aq.) at room temperature. The resulting mixture was extracted with Ethyl acetate. The combined organic layers were washed with water, dried over anhydrous Sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by C18 silica gel column chromatography, eluted with Acetonitrile/water (4:1) to afford ethyl 7-[7-(tert-butoxycarbonyl)-2,2-difluoro- 7-azaspiro[3.5]nonan-6-yl]-1-{[2-(trimethylsilyl) ethoxy]methyl}indazole-4-carboxylate (200 mg, 48.46% yield) as a light yellow solid. LCMS: (ESI, m/z): 580.4 [M+H]⁺. [00880] Step 5: Ethyl 7-{2,2-difluoro-7-azaspiro[3.5]nonan-6-yl}-1-{[2- (trimethylsilyl)ethoxy]methyl}indazole-4-carboxylate [00881] A solution of ethyl 7-[7- ro-7-azaspiro[3.5]nonan-6-yl]-1-{[2- (trimethylsilyl)ethoxy]methyl}indazo

le-4-carboxylate (320 mg, 0.55 mmol, 1 equiv) in toluene (6 mL) was treated with Silica gel (3.2 g) at 110 °C for 1.5 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with Dichloromethane/Methanol (10:1) to afford ethyl 7-{2,2-difluoro-7-azaspiro[3.5]nonan-6-yl}-1-{[2- (trimethylsilyl)ethoxy]methyl}indazole-4-carboxylate (150 mg, 56.66% yield) as a light yellow solid. LCMS: (ESI, m/z): 480.4 [M+H]⁺. [00882] Step 6: Ethyl 7-(7-{[1-(tert-butoxycarbonyl)-5-methoxy-7-methylindol-4-yl]methyl}-2,2- difluoro-7-azaspiro[3.5]nonan-6-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}indazole-4-carboxylate [00883] A solution of ethyl 7-{2,

-6-yl}-1-{[2- (trimethylsilyl)ethoxy]methyl}indazole-4-carboxylate (160 mg, 0.33 mmol, 1 equiv), tert-butyl 4- (chloromethyl)-5-methoxy-7-methylindole-1-carboxylate (206.68 mg, 0.67 mmol, 2 equiv), Potassium iodide (66.45 mg, 0.40 mmol, 1.2 equiv) in DMF (3 mL) was treated with Cesium carbonate (326.06 mg, 1.00 mmol, 3 equiv) at 50 °C for 1h. The mixture was allowed to cool down to room temperature. The reaction was quenched with sat. Ammonium chloride (aq.) at room temperature. The resulting mixture was extracted with Ethyl acetate. The combined organic layers were washed with water, dried over anhydrous Sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by C18 silica gel column chromatography, eluted with Acetonitrile/water (10:1) to afford ethyl 7-(7-{[1-(tert- butoxycarbonyl)-5-methoxy-7-methylindol-4-yl]methyl}-2,2-difluoro-7-azaspiro[3.5]nonan-6-yl)-1-{[2- (trimethylsilyl)ethoxy] methyl}indazole-4-carboxylate (130 mg, 51.75% yield) as a light yellow solid. LCMS: (ESI, m/z): 753.5 [M+H]⁺. [00884] Step 7: Ethyl 7-(7-{[1-(tert-butoxycarbonyl)-5-methoxy-7-methylindol-4-yl]methyl}-2,2- difluoro-7-azaspiro [3.5]nonan-6-yl)-1H-indazole-4-carboxylate [00885] A solution of ethyl 7-(7- hoxy-7-methylindol-4-yl]methyl}-2,2-

difluoro-7-azaspiro[3.5]nonan-6-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}indazole-4-carboxylate (100 mg, 0.13 mmol, 1 equiv) in Tetrahydrofuran (2 mL) was treated with Tetrabutylammonium fluoride (173.62 mg, 0.66 mmol, 5 equiv) at 60 °C for overnight. The mixture was allowed to cool down to room temperature. The reaction was quenched with water at room temperature. The resulting mixture was extracted with Ethyl acetate. The combined organic layers were washed with water, dried over anhydrous Sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by C18 silica gel column chromatography, eluted with Acetonitrile/water (4:1) to afford ethyl 7-(7-{[1-(tert-butoxycarbonyl)- 5-methoxy-7-methylindol-4-yl]methyl}-2,2-difluoro-7-azaspiro[3.5]nonan-6-yl)-1H-indazole-4-carboxylate (25 mg, 29.29% yield) as a yellow solid. LCMS: (ESI, m/z): 623.4 [M+H]⁺. [00886] Step 8: 7-{2,2-Difluoro-7-[(5-methoxy-7-methyl-1H-indol-4-yl)methyl]-7-azaspiro[3.5]nonan-6- yl}-1H-indazole-4-carboxylic acid [00887] A solution of ethyl 7-(7-{[

ethoxy-7-methylindol-4-yl]methyl}-2,2- difluoro-7-azaspiro[3.5]nonan-6-yl)-1H-indazole-4-carboxylate (25 mg, 0.04 mmol, 1 equiv) in Ethanol (1.5 mL) and water (0.5 mL) was treated with Potassium hydroxide (22.52 mg, 0.40 mmol, 10 equiv) at 80 °C for 2.5 h. The mixture was allowed to cool down to room temperature. The mixture was acidified to pH< 7 with sat. citric acid. The residue was purified by C18 silica gel column chromatography, eluted with Acetonitrile/water (Ammonium bicarbonate) (1:4) to afford 7-{2,2-difluoro-7-[(5-methoxy-7-methyl-1H- indol-4-yl)methyl]-7-azaspiro[3.5]nonan-6-yl}-1H-indazole-4-carboxylic acid (9.1 mg, 44.05% yield) as an off-white solid. LCMS: (ESI, m/z): 495.3 [M+H]⁺.¹H NMR (300 MHz, DMSO-d₆) δ 10.81 (d, J = 2.5 Hz, 1H), 8.45 (s, 1H), 8.04 – 7.58 (m, 2H), 7.21 (s, 1H), 6.62 (s, 1H), 6.30 (s, 1H), 3.74 (s, 1H), 3.68 – 3.46 (m, 5H), 3.30 – 3.05 (m, 3H), 2.79 – 2.59 (m, 1H), 2.39 (s, 3H), 2.29 (t, J = 13.0 Hz, 2H), 2.15 – 1.97 (m, 1H), 1.80 – 1.63 (m, 2H), 1.60 – 1.42 (m, 1H). [00888] Example 42.4-[(6R)-2,2-Difluoro-7-[(5-methoxy-7-methyl-1H-indol-4-yl)methyl]-7- azaspiro[3.5]nonan-6-yl]-3-acetamidobenzoic acid & 4-[(6S)-2,2-difluoro-7-[(5-methoxy-7-methyl-1H-indol- 4-yl)methyl]-7-azaspiro[3.5]nonan-6-yl]-3-acetamidobenzoic acid.

azaspiro[3.5]nonan-7-yl}methyl)-5-methoxy-7-methylindole-1-carboxylate. O O F F [00891] A mixture of tert-butyl 4-

y onyl)phenyl]-2,2-difluoro-7- azaspiro[3.5]nonan-7-yl}methyl)-5-methoxy-7-methylindole-1-carboxylate (150 mg, 0.26 mmol, 1 equiv) and acetic anhydride (26 mg, 0.26 mmol, 0.99 equiv) and Triethylamine (29 mg, 0.29 mmol, 1.12 equiv) in Dichloromethane (2 mL) was stirred at 0 °C for 1h. The reaction was quenched with sat. Ammonium chloride (aq.) at room temperature. The resulting mixture was extracted with Dichloromethane. The combined organic layers were washed with water, dried over anhydrous Sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in Water (10mmol/L Ammonium bicarbonate), 10% to 50% gradient in 10 min; detector, UV 254 nm. to afford tert-butyl 4-({6-[2-acetamido- 4-(methoxycarbonyl)phenyl]-2,2-difluoro-7-azaspiro[3.5]nonan-7-yl}methyl)-5-methoxy-7-methylindole-1- carboxylate (160 mg) as a yellow solid. LCMS (ESI, m/z): [M+H]⁺ = 626.7 [00892] Step 2: tert-Butyl 4-{[(6S)-6-[2-acetamido-4-(methoxycarbonyl)phenyl]-2,2-difluoro-7- azaspiro[3.5]nonan-7-yl]methyl}-5-methoxy-7-methylindole-1-carboxylate (isomer 1, faster peak) & tert- butyl 4-{[(6S)-6-[2-acetamido-4-(methoxycarbonyl)phenyl]-2,2-difluoro-7-azaspiro[3.5]nonan-7-yl]methyl}- 5-methoxy-7-methylindole-1-carboxylate (isomer 2, slower peak) [00893] tert-butyl 4-({6-[2-acetamido-4-(methoxycarbonyl)phenyl]-2,2-difluoro-7-azaspiro[3.5]nonan-7- yl}methyl)-5-methoxy-7-methylindole-1-carboxylate(160 mg, 0.25 mmol) for further separation by Chiral HPLC with the following condition: Column: UniChiral OD-5H, 2*25 cm, 5 μm; Mobile Phase A: HEX(0.5% 2M NH3-Methanol), Mobile Phase B: Ethanol; Flow rate: 20 mL/min; Gradient: isocratic 10; Wave Length: 220/254 nm; RT1(min): 7.676; RT2(min): 12.512; Sample Solvent: ETOH; Injection Volume: 0.7 mL; Number Of Runs: 10 [00894] tert-butyl 4-{[(6S)-6-[2-acetamido-4-(methoxycarbonyl)phenyl]-2,2-difluoro-7- azaspiro[3.5]nonan-7-yl]methyl}-5-methoxy-7-methylindole-1-carboxylate (isomer 1, faster peak, 60 mg, 37.5 yield) LCMS (ESI, m/z): [M+H]⁺ = 626.7. tR =2.18 min(CHIRALCELOD, Hex(0.1%DEA): Ethanol=90: 10, 1mL/min). [00895] tert-butyl 4-{[(6R)-6-[2-acetamido-4-(methoxycarbonyl)phenyl]-2,2-difluoro-7- azaspiro[3.5]nonan-7-yl]methyl}-5-methoxy-7-methylindole-1-carboxylate(isomer 2, slower peak, 60 mg, 37.5 yield) LCMS (ESI, m/z): [M+H]⁺ = 626.7. tR =2.18 min (CHIRALCELOD, Hex(0.1%DEA): Ethanol=90: 10, 1mL/min). [00896] Step 3: 4-[(6S)-2,2-Difluoro-7-[(5-methoxy-7-methyl-1H-indol-4-yl)methyl]-7- azaspiro[3.5]nonan-6-yl]-3-acetamidobenzoic acid & 4-[(6R)-2,2-difluoro-7-[(5-methoxy-7-methyl-1H-indol- 4-yl)methyl]-7-azaspiro[3.5]nonan-6-yl]-3-acetamidobenzoic acid [00897] A mixtur enyl]-2,2-difluoro-7-

azaspiro[3.5]nonan-7-yl]methyl}-5-methoxy-7-methylindole-1-carboxylate (isomer 1, faster peak, 60 mg, 0.096 mmol, 1 equiv) and Potassium hydroxide (54 mg, 0.96 mmol, 10.04 equiv) in Ethanol (1.5 mL) and water (0.5 mL) was stirred at 80 °C for 1 h . The mixture was acidified to pH< 7 with sat. citric acid. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in Water (10mmol/L Ammonium bicarbonate), 10% to 50% gradient in 10 min; detector, UV 254 nm.to afford 4-[(6S)-2,2-difluoro-7-[(5-methoxy-7-methyl-1H-indol-4-yl)methyl]- 7-azaspiro[3.5]nonan-6-yl]-3-acetamidobenzoic acid (39.4 mg, 80.32% yield) as a white solid. LCMS (ESI, m/z): [M+H]⁺ = 512.6.¹H NMR (300 MHz, DMSO-d6) δ 12.94 (s, 1H), 11.33 (s, 1H), 10.92 (s, 1H), 8.85 (s, 1H), 7.75 – 7.39 (m, 2H), 7.31 (s, 1H), 6.69 (s, 1H), 6.42 – 6.34 (m, 1H), 3.78 – 3.72 (m, 1H), 3.66 (s, 3H), 3.56 – 3.45 (m, 1H), 3.20 (d, J = 11.7 Hz, 1H), 2.80 – 2.60 (m, 2H), 2.48 – 2.39 (m, 4H), 2.39 – 2.15 (m, 2H), 2.14 – 2.02 (m, 2H), 2.00 – 1.87 (m, 3H), 1.72 – 1.50 (m, 3H). [00898] A mixture of tert-butyl 4-{[(6R)-6-[2-acetamido-4-(methoxycarbonyl)phenyl]-2,2-difluoro-7- azaspiro[3.5]nonan-7-yl]methyl}-5-methoxy-7-methylindole-1-carboxylate (isomer 2, slower peak, 55 mg, 60 mg, 0.096 mmol, 1 equiv) and Potassium hydroxide (54 mg, 0.96 mmol, 10.04 equiv) in Ethanol (1.5 mL) and water (0.5 mL) was stirred at 80 °C for 2 h. The mixture was acidified to pH< 7 with sat. citric acid. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in Water (10mmol/L Ammonium bicarbonate), 10% to 50% gradient in 10 min; detector, UV 254 nm. to afford 4-[(6R)-2,2-difluoro-7-[(5-methoxy-7-methyl-1H-indol-4-yl)methyl]- 7-azaspiro[3.5]nonan-6-yl]-3-acetamidobenzoic acid (38.9 mg, 79.30% yield) as a white solid. LCMS (ESI, m/z): [M+H]⁺=512.6.¹H NMR (300 MHz, DMSO-d6) δ 12.92 (s, 1H), 11.33 (s, 1H), 10.92 (s, 1H), 8.85 (s, 1H), 7.55 (d, J = 54.2 Hz, 2H), 7.31 (s, 1H), 6.69 (s, 1H), 6.42 – 6.34 (m, 1H), 3.75 (s, 1H), 3.66 (s, 3H), 3.51 (d, J = 11.9 Hz, 1H), 3.20 (d, J = 11.7 Hz, 1H), 2.80 – 2.61 (m, 2H), 2.48 – 2.39 (m, 4H), 2.41 – 2.26 (m, 2H), 2.02 (d, J = 27.9 Hz, 5H), 1.74 – 1.49 (m, 3H). [00899] Example 43.5-((6S)-2,2-Difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)-6-(3,3-difluoroazetidin-1-yl)pyridine-2-carboxylic acid & 5-((6R)-2,2-Difluoro-7- ((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)-6-(3,3-difluoroazetidin-1- yl)pyridine-2-carboxylic acid.

, [00902] A solution of methyl 5-brom rboxylate (1.00 g, 4.27 mmol), 3,3- difluoroazetidine (795 mg, 8.54 mmol) a

nd triethylamine (1.10 g, 10.87 mmol) in N, N-dimethylformamide (20 mL) was stirred at 60 °C for 4 hours. The reaction was quenched with water. The resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with petroleum ether/ethyl acetate (65:35) to afford the title compound (1.05 g, 80.02%) as a white solid. LCMS (ESI, m/z): [M+H] ⁺ =306.9. [00903] Step 2: Methyl 6-(3,3-difluoroazetidin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)pyridine-2-carboxylate [00904] A solution of methyl 5-brom

n-1-yl)pyridine-2-carboxylate (1.00 g, 3.26 mmol), bis(pinacolato)diboron (1.66 g, 6.52 mmol ), 1,1’-Bis(diphenylphosphino)ferrocene- palladium(II)dichloride dichloromethane complex (270 mg, 0.33 mmol) and potassium acetate (960 mg, 9.78 mmol) in 1,4-dioxane (15 mL) was stirred at 90 °C for 3 hours under nitrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with tetrahydrofuran. The filtrate was concentrated under reduced pressure. The crude product was used in the next step directly without further purification. LCMS (ESI, m/z): [M+H] ⁺ =355.0. [00905] Step 3: tert-Butyl 6-(2-(3,3-difluoroazetidin-1-yl)-6-(methoxycarbonyl)pyridin-3-yl)-2,2- difluoro-7-azaspiro[3.5]non-5-ene-7-carboxylate [00906] A solution of methyl 6-(3

, ,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)pyridine-2-carboxylate (1.00 g, 2.82 mmol), tert-butyl 2,2-difluoro-6-(trifluoromethanesulfonyloxy)-7- azaspiro[3.5]non-5-ene-7-carboxylate (1.11 g, 2.72 mmol), 1,1’-Bis(diphenylphosphino)ferrocene- palladium(II)dichloride dichloromethane complex (223 mg, 0.27 mmol) and sodium carbonate (870 mg, 8.21 mmol) in 1,4-dioxane (12 mL) and water (3 mL) was stirred at 90 °C for 3 hours under nitrogen atmosphere. The reaction mixture was quenched by water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with petroleum ether/ethyl acetate (90:10) to afford the title compound (1.06 g, 80.13%) as a white solid. LCMS (ESI, m/z): [M+H] ⁺ =486.1 [00907] Step 4: tert-Butyl 6-(2-(3,3-difluoroazetidin-1-yl)-6-(methoxycarbonyl)pyridin-3-yl)-2,2- difluoro-7-azaspiro[3.5]nonane-7-carboxylate [00908] A solution of tert-butyl 6- -6-(methoxycarbonyl) pyridin-3-yl)-2,2-

difluoro-7-azaspiro[3.5]non-5-ene-7-carboxylate (440 mg, 0.91 mmol) and 10% Pd/C (100 mg) in methanol (10 mL) was stirred at 50 °C for 6 hours under hydrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with ethyl acetate. The filtrate was concentrated under reduced pressure. The crude product was used in the next step directly without further purification. LCMS (ESI, m/z): [M+H] ⁺ = 488.1 [00909] Step 5: Methyl 5-(2,2-difluoro-7-azaspiro[3.5]nonan-6-yl)-6-(3,3-difluoroazetidin-1-yl)pyridine- 2-carboxylate [00910] A solution of tert-butyl 6

6-(methoxycarbonyl) pyridin-3-yl)-2,2- difluoro-7-azaspiro[3.5]nonane-7-carboxylate (420 mg, 0.86 mmol,) in dichloromethane (4 mL) and trifluoroacetic acid (2 mL) was stirred at room temperature for 3 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography (acetonitrile /10 mmol/L Ammonium bicarbonate in water) to afford the title compound (220 mg, 65.92%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ =388.1 [00911] Step 6: tert-Butyl 4-((6-(2-(3,3-difluoroazetidin-1-yl)-6-(methoxycarbonyl) pyridin-3-yl)-2,2- difluoro-7-azaspiro[3.5]nonan-7-yl)methyl)-5-methoxy-7-methylindole-1-carboxylate [00912] A solution of methyl 5-(2 an-6-yl)-6-(3,3-difluoroazetidin-1-

yl)pyridine-2-carboxylate (300 mg, 0.77 mmol), tert-butyl 4-formyl-5-methoxy-7-methylindole-1-carboxylate (290 mg, 1.00 mmol), triethylamine (1175 mg, 11.61 mmol) and sodium triacetoxyborohydride (490 mg, 2.31 mmol) in tetrahydrofuran (5 mL) was stirred at room temperature for 4 hours. The reaction was quenched with water. The resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with petroleum ether/ethyl acetate (90:10) to afford the title compound (380 mg, 93.45%) as a white solid. LCMS (ESI, m/z): [M+H] ⁺ =661.4. [00913] Step 7: tert-Butyl 4-(((6S)-6-(2-(3,3-difluoroazetidin-1-yl)-6-(methoxycarbonyl) pyridin-3-yl)- 2,2-difluoro-7-azaspiro[3.5]nonan-7-yl)methyl)-5-methoxy-7-methylindole-1-carboxylate & tert-Butyl 4- (((6S)-6-(2-(3,3-difluoroazetidin-1-yl)-6-(methoxycarbonyl) pyridin-3-yl)-2,2-difluoro-7-azaspiro[3.5]nonan- 7-yl)methyl)-5-methoxy-7-methylindole-1-carboxylate [00914] The crude product was further separated by Chiral HPLC with the following conditions: CHIRALPAK IA, 2*25 cm, 5 μm; Mobile Phase A: Hex(0.5% 2M NH3-Methanol)--HPLC, Mobile Phase B: Ethanol--HPLC; Flow rate: 20 mL/min; Gradient: isocratic 5; Wave Length: 220/254 nm; RT1(min): 5.428; RT2(min): 6.57; Sample Solvent: Ethanol. [00915] tert-Butyl 4-(((6S)-6-(2-(3,3-difluoroazetidin-1-yl)-6-(methoxycarbonyl) pyridin-3-yl)-2,2- difluoro-7-azaspiro[3.5]nonan-7-yl)methyl)-5-methoxy-7-methylindole-1-carboxylate (140 mg, 34.43% yield) as a white solid. LCMS (ESI, m/z): [M+H] ⁺ = 661.4. tR = 1.38 min (CHIRALPAK IA‐3, 4.6*50 mm, 3 μm, Hex(0.1%DEA): Ethanol = 95:5, 1.0 mL/min, 254 nm). [00916] tert-Butyl 4-(((6R)-6-(2-(3,3-difluoroazetidin-1-yl)-6-(methoxycarbonyl) pyridin-3-yl)-2,2- difluoro-7-azaspiro[3.5]nonan-7-yl)methyl)-5-methoxy-7-methylindole-1-carboxylate (185 mg, 36.15% yield) as a white solid. LCMS (ESI, m/z): [M+H] ⁺ = 661.4. tR = 1.68 min (CHIRALPAK IA‐3, 4.6*50 mm, 3 μm, Hex(0.1%DEA): Ethanol = 95:5, 1.0 mL/min, 254 nm). [00917] Step 8: 5-((6S)-2,2-Difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)-6-(3,3-difluoroazetidin-1-yl)pyridine-2-carboxylic acid & 5-((6R)-2,2-Difluoro-7- ((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)-6-(3,3-difluoroazetidin-1- yl)pyridine-2-carboxylic acid [00918] A soluti oxycarbonyl)pyridin-3-

yl)-2,2-difluoro-7-azaspiro[3.5]nonan-7-yl)methyl)-5-methoxy-7-methylindole-1-carboxylate (137 mg, 0.21 mmol) and potassium hydroxide (116 mg, 2.1 mmol) in ethanol (1.6 mL) and water (0.4 mL) was stirred at 80 °C for 3 hours. The mixture was neutralized to pH 7 with saturated citric acid aqueous solution. The residue was purified by reversed-phase flash chromatography to afford the title compound (82.3 mg, 72.62% yield) as an off-white solid. LCMS (ESI, m/z): [M+H] ⁺ =547.3.¹H NMR (400 MHz, DMSO-d6) δ 12.83 (s, 1H), 10.83 (s, 1H), 8.22 (d, J = 7.7 Hz, 1H), 7.70 (d, J = 7.7 Hz, 1H), 7.25 (t, J = 2.8 Hz, 1H), 6.64 (s, 1H), 6.38 (dd, J = 3.1, 1.9 Hz, 1H), 4.71 (q, J = 12.1 Hz, 2H), 4.56 (q, J = 12.0 Hz, 2H), 3.68 (s, 3H), 3.48 (d, J = 11.8 Hz, 1H), 3.24 (d, J = 11.3 Hz, 1H), 3.15 (d, J = 11.9 Hz, 1H), 2.69 (d, J = 12.0 Hz, 1H), 2.58 – 2.51 (m, 2H), 2.41 (s, 3H), 2.36 – 2.23 (m, 2H), 2.12 (t, J = 12.1 Hz, 1H), 1.84 (d, J = 13.3 Hz, 1H), 1.73 – 1.61 (m, 1H), 1.60 – 1.46 (m, 2H). [00919] A solution of tert-butyl 4-(((6R)-6-(2-(3,3-difluoroazetidin-1-yl)-6-(methoxycarbonyl)pyridin-3- yl)-2,2-difluoro-7-azaspiro[3.5]nonan-7-yl)methyl)-5-methoxy-7-methylindole-1-carboxylate (185 mg, 0.28 mmol) and potassium hydroxide (157 mg, 2.80 mmol) in ethanol (2.2 mL) and water (0.6 mL) was stirred at 80 °C for 3 hours. The mixture was neutralized to pH 7 with saturated citric acid aqueous solution. The residue was purified by reversed-phase flash chromatography to afford the title compound (86.6 mg, 56.59% yield) as an off-white solid. LCMS (ESI, m/z): [M+H] ⁺ =547.3.¹H NMR (500 MHz, DMSO-d₆) δ 12.82 (s, 1H), 10.82 (s, 1H), 8.22 (d, J = 7.7 Hz, 1H), 7.70 (d, J = 7.7 Hz, 1H), 7.25 (t, J = 2.8 Hz, 1H), 6.64 (s, 1H), 6.38 (t, J = 2.5 Hz, 1H), 4.71 (q, J = 12.8 Hz, 2H), 4.56 (q, J = 12.1 Hz, 2H), 3.68 (s, 3H), 3.48 (d, J = 11.9 Hz, 1H), 3.24 (d, J = 11.1 Hz, 1H), 3.15 (d, J = 11.9 Hz, 1H), 2.69 (d, J = 12.4 Hz, 1H), 2.57 – 2.51 (m, 2H), 2.41 (s, 3H), 2.35 – 2.25 (m, 2H), 2.16 – 2.07 (m, 1H), 1.84 (d, J = 13.3 Hz, 1H), 1.66 (t, J = 12.5 Hz, 1H), 1.59 – 1.48 (m, 2H). [00920] Example 44.4-[(6R)-2,2-Difluoro-7-[(5-methoxy-7-methyl-1H-indol-4-yl)methyl]-7- azaspiro[3.5]nonan-6-yl]-3-methanesulfonamidobenzoic acid & 4-[(6S)-2,2-difluoro-7-[(5-methoxy-7- methyl-1H-indol-4-yl)methyl]-7-azaspiro[3.5]nonan-6-yl]-3-methanesulfonamidobenzoic acid. [00921] Procedur

O O O O O O S O O S O O S NH O ₂ F NH NH NH F F [0

- azaspiro[3.5]nonan-7-yl}methyl)-5-methoxy-7-methylindole-1-carboxylate [00923] To a stirred solution of te

thoxycarbonyl)phenyl]-2,2-difluoro-7- azaspiro[3.5]nonan-7-yl}methyl)-5-methoxy-7-methylindole-1-carboxylate (150 mg, 0.26 mmol, 1 equiv) and pyridine (61 mg, 0.77 mmol, 3.00 equiv) in Dichloromethane (3 mL) was added methanesulfonic anhydride (54 mg, 0.31 mmol, 1.21 equiv) dropwise at 0 °C and stirred for 1 hour. The reaction was quenched with sat. Ammonium chloride (aq.) at room temperature. The resulting mixture was extracted with Dichloromethane. The combined organic layers were washed with water, dried over anhydrous Sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with Petroleum ether/Ethyl acetate (3:1) to afford tert-butyl 4-({2,2-difluoro-6-[2- methanesulfonamido-4-(methoxycarbonyl)phenyl]-7-azaspiro[3.5]nonan-7-yl}methyl)-5-methoxy-7- methylindole-1-carboxylate (150 mg, 88.20% yield) as a yellow solid. LCMS (ESI, m/z): [M+H]⁺ = 662.7. [00924] Step 2: tert-Butyl 4-{[(6R)-2,2-difluoro-6-[2-methanesulfonamido-4-(methoxycarbonyl)phenyl]- 7-azaspiro[3.5]nonan-7-yl]methyl}-5-methoxy-7-methylindole-1-carboxylate (isomer 1, faster peak) & tert- Butyl 4-{[(6S)-2,2-difluoro-6-[2-methanesulfonamido-4-(methoxycarbonyl)phenyl]-7-azaspiro[3.5]nonan-7- yl]methyl}-5-methoxy-7-methylindole-1-carboxylate (isomer 2, slower peak) [00925] tert-butyl

nyl)phenyl]-7- azaspiro[3.5]nonan-7-yl}methyl)-5-methoxy-7-methylindole-1-carboxylate(140 mg, 0.21 mmol) was applied for further separation by Chiral HPLC with the following condition: Column: CHIRALPAK IH, 2*25 cm, 5 μm; Mobile Phase A: Hex(0.5% 2M NH₃-Methanol)--HPLC, Mobile Phase B: Ethanol--HPLC; Flow rate: 20 mL/min; Gradient: isocratic 30; Wave Length: 220/254 nm; RT1(min): 5.97; RT2(min): 9; Sample Solvent: Ethanol; Injection Volume: 0.7 mL; Number Of Runs: 8. [00926] tert-butyl 4-{[(6R)-2,2-difluoro-6-[2-methanesulfonamido-4-(methoxycarbonyl)phenyl]-7- azaspiro[3.5]nonan-7-yl]methyl}-5-methoxy-7-methylindole-1-carboxylate (isomer 1, faster peak, 65 mg, 46.4% yield) as a white solid. LCMS(ESI, m/z): [M+H]⁺=662.7. tR=1.31 min (CHIRALPAK IH, Hex(0.1%DEA): Ethanol=70: 30, 1 mL/min). [00927] tert-butyl 4-{[(6S)-2,2-difluoro-6-[2-methanesulfonamido-4-(methoxycarbonyl)phenyl]-7- azaspiro[3.5]nonan-7-yl]methyl}-5-methoxy-7-methylindole-1-carboxylate (isomer 2, slower peak, 65 mg, 46.4% yield) as a white solid. LCMS (ESI, m/z): [M+H]⁺=662.7. tR=1.96 min (CHIRALPAK IH, Hex(0.1%DEA): Ethanol=70: 30, 1 mL/min). [00928] Step 3: 4-[(6R)-2,2-Difluoro-7-[(5-methoxy-7-methyl-1H-indol-4-yl)methyl]-7- azaspiro[3.5]nonan-6-yl]-3-methanesulfonamidobenzoic acid & 4-[(6S)-2,2-difluoro-7-[(5-methoxy-7- methyl-1H-indol-4-yl)methyl]-7-azaspiro[3.5]nonan-6-yl]-3-methanesulfonamidobenzoic acid [00929] A mixture -4-

(methoxycarbonyl)phenyl]-7-azaspiro[3.5]nonan-7-yl]methyl}-5-methoxy-7-methylindole-1-carboxylate (isomer 1, faster peak) (65 mg, 0.098 mmol, 1 equiv) and Potassium hydroxide (55 mg, 0.98 mmol, 9.98 equiv) in Ethanol (1.5 mL) and water (0.5 mL, 0.028 mmol, 0.28 equiv) was stirred at 80 °C for 2 h . The mixture was acidified to pH< 7 with sat. citric acid. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in Water (10mmol/L Ammonium bicarbonate), 10% to 50% gradient in 10 min; detector, UV 254 nm.to afford 4- [(6R)-2,2-difluoro-7-[(5-methoxy-7-methyl-1H-indol-4-yl)methyl]-7-azaspiro[3.5]nonan-6-yl]-3- methanesulfonamidobenzoic acid (40.7 mg, 75.67% yield) as a white solid. LCMS (ESI, m/z): [M+H]⁺ =548.1.¹H NMR (300 MHz, DMSO-d6) δ 11.01 (d, J = 57.4 Hz, 1H), 7.96 (s, 2H), 7.56 (d, J = 55.6 Hz, 1H), 7.28 (s, 1H), 6.68 (s, 1H), 6.41 (s, 1H), 3.99 – 3.38 (m, 6H), 3.27(s,1H), 3.15 (s, 3H), 2.80 – 2.58 (m, 2H), 2.43 (s, 3H), 2.40 – 2.28 (m, 2H), 2.14 – 1.95 (m, 2H), 1.73 (s, 1H), 1.55 (s, 2H). [00930] A mixture of tert-butyl 4-{[(6S)-2,2-difluoro-6-[2-methanesulfonamido-4- (methoxycarbonyl)phenyl]-7-azaspiro[3.5]nonan-7-yl]methyl}-5-methoxy-7-methylindole-1-carboxylate (isomer 2, slower peak) (65 mg, 0.098 mmol, 1 equiv) and Potassium hydroxide (55 mg, 0.98 mmol, 9.98 equiv) in Ethanol (1.5 mL) and water (0.5 mL) was stirred at 80 °C for 2h under air atmosphere. The mixture was acidified to pH< 7 with sat. citric acid. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in Water (10mmol/L Ammonium bicarbonate), 10% to 50% gradient in 10 min; detector, UV 254 nm.to afford 4-[(6S)-2,2- difluoro-7-[(5-methoxy-7-methyl-1H-indol-4-yl)methyl]-7-azaspiro[3.5]nonan-6-yl]-3- methanesulfonamidobenzoic acid (30.3 mg, 56.33% yield) as a white solid. LCMS (ESI, m/z): [M+H]⁺ =548.1.¹H NMR (300 MHz, DMSO-d6) δ 13.09 (s, 1H), 11.30 – 10.73 (m, 2H), 7.97 (s, 2H), 7.74 – 7.46 (m, 1H), 7.29 (s, 1H), 6.68 (s, 1H), 6.41 (s, 1H), 4.00 – 3.50 (m, 6H), 3.27(s,1H), 3.15 (s, 3H), 2.77 – 2.58 (m, 2H), 2.46 – 2.31 (m, 5H), 2.06 (s, 2H), 1.73 (s, 1H), 1.56 (s, 2H). [00931] Example 45.4-[(5S)-6-[(5-Methoxy-7-methyl-1H-indol-4-yl)methyl]-6-azaspiro[2.5]octan-5-yl]- 3-(methylamino)benzoic acid& 4-[(5R)-6-[(5-methoxy-7-methyl-1H-indol-4-yl)methyl]-6- azaspiro[2.5]octan-5-yl]-3-(methylamino)benzoic acid.

[00934] A solution of 6-azaspiro[2.5]octan

g, . mmol) in Dichloromethane (50 mL) was added with triethylamine (6.8 g, 67.20 mmol) and di-tert-butyl dicarbonate (10 g, 45.82 mmol) 0 °C. The resulting mixture was stirred for 3 h at room temperature. The resulting mixture was quenched with water and extracted with Ethyl acetate. The combined organic layers were dried over anhydrous Sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to afford the title compound (7 g crude) as a white solid. LCMS (ESI, m/z): [M+H]⁺ = 212.2. [00935] Step 2: tert-Butyl 5-oxo-6-azaspiro[2.5]octane-6-carboxylate. [00936] A mixture of tert-butyl 6-azaspiro carboxylate (6 g, 28.395 mmol) and Ruodium

(Ⅲ) chloride hydrate (1.2 g, 5.32 mmol) and Sodium periodate (12 g, 56.10 mmol) in water (30 mL) and Ethyl acetate (30 mL) was stirred for 1 h at 0 °C. The resulting mixture was extracted with Ethyl acetate. The combined organic layers were washed with water, dried over anhydrous Sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by reverse phase flash with the following conditions (column, C18 silica gel; mobile phase, Acetonitrile in Water (0.1% Ammonium hydroxide), 40% to 60% gradient in 10 min; detector, UV 254 nm) to afford the title compound (4.9 g, 76.60% yield) as a white oil. LCMS (ESI, m/z): [M+H]⁺ = 226.3. [00937] Step 3: tert-Butyl 5-(trifluoromethanesulfonyloxy)-6-azaspiro[2.5]oct-4-ene-6-carboxylate [00938] A solution of tert-butyl 5-oxo-6-

ane-6-carboxylate (4.3 g, 19.08 mmol) in Tetrahydrofuran (40 mL) was added with 1 M Potassium bis(trimethylsilyl)amide in Tetrahydrofuran (20 mL, 20 mmol) in 30 min at -78 °C under nitrogen atmosphere followed by the addition of 1,1,1-trifluoro-N- phenyl-N-(trifluoromethane)sulfonylmethanesulfonamide (10.30 g, 28.83 mmol) in portions at -78 °C. The reaction was quenched with sat. Ammonium chloride (aq.) at room temperature. The resulting mixture was extracted with Ethyl acetate. The combined organic layers were washed with water, dried over anhydrous Sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with Petroleum ether/Ethyl acetate (7:1) to afford the title compound (12 g crude) as a white solid. LCMS (ESI, m/z): [M+H]⁺ = 358.1. [00939] Step 4: tert-Butyl 5-(4-(methoxycarbonyl)-2-nitrophenyl)-6-azaspiro[2.5]oct-4-ene-6-carboxylate [00940] A mixture of tert-butyl 5-(tr

y xy)-6-azaspiro[2.5]oct-4-ene-6-carboxylate (2 g, 5.60 mmol), 4-(methoxycarbonyl)-2-nitrophenylboronic acid (2.53 g, 11.25 mmol), Tris(dibenzylideneacetone)dipalladium (512 mg, 0.56 mmol), Tri-tert-butylphosphine tetrafluoroborate (324 mg, 1.12 mmol) and Potassium fluoride (972 mg, 16.73 mmol) in Tetrahydrofuran (5 mL) and water (0.5 mL) was stirred for 1 h at 60 °C under nitrogen atmosphere. The resulting mixture was quenched with water and extracted with Ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in Water (0.1% Ammonium bicarbonate), 40% to 60% gradient in 10 min; detector, UV 254 nm to afford the title compound (1.12 g, 51.52%) as a yellow solid. LCMS (ESI, m/z): [M+H]⁺ =389.1. [00941] Step 5: tert-Butyl 5-(2-amino-4-(methoxycarbonyl)phenyl)-6-azaspiro[2.5]oct-4-ene-6- carboxylate [00942] A mixture of tert-butyl 5-(4 ophenyl)-6-azaspiro[2.5]oct-4-ene-6-

carboxylate (1.2 g, 3.08 mmol), Iron (560 mg, 0.072 mmol), and ammonium chloride (1.00 g, 18.63 mmol) in ethanol (5 mL) and water (5 mL) was stirred for 1 h at 80 °C under air atmosphere. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with Petroleum ether/Ethyl acetate (12:1) to afford the title compound (500 mg, 38.38%) as a yellow solid. LCMS (ESI, m/z): [M+H]⁺ = 359.4. [00943] Step 6: tert-Butyl 5-(4-(methoxycarbonyl)-2-(methylamino)phenyl)-6-azaspiro[2.5]oct-4-ene-6- carboxylate [00944] A mixture of tert-butyl 5-(2

yl)phenyl)-6-azaspiro[2.5]oct-4-ene-6- carboxylate (600 mg, 1.67 mmol), Paraformaldehyde (50 mg, 1.67 mmol) and Sodium cyanoborohydride (316 mg, 5.03 mmol) in methanol (9 mL) was stirred for 1 h at 70 °C under air atmosphere. The solvent was removed under vacuum. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in Water (0.1% Ammonium bicarbonate), 10% to 50% gradient in 10 min; detector, UV 254 nm. to afford the title compound (300 mg, 32.08% yield) as a yellow solid. LCMS (ESI, m/z): [M+H]⁺ = 373.4. [00945] Step 7: Methyl 3-(methylamino)-4-(6-azaspiro[2.5]octan-5-yl)benzoate [00946] A mixture of tert-butyl 5-(4 ethylamino)phenyl)-6-azaspiro[2.5]oct-4- ene-6-carboxylate (250 mg, 0.67 mmol)

and Sodium cyanoborohydride (423 mg, 6.73 mmol) in Trifluoroacetic acid (2 mL) and Dichloromethane (2 mL) was stirred for 1 h at room temperature under air atmosphere. The solvent was removed under vacuum. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in Water (0.1% Ammonium bicarbonate), 50% to 60% gradient in 10 min; detector, UV 254 nm. This resulted in the title compound (100 mg, 54.30%) as a yellow oil. LCMS (ESI, m/z): [M+H]⁺ = 275.4. [00947] Step 8: tert-Butyl 5-methoxy-4-((5-(4-(methoxycarbonyl)-2-(methylamino)phenyl)-6- azaspiro[2.5]octan-6-yl)methyl)-7-methyl-1H-indole-1-carboxylate [00948] A solution of tert-butyl 4-fo

l-1H-indole-1-carboxylate (100 mg, 0.33 mol), Methyl 3-(methylamino)-4-(6-azaspiro[2.5]octan-5-yl)benzoate (90 mg, 0.33 mmol) in 1,2- Dichloroethane (2 mL) was added acetic acid (25 mg, 0.42 mmol) and stirred for 2 h at 70 °C under air atmosphere, followed by the addition of sodium triacetoxyborohydride (208 mg, 9.82 mmol) in portions at room temperature. The resulting mixture was stirred for 12 h at 70 °C under air atmosphere. To the above mixture was added sodium borohydride (37 mg, 9.90 mmol) in portions over 1 min at room temperature. The resulting mixture was stirred for additional 1 h at 70 °C. The resulting mixture was quenched with water and extracted with Ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in Water (10mmol/L Ammonium bicarbonate), 10% to 50% gradient in 10 min; detector, UV 254 nm. to afford the title compound (200 mg, 55.55%) as a white solid. LCMS (ESI, m/z): [M+H]+ = 548.3. [00949] Step 9: tert-Butyl 5-methoxy-4-{[(5S)-5-[4-(methoxycarbonyl)-2-(methylamino)phenyl]-6- azaspiro[2.5]octan-6-yl]methyl}-7-methylindole-1-carboxylate & tert-Butyl 5-methoxy-4-{[(5R)-5-[4- (methoxycarbonyl)-2-(methylamino)phenyl]-6-azaspiro[2.5]octan-6-yl]methyl}-7-methylindole-1- carboxylate [00950] tert-butyl 5-me )phenyl)-6-azaspiro[2.5]octan-

6-yl)methyl)-7-methyl-1H-indole-1-carboxylate was applied for further separation by Chiral HPLC with the following condition: Column: CHIRALPAK IH 3*25 cm, 5 μm; Mobile Phase A: CO2, Mobile Phase B: IPA(0.1% 7M NH3-Methanol); Flow rate: 100 mL/min; Gradient: isocratic 13% B; RT1(min): 10; RT2(min): 13; Sample Solvent: MEOH; Injection Volume: 3 mL; Number Of Runs: 10. [00951] tert-Butyl 5-methoxy-4-{[(5S)-5-[4-(methoxycarbonyl)-2-(methylamino)phenyl]-6- azaspiro[2.5]octan-6-yl]methyl}-7-methylindole-1-carboxylate (isomer 1, faster peak, 100mg, 50% yield) LCMS (ESI, m/z): [M+H]⁺ = 548.3. tR =1.28min(Column: CHIRALPAK IH-3, 4.6*50mm, 3μm; Mobile Phase B: IPA(0.1%DEA); Flow rate: 4 mL/min; Gradient: isocratic % B) 5% to 20% in 2 min,hold 1 min at 20%. [00952] tert-Butyl 5-methoxy-4-{[(5R)-5-[4-(methoxycarbonyl)-2-(methylamino)phenyl]-6- azaspiro[2.5]octan-6-yl]methyl}-7-methylindole-1-carboxylate (isomer 2, slower peak, 100 mg, 50% yield) LCMS (ESI, m/z): [M+H]⁺ = 548.3. tR =1.43min(Column: CHIRALPAK IH-3, 4.6*50mm, 3μm; Mobile Phase B: IPA(0.1%DEA); Flow rate: 4 mL/min; Gradient: isocratic % B) 5% to 20% in 2 min,hold 1 min at 20%. [00953] Step 10: 4-[(5R)-6-[(5-methoxy-7-methyl-1H-indol-4-yl)methyl]-6-azaspiro[2.5]octan-5-yl]-3- (methylamino)benzoic acid& 4-[(5R)-6-[(5-methoxy-7-methyl-1H-indol-4-yl)methyl]-6-azaspiro[2.5]octan- 5-yl]-3-(methylamino)benzoic acid [00954] A mixture of

)-2-(methylamino)phenyl]-6- azaspiro[2.5]octan-6-yl]methyl}-7-methylindole-1-carboxylate (100 mg, 0.18 mmol, 1 equiv) and Potassium hydroxide (132 mg, 2.35 mmol, 9.99 equiv) in Ethanol (0.9 mL) and water (0.3 mL) was stirred at 80 °C for 2 h . The mixture was acidified to pH< 7 with sat. citric acid. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in Water (10mmol/L Ammonium bicarbonate), 10% to 50% gradient in 10 min; detector, UV 254 nm. To afford 4- [(5S)-6-[(5-methoxy-7-methyl-1H-indol-4-yl)methyl]-6-azaspiro[2.5]octan-5-yl]-3-(methylamino)benzoic acid (66.2 mg, 66.20% yield) as a white solid. LCMS (ESI, m/z): [M+H]⁺ = 434.6.¹H NMR (300 MHz, DMSO-d6) δ 12.58 (s, 1H), 10.87 (s, 1H), 7.32 – 7.23 (m, 1H), 7.24 – 7.16 (m, 2H), 7.12 (s, 1H), 6.68 (s, 1H), 6.28 – 6.21 (m, 1H), 3.71 (s, 4H), 3.47 (d, J = 11.2 Hz, 1H), 3.29 (d, J = 12.0 Hz, 1H), 2.81 (d, J = 4.4 Hz, 3H), 2.74 (d, J = 11.6 Hz, 1H), 2.61 (d, J = 13.4 Hz, 1H), 2.43 (s, 3H), 2.21 – 2.07 (m, 1H), 1.90 – 1.76 (m, 1H), 0.80 – 0.66 (m, 2H), 0.38 (s, 1H), 0.29 (s, 3H). [00955] A mixture of tert-Butyl 5-methoxy-4-{[(5R)-5-[4-(methoxycarbonyl)-2-(methylamino)phenyl]-6- azaspiro[2.5]octan-6-yl]methyl}-7-methylindole-1-carboxylate (100 mg, 0.18 mmol, 1 equiv) and Potassium hydroxide (132.01 mg, 2.36 mmol, 9.99 equiv) in Ethanol (0.9 mL) and water (0.3 mL) was stirred at 80 °C for 2 h . The mixture was acidified to pH< 7 with sat. citric acid. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in Water (10mmol/L Ammonium bicarbonate), 10% to 50% gradient in 10 min; detector, UV 254 nm. To afford 4-[(5R)-6-[(5-methoxy-7-methyl-1H-indol-4-yl)methyl]-6-azaspiro[2.5]octan-5-yl]-3-(methylamino)benzoic acid (65.7 mg, 65.70% yield) as a white solid. LCMS (ESI, m/z): [M+H]⁺ = 434.6.¹H NMR (300 MHz, DMSO-d6) δ 12.56 (s, 1H), 10.87 (s, 1H), 7.32 – 7.24 (m, 1H), 7.20 (s, 2H), 7.12 (s, 1H), 6.68 (s, 1H), 6.28 – 6.21 (m, 1H), 3.71 (s, 4H), 3.47 (d, J = 11.1 Hz, 1H), 3.29 (d, J = 12.2 Hz, 1H), 2.81 (d, J = 4.4 Hz, 3H), 2.74 (d, J = 11.3 Hz, 1H), 2.43 (s, 3H), 2.20 – 2.06 (m, 1H), 1.90 – 1.73 (m, 1H), 0.80 – 0.66 (m, 2H), 0.38 (s, 1H), 0.28 (s, 3H). [00956] Example 46.4-[(6R)-2-Methanesulfonyl-7-[(5-methoxy-7-methyl-1H-indol-4-yl)methyl]-2,7- diazaspiro[3.5]nonan-6-yl]-3-(methylamino)benzoic acid & 4-[(6S)-2-methanesulfonyl-7-[(5-methoxy-7- methyl-1H-indol-4-yl)methyl]-2,7-diazaspiro[3.5]nonan-6-yl]-3-(methylamino)benzoic acid. [00957] Proce

[00959] A solution of tert-butyl 2,7-dia

. 7-carboxylate (15 g, 66.28 mmol, 1 equiv), methanesulfonic anhydride (17.32 g, 99.42 mmol, 1.5 equiv) in Dichloromethane (200 mL) was treated with N,N-Diisopropylethylamine (18.85 g, 145.81 mmol, 2.2 equiv) at room temperature for 1h. The reaction was quenched with sat. Ammonium chloride (aq.) at room temperature. The resulting mixture was extracted with Ethyl acetate. The combined organic layers were washed with water, dried over anhydrous Sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to afford tert-butyl 2-methanesulfonyl- 2,7-diazaspiro[3.5]nonane-7-carboxylate (19 g crude) as a white solid. LCMS: (ESI, m/z): 290.1 [M-(t- Bu)+Acetonitrile]⁺. [00960] Step 2: tert-Butyl 2-methanesulfonyl-6-oxo-2,7-diazaspiro[3.5]nonane-7-carboxylate [00961] A solution of tert-butyl 2-met aspiro[3.5]nonane-7-carboxylate (19 g, 62.42

mmol, 1 equiv), Sodium periodate (26.70 g, 124.83 mmol, 2 equiv) in ethyl acetate (150 mL) and water (150 mL) was treated with trichlororuthenium hydrate (1.41 g, 6.24 mmol, 0.1 equiv) at room temperature for 1h. The resulting mixture was filtered, the filter cake was washed with ethyl acetate (3 × 50 mL). The filtrate was concentrated under reduced pressure. The resulting mixture was extracted with Ethyl acetate (3 × 50 mL). The combined organic layers were washed with brine (3 × 50 mL), dried over anhydrous Sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by C18 silica gel column chromatography, eluted with Acetonitrile/water (1:4) to afford tert-butyl 2-methanesulfonyl-6- oxo-2,7-diazaspiro[3.5]nonane-7-carboxylate (9.4 g, 49.01%) as a white solid. LCMS: (ESI, m/z): 263.1 [M- (t-Bu)]⁺. [00962] Step 3: tert-Butyl 2-methanesulfonyl-6-(trifluoromethanesulfonyloxy)-2,7-diazaspiro[3.5]non-5- ene-7-carboxylate [00963] A solution of tert-butyl 2-met

,7-diazaspiro[3.5]nonane-7-carboxylate (6 g, 18.84 mmol, 1 equiv) in Tetrahydrofuran (70 mL) was treated with Lithium bis(trimethylsilyl)amide (1M in Tetrahydrofuran) (28.27 mL, 28.27 mmol, 1.5 equiv) at -78 °C for 40 mins under nitrogen. Then the 1,1,1- trifluoro-N-phenyl-N-(trifluoromethane)sulfonyl-methanesulfonamide (13.46 g, 37.69 mmol, 2 equiv) was added and stirred at -78 °C for 40 mins. The reaction was quenched with sat. Ammonium chloride (aq.) at room temperature. The resulting mixture was extracted with Ethyl acetate. The combined organic layers were washed with water, dried over anhydrous Sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with Acetonitrile/water (1:4) to afford tert-butyl 2-methanesulfonyl-6-(trifluoromethanesulfonyloxy)-2,7- diazaspiro[3.5]non-5-ene-7-carboxylate (1.3 g, 12.25%) as a yellow solid. LCMS: (ESI, m/z): 436.1 [M-(t- Bu)+Acetonitrile]⁺. [00964] Step 4: tert-butyl 2-methanesulfonyl-6-[4-(methoxycarbonyl)-2-nitrophenyl]-2,7- diazaspiro[3.5]non-5-ene-7-carboxylate [00965] A solution of tert-butyl ethanesulfonyloxy)-2,7-

diazaspiro[3.5]non-5-ene-7-carboxylate (1.3 g, 2.89 mmol, 1 equiv), 4-(methoxycarbonyl)-2- nitrophenylboronic acid (0.97 g, 4.33 mmol, 1.5 equiv), 1,1’-Bis(diphenylphosphino)ferrocene- palladium(II)dichloride dichloromethane complex (235.69 mg, 0.29 mmol, 0.1 equiv) in 1,4-dioxane (16 mL) and water (3.2 mL) was treated with Sodium carbonate (611.78 mg, 5.77 mmol, 2 equiv) at 90 °C for 1 h under nitrogen. The reaction was quenched with sat. Ammonium chloride (aq.) at room temperature. The resulting mixture was extracted with Ethyl acetate. The combined organic layers were washed with water, dried over anhydrous Sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by C18 silica gel column chromatography, eluted with Acetonitrile/water (1:4) to afford tert-butyl 2-methanesulfonyl-6-[4-(methoxycarbonyl)-2-nitrophenyl]-2,7-diazaspiro[3.5]non-5-ene-7- carboxylate (420 mg, 28.71%) as a yellow solid. LCMS: (ESI, m/z): 426.1 [M-(t-Bu)]⁺. [00966] Step 5: Methyl 4-{2-methanesulfonyl-2,7-diazaspiro[3.5]nonan-6-yl}-3-nitrobenzoate [00967] A solution of tert-butyl 2

ycarbonyl)-2-nitrophenyl]-2,7-diazaspiro [3.5]non-5-ene-7-carboxylate (400 mg, 0.83 mmol, 1 equiv) in Dichloromethane (4 mL) and trifluoroacetic acid (4 mL) was treated with Sodium cyanoborohydride (522.01 mg, 8.31 mmol, 10 equiv) at room temperature for 1h. The resulting mixture was concentrated under vacuum. The mixture was basified to pH 7 with saturated Sodium bicarbonate (aq.). The resulting mixture was extracted with Dichloromethane (3 × 10 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with Acetonitrile/water (3:7) to afford methyl 4-{2- methanesulfonyl-2,7-diazaspiro[3.5]nonan-6-yl}-3-nitrobenzoate (270 mg, 69.51%) as a yellow solid. LCMS: (ESI, m/z): 384.2 [M+H]⁺. [00968] Step 6: tert-butyl 4-({2-methanesulfonyl-6-[4-(methoxycarbonyl)-2-nitrophenyl]-2,7- diazaspiro[3.5]nonan-7-yl}methyl)-5-methoxy-7-methylindole-1-carboxylate [00969] A solution of methyl 4-{ o[3.5]nonan-6-yl}-3-nitrobenzoate (240

mg, 0.63 mmol, 1 equiv), tert-butyl 4-(chloromethyl)-5-methoxy-7-methylindole-1-carboxylate (387.82 mg, 1.25 mmol, 2 equiv), Potassium iodide (124.69 mg, 0.75 mmol, 1.2 equiv) in DMF (4 mL) was treated with Cesium carbonate (611.83 mg, 1.88 mmol, 3 equiv) at 50 °C for 1h. The reaction was quenched with sat. Ammonium chloride (aq.) at room temperature. The resulting mixture was extracted with Ethyl acetate. The combined organic layers were washed with water, dried over anhydrous Sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by C18 silica gel column chromatography, eluted with Acetonitrile/water (Ammonium bicarbonate) (4:1) to afford tert-butyl 4-({2- methanesulfonyl-6-[4-(methoxycarbonyl)-2-nitrophenyl]-2,7-diazaspiro[3.5]nonan-7-yl}methyl)-5-methoxy- 7-methylindole-1-carboxylate (200 mg, 43.79%) as a yellow solid. LCMS: (ESI, m/z): 657.3 [M+H]⁺. [00970] Step 7: tert-Butyl 4-({6-[2-amino-4-(methoxycarbonyl)phenyl]-2-methanesulfonyl-2,7- diazaspiro[3.5]nonan-7-yl}methyl)-5-methoxy-7-methylindole-1-carboxylate [00971] A solution of tert-butyl 4

hoxycarbonyl)-2-nitrophenyl]-2,7- diazaspiro[3.5]nonan-7-yl}methyl)-5-methoxy-7-methylindole-1-carboxylate (200 mg, 0.30 mmol, 1 equiv) in ethyl acetate (8 mL) was treated with 10% Pd/C (399.92 mg) at room temperature for overnight under hydrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with Methanol (3 × 20 mL). The filtrate was concentrated under reduced pressure. The residue was purified by C18 silica gel column chromatography, eluted with Acetonitrile/water (1:3) to afford tert-butyl 4-({6-[2-amino-4- (methoxycarbonyl)phenyl]-2-methanesulfonyl-2,7-diazaspiro[3.5]nonan-7-yl}methyl)-5-methoxy-7- methylindole-1-carboxylate (120 mg, 59.73%) as a light yellow solid. LCMS: (ESI, m/z): 627.4 [M+H]⁺. [00972] Step 8: tert-Butyl 4-{[(6R)-2-methanesulfonyl-6-[4-(methoxycarbonyl)-2-(methylamino)phenyl]- 2,7-diazaspiro[3.5]nonan-7-yl]methyl}-5-methoxy-7-methylindole-1-carboxylate & tert-butyl 4-{[(6S)-2- methanesulfonyl-6-[4-(methoxycarbonyl)-2-(methylamino)phenyl]-2,7-diazaspiro[3.5] nonan-7-yl]methyl}- 5-methoxy-7-methylindole-1-carboxylate [00973] A soluti nyl]-2,7-

diazaspiro[3.5]nonan-7-yl}methyl)-5-methoxy-7-methylindole-1-carboxylate (110 mg, 0.19 mmol, 1 equiv), Paraformaldehyde (27.93 mg, 0.93 mmol, 5 equiv) in methanol (2 mL) was treated with Sodium cyanoborohydride (35.10 mg, 0.558 mmol, 3 equiv) at 70 °C for 2h. The resulting mixture was quenched with water and extracted with Ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in Water (10mmol/L Ammonium bicarbonate), 10% to 50% gradient in 10 min; detector, UV 254 nm. to afford the title compound (60 mg, 16.70%) as a white solid. LCMS (ESI, m/z): [M+H]⁺ = 641.3. The filtrate was concentrated under reduced pressure. The residue was applied for further separation by Chiral HPLC with the following condition: Column: Lux 5um Cellulose-4, 2.12*25 cm, 5 μm; Mobile Phase A: HEX(0.5% 2M NH3-Methanol), Mobile Phase B: Ethanol; Flow rate: 20 mL/min; Gradient: isocratic 70; Wave Length: 220/254 nm; RT1(min): 10.237; RT2(min): 13.342; Sample Solvent: ETOH. [00974] (isomer 1, faster peak) (30 mg, 24.64% yield, white solid). LCMS: (ESI, m/z): 641.3 [M+H]⁺. t_R = 2.00 min (Lux 5um Cellulose-4, 2.12*25 cm, 5 μm, Hex(0.1%DEA): EtOH=30: 70; Flow rate: 1.0 mL/min, Wave Length: 254 nm). [00975] (isomer 2, slower peak) (30 mg, 24.64% yield, white solid). LCMS: (ESI, m/z): 641.3 [M+H]⁺. t_R = 2.79 min (Lux 5um Cellulose-4, 2.12*25 cm, 5 μm, Hex(0.1%DEA): EtOH=30: 70; Flow rate: 1.0 mL/min, Wave Length: 254 nm). [00976] Step 9: 4-[(6S)-2-methanesulfonyl-7-[(5-methoxy-7-methyl-1H-indol-4-yl)methyl]-2,7- diazaspiro[3.5] nonan-6-yl]-3-(methylamino)benzoic acid & 4-[(6R)-2-methanesulfonyl-7-[(5-methoxy-7- methyl-1H-indol-4-yl)methyl]-2,7-diazaspiro[3.5]nonan-6-yl]-3-(methylamino)benzoic acid [00977] A sol water (1 mL) was

treated with Potassium hydroxide (30.73 mg, 0.55 mmol, 10 equiv) at 80 °C for 2.5h. The mixture was allowed to cool down to room temperature. The mixture was acidified to pH 6 with citric acid. The residue was purified by C18 silica gel column chromatography, eluted with Acetonitrile/water(Ammonium bicarbonate) (1:4) to afford the product (12.6 mg, 21.62%, white solid). LCMS: (ESI, m/z): 527.4 [M+H]⁺.¹H NMR (300 MHz, DMSO-d₆) δ 12.68 (s, 1H), 10.89 (s, 1H), 7.48 – 7.18 (m, 3H), 7.13 (d, J = 1.4 Hz, 1H), 6.91 (s, 1H), 6.68 (s, 1H), 6.24 (s, 1H), 3.90 (s, 1H), 3.80 – 3.60 (m, 6H), 3.53 (s, 3H), 3.20 (d, J = 11.8 Hz, 2H), 2.79 (d, J = 4.3 Hz, 3H), 2.68 (d, J = 12.1 Hz, 1H), 2.43 (s, 3H), 2.38 – 2.19 (s, 1H), 2.01 – 1.83 (m, 1H), 1.83 – 1.66 (m, 3H), 1.63 – 1.38 (m, 1H). [00978] A solution of isomer 2 (30 mg, 0.047 mmol, 1 equiv) in Ethanol (3 mL) and water (1 mL) was treated with Potassium hydroxide (30.73 mg, 0.55 mmol, 10 equiv) at 80 °C for 2.5h. The mixture was allowed to cool down to room temperature. The mixture was acidified to pH 6 with citric acid. The residue was purified by C18 silica gel column chromatography, eluted with Acetonitrile/water(Ammonium bicarbonate) (1:4) to afford the product(18.5 mg, 31.10%, white solid). LCMS: (ESI, m/z): 527.4 [M+H]⁺.¹H NMR (300 MHz, DMSO-d6) δ 12.69 (s, 1H), 10.88 (s, 1H), 7.42 – 7.17 (m, 3H), 7.13 (d, J = 1.4 Hz, 1H), 6.92 (s, 1H), 6.68 (s, 1H), 6.24 (s, 1H), 3.90 (s, 1H), 3.81 – 3.60 (m, 6H), 3.53 (s, 2H), 3.20 (d, J = 11.9 Hz, 1H), 2.99 (s, 3H), 2.79 (d, J = 4.3 Hz, 3H), 2.68 (d, J = 12.2 Hz, 1H), 2.47 – 2.38 (m, 3H), 2.37 – 2.17 (m, 1H), 1.91 (s, 1H), 1.85 – 1.66 (m, 2H), 1.64 – 1.40 (m, 1H). [00979] Example 47.4-[(6S)-2,2-Difluoro-7-[(5-methoxy-7-methyl-1H-indol-4-yl)methyl]-7- azaspiro[3.5]nonan-6-yl]-3-(isopropylamino)benzoic acid & 4-[(6R)-2,2-difluoro-7-[(5-methoxy-7-methyl- 1H-indol-4-yl)methyl]-7-azaspiro[3.5]nonan-6-yl]-3-(isopropylamino)benzoic acid.

[00980] Procedure: [0

azaspiro[3.5]nonan-7-yl}methyl)-5-methoxy-7-methylindole-1-carboxylate [00982] A solution of tert-butyl 4-

onyl)phenyl]-2,2-difluoro-7- azaspiro[3.5]nonan-7-yl}methyl)-5-methoxy-7-methylindole-1-carboxylate (200 mg, 0.34 mmol, 1 equiv) and Sodium cyanoborohydride (53.83 mg, 0.86 mmol, 2.5 equiv), acetone (298.52 mg, 5.15 mmol, 15 equiv) in Tetrahydrofuran (1 mL) and Acetic acid (1 mL) was stirred at room temperature for 1h. The reaction was quenched with water at room temperature. The resulting mixture was extracted with Ethyl acetate. The combined organic layers were washed with water, dried over anhydrous Sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in Water (10mmol/L Ammonium bicarbonate), 10% to 50% gradient in 10 min; detector, UV 254 nm. to afford tert- butyl 4-({2,2-difluoro-6-[2-(isopropylamino)-4-(methoxycarbonyl)phenyl]-7-azaspiro[3.5]nonan-7- yl}methyl)-5-methoxy-7-methylindole-1-carboxylate (150 mg, 69.96% yield) as a yellow solid. LCMS (ESI, m/z): [M+H]⁺ = 478.5 [00983] Step 2: tert-Butyl 4-{[(6R)-2,2-difluoro-6-[2-(isopropylamino)-4-(methoxycarbonyl)phenyl]-7- azaspiro[3.5]nonan-7-yl]methyl}-5-methoxy-7-methylindole-1-carboxylate & tert-butyl 4-{[(6S)-2,2- difluoro-6-[2-(isopropylamino)-4-(methoxycarbonyl)phenyl]-7-azaspiro[3.5]nonan-7-yl]methyl}-5-methoxy- 7-methylindole-1-carboxylate [00984] The title ith the following

condition: Column: CHIRALPAK AY-H, 4.6*250mm, 5um; Mobile Phase A: HEX(0.5% 2M NH3- Methanol), Mobile Phase B: Ethanol; Flow rate: 20 mL/min; Gradient: isocratic 10; Wave Length: 220/254 nm; RT1(min): 4.849; RT2(min): 10.144; Sample Solvent: ETOH. [00985] tert-butyl 4-{[(6R)-2,2-difluoro-6-[2-(isopropylamino)-4-(methoxycarbonyl)phenyl]-7- azaspiro[3.5]nonan-7-yl]methyl}-5-methoxy-7-methylindole-1-carboxylate(isomer 1, faster peak, 55 mg, 36% yield) LCMS: (ESI, m/z): 625.3 [M+H]⁺. tR = 1.083 min (CHIRALPAK AY-3, 4.6*50 mm, 3 μm, HEX(0.1%DEA):Ethanol=95:5, 1.0 mL/min, 254 nm). [00986] tert-butyl 4-{[(6S)-2,2-difluoro-6-[2-(isopropylamino)-4-(methoxycarbonyl)phenyl]-7- azaspiro[3.5]nonan-7-yl]methyl}-5-methoxy-7-methylindole-1-carboxylate(isomer 2, slower peak, 50 mg, 30% yield) LCMS: (ESI, m/z): 625.3 [M+H]⁺. tR = 4.120 min (CHIRALPAK AY-3, 4.6*50 mm 3 μm, HEX(0.1%DEA): Ethanol=95:5, 1.0 mL/min, 254 nm). [00987] Step 3: 4-[(6R)-2,2-Difluoro-7-[(5-methoxy-7-methyl-1H-indol-4-yl)methyl]-7- azaspiro[3.5]nonan-6-yl]-3-(isopropylamino)benzoic acid& 4-[(6S)-2,2-difluoro-7-[(5-methoxy-7-methyl- 1H-indol-4-yl)methyl]-7-azaspiro[3.5]nonan-6-yl]-3-(isopropylamino)benzoic acid [00988] A solution

, (methoxycarbonyl)phenyl]-7-azaspiro[3.5]nonan-7-yl]methyl}-5-methoxy-7-methylindole-1-carboxylate (150 mg, 0.24 mmol, 1 equiv) and Potassium hydroxide (134.49 mg, 2.40 mmol, 10.00 equiv) in Ethanol (0.9 mL) and water (0.3 mL) was stirred at 80 °C for 3h. The mixture was acidified to pH< 7 with sat. citric acid. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in Water (10mmol/L Ammonium bicarbonate), 10% to 50% gradient in 10 min; detector, UV 254 nm.This resulted in 4-[(6R)-2,2-difluoro-7-[(5-methoxy-7-methyl-1H- indol-4-yl)methyl]-7-azaspiro[3.5]nonan-6-yl]-3-(isopropylamino)benzoic acid (39.4 mg, 32.13% yield) as a white solid.(44.3 mg, 36.12% yield) as a white solid. LCMS (ESI, m/z): [M+H]⁺ = 512.2.¹H NMR (300 MHz, DMSO-d6) δ 12.61 (s, 1H), 10.87 (s, 1H), 7.29 – 7.25 (m, 1H), 7.19 (s, 3H), 6.87 (s, 1H), 6.68 (s, 1H), 6.36 (s, 1H), 3.69 (s, 4H), 3.63 (s, 1H), 3.26 (s, 1H), 2.79 – 2.71 (m, 1H), 2.66 – 2.56 (m, 1H), 2.43 (s, 5H), 2.39 – 2.30 (m, 3H), 2.29 (s, 1H), 1.95 (s, 1H), 1.54 (s, 3H), 1.21 – 1.16 (m, 2H), 1.09 (s, 3H). [00989] A solution of tert-butyl 4-{[(6S)-2,2-difluoro-6-[2-(isopropylamino)-4- (methoxycarbonyl)phenyl]-7-azaspiro[3.5]nonan-7-yl]methyl}-5-methoxy-7-methylindole-1-carboxylate (150 mg, 0.240 mmol, 1 equiv) and Potassium hydroxide (134.49 mg, 2.397 mmol, 10.00 equiv) in Ethanol (0.9 mL) and water (0.3 mL) was stirred at 80 °C for 3h . The mixture was acidified to pH< 7 with sat. citric acid. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in Water (10mmol/L Ammonium bicarbonate), 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in 4-[(6S)-2,2-difluoro-7-[(5-methoxy-7-methyl- 1H-indol-4-yl) methyl]-7-azaspiro[3.5] nonan-6-yl]- 3-(isopropylamino)benzoic acid (44.3 mg, 36.12% yield) as a white solid. LCMS (ESI, m/z): [M+H]⁺ = 512.2.¹H NMR (300 MHz, DMSO-d6) δ 12.60 (s, 1H), 10.87 (s, 1H), 7.27 (s, 1H), 7.19 (s, 2H), 6.86 (s, 1H), 6.68 (s, 1H), 6.36 (s, 1H), 3.69 (s, 4H), 3.66 – 3.57 (m, 1H), 3.26 (s, 1H), 2.78 – 2.70 (m, 1H), 2.66 – 2.56 (m, 1H), 2.43 (s, 5H), 2.40 – 2.26 (m, 3H), 1.97 (s, 1H), 1.54 (s, 3H), 1.22 – 1.14 (m, 3H), 1.13 – 1.05 (m, 3H). [00990] Example 48.4-[(6R)-2,2-Difluoro-7-[(5-methoxy-7-methyl-1H-indol-4-yl)methyl]-7- azaspiro[3.5]nonan-6-yl]-3-(dimethylamino)benzoic acid & 4-[(6S)-2,2-difluoro-7-[(5-methoxy-7-methyl- 1H-indol-4-yl)methyl]-7-azaspiro[3.5]nonan-6-yl]-3-(dimethylamino)benzoic acid. z [00991] Procedur

[0

azaspiro[3.5]nonan-7-yl}methyl)-5-methoxy-7-methylindole-1-carboxylate [00993] A solution of tert-butyl 4-

arbonyl)-2-nitrophenyl)-7- azaspiro[3.5]nonan-7-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (600 mg, 0.98 mmol, 1 equiv) and 10% Pd/C (300 mg) in ethyl acetate (6 mL) was stirred at room temperature for 2 h under hydrogen atmosphere.The resulting mixture was filtered, the filter cake was washed with Methanol (3 × 10 mL). The filtrate was concentrated under reduced pressure. This resulted in tert-butyl 4-({6-[2-amino-4- (methoxycarbonyl)phenyl]-2,2-difluoro-7-azaspiro[3.5]nonan-7-yl}methyl)-5-methoxy-7-methylindole-1- carboxylate (500 mg, 87.61% yield) as a yellow solid. LCMS (ESI, m/z): [M+H]⁺ = 584.7 [00994] Step 2: tert-Butyl 4-((6-(2-(dimethylamino)-4-(methoxycarbonyl)phenyl)-2,2-difluoro-7- azaspiro[3.5]nonan-7-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate O N O F F [00995] A solution of tert-butyl 4- onyl)phenyl]-2,2-difluoro-7-

azaspiro[3.5]nonan-7-yl}methyl)-5-methoxy-7-methylindole-1-carboxylate (200 mg, 0.33 mmol, 1 equiv) and paraformaldehyde (100 mg, 3.3 mmol), Sodium cyanoborohydride (51.20 mg, 0.82 mmol, 2.5 equiv) in Tetrahydrofuran (1 mL) and Acetic acid (1 mL) was stirred at 50 °C for 1h. The resulting mixture was quenched with water and extracted with Ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in Water (10 mmol/L Ammonium bicarbonate), 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in tert-butyl 4-((6-(2-(dimethylamino)-4- (methoxycarbonyl)phenyl)-2,2-difluoro-7-azaspiro[3.5]nonan-7-yl)methyl)-5-methoxy-7-methyl-1H-indole- 1-carboxylate (140 mg, 73.60% yield) as a yellow oil. LCMS (ESI, m/z): [M+H]⁺ = 612.7 [00996] Step 3: tert-Butyl (R)-4-((6-(2-(dimethylamino)-4-(methoxycarbonyl)phenyl)-2,2-difluoro-7- azaspiro[3.5]nonan-7-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate & tert-butyl (S)-4-((6-(2- (dimethylamino)-4-(methoxycarbonyl)phenyl)-2,2-difluoro-7-azaspiro[3.5]nonan-7-yl)methyl)-5-methoxy-7- methyl-1H-indole-1-carboxylate [00997] Column:

, DEA)--HPLC, Mobile Phase B: IPA--HPLC; Flow rate: 20 mL/min; Gradient: isocratic 1; Wave Length: 220/254 nm; Sample Solvent: Ethanol. [00998] tert-Butyl (R)-4-((6-(2-(dimethylamino)-4-(methoxycarbonyl)phenyl)-2,2-difluoro-7- azaspiro[3.5]nonan-7-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (isomer 1, faster peak, 50 mg, 38% yield) LCMS: (ESI, m/z): 612.1[M+H]⁺. tR = 1.521 min (Enantiocel C9‐3, 4.6*50 mm 3 μm), HEX(0.1%DEA):IPA=98:2, 1.0 mL/min, 254 nm). [00999] tert-Butyl (S)-4-((6-(2-(dimethylamino)-4-(methoxycarbonyl)phenyl)-2,2-difluoro-7- azaspiro[3.5]nonan-7-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (isomer 2, slower peak, 50 mg, 38% yield) LCMS: (ESI, m/z): 612.1[M+H]⁺. t_R = 2.158 min (Enantiocel C9‐3, 4.6*50 mm 3 μm), HEX(0.1%DEA):IPA=98:2, 1.0 mL/min, 254 nm). [01000] Step 4: 4-[(6R)-2,2-Difluoro-7-[(5-methoxy-7-methyl-1H-indol-4-yl)methyl]-7- azaspiro[3.5]nonan-6-yl]-3-(dimethylamino)benzoic acid & 4-[(6S)-2,2-difluoro-7-[(5-methoxy-7-methyl- 1H-indol-4-yl)methyl]-7-azaspiro[3.5]nonan-6-yl]-3-(dimethylamino)benzoic acid [01001] A solutio nyl)phenyl)-2,2-difluoro-

7-azaspiro[3.5]nonan-7-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (100 mg, 0.16 mmol, 1 equiv) and Potassium hydroxide (91.72 mg, 1.63 mmol, 10 equiv) in Ethanol (0.9 mL) and water (0.3 mL) was stirred at 80 °C for 3h. The mixture was acidified to pH< 7 with sat. citric acid. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in Water (10mmol/L Ammonium bicarbonate), 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in 4-[(6R)-2,2- difluoro-7-[(5-methoxy-7-methyl-1H-indol-4-yl)methyl]-7-azaspiro[3.5]nonan-6-yl]-3- (dimethylamino)benzoic acid (26.7 mg, 32.82% yield) as a white solid. LCMS (ESI, m/z): [M+H]⁺ = 498.3. ¹H NMR (300 MHz, DMSO-d6) δ 12.88 (s, 1H), 10.81 (s, 1H), 7.93 – 7.84 (m, 1H), 7.84 – 7.73 (m, 2H), 7.28 – 7.20 (m, 1H), 6.64 (s, 1H), 6.44 – 6.36 (m, 1H), 3.81 (s, 1H), 3.70 (s, 3H), 3.35 (s, 1H), 3.19 – 3.09 (m, 1H), 2.71 (s, 7H), 2.57 (s, 1H), 2.47 (s, 1H), 2.41 (s, 3H), 2.39 – 2.24 (m, 2H), 2.03 (s, 1H), 1.73 (s, 1H), 1.54 (s, 2H). [01002] A solution of tert-butyl (S)-4-((6-(2-(dimethylamino)-4-(methoxycarbonyl)phenyl)-2,2-difluoro- 7-azaspiro[3.5]nonan-7-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (100 mg, 0.16 mmol, 1 equiv) and Potassium hydroxide (91.72 mg, 1.63 mmol, 10 equiv) in Ethanol (0.9 mL) and water (0.3 mL) was stirred at 80 °C for 3h. The mixture was acidified to pH< 7 with sat. citric acid. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in Water (10mmol/L Ammonium bicarbonate), 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in 4-[(6S)-2,2- difluoro-7-[(5-methoxy-7-methyl-1H-indol-4-yl)methyl]-7-azaspiro[3.5]nonan-6-yl]-3- (dimethylamino)benzoic acid(26.7 mg, 32.82% yield) as a white solid. LCMS (ESI, m/z): [M+H]⁺ = 498.3. ¹H NMR (300 MHz, DMSO-d6) δ 10.81 (s, 1H), 7.93 – 7.84 (m, 1H), 7.83 – 7.73 (m, 2H), 7.28 – 7.20 (m, 1H), 6.64 (s, 1H), 6.43 – 6.36 (m, 1H), 3.81 (s, 1H), 3.70 (s, 3H), 3.39 (s, 1H), 3.19 – 3.09 (m, 2H), 2.71 (s, 7H), 2.57 (s, 1H), 2.47 (s, 1H), 2.41 (s, 3H), 2.38 – 2.24 (m, 2H), 2.02 (s, 1H), 1.73 (s, 2H), 1.54 (s, 1H). [01003] Example 49.4-[(6S)-2,2-Difluoro-7-[(5-methoxy-7-methyl-1H-indol-4-yl)methyl]-7- azaspiro[3.5]nonan-6-yl]-3-[(oxan-4-ylmethyl)amino]benzoic acid & 4-[(6R)-2,2-difluoro-7-[(5-methoxy-7- methyl-1H-indol-4-yl)methyl]-7-azaspiro[3.5]nonan-6-yl]-3-[(oxan-4-ylmethyl)amino]benzoic acid.

[01005] Step 1: tert-Butyl 2,2-difluoro-6-[4-(methoxycarbonyl)-2-[(oxan-4-ylmethyl)amino]phenyl]-7- azaspiro[3.5]non-5-ene-7-carboxylate [01006] A solution of tert-butyl 6 l)phenyl]-2,2-difluoro-7-

azaspiro[3.5]non-5-ene-7-carboxylate (500 mg, 1.17 mmol, 1 equiv) and 1-(oxan-4-yl)methanamine (471.07 mg, 4.09 mmol, 3.5 equiv), Cesium carbonate (761.49 mg, 2.34 mmol, 2 equiv), 3-chloropyridine;{1,3- bis[2,6-bis(heptan-4-yl)phenyl]-4,5-dichloro-2,3-dihydro-1H-imidazol-2-yl}dichloropalladium (113.80 mg, 0.12 mmol, 0.1 equiv) in 1,4-dioxane (5 mL) was stirred at 110 °C for 12 h under nitrogen atmosphere. The reaction was quenched with sat. Ammonium chloride (aq.) at room temperature. The resulting mixture was extracted with Ethyl acetate. The combined organic layers were washed with water, dried over anhydrous Sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in Water (10mmol/L Ammonium bicarbonate), 10% to 50% gradient in 10 min; detector, UV 254 nm. to afford tert-butyl 2,2-difluoro-6-[4-(methoxycarbonyl)-2-[(oxan-4- ylmethyl)amino]phenyl]-7-azaspiro[3.5]non-5-ene-7-carboxylate (220 mg, 37.16% yield) as a yellow solid. LCMS (ESI, m/z): [M+H]⁺ = 506.6 [01007] Step 2: Methyl 4-{2,2-difluoro-7-azaspiro[3.5]nonan-6-yl}-3-[(oxan-4-ylmethyl)amino]benzoate [01008] A solution of tert-butyl 2,

onyl)-2-[(oxan-4- ylmethyl)amino]phenyl]-7-azaspiro[3.5]non-5-ene-7-carboxylate (170 mg, 0.34 mmol, 1 equiv) and 10% Pd/C (100 mg) in ethyl acetate (2 mL) was stirred at room temperature for 2h under hydrogen atmosphere.The resulting mixture was filtered, the filter cake was washed with Methanol (3 × 20 mL). The filtrate was concentrated under reduced pressure to afford tert-butyl 2,2-difluoro-6-[4-(methoxycarbonyl)-2- [(oxan-4-ylmethyl)amino]phenyl]-7-azaspiro[3.5]nonane-7-carboxylate(120 mg crude) as a yellow oil. Then the solution of tert-butyl 2,2-difluoro-6-[4-(methoxycarbonyl)-2-[(oxan-4-ylmethyl)amino]phenyl]-7- azaspiro[3.5]nonane-7-carboxylate (120 mg) in trifluoroacetic acid (2 mL) was stirred at room temperature for 1h . The reaction was quenched with sat. Sodium bicarbonate (aq.) at room temperature. The resulting mixture was extracted with Ethyl acetate. The combined organic layers were washed with water, dried over anhydrous Sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in Water (10mmol/L Ammonium bicarbonate), 10% to 50% gradient in 10 min; detector, UV 254 nm to afford methyl 4-{2,2-difluoro-7-azaspiro[3.5]nonan-6-yl}-3-[(oxan-4- ylmethyl)amino]benzoate (90 mg, 93.38% yield) as an oil. LCMS: (ESI, m/z): 408.5 [M+H]⁺. [01009] Step 3: tert-Butyl 4-({2,2-difluoro-6-[4-(methoxycarbonyl)-2-[(oxan-4-ylmethyl)amino]phenyl]- 7-azaspiro[3.5]nonan-7-yl}methyl)-5-methoxy-7-methylindole-1-carboxylate [01010] A solution of methyl 4-{2

nan-6-yl}-3-[(oxan-4- ylmethyl)amino]benzoate (350 mg, 0.86 mmol, 1 equiv) and tert-butyl 4-(chloromethyl)-5-methoxy-7- methylindole-1-carboxylate (530.86 mg, 1.71 mmol, 2 equiv), Potassium iodide (213.35 mg, 1.29 mmol, 1.5 equiv), Cesium carbonate (837.50 mg, 2.57 mmol, 3.00 equiv) in DMF (4 mL) was stirred at 50 °C for 1h . The reaction was quenched with sat. Ammonium chloride (aq.) at room temperature. The resulting mixture was extracted with Ethyl acetate. The combined organic layers were washed with water, dried over anhydrous Sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in Water (10mmol/L Ammonium bicarbonate), 10% to 50% gradient in 10 min; detector, UV 254 nm. to afford tert-butyl4-({2,2-difluoro-6-[4-(methoxycarbonyl)-2-[(oxan-4- ylmethyl)amino]phenyl]-7-azaspiro[3.5]nonan-7-yl}methyl)-5-methoxy-7-methylindole-1-carboxylate (300 mg, 51.35% yield) as a white solid. LCMS (ESI, m/z): [M+H]⁺ = 681.8 [01011] Step 4: tert-Butyl 4-{[(6R)-2,2-difluoro-6-[4-(methoxycarbonyl)-2-[(oxan-4- ylmethyl)amino]phenyl]-7-azaspiro[3.5]nonan-7-yl]methyl}-5-methoxy-7-methylindole-1-carboxylate & tert- butyl4-{[(6S)-2,2-difluoro-6-[4-(methoxycarbonyl)-2-[(oxan-4-ylmethyl)amino]phenyl]-7- azaspiro[3.5]nonan-7-yl]methyl}-5-methoxy-7-methylindole-1-carboxylate

[01012] The cru ing conditions: Column:

CHIRALPAK C92*25 cm, 5 μm; Mobile Phase A: HEX(0.5% 2M NH3-Methanol), Mobile Phase B: IPA; Flow rate: 20 mL/min; Gradient: isocratic 40; Wave Length: 220/254 nm; RT1(min): 8.738; RT2(min): 10.359; Sample Solvent: ETOH. [01013] tert-Butyl 4-{[(6S)-2,2-difluoro-6-[4-(methoxycarbonyl)-2-[(oxan-4-ylmethyl)amino]phenyl]-7- azaspiro[3.5]nonan-7-yl]methyl}-5-methoxy-7-methylindole-1-carboxylate(isomer 1, faster peak, 120 mg, 40% yield) LCMS: (ESI, m/z): 681.4[M+H]⁺. tR=1.825 min (Enantiocel C9‐3, 4.6*50 mm 3 μm), HEX(0.1%DEA):IPA=60:40, 1.0 mL/min, 254 nm). [01014] tert-Butyl 4-{[(6R)-2,2-difluoro-6-[4-(methoxycarbonyl)-2-[(oxan-4-ylmethyl)amino]phenyl]-7- azaspiro[3.5]nonan-7-yl]methyl}-5-methoxy-7-methylindole-1-carboxylate(isomer 2, slower peak, 120 mg, 40% yield) LCMS: (ESI, m/z):681.4[M+H]⁺. tR=2.222 min (Enantiocel C9‐3, 4.6*50 mm 3 μm), HEX(0.1%DEA):IPA=60:40, 1.0 mL/min, 254 nm). [01015] Step 5: 4-[(6S)-2,2-Difluoro-7-[(5-methoxy-7-methyl-1H-indol-4-yl)methyl]-7- azaspiro[3.5]nonan-6-yl]-3-[(oxan-4-ylmethyl)amino]benzoic acid & 4-[(6R)-2,2-difluoro-7-[(5-methoxy-7- methyl-1H-indol-4-yl)methyl]-7-azaspiro[3.5]nonan-6-yl]-3-[(oxan-4-ylmethyl)amino]benzoic acid [01016] A solut

, (oxan-4- ylmethyl)amino]phenyl]-7-azaspiro[3.5]nonan-7-yl]methyl}-5-methoxy-7-methylindole-1-carboxylate (120 mg, 0.18 mmol, 1 equiv) and Potassium hydroxide (98.74 mg, 1.76 mmol, 10 equiv) in Ethanol (0.9 mL) and water (0.3 mL) was stirred at 80 °C for 2h. The mixture was acidified to pH< 7 with sat. citric acid. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in Water (10mmol/L Ammonium bicarbonate), 10% to 50% gradient in 10 min; detector, UV 254 nm.to afford 4-[(6S)-2,2-difluoro-7-[(5-methoxy-7-methyl-1H-indol-4-yl)methyl]- 7-azaspiro[3.5]nonan-6-yl]-3-[(oxan-4-ylmethyl)amino]benzoic acid (32.3 mg, 32.33% yield) as a white solid. LCMS (ESI, m/z): [M+H]⁺ = 568.3.¹H NMR (300 MHz, DMSO-d6) δ 10.86 (s, 1H), 7.30 – 7.08 (m, 4H), 6.97 (s, 1H), 6.66 (s, 1H), 6.15 (s, 1H), 3.66 (s, 5H), 3.28 – 3.11 (m, 5H), 3.00 (s, 1H), 2.92 (s, 1H), 2.77 – 2.67 (m, 2H), 2.65 – 2.56 (m, 1H), 2.41 (s, 4H), 2.35 – 2.22 (m, 3H), 1.98 (s, 1H), 1.55 (s, 5H), 1.25 – 1.15 (m, 2H). [01017] A solution of tert-butyl 4-{[(6R)-2,2-difluoro-6-[4-(methoxycarbonyl)-2-[(oxan-4- ylmethyl)amino]phenyl]-7-azaspiro[3.5]nonan-7-yl]methyl}-5-methoxy-7-methylindole-1-carboxylate (120 mg, 0.18 mmol, 1 equiv) and Potassium hydroxide (98.74 mg, 1.76 mmol, 10 equiv) in Ethanol (0.9 mL) and water (0.3 mL) was stirred at 80 °C for 2h. The mixture was acidified to pH< 7 with sat. citric acid. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in Water (10mmol/L Ammonium bicarbonate), 10% to 50% gradient in 10 min; detector, UV 254 nm.to afford 4-[(6R)-2,2-difluoro-7-[(5-methoxy-7-methyl-1H-indol-4-yl)methyl]- 7-azaspiro[3.5]nonan-6-yl]-3-[(oxan-4-ylmethyl)amino]benzoic acid (34.3 mg, 34.33% yield) as a white solid. LCMS (ESI, m/z): [M+H]⁺ = 568.3.¹H NMR (300 MHz, DMSO-d6) δ 12.62 (s, 1H), 10.86 (s, 1H), 7.30 – 7.10 (m, 4H), 6.98 (s, 1H), 6.66 (s, 1H), 6.15 (s, 1H), 3.66 (s, 6H), 3.28 – 3.12 (m, 4H), 3.05 – 2.88 (m, 2H), 2.77 – 2.55 (m, 2H), 2.41 (s, 4H), 2.35 – 2.23 (m, 2H), 1.98 (s, 1H), 1.55 (s, 6H), 1.28 – 1.10 (m, 3H). [01018] Example 50.4-[(6R)-2,2-Difluoro-7-[(5-methoxy-7-methyl-1H-indol-4-yl)methyl]-7- azaspiro[3.5]nonan-6-yl]-3-[(oxetan-3-ylmethyl)amino]benzoic acid& 4-[(6S)-2,2-difluoro-7-[(5-methoxy-7- methyl-1H-indol-4-yl)methyl]-7-azaspiro[3.5]nonan-6-yl]-3-[(oxetan-3-ylmethyl)amino]benzoic acid. [01019] Procedure:

]-7-

azaspiro[3.5]non-5-ene-7-carboxylate (500 mg, 1.17 mmol, 1 equiv) and 1-(oxetan-3-yl)methanamine (356.33 mg, 4.09 mmol, 3.5 equiv), Cesium carbonate (761.49 mg, 2.34 mmol, 2 equiv), 3-chloropyridine [1,3-bis[2,6-bis(heptan-4-yl)phenyl]-4,5-dichloro-2,3-dihydro-1H-imidazol-2-yl]dichloropalladium (45.52 mg, 0.047 mmol, 0.1 equiv) in 1,4-dioxane (5 mL) was stirred at 110 °C for 12h under nitrogen atmosphere. The reaction was quenched with sat. Ammonium chloride (aq.) at room temperature. The resulting mixture was extracted with Ethyl acetate. The combined organic layers were washed with water, dried over anhydrous Sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with Petroleum ether/Ethyl acetate (5:1) to afford tert- butyl 2,2-difluoro-6-[4-(methoxycarbonyl)-2-[(oxetan-3-ylmethyl)amino]phenyl]-7-azaspiro[3.5]non-5-ene- 7-carboxylate (350 mg, 62.59% yield) as a yellow oil. LCMS (ESI, m/z): [M+H]⁺ = 478.5 [01022] Step 2: Methyl 4-{2,2-difluoro-7-azaspiro[3.5]nonan-6-yl}-3-[(oxetan-3- ylmethyl)amino]benzoate [01023] A solution of tert-butyl 2,

y onyl)-2-[(oxetan-3- ylmethyl)amino]phenyl]-7-azaspiro[3.5]non-5-ene-7-carboxylate (400 mg, 0.73 mmol, 1 equiv) and 10% Pd/C (200 mg) in ethyl acetate (10 mL) was stirred at room temperature for 3h under hydrogen atmosphere.The resulting mixture was filtered, the filter cake was washed with ethyl acetate (3 × 30 mL). The filtrate was concentrated under reduced pressure to afford tert-butyl 2,2-difluoro-6-(4-(methoxycarbonyl)-2- ((oxetan-3-ylmethyl)amino)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (350 mg crude) as a yellow solid. Then a solution of tert-butyl 2,2-difluoro-6-(4-(methoxycarbonyl)-2-((oxetan-3-ylmethyl)amino)phenyl)-7- azaspiro[3.5]nonane-7-carboxylate (350 mg) in trifluoroacetic acid (2 mL) and Dichloromethane (2 mL) was stirred at 0 °C for 1h. The reaction was quenched with sat. Sodium bicarbonate (aq.) at room temperature. The resulting mixture was extracted with Ethyl acetate. The combined organic layers were washed with water, dried over anhydrous Sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in Water (10mmol/L Ammonium bicarbonate), 10% to 50% gradient in 10 min; detector, UV 254 nm. to afford methyl 4-{2,2-difluoro-7-azaspiro[3.5]nonan-6-yl}-3- [(oxetan-3-ylmethyl)amino]benzoate (100 mg, 36.09% yield) as a white solid. LCMS (ESI, m/z): [M+H]⁺ = 380.4 [01024] Step 3: tert-Butyl 4-({2,2-difluoro-6-[4-(methoxycarbonyl)-2-[(oxetan-3- ylmethyl)amino]phenyl]-7-azaspiro[3.5]nonan-7-yl}methyl)-5-methoxy-7-methylindole-1-carboxylate O O F F [01025] A solution of methyl 4-{2

nan-6-yl}-3-[(oxetan-3- ylmethyl)amino]benzoate (150 mg, 0.39 mmol, 1 equiv) and tert-butyl 4-(chloromethyl)-5-methoxy-7- methylindole-1-carboxylate (244.29 mg, 0.79 mmol, 2 equiv) Potassium iodide (98.18 mg, 0.59 mmol, 1.5 equiv), Cesium carbonate (385.40 mg, 1.18 mmol, 3 equiv) in N,N-Dimethylformamide (2 mL) was stirred at 50 °C for 1h. The reaction was quenched with sat. Ammonium chloride (aq.) at room temperature. The resulting mixture was extracted with Ethyl acetate. The combined organic layers were washed with water, dried over anhydrous Sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in Water (10mmol/L Ammonium bicarbonate), 10% to 50% gradient in 10 min; detector, UV 254 nm. to afford tert-butyl 4-({2,2-difluoro-6-[4-(methoxycarbonyl)-2- [(oxetan-3-ylmethyl)amino]phenyl]-7-azaspiro[3.5]nonan-7-yl}methyl)-5-methoxy-7-methylindole-1- carboxylate (100 mg, 38.79% yield) as a white solid. LCMS (ESI, m/z): [M+H]⁺ = 653.8 [01026] Step 4: tert-Butyl 4-{[(6R)-2,2-difluoro-6-[4-(methoxycarbonyl)-2-[(oxetan-3- ylmethyl)amino]phenyl]-7-azaspiro[3.5]nonan-7-yl]methyl}-5-methoxy-7-methylindole-1-carboxylate & tert- butyl 4-{[(6S)-2,2-difluoro-6-[4-(methoxycarbonyl)-2-[(oxetan-3-ylmethyl)amino]phenyl]-7- azaspiro[3.5]nonan-7-yl]methyl}-5-methoxy-7-methylindole-1-carboxylate [01027] The crude wing conditions: Column:

Lux 5um Cellulose-4, 2.12*25 cm, 5 μm; Mobile Phase A: Hex(0.5% 2M NH3-Methanol)--HPLC, Mobile Phase B: Ethanol--HPLC; Flow rate: 20 mL/min; Gradient: isocratic 15; Wave Length: 220/254 nm; RT1(min): 9.14; RT2(min): 11.076; Sample Solvent: Ethanol. [01028] tert-Butyl 4-{[(6R)-2,2-Difluoro-6-[4-(methoxycarbonyl)-2-[(oxetan-3-ylmethyl)amino]phenyl]- 7-azaspiro[3.5]nonan-7-yl]methyl}-5-methoxy-7-methylindole-1-carboxylate(isomer 1, faster peak, 50 mg, 33% yield) LCMS: (ESI, m/z): 653.3 [M+H]⁺. tR = 1.258 min (Lux Cellulose‐4, 4.6*50 mm, 3 μm, Hex(0.1%DEA):Ethanol=70:30, 1.0 mL/min, 254 nm). [01029] tert-Butyl 4-{[(6S)-2,2-Difluoro-6-[4-(methoxycarbonyl)-2-[(oxetan-3-ylmethyl)amino]phenyl]- 7-azaspiro[3.5]nonan-7-yl]methyl}-5-methoxy-7-methylindole-1-carboxylate(isomer 2, slower peak, 45 mg, 30% yield) LCMS: (ESI, m/z): 653.3 [M+H]⁺. tR = 1.558 min (Lux Cellulose‐4, 4.6*50 mm, 3 μm, Hex(0.1%DEA):Ethanol=70:30, 1.0 mL/min, 254 nm). [01030] Step 5: 4-[(6R)-2,2-Difluoro-7-[(5-methoxy-7-methyl-1H-indol-4-yl)methyl]-7- azaspiro[3.5]nonan-6-yl]-3-[(oxetan-3-ylmethyl)amino]benzoic acid & 4-[(6S)-2,2-Difluoro-7-[(5-methoxy- 7-methyl-1H-indol-4-yl)methyl]-7-azaspiro[3.5]nonan-6-yl]-3-[(oxetan-3-ylmethyl)amino]benzoic acid [01031] A solut

y , y y (oxetan-3- ylmethyl)amino]phenyl]-7-azaspiro[3.5]nonan-7-yl]methyl}-5-methoxy-7-methylindole-1-carboxylate (100 mg, 0.15 mmol, 1 equiv) and Potassium hydroxide (85.82 mg, 1.53 mmol, 10 equiv) in Ethanol (0.9 mL) and water (0.5ml) was stirred at 80 °C for 2h . The mixture was acidified to pH = 6 with sat. citric acid. The solvent was removed. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in Water (10mmol/L Ammonium bicarbonate), 10% to 50% gradient in 10 min; detector, UV 254 nm.to afford 4-[(6R)-2,2-difluoro-7-[(5-methoxy-7-methyl- 1H-indol-4-yl)methyl]-7-azaspiro[3.5]nonan-6-yl]-3-[(oxetan-3-ylmethyl)amino]benzoic acid (20.9 mg, 25.32 % yield) as a white solid. LCMS (ESI, m/z): [M+H]⁺ = 540.3.¹H NMR (300 MHz, DMSO-d6) δ 12.69 (s, 1H), 10.88 (s, 1H), 7.32 – 7.26 (m, 1H), 7.24 (s, 2H), 7.20 (s, 1H), 6.68 (s, 1H), 6.18 (s, 1H), 4.62 – 4.47 (m, 2H), 4.37 – 4.27 (m, 1H), 4.27 – 4.19 (m, 1H), 3.73 (s, 1H), 3.67 (s, 3H), 3.44 – 3.35 (m, 2H), 3.28 – 3.12 (m, 3H), 2.76 – 2.53 (m, 3H), 2.49 – 2.40 (m, 4H), 2.40 – 2.22 (m, 3H), 2.00 (s, 1H), 1.61 – 1.42 (m, 3H). [01032] A solution of tert-butyl 4-{[(6S)-2,2-difluoro-6-[4-(methoxycarbonyl)-2-[(oxetan-3- ylmethyl)amino]phenyl]-7-azaspiro[3.5]nonan-7-yl]methyl}-5-methoxy-7-methylindole-1-carboxylate (100 mg, 0.15 mmol, 1 equiv) and Potassium hydroxide (85.82 mg, 1.53 mmol, 10 equiv) in Ethanol (0.9 mL) and water (0.5ml) was stirred at 80 °C for 2h. The mixture was acidified to pH = 6 with sat. citric acid. The solvent was removed. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in Water (10mmol/L Ammonium bicarbonate), 10% to 50% gradient in 10 min; detector, UV 254 nm. to afford 4-[(6S)-2,2-difluoro-7-[(5-methoxy-7- methyl-1H-indol-4-yl)methyl]-7-azaspiro[3.5]nonan-6-yl]-3-[(oxetan-3-ylmethyl)amino]benzoic acid (18 mg, 21.81% yield) as a white solid. LCMS (ESI, m/z): [M+H]⁺ = 540.3.¹H NMR (300 MHz, DMSO-d6) δ 12.60 (s, 1H), 10.89 (s, 1H), 7.32 – 7.26 (m, 1H), 7.23 (s, 2H), 7.20 (s, 1H), 6.68 (s, 1H), 6.18 (s, 1H), 4.62 – 4.47 (m, 2H), 4.37 – 4.28 (m, 1H), 4.28 – 4.19 (m, 1H), 3.76 – 3.68 (m, 1H), 3.67 (s, 3H), 3.47 – 3.38 (m, 2H), 3.28 – 3.12 (m, 3H), 2.79 – 2.57 (m, 3H), 2.49 – 2.40 (m, 4H), 2.40 – 2.22 (m, 3H), 2.09 – 1.97 (m, 1H), 1.61 – 1.40 (m, 3H). [01033] Example 51.4-[(6S)-2,2-Difluoro-7-[(5-methoxy-7-methyl-1H-indol-4-yl)methyl]-7- azaspiro[3.5]nonan-6-yl]-3-[(2-methanesulfonylethyl)amino]benzoic acid & 4-[(6R)-2,2-difluoro-7-[(5- methoxy-7-methyl-1H-indol-4-yl)methyl]-7-azaspiro[3.5]nonan-6-yl]-3-[(2- methanesulfonylethyl)amino]benzoic acid.

[01034] Procedure: [0

(methoxycarbonyl)p

henyl}-7-azaspiro[3.5]non-5-ene-7-carboxylate [01036] A mixture of tert-butyl 6-[

l)phenyl]-2,2-difluoro-7- azaspiro[3.5]non-5-ene-7-carboxylate (500 mg, 1.17 mmol, 1 equiv) and 2-methanesulfonylethanamine (650 mg, 5.28 mmol, 4.52 equiv) and {1,3-bis[2,6-bis(heptan-4-yl)phenyl]-4,5-dichloro-2,3-dihydro-1H-imidazol- 2-yl}dichloro(3-chloro-1lambda4-pyridin-1-yl)palladium (102 mg, 0.11 mmol, 0.09 equiv) and cesium carbonate (1139 mg, 3.50 mmol, 2.99 equiv) in 1,4-dioxane (6 mL) was stirred at 110 °C for 3h. The reaction was quenched with sat. Ammonium chloride (aq.) at room temperature. The resulting mixture was extracted with Ethyl acetate. The combined organic layers were washed with water, dried over anhydrous Sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in Water (10mmol/L Ammonium bicarbonate), 10% to 50% gradient in 10 min; detector, UV 254 nm.to afford tert-butyl 2,2-difluoro-6-{2-[(2-methanesulfonylethyl)amino]-4-(methoxycarbonyl)phenyl}- 7-azaspiro[3.5]non-5-ene-7-carboxylate (200 mg) as a yellow solid. LCMS (ESI, m/z): [M+H]⁺ = 515.5. [01037] Step 2: Methyl 4-{2,2-difluoro-7-azaspiro[3.5]nonan-6-yl}-3-[(2- methanesulfonylethyl)amino]benzoate [01038] A mixture of tert-butyl 2, lfonylethyl)amino]-4-

(methoxycarbonyl)phenyl}-7-azaspiro[3.5]non-5-ene-7-carboxylate (200 mg, 0.39 mmol, 1 equiv) and Sodium borohydride (146.00 mg, 3.86 mmol, 9.93 equiv) in Dichloromethane (2 mL) and trifluoroacetic acid (1 mL) was stirred at room temperature for 1h .The mixture was basified to pH 8 with saturated Sodium bicarbonate (aq.). The resulting mixture was extracted with Dichloromethane. The combined organic layers were washed with water, dried over anhydrous Sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in Water (10mmol/L Ammonium bicarbonate), 10% to 50% gradient in 10 min; detector, UV 254 nm. to afford methyl4-{2,2-difluoro-7-azaspiro[3.5]nonan- 6-yl}-3-[(2-methanesulfonylethyl)amino]benzoate (150 mg) as a white solid. LCMS (ESI, m/z): [M+H]⁺ = 417.4. [01039] Step 3: tert-Butyl 4-[(2,2-difluoro-6-{2-[(2-methanesulfonylethyl)amino]-4- (methoxycarbonyl)phenyl}-7-azaspiro[3.5]nonan-7-yl)methyl]-5-methoxy-7-methylindole-1-carboxylate [01040] A solution of methyl 4-{2

, p . nan-6-yl}-3-[(2- methanesulfonylethyl)amino]benzoate (150 mg, 0.36 mmol, 1 equiv) in 1,2-Dichloroethane (1 mL) was treated with tert-butyl 4-formyl-5-methoxy-7-methylindole-1-carboxylate (150 mg, 0.52 mmol, 1.44 equiv) and AcOH (22 mg, 0.37 mmol, 1.02 equiv) at 70 °C for 1h, followed by the addition of sodium bis(acetyloxy)boranuidyl acetate (230 mg, 1.09 mmol, 3.01 equiv) in portions at 70 °C.The resulting mixture was stirred at 70 °C for 10 h. The reaction was quenched with sat. Ammonium chloride (aq.) at room temperature. The resulting mixture was extracted with Ethyl acetate. The combined organic layers were washed with water, dried over anhydrous Sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with Petroleum ether/Ethyl acetate (12:1) to afford tert-butyl 4-[(2,2-difluoro-6-{2-[(2-methanesulfonylethyl)amino]-4- (methoxycarbonyl)phenyl}-7-azaspiro[3.5]nonan-7-yl)methyl]-5-methoxy-7-methylindole-1-carboxylate (100 mg) as a yellow solid. LCMS (ESI, m/z): [M+H]⁺ = 690.8. [01041] Step 4: tert-Butyl 4-{[(6S)-2,2-difluoro-6-{2-[(2-methanesulfonylethyl)amino]-4- (methoxycarbonyl)phenyl}-7-azaspiro[3.5]nonan-7-yl]methyl}-5-methoxy-7-methylindole-1-carboxylate (isomer 1, faster peak) & tert-Butyl 4-{[(6R)-2,2-difluoro-6-{2-[(2-methanesulfonylethyl)amino]-4- (methoxycarbonyl)phenyl}-7-azaspiro[3.5]nonan-7-yl]methyl}-5-methoxy-7-methylindole-1-carboxylate (isomer 2, slower peak) [01042] tert-Butyl

ethoxycarbonyl)phenyl}- 7-azaspiro[3.5]nonan-7-yl)methyl]-5-methoxy-7-methylindole-1-carboxylate (100 mg,0.144 mmol)was applied for further separation by Chiral HPLC with the following condition: Column: CHIRALPAK IA 2*25 cm, 5 μm; Mobile Phase A: HEX(0.5% 2M NH3-Methanol), Mobile Phase B: Ethanol; Flow rate: 20 mL/min; Gradient: isocratic 30; Wave Length: 220/254 nm; RT1(min): 7.002; RT2(min): 8.362; Sample Solvent: ETOH; Injection Volume: 0.3 mL; Number Of Runs: 18. [01043] tert-Butyl 4-{[(6S)-2,2-difluoro-6-{2-[(2-methanesulfonylethyl)amino]-4- (methoxycarbonyl)phenyl}-7-azaspiro[3.5]nonan-7-yl]methyl}-5-methoxy-7-methylindole-1-carboxylate (isomer 1, faster peak, 50 mg, 40 mg,40.0% yield) as a white solid. LCMS (ESI, m/z): [M+H]⁺ = 690.8. t_R = 1.48 min (CHIRALPAK IA-34.6*50 mm 3 μm; Mobile phase: Hex(0.1%DEA):EtOH=70:30 Flow rate: Flow 1.000 mL/min; [01044] tert-Butyl 4-{[(6R)-2,2-difluoro-6-{2-[(2-methanesulfonylethyl)amino]-4- (methoxycarbonyl)phenyl}-7-azaspiro[3.5]nonan-7-yl]methyl}-5-methoxy-7-methylindole-1-carboxylate (isomer 2, slower peak, 38 mg,38.0% yield) as a white solid. LCMS (ESI, m/z): [M+H]⁺ = 690.8. t_R = 1.76 min (CHIRALPAK IA-34.6*50 mm 3 μm; Mobile phase: Hex(0.1%DEA):EtOH=70:30 Flow rate: Flow 1.000 mL/min; [01045] Step 5: 4-[(6S)-2,2-difluoro-7-[(5-methoxy-7-methyl-1H-indol-4-yl)methyl]-7- azaspiro[3.5]nonan-6-yl]-3-[(2-methanesulfonylethyl)amino]benzoic acid & 4-[(6R)-2,2-difluoro-7-[(5- methoxy-7-methyl-1H-indol-4-yl)methyl]-7-azaspiro[3.5]nonan-6-yl]-3-[(2- methanesulfonylethyl)amino]benzoic acid [01046] A mixt yl)amino]-4-

(methoxycarbonyl)phenyl}-7-azaspiro[3.5]nonan-7-yl]methyl}-5-methoxy-7-methylindole-1-carboxylate (isomer 1, faster peak) (40 mg, 0.058 mmol, 1 equiv) and Potassium hydroxide (32.01 mg, 0.57 mmol, 9.84 equiv) in Ethanol (0.9 mL) and water (0.3 mL) was stirred at 80 °C for 1.5 h. The mixture was acidified to pH = 6 with sat. citric acid. The solvent was removed. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in Water (10mmol/L Ammonium bicarbonate), 10% to 50% gradient in 10 min; detector, UV 254 nm. to afford 4- [(6S)-2,2-difluoro-7-[(5-methoxy-7-methyl-1H-indol-4-yl)methyl]-7-azaspiro[3.5]nonan-6-yl]-3-[(2- methanesulfonylethyl)amino]benzoic acid (14.9 mg, 44.64% yield) as a white solid. LCMS (ESI, m/z): [M+H]⁺=576.6.¹H NMR (300 MHz, DMSO-d6) δ 10.91 (s, 1H), 7.33 – 7.21 (m, 3H), 7.18 (s, 1H), 6.69 (s, 1H), 6.27 (s, 1H), 3.75 – 3.51 (m, 6H), 3.48 – 3.38(m, 2H), 3.33 – 3.22(m, 3H), 3.03 (s, 3H), 2.69 (s, 2H), 2.48 – 2.36 (m, 4H), 2.34 – 2.20 (m, 3H), 1.98(s, 1H), 1.64 (s, 1H), 1.54 – 1.43 (m, 2H). [01047] A mixture of tert-butyl 4-{[(6S)-2,2-difluoro-6-{2-[(2-methanesulfonylethyl)amino]-4- (methoxycarbonyl)phenyl}-7-azaspiro[3.5]nonan-7-yl]methyl}-5-methoxy-7-methylindole-1-carboxylate (isomer 2, slower peak) (40 mg, 0.058 mmol, 1 equiv) and Potassium hydroxide (32.01 mg, 0.57 mmol, 9.84 equiv) in Ethanol (0.9 mL) and water (0.3 mL) was stirred at 80 °C for 1.5h. The mixture was acidified to pH = 6 with sat. citric acid. The solvent was removed. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in Water (10mmol/L Ammonium bicarbonate), 10% to 50% gradient in 10 min; detector, UV 254 nm.to afford 4- [(6R)-2,2-difluoro-7-[(5-methoxy-7-methyl-1H-indol-4-yl)methyl]-7-azaspiro[3.5]nonan-6-yl]-3-[(2- methanesulfonylethyl)amino]benzoic acid (17.4 mg, 52.13% yield) as a white solid. LCMS (ESI, m/z): [M+H]⁺ = 576.6.¹H NMR (300 MHz, DMSO-d6) δ 10.91 (s, 1H), 7.35 – 7.12 (m, 4H), 6.69 (s, 1H), 6.27 (s, 1H), 3.76 – 3.55 (m, 6H), 3.48 – 3.38(m,2H), 3.28 – 3.19 (m, 2H), 3.03 (s, 3H), 2.76 – 2.66 (m, 2H), 2.48 – 2.40 (m, 4H), 2.35 – 2.21 (m, 3H), 1.96 (s, 1H), 1.71 – 1.57 (m, 2H), 1.53 – 1.43 (m, 2H). [01048] Example 52. (S)-4-(2,2-Difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)-3-((2-methoxyethyl)amino)benzoic acid & (R)-4-(2,2-difluoro-7-((5-methoxy-7- methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)-3-((2-methoxyethyl)amino)benzoic acid. F F

p y , y y y y p y azaspiro[3.5]non-5-ene-7-carboxylate [01051] A solution of tert-butyl 6- l)phenyl]-2,2-difluoro-7-

azaspiro[3.5]non-5-ene-7-carboxylate (1 g, 2.34 mmol), (SP-4-1)-[1,3-BIs[2,6-bis(1-ethylpropyl)phenyl]-4,5- dichloro-1,3-dihydro-2H-imidazol-2-ylidene]dichloro(2-methylpyridine)palladium (200 mg, 0.24 mmol), Cesium carbonate (1.52 g, 4.67 mmol) in 1,4-dioxane (15 mL) was treated with ethanamine, 2-methoxy- (0.88 g, 11.72 mmol) at room temperature. The resulting mixture was stirred at 80 °C for 1h under nitrogen atmosphere. The resulting mixture was quenched with water and extracted with Ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with Petroleum ether/Ethyl acetate (5:1) to afford the title compound (600 mg, 49.53% yield) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ =467.2 [01052] Step 2: methyl 4-(2,2-difluoro-7-azaspiro[3.5]nonan-6-yl)-3-((2-methoxyethyl)amino)benzoate [01053] To a stirred solution of te

hoxycarbonyl)-2-[(2- methoxyethyl)amino]phenyl]-7-azaspiro[3.5]non-5-ene-7-carboxylate (800 mg, 1.72 mmol) and Sodium borohydride (600 mg, 15.86 mmol) in Dichloromethane (8 mL) was added Trifluoroacetic acid (8 mL) dropwise at 0 °C. The reaction was quenched with sat. Sodium bicarbonate (aq.). The resulting mixture was extracted with Dichloromethane. The combined organic layers were washed with brine, dried over anhydrous Sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with Dichloromethane/Methanol (10:1) to afford the title compound (400 mg, 56.98% yield) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ =369.2 [01054] Step 3: tert-Butyl 4-((2,2-difluoro-6-(4-(methoxycarbonyl)-2-((2-methoxyethyl)amino)phenyl)-7- azaspiro[3.5]nonan-7-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate

[01055] A solution of methyl 4-{2 nan-6-yl}-3-[(2-

methoxyethyl)amino]benzoate (300 mg, 0.82 mmol), Cesium carbonate (780 mg, 2.39 mmol),Potassium iodide (150 mg, 0.91 mmol) and tert-butyl 4-(chloromethyl)-5-methoxy-7-methylindole-1-carboxylate (510 mg, 1.65 mmol) in DMF (5 mL) was stirred at 50 °C for 1h. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with water. The resulting mixture was extracted with Ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in Water (10mmol/L Ammonium bicarbonate), 5% to 100% gradient in 30 min; detector, UV 254 nm to afford the title compound (220 mg, 39.99% yield) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ =642.3 [01056] Step 4: tert-Butyl (S)-4-((2,2-difluoro-6-(4-(methoxycarbonyl)-2-((2- methoxyethyl)amino)phenyl)-7-azaspiro[3.5]nonan-7-yl)methyl)-5-methoxy-7-methyl-1H-indole-1- carboxylate (isomer 1, faster peak) & tert-butyl (R)-4-((2,2-difluoro-6-(4-(methoxycarbonyl)-2-((2- methoxyethyl)amino)phenyl)-7-azaspiro[3.5]nonan-7-yl)methyl)-5-methoxy-7-methyl-1H-indole-1- carboxylate (isomer 2, slower peak) [01057] tert-Butyl

, l)amino)phenyl)-7- azaspiro[3.5]nonan-7-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (220 mg, 0.34 mmol) was applied for further separation by Chiral HPLC with the following condition: Column: CHIRALPAK AD 2*25 cm, 5 μm; Mobile Phase A: HEX(0.5% 2M NH3-Methanol), Mobile Phase B: IPA; Flow rate: 20 mL/min; Gradient: isocratic 5; Wave Length: 220/254 nm; RT1(min): 9.177; RT2(min): 15.749; Sample Solvent: ETOH; Injection Volume: 1.0 mL; Number Of Runs: 6. [01058] tert-Butyl (S)-4-((2,2-difluoro-6-(4-(methoxycarbonyl)-2-((2-methoxyethyl)amino)phenyl)-7- azaspiro[3.5]nonan-7-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (isomer 1, faster peak) (100 mg, 45.46% yield) . LCMS (ESI, m/z): [M+H]⁺ =642.3. tR = 2.172 min (CHIRALPAK AD‐34.6*50 mm,3 um), Hex(0.1%DEA):IPA=95:5, 1.0 mL/min, 254 nm). [01059] tert-Butyl (R)-4-((2,2-difluoro-6-(4-(methoxycarbonyl)-2-((2-methoxyethyl)amino)phenyl)-7- azaspiro[3.5]nonan-7-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (isomer 2, slower peak) (90 mg, 40.91% yield) as a white solid. LCMS (ESI, m/z): [M+H]⁺ = 642.3. tR = 3.417 min (CHIRALPAK AD‐3 4.6*50 mm,3 um), Hex(0.1%DEA):IPA=95:5, 1.0 mL/min, 254 nm). [01060] Step 6: (S)-4-(2,2-Difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)-3-((2-methoxyethyl)amino)benzoic acid & (R)-4-(2,2-difluoro-7-((5-methoxy-7- methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)-3-((2-methoxyethyl)amino)benzoic acid [01061] A soluti

2- methoxyethyl)amino)phenyl)-7-azaspiro[3.5]nonan-7-yl)methyl)-5-methoxy-7-methyl-1H-indole-1- carboxylate (isomer 1, faster peak) (90 mg, 0.14 mmol) and Potassium hydroxide (119 mg, 2.12 mmol) in ethanol (2 mL) and water (2 mL) was stirred for 1h at 80 °C. The reaction mixture was acidified to pH = 6 with sat. citric acid solution. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in Water (10mmol/L Ammonium bicarbonate), 5% to 50% gradient in 20 min; detector, UV 220 nm. The resulting mixture was concentrated under reduced pressure. The resulting liquid was dried by lyophilization. This resulted in (S)-4-(2,2-difluoro- 7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)-3-((2- methoxyethyl)amino)benzoic acid (47.5 mg, 64.13% yield) as a white solid. LCMS (ESI, m/z): [M+H] ⁺ =528.4.¹H NMR (300 MHz, DMSO-d₆) δ 12.64 (s, 1H), 10.89 (s, 1H), 7.30 – 7.14 (m, 5H), 6.68 (s, 1H), 6.34 (s, 1H), 3.78 – 3.64 (m, 4H), 3.54 – 3.44 (m, 2H), 3.41 – 3.31 (m, 4H), 3.21 (s, 3H), 2.79 – 2.55 (m, 2H), 2.43 (s, 4H), 2.38 – 2.23 (m, 3H), 1.93 (s, 1H), 1.53 (s, 3H). [01062] A solution of tert-butyl (R)-4-((2,2-difluoro-6-(4-(methoxycarbonyl)-2-((2- methoxyethyl)amino)phenyl)-7-azaspiro[3.5]nonan-7-yl)methyl)-5-methoxy-7-methyl-1H-indole-1- carboxylate (isomer 2, slower peak) (90 mg, 0.14 mmol) and Potassium hydroxide (119 mg, 2.12 mmol) in ethanol (2 mL) and water (2 mL) was stirred for 1h at 80 °C. The reaction mixture was acidified to pH = 6 with sat. citric acid solution. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in Water (10mmol/L Ammonium bicarbonate), 5% to 50% gradient in 20 min; detector, UV 220 nm. The resulting mixture was concentrated under reduced pressure. The resulting liquid was dried by lyophilization. This resulted in (R)-4-(2,2-difluoro- 7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)-3-((2- methoxyethyl)amino)benzoic acid (53.8 mg, 72.56% yield) as a white solid. LCMS (ESI, m/z): [M+H] ⁺ =528.4.¹H NMR (300 MHz, DMSO-d6) δ 12.64 (s, 1H), 10.87 (s, 1H), 7.34 – 7.06 (m, 5H), 6.68 (s, 1H), 6.39 – 6.31 (m, 1H), 3.69 (s, 4H), 3.53 – 3.43 (m, 2H), 3.39 – 3.26 (m, 4H), 3.21 (s, 3H), 2.74 – 2.56 (m, 2H), 2.43 (s, 4H), 2.38 – 2.24 (m, 3H), 1.93 (s, 1H), 1.52 (s, 3H). [01063] Example 53.3-[(Cyclopropylmethyl)amino]-4-[(6S)-2,2-difluoro-7-[(5-methoxy-7-methyl-1H- indol-4-yl)methyl]-7-azaspiro[3.5]nonan-6-yl]benzoic acid & 3-[(cyclopropylmethyl)amino]-4-[(6S)-2,2- difluoro-7-[(5-methoxy-7-methyl-1H-indol-4-yl)methyl]-7-azaspiro[3.5]nonan-6-yl]benzoic acid.

[ ro-7-

azaspiro[3.5]non-5-ene-7-carboxylate

l)phenyl]-2,2-difluoro-7- azaspiro[3.5]non-5-ene-7-carboxylate (500 mg, 1.17 mmol, 1 equiv) and 1-cyclopropylmethanamine (290.90 mg, 4.09 mmol, 3.5 equiv), Cesium carbonate (761.49 mg, 2.34 mmol, 2 equiv), 3-chloropyridine;{1,3- bis[2,6-bis(heptan-4-yl)phenyl]-4,5-dichloro-2,3-dihydro-1H-imidazol-2-yl}dichloropalladium (113.80 mg, 0.12 mmol, 0.1 equiv) in 1,4-dioxane (2 mL) was stirred at 80 °C for 12h. The resulting mixture was diluted with water. The resulting mixture was extracted with Ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with Petroleum ether/Ethyl acetate (5:1) to afford tert-butyl 6-{2-[(cyclopropylmethyl)amino]-4-(methoxycarbonyl)phenyl}- 2,2-difluoro-7-azaspiro[3.5]non-5-ene-7-carboxylate (300 mg, 55.50% yield) as a yellow oil. LCMS (ESI, m/z): [M+H]⁺ = 426.5 [01067] Step 2: Methyl 3-[(cyclopropylmethyl)amino]-4-{2,2-difluoro-7-azaspiro[3.5]nonan-6- yl}benzoate [01068] A solution of tert-butyl 6 o]-4-(methoxycarbonyl)phenyl}-2,2- difluoro-7-azaspiro[3.5]non-5-ene-7-c

arboxylate (400 mg, 0.87 mmol, 1 equiv) and Sodium cyanoborohydride (543.44 mg, 8.65 mmol, 10 equiv) in Dichloromethane (4 mL) and trifluoroacetic acid (4 mL) was stirred at 0 °C for 1h. The reaction was quenched with sat. Sodium bicarbonate (aq.) at room temperature. The resulting mixture was extracted with Dichloromethane. The combined organic layers were washed with water, dried over anhydrous Sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in Water (10mmol/L Ammonium bicarbonate), 10% to 50% gradient in 10 min; detector, UV 254 nm.to afford methyl 3-[(cyclopropylmethyl)amino]-4-{2,2- difluoro-7-azaspiro[3.5]nonan-6-yl}benzoate (200 mg, 63.46% yield) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 364.4 [01069] Step 3: tert-Butyl 4-[(6-{2-[(cyclopropylmethyl)amino]-4-(methoxycarbonyl)phenyl}-2,2- difluoro-7-azaspiro[3.5]nonan-7-yl)methyl]-5-methoxy-7-methylindole-1-carboxylate [01070] A solution of methyl 3-[(

{2,2-difluoro-7-azaspiro[3.5]nonan-6- yl}benzoate (100 mg, 0.27 mmol, 1 equiv) and tert-butyl 4-formyl-5-methoxy-7-methylindole-1-carboxylate (158.78 mg, 0.55 mmol, 2 equiv) sodium bis(acetyloxy)boranuidyl acetate (174.47 mg, 0.82 mmol, 3 equiv) in 1,2-Dichloroethane (1 mL), Acetic acid (1 mL) was stirred at 70 °C for overnight. The resulting mixture was diluted with water. The resulting mixture was extracted with Ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in Water (10mmol/L Ammonium bicarbonate), 10% to 50% gradient in 10 min; detector, UV 254 nm. to afford tert-butyl 4-[(6-{2- [(cyclopropylmethyl)amino]-4-(methoxycarbonyl)phenyl}-2,2-difluoro-7-azaspiro[3.5]nonan-7-yl)methyl]-5- methoxy-7-methylindole-1-carboxylate (100 mg, 57.14% yield) as a white solid. LCMS (ESI, m/z): [M+H]⁺ = 637.8 [01071] Step 4: tert-Butyl 4-{[(6R)-6-{2-[(cyclopropylmethyl)amino]-4-(methoxycarbonyl)phenyl}-2,2- difluoro-7-azaspiro[3.5]nonan-7-yl]methyl}-5-methoxy-7-methylindole-1-carboxylate & tert-butyl 4-{[(6S)- 6-{2-[(cyclopropylmethyl)amino]-4-(methoxycarbonyl)phenyl}-2,2-difluoro-7-azaspiro[3.5]nonan-7- yl]methyl}-5-methoxy-7-methylindole-1-carboxylate [01072] The crud ing conditions: Column:

CHIRALPAK SB 2*25 cm, 5 μm; Mobile Phase A: HEX(0.5% 2M NH3-Methanol), Mobile Phase B: Ethanol; Flow rate: 20 mL/min; Gradient: isocratic 10; Wave Length: 220/254 nm; RT1(min): 5.558; RT2(min): 6.295; Sample Solvent: ETOH. [01073] tert-butyl 4-{[(6R)-6-{2-[(cyclopropylmethyl)amino]-4-(methoxycarbonyl)phenyl}-2,2-difluoro- 7-azaspiro[3.5]nonan-7-yl]methyl}-5-methoxy-7-methylindole-1-carboxylate(isomer 1, faster peak, 30 mg, 30% yield) LCMS: (ESI, m/z): 637.3 [M+H]⁺. tR = 1.66 min (CHIRALPAK IK-3, 4.6*50 mm 3 μm, HEX(0.1%DEA):IPA=98:2, 1.0 mL/min, 254 nm). [01074] tert-butyl 4-{[(6S)-6-{2-[(cyclopropylmethyl)amino]-4-(methoxycarbonyl)phenyl}-2,2-difluoro- 7-azaspiro[3.5]nonan-7-yl]methyl}-5-methoxy-7-methylindole-1-carboxylate(isomer 2, slower peak, 35 mg, 35% yield) LCMS: (ESI, m/z): 637.3 [M+H]⁺. tR = 1.86 min (CHIRALPAK IK-3, 4.6*50 mm 3 μm, HEX(0.1%DEA):IPA=98:2, 1.0 mL/min, 254 nm) [01075] Step 5: 3-[(Cyclopropylmethyl)amino]-4-[(6R)-2,2-difluoro-7-[(5-methoxy-7-methyl-1H-indol-4- yl)methyl]-7-azaspiro[3.5]nonan-6-yl]benzoic acid & 3-[(cyclopropylmethyl)amino]-4-[(6S)-2,2-difluoro-7- [(5-methoxy-7-methyl-1H-indol-4-yl)methyl]-7-azaspiro[3.5]nonan-6-yl]benzoic acid

[01076] A soluti thoxycarbonyl)phenyl}-

2,2-difluoro-7-azaspiro[3.5]nonan-7-yl]methyl}-5-methoxy-7-methylindole-1-carboxylate (30 mg, 0.16 mmol, 1 equiv) and Potassium hydroxide (87.97 mg, 1.57 mmol, 10.00 equiv) in Ethanol (0.9 mL), water (0.3 mL) was stirred at 80 °C for 2h. The mixture was acidified to pH< 7 with sat. citric acid. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in Water (10mmol/L Ammonium bicarbonate), 10% to 50% gradient in 10 min; detector, UV 254 nm. to afford 3-[(cyclopropylmethyl)amino]-4-[(6R)-2,2-difluoro-7-[(5-methoxy-7-methyl- 1H-indol-4-yl)methyl]-7-azaspiro[3.5]nonan-6-yl]benzoic acid (14.9 mg, 18.15% yield) as a white solid. LCMS (ESI, m/z): [M+H]⁺ = 524.4.¹H NMR (300 MHz, DMSO-d6) δ 12.66 (s, 1H), 10.87 (s, 1H), 7.39 (s, 2H), 7.26 (s, 4H), 6.66 (s, 1H), 6.30 – 6.23 (m, 2H), 6.14 – 6.07 (m, 2H), 3.66 (s, 5H), 3.44 – 3.34 (m, 2H), 3.27 – 3.20 (m, 1H), 2.74 – 2.56 (m, 2H), 2.41 (s, 4H), 2.35 – 2.23 (m, 3H), 1.95 (s, 1H), 1.51 (s, 3H). [01077] A solution of tert-butyl 4-{[(6S)-6-{2-[(cyclopropylmethyl)amino]-4-(methoxycarbonyl)phenyl}- 2,2-difluoro-7-azaspiro[3.5]nonan-7-yl]methyl}-5-methoxy-7-methylindole-1-carboxylate (35 mg, 0.16 mmol, 1 equiv) and Potassium hydroxide (87.97 mg, 1.57 mmol, 10.00 equiv) in Ethanol (0.9 mL), water (0.3 mL) was stirred at 80 °C for 2h . The mixture was acidified to pH< 7 with sat. citric acid. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in Water (10mmol/L Ammonium bicarbonate), 10% to 50% gradient in 10 min; detector, UV 254 nm.to afford 3-[(cyclopropylmethyl)amino]-4-[(6S)-2,2-difluoro-7-[(5-methoxy-7-methyl- 1H-indol-4-yl)methyl]-7-azaspiro[3.5]nonan-6-yl]benzoic acid (17.5 mg, 21.31% yield) as a white solid. LCMS (ESI, m/z): [M+H]⁺ = 524.4.¹H NMR (300 MHz, DMSO-d6) δ 10.87 (s, 1H), 7.66 – 7.08 (m, 5H), 6.68 – 5.89 (m, 3H), 3.66 (s, 5H), 3.45 – 3.35 (m, 5H), 3.27 – 3.19 (m, 3H), 3.06 – 2.52 (m, 2H), 2.45 – 2.17 (m, 7H), 1.96 (s, 1H), 1.51 (s, 3H). [01078] Example 54. (R)-4-(2,2-Difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)-3-(3,3-difluoroazetidin-1-yl)benzoic acid & (S)-4-(2,2-difluoro-7-((5-methoxy-7- methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)-3-(3,3-difluoroazetidin-1-yl)benzoic acid. ^F F

-7- azaspiro[3.5]non-5-ene-7-carboxylate

yl)phenyl]-2,2-difluoro-7- azaspiro[3.5]non-5-ene-7-carboxylate (2 g, 4.67 mmol), 3,3-difluoroazetidine (1.3 g, 14.02 mmol), (SP-4-1)- [1,3-Bis[2,6-bis(1-propylbutyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazol-2-ylidene]dichloro(3- chloropyridine-κN)-Palladium (393 mg, 0.47 mmol) and Cesium carbonate (7.62 g, 23.37 mmol) in 1,4- dioxane (20 mL) was stirred at 110 °C for 2h under nitrogen atmosphere. The resulting mixture was diluted with water. The resulting mixture was extracted with Ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with Petroleum ether/Ethyl acetate (9:1) to afford the title compound (0.9 g, 39.79% yield) as a yellow solid. LCMS (ESI, m/z): [M+H]⁺ = 485.1. [01082] Step 2: Methyl 4-(2,2-difluoro-7-azaspiro[3.5]nonan-6-yl)-3-(3,3-difluoroazetidin-1-yl)benzoate [01083] A solution of tert-butyl 6- -4-(methoxycarbonyl)phenyl)-2,2-

difluoro-7-azaspiro[3.5]non-5-ene-7-carboxylate (800 mg, 1.65 mmol) and 10% Pd/C (300 mg) in Methanol (10 mL) was stirred at room temperature for 2 h under hydrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with ethyl acetate. The filtrate was concentrated under reduced pressure. The residue was dissolved in Dichloromethane (4 mL) and Trifluoroacetic acid (4 mL) and stirred at room temperature for 1 hour. The resulting mixture was concentrated under reduced pressure. The residue was basified to pH=8 with N,N-Diisopropylethylamine. The resulting mixture was diluted with water. The resulting mixture was extracted with Dichloromethane. The combined organic layers were washed with brine, dried over anhydrous Sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in Water (10mmol/L Ammonium bicarbonate), 40% to 50% gradient in 5 min; detector, UV 254 nm. to afford the title compound (550 mg, 86.20% yield) as yellow oil. LCMS (ESI, m/z): [M+H]⁺ = 387.2. [01084] Step 3: tert-Butyl 4-((6-(2-(3,3-difluoroazetidin-1-yl)-4-(methoxycarbonyl)phenyl)-2,2-difluoro- 7-azaspiro[3.5]nonan-7-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate [01085] A solution of methyl 4-{2

, - uo o- -a asp o . onan-6-yl}-3-(3,3-difluoroazetidin-1- yl)benzoate (500 mg, 1.29 mmol), tert-butyl 4-formyl-5-methoxy-7-methylindole-1-carboxylate (600 mg, 2.07 mmol), tetrakis(propan-2-yloxy)titanium (750 mg, 2.64 mmol) and Sodium triacetoxyborohydride (850 mg, 4.00 mmol) in Tetrahydrofuran (50 mL) was stirred at room temperature for 1 day. The resulting mixture was filtered, the filter cake was washed with ethyl acetate. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with Petroleum ether/Ethyl acetate (7:1) to afford the title compound (160 mg, 18.71% yield) as yellow oil. LCMS (ESI, m/z): [M+H]⁺ =660.5. [01086] Step 4: tert-Butyl (S)-4-((6-(2-(3,3-difluoroazetidin-1-yl)-4-(methoxycarbonyl)phenyl)-2,2- difluoro-7-azaspiro[3.5]nonan-7-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (isomer 1, faster peak) & tert-butyl (R)-4-((6-(2-(3,3-difluoroazetidin-1-yl)-4-(methoxycarbonyl)phenyl)-2,2-difluoro-7- azaspiro[3.5]nonan-7-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (isomer 2, slower peak) [01087] tert-butyl

nyl)-2,2-difluoro-7- azaspiro[3.5]nonan-7-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (160 mg, 0.24mmol) was applied for further separation by Chiral HPLC with the following condition: Column: CHIRALPAK IA, 2*25 cm, 5 μm; Mobile Phase A: HEX(0.5% 2M NH3-Methanol), Mobile Phase B: IPA--HPLC; Flow rate: 20 mL/min; Gradient: isocratic 2; Wave Length: 220/254 nm; RT1(min): 7.69; RT2(min): 10.3; Sample Solvent: Ethanol; Injection Volume: 0.5 mL; Number Of Runs: 12 [01088] tert-butyl (S)-4-((6-(2-(3,3-difluoroazetidin-1-yl)-4-(methoxycarbonyl)phenyl)-2,2-difluoro-7- azaspiro[3.5]nonan-7-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (isomer 1, faster peak) (71 mg) as a white solid. LCMS (ESI, m/z): [M+H]⁺ = 660.5, tR = 1.35 min (CHIRALPAK IA-3, 4.6*50 mm, 3.0 µm, Hex(0.1%DEA):Ethanol=98:2, 1.0 mL/min, 254 nm) [01089] tert-butyl (R)-4-((6-(2-(3,3-difluoroazetidin-1-yl)-4-(methoxycarbonyl)phenyl)-2,2-difluoro-7- azaspiro[3.5]nonan-7-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (isomer 2, slower peak) (55 mg) as a white solid. LCMS (ESI, m/z): [M+H]⁺ = 660.5, tR = 1.91 min (CHIRALPAK IA-3, 4.6*50 mm, 3.0 µm, Hex(0.1%DEA):Ethanol=98:2, 1.0 mL/min, 254 nm). [01090] Step 5: (S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan- 6-yl)-3-(3,3-difluoroazetidin-1-yl)benzoic acid & (R)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4- yl)methyl)-7-azaspiro[3.5]nonan-6-yl)-3-(3,3-difluoroazetidin-1-yl)benzoic acid [01091] A soluti ycarbonyl)phenyl)-2,2-

difluoro-7-azaspiro[3.5]nonan-7-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (isomer 1, faster peak) (70 mg, 0.10 mmol) and potassium hydroxide (72 mg, 1.28 mmol) in Ethanol (1.5 mL) and water (0.5 mL) was stirred at 80 °C for 2h. The mixture was acidified to pH 6 with citric acid. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in Water (10mmol/L Ammonium bicarbonate), 30% to 35% gradient in 5 min; detector, UV 254 nm. to afford (S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)- 3-(3,3-difluoroazetidin-1-yl)benzoic acid (38.6 mg, 66.68% yield) as a white solid. LCMS (ESI, m/z): [M+H]⁺ = 546.4.¹H NMR (300 MHz, DMSO-d6) δ 12.79 (s, 1H), 10.75 (s, 1H), 7.83 (d, J = 8.1 Hz, 1H), 7.55 (d, J = 8.0 Hz, 1H), 7.17 (d, J = 7.3 Hz, 2H), 6.58 (s, 1H), 6.47 – 6.25 (m, 1H), 4.55 – 4.25 (m, 4H), 3.62 (s, 3H), 3.48 – 3.36 (m, 1H), 3.21 (s, 1H), 3.08 (d, J = 12.0 Hz, 1H), 2.60 (d, J = 11.8 Hz, 1H), 2.50 – 2.46 (m, 1H), 2.40 (s, 1H), 2.34 (s, 3H), 2.30 – 2.15 (m, 2H), 2.01 (s, 1H), 1.81 – 1.55 (m, 2H), 1.45 (s, 2H). [01092] A solution of tert-butyl (R)-4-((6-(2-(3,3-difluoroazetidin-1-yl)-4-(methoxycarbonyl)phenyl)-2,2- difluoro-7-azaspiro[3.5]nonan-7-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (isomer 2, slower peak) (55 mg, 0.083 mmol) and Potassium hydroxide (56 mg, 0.99 mmol) in Ethanol (1.5 mL) and water (0.5 mL) was stirred at 80 °C for 2h. The mixture was acidified to pH 6 with citric acid. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in Water (5mmol/L Ammonium bicarbonate), 30% to 35% gradient in 5 min; detector, UV 254 nm. to afford (R)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)- 3-(3,3-difluoroazetidin-1-yl)benzoic acid (26.2 mg, 57.60% yield) as a white solid. LCMS (ESI, m/z): [M+H]⁺ = 546.4.¹H NMR (300 MHz, DMSO-d₆) δ 12.77 (s, 1H), 10.74 (s, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.54 (d, J = 7.9 Hz, 1H), 7.24 – 7.12 (m, 2H), 6.57 (s, 1H), 6.45 – 6.33 (m, 1H), 4.52 – 4.27 (m, 4H), 3.62 (s, 3H), 3.40 (d, J = 11.7 Hz, 1H), 3.23 (s, 1H), 3.08 (d, J = 11.8 Hz, 1H), 2.69 – 2.53 (m, 1H), 2.47 (s, 1H), 2.39 (s, 1H), 2.34 (s, 3H), 2.30 – 2.16 (m, 2H), 2.01 (s, 1H), 1.79 – 1.56 (m, 2H), 1.45 (s, 2H). [01093] Example 55.7-[(6S)-2,2-Difluoro-7-[(5-methoxy-7-methyl-1H-indol-4-yl)methyl]-7- azaspiro[3.5]nonan-6-yl]-1H-indole-4-carboxylic acid & 7-[(6R)-2,2-difluoro-7-[(5-methoxy-7-methyl-1H- indol-4-yl)methyl]-7-azaspiro[3.5]nonan-6-yl]-1H-indole-4-carboxylic acid.

[01094] Procedure:

[01095] Step 1: methyl 7-bromo-lH-indole-4-carboxylate

[01096] A solution of methyl 4-bromo-3-nitrobenzoate (20 g, 76.910 mmol, 1 equiv) in Tetrahydrofuran

(200 mL) was stirred for 5min at - 40 °C under nitrogen atmosphere followed by the addition of bromo(ethenyl)magnesium (230 mL, 3 equiv) dropwise at - 40 °C. The resulting mixture was stirred for Ih at - 40 °C under nitrogen atmosphere. The resulting mixture was diluted with water. The resulting mixture was extracted with Ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in Water (10mmol/L Ammonium bicarbonate), 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in methyl 7-bromo-1H-indole-4-carboxylate (8 g, 20.47% yield) as a yellow solid. LCMS (ESI, m/z): [M+H]⁺ = 255.0. [01097] Step 2: Methyl 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-4-carboxylate [01098] A mixture of methyl 7-bro te (2 g, 7.87 mmol, 1 equiv) and

bis(pinacolato)diboron (3 g, 11.81 mmol, 1.50 equiv) and 1,1’-Bis(diphenylphosphino)ferrocene- palladium(II)dichloride dichloromethane complex (642 mg, 0.79 mmol, 0.10 equiv) and Potassium Acetate (1.54 g, 15.69 mmol, 1.99 equiv) in 1,4-dioxane (20 mL) was stirred at 90 °C for 1h. The resulting mixture was diluted with water. The resulting mixture was extracted with Ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with Dichloromethane/ Petroleum ether (1:1) to afford methyl 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H- indole-4-carboxylate (1.2 g, 50.62% yield) as a yellow solid. LCMS (ESI, m/z): [M+H]+ = 302.1. [01099] Step 3: tert-Butyl 2,2-difluoro-6-[4-(methoxycarbonyl)-1H-indol-7-yl]-7-azaspiro[3.5]non-5-ene- 7-carboxylate [01100] A mixture of tert-butyl 2,

esulfonyloxy)-7-azaspiro[3.5]non-5-ene- 7-carboxylate (1.1 g, 2.70 mmol, 1 equiv), methyl 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole- 4-carboxylate (1.21 g, 4.02 mmol, 1.49 equiv), Palladium (II) Acetate (79 mg, 0.35 mmol, 0.13 equiv) and Potassium phosphate tribasic (1.68 g, 7.92 mmol, 2.93 equiv) in 1,4-dioxane (8 mL) and water (2 mL) was stirred at 100 °C for 1h. The resulting mixture was diluted with water. The resulting mixture was extracted with Ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in Water (10mmol/L Ammonium bicarbonate), 10% to 50% gradient in 10 min; detector, UV 254 nm. to afford tert-butyl 2,2-difluoro-6-[4-(methoxycarbonyl)-1H-indol-7-yl]-7-azaspiro[3.5]non-5-ene-7- carboxylate (1.1 g, 70.64%) as a yellow solid. LCMS (ESI, m/z): [M+H]+ = 432.4. [01101] Step 4: tert-Butyl 2,2-difluoro-6-[4-(methoxycarbonyl)-1H-indol-7-yl]-7-azaspiro[3.5]nonane-7- carboxylate. [01102] A mixture of tert-butyl 2, onyl)-1H-indol-7-yl]-7-azaspiro[3.5]non-

5-ene-7-carboxylate (300 mg, 0.69 mmol, 1 equiv) and 10% Pd/C (300 mg,) in methanol (5 mL) was stirred at room temperature for 3 h under hydrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with methanol. The filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in Water (10mmol/L Ammonium bicarbonate), 10% to 50% gradient in 10 min; detector, UV 254 nm. to afford tert-butyl 2,2-difluoro-6-[4-(methoxycarbonyl)-1H-indol-7-yl]-7-azaspiro[3.5]nonane-7- carboxylate (350 mg) as a yellow oil.LCMS (ESI, m/z): [M+H]⁺ = 434.4 [01103] Step 5: Methyl 7-{2,2-difluoro-7-azaspiro[3.5]nonan-6-yl}-1H-indole-4-carboxylate. [01104] A solution of tert-butyl 2,

onyl)-1H-indol-7-yl]-7- azaspiro[3.5]nonane-7-carboxylate (300 mg, 0.690 mmol, 1 equiv) in trifluoroacetic acid (2 mL) and Dichloromethane (2 mL) was stirred at room temperature for 30 mins. The mixture was basified to pH=8 with saturated Sodium bicarbonate (aq.). The resulting mixture was extracted with Dichloromethane. The combined organic layers were washed with brine, dried over anhydrous Sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in Water (10mmol/L Ammonium bicarbonate), 10% to 50% gradient in 10 min; detector, UV 254 nm.to afford methyl 7-{2,2-difluoro-7-azaspiro[3.5]nonan-6-yl}-1H-indole-4-carboxylate (120 mg) as a yellow oil. LCMS (ESI, m/z): [M+H]⁺ = 344.3. [01105] Step 6: tert-Butyl 4-({2,2-difluoro-6-[4-(methoxycarbonyl)-1H-indol-7-yl]-7-azaspiro[3.5]nonan- 7-yl}methyl)-5-methoxy-7-methylindole-1-carboxylate. [01106] A mixture of methyl 7-{2, an-6-yl}-1H-indole-4-carboxylate (300

mg, 0.90 mmol, 1 equiv) and tert-butyl 4-formyl-5-methoxy-7-methylindole-1-carboxylate (390 mg, 1.35 mmol, 1.50 equiv), sodium bis(acetyloxy)boranuidyl acetate (508 mg, 2.40 mmol, 2.67 equiv), Titanium tetraisopropanolate (569 mg, 2.50 mmol, 2.78 equiv) in 1,2-dichloroethane (3 mL) was stirred at 70 °C for 1h. The resulting mixture was diluted with water. The resulting mixture was extracted with Ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in Water (10mmol/L Ammonium bicarbonate), 75% to 80% gradient in 10 min; detector, UV 254 nm.to afford the title compound (85 mg) as a yellow oil. LCMS (ESI, m/z): [M+H]⁺ = 607.6. [01107] Step 7: tert-Butyl 4-{[(6S)-2,2-difluoro-6-[4-(methoxycarbonyl)-1H-indol-7-yl]-7- azaspiro[3.5]nonan-7-yl]methyl}-5-methoxy-7-methylindole-1-carboxylate (isomer 1, faster peak) & tert- Butyl 4-{[(6R)-2,2-difluoro-6-[4-(methoxycarbonyl)-1H-indol-7-yl]-7-azaspiro[3.5]nonan-7-yl]methyl}-5- methoxy-7-methylindole-1-carboxylate (isomer 2, slower peak). [01108] tert-bu

piro[3.5]nonan-7- yl}methyl)-5-methoxy-7-methylindole-1-carboxylate (85 mg) was applied for further separation by Chiral HPLC with the following condition: Column: CHIRALPAK IG 2*25 cm, 5 μm; Mobile Phase A: HEX(0.5% 2M NH3-Methanol), Mobile Phase B: Ethanol; Flow rate: 20 mL/min; Gradient: isocratic 10; Wave Length: 220/254 nm; RT1(min): 10.615; RT2(min): 16.052; Sample Solvent: ETOH; Injection Volume: 1.0 mL; Number Of Runs: 6. [01109] tert-butyl 4-{[(6S)-2,2-difluoro-6-[4-(methoxycarbonyl)-1H-indol-7-yl]-7-azaspiro[3.5]nonan-7- yl]methyl}-5-methoxy-7-methylindole-1-carboxylate (isomer 1, faster peak,40 mg 47.0% yield) as a white solid. LCMS (ESI, m/z): [M+H]⁺ = 493.5. tR = 2.24 min (CHIRALPAK IG-3, 4.6*50 mm, 3um, Hex(0.1%DEA): Ethanol=90: 10, 1 mL/min). [01110] tert-butyl 4-{[(6R)-2,2-difluoro-6-[4-(methoxycarbonyl)-1H-indol-7-yl]-7-azaspiro[3.5]nonan-7- yl]methyl}-5-methoxy-7-methylindole-1-carboxylate (isomer 2, slower peak,41 mg 48.2% yield) as a white solid. LCMS (ESI, m/z): [M+H]+ = 493.5. tR = 3.72 min (CHIRALPAK IG-3, 4.6*50 mm, 3um, Hex(0.1%DEA): Ethanol=90: 10, 1 mL/min). [01111] Step 8: 7-[(6S)-2,2-Difluoro-7-[(5-methoxy-7-methyl-1H-indol-4-yl)methyl]-7- azaspiro[3.5]nonan-6-yl]-1H-indole-4-carboxylic acid & 7-[(6R)-2,2-difluoro-7-[(5-methoxy-7-methyl-1H- indol-4-yl)methyl]-7-azaspiro[3.5]nonan-6-yl]-1H-indole-4-carboxylic acid [01112] A mixtur H-indol-7-yl]-7-

azaspiro[3.5]nonan-7-yl]methyl}-5-methoxy-7-methylindole-1-carboxylate (isomer 1, faster peak) (40 mg, 0.066 mmol, 1 equiv) and Potassium hydroxide (36.93 mg, 0.66 mmol, 10 equiv) in Ethanol (0.5 mL) and water (0.5 mL) was stirred at 80 °C for 1h. The mixture was acidified to pH< 7 with sat. citric acid. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in Water (10mmol/L Ammonium bicarbonate), 10% to 50% gradient in 10 min; detector, UV 254 nm.to afford 7-[(6S)-2,2-difluoro-7-[(5-methoxy-7-methyl-1H-indol-4-yl)methyl]- 7-azaspiro[3.5]nonan-6-yl]-1H-indole-4-carboxylic acid (19.4 mg, 59.72% yield) as a white solid. LCMS (ESI, m/z): [M+H]⁺= 494.5.¹H NMR (400 MHz, Methanol-d4) δ 7.98 – 7.80 (m, 1H), 7.46 (d, J = 3.1 Hz, 2H), 7.20 (d, J = 3.2 Hz, 2H), 6.67 (s, 1H), 6.11 (s, 1H), 4.12 – 3.83 (m, 2H), 3.71 – 3.60 (m, 4H), 3.35 (s, 2H), 2.73 (s, 1H), 2.64 – 2.55 (m, 1H), 2.48 – 2.43 (m, 3H), 2.41 – 2.23 (m, 4H), 2.00 – 1.73 (m, 3H). [01113] A mixture of tert-butyl 4-{[(6R)-2,2-difluoro-6-[4-(methoxycarbonyl)-1H-indol-7-yl]-7- azaspiro[3.5]nonan-7-yl]methyl}-5-methoxy-7-methylindole-1-carboxylate (isomer 2, slower peak) (41 mg, 0.067 mmol, 1 equiv) and Potassium hydroxide (37.85 mg, 0.670 mmol, 10 equiv) in Ethanol (0.5 mL) and water (0.5 mL) was stirred at 80 °C for 1h under air atmosphere. The mixture was acidified to pH< 7 with sat. citric acid. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in Water (10mmol/L Ammonium bicarbonate), 10% to 50% gradient in 10 min; detector, UV 254 nm.to afford 7-[(6R)-2,2-difluoro-7-[(5-methoxy-7-methyl-1H- indol-4-yl)methyl]-7-azaspiro[3.5]nonan-6-yl]-1H-indole-4-carboxylic acid (19.5 mg, 58.56% yield) as a white solid. LCMS (ESI, m/z): [M+H]⁺ = 494.5.¹H NMR (400 MHz, Methanol-d4) δ 7.87 (s, 1H), 7.52 – 7.28 (m, 2H), 7.20 (d, J = 3.1 Hz, 2H), 6.68 (s, 1H), 6.11 (s, 1H), 4.60 (s, 1H), 4.19 – 3.88 (m, 2H), 3.67 (s, 3H), 2.85 – 2.53 (m, 3H), 2.46 (s, 3H), 2.43 – 2.20 (m, 4H), 2.00 – 1.73 (m, 3H). [01114] Example 56.4-[(6S)-2,2-Difluoro-7-[(5-methoxy-7-methyl-1H-indol-4-yl)methyl]-7- azaspiro[3.5]nonan-6-yl]-3-(pyrrolidin-1-yl)benzoic acid & 4-[(6R)-2,2-difluoro-7-[(5-methoxy-7-methyl- 1H-indol-4-yl)methyl]-7-azaspiro[3.5]nonan-6-yl]-3-(pyrrolidin-1-yl)benzoic acid.

azaspiro[3.5]non-5-ene-7-carboxylate [01117] A solution of tert-butyl 6- l)phenyl]-2,2-difluoro-7- azaspiro[3.5]non-5-ene-7-carboxylate

(1 g, 2.34 mmol, 1 equiv), (SP-4-1)-[1,3-Bis[2,6-bis(1- propylbutyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazol-2-ylidene]dichloro(3-chloropyridine-κN)- Palladium (200 mg, 0.24 mmol, 0.10 equiv) and Cesium carbonate (1.70 g, 5.22 mmol, 2.23 equiv) in 1,4- dioxane (10 mL) was treated with pyrrolidine (800 mg, 11.25 mmol, 4.81 equiv) for overnight at 80 °C under nitrogen atmosphere. The resulting mixture was diluted with water. The resulting mixture was extracted with Ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with Petroleum ether/Ethyl acetate (4:1) to afford tert-butyl 6-[2- (cyclopropylamino)-4-(methoxycarbonyl)phenyl]-2,2-difluoro-7-azaspiro[3.5]non-5-ene-7-carboxylate (400 mg, 26.71% yield) as a yellow solid. LCMS (ESI, m/z): [M+H]⁺ = 463.3 [01118] Step 2: Methyl 4-{2,2-difluoro-7-azaspiro[3.5]nonan-6-yl}-3-(pyrrolidin-1-yl)benzoate [01119] A solution of tert-butyl 2

onyl)-2-(pyrrolidin-1-yl)phenyl]-7- azaspiro[3.5]non-5-ene-7-carboxylate (600 mg, 1.30 mmol, 1 equiv) and 10% Pd/C (200 mg) in Methanol (10 mL) was stirred at room temperature for 3 h under hydrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with ethyl acetate. The filtrate was concentrated under reduced pressure. The residue was dissolved in Dichloromethane (4 mL) and Trifluoroacetic acid (4 mL) and stirred at room temperature for 1 hour. The resulting mixture was concentrated under reduced pressure. The residue was basified to pH = 8 with N,N-Diisopropylethylamine. The resulting mixture was diluted with water. The resulting mixture was extracted with Dichloromethane. The combined organic layers were washed with brine, dried over anhydrous Sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in Water (10mmol/L Ammonium bicarbonate), 40% to 50% gradient in 5 min; detector, UV 254 nm. to afford the title compound (280 mg, 59.23% yield) as a white solid. LCMS (ESI, m/z): [M+H]⁺ = 465.3 [01120] Step 3: tert-Butyl 4-({2,2-difluoro-6-[4-(methoxycarbonyl)-2-(pyrrolidin-1-yl)phenyl]-7- azaspiro[3.5]nonan-7-yl}methyl)-5-methoxy-7-methylindole-1-carboxylate [01121] A solution of methyl 4-{2 nan-6-yl}-3-(pyrrolidin-1-yl)benzoate

(500 mg, 1.37 mmol, 1 equiv),Titanium(IV) ethoxide (1 g, 4.38 mmol, 3.20 equiv) in 1,2-Dichloroethane (10 mL) was treated with tert-butyl 4-formyl-5-methoxy-7-methylindole-1-carboxylate (800 mg, 2.77 mmol, 2.02 equiv) for 40 mins at 70 °C followed by the addition of Sodium triacetoxyborohydride (900 mg, 4.25 mmol, 3.10 equiv) dropwise at room temperature. The resulting mixture was stirred for 1h at 70 °C. The resulting mixture was diluted with water. The resulting mixture was extracted with Dichloromethane. The combined organic layers were washed with brine, dried over anhydrous Sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with Petroleum ether/Ethyl acetate (5:1) to afford the crude product. The residue was purified by reversed- phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in Water (10mmol/L Ammonium bicarbonate), 5% to 100% gradient in 40 min; detector, UV 254 nm to afford tert-butyl 4-({2,2-difluoro-6-[4-(methoxycarbonyl)-2-(pyrrolidin-1-yl)phenyl]-7-azaspiro[3.5]nonan-7- yl}methyl)-5-methoxy-7-methylindole-1-carboxylate (220 mg, 23.89% yield) as a white solid. LCMS (ESI, m/z): [M+H]⁺ = 638.3. [01122] Step 4: tert-Butyl 4-{[(6S)-2,2-difluoro-6-[4-(methoxycarbonyl)-2-(pyrrolidin-1-yl)phenyl]-7- azaspiro[3.5]nonan-7-yl]methyl}-5-methoxy-7-methylindole-1-carboxylate & tert-butyl 4-{[(6R)-2,2- difluoro-6-[4-(methoxycarbonyl)-2-(pyrrolidin-1-yl)phenyl]-7-azaspiro[3.5]nonan-7-yl]methyl}-5-methoxy- 7-methylindole-1-carboxylate [01123] The crude p

p y lowing conditions: Column: (R, R)-WHELK-O1-Kromasil, 2.12*25 cm, 5 μm; Mobile Phase A: Hex(0.1% DEA)--HPLC, Mobile Phase B: Ethanol--HPLC; Flow rate: 20 mL/min; Gradient: isocratic 2; Wave Length: 220/254 nm; RT1(min): 33.8; RT2(min): 39.1; Sample Solvent: Ethanol. [01124] tert-Butyl 4-{[(6S)-2,2-Difluoro-6-[4-(methoxycarbonyl)-2-(pyrrolidin-1-yl)phenyl]-7- azaspiro[3.5]nonan-7-yl]methyl}-5-methoxy-7-methylindole-1-carboxylate(isomer 1, faster peak, 50 mg, 30% yield) LCMS: (ESI, m/z): 637.3 [M+H]⁺. t_R = 3.74 min ((R,R)-Whelk, 4.6*50mm, 3.5um, HEX(0.1%DEA):Ethanol=98:2, 1.0 mL/min, 254 nm). [01125] tert-Butyl 4-{[(6R)-2,2-Difluoro-6-[4-(methoxycarbonyl)-2-(pyrrolidin-1-yl)phenyl]-7- azaspiro[3.5]nonan-7-yl]methyl}-5-methoxy-7-methylindole-1-carboxylate(isomer 2, slower peak, 60 mg, 40% yield) LCMS: (ESI, m/z): 637.3 [01126] [M+H]⁺. tR = 4.45 min ((R,R)-Whelk, 4.6*50mm, 3.5um, HEX(0.1%DEA):Ethanol=98:2, 1.0 mL/min, 254 nm). [01127] Step 5: 4-[(6S)-2,2-Difluoro-7-[(5-methoxy-7-methyl-1H-indol-4-yl)methyl]-7- azaspiro[3.5]nonan-6-yl]-3-(pyrrolidin-1-yl)benzoic acid & 4-[(6R)-2,2-difluoro-7-[(5-methoxy-7-methyl- 1H-indol-4-yl)methyl]-7-azaspiro[3.5]nonan-6-yl]-3-(pyrrolidin-1-yl)benzoic acid [01128] tert-Butyl

-yl)phenyl]-7- azaspiro[3.5]nonan-7-yl]methyl}-5-methoxy-7-methylindole-1-carboxylate (60 mg, 0.094 mmol, 1 equiv) and Potassium hydroxide (52.78 mg, 0.94 mmol, 10 equiv) in Ethanol (0.9 mL), water (0.3 mL) was stirred at 80 °C for 2.5h. The mixture was acidified to pH< 7 with sat. citric acid. The residue was purified by reversed- phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in Water (10mmol/L Ammonium bicarbonate), 10% to 50% gradient in 10 min; detector, UV 254 nm.to afford 4-[(6S)-2,2-difluoro-7-[(5-methoxy-7-methyl-1H-indol-4-yl)methyl]-7-azaspiro[3.5]nonan-6-yl]-3- (pyrrolidin-1-yl)benzoic acid (26.4 mg, 53.54% yield) as a white solid. LCMS (ESI, m/z): [M+H]⁺ = 524.5. ¹H NMR (500 MHz, Methanol-d4) δ 8.02 – 7.97 (m, 1H), 7.95 – 7.88 (m, 1H), 7.69 – 7.60 (m, 1H), 7.33 – 7.29 (m, 1H), 6.79 – 6.74 (m, 1H), 6.38 – 6.33 (m, 1H), 4.88 (s, 1H), 4.87 (s, 1H), 4.23 – 4.17 (m, 1H), 4.00 (s, 1H), 3.82 – 3.75 (m, 2H), 3.49 – 3.43 (m, 1H), 3.35 (s, 3H), 3.07 (s, 2H), 2.77 – 2.71 (m, 1H), 2.67 – 2.61 (m, 1H), 2.55 – 2.46 (m, 4H), 2.35 – 2.25 (m, 1H), 2.15 – 2.04 (m, 6H), 1.94 – 1.87 (m, 1H), 1.31 (s, 1H). [01129] tert-Butyl 4-{[(6R)-2,2-difluoro-6-[4-(methoxycarbonyl)-2-(pyrrolidin-1-yl)phenyl]-7- azaspiro[3.5]nonan-7-yl]methyl}-5-methoxy-7-methylindole-1-carboxylate (60 mg, 0.094 mmol, 1 equiv) and Potassium hydroxide (52.78 mg, 0.94 mmol, 10 equiv) in Ethanol (0.9 mL) and water (0.3 mL) was stirred at 80 °C for 2.5h. The mixture was acidified to pH< 7 with sat. citric acid. The residue was purified by reversed- phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in Water (10mmol/L Ammonium bicarbonate), 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in 4-[(6R)-2,2-difluoro-7-[(5-methoxy-7-methyl-1H-indol-4-yl)methyl]-7-azaspiro[3.5]nonan-6-yl]- 3-(pyrrolidin-1-yl)benzoic acid (25.9 mg, 52.47% yield) as a white solid. LCMS (ESI, m/z): [M+H]⁺ = 524.5. ¹H NMR (500 MHz, Methanol-d4) δ 8.02 – 7.98 (m, 1H), 7.95 – 7.89 (m, 1H), 7.66 – 7.61 (m, 1H), 7.34 – 7.30 (m, 1H), 6.77 (s, 1H), 6.38 – 6.34 (m, 1H), 4.88 (s, 1H), 4.24 – 4.18 (m, 1H), 4.01 (s, 1H), 3.78 (s, 3H), 3.37 – 3.35 (m, 1H), 3.32 (s, 3H), 3.09 – 3.04 (m, 2H), 2.78 – 2.70 (m, 1H), 2.70 – 2.59 (m, 1H), 2.52 (s, 5H), 2.35 – 2.26 (m, 1H), 2.18 – 2.01 (m, 6H), 1.94 – 1.88 (m, 1H). [01130] Example 57.3-(Cyclopropylamino)-4-[(6S)-2,2-difluoro-7-[(5-methoxy-7-methyl-1H-indol-4- yl)methyl]-7-azaspiro[3.5]nonan-6-yl]benzoic acid & 3-(cyclopropylamino)-4-[(6R)-2,2-difluoro-7-[(5- methoxy-7-methyl-1H-indol-4-yl)methyl]-7-azaspiro[3.5]nonan-6-yl]benzoic acid. O O NH

1 [01132] Step 1: tert-Butyl 6-[2-(cyclopropylamino)-4-(methoxycarbonyl)phenyl]-2,2-difluoro-7- azaspiro[3.5]non-5-ene-7-carboxylate [01133] A solution of tert-butyl 6 l)phenyl]-2,2-difluoro-7-

azaspiro[3.5]non-5-ene-7-carboxylate (1 g, 2.34 mmol, 1 equiv), (SP-4-1)-[1,3-Bis[2,6-bis(1- propylbutyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazol-2-ylidene]dichloro(3-chloropyridine-κN)- Palladium (200 mg, 0.24 mmol, 0.10 equiv) and Cesium carbonate (1.70 g, 5.21 mmol, 2.23 equiv) in 1,4- dioxane (10 mL) was treated with aminocyclopropane (800 mg, 14.01 mmol, 6.00 equiv) for overnight at 80 °C under nitrogen atmosphere. The resulting mixture was diluted with water. The resulting mixture was extracted with Ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with Petroleum ether/Ethyl acetate (4:1) to afford tert- butyl 6-[2-(cyclopropylamino)-4-(methoxycarbonyl)phenyl]-2,2-difluoro-7-azaspiro[3.5]non-5-ene-7- carboxylate (750 mg, 60.82% yield) as a yellow solid. LCMS (ESI, m/z): [M+H]+ = 448.5 [01134] Step 2: Methyl 3-(cyclopropylamino)-4-{2,2-difluoro-7-azaspiro[3.5]nonan-6-yl}benzoate [01135] A solution of tert-butyl 6

hoxycarbonyl)phenyl]-2,2-difluoro-7- azaspiro[3.5]non-5-ene-7-carboxylate (200 mg, 0.45 mmol, 1 equiv) and Sodium borohydride (340 mg, 8.99 mmol, 20.16 equiv) in Dichloromethane (5 mL) was stirred at room temperature. To the above mixture was added Trifluoroacetic acid (5 mL) dropwise over 5 mins at 0 °C. The resulting mixture was stirred at 0 °C for additional 1h. The residue was neutralized to pH 7 with saturated Sodium bicarbonate (aq.) at 0 °C. The resulting mixture was diluted with water. The resulting mixture was extracted with Dichloromethane. The combined organic layers were washed with brine, dried over anhydrous Sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to afford methyl 3-(cyclopropylamino)-4-{2,2-difluoro-7- azaspiro[3.5]nonan-6-yl}benzoate (100 mg, crude) as yellow oil. The crude product mixture was used in the next step directly without further purification. LCMS (ESI, m/z): [M+H]⁺ =350.4. [01136] Step 3: tert-Butyl 4-({6-[2-(cyclopropylamino)-4-(methoxycarbonyl)phenyl]-2,2-difluoro-7- azaspiro[3.5]non-5-en-7-yl}methyl)-5-methoxy-7-methylindole-1-carboxylate [01137] A solution of methyl 3-(c oro-7-azaspiro[3.5]nonan-6-yl}benzoate

(200 mg, 0.57 mmol, 1 equiv), (acetylacetonato)dicarbonyliridium(i) (20 mg, 0.058 mmol, 0.10 equiv) and tert-butyl 4-formyl-5-methoxy-7-methylindole-1-carboxylate (250 mg, 0.86 mmol, 1.51 equiv) in Ethanol (5 mL) was stirred for 4h at 70 °C under hydrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with Dichloromethane. The filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in Water (10mmol/L Ammonium bicarbonate), 40% to 50% gradient in 5 min; detector, UV 254 nm. to afford the title compound (200 mg, 56.36% yield) as a black solid. LCMS (ESI, m/z): [M+H]⁺ = 623.7 [01138] Step 4: tert-Butyl 4-{[(6S)-6-[2-(cyclopropylamino)-4-(methoxycarbonyl)phenyl]-2,2-difluoro-7- azaspiro[3.5]nonan-7-yl]methyl}-5-methoxy-7-methylindole-1-carboxylate & tert-butyl 4-{[(6R)-6-[2- (cyclopropylamino)-4-(methoxycarbonyl)phenyl]-2,2-difluoro-7-azaspiro[3.5]nonan-7-yl]methyl}-5- methoxy-7-methylindole-1-carboxylate [01139] The crude

owing conditions: Column: (R, R)-WHELK-O1-Kromasil, 2.12*25 cm, 5 μm; Mobile Phase A: Hex(0.1% DEA)--HPLC, Mobile Phase B: Ethanol--HPLC; Flow rate: 20 mL/min; Gradient: isocratic 2; Wave Length: 220/254 nm; RT1(min): 33.8; RT2(min): 39.1; Sample Solvent: Ethanol. [01140] tert-Butyl 4-{[(6S)-6-[2-(cyclopropylamino)-4-(methoxycarbonyl)phenyl]-2,2-difluoro-7- azaspiro[3.5]nonan-7-yl]methyl}-5-methoxy-7-methylindole-1-carboxylate( isomer 1, faster peak, 100 mg, 50% yield) LCMS: (ESI, m/z): 623.7 [M+H]⁺. tR = 0.99 min (CHIRALPAK IA-3, 4.6*50 mm 3um, HEX(0.1%DEA):IPA=85:15, 1.0 mL/min, 254 nm) [01141] tert-Butyl 4-{[(6R)-6-[2-(cyclopropylamino)-4-(methoxycarbonyl)phenyl]-2,2-difluoro-7- azaspiro[3.5]nonan-7-yl]methyl}-5-methoxy-7-methylindole-1-carboxylate(isomer 2, slower peak, 90 mg, 45% yield) LCMS: (ESI, m/z): 623.7 [M+H]⁺. t_R = 1.46 min (CHIRALPAK IA-3, 4.6*50mm 3um, HEX(0.1%DEA):IPA=85:15, 1.0 mL/min, 254 nm). [01142] Step 5: 3-(Cyclopropylamino)-4-[(6S)-2,2-difluoro-7-[(5-methoxy-7-methyl-1H-indol-4- yl)methyl]-7-azaspiro[3.5]nonan-6-yl]benzoic acid & 3-(cyclopropylamino)-4-[(6R)-2,2-difluoro-7-[(5- methoxy-7-methyl-1H-indol-4-yl)methyl]-7-azaspiro[3.5]nonan-6-yl]benzoic acid [01143] A solutio carbonyl)phenyl}-2,2-

difluoro-7-azaspiro[3.5]nonan-7-yl)methyl]-5-methoxy-7-methylindole-1-carboxylate (100 mg, 0.15 mmol, 1 equiv) and Potassium hydroxide (86.62 mg, 1.54 mmol, 10 equiv) in water (0.3 mL) and Ethanol (0.9 mL) was stirred at 80 °C for 2.5h under air atmosphere. The mixture was acidified to pH<7 with sat. citric acid. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in Water (10mmol/L Ammonium bicarbonate), 10% to 50% gradient in 10 min; detector, UV 254 nm. to afford 3-(cyclopropylamino)-4-[(6S)-2,2-difluoro-7-[(5- methoxy-7-methyl-1H-indol-4-yl)methyl]-7-azaspiro[3.5]nonan-6-yl]benzoic acid (33.6 mg, 39.48% yield) as a white solid. LCMS (ESI, m/z): [M+H]⁺ = 510.2.¹H NMR (300 MHz, Methanol-d4) δ 7.90 (s, 1H), 7.57 – 7.22 (m, 2H), 6.72 (s, 1H), 6.47 – 6.18 (m, 1H), 4.57 – 4.31 (m, 2H), 4.20 – 3.98 (m, 2H), 3.77 (s, 3H), 3.57 – 3.40 (m, 1H), 3.09 (s, 1H), 2.49 (s, 10H), 2.04 – 1.41 (m, 3H), 0.83 (s, 2H), 0.56 (s, 2H). [01144] A solution of tert-butyl 4-[(6-{2-[(2,2-difluoroethyl)amino]-4-(methoxycarbonyl)phenyl}-2,2- difluoro-7-azaspiro[3.5]nonan-7-yl)methyl]-5-methoxy-7-methylindole-1-carboxylate (100 mg, 0.15 mmol, 1 equiv) and Potassium hydroxide (86.62 mg, 1.54 mmol, 10 equiv) in water (0.9 mL) and Ethanol (0.3 mL) was stirred at 80 °C for 2.5h. The mixture was acidified to pH< 7 with sat. citric acid. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in Water (10mmol/L Ammonium bicarbonate), 10% to 50% gradient in 10 min; detector, UV 254 nm. to afford.3-(cyclopropylamino)-4-[(6R)-2,2-difluoro-7-[(5-methoxy-7-methyl-1H- indol-4-yl) methyl]-7-azaspiro[3.5]nonan-6-yl]benzoic acid (32.7 mg, 38.70% yield) as a white solid. LCMS (ESI, m/z): [M+H]⁺ = 510.2.¹H NMR (300 MHz, Methanol-d4) δ 8.00 – 7.68 (m, 2H), 7.62 – 7.07 (m, 3H), 6.73 (s, 1H), 6.49 – 6.07 (m, 2H), 4.45 (s, 1H), 4.02 (s, 1H), 3.78 (s, 3H), 2.50 (s, 10H), 2.13 – 1.41 (m, 4H), 0.84 (s, 2H), 0.57 (s, 2H). [01145] Example 58.3-(Azetidin-1-yl)-4-[(6S)-2,2-difluoro-7-[(5-methoxy-7-methyl-1H-indol-4- yl)methyl]-7-azaspiro[3.5]nonan-6-yl]benzoic acid & 3-(azetidin-1-yl)-4-[(6R)-2,2-difluoro-7-[(5-methoxy-7- methyl-1H-indol-4-yl)methyl]-7-azaspiro[3.5]nonan-6-yl]benzoic acid.

-5- ene-7-carboxylate [01148] A mixture of tert-butyl 2,2

esulfonyloxy)-7-azaspiro[3.5]non-5-ene- 7-carboxylate (1 g, 2.46 mmol, 1 equiv) and 2-chloro-4-(methoxycarbonyl)phenylboronic acid (683 mg, 3.19 mmol, 1.30 equiv) and 1,1’-Bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (200 mg, 0.25 mmol, 0.10 equiv) and Sodium carbonate (500 mg, 4.73 mmol, 1.92 equiv) in 1,4- dioxane (90 mL) and water (30 mL) was stirred for 2h at 90 °C under nitrogen atmosphere. The resulting mixture was diluted with water. The resulting mixture was extracted with Ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in Water (10mmol/L Ammonium bicarbonate), 10% to 50% gradient in 10 min; detector, UV 254 nm.to afford tert-butyl 6-[2-chloro-4- (methoxycarbonyl)phenyl]-2,2-difluoro-7-azaspiro[3.5]non-5-ene-7-carboxylate (700 mg, 66.64%) as a yellow oil. LCMS (ESI, m/z): [M+H]⁺ = 428.9 [01149] Step 2: tert-Butyl 6-[2-(azetidin-1-yl)-4-(methoxycarbonyl)phenyl]-2,2-difluoro-7- azaspiro[3.5]non-5-ene-7-carboxylate [01150] A mixture of tert-butyl 6-

)phenyl]-2,2-difluoro-7- azaspiro[3.5]non-5-ene-7-carboxylate (500 mg, 1.17 mmol, 1 equiv) and azetidine (332 mg, 5.82 mmol, 4.98 equiv) and (SP-4-1)-[1,3-Bis[2,6-bis(1-propylbutyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazol-2- ylidene]dichloro(3-chloropyridine-κN)-Palladium (98.3 mg, 0.12 mmol, 0.10 equiv) and Cesium carbonate (1.15 g, 3.53 mmol, 3.02 equiv) in 1,4-dioxane (5 mL) was stirred for 1h at 110 °C under nitrogen atmosphere.The resulting mixture was extracted with Ethyl acetate (3 × 20mL). The resulting mixture was diluted with water. The resulting mixture was extracted with Ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in Water (10mmol/L Ammonium bicarbonate), 10% to 50% gradient in 10 min; detector, UV 254 nm. to afford tert-butyl 6-[2-(azetidin-1-yl)-4- (methoxycarbonyl)phenyl]-2,2-difluoro-7-azaspiro[3.5]non-5-ene-7-carboxylate (300mg, 60.2% yeild) as a white solid.. LCMS (ESI, m/z): [M+H]⁺ = 449.5 [01151] Step 3: Methyl 3-(azetidin-1-yl)-4-{2,2-difluoro-7-azaspiro[3.5]nonan-6-yl}benzoate O F [01152] A solution of tert-butyl 6-

- a e - -y - - e o ycarbonyl)phenyl]-2,2-difluoro-7- azaspiro[3.5]non-5-ene-7-carboxylate (300 mg, 0.67 mmol, 1 equiv) in Dichloromethane (3 mL) was treated with Sodium cyanoborohydride (421 mg, 6.70 mmol, 10.02 equiv) for 5 mins at 0 °C followed by the addition of Trifluoroacetic acid (2 mL) dropwise at 0 °C.The resulting mixture was stirred for 30 mins at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was basified to pH=8 with N,N-Diisopropylethylamine. The resulting mixture was diluted with water. The resulting mixture was extracted with Dichloromethane. The combined organic layers were washed with brine, dried over anhydrous Sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in Water (10mmol/L Ammonium bicarbonate), 40% to 50% gradient in 5 min; detector, UV 254 nm. to afford the title compound (160 mg, 68.26% yeild) as a yellow solid. LCMS (ESI, m/z): [M+H]+ = 351.4 [01153] Step 4: tert-Butyl 4-({6-[2-(azetidin-1-yl)-4-(methoxycarbonyl)phenyl]-2,2-difluoro-7- azaspiro[3.5]nonan-7-yl}methyl)-5-methoxy-7-methylindole-1-carboxylate. [01154] A mixture of methyl 3-(a

-azaspiro[3.5]nonan-6-yl}benzoate (280 mg, 0.780 mmol, 1 equiv) and tert-butyl 4-formyl-5-methoxy-7-methylindole-1-carboxylate (467 mg, 1.61 mmol, 2.02 equiv) and (acetylacetonato)dicarbonyliridium(I) (61 mg, 0.18 mmol, 0.22 equiv) in Ethanol (4 mL) was stirred at 70 °C for 6h under hydrogen atmosphere. The resulting mixture was diluted with water. The resulting mixture was extracted with Ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in Water (10mmol/L Ammonium bicarbonate), 10% to 50% gradient in 10 min; detector, UV 254 nm.to afford tert-butyl 4-({6-[2-(azetidin-1-yl)-4- (methoxycarbonyl)phenyl]-2,2-difluoro-7-azaspiro[3.5]nonan-7-yl}methyl)-5-methoxy-7-methylindole-1- carboxylate (110 mg 39.3%yeild) as a white solid.LCMS (ESI, m/z): [M+H]+ = 624.7 [01155] Step 5: tert-Butyl 4-{[(6S)-6-[2-(azetidin-1-yl)-4-(methoxycarbonyl)phenyl]-2,2-difluoro-7- azaspiro[3.5]nonan-7-yl]methyl}-5-methoxy-7-methylindole-1-carboxylate (isomer 1, faster peak) & tert- Butyl 4-{[(6R)-6-[2-(azetidin-1-yl)-4-(methoxycarbonyl)phenyl]-2,2-difluoro-7-azaspiro[3.5]nonan-7- yl]methyl}-5-methoxy-7-methylindole-1-carboxylate (isomer 2, slower peak). [01156] tert- -7-

azaspiro[3.5]nonan-7-yl}methyl)-5-methoxy-7-methylindole-1-carboxylate (110 mg) was applied for further separation by Chiral HPLC with the following condition: Column: CHIRALPAK IA 2*25 cm, 5 μm; Mobile Phase A: HEX(0.5% 2M NH3-Methanol), Mobile Phase B: Ethanol; Flow rate: 20 mL/min; Gradient: isocratic 10; Wave Length: 220/254 nm; RT1(min): 5.144; RT2(min): 6.445; Sample Solvent: ETOH; Injection Volume: 0.3 mL; Number Of Runs: 28. [01157] tert-butyl 4-{[(6S)-6-[2-(azetidin-1-yl)-4-(methoxycarbonyl)phenyl]-2,2-difluoro-7- azaspiro[3.5]nonan-7-yl]methyl}-5-methoxy-7-methylindole-1-carboxylate (isomer 1, faster peak, 40 mg 36.3% yield) as a white solid. LCMS (ESI, m/z): [M+H]⁺ = 624.7. t_R= 1.16 min (CHIRALPAK IA-3, 4.6*50 mm 3 μm), Mobile phase: Hex(0.1%DEA):EtOH=95:5, Flow 1.000 mL/min. [01158] tert-butyl 4-{[(6R)-6-[2-(azetidin-1-yl)-4-(methoxycarbonyl)phenyl]-2,2-difluoro-7- azaspiro[3.5]nonan-7-yl]methyl}-5-methoxy-7-methylindole-1-carboxylate (isomer 2, slower peak, 48 mg 43.6% yield) as a white solid. LCMS (ESI, m/z): [M+H]⁺ = 624.7. t_R= 1.66 min (CHIRALPAK IA-3, 4.6*50 mm 3 μm), Mobile phase: Hex(0.1%DEA):EtOH=95:5, Flow 1.000 mL/min. [01159] Step 6: 3-(Azetidin-1-yl)-4-[(6S)-2,2-difluoro-7-[(5-methoxy-7-methyl-1H-indol-4-yl)methyl]-7- azaspiro[3.5]nonan-6-yl]benzoic acid & 3-(azetidin-1-yl)-4-[(6R)-2,2-difluoro-7-[(5-methoxy-7-methyl-1H- indol-4-yl)methyl]-7-azaspiro[3.5]nonan-6-yl]benzoic acid [01160] A mixtur

yl)phenyl]-2,2-difluoro-7- azaspiro[3.5]nonan-7-yl]methyl}-5-methoxy-7-methylindole-1-carboxylate (isomer 1, faster peak) (40 mg, 0.064 mmol, 1 equiv) and Potassium hydroxide (36 mg, 0.64 mmol, 10.01 equiv) in Ethanol (0.9 mL) and water (0.3 mL) was stirred at 80 °C for 1h . The mixture was acidified to pH< 7 with sat. citric acid. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in Water (10mmol/L Ammonium bicarbonate), 10% to 50% gradient in 10 min; detector, UV 254 nm.to afford 3-(azetidin-1-yl)-4-[(6S)-2,2-difluoro-7-[(5-methoxy-7-methyl-1H- indol-4-yl)methyl]-7-azaspiro[3.5]nonan-6-yl]benzoic acid (10.6 mg, 31.5% yield) as a white solid. LCMS (ESI, m/z): [M+H]⁺ = 510.2.¹H NMR (400 MHz, Methanol-d4) δ 7.76 – 7.69 (m, 1H), 7.51 (d, J = 8.1 Hz, 1H), 7.44 (s, 1H), 7.30 (d, J = 3.1 Hz, 1H), 6.74 (s, 1H), 6.31 (s, 1H), 4.43 (d, J = 12.3 Hz, 1H), 4.28 – 4.18 (m, 2H), 4.10 (d, J = 12.6 Hz, 1H), 3.98 (d, J = 12.8 Hz, 1H), 3.87 (d, J = 7.2 Hz, 2H), 3.75 (s, 3H), 3.40 (d, J = 12.9 Hz, 1H), 3.27 (d, J = 13.3 Hz, 1H), 2.78 – 2.58 (m, 2H), 2.46 (d, J = 32.7 Hz, 7H), 2.31 – 2.20 (m, 1H), 2.12 (d, J = 14.4 Hz, 1H), 2.02 (s, 1H), 1.87 (d, J = 14.5 Hz, 1H). [01161] A mixture of tert-butyl 4-{[(6R)-6-[2-(azetidin-1-yl)-4-(methoxycarbonyl)phenyl]-2,2-difluoro-7- azaspiro[3.5]nonan-7-yl]methyl}-5-methoxy-7-methylindole-1-carboxylate (isomer 2, slower peak) (48 mg, 0.077 mmol, 1 equiv) and Potassium hydroxide (43 mg, 0.77 mmol, 9.96 equiv) in Ethanol (0.9 mL) and water (0.3 mL) was stirred at 80 °C for 1h . The mixture was acidified to pH< 7 with sat. citric acid. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in Water (10mmol/L Ammonium bicarbonate), 10% to 50% gradient in 10 min; detector, UV 254 nm.to afford 3-(azetidin-1-yl)-4-[(6R)-2,2-difluoro-7-[(5-methoxy-7-methyl-1H- indol-4-yl)methyl]-7-azaspiro[3.5]nonan-6-yl]benzoic acid (21.9 mg, 54.9% yeild) as a white solid. LCMS (ESI, m/z): [M+H]⁺ = 510.2.¹H NMR (400 MHz, Methanol-d4) δ 7.76 – 7.69 (m, 1H), 7.52 (d, J = 8.1 Hz, 1H), 7.45 (s, 1H), 7.30 (d, J = 3.1 Hz, 1H), 6.74 (s, 1H), 6.31 (d, J = 3.0 Hz, 1H), 4.42 (d, J = 12.2 Hz, 1H), 4.28 – 4.18 (m, 2H), 4.10 (d, J = 12.6 Hz, 1H), 3.98 (d, J = 12.6 Hz, 1H), 3.87 (d, J = 7.1 Hz, 2H), 3.75 (s, 3H), 3.40 (d, J = 13.0 Hz, 1H), 3.28 (s, 1H), 2.78 – 2.54 (m, 3H), 2.46 (d, J = 32.1 Hz, 7H), 2.31 – 2.20 (m, 1H), 2.12 (d, J = 14.4 Hz, 1H), 2.02 (s, 1H), 1.87 (d, J = 14.4 Hz, 1H). [01162] Example 59.4-{1-[(5-Methoxy-7-methyl-1H-indol-4-yl)methyl]piperidin-2-yl}-3-(pyrrolidin-1- yl)benzoic acid. [01163] Procedure:

TfO O O O Cl N O Cl N O HN O Boc NaBH₄, TFA, DCM, r.t.

carboxylate [01165] A mixture of 2-chloro-4-(met

oronic acid (3 g, 13.99 mmol, 1 equiv) and tert-butyl 2-(trifluoromethanesulfonyloxy)-5,6-dihydro-4H-pyridine-1-carboxylate (5.56 mg, 16.79 mmol, 1.2 equiv) and [1,1’-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1.02 mg, 1.40 mmol, 0.1 equiv) and Sodium carbonate (2.97 mg, 27.98 mmol, 2 equiv) in water (4 mL) and 1,4-dioxane (16 mL) was stirred for 1 h at 90 °C under nitrogen atmosphere. The reaction was quenched with sat. Ammonium chloride (aq.) at 0 °C. The resulting mixture was extracted with Dichloromethane. The combined organic layers were washed with brine, dried over anhydrous Sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with Petroleum ether/Ethyl acetate (5:1) to afford tert-butyl 2-[2-chloro-4-(methoxycarbonyl)phenyl]-5,6-dihydro-4H-pyridine-1- carboxylate (2 g, 40.63% yield) as a yellow oil. LCMS: (ESI, m/z): 295.9 [M-(t-Bu)]⁺. [01166] Step 2: tert-butyl 2-[4-(methoxycarbonyl)-2-(pyrrolidin-1-yl)phenyl]-5,6-dihydro-4H-pyridine-1- carboxylate [01167] A mixture of tert-butyl 2-[2-c

onyl)phenyl]-5,6-dihydro-4H-pyridine-1- carboxylate (2.2 g, 6.25 mmol, 1 equiv) and pyrrolidine (2.22 g, 31.26 mmol, 5 equiv) and Pd-PEPPSI- IPentCl 2-methylpyridine (o-picoline (525.98 mg, 0.63 mmol, 0.1 equiv) and Cesium carbonate (6.11 g, 18.76 mmol, 3 equiv) in 1,4-dioxane (20 mL) was stirred for 1h at 100 °C under nitrogen atmosphere. The resulting mixture was extracted with Ethyl acetate (3 × 50 mL). The combined organic layers were washed with water (3 × 20 mL), dried over anhydrous Sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in Water , 10% to 50% gradient in 30 min; detector, UV 254 nm. to afford tert-butyl 2-[4-(methoxycarbonyl)-2-(pyrrolidin-1-yl)phenyl]-5,6-dihydro-4H- pyridine-1-carboxylate (500 mg, 20.69% yield) as a yellow oil. LCMS: (ESI, m/z): 387.1 [M+H]⁺. [01168] Step 3: methyl 4-(piperidin-2-yl)-3-(pyrrolidin-1-yl)benzoate [01169] A solution of tert-butyl 2-[4-( pyrrolidin-1-yl)phenyl]-5,6-dihydro-4H-

pyridine-1-carboxylate (800 mg, 2.07 mmol, 1 equiv) in Dichloromethane (6 mL) and Trifluoroacetic acid (6 mL) was treated with Sodium borohydride (783.04 mg, 20.70 mmol, 10 equiv) at room temperature for 2 h. The resulting mixture was concentrated under vacuum. The resulting mixture was extracted with Dichloromethane (3 × 5 mL). The combined organic layers were washed with brine (3 × 5 mL), dried over anhydrous Sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by C18 silica gel column chromatography, eluted with Acetonitrile/water (1:1) to afford methyl 4-(piperidin-2-yl)-3-(pyrrolidin-1-yl)benzoate (700 mg, 89.12% yield) as a yellow oil. LCMS: (ESI, m/z): 288.9 [M+H]⁺. [01170] Step 4: tert-butyl 5-methoxy-4-({2-[4-(methoxycarbonyl)-2-(pyrrolidin-1-yl)phenyl]piperidin-1- yl}methyl)-7-methylindole-1-carboxylate [01171] A solution of methyl 4-(piper

n-1-yl)benzoate (200 mg, 0.69 mmol, 1 equiv), tert-butyl 4-formyl-5-methoxy-7-methylindole-1-carboxylate (401.30 mg, 1.39 mmol, 2 equiv) in 1,2- Dichloroethane (4 mL) was treated with Titanium(IV) ethoxide (316.39 mg, 1.39 mmol, 2 equiv) at 70 °C for 1 h. Then the Sodium triacetoxyborohydride (440.94 mg, 2.08 mmol, 3 equiv) was added and stirred at 70 °C for 1 h. The resulting mixture was quenched with water and extracted with Dichloromethane. The combined organic layers were washed with brine, dried over anhydrous Sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by C18 silica gel column chromatography, eluted with Acetonitrile/water (8:1) to afford tert-butyl 5-methoxy-4-({2-[4-(methoxycarbonyl)-2-(pyrrolidin- 1-yl)phenyl]piperidin-1-yl}methyl)-7-methylindole-1-carboxylate (80 mg, 20.54% yield) as a yellow solid. LCMS: (ESI, m/z): 562.4 [M+H]⁺. [01172] Step 5: 4-(1-((5-Methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl)-3-(pyrrolidin-1- yl)benzoic acid [01173] A solution of tert-butyl 5-met xycarbonyl)-2-(pyrrolidin-1-

yl)phenyl]piperidin-1-yl}methyl)-7-methylindole-1-carboxylate (70 mg, 0.12 mmol, 1 equiv) in Ethanol (1.2 mL) and water (0.4 mL) was treated with Potassium hydroxide (69.92 mg, 1.25 mmol, 10 equiv) at 80 °C for 2 h. The mixture was acidified to pH 6 with citric acid. The resulting mixture was concentrated under vacuum. The residue was purified by C18 silica gel column chromatography, eluted with Acetonitrile/water (0.1% Ammonium bicarbonate) (1:4) to afford 4-{1-[(5-methoxy-7-methyl-1H-indol-4-yl)methyl]piperidin-2- yl}-3-(pyrrolidin-1-yl)benzoic acid (47.0 mg, 83.59% yield) as a yellow solid. LCMS: (ESI, m/z): 448.3 [M+H]⁺.¹H NMR (400 MHz, Methanol-d4) δ 7.96 (d, J = 1.6 Hz, 1H), 7.94 – 7.87 (m, 1H), 7.64 (d, J = 8.1 Hz, 1H), 7.32 (d, J = 3.1 Hz, 1H), 6.76 (s, 1H), 6.32 (d, J = 3.2 Hz, 1H), 5.01 – 4.91 (m, 1H), 4.21 (d, J = 12.7 Hz, 1H), 4.04 (d, J = 12.7 Hz, 1H), 3.76 (s, 3H), 3.54 – 3.45 (m, 1H), 3.44 – 3.34 (m, 3H), 3.08 – 2.97 (m, 2H), 2.51 (s, 3H), 2.16 (s, 2H), 2.12 – 1.95 (m, 5H), 1.95 – 1.72 (m, 3H). [01174] Example 60.3-(Ethylamino)-4-{7-[(5-methoxy-7-methyl-1H-indol-4-yl)methyl]-2-oxa-7- azaspiro[3.5]nonan-6-yl}benzoic acid. [01175] Procedure:

[0 5-

ene-7-carboxylate [01177] A solution of tert-butyl 6-[2-

nyl)phenyl]-2-oxa-7-azaspiro[3.5]non-5- ene-7-carboxylate (600 mg, 1.60 mmol, 1 equiv), acetaldehyde (352.95 mg, 8.01 mmol, 5 equiv) in Methanol (8 mL) was treated with Sodium cyanoborohydride (302.09 mg, 4.81 mmol, 3 equiv) at 50 °C for 3 h. The resulting mixture was quenched with water and extracted with Ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by C18 silica gel column chromatography, eluted with Acetonitrile/water (1:1) to afford tert-butyl 6-[2-(ethylamino)-4-(methoxycarbonyl)phenyl]-2-oxa-7- azaspiro[3.5]non-5-ene-7-carboxylate (280 mg, 43.41%) as a light yellow solid. LCMS: (ESI, m/z): 403.1 [M+H]⁺. [01178] Step 2: Methyl 3-(ethylamino)-4-{2-oxa-7-azaspiro[3.5]nonan-6-yl}benzoate [01179] A solution of tert-butyl 6-[2-

ycarbonyl)phenyl]-2-oxa-7- azaspiro[3.5]non-5-ene-7-carboxylate (330 mg, 0.82 mmol, 1 equiv) in Dichloromethane (2 mL) was treated with Sodium cyanoborohydride (515.22 mg, 8.20 mmol, 10 equiv) at 0 °C. Then the Trifluoroacetic acid (2 mL) was added at 0 °C and stirred at r.t. for 1h. The resulting mixture was concentrated under vacuum. The resulting mixture was extracted with Dichloromethane (3 × 5 mL). The combined organic layers were washed with brine (3 × 5 mL), dried over anhydrous Sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by C18 silica gel column chromatography, eluted with Acetonitrile/water (1:4) to afford methyl 3-(ethylamino)-4-{2-oxa-7-azaspiro [3.5]nonan-6-yl}benzoate (240 mg, 96.0%) as a yellow solid. LCMS: (ESI, m/z): 305.1 [M+H]⁺. [01180] Step 3: tert-Butyl 4-({6-[2-(ethylamino)-4-(methoxycarbonyl)phenyl]-2-oxa-7- azaspiro[3.5]nonan-7-yl}methyl)-5-methoxy-7-methylindole-1-carboxylate [01181] A solution of methyl 3-(ethy piro[3.5]nonan-6-yl}benzoate (270 mg, 0.89

mmol, 1 equiv), tert-butyl 4-formyl-5-methoxy-7-methylindole-1-carboxylate (513.28 mg, 1.77 mmol, 2 equiv) in Ethanol (4 mL) was treated with Ir(co)₂(acac) (40 mg, 0.12 mmol, 0.13 equiv) in Ethanol (4 mL) was stirred at 70 °C for 6 h under hydrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was filtered, the filter cake was washed with Methanol (3 × 1 mL). The filtrate was concentrated under reduced pressure. Then the mixture was treated with Sodium cyanoborohydride (557.40 mg, 8.87 mmol, 10 equiv) in 1,2-Dichloroethane (5 mL) at 40 °C for 3 h. The resulting mixture was concentrated under vacuum. The residue was purified by C18 silica gel column chromatography, eluted with Acetonitrile/water(Ammonium bicarbonate) (8:1) to afford tert-butyl 4-({6-[2- (ethylamino)-4-(methoxycarbonyl)phenyl]-2-oxa-7-azaspiro[3.5]nonan-7-yl}methyl)-5-methoxy-7- methylindole-1-carboxylate (120 mg, 23.42% yield) as a light yellow solid. LCMS: (ESI, m/z): 578.4 [M+H]⁺. [01182] Step 4: 3-(Ethylamino)-4-{7-[(5-methoxy-7-methyl-1H-indol-4-yl)methyl]-2-oxa-7- azaspiro[3.5]nonan-6-yl} benzoic acid [01183] A solution of tert-butyl 4-({

y hoxycarbonyl)phenyl]-2-oxa-7- azaspiro[3.5] nonan-7-yl}methyl)-5-methoxy-7-methylindole-1-carboxylate (30 mg, 0.05 mmol, 1 equiv) in Ethanol (1.2 mL) and water (0.4 mL) was treated with Potassium hydroxide (29.13 mg, 0.52 mmol, 10 equiv) at 80 °C for 2 h. The mixture was acidified to pH 6 with citric acid. The resulting mixture was concentrated under vacuum. The residue was purified by C18 silica gel column chromatography, eluted with Acetonitrile/water(Ammonium bicarbonate) (1:4) to afford 3-(ethylamino)-4-{7-[(5-methoxy-7-methyl-1H- indol-4-yl)methyl]-2-oxa-7-azaspiro[3.5]nonan-6-yl}benzoic acid (10.6 mg, 43.99% yield) as a white solid. LCMS: (ESI, m/z): 464.3 [M+H]⁺.¹H NMR (400 MHz, Methanol-d₄) δ 7.67 – 7.01 (m, 4H), 6.72 (s, 1H), 6.22 (s, 1H), 4.68 – 4.51 (m, 2H), 4.39 (s, 2H), 4.18 – 3.80 (m, 1H), 3.75 (s, 4H), 3.29 – 2.74 (m, 3H), 2.49 (s, 4H), 2.38 – 1.47 (m, 4H), 1.25 (s, 4H). [01184] Example 61. (S)-3-(Cyclopropylamino)-4-(1-((5-methoxy-7-methyl-1H-indol-4- yl)methyl)piperidin-2-yl)benzoic acid & (R)-3-(cyclopropylamino)-4-(1-((5-methoxy-7-methyl-1H-indol-4- yl)methyl)piperidin-2-yl)benzoic acid.

[

[01187] Into a 40 mL vial were added

peridin-2-yl)benzoate (2 g, 7.88 mmol), N,N- Diisopropylethylamine (2.00 g, 15.47 mmol) and Di-tert-butyl dicarbonate (5.16 g, 23.64 mmol) at room temperature. The resulting mixture was stirred for additional 30 min at room temperature. The resulting mixture was quenched with water and extracted with Ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with Petroleum ether/Ethyl acetate (5:1) to afford the title compound (1.4 g, 50.20% yield) as colorless oil. LCMS (ESI, m/z): [M+H] ⁺ =354.1 [01188] Step 2: tert-Butyl 2-(2-(cyclopropylamino)-4-(methoxycarbonyl)phenyl)piperidine-1-carboxylate [01189] A solution of tert-butyl 2-[2-c

onyl)phenyl]piperidine-1-carboxylate (1 g, 2.83 mmol), (SP-4-1)-[1,3-Bis[2,6-bis(1-propylbutyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazol-2- ylidene]dichloro(3-chloropyridine-κN)-Palladium (0.31 g, 0.36 mmol), Cesium carbonate (1.84 g, 5.65 mmol) in 1,4-dioxane (10 mL) was treated with aminocyclopropane (1.20 g, 21.03 mmol) for 2h at 80 °C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The reaction was diluted with water and extracted with Ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with Petroleum ether/Ethyl acetate (10:1) to afford the title compound (300 mg, 28.35% yield) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ =375.2 [01190] Step 3: Methyl 3-(cyclopropylamino)-4-(piperidin-2-yl)benzoate [01191] A solution of tert-butyl 2-[2-( (methoxycarbonyl)phenyl]piperidine-1-

carboxylate (500 mg, 1.34 mmol) and Trifluoroacetic acid (3 mL, 40.39 mmol) in Dichloromethane (3 mL) was stirred for 50 min at room temperature. The reaction was quenched with sat. Ammonium bicarbonate (aq.) at 0 °C. The resulting mixture was quenched with water and extracted with Ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with Dichloromethane/Methanol (10:1) to afford the title compound (200 mg, 54.60% yield) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ =275.2 [01192] Step 4: tert-Butyl 4-((2-(2-(cyclopropylamino)-4-(methoxycarbonyl)phenyl)piperidin-1- yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate O [01193] A solution of methyl 3-(cyclo

idin-2-yl)benzoate (500 mg, 1.82 mmol), Titanium(IV) ethoxide (1.26 g, 5.53 mmol) in 1,2-Dichloroethane (8 mL) was treated with tert-butyl 4- formyl-5-methoxy-7-methylindole-1-carboxylate (1.05 g, 3.63 mmol) for 30 min at 70 °C followed by the addition of Sodium triacetoxyborohydride (1.15 g, 5.43 mmol) dropwise at room temperature. The resulting mixture was stirred for 40 min at 70 °C. The resulting mixture was filtered, the filter cake was washed with Acetonitrile. The filtrate was concentrated under reduced pressure. A solution of the crude product (350 mg, and Sodium cyanoborohydride (795 mg, 12.82 mmol) in 1,2-Dichloroethane (15 mL) was stirred for 1h at room temperature. The resulting mixture was quenched with water and extracted with Ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in Water (10mmol/L Ammonium bicarbonate), 5% to 100% gradient in 30 min; detector, UV 220 nm. This resulted in the title compound (110 mg, 31.32%) as a white solid. LCMS (ESI, m/z): [M+H] ⁺ =548.3 [01194] Step 5: tert-Butyl (S)-4-((2-(2-(cyclopropylamino)-4-(methoxycarbonyl)phenyl)piperidin-1- yl)methyl)-5-methoxy-7-methyl-1H-indole-1- carboxylate (isomer 1, faster peak) & tert-butyl (R)-4-((2-(2- (cyclopropylamino)-4-(methoxycarbonyl)phenyl)piperidin-1-yl)methyl)-5-methoxy-7-methyl-1H-indole-1- carboxylate (isomer 2, slower peak) [01195] tert-butyl 4-((2-( nyl)piperidin-1-yl)methyl)-5-

methoxy-7-methyl-1H-indole-1-carboxylate (100 mg) was applied for further separation by Chiral HPLC with the following condition: Column: CHIRALPAK IA, 2*25 cm, 5 μm; Mobile Phase A: HEX(0.5% 2M NH₃-Methanol), Mobile Phase B: IPA; Flow rate: 20 mL/min; Gradient: isocratic 7; Wave Length: 220/254 nm; RT1(min): 6.645; RT2(min): 8.719; Sample Solvent: Ethanol; Injection Volume: 0.5 mL; Number Of Runs: 11. [01196] tert-butyl (S)-4-((2-(2-(cyclopropylamino)-4-(methoxycarbonyl)phenyl)piperidin-1-yl)methyl)-5- methoxy-7-methyl-1H-indole-1-carboxylate (isomer 1, faster peak) (35 mg, 31.82% yield) . LCMS (ESI, m/z): [M+H]⁺ =547.3. t_R = 1.43 min (CHIRALPAK IA-3, 4.6*50mm, 3um, Hex(0.1%DEA): IPA=93: 7, 1.0 mL/min, 254 nm). [01197] tert-butyl (R)-4-((2-(2-(cyclopropylamino)-4-(methoxycarbonyl)phenyl)piperidin-1-yl)methyl)-5- methoxy-7-methyl-1H-indole-1-carboxylate (isomer 2, slower peak) (40 mg, 36.36% yield) as a white solid. LCMS (ESI, m/z): [M+H]⁺ = 547.3. tR = 1.91 min (CHIRALPAK IA-3, 4.6*50mm, 3um, Hex(0.1%DEA): IPA=93: 7, 1.0 mL/min, 254 nm). [01198] Step 6: (S)-3-(Cyclopropylamino)-4-(1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2- yl)benzoic acid & (R)-3-(cyclopropylamino)-4-(1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2- yl)benzoic acid [01199] A solution of te xycarbonyl)phenyl)piperidin-1-

yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (isomer 1, faster peak) (35 mg, 0.064 mmol) and Potassium hydroxide (36 mg, 0.64 mmol) in Ethanol(2 mL) and water (1 mL) was stirred for 1h at 80 °C. The reaction mixture was acidified to pH = 6 with sat. citric acid solution. The residue was purified by reversed- phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in Water (10mmol/L Ammonium bicarbonate), 5% to 50% gradient in 20 min; detector, UV 220 nm. The resulting mixture was concentrated under reduced pressure. The resulting liquid was dried by lyophilization. This resulted in (S)-3-(cyclopropylamino)-4-(1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2- yl)benzoic acid(15.0 mg, 54.13% yield) as a white solid. LCMS (ESI, m/z): [M+H] ⁺ =434.4.¹H NMR (300 MHz, Methanol-d₄) δ 7.89 (s, 1H), 7.53 (s, 1H), 7.44 (s, 1H), 7.29 (s, 1H), 6.76 (s, 1H), 6.22 (s, 1H), 4.42 – 4.18 (m, 2H), 3.78 (s, 3H), 3.57 – 3.45 (m, 1H), 3.22 – 3.08 (m, 1H), 2.60 – 2.46 (m, 4H), 2.16 – 1.66 (m, 7H), 0.85 (s, 2H), 0.56 (s, 2H). [01200] A solution of tert-butyl (R)-4-((2-(2-(cyclopropylamino)-4-(methoxycarbonyl)phenyl)piperidin- 1-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (isomer 2, slower peak) (40 mg, 0.073 mmol) and Potassium hydroxide (41 mg, 0.73 mmol) in Ethanol (2 mL) and water (1 mL) was stirred for 1h at 80 °C. The reaction mixture was acidified to pH = 6 with sat. citric acid solution. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in Water (10mmol/L Ammonium bicarbonate), 5% to 50% gradient in 20 min; detector, UV 220 nm. The resulting mixture was concentrated under reduced pressure. The resulting liquid was dried by lyophilization. This resulted in (R)-3-(cyclopropylamino)-4-(1-((5-methoxy-7-methyl-1H-indol-4- yl)methyl)piperidin-2-yl)benzoic acid (16.2 mg, 51.16% yield) as a white solid. LCMS (ESI, m/z): [M+H] ⁺ =434.4.¹H NMR (400 MHz, Methanol-d₄) δ 7.87 (s, 1H), 7.60 – 7.35 (m, 2H), 7.27 (s, 1H), 6.74 (s, 1H), 6.23 (s, 1H), 4.69 – 3.89 (m, 2H), 3.80 – 3.74 (m, 3H), 3.66 – 3.48 (m, 1H), 3.29 – 3.18 (m, 1H), 2.55 – 2.43 (m, 4H), 2.15 – 1.71 (m, 7H), 0.84 (s, 2H), 0.58 – 0.50 (m, 2H). [01201] Example 62. 3-(Dimethylamino)-4-[(2R)-1-[(5-methoxy-7-methyl-1H-indol-4- yl)methyl]piperidin-2-yl]benzoic acid & 3-(dimethylamino)-4-[(2S)-1-[(5-methoxy-7-methyl-1H-indol-4- yl)methyl]piperidin-2-yl]benzoic acid.

hyl)- 5-methoxy-7-methylindole-1-carboxylate [01204] A solution of tert-butyl 4-({2-

carbonyl)phenyl]piperidin-1-yl}methyl)-5- methoxy-7-methylindole-1-carboxylate (700 mg, 1.38 mmol, 1 equiv), paraformaldehyde (252 mg, 8.28 mmol) and Sodium cyanoborohydride(173.31 mg, 2.76 mmol, 2 equiv) in Acetic acid (2.5 mL) and Tetrahydrofuran (2.5 mL) was stirred at room temperature for 1h . The resulting mixture was quenched with water and extracted with Ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in Water (10mmol/L Ammonium bicarbonate), 10% to 50% gradient in 10 min; detector, UV 254 nm. to afford tert-butyl 4-({2-[2-(dimethylamino)-4-(methoxycarbonyl)phenyl]piperidin-1- yl}methyl)-5-methoxy-7-methylindole-1-carboxylate (500 mg, 60.92% yield) as a yellow oil. LCMS (ESI, m/z): [M+H]⁺ = 536.4 [01205] Step 2: tert-butyl 4-{[(2R)-2-[2-(dimethylamino)-4-(methoxycarbonyl)phenyl]piperidin-1- yl]methyl}-5-methoxy-7-methylindole-1-carboxylate & tert-butyl 4-{[(2S)-2-[2-(dimethylamino)-4- (methoxycarbonyl)phenyl]piperidin-1-yl]methyl}-5-methoxy-7-methylindole-1-carboxylate [01206] tert-butyl 4-({2-[ l]piperidin-1-yl}methyl)-5-

methoxy-7-methylindole-1-carboxylate was applied for further separation by Chiral HPLC with the following condition: CHIRALPAK IG 2*25 cm, 5 μm; Mobile Phase A: HEX(0.5% 2M NH3-Methanol), Mobile Phase B: IPA; Flow rate: 20 mL/min; Gradient: isocratic 2; Wave Length: 220/254 nm; RT1(min): 9.526; RT2(min): 19.84; Sample Solvent: ETOH; [01207] tert-butyl 4-{[(2R)-2-[2-(dimethylamino)-4-(methoxycarbonyl)phenyl]piperidin-1-yl]methyl}-5- methoxy-7-methylindole-1-carboxylate (isomer 1, faster peak, 200 mg, 40% yield) LCMS: (ESI, m/z): 536.4 [M+H]⁺. tR = 2.07 min (CHIRALPAK IG-3, 4.6*50mm, 3um, HEX(0.1%DEA):IPA=98:2, 1.0 mL/min, 254 nm) [01208] tert-butyl 4-{[(2S)-2-[2-(dimethylamino)-4-(methoxycarbonyl)phenyl]piperidin-1-yl]methyl}-5- methoxy-7-methylindole-1-carboxylate (isomer 2, slower peak, 200 mg, 40% yield) LCMS: (ESI, m/z): 536.4 [M+H]⁺. tR = 3.58 min (CHIRALPAK IG-3, 4.6*50mm, 3um, HEX(0.1%DEA):IPA=98:2, 1.0 mL/min, 254 nm) [01209] Step 3: 3-(Dimethylamino)-4-[(2R)-1-[(5-methoxy-7-methyl-1H-indol-4-yl)methyl]piperidin-2- yl]benzoic acid & 3-(dimethylamino)-4-[(2S)-1-[(5-methoxy-7-methyl-1H-indol-4-yl)methyl]piperidin-2- yl]benzoic acid [01210] A solution of ter xycarbonyl)phenyl]piperidin-1-

yl]methyl}-5-methoxy-7-methylindole-1-carboxylate (200 mg, 0.38 mmol, 1 equiv) and Potassium hydroxide (230.42 mg, 4.10 mmol, 11 equiv) in water (0.6 mL) Ethanol (1.8 mL) was stirred at 80 °C for 2h . The mixture was acidified to pH = 6 with sat. citric acid. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in Water (10mmol/L Ammonium bicarbonate), 10% to 50% gradient in 10 min; detector, UV 254 nm. to afford 3- (dimethylamino)-4-[(2R)-1-[(5-methoxy-7-methyl-1H-indol-4-yl)methyl]piperidin-2-yl]benzoic acid (42.5 mg, 26.84% yield) as a white solid. LCMS (ESI, m/z): [M+H]⁺ = 422.1.¹H NMR (300 MHz, Methanol-d4) δ 8.07 – 8.01 (m, 1H), 8.01 – 7.92 (m, 1H), 7.68 – 7.59 (m, 2H), 7.37 – 7.30 (m, 1H), 6.38 – 6.31 (m, 1H), 5.12 – 5.01 (m, 1H), 4.36 – 4.26 (m, 1H), 4.18 – 4.08 (m, 1H), 3.78 (s, 3H), 3.54 – 3.35 (m, 2H), 2.71 (s, 6H), 2.52 (s, 3H), 2.18 (s, 2H), 2.02 – 1.76 (m, 4H). [01211] A solution of tert-butyl 4-{[(2S)-2-[2-(dimethylamino)-4-(methoxycarbonyl)phenyl]piperidin-1- yl]methyl}-5-methoxy-7-methylindole-1-carboxylate (200 mg, 0.38 mmol, 1 equiv) and Potassium hydroxide (230.42 mg, 4.10 mmol, 11 equiv) in water (0.6 mL) and Ethanol (1.8 mL) was stirred at 80 °C for 2h under air atmosphere. The mixture was acidified to pH = 6 with sat. citric acid. The solvent was removed. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in Water (10mmol/L Ammonium bicarbonate), 10% to 50% gradient in 10 min; detector, UV 254 nm. to afford 3-(dimethylamino)-4-[(2S)-1-[(5-methoxy-7-methyl-1H-indol-4- yl)methyl]piperidin-2-yl]benzoic acid (41.4 mg, 26.20% yield) as a white solid. LCMS (ESI, m/z): [M+H]⁺ = 422.1¹H NMR (300 MHz, Methanol-d4) δ 8.07 – 8.01 (m, 1H), 8.01 – 7.92 (m, 1H), 7.68 – 7.59 (m, 2H), 7.37 – 7.30 (m, 1H), 6.38 – 6.31 (m, 1H), 5.12 – 5.01 (m, 1H), 4.36 – 4.26 (m, 1H), 4.18 – 4.07 (m, 1H), 3.78 (s, 3H), 3.40 – 3.34 (m, 2H), 2.71 (s, 6H), 2.55 – 2.49 (m, 3H), 2.18 (s, 2H), 2.05 – 1.69 (m, 4H). [01212] Example 63.4-{7-[(5-Methoxy-7-methyl-1H-indol-4-yl)methyl]-2-oxa-7-azaspiro[3.5]nonan-6- yl}-3-(methylamino)benzoic acid.

[01215] A solution of 2-amino-4-(m

oronic acid (4.4 g, 22.57 mmol, 1 equiv), Di- tert-butyl dicarbonate (5.91 g, 27.08 mmol, 1.2 equiv), Triethylamine (6.85 g, 67.70 mmol, 3 equiv) in Acetonitrile (60 mL) was treated with 4-Dimethylaminopyridine (0.28 g, 2.26 mmol, 0.1 equiv) for overnight at 40 °C. The resulting mixture was quenched with water and extracted with Ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by C18 silica gel column chromatography, eluted with Acetonitrile/water (1:3) to afford 2-[(tert-butoxycarbonyl)amino]-4- (methoxycarbonyl)phenylboronic acid (1.4 g, 21.02% yield) as a light yellow solid. LCMS: (ESI, m/z): 294.0 [M-H]⁺. [01216] Step 2: tert-Butyl 6-[2-amino-4-(methoxycarbonyl)phenyl]-2-oxa-7-azaspiro[3.5]non-5-ene-7- carboxylate [01217] A solution of tert-butyl 6-(tr xy)-2-oxa-7-azaspiro[3.5]non-5-ene-7-

carboxylate (1.5 g, 4.02 mmol, 1 equiv), 2-[(tert-butoxycarbonyl)amino]-4-(methoxycarbonyl) phenylboronic acid (1.54 g, 5.22 mmol, 1.3 equiv), 1,1’-Bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (0.33 g, 0.40 mmol, 0.1 equiv) in dioxane (20 mL) and water (4 mL) was treated with Sodium carbonate (1.28 g, 12.05 mmol, 3 equiv) for 1h at 90 °C under nitrogen atmosphere. The resulting mixture was quenched with water and extracted with Ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by C18 silica gel column chromatography, eluted with Acetonitrile/water (1:3) to afford tert-butyl 6-[2-amino-4-(methoxycarbonyl)phenyl]-2-oxa-7- azaspiro[3.5]non-5-ene-7-carboxylate (600 mg, 39.88% yield) as a light yellow solid. LCMS: (ESI, m/z): 375.1 [M+H]⁺. [01218] Step 3: tert-Butyl 6-[4-(methoxycarbonyl)-2-(methylamino)phenyl]-2-oxa-7-azaspiro[3.5]non-5- ene-7-carboxylate [01219] A solution of tert-butyl 6-[2-

nyl)phenyl]-2-oxa-7-azaspiro[3.5]non-5- ene-7-carboxylate (400 mg, 1.07 mmol, 1 equiv), formaldehyde (128.30 mg, 4.27 mmol, 4 equiv), Titanium(IV) ethoxide (487.36 mg, 2.14 mmol, 2 equiv) in Methanol (6 mL) was treated with Sodium cyanoborohydride (201.39 mg, 3.20 mmol, 3 equiv) for 1h at 70 °C. The reaction was quenched with sat. Ammonium chloride (aq.) at room temperature. The resulting mixture was extracted with Ethyl acetate (3 × 5mL). The combined organic layers were washed with brine (3 × 5 mL), dried over anhydrous Sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by C18 silica gel column chromatography, eluted with Acetonitrile/water (1:1) to afford tert-butyl 6-[4- (methoxycarbonyl)-2-(methylamino)phenyl]-2-oxa-7-azaspiro[3.5]non-5-ene-7-carboxylate (100 mg, 24.10% yield) as a yellow solid. LCMS: (ESI, m/z): 389.1 [M+H]⁺. [01220] Step 4: Methyl 3-(methylamino)-4-{2-oxa-7-azaspiro[3.5]nonan-6-yl}benzoate O H N O O [01221] A solution of tert-butyl 6-[4- ethylamino)phenyl]-2-oxa-7- azaspiro[3.5]non-5-ene-7-carboxylate (12

0 mg, 0.31 mmol, 1 equiv) in Trifluoroacetic acid (1 mL) and Dichloromethane (1 mL) was treated with Sodium cyanoborohydride (194.12 mg, 3.09 mmol, 10 equiv) at room temperature for 1h. The reaction was quenched with sat. Sodium bicarbonate (aq.). The resulting mixture was extracted with Dichloromethane. The combined organic layers were washed with brine, dried over anhydrous Sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by C18 silica gel column chromatography, eluted with Acetonitrile/water (1:1) to afford methyl 3-(methylamino)-4-{2-oxa-7-azaspiro[3.5]nonan-6-yl}benzoate (70 mg, 78.04% yield) as a yellow solid. LCMS: (ESI, m/z): 290.9 [M+H]⁺. [01222] Step 5: tert-Butyl 5-methoxy-4-({6-[4-(methoxycarbonyl)-2-(methylamino)phenyl]-2-oxa-7- azaspiro[3.5] nonan-7-yl}methyl)-7-methylindole-1-carboxylate [01223] A solution of methyl 3-(met

aspiro[3.5]nonan-6-yl}benzoate (90 mg, 0.31 mmol, 1 equiv), tert-butyl 4-formyl-5-methoxy-7-methylindole-1-carboxylate (179.36 mg, 0.62 mmol, 2 equiv) was treated with (acetylacetonato)dicarbonyliridium(i) (40 mg, 0.12 mmol, 0.37 equiv) in Ethanol (4 mL) was stirred at 70 °C for 6h under hydrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with Methanol (3 × 2 mL). The filtrate was concentrated under reduced pressure. The mixture was added Sodium cyanoborohydride (97.39 mg, 1.55 mmol, 5 equiv) and was stirred at r.t. for 1h in 1,2- Dichloroethane (2 mL). The resulting mixture was extracted with Dichloromethane (3 × 2 mL). The combined organic layers were washed with brine (3 × 10 mL), dried over anhydrous Sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by C18 silica gel column chromatography, eluted with Acetonitrile/water (Ammonium bicarbonate) (9:1) to afford tert-butyl 5- methoxy-4-({6-[4-(methoxycarbonyl)-2-(methylamino)phenyl]-2-oxa-7-azaspiro [3.5]nonan-7-yl}methyl)-7- methylindole-1-carboxylate (20 mg, 11.45% yield) as a light yellow solid. LCMS: (ESI, m/z): 564.5 [M+H]⁺. [01224] Step 6: 4-{7-[(5-Methoxy-7-methyl-1H-indol-4-yl)methyl]-2-oxa-7-azaspiro[3.5]nonan-6-yl}-3- (methylamino)benzoic acid [01225] A solution of tert-butyl 5-m carbonyl)-2-(methylamino)phenyl]-2-oxa-

7-azaspiro[3.5]nonan-7-yl}methyl)-7-methylindole-1-carboxylate (20 mg, 0.04 mmol, 1 equiv) in Ethanol (1.5 mL) and water (0.5 mL) was treated with Potassium hydroxide (19.91 mg, 0.35 mmol, 10 equiv) at 80 °C for 2h. The mixture was acidified to pH = 6 with sat. citric acid. The solvent was removed. The residue was purified by C18 silica gel column chromatography, eluted with Acetonitrile/water(Ammonium bicarbonate) (1:4) to afford 4-{7-[(5-methoxy-7-methyl-1H-indol-4-yl)methyl]-2-oxa-7-azaspiro[3.5]nonan-6-yl}-3- (methylamino)benzoic acid (8.2 mg, 50.43% yield) as a white solid. LCMS: (ESI, m/z): 291.1 [M+H]⁺.¹H NMR (500 MHz, Methanol-d4) δ 7.61 – 7.13 (m, 4H), 6.72 (s, 1H), 6.24 (s, 1H), 4.73 (s, 1H), 4.64 (s, 1H), 4.39 (s, 2H), 4.05 – 3.60 (m, 5H), 3.34 (s, 1H), 2.89 (s, 4H), 2.49 (s, 4H), 2.36 (s, 1H), 2.28 – 1.51 (m, 3H). [01226] Example 64. (S)-5-(2,2-Difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)-6-(ethylamino)picolinic acid acid & (R)-5-(2,2-difluoro-7-((5-methoxy-7-methyl- 1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)-6-(ethylamino)picolinic acid. O O N NH F F [01227] Procedu

[0

azaspiro[3.5]nonan-7-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate [01229] A solution of tert-butyl 4-

onyl)pyridin-3-yl)-2,2-difluoro-7- azaspiro[3.5]nonan-7-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (120 mg, 0.20 mmol), Sodium cyanoborohydride (37 mg, 0.59 mmol) and acetaldehyde (45 mg, 1.02 mmol) in Methanol (2 mL) was stirred for 1 h at 50 °C. The resulting mixture was quenched with water and extracted with Ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in Water (10mmol/L Ammonium bicarbonate), 5% to 100% gradient in 30 min; detector, UV 220 nm. to afford the title compound (90 mg, 71.57% yield) as a white solid. LCMS (ESI, m/z): [M+H] ⁺ =613.3 [01230] Step 2: tert-Butyl (R)-4-((6-(2-(ethylamino)-6-(methoxycarbonyl)pyridin-3-yl)-2,2-difluoro-7- azaspiro[3.5]nonan-7-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (isomer 1, faster peak) & tert-butyl (S)-4-((6-(2-(ethylamino)-6-(methoxycarbonyl)pyridin-3-yl)-2,2-difluoro-7-azaspiro[3.5]nonan-7- yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (isomer 2, slower peak) [01231] tert-Butyl 2-difluoro-7-

azaspiro[3.5]nonan-7-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (95 mg, 0.155 mmol) was applied for further separation by Chiral HPLC with the following condition: Column: CHIRALPAK IC, 2*25 cm, 5 μm; Mobile Phase A: HEX(0.5% 2M NH3-Methanol), Mobile Phase B: ETOH; Flow rate: 20 mL/min; Gradient: isocratic 7; Wave Length: 220/254 nm; RT1(min): 10.537; RT2(min): 13.65; Sample Solvent: Ethanol; Injection Volume: 0.5 mL; Number Of Runs: 11. [01232] tert-Butyl (S)-4-((6-(2-(ethylamino)-6-(methoxycarbonyl)pyridin-3-yl)-2,2-difluoro-7- azaspiro[3.5]nonan-7-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (isomer 1, faster peak) (45 mg, 47.37% yield) . LCMS (ESI, m/z): [M+H]⁺ = 613.3. t_R = 1.96 min (CHIRALPAK IC-3, 4.6*50mm, 3um, Hex(0.1%DEA):Ethanol=90:10, 1.0 mL/min, 254 nm). [01233] tert-butyl (R)-4-((6-(2-(ethylamino)-6-(methoxycarbonyl)pyridin-3-yl)-2,2-difluoro-7- azaspiro[3.5]nonan-7-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (isomer 2, slower peak) (40 mg, 42.11% yield) as a white solid. LCMS (ESI, m/z): [M+H]⁺ = 613.3. tR = 2.43 min (CHIRALPAK IC-3, 4.6*50mm, 3um, Hex(0.1%DEA):Ethanol=90:10, 1.0 mL/min, 254 nm). [01234] Step 3: (S)-5-(2,2-Difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)-6-(ethylamino)picolinic acid & (R)-5-(2,2-difluoro-7-((5-methoxy-7-methyl-1H- indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)-6-(ethylamino)picolinic acid [01235] A solutio

yridin-3-yl)-2,2-difluoro- 7-azaspiro[3.5]nonan-7-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (isomer 1, faster peak) (40 mg, 0.065 mmol) and Potassium hydroxide (40 mg, 0.713 mmol) in ethanol (0.7 mL) and water (0.3 mL) was stirred for 1 h at 80 °C. The reaction mixture was acidified to pH = 6 with sat. citric acid solution. The solvent was removed under vacuum. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in Water (10mmol/L Ammonium bicarbonate), 5% to 50% gradient in 20 min; detector, UV 220 nm. The resulting mixture was concentrated under reduced pressure. The resulting liquid was dried by lyophilization. This resulted in (S)-5-(2,2-difluoro- 7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)-6-(ethylamino)picolinic acid (10.5 mg, 32.26% yield) as a white solid. LCMS (ESI, m/z): [M+H] ⁺ =499.1.¹H NMR (300 MHz, Methanol- d₄) δ 7.66 (d, J = 7.3 Hz, 1H), 7.34 – 7.23 (m, 2H), 6.80 (s, 1H), 6.59 (d, J = 3.1 Hz, 1H), 5.04 – 4.91 (m, 2H), 3.98 (s, 3H), 3.45 – 3.36 (m, 1H), 3.09 – 2.99 (m, 1H), 2.52 (s, 3H), 2.48 – 2.35 (m, 3H), 2.32 – 2.11 (m, 2H), 2.07 – 1.95 (m, 2H), 1.93 – 1.79 (m, 1H), 1.74 – 1.68 (m, 2H), 1.52 – 1.42 (m, 1H), 0.86 – 0.75 (m, 3H). [01236] A solution of tert-butyl (R)-4-((6-(2-(ethylamino)-6-(methoxycarbonyl)pyridin-3-yl)-2,2- difluoro-7-azaspiro[3.5]nonan-7-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (isomer 2, slower peak) (40 mg, 0.065 mmol, 1 equiv) and Potassium hydroxide (40 mg, 0.710 mmol, 10.92 equiv) in ethanol (0.7mL) and water (0.3mL) was stirred for 1h at 80 °C. The reaction mixture was acidified to pH = 6 with sat. citric acid solution. The solvent was removed under vacuum. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in Water (10mmol/L Ammonium bicarbonate), 5% to 50% gradient in 20 min; detector, UV 220 nm. The resulting mixture was concentrated under reduced pressure. The resulting liquid was dried by lyophilization. This resulted in (R)-5-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6- yl)-6-(ethylamino)picolinic acid (20.5 mg, 62.98% yield) as a white solid. LCMS (ESI, m/z): [M+H] ⁺ =499.1.¹H NMR (300 MHz, Methanol-d4) δ 7.65 (d, J = 7.3 Hz, 1H), 7.31 (s, 1H), 7.28 (d, J = 7.2 Hz, 1H), 6.80 (s, 1H), 6.59 (d, J = 3.1 Hz, 1H), 4.95 (d, J = 6.1 Hz, 2H), 3.98 (s, 3H), 3.45 – 3.36 (m, 1H), 3.09 – 2.99 (m, 1H), 2.52 (s, 3H), 2.49 – 2.33 (m, 3H), 2.33 – 2.09 (m, 2H), 2.07 – 1.97 (m, 2H), 1.93 – 1.79 (m, 1H), 1.76 – 1.66 (m, 2H), 1.47 (d, J = 13.1 Hz, 1H), 0.86 – 0.75 (m, 3H). [01237] Example 65. (S)-6-(Azetidin-1-yl)-5-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4- yl)methyl)-7-azaspiro[3.5]nonan-6-yl)picolinic acid & (R)-6-(azetidin-1-yl)-5-(2,2-difluoro-7-((5-methoxy-7- methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)picolinic acid. [01238] Procedu

[0

[01240] A mixture of methyl 5-bromo-

arboxylate (6 g, 23.95 mmol) and Caesium fluoride (21.8 g, 143.72 mmol) and azetidine (2.76g, 48.39 mmol) in N,N-Dimethylformamide (100 mL) was stirred for 12h at room temperature. The resulting mixture was quenched with water and extracted with Ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in Water, 30% to 60% gradient in 30 min; detector, UV 254 nm. to afford the title compound (4 g, 61.59% yield) as a white solid. LCMS (ESI, m/z): [M+H]⁺ = 272.1. [01241] Step 2: Methyl 6-(azetidin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinate [01242] A mixture of methyl 6-(azet

ne-2-carboxylate (4 g, 14.71 mmol) and bis(pinacolato)diboron (5.62 g, 22.13 mmol) and [1,1’- Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1.18 g, 1.62 mmol) and Potassium Acetate (4 g, 40.72 mmol) in 1,4-dioxane (40 mL) was stirred for 1h at 90 °C under nitrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with Petroleum ether (4 × 100 mL). The filtrate was concentrated under reduced pressure to afford the crude product (5 g). The crude product was used in the next step directly without further purification. LCMS (ESI, m/z): [M+H]⁺ = 319.2 [01243] Step 3: tert-Butyl 6-(2-(azetidin-1-yl)-6-(methoxycarbonyl)pyridin-3-yl)-2,2-difluoro-7- azaspiro[3.5]non-5-ene-7-carboxylate [01244] A mixture of methyl 6-(a ethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-

carboxylate (4 g, 12.57 mmol) and tert-butyl 2,2-difluoro-6-(((trifluoromethyl)sulfonyl)oxy)-7- azaspiro[3.5]non-5-ene-7-carboxylate (2.56 g, 6.286 mmol) and [1,1’- Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (459.93 mg, 0.63 mmol) and Sodium carbonate (1.33 g, 12.57 mmol) in 1,4-dioxane (20 mL) and water (5 mL) was stirred for 1h at 90 °C under nitrogen atmosphere. The resulting mixture was quenched with water and extracted with Ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with Petroleum ether/Ethyl acetate (5:1) to afford the the title compound (2 g, 49.55% yield) as a white solid. LCMS (ESI, m/z): [M+H]⁺ = 450.2. [01245] Step 4: Methyl 6-(azetidin-1-yl)-5-(2,2-difluoro-7-azaspiro[3.5]nonan-6-yl)picolinate [01246] A mixture of tert-butyl 6-

carbonyl)pyridin-3-yl)-2,2-difluoro-7- azaspiro[3.5]non-5-ene-7-carboxylate (1 g, 2.23 mmol) and 10% Pd/C (500 mg) in Methanol (20 mL) was stirred for 1h at 25 °C under hydrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with Methanol. The filtrate was concentrated under reduced pressure. The residue in Dichloromethane (5 mL) and Trifluoroacetic acid (5 mL, 94.22 mmol) was stirred for 1h at room temperature. The mixture was basified to pH 7 with N,N-Diisopropylethylamine. The resulting mixture was quenched with water and extracted with Ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in Water (10mmol/L Ammonium bicarbonate), 30% to 50% gradient in 30 min; detector, UV 254 nm. to afford the title compound(400 mg, 51.40% yield) as a white solid. LCMS (ESI, m/z): [M+H]⁺ = 352.2 [01247] Step 5: tert-butyl 4-((6-(2-(azetidin-1-yl)-6-(methoxycarbonyl)pyridin-3-yl)-2,2-difluoro-7- azaspiro[3.5]nonan-7-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate [01248] A mixture of methyl 6-(az -azaspiro[3.5]nonan-6-yl)picolinate (220

mg, 0.63 mmol) and tert-butyl 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylate (362.28 mg, 1.25 mmol) and Titanium(IV) ethoxide (285.62 mg, 1.25 mmol) in 1,2-Dichloroethane (3 mL) was stirred for 40 min at 70 °C. To the above mixture was added Sodium triacetoxyborohydride (398.07 mg, 1.88 mmol) dropwise at room temperature. The resulting mixture was stirred for additional 1h at 70 °C. The resulting mixture was quenched with water and extracted with Dichloromethane. The combined organic layers were washed with brine, dried over anhydrous Sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in Water (10mmol/L Ammonium bicarbonate), 10% to 80% gradient in 50 min; detector, UV 254 nm. to afford the title compound (180 mg) as a white solid. LCMS (ESI, m/z): [M+H]⁺ = 625.3 [01249] Step 6: tert-butyl (S)-4-((6-(2-(azetidin-1-yl)-6-(methoxycarbonyl)pyridin-3-yl)-2,2-difluoro-7- azaspiro[3.5]nonan-7-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (isomer 1, faster peak) & tert-butyl (R)-4-((6-(2-(azetidin-1-yl)-6-(methoxycarbonyl)pyridin-3-yl)-2,2-difluoro-7-azaspiro[3.5]nonan-7- yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (isomer 2, slower peak) [01250] tert-butyl

y y y py y ,2-difluoro-7- azaspiro[3.5]nonan-7-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (180 mg, 0.28 mmol) was applied for further separation by Chiral HPLC with the following condition: Column: CHIRALPAK IA, 2*25 cm, 5 μm; Mobile Phase A: HEX(0.5% 2M NH3-Methanol), Mobile Phase B: IPA; Flow rate: 20 mL/min; Gradient: isocratic 20; Wave Length: 220/254 nm; RT1(min): 4.32; RT2(min): 5.735; Sample Solvent: Ethanol; Injection Volume: 0.5 mL; Number Of Runs: 14 [01251] tert-Butyl (S)-4-((6-(2-(azetidin-1-yl)-6-(methoxycarbonyl)pyridin-3-yl)-2,2-difluoro-7- azaspiro[3.5]nonan-7-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (isomer 1, faster peak) (70 mg, 35% yield) LCMS (ESI, m/z): [M+H]⁺ = 625.3. t_R = 0.93 min (CHIRALPAK IA-3, 4.6*50 mm 3um, Hex(0.1%DEA): IPA=80: 20, 1.0 mL/min, 254 nm). [01252] tert-Butyl (R)-4-((6-(2-(azetidin-1-yl)-6-(methoxycarbonyl)pyridin-3-yl)-2,2-difluoro-7- azaspiro[3.5]nonan-7-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (isomer 2, slower peak) (50 mg, 25% yield) LCMS (ESI, m/z): [M+H]⁺ = 625.3. tR = 1.22 min (CHIRALPAK IA-3, 4.6*50 mm, 3um, Hex(0.1%DEA): IPA=80: 20, 1.0 mL/min, 254 nm). [01253] Step 7: (S)-6-(Azetidin-1-yl)-5-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)picolinic acid & (R)-6-(Azetidin-1-yl)-5-(2,2-difluoro-7-((5-methoxy-7-methyl-1H- indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)picolinic acid [01254] A soluti

pyridin-3-yl)-2,2- difluoro-7-azaspiro[3.5]nonan-7-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (isomer 1, faster peak) (70 mg, 0.11 mmol) and Potassium hydroxide (63 mg, 1.12 mmol) in Ethanol (1.5 mL) and water (0.5 mL) was stirred for 2 h at 80 °C. The mixture was acidified to pH< 7 with citric acid. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in Water (10mmol/L Ammonium bicarbonate), 25% to 30% gradient in 5 min; detector, UV 254 nm. to afford (S)-6-(azetidin-1-yl)-5-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4- yl)methyl)-7-azaspiro[3.5]nonan-6-yl)picolinic acid (47.5 mg, 81.37% yield) as a white solid. LCMS (ESI, m/z): [M+H]⁺ = 511.3.¹H NMR (400 MHz, Methanol-d₄) δ 7.85 (d, J = 7.8 Hz, 1H), 7.64 (d, J = 7.7 Hz, 1H), 7.29 (d, J = 3.1 Hz, 1H), 6.68 (s, 1H), 6.29 (d, J = 3.2 Hz, 1H), 4.51 – 4.39 (m, 2H), 4.16 (d, J = 11.0 Hz, 1H), 3.98 – 3.82 (m, 3H), 3.78 (d, J = 12.5 Hz, 1H), 3.72 (s, 3H), 3.32 (s, 1H), 3.25 – 3.11 (m, 1H), 2.74 – 2.50 (m, 2H), 2.50 – 2.31 (m, 7H), 2.02 (d, J = 23.5 Hz, 3H), 1.80 (d, J = 14.4 Hz, 1H). [01255] A solution of tert-butyl (R)-4-((6-(2-(azetidin-1-yl)-6-(methoxycarbonyl)pyridin-3-yl)-2,2- difluoro-7-azaspiro[3.5]nonan-7-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (isomer 2, slower peak) (50 mg, 0.08 mmol) and Potassium hydroxide (45 mg, 0.80 mmol) in Ethanol (1.5 mL) and water (0.5 mL) was stirred for 2 h at 80 °C. The mixture was acidified to pH< 7 with citric acid. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in Water (10mmol/L Ammonium bicarbonate), 25% to 30% gradient in 5 min; detector, UV 254 nm. to afford (R)-6-(azetidin-1-yl)-5-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4- yl)methyl)-7-azaspiro[3.5]nonan-6-yl)picolinic acid (27.8 mg, 67.35% yield) as a white solid. LCMS (ESI, m/z): [M+H]⁺ = 511.2.¹H NMR (400 MHz, Methanol-d₄) δ 7.87 (d, J = 7.8 Hz, 1H), 7.63 (d, J = 7.8 Hz, 1H), 7.30 (d, J = 3.2 Hz, 1H), 6.69 (s, 1H), 6.32 (d, J = 3.2 Hz, 1H), 4.55 – 4.45 (m, 2H), 4.19 (s, 1H), 4.03 – 3.90 (m, 3H), 3.84 (d, J = 12.5 Hz, 1H), 3.72 (s, 3H), 3.35 (s, 1H), 3.27 – 3.12 (m, 1H), 2.73 – 2.51 (m, 2H), 2.43 (d, J = 29.3 Hz, 7H), 2.10 (s, 2H), 2.04 – 1.92 (m, 1H), 1.81 (d, J = 14.4 Hz, 1H). [01256] Example 66.4-(6-((5-Methoxy-7-methyl-1H-indol-4-yl)methyl)-6-azaspiro[2.5]octan-5-yl)-3- (methylamino)benzoic acid. [01257] Procedure:

S

[01258] A solution of 6-azaspiro[2.5]octa

mmol) in Dichloromethane (50 mL) was added with Triethylamine (6.8 g, 67.20 mmol) and Di-tert-butyl dicarbonate (10 g, 45.820 mmol) 0 °C. The resulting mixture was stirred for 3 h at room temperature under air atmosphere. The resulting mixture was quenched with water and extracted with Ethyl acetate. The combined organic layers were dried over anhydrous Sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to afford the title compound (7 g crude) as a white solid. LCMS (ESI, m/z): [M+H]⁺ = 212.2. [01259] Step 2: tert-Butyl 5-oxo-6-azaspiro[2.5]octane-6-carboxylate. [01260] A mixture of tert-butyl 6-azaspiro

carboxylate (6 g, 28.395 mmol) and Ruodium (Ⅲ) chloride hydrate (1.2 g, 5.32 mmol) and Sodium periodate (12 g, 56.10 mmol) in water (30 mL) and Ethyl acetate (30 mL) was stirred for 1 h at 0 °C under air atmosphere. The resulting mixture was extracted with Ethyl acetate. The combined organic layers were washed with water, dried over anhydrous Sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by reverse phase flash with the following conditions (column, C18 silica gel; mobile phase, Acetonitrile in Water (0.1% Ammonium hydroxide), 40% to 60% gradient in 10 min; detector, UV 254 nm) to afford the title compound (4.9 g, 76.60% yield) as a white oil. LCMS (ESI, m/z): [M+H]⁺ = 226.3. [01261] Step 3: tert-Butyl 5-(trifluoromethanesulfonyloxy)-6-azaspiro[2.5]oct-4-ene-6-carboxylate [01262] A solution of tert-butyl 5-oxo-6- ane-6-carboxylate (4.3 g, 19.08 mmol) in Tetrahydrofuran (40 mL) was added with 1 M

Potassium bis(trimethylsilyl)amide in Tetrahydrofuran (20 mL, 20 mmol) in 30 min at -78 °C under nitrogen atmosphere followed by the addition of 1,1,1-trifluoro-N- phenyl-N-(trifluoromethane)sulfonylmethanesulfonamide (10.30 g, 28.83 mmol) in portions at -78 °C. The reaction was quenched with sat. Ammonium chloride (aq.) at room temperature. The resulting mixture was extracted with Ethyl acetate. The combined organic layers were washed with water, dried over anhydrous Sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with Petroleum ether/Ethyl acetate (7:1) to afford the title compound (12 g crude) as a white solid. LCMS (ESI, m/z): [M+H]⁺ = 358.1. [01263] Step 4: tert-Butyl 5-(4-(methoxycarbonyl)-2-nitrophenyl)-6-azaspiro[2.5]oct-4-ene-6-carboxylate [01264] A mixture of tert-butyl 5-(t

y)-6-azaspiro[2.5]oct-4-ene-6-carboxylate (2 g, 5.60 mmol), 4-(methoxycarbonyl)-2-nitrophenylboronic acid (2.53 g, 11.25 mmol), Tris(dibenzylideneacetone)dipalladium (512 mg, 0.56 mmol), Tri-tert-butylphosphine tetrafluoroborate (324 mg, 1.12 mmol) and Potassium fluoride (972 mg, 16.73 mmol) in Tetrahydrofuran (5 mL) and water (0.5 mL) was stirred for 1 h at 60 °C under nitrogen atmosphere. The resulting mixture was quenched with water and extracted with Ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in Water (0.1% Ammonium bicarbonate), 40% to 60% gradient in 10 min; detector, UV 254 nm to afford the title compound (1.12 g, 51.52% yield) as a yellow solid. LCMS (ESI, m/z): [M+H]⁺ =389.1. [01265] Step 5: tert-Butyl 5-(2-amino-4-(methoxycarbonyl)phenyl)-6-azaspiro[2.5]oct-4-ene-6- carboxylate [01266] A mixture of tert-Butyl 5-(4

y y trophenyl)-6-azaspiro[2.5]oct-4-ene-6- carboxylate (1.2 g, 3.08 mmol), Iron (560 mg, 0.072 mmol), and ammonium chloride (1.00 g, 18.63 mmol) in ethanol (5 mL) and water (5 mL) was stirred for 1h at 80 °C under air atmosphere. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with Petroleum ether/Ethyl acetate (12:1) to afford the title compound (500 mg, 38.38% yield) as a yellow solid. LCMS (ESI, m/z): [M+H]⁺ = 359.4. [01267] Step 6: tert-Butyl 5-(4-(methoxycarbonyl)-2-(methylamino)phenyl)-6-azaspiro[2.5]oct-4-ene-6- carboxylate [01268] A mixture of tert-Butyl 5-( nyl)phenyl)-6-azaspiro[2.5]oct-4-ene-6-

carboxylate (600 mg, 1.67 mmol), Paraformaldehyde (50 mg, 1.67 mmol) and Sodium cyanoborohydride (316 mg, 5.03 mmol) in methanol (9 mL) was stirred for 1 h at 70 °C under air atmosphere. The solvent was removed under vacuum. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in Water (0.1% Ammonium bicarbonate), 10% to 50% gradient in 10 min; detector, UV 254 nm.to afford the title compound (300 mg, 32.08% yield) as a yellow solid. LCMS (ESI, m/z): [M+H]⁺ = 373.4. [01269] Step 7: Methyl 3-(methylamino)-4-(6-azaspiro[2.5]octan-5-yl)benzoate [01270] A mixture of tert-Butyl 5-(

ethylamino)phenyl)-6-azaspiro[2.5]oct-4- ene-6-carboxylate (250 mg, 0.67 mmol) and Sodium cyanoborohydride (423 mg, 6.73 mmol) in Trifluoroacetic acid (2 mL) and Dichloromethane (2 mL) was stirred for 1 h at room temperature under air atmosphere. The solvent was removed under vacuum. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in Water (0.1% Ammonium bicarbonate), 50% to 60% gradient in 10 min; detector, UV 254 nm. This resulted in the title compound (100 mg, 54.30% yield) as a yellow oil. LCMS (ESI, m/z): [M+H]⁺ = 275.4. [01271] Step 8: tert-Butyl 5-methoxy-4-((5-(4-(methoxycarbonyl)-2-(methylamino)phenyl)-6- azaspiro[2.5]octan-6-yl)methyl)-7-methyl-1H-indole-1-carboxylate [01272] A solution of tert-butyl 4-fo l-1H-indole-1-carboxylate (100 mg, 0.33

mol), Methyl 3-(methylamino)-4-(6-azaspiro[2.5]octan-5-yl)benzoate (90 mg, 0.33 mmol) in 1,2- Dichloroethane (2 mL) was added acetic acid (25 mg, 0.42 mmol) and stirred for 2 h at 70 °C under air atmosphere, followed by the addition of sodium triacetoxyborohydride (208 mg, 9.82 mmol) in portions at room temperature. The resulting mixture was stirred for 12 h at 70 °C under air atmosphere. To the above mixture was added sodium borohydride (37 mg, 9.90 mmol) in portions over 1 min at room temperature. The resulting mixture was stirred for additional 1 h at 70 °C. The resulting mixture was quenched with water and extracted with Ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in Water (10mmol/L Ammonium bicarbonate), 10% to 50% gradient in 10 min; detector, UV 254 nm. to afford the title compound (60 mg, 16.70% yield) as a white solid. LCMS (ESI, m/z): [M+H]⁺ = 548.3. [01273] Step 9: 4-(6-((5-Methoxy-7-methyl-1H-indol-4-yl)methyl)-6-azaspiro[2.5]octan-5-yl)-3- (methylamino)benzoic acid [01274] A mixture of tert-Butyl 5-m

ycarbonyl)-2-(methylamino)phenyl)-6- azaspiro[2.5]octan-6-yl)methyl)-7-methyl-1H-indole-1-carboxylate (55 mg, 0.10 mmol) and potassium hydroxide (55 mg, 0.98 mmol) in methanol (0.9 mL) and water (0.3 mL) was stirred for 1 h at 75 °C under air atmosphere. The mixture was acidified to pH 6 with citric acid. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in Water (10mmol/L Ammonium bicarbonate), 10% to 50% gradient in 10 min; detector, UV 254 nm. to afford the title compound (10.5 mg, 24.00% yield) as a white solid. LCMS (ESI, m/z): [M+H]⁺ = 434.1.¹H NMR (400 MHz, Methanol-d₄) δ 7.71 – 7.31 (m, 3H), 7.31 – 7.23 (m, 1H), 6.74 (s, 1H), 6.22 (s, 1H), 4.78 – 4.03 (m, 3H), 3.76 (s, 3H), 3.58 (s, 1H), 2.93 (s, 3H), 2.67 (s, 1H), 2.50 (s, 3H), 2.35 – 2.21 (m, 1H), 1.32 – 0.81 (m, 3H), 0.79 – 0.30 (m, 4H). [01275] Example 67.3-(Azetidin-1-yl)-4-[(2S)-1-[(5-methoxy-7-methyl-1H-indol-4-yl)methyl]piperidin- 2-yl]benzoic acid & 3-(azetidin-1-yl)-4-[(2R)-1-[(5-methoxy-7-methyl-1H-indol-4-yl)methyl]piperidin-2- yl]benzoic acid. O O N N HO HO

p y y y p y , y py carboxylate [01278] A solution of 2-chloro-4-(me oronic acid (5.5 g, 25.65 mmol, 1 equiv), tert-butyl 2-(trifluoromethanesulfonyloxy

)-5,6-dihydro-4H-pyridine-1-carboxylate (25.50 g, 76.96 mmol, 3 equiv), 1,1’-Bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (2.09 g, 2.56 mmol, 0.1 equiv) and Sodium carbonate (8.16 g, 76.96 mmol, 3 equiv) in 1,4-dioxane (100 mL) and water (20 mL) was treated for 1h at 90 °C under nitrogen. The resulting mixture was quenched with water and extracted with Ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with Petroleum ether/Ethyl acetate (9:1) to afford tert- butyl 2-[2-chloro-4-(methoxycarbonyl)phenyl]-5,6-dihydro-4H-pyridine-1-carboxylate (3 g, 33.24% yield) as a yellow oil. LCMS: (ESI, m/z): 295.9 [M-(t-Bu)]⁺. [01279] Step 2: Methyl 3-chloro-4-(piperidin-2-yl)benzoate [01280] A solution of tert-butyl 2-[2-c

onyl)phenyl]-5,6-dihydro-4H-pyridine-1- carboxylate (1 g, 2.84 mmol, 1 equiv) in Dichloromethane (8 mL) was treated with Sodium cyanoborohydride (1.79 g, 28.42 mmol, 10 equiv). Then Trifluoroacetic acid (8 mL) was added at 0 °C and was stirred for 1h at room temperature. The resulting mixture was concentrated under vacuum. The resulting mixture was extracted with Ethyl acetate (3 × 20 mL). The combined organic layers were washed with brine (3x20 mL), dried over anhydrous Sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by C18 ilica gel column chromatography, eluted with Acetonitrile/water (1:4) to afford methyl 3-chloro-4-(piperidin-2-yl)benzoate (600 mg, 83.20% yield) as a yellow oil. LCMS: (ESI, m/z): 253.9 [M+H]⁺. [01281] Step 3: tert-Butyl 4-({2-[2-chloro-4-(methoxycarbonyl)phenyl]piperidin-1-yl}methyl)-5- methoxy-7-methylindole-1-carboxylate [01282] A solution of methyl 3-chloro zoate (700 mg, 2.76 mmol, 1 equiv), tert-

butyl 4-formyl-5-methoxy-7-methylindole-1-carboxylate (1.20 g, 4.14 mmol, 1.5 equiv) in Ethanol (15 mL) was treated with (acetylacetonato)dicarbonyliridium(i) (140 mg, 0.40 mmol, 0.15 equiv) for overnight at 70 °C under hydrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with acetonitrile (3x10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by C18 silica gel column chromatography, eluted with Acetonitrile/water(Ammonium bicarbonate) (10:1) to afford tert-butyl 4-({2-[2-chloro-4-(methoxycarbonyl)phenyl]piperidin-1-yl}methyl)-5-methoxy-7- methylindole-1-carboxylate (180 mg, 12.38% yield) as a yellow oil. LCMS: (ESI, m/z): 527.2 [M+H]⁺. [01283] Step 4: tert-butyl (R)-4-((2-(2-(azetidin-1-yl)-4-(methoxycarbonyl)phenyl)piperidin-1-yl)methyl)- 5-methoxy-7-methyl-1H-indole-1-carboxylate (isomer 1, faster peak) & tert-butyl(S)-4-((2-(2-(azetidin-1-yl)- 4-(methoxycarbonyl)phenyl)piperidin-1-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (isomer 2, slower peak) [01284] A solution of tert-b

henyl]piperidin-1-yl}methyl)-5- methoxy-7-methylindole-1-carboxylate (160 mg, 0.30 mmol, 1 equiv), azetidine (69.33 mg, 1.22 mmol, 4 equiv), (SP-4-1)-[1,3-Bis[2,6-bis(1-propylbutyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazol-2- ylidene]dichloro(3-chloropyridine-κN)-Palladium (25.54 mg, 0.030 mmol, 0.1 equiv) in 1,4-dioxane (3 mL) was treated with Cesium carbonate (296.73 mg, 0.91 mmol, 3 equiv) for overnight at 110 °C under nitrogen atmosphere. The resulting mixture was quenched with water and extracted with Ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by C18 silica gel column chromatography, eluted with Acetonitrile/water(Ammonium bicarbonate) (10:1) to afford tert-butyl 4-({2-[2-(azetidin-1-yl)-4- (methoxycarbonyl)phenyl]piperidin-1-yl}methyl)-5-methoxy-7-methylindole-1-carboxylate (80 mg, 48.12% yield) as a yellow oil. The crude product was applied for further separation by Chiral HPLC with the following condition: Column: CHIRALPAK IF, 2*25 cm, 5 μm; Mobile Phase A: HEX(0.5% 2M NH3- Methanol), Mobile Phase B: IPA; Flow rate: 20 mL/min; Gradient: isocratic 5; Wave Length: 220/254 nm; RT1(min): 7.657; RT2(min): 9.847; Sample Solvent: Ethanol; Injection Volume: 0.5 mL; Number Of Runs: 18. [01285] tert-butyl (S)-4-((2-(2-(azetidin-1-yl)-4-(methoxycarbonyl)phenyl)piperidin-1-yl)methyl)-5- methoxy-7-methyl-1H-indole-1-carboxylate (isomer 1, faster peak) (50 mg, 30.05% yield, off-white solid). LCMS: (ESI, m/z): 548.3 [M+H]⁺. tR = 1.49 min (CHIRALPAK IF, 2*25 cm, 5 μm, HEX(0.1%DEA):IPA=95:5, Flow rate: 1.0 mL/min, Wave Length: 254 nm). [01286] tert-butyl (R)-4-((2-(2-(azetidin-1-yl)-4-(methoxycarbonyl)phenyl)piperidin-1-yl)methyl)-5- methoxy-7-methyl-1H-indole-1-carboxylate (isomer 2, slower peak) (50 mg, 30.05% yield, off-white solid, off-white solid). LCMS: (ESI, m/z): 548.3 [M+H]⁺. tR = 1.70 min (CHIRALPAK IF, 2*25 cm, 5 μm, HEX(0.1%DEA):IPA=95:5, Flow rate: 1.0 mL/min, Wave Length: 254 nm). [01287] Step 5: 3-(azetidin-1-yl)-4-[(2S)-1-[(5-methoxy-7-methyl-1H-indol-4-yl)methyl]piperidin-2- yl]benzoic acid & 3-(azetidin-1-yl)-4-[(2R)-1-[(5-methoxy-7-methyl-1H-indol-4-yl)methyl]piperidin-2- yl]benzoic acid [01288] A solution of te

bonyl)phenyl)piperidin-1- yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (isomer 1, faster peak) (50 mg, 0.09 mmol, 1 equiv) in Ethanol (1 mL) and water (0.3 mL) was treated with Potassium hydroxide (51.22 mg, 0.92 mmol, 10 equiv) for 2h at 80 °C. The mixture was acidified to pH 6 with citric acid. Then the crude product was purified by Prep-HPLC to afford 3-(azetidin-1-yl)-4-[(2S)-1-[(5-methoxy-7-methyl-1H-indol-4- yl)methyl]piperidin-2-yl]benzoic acid (27.4 mg, 33.68% yield, white solid). LCMS: (ESI, m/z): 434.2 [M+H]⁺.¹H NMR (500 MHz, Methanol-d4) δ 7.73 (d, J = 8.1, 1H), 7.52 (d, J = 8.0 Hz, 1H), 7.49 (s, 1H), 7.32 (d, J = 3.2 Hz, 1H), 6.76 (s, 1H), 6.34 (d, J = 3.2 Hz, 1H), 4.54 (d, J = 11.4 Hz, 1H), 4.30 – 4.11 (m, 3H), 4.03 (d, J = 12.7 Hz, 1H), 3.94 – 3.83 (m, 2H), 3.78 (s, 3H), 3.51 – 3.42 (m, 1H), 3.35 (s, 1H), 2.51 (s, 3H), 2.45 – 2.32 (m, 2H), 2.19 – 2.01 (m, 2H), 2.01 – 1.91 (m, 1H), 1.91 – 1.69 (m, 3H). [01289] A solution of tert-butyl (R)-4-((2-(2-(azetidin-1-yl)-4-(methoxycarbonyl)phenyl)piperidin-1- yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (isomer 2, slower peak) (50 mg, 0.09 mmol, 1 equiv) in Ethanol (1 mL) and water (0.3 mL) was treated with Potassium hydroxide (51.22 mg, 0.92 mmol, 10 equiv) for 2h at 80 °C. The mixture was acidified to pH 6 with citric acid. Then the crude product was purified by Prep-HPLC to afford 3-(azetidin-1-yl)-4-[(2R)-1-[(5-methoxy-7-methyl-1H-indol-4- yl)methyl]piperidin-2-yl]benzoic acid (30.2 mg, 37.24% yield, white solid). LCMS: (ESI, m/z): 434.2 [M+H]⁺.¹H NMR (500 MHz, Methanol-d4) δ 7.74 (d, J = 8.1, 1H), 7.52 (d, J = 8.0 Hz, 1H), 7.48 (d, J = 1.6 Hz, 1H), 7.32 (d, J = 3.1 Hz, 1H), 6.75 (s, 1H), 6.33 (d, J = 3.1 Hz, 1H), 4.53 (d, J = 11.4 Hz, 1H), 4.27 – 4.14 (m, 3H), 4.01 (d, J = 12.7 Hz, 1H), 3.91 – 3.81 (m, 2H), 3.78 (s, 3H), 3.50 – 3.41 (m, 1H), 3.36 (d, J = 8.4 Hz, 1H), 2.51 (s, 3H), 2.47 – 2.32 (m, 2H), 2.16 – 2.02 (m, 2H), 2.01 – 1.92 (m, 1H), 1.91 – 1.67 (m, 3H). [01290] Example 68.3-Amino-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl-d2)-7- azaspiro[3.5]nonan-6-yl)benzoic acid.

, nonan- 7-yl)methyl-d2)-5-hydroxy-7-methyl-1H-indole-1-carboxylate O NO O ₂ F F [01293] Methyl 4-(2,2-difluoro-7-az nitrobenzoate 2,2,2-trifluoroacetate (344 mg,

0.76 mmol), tert-butyl 5-hydroxy-7-methyl-1H-indole-1-carboxylate (187 mg, 0.76 mmol) and formaldehyde- d2 (121 mg, 3.79 mmol) were combined in acetic acid (3.0 mL) and the reaction mixture was stirred at room temperature overnight. The crude was concentrated to dryness and the residue was dissolved in EtOAc and washed with NaHCO3 sat solution and water, dried over Na2SO4, and concentrated to dryness. The crude product was dissolved in DCM and purified via normal phase FCC to yield the title compound (324 mg, 60% yield) as a slightly yellow oil that solidified upon standing. LCMS (ESI): [M+H] ⁺ = 602.3. [01294] Step 2: tert-butyl 4-((2,2-difluoro-6-(4-(methoxycarbonyl)-2-nitrophenyl)-7-azaspiro[3.5]nonan- 7-yl)methyl-d2)-5-methoxy-7-methyl-1H-indole-1-carboxylate [01295] To a solution of step 1 (173 m

MF (1.5 mL), cesium carbonate (281 mg, 0.86 mmol) and methyl iodide (46.9 mg, 20.7 μL, 0.33 mmol) were added and the reaction mixture was stirred at room temperature over the weekend. The crude mixture was diluted in EtOAc and washed with water (3x). The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The crude product was dissolved in DCM and purified via normal phase FCC to yield the title compound (127 mg, 72% yield) as a yellow oil. LCMS (ESI): [M+H] ⁺ = 616.3 [01296] Step 3: tert-butyl 4-((6-(2-amino-4-(methoxycarbonyl)phenyl)-2,2-difluoro-7- azaspiro[3.5]nonan-7-yl)methyl-d2)-5-methoxy-7-methyl-1H-indole-1-carboxylate [01297] To a solution of step 2 (128 m

g, . mmo n 1.0 mL), 4,4'-bipyridine (325 μg, 0.21 mmol) was added. The reaction mixture was cooled to 0 °C and hypodiboric acid (55.9 mg, 0.62 mmol) was added. Then the ice bath was removed, and the mixture stirred at room temperature for 1 h. The reaction mixture was partitioned between EtOAc (25 mL) and water (10 mL) and the layers were separated. The aqueous layer was diluted further with 10 mL of water and was then extracted with EtOAc (3x 15 mL). The organic layers were combined, washed with water (3x 10 mL) and brine (10 mL), dried with anhydrous Na2SO4, filtered and concentrated under vacuum. The crude product was dissolved in DCM and purified via normal phase FCC to yield the title compound (62 mg, 48% yield) as a yellow oil. LCMS (ESI): [M+H] ⁺ = 586.3. [01298] Step 4: 3-amino-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl-d2)-7- azaspiro[3.5]nonan-6-yl)benzoic acid To a solution of step 3 (62.0 mg, 0.1 mm H (2.4 mL) and water (0.50 mL), KOH (60.8

mg, 85% Wt, 0.92 mmol) was added. The resulting mixture was stirred for 2 h at 80 °C. The reaction mixture was allowed to cool down to ambient temperature and was quenched with water (2.0 mL) and citric acid (177 mg, 0.92 mmol). The resulting mixture was stirred for 10 minutes at room temperature and then it was concentrated to dryness. The crude was dissolved in DMSO (3.0 mL) and purified via preparative HPLC (C18 silica gel; mobile phase, MeCN/NH4HCO310 mM). The fractions containing the product were lyophilized to yield the title compound (32 mg, 69 % yield) as a white solid. LCMS (ESI): [M+H] ⁺ = 472.2.¹H NMR (400 MHz, DMSO) δ 10.84 (s, 1H), 7.32 (d, J= 1.5 Hz, 1H), 7.24 (dd, J= 2.8, 2.8 Hz, 1H), 7.14 (br s, 2H), 6.67 (s, 1H), 6.47 (dd, J = 2.5, 2.5 Hz, 1H), 5.96 (br s, 2H), 3.71 (s, 3H), 2.60 (d, J= 12.1 Hz, 2H), 2.42 (s, 3H), 2.38 (d, J= 13.4 Hz, 1H), 2.28 (d, J= 13.3 Hz, 1H), 2.05 – 1.80 (m, 2H), 1.49 (br s, 3H), 1.24 (br s, 1H). [01299] Example 69. 4-(2,2-Difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl-d2)-7- azaspiro[3.5]nonan-6-yl)-3-(methylamino)benzoic acid. [01300] Procedure:

acetamido)phenyl)-

7-azaspiro[3.5]nonan-7-yl)methyl-d2)-5-methoxy-7-methyl-1H-indole-1-carboxylate [01302] To a solution of te

-(methoxycarbonyl)phenyl)-2,2-difluoro-7- azaspiro[3.5]nonan-7-yl)methyl-d2)-5-methoxy-7-methyl-1H-indole-1-carboxylate (60.0 mg, 0.096 mmol) in DCM (0.5 mL), triethylamine (29.2 mg, 40.3 μL, 0.29 mmol), TFAA (30.3 mg, 20.4 μL, 0.14 mmol) and DMAP (1.18 mg, 9.63 μmol) were added. The resulting mixture was stirred for 1 h at 0 °C. Then, water (5.0 mL) and DCM (10.0 mL) were added. The layers were separated, and the organic layer was washed with water (3x 4 mL), dried with anhydrous Na2SO4, filtered and concentrated under vacuum to give the title compound as a yellow oil, assuming quantitative yield. The isolated material was used directly as such in the next step. LCMS (ESI): [M+H] ⁺ = 682.3. [01303] Step 2: tert-butyl 4-((2,2-difluoro-6-(4-(methoxycarbonyl)-2-(2,2,2-trifluoro-N- methylacetamido)phenyl)-7-azaspiro[3.5]nonan-7-yl)methyl-d2)-5-methoxy-7-methyl-1H-indole-1- carboxylate [01304] To a solution of step 1 (60.9 F (1.2 mL), K2CO3 (37.0 mg, 0.27 mmol) and

MeI (15.2 mg, 6.70 μL, 0.11 mmol) were added. The resulting mixture was stirred overnight at room temperature. Additional MeI was added, and the mixture was stirred further until full conversion. The resulting mixture was diluted with DMSO (2.0 mL) and was directly purified via preparative HPLC (C18 silica gel; mobile phase, MeCN/NH4HCO310 mM). The fractions containing the product were lyophilized to yield the title compound (29.4 mg, 45% yield) as a white solid. LCMS (ESI): [M+H] ⁺ = 696.4. [01305] Step 3: 4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl-d2)-7-azaspiro[3.5]nonan- 6-yl)-3-(methylamino)benzoic acid To a solution of step 2 (29.4 mg, 0.04 m

(0.65 mL) and water (0.14 mL), KOH (21.1 mg, 0.38 mmol) was added. The resulting mixture was stirred for 4 h at 80 °C. The reaction mixture was allowed to cool down to ambient temperature and was quenched with water (2.0 mL) and citric acid (72.2 mg, 0.38 mmol). The resulting mixture was stirred for 10 minutes at room temperature and then it was concentrated to dryness. The crude was dissolved in DMSO (2.0 mL) and purified via preparative HPLC (C18 silica gel; mobile phase, MeCN/NH4HCO3 10 mM). The fractions containing the product were lyophilized to yield the title compound (14.7 mg, 75% yield) as a white solid. LCMS (ESI): [M+H] ⁺ = 486.2.¹H NMR (400 MHz, DMSO) δ 10.86 (s, 1H), 7.27 (s, 1H), 7.21 (s, 1H), 7.12 (t, J = 1.0 Hz, 1H), 6.93 (s, 1H), 6.67 (s, 1H), 6.22 (s, 1H), 3.70 (s, 3H), 2.78 (d, J = 4.5 Hz, 3H), 2.71 – 2.54 (m, 2H), 2.46 – 2.35 (m, 4H), 2.37 – 2.24 (m, 3H), 1.93 (d, J = 19.3 Hz, 2H), 1.52 (s, 3H), 1.24 (s, 1H). [01306] Example 70. (R)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl-d2)-7- azaspiro[3.5]nonan-6-yl)-3-((methyl-d3)amino)benzoic acid & (S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl- 1H-indol-4-yl)methyl-d2)-7-azaspiro[3.5]nonan-6-yl)-3-((methyl-d3)amino)benzoic acid. F F [0

d3)acetamido)phenyl)-7-azaspiro[3.5]nonan-7-yl)methyl-d2)-5-methoxy-7-methyl-1H-indole-1-carboxylate [01308] To a solution of

,2-difluoro-6-(4-(methoxycarbonyl)-2-(2,2,2- trifluoroacetamido)phenyl)-7-azaspiro[3.5]nonan-7-yl)methyl-d2)-5-methoxy-7-methyl-1H-indole-1- carboxylate (302 mg, 0.42 mmol) in DMF (5 mL), K2CO3 (174 mg, 1.26 mmol) and iodomethane-d3 (72.9 mg, 31.3 μL, 0.5 mmol) were added. The resulting mixture was stirred overnight at room temperature. Additional iodomethane-d3 was added, and the mixture stirred further until full conversion. The resulting mixture was directly purified via preparative HPLC (C18 silica gel; mobile phase, MeCN/NH₄HCO₃10 mM). The fractions containing the product were lyophilized to yield the title compound (234 mg, 76% yield) as a white solid. LCMS (ESI): [M+H] ⁺ = 699.4. [01309] Step 2: 4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl-d2)-7-azaspiro[3.5]nonan- 6-yl)-3-((methyl-d3)amino)benzoic acid [01310] To a solution of step 1 (100 ure of EtOH (1.95 mL) and water (0.42 mL),

KOH (84.0 mg, 85% Wt, 1.27 mmol) was added. The resulting mixture was stirred for 6 h at 80 °C. The reaction mixture was allowed to cool down to ambient temperature and was quenched with water (1.0 mL) and citric acid (244 mg, 1.27 mmol). The resulting mixture was stirred for 10 minutes at room temperature and then it was concentrated to dryness. The crude was dissolved in DMSO (1.0 mL) and purified via preparative HPLC (C18 silica gel; mobile phase, MeCN/NH4HCO310 mM). The fractions containing the product were lyophilized to yield the title compound (56 mg, 84% yield) as a white solid. LCMS (ESI): [M+H] ⁺ = 489.3. [01311] Step 3: (R)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl-d2)-7- azaspiro[3.5]nonan-6-yl)-3-((methyl-d3)amino)benzoic acid & (S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl- 1H-indol-4-yl)methyl-d2)-7-azaspiro[3.5]nonan-6-yl)-3-((methyl-d3)amino)benzoic acid [01312] The compoun

using chiral SFC. Conditions for chiral SFC: Column: Lux Cellulose-2 (250 x 21.20 mm; 5 μm); Temperature: 42 °C. Mobile Phase A: 70% CO2, Mobile Phase B: 30% Methanol + 0.2% NH4OH (25%, aq); Total flow: 100 mL/min; Gradient: isocratic; Total Run Time: 7.0 min; PDA Detection : 215 nm; Sample Solvent/concentration: MeOH/ 10 mg/mL; Injection Volume: 0.8 mL. The pure fractions of the two enantiomers were collected separately, concentrated under vacuum and lyophilized to obtain: [01313] Peak 1: assigned as R-enantiomer, 27 mg, white solid. >98% ee. LCMS (ESI): [M+H] ⁺ = 489.2 ¹H NMR (400 MHz, DMSO) δ 10.86 (s, 1H), 7.27 (s, 1H), 7.20 (s, 1H), 7.12 (s, 1H), 6.87 (s, 1H), 6.67 (s, 1H), 6.22 (s, 1H), 3.70 (s, 3H), 2.73 – 2.58 (m, 3H), 2.42 (s, 3H), 2.36 – 2.23 (m, 2H), 1.95 (t, J = 21.4 Hz, 2H), 1.51 (s, 3H), 1.23 (s, 1H). [01314] Peak 2: assigned as S-enantiomer, 29 mg, white solid. >98% ee. LCMS (ESI): [M+H] ⁺ = 489.2 ¹H NMR (400 MHz, DMSO) δ 10.86 (s, 1H), 7.27 (s, 1H), 7.20 (s, 1H), 7.13 (s, 1H), 6.87 (s, 1H), 6.67 (s, 1H), 6.22 (s, 1H), 3.70 (s, 3H), 2.70 – 2.62 (m, 3H), 2.42 (s, 3H), 2.36 – 2.23 (m, 2H), 1.92 (d, J = 18.3 Hz, 2H), 1.51 (s, 3H), 1.23 (s, 1H) [01315] Example 71. (S)-6-((2-Amino-2-oxoethyl)(methyl)amino)-5-(2,2-difluoro-7-((5-methoxy-7- methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)picolinic acid & (R)-6-((2-amino-2- oxoethyl)(methyl)amino)-5-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)picolinic acid. [01316] Procedu

[01317] Step 1: tert-butyl (S)-4-((6-(2-((2-amino-2-oxoethyl)(methyl)amino)-6- (methoxycarbonyl)pyridin-3-yl)-2,2-difluoro-7-azaspiro[3.5]nonan-7-yl)methyl)-5-methoxy-7-methyl-1H- indole-1-carboxylate (isomer 1, faster peak) & tert-butyl (R)-4-((6-(2-((2-amino-2-oxoethyl)(methyl)amino)- 6-(methoxycarbonyl)pyridin-3-yl)-2,2-difluoro-7-azaspiro[3.5]nonan-7-yl)methyl)-5-methoxy-7-methyl-1H- indole-1-carboxylate (isomer 2, slower peak) [01318] tert-but onyl)pyridin-3-yl)-2,2-

difluoro-7-azaspiro[3.5]nonan-7-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (280 mg, 0.42 mmol) was applied for further separation by Chiral HPLC with the following condition: Column: (R, R)- WHELK-O1-Kromasil, 2.11*25 cm, 5 μm; Mobile Phase A: HEX(0.5% 2M NH₃-MeOH), Mobile Phase B: EtOH; Flow rate: 20 mL/min; Gradient (B%): isocratic 30; Wave Length: 220/254 nm; RT1(min): 27.479; RT2(min): 32.341; Sample Solvent: IPA; Injection Volume: 0.6 mL; Number Of Runs: 11 [01319] tert-butyl (S)-4-((6-(2-((2-amino-2-oxoethyl)(methyl)amino)-6-(methoxycarbonyl)pyridin-3-yl)- 2,2-difluoro-7-azaspiro[3.5]nonan-7-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (isomer 1, faster peak) (120 mg, 42% yield). LCMS (ESI, m/z): [M+H] ⁺ =656.3. t_R = 3.38 min, ((R, R)-WHELK-O1- Kromasil, 4.6*50 mm, 3 μm, Hex(0.1%DEA): EtOH=70: 30, 1.0 mL/min, 254 nm) [01320] tert-butyl (R)-4-((6-(2-((2-amino-2-oxoethyl)(methyl)amino)-6-(methoxycarbonyl)pyridin-3-yl)- 2,2-difluoro-7-azaspiro[3.5]nonan-7-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (isomer 2, slower peak) (125 mg, 44% yield). LCMS (ESI, m/z): [M+H] ⁺ =656.3. tR = 3.88 min, ((R, R)-WHELK-O1- Kromasil 4.6*50 mm, 3 μm, Hex(0.1%DEA): EtOH=70: 30, 1.0 mL/min, 254 nm) [01321] Step 2: (S)-6-((2-amino-2-oxoethyl)(methyl)amino)-5-(2,2-difluoro-7-((5-methoxy-7-methyl-1H- indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)picolinic acid & (R)-6-((2-amino-2-oxoethyl)(methyl)amino)- 5-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)picolinic acid [01322] A soluti )-6-

(methoxycarbonyl)pyridin-3-yl)-2,2-difluoro-7-azaspiro[3.5]nonan-7-yl)methyl)-5-methoxy-7-methyl-1H- indole-1-carboxylate (isomer 1, faster peak) (110 mg, 0.17 mmol) and Potassium trimethylsilanolate (100 mg, 0.78 mmol) in Acetonitrile (6 mL) was stirred at room temperature for overnight under nitrogen atmosphere. The mixture was neutralized to pH = 6 with saturated citric acid solution. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in Water (10 mmol/L Ammonium Bicarbonate), 5% to 24% gradient in 15 min; detector, UV 254 nm. This resulted in 6-[(carbamoylmethyl)(methyl)amino]-5-[(6S)-2,2-difluoro-7-[(5-methoxy-7-methyl-1H- indol-4-yl)methyl]-7-azaspiro[3.5]nonan-6-yl]pyridine-2-carboxylic acid (65.2 mg, 71.76% yield) as a white solid. LCMS (ESI, m/z): [M+H] ⁺ = 542.0.¹H NMR (400 MHz, DMSO-d₆) δ 13.2 – 11.5 (m, 1H), 10.83 (s, 1H), 8.23 (d, J = 7.8 Hz, 1H), 7.76 (d, J = 7.8 Hz, 1H), 7.60 (s, 1H), 7.28 – 7.21 (m, 2H), 6.63 (s, 1H), 6.30 (t, J = 2.5 Hz, 1H), 3.91 – 3.81 (m, 1H), 3.68 (s, 3H), 3.65 – 3.62 (m, 1H) , 3.59 – 3.51 (m, 1H), 3.44 – 3.37 (m, 1H), 3.16 (d, J = 11.6 Hz, 1H), 2.91 (s, 3H), 2.71 – 2.64 (m, 1H), 2.63 – 2.53 (m, 1H), 2.47 – 2.43 (m, 1H), 2.41 (s, 3H), 2.36 – 2.22 (m, 2H), 2.11 – 2.01 (m, 1H), 1.88 – 1.80 (m, 1H), 1.76 – 1.65 (m, 1H), 1.60 – 1.46 (m, 2H). [01323] A solution of tert-butyl (R)-4-((6-(2-((2-amino-2-oxoethyl)(methyl)amino)-6- (methoxycarbonyl)pyridin-3-yl)-2,2-difluoro-7-azaspiro[3.5]nonan-7-yl)methyl)-5-methoxy-7-methyl-1H- indole-1-carboxylate (isomer 2, slower peak) (110 mg, 0.17 mmol) and Potassium trimethylsilanolate (100 mg, 0.78 mmol,) in Acetonitrile (6 mL) was stirred at room temperature for overnight under nitrogen atmosphere. The mixture was neutralized to pH = 6 with saturated citric acid solution. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in Water (10 mmol/L Ammonium Bicarbonate), 5% to 24% gradient in 15 min; detector, UV 254 nm. This resulted in 6-[(carbamoylmethyl)(methyl)amino]-5-[(6R)-2,2-difluoro-7-[(5- methoxy-7-methyl-1H-indol-4-yl)methyl]-7-azaspiro[3.5]nonan-6-yl]pyridine-2-carboxylic acid (53.7 mg, 59.11% yield) as a white solid. LCMS (ESI, m/z): [M+H] ⁺ =542.0.¹H NMR (400 MHz, DMSO-d6) δ 10.82 (s, 1H), 8.22 (d, J = 7.8 Hz, 1H), 7.75 (d, J = 7.7 Hz, 1H), 7.63 (s, 1H), 7.28 – 7.21 (m, 2H), 6.63 (s, 1H), 6.30 (t, J = 2.5 Hz, 1H), 3.91 – 3.81 (m, 1H), 3.68 (s, 3H), 3.65 – 3.62 (m, 1H), 3.59 – 3.50 (m, 1H), 3.44 – 3.37 (m, 1H), 3.16 (d, J = 11.7 Hz, 1H), 2.91 (s, 3H), 2.72 – 2.65 (m, 1H), 2.63 – 2.54 (m, 1H), 2.43 – 2.42 (m, 1H), 2.41 (s, 3H), 2.33 – 2.23 (m, 2H), 2.11 – 2.01 (m, 1H), 1.88 – 1.78 (m, 1H), 1.76 – 1.64 (m, 1H), 1.59 – 1.45 (m, 2H). [01324] Example 72.4-[(5S)-6-[(5-Methoxy-7-methyl-1H-indol-4-yl)methyl]-6-azaspiro[2.5]octan-5-yl]- 3-(3-methoxyazetidin-1-yl)benzoic acid & 4-[(5R)-6-[(5-methoxy-7-methyl-1H-indol-4-yl)methyl]-6- azaspiro[2.5]octan-5-yl]-3-(3-methoxyazetidin-1-yl)benzoic acid. [01325] Procedure:

[0

carboxylate [01327] A solution of 2-chloro-4-(meth

o yca o y p e yboronic acid (1 g, 4.66 mmol) and tert-butyl 5-(trifluoromethanesulfonyloxy)-6-azaspiro[2.5]oct-4-ene-6-carboxylate (2.50 g, 6.99 mmol), Sodium carbonate (1.48 g, 13.99 mmol), 1,1’-Bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (0.38 g, 0.47 mmol) in 1,4-dioxane (8 mL) and Water (2 mL) was stirred at 90 °C for 1 h under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with water. The resulting mixture was extracted with Ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with Petroleum Ether/Ethyl acetate (1:1) to afford tert-butyl 5-[2-chloro-4-(methoxycarbonyl)phenyl]-6- azaspiro[2.5]oct-4-ene-6-carboxylate (1.1 g, 62.42%yield) as a yellow solid. LCMS (ESI, m/z): [M+H-56] ⁺ = 322.1 [01328] Step 2: tert-butyl 5-[2-(3-methoxyazetidin-1-yl)-4-(methoxycarbonyl)phenyl]-6-azaspiro[2.5]oct- 4-ene-6-carboxylate [01329] A solution of tert-butyl 5-[2-

onyl)phenyl]-6-azaspiro[2.5]oct-4-ene-6- carboxylate (1 g, 2.64 mmol) and 3-methoxyazetidine (0.46 g, 5.29 mmol), Cesium Carbonate (2.59 g, 7.93 mmol), (SP-4-1)-[1,3-BIs[2,6-bis(1-ethylpropyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazol-2- ylidene]dichloro(2-methylpyridine)palladium (0.22 g, 0.27 mmol) in 1,4-dioxane (10 mL) was stirred at 80°C for 1 h under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with water. The resulting mixture was extracted with Ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with Petroleum Ether/Ethyl acetate (5:1) to afford tert-butyl 5-[2-(3-methoxyazetidin-1-yl)-4- (methoxycarbonyl)phenyl]-6-azaspiro[2.5]oct-4-ene-6-carboxylate (700 mg, 61.72%yield) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 429.3 [01330] Step 3: methyl 4-{6-azaspiro[2.5]octan-5-yl}-3-(3-methoxyazetidin-1-yl)benzoate [01331] A solution of tert-butyl 5-[2-(3

yl)-4-(methoxycarbonyl)phenyl]-6- azaspiro[2.5]oct-4-ene-6-carboxylate (700 mg, 1.63 mmol) and Sodium cyanoborohydride (1026.49 mg, 16.33 mmol) in trifluoroacetic acid (0.5 mL), Dichloromethane (0.5 mL) was stirred at room temperature for 1h. The reaction was quenched by the addition of Water/Ice at 0°C. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in Water (10 mmol/L Ammonium Bicarbonate), 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in methyl 4 - {6-azaspiro [2.5] octan-5-yl}-3-(3-methoxyazetidin-1-yl) benzoate (400 mg, 74.11%yield) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 331.1 [01332] Step 4: tert-butyl 5-methoxy-4-({5-[2-(3-methoxyazetidin-1-yl)-4-(methoxycarbonyl)phenyl]-6- azaspiro[2.5]octan-6-yl}methyl)-7-methylindole-1-carboxylate [01333] A solution of methyl 4-{6-az 3-(3-methoxyazetidin-1-yl)benzoate (400

mg, 1.21 mmol) and tert-butyl 4-(chloromethyl)-5-methoxy-7-methylindole-1-carboxylate (562.52 mg, 1.81 mmol), Cesium Carbonate (1183.26 mg, 3.63 mmol), Potassium iodide (301.43 mg, 1.81 mmol) in N,N- dimethylformamide (4 mL) was stirred at 50°C for 1h. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with water. The resulting mixture was extracted with Ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in Water (10 mmol/L Ammonium Bicarbonate), 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in tert-butyl 5-methoxy-4-({5-[2-(3-methoxyazetidin-1-yl)-4-(methoxycarbonyl)phenyl]-6- azaspiro[2.5]octan-6-yl}methyl)-7-methylindole-1-carboxylate (250 mg, 34.21%yield) as a yellow solid. [01334] LCMS (ESI, m/z): [M+H] ⁺ = 604.3 [01335] Step 5: tert-butyl (S)-5-methoxy-4-((5-(2-(3-methoxyazetidin-1-yl)-4-(methoxycarbonyl)phenyl)- 6-azaspiro[2.5]octan-6-yl)methyl)-7-methyl-1H-indole-1-carboxylate (isomer 1, faster peak) & tert-butyl (R)- 5-methoxy-4-((5-(2-(3-methoxyazetidin-1-yl)-4-(methoxycarbonyl)phenyl)-6-azaspiro[2.5]octan-6- yl)methyl)-7-methyl-1H-indole-1-carboxylate (isomer 2, slower peak)

[01336] tert-butyl 5-methoxy-4-({5-[2-(3-methoxyazetidin-1-yl)-4-(methoxycarbonyl)phenyl]-6- azaspiro[2.5]octan-6-yl}methyl)-7-methylindole-1-carboxylate (250 mg) was applied for further separation by Chiral HPLC with the following condition: Column: CHIRALPAK PAK AD-H, 30*250mm; Mobile Phase A: CO2, Mobile Phase B: IPA; Flow rate: 100 mL/min; Gradient (B%): isocratic 20% B; Back Pressure(bar): 100; Wave Length: 220 nm; RT1(min): 4.65; RT2(min): 6.45; Sample Solvent: MEOH; Injection Volume: 3 mL [01337] tert-butyl (S)-5-methoxy-4-((5-(2-(3-methoxyazetidin-1-yl)-4-(methoxycarbonyl)phenyl)-6- azaspiro[2.5]octan-6-yl)methyl)-7-methyl-1H-indole-1-carboxylate (isomer 1, faster peak) (100 mg, 40%yield). LCMS (ESI, m/z): [M+H] ⁺ =604.3. tR = 0.823 min (CHIRALPAK AD-34.6*50mm,3 μm), IPA (0.1% DEA), 4 mL/min, 220 nm). [01338] tert-butyl (R)-5-methoxy-4-((5-(2-(3-methoxyazetidin-1-yl)-4-(methoxycarbonyl)phenyl)-6- azaspiro[2.5]octan-6-yl)methyl)-7-methyl-1H-indole-1-carboxylate (isomer 2, slower peak) (100 mg, 40%yield). LCMS (ESI, m/z): [M+H] ⁺ =604.3. tR = 0.957 min (CHIRALPAK AD-34.6*50mm,3 μm), IPA (0.1% DEA), 4 mL/min, 220 nm). [01339] Step 6: 4-[(5S)-6-[(5-methoxy-7-methyl-1H-indol-4-yl)methyl]-6-azaspiro[2.5]octan-5-yl]-3-(3- methoxyazetidin-1-yl)benzoic acid & 4-[(5R)-6-[(5-methoxy-7-methyl-1H-indol-4-yl)methyl]-6- azaspiro[2.5]octan-5-yl]-3-(3-methoxyazetidin-1-yl)benzoic acid [01340] A solution of tert

din-1-yl)-4- (methoxycarbonyl)phenyl)-6-azaspiro[2.5]octan-6-yl)methyl)-7-methyl-1H-indole-1-carboxylate (isomer 1, faster peak) (100 mg, 40%yield) and Potassium hydroxide (92.93 mg) in Ethanol (0.75 mL), Water (0.25 mL) was stirred at 50°C for 2h. The reaction mixture was acidified to pH = 6 with sat. citric acid solution. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in Water (10 mmol/L Ammonium Bicarbonate), 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in 4-[(5S)-6-[(5-methoxy-7-methyl-1H-indol-4-yl)methyl]-6- azaspiro[2.5]octan-5-yl]-3-(3-methoxyazetidin-1-yl)benzoic acid (71.2 mg, 87.80%yield) as a white solid. LCMS (ESI, m/z): [M+H] ⁺ = 490.30.¹H NMR (400 MHz, DMSO-d6) δ 12.77 (s, 1H), 10.80 (s, 1H), 7.86 (d, J = 8.0 Hz, 1H), 7.52 (d, J = 7.9 Hz, 1H), 7.27 – 7.22 (m, 1H), 7.11 (d, J = 1.6 Hz, 1H), 6.64 (s, 1H), 6.51 – 6.45 (m, 1H), 4.34 – 4.22 (m, 2H), 4.17 – 4.09 (m, 1H), 3.82 – 3.74 (m, 1H), 3.70 (s, 3H), 3.69 – 3.65 (m, 1H), 3.53 – 3.42 (m, 2H), 3.27 (s, 3H), 3.16 (d, J = 10.4 Hz, 1H), 2.74 (d, J = 11.2 Hz, 1H), 2.41 (s, 3H), 2.20 – 2.09 (m, 1H), 2.01 – 1.91 (m, 1H), 1.85 – 1.74 (m, 1H), 1.01 (d, J = 13.3 Hz, 1H), 0.71 (d, J = 12.9 Hz, 1H), 0.30 – 0.25 (m, 4H). [01341] A solution of tert-butyl (R)-5-methoxy-4-((5-(2-(3-methoxyazetidin-1-yl)-4- (methoxycarbonyl)phenyl)-6-azaspiro[2.5]octan-6-yl)methyl)-7-methyl-1H-indole-1-carboxylate (isomer 2, slower peak) (100 mg, 40% yield) and Potassium hydroxide (92.93 mg, 1.66 mmol) in Ethanol (0.75 mL), Water (0.25 mL) was stirred at 50°C for 2h. The reaction mixture was acidified to pH = 6 with sat. citric acid solution. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in Water (10 mmol/L Ammonium Bicarbonate), 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in 4-[(5R)-6-[(5-methoxy-7-methyl-1H-indol-4- yl)methyl]-6-azaspiro[2.5]octan-5-yl]-3-(3-methoxyazetidin-1-yl)benzoic acid LCMS (ESI, m/z): [M+H] ⁺ = 490.30.¹H NMR (400 MHz, DMSO-d6) δ 12.76 (s, 1H), 10.80 (s, 1H), 7.86 (d, J = 8.0 Hz, 1H), 7.51 (d, J = 8.1 Hz, 1H), 7.27 – 7.21 (m, 1H), 7.11 (d, J = 1.6 Hz, 1H), 6.64 (s, 1H), 6.51 – 6.45 (m, 1H), 4.34 – 4.21 (m, 2H), 4.17 – 4.09 (m, 1H), 3.82 – 3.74 (m, 1H), 3.70 (s, 3H), 3.69 – 3.63 (m, 1H), 3.53 – 3.42 (m, 2H), 3.28 (s, 3H), 3.15 (d, J = 11.5 Hz, 1H), 2.74 (d, J = 11.4 Hz, 1H), 2.41 (s, 3H), 2.20 – 2.09 (m, 1H), 2.01 – 1.91 (m, 1H), 1.85 – 1.74 (m, 1H), 1.01 (d, J = 13.2 Hz, 1H), 0.71 (d, J = 12.8 Hz, 1H), 0.30 – 0.25 (m, 4H). [01342] Example 73.5-{6-[(5-methoxy-7-methyl-1H-indol-4-yl)methyl]-6-azaspiro[2.5]octan-5-yl}-6- (methylamino)pyridine-2-carboxylic acid. [01343] Procedure:

[01344] carboxylate

[01345] A solution of methyl 6-amino- arboxylate (1 g, 4.32 mmol) and

Bis(pinacolato)diboron (5.50 g, 21.64 mmol), 1,1’-Bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (0.35 g, 0.43 mmol), Potassium acetate (1.27 g, 12.98 mmol) in 1,4-dioxane (10 mL) was stirred at 80°C for 1h under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with water. The resulting mixture was extracted with Ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by trituration with PE (50 mL). The crude product was used in the next step directly without further purification. LCMS (ESI, m/z): [M+H] ⁺ = 279.1 [01346] Step 2: tert-butyl 5-[2-amino-6-(methoxycarbonyl)pyridin-3-yl]-6-azaspiro[2.5]oct-4-ene-6- carboxylate [01347] A solution of methyl 6-amino-

yl-1,3,2-dioxaborolan-2-yl)pyridine-2- carboxylate (1 g, 3.59 mmol) and tert-butyl 5-(trifluoromethanesulfonyloxy)-6-azaspiro[2.5]oct-4-ene-6- carboxylate (1.93 g, 5.39 mmol), Potassium fluoride (0.63 g, 10.78 mmol), Tetrakis(triphenylphosphine)palladium (0.42 g, 0.36 mmol) in 2-MeTHF (8 mL) and Water (2 mL) was stirred at 75°C for 1h under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with water. The resulting mixture was extracted with Ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with Petroleum Ether/Ethyl acetate (5:1) to afford tert-butyl 5-[2-amino-6- (methoxycarbonyl)pyridin-3-yl]-6-azaspiro[2.5]oct-4-ene-6-carboxylate (360 mg, 27.86%yield) as a brown solid. LCMS (ESI, m/z): [M+H] ⁺ = 360.1 [01348] Step 3: tert-butyl 5-(6-(methoxycarbonyl)-2-(methylamino)pyridin-3-yl)-6-azaspiro[2.5]oct-4- ene-6-carboxylate [01349] A solution of tert-butyl 5-[2-a onyl)pyridin-3-yl]-6-azaspiro[2.5]oct-4-ene-

6-carboxylate (360 mg, 1.00 mmol) and Paraformaldehyde (30.08 mg, 1.00 mmol), Sodium cyanoborohydride (125.88 mg, 2.00 mmol) in THF (2 mL) and HOAc (2 mL) was stirred at 50°C for 1h. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with water. The resulting mixture was extracted with Ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in Water (0.1% TFA), 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in tert-butyl 5-[6-(methoxycarbonyl)-2-(methylamino)pyridin-3-yl]-6- azaspiro[2.5]oct-4-ene-6-carboxylate (130 mg, 34.75%yield) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 374.2 [01350] Step 4: methyl 6-(methylamino)-5-(6-azaspiro[2.5]octan-5-yl)picolinate [01351] A solution of tert-butyl 5-[6-(

methylamino)pyridin-3-yl]-6- azaspiro[2.5]oct-4-ene-6-carboxylate (200 mg, 0.53 mmol) in hydrogen chloride (4.0 M in ethyl acetate) (1 mL) was stirred at room temperature for 1h. The resulting mixture was concentrated under reduced pressure. This resulted in methyl 5-{6-azaspiro[2.5]oct-4-en-5-yl}-6-(methylamino)pyridine-2-carboxylate (140 mg) as a yellow solid. A solution of methyl 5-{6-azaspiro[2.5]oct-4-en-5-yl}-6-(methylamino)pyridine-2-carboxylate (140 mg) and Sodium cyanoborohydride (96.56 mg, 1.64 mmol) in Dichloromethane (1.8 mL) methanol (0.2 mL) was stirred at room temperature for 1h. The resulting mixture was diluted with water. The resulting mixture was extracted with Ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in Water (10 mmol/L Ammonium Bicarbonate), 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in methyl 5-{6-azaspiro[2.5]octan-5-yl}-6-(methylamino)pyridine-2- carboxylate (100 mg, 66.18%yield) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 256.2 [01352] Step 5: tert-butyl 5-methoxy-4-((5-(6-(methoxycarbonyl)-2-(methylamino)pyridin-3-yl)-6- azaspiro[2.5]octan-6-yl)methyl)-7-methyl-1H-indole-1-carboxylate [01353] A solution of methyl 5-{6-aza -6-(methylamino)pyridine-2-carboxylate (100

mg, 0.36 mmol) and tert-butyl 4-(chloromethyl)-5-methoxy-7-methylindole-1-carboxylate (168.76 mg, 0.54 mmol), Cesium Carbonate (236.66 mg, 0.72 mmol), Potassium iodide (180.86 mg, 1.08 mmol) in N,N- dimethylformamide (1 mL) was stirred at 50°C for 1h. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with water. The resulting mixture was extracted with Ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in Water (10 mmol/L Ammonium Bicarbonate), 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in tert-butyl 5-methoxy-4-({5-[6-(methoxycarbonyl)-2-(methylamino)pyridin-3-yl]-6- azaspiro[2.5]octan-6-yl}methyl)-7-methylindole-1-carboxylate (70 mg, 35.13%yield) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 549.1 [01354] Step 6: 5-(6-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-6-azaspiro[2.5]octan-5-yl)-6- (methylamino)picolinic acid [01355] A solution of tert-butyl 5-meth

xycarbonyl)-2-(methylamino)pyridin-3-yl]-6- azaspiro[2.5]octan-6-yl}methyl)-7-methylindole-1-carboxylate (70 mg, 0.12 mmol) and Potassium hydroxide (71.58 mg, 1.28 mmol) in Ethanol (0.75 mL), Water (0.25 mL) was stirred at 80°C for 2h. The reaction mixture was acidified to pH = 6 with sat. citric acid solution. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in Water (10 mmol/L Ammonium Bicarbonate), 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in 5-{6-[(5-methoxy-7-methyl-1H-indol-4-yl)methyl]-6-azaspiro[2.5]octan-5-yl}-6- (methylamino)pyridine-2-carboxylic acid (40.5 mg, 73.05%yield, 98.8%purity) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 435.2.¹H NMR (400 MHz, DMSO-d6) δ 10.89 (s, 1H), 7.52 (d, J = 6.2 Hz, 2H), 7.32 – 7.26 (m, 1H), 7.21 (d, J = 7.3 Hz, 1H), 6.68 (s, 1H), 6.33 – 6.27 (m, 1H), 3.71 (s, 4H), 3.44 (d, J = 11.1 Hz, 1H), 3.32 (d, J = 11.8 Hz, 2H), 2.95 (d, J = 4.7 Hz, 3H), 2.74 (d, J = 11.4 Hz, 1H), 2.43 (s, 3H), 2.20 – 2.10 (m, 1H), 1.88 – 1.77 (m, 1H), 0.72 (d, J = 11.4 Hz, 2H), 0.38 (s, 1H), 0.28 (s, 3H). [01356] Example 74.3-[(cyanomethyl)amino]-4-[(5S)-6-[(5-methoxy-7-methyl-1H-indol-4-yl)methyl]-6- azaspiro[2.5]octan-5-yl]benzoic acid & 3-[(cyanomethyl)amino]-4-[(5R)-6-[(5-methoxy-7-methyl-1H-indol- 4-yl)methyl]-6-azaspiro[2.5]octan-5-yl]benzoic acid.

azaspiro[2.5]octan-6-yl)methyl]-5-methoxy-7-methylindole-1-carboxylate [01359] A mixture of tert-butyl 4-({ rbonyl)phenyl]-6-azaspiro[2.5]octan-6-

yl}methyl)-5-methoxy-7-methylindole-1-carboxylate(2.5 g, 4.68 mmol) and iodoacetonitrile (1.5 g, 8.98 mmo) and N,N-Diisopropylethylamine (1.2 g, 9.28 mmol) in N,N-dimethylformamide (30 mL) was stirred at 80°C for 12h. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with water. The resulting mixture was extracted with Ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in Water 20% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in the title compound (700 mg, 26.09%yield) as a yellow oil. LCMS (ESI, m/z) [M+H] ⁺ = 574.3. [01360] Step 2: methyl 3-[(cyanomethyl)amino]-4-{6-[(5-methoxy-7-methyl-1H-indol-4-yl)methyl]-6- azaspiro[2.5]octan-5-yl}benzoate [01361] A mixture of tert-butyl 4-[(5

o]-4-(methoxycarbonyl)phenyl}-6- azaspiro[2.5]octan-6-yl)methyl]-5-methoxy-7-methylindole-1-carboxylate (700 mg, 1.22 mmol) in Dichloromethane (8 mL) was stirred at 0°C for 2 min under air atmosphere. To the above mixture was added 2,6-Lutidine (262.0 mg, 2.44 mmol) and trimethylsilyl trifluoromethanesulfonate (543 mg, 2.44 mmol) dropwise over 0.5 h at 0°C. The resulting mixture was stirred at room temperature for additional 1h. The resulting mixture was diluted with water. The resulting mixture was extracted with Ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in Water, 20% to 50% gradient in 30 min; detector, UV 254 nm. This resulted in the title compound (220 mg, 38.09%yield) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 474.3. [01362] Step 3: methyl 3-[(cyanomethyl)amino]-4-[(5S)-6-[(5-methoxy-7-methyl-1H-indol-4-yl)methyl]- 6-azaspiro[2.5]octan-5-yl]benzoate (isomer 1, faster peak) & methyl 3-[(cyanomethyl)amino]-4-[(5R)-6-[(5- methoxy-7-methyl-1H-indol-4-yl)methyl]-6-azaspiro[2.5]octan-5-yl]benzoate (isomer 2, slower peak) [01363] Methyl 3-[(cya indol-4-yl)methyl]-6-

azaspiro[2.5]octan-5-yl}benzoate (220 mg) was applied for further separation by Chiral HPLC with the following condition: Column: CHIRALPAK IF 3*25 cm, 5 μm; Mobile Phase A: HEX(0.5% 2M NH3- MeOH)--HPLC, Mobile Phase B: EtOH--HPLC; Flow rate: 30 mL/min; Gradient (B%): isocratic 20; Wave Length: 220/254 nm; RT1(min): 10.649; RT2(min): 15.885; Sample Solvent: EtOH--HPLC; Injection Volume: 2.0 mL; Number Of Runs: 4 [01364] Methyl 3-[(cyanomethyl)amino]-4-[(5S)-6-[(5-methoxy-7-methyl-1H-indol-4-yl)methyl]-6- azaspiro[2.5]octan-5-yl]benzoate (isomer 1, faster peak)(90 mg, 41% yield) LCMS (ESI, m/z): [M+H] ⁺ = 474.3. tR = 1.24 min (CHIRALPAK IF, 3*25 cm, 5 μm, Hex(0.1%DEA): Ethanol =80: 20, 1.0 mL/min. 254nm) [01365] Methyl 3-[(cyanomethyl)amino]-4-[(5R)-6-[(5-methoxy-7-methyl-1H-indol-4-yl)methyl]-6- azaspiro[2.5]octan-5-yl]benzoate (isomer 2, slower peak)(90 mg, 41% yield) LCMS (ESI, m/z): [M+H] ⁺ = 474.3. tR = 1.92 min (CHIRALPAK IF, 3*25 cm, 5 μm, Hex(0.1%DEA): Ethanol = 80: 20, 1.0 mL/min. 254nm) [01366] Step 4: 3-[(cyanomethyl)amino]-4-[(5S)-6-[(5-methoxy-7-methyl-1H-indol-4-yl)methyl]-6- azaspiro[2.5]octan-5-yl]benzoic acid & 3-[(cyanomethyl)amino]-4-[(5R)-6-[(5-methoxy-7-methyl-1H-indol- 4-yl)methyl]-6-azaspiro[2.5]octan-5-yl]benzoic acid N N O O NH [01367] A mixture -methyl-1H-indol-4-

yl)methyl]-6-azaspiro[2.5]octan-5-yl]benzoate (isomer 1, faster peak) (90 mg, 0.19 mmol) and Cesium Carbonate (125 mg, 0.38 mmol) in THF (0.5 mL) and methanol (0.5 mL) and Water (0.5 mL) was stirred at 50°C for 6h under air atmosphere. The mixture was acidified to pH = 7 with citric acid. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in Water (10 mmol/L Ammonium Bicarbonate), 20% to 60% gradient in 30 min; detector, UV 254 nm. The crude product was purified by reverse phase flash with the following conditions (Column: XSelect CSH Prep C18 OBD Column 30*150 mm, 5um; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient (B%): 6% B to 23% B in 10 min; Wave Length: 254nm/220nm nm; RT1(min): 9.35). This resulted in the product (16.4 mg, 18.78%yield) as a white solid. LCMS (ESI, m/z): [M+H] ⁺ = 459.2.¹H NMR (500 MHz, DMSO-d₆) δ 10.94 (s, 1H), 8.50 (s, 1H), 7.35 (d, J = 1.3 Hz, 1H), 7.29 (d, J = 7.5 Hz, 1H), 7.24 – 7.19 (m, 1H), 7.11 (s, 1H), 6.67 (s, 1H), 6.50 – 6.18 (m, 1H), 4.35 – 4.26 (m, 2H), 4.05 (s, 1H), 3.78 (d, J = 12.1 Hz, 1H), 3.71 (s, 3H), 3.37 – 3.25 (m, 2H), 2.90 – 2.63 (m, 1H), 2.42 (s, 3H), 2.10 (s, 1H), 1.93 – 1.83 (m, 1H), 0.75 (d, J = 13.3 Hz, 1H), 0.70 (d, J = 13.1 Hz, 1H), 0.38 (d, J = 9.2 Hz, 1H), 0.27 (s, 3H). [01368] A mixture of methyl 3-[(cyanomethyl)amino]-4-[(5R)-6-[(5-methoxy-7-methyl-1H-indol-4- yl)methyl]-6-azaspiro[2.5]octan-5-yl]benzoate (isomer 2, slower peak) (90 mg, 0.19 mmol) and Cesium Carbonate (125 mg, 0.38 mmol) in THF (0.5 mL) and methanol (0.5 mL) and Water (0.5 mL) was stirred at 50°C for 6 h under air atmosphere. The mixture was acidified to pH = 7 with citric acid. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in Water (10 mmol/L Ammonium Bicarbonate),20% to 60% gradient in 30 min; detector, UV 254 nm. The crude product was purified by reverse phase flash with the following conditions (Column: XSelect CSH Prep C18 OBD Column 30*150 mm, 5um; Mobile Phase A: Water(0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient (B%): 6% B to 23% B in 10 min; Wave Length: 254nm/220nm nm; RT1(min): 9.35) This resulted in the product (17.8 mg, 20.38%yield) as a white solid. LCMS (ESI, m/z): [M+H] ⁺ = 459.1.¹H NMR (500 MHz, DMSO-d6) δ 10.89 (s, 1H), 8.49 (s, 1H), 7.32 (d, J = 1.3 Hz, 1H), 7.27 (d, J = 7.5 Hz, 1H), 7.20 (s, 1H), 6.68 (s, 1H), 6.51 – 6.25 (m, 1H), 4.38 – 4.29 (m, 2H), 4.05 (s, 1H), 3.77 (d, J = 12.0 Hz, 1H), 3.71 (s, 3H), 3.29 – 3.05 (m, 3H), 3.11 –2.64 (m, 1H), 2.42 (s, 3H), 2.12 (s, 1H), 1.91 – 1.83 (m, 1H), 0.76 (d, J = 13.2 Hz, 1H), 0.73 – 0.67 (m, 1H), 0.39 (d, J = 7.1 Hz, 1H), 0.27 (d, J = 5.5 Hz, 3H). [01369] Example 75. (S)-7-(1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl)-1H-indazole- 4-carboxylic acid & (R)-7-(1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl)-1H-indazole-4- carboxylic acid. O N O N NH NH HO HO

p y y [01372] A solution of 4-bromo-7-chlor , 28.51 mmol) and tributyl(1- ethoxyethenyl)stannane (12.36 g, 34.21 mm

ol), Bis(triphenylphosphine)palladium(II) Dichloride (2.01 g, 2.85 mmol) in N,N-dimethylformamide (80 mL) was stirred at 90°C for 6 hours under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with Ethyl acetate (40 mL). The reaction was quenched with sat. Potassium fluoride (aq.) at room temperature. The resulting mixture was extracted with Ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with Petroleum Ether/Ethyl acetate (6:1) to afford title compound (4 g, 63.00%yield) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 223.1 [01373] Step 2: ethyl 7-chloro-1H-indazole-4-carboxylate [01374] To a stirred mixture of 7-chlo

1H-indazole (3.65 g, 16.39 mmol) and Sodium periodate (14.02 g, 65.56 mmol) in 1,4-dioxane (400 mL), Water (80 mL) was added Potassium permanganate (2.07 g, 13.11 mmol) in Water (80 mL) dropwise at 0°C. The resulting mixture was stirred at room temperature for additional 1h. The resulting mixture was diluted with water. The resulting mixture was extracted with Ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in Water (10 mmol/L Ammonium Bicarbonate), 0% to 100% gradient in 30 minutes; detector, UV 254 nm. This resulted in title compound (820 mg, 22.27%yield) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 225.0 [01375] Step 3: ethyl 7-(1-(tert-butoxycarbonyl)-1,4,5,6-tetrahydropyridin-2-yl)-1H-indazole-4- carboxylate [01376] A solution of ethyl 7-chloro-

y ate (240 mg, 1.06 mmol) and Bis(pinacolato)diboron (542.61 mg, 2.13 mmol), 1,1’-Bis(diphenylphosphino)ferrocene- palladium(II)dichloride dichloromethane complex (87.25 mg, 0.11 mmol), Potassium acetate (314.56 mg, 3.20 mmol) in 1,4-dioxane (5 mL) was stirred at 100°C for 3 hours under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. To the above mixture was added tert-butyl 6- (((trifluoromethyl)sulfonyl)oxy)-3,4-dihydropyridine-1(2H)-carboxylate (542.61 mg, 2.13 mmol), Tri-tert- butylphosphonium tetrafluoroborate (31.00 mg, 0.11 mmol), Water (2 mL) in portions at room temperature. The resulting mixture was stirred at 90°C for additional overnight. The resulting mixture was diluted with water. The resulting mixture was extracted with Ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in Water (10 mmol/L Ammonium Bicarbonate), 0% to 100% gradient in 30 minutes; detector, UV 254 nm. This resulted in title compound (200 mg, 50.40%yield) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 372.2 [01377] Step 4: ethyl 7-(1-(tert-butoxycarbonyl)piperidin-2-yl)-1H-indazole-4-carboxylate [01378] A solution of ethyl 7-(1-(ter

-tetrahydropyridin-2-yl)-1H-indazole-4- carboxylate (330 mg, 0.89 mmol) and Pd/C (200 mg) in Ethanol (30 mL) was stirred at room temperature for 1 hour under hydrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with Ethanol. The filtrate was concentrated under reduced pressure. This resulted in title compound (320 mg, 96.45%yield) as a white solid. LCMS (ESI, m/z): [M+H] ⁺ = 374.2 [01379] Step 5: ethyl 7-(piperidin-2-yl)-1H-indazole-4-carboxylate [01380] A solution of ethyl 7-(1-(tert

in-2-yl)-1H-indazole-4-carboxylate (320 mg, 0.85 mmol) in HCl (4M in EA) (8 mL) was stirred at room temperature for 1 hour under air atmosphere. The resulting mixture was concentrated under reduced pressure. This resulted in title compound (320 mg, crude) as a white solid. LCMS (ESI, m/z): [M+H] ⁺ = 274.1 [01381] Step 6: ethyl 7-(1-((1-(tert-butoxycarbonyl)-5-methoxy-7-methyl-1H-indol-4- yl)methyl)piperidin-2-yl)-1H-indazole-4-carboxylate [01382] To a stirred solution of ethyl dazole-4-carboxylate (320 mg, 1.17 mmol)

and Potassium iodide (291.51 mg, 1.75 mmol), Cesium Carbonate (1.14 g, 3.51 mmol) in N,N- dimethylformamide (5 mL) was added tert-butyl 4-(chloromethyl)-5-methoxy-7-methylindole-1-carboxylate (362.68 mg, 1.17 mmol) dropwise at room temperature under air atmosphere. The resulting mixture was stirred at room temperature for 1 hour. The resulting mixture was diluted with water. The resulting mixture was extracted with Ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with Petroleum Ether/Ethyl acetate = 3:1 to afford title compound (130 mg, 20.31%yield) as a white solid. LCMS (ESI, m/z): [M+H] ⁺ = 547.3 [01383] Step 7: ethyl (S)-7-(1-((1-(tert-butoxycarbonyl)-5-methoxy-7-methyl-1H-indol-4- yl)methyl)piperidin-2-yl)-1H-indazole-4-carboxylate (isomer 1, faster peak) & ethyl (R)-7-(1-((1-(tert- butoxycarbonyl)-5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl)-1H-indazole-4-carboxylate (isomer 2, slower peak) [01384] ethyl 7-(1-((1-(

l-4-yl)methyl)piperidin-2-yl)- 1H-indazole-4-carboxylate (130 mg, 0.23 mmol) was applied for further separation by Chiral HPLC with the following condition: Column: Lux 5um Cellulose-4, 2.12*25 cm, 5 μm; Mobile Phase A: Hex(0.5% 2M NH3- MeOH)--HPLC, Mobile Phase B: EtOH--HPLC; Flow rate: 20 mL/min; Gradient (B%): isocratic 5; Wave Length: 220/254 nm; RT1(min): 11.369; RT2(min): 17.711; Sample Solvent: EtOH--HPLC; Injection Volume: 0.8 mL; Number Of Runs: 20. [01385] ethyl (S)-7-(1-((1-(tert-butoxycarbonyl)-5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2- yl)-1H-indazole-4-carboxylate (isomer 1, faster peak) (30 mg, 42.86%yield). LCMS (ESI, m/z): [M+H] ⁺ =547.3. t_R = 1.94 min (Lux Cellulose‐44.6*50 mm,3 um), Hex(0.1%DEA):EtOH=95:5, 1.0 mL/min, 254 nm). [01386] ethyl (R)-7-(1-((1-(tert-butoxycarbonyl)-5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2- yl)-1H-indazole-4-carboxylate (isomer 2, slower peak) (30 mg, 42.86%yield). LCMS (ESI, m/z): [M+H] ⁺ =547.3. tR = 2.35 min (Lux Cellulose‐44.6*50 mm,3 um), Hex(0.1%DEA): EtOH=95:5, 1.0 mL/min, 254 nm). [01387] Step 8: (S)-7-(1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl)-1H-indazole-4- carboxylic acid & (R)-7-(1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl)-1H-indazole-4- carboxylic acid O N O N NH NH HO HO [01388] A solution of et 7-methyl-1H-indol-4-

yl)methyl)piperidin-2-yl)-1H-indazole-4-carboxylate (isomer 1, faster peak) (30 mg, 0.05 mmol) and Potassium hydroxide (39.99 mg, 0.71 mmol) in Ethanol (2 mL), Water(0.5 mL) was stirred at 80°C for 5 hours under air atmosphere. The mixture was allowed to cool down to room temperature. The mixture was acidified to pH = 6 with citric acid. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in Water (10 mmol/L Ammonium Bicarbonate), 10% to 40% gradient in 10 minutes; detector, UV 254 nm. The resulting mixture was concentrated under reduced pressure. The resulting liquid was dried by lyophilization. This resulted in (S)-7-(1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl)-1H-indazole-4-carboxylic acid (19.6 mg, 25.60%yield) as a white solid. LCMS (ESI, m/z): [M+H] ⁺ = 419.20.¹H NMR (300 MHz, DMSO-d6) δ 13.21 (s, 1H), 10.82 (s, 1H), 8.45 (s, 1H), 7.86 (d, J = 7.5 Hz, 1H), 7.69 (d, J = 7.5 Hz, 1H), 7.23 (q, J = 2.7 Hz, 1H), 6.65 (s, 1H), 6.31 (s, 1H), 3.81-3.70 (s, 1H), 3.65 (s, 3H), 3.60 (d, J = 12.0, 1H), 3.28 (s, 2H), 2.84 (d, J = 11.7 Hz, 1H), 2.41 (s, 3H), 2.14 – 2.01 (m, 1H), 1.84 – 1.65 (m, 3H), 1.61 – 1.35 (m, 3H). [01389] A solution of ethyl (R)-7-(1-((1-(tert-butoxycarbonyl)-5-methoxy-7-methyl-1H-indol-4- yl)methyl)piperidin-2-yl)-1H-indazole-4-carboxylate (isomer 2, slower peak) (30 mg, 0.05 mmol) and Potassium hydroxide (39.99 mg, 0.71 mmol) in Ethanol (2 mL), Water(0.5 mL) was stirred at 80°C for 5 hours under air atmosphere. The mixture was allowed to cool down to room temperature. The mixture was acidified to pH = 6 with citric acid. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in Water (10 mmol/L Ammonium Bicarbonate), 10% to 40% gradient in 10 minutes; detector, UV 254 nm. The resulting mixture was concentrated under reduced pressure. The resulting liquid was dried by lyophilization. This resulted in (R)-7-(1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl)-1H-indazole-4-carboxylic acid (20.6 mg, 26.91%yield) as a white solid. LCMS (ESI, m/z): [M+H] ⁺ = 419.20.¹H NMR (300 MHz, DMSO-d6) δ 13.21 (s, 1H), 10.82 (s, 1H), 8.45 (s, 1H), 7.86 (d, J = 7.4 Hz, 1H), 7.69 (d, J = 7.5 Hz, 1H), 7.23 (q, J = 2.7 Hz, 1H), 6.65 (s, 1H), 6.30 (s, 1H), 3.82 – 3.68 (m, 1H), 3.65 (s, 3H), 3.60 (d, J = 11.7, 1H), 3.28 (s, 2H), 2.84 (d, J = 11.7 Hz, 1H), 2.41 (s, 3H), 2.14 – 2.01 (m, 1H), 1.83 – 1.68(m, 3H), 1.60 – 1.36 (m, 3H). [01390] Example 76.4-[(2S,4S)-4-ethoxy-1-[(5-methoxy-7-methyl-1H-indol-4-yl)methyl]piperidin-2-yl]- 3-(methylamino)benzoic acid & 4-[(2R,4R)-4-ethoxy-1-[(5-methoxy-7-methyl-1H-indol-4- yl)methyl]piperidin-2-yl]-3-(methylamino)benzoic acid & 4-[(2R,4S)-4-ethoxy-1-[(5-methoxy-7-methyl-1H- indol-4-yl)methyl]piperidin-2-yl]-3-(methylamino)benzoic acid & 4-[(2S,4R)-4-ethoxy-1-[(5-methoxy-7- methyl-1H-indol-4-yl)methyl]piperidin-2-yl]-3-(methylamino)benzoic acid. [0

O Cl NH O [

[01393] A solution of 4-bromo-3-chl

84.79 mmol) in THF (400 mL) was treated with 1.3 M Isopropylmagnesium chloride - Lithium chloride complex in THF (180 mL, 234.00 mmol) at 0°C for 1h under nitrogen atmosphere followed by the addition of 4-methoxypyridine (18 g, 164.94 mmol) dropwise at -40°C for 10 min followed by the addition of Benzyl chloroformate (28 g, 164.13 mmol) at - 40°C, then the reaction was stirred at -40°C for 1 h. The resulting mixture was diluted with water. The resulting mixture was extracted with Ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with Petroleum Ether/Ethyl acetate (5:1) to afford benzyl 2-(2-chloro-4-cyanophenyl)-4-oxo-2,3-dihydropyridine-1-carboxylate (30 g, 44.26%yield) as a yellow oil. LCMS: (ESI, m/z): [M+H] ⁺ = 367.8. [01394] Step 2: benzyl 2-(2-chloro-4-cyanophenyl)-4-oxopiperidine-1-carboxylate [01395] A mixture of benzyl 2-(2-chl oxo-2,3-dihydropyridine-1-carboxylate (12 g, 32.71 mmol) and Zinc (21.00 g, 321.19 m

mol) in HOAc (150 mL) was stirred at 100°C for 1h. The resulting mixture was filtered, the filter cake was washed with Ethyl acetate. The resulting mixture was diluted with water. The resulting mixture was extracted with Ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with Petroleum Ether/Ethyl acetate (10:1) to afford benzyl 2-(2-chloro-4-cyanophenyl)-4-oxopiperidine-1-carboxylate (10 g, 82.88% yield) as a white solid. LCMS: (ESI, m/z): [M+H] ⁺ =369.8 [01396] Step 3: benzyl 2-(2-chloro-4-cyanophenyl)-4-hydroxypiperidine-1-carboxylate [01397] A mixture of benzyl 2-(2-ch

xopiperidine-1-carboxylate (16 g, 43.38 mmol) and NaBH4 (3.20 g, 84.58 mmol) in THF (160 mL) was stirred at room temperature for 1h. The resulting mixture was quenched with water and extracted with Ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to afford benzyl 2-(2-chloro-4-cyanophenyl)-4-hydroxypiperidine-1-carboxylate (15 g curde) as a white oil. LCMS: (ESI, m/z): [M+H] ⁺ = 341.8 [01398] Step 4: benzyl 2-(2-chloro-4-cyanophenyl)-4-ethoxypiperidine-1-carboxylate [01399] A solution of benzyl 2-(2-c

droxypiperidine-1-carboxylate (15 g, 40.45 mmol) in N,N-dimethylformamide (150 mL) was treated with Sodium hydride (1.94 g, 80.84 mmol) at 0°C for 1 h under nitrogen atmosphere followed by the addition of iodoethane (19 g, 133.86 mmol) dropwise at 0°C. The resulting mixture was stirred at 0°C for 40 min under nitrogen atmosphere. The resulting mixture was quenched with water and extracted with Ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with Petroleum Ether/Ethyl acetate (10:1) to afford benzyl 2-(2-chloro-4-cyanophenyl)-4-ethoxypiperidine-1-carboxylate (7 g, 43.38%yield) as a yellow oil. LCMS: (ESI, m/z): [M+H] ⁺ = 399.9 [01400] Step 5: 4-{1-[(benzyloxy)carbonyl]-4-ethoxypiperidin-2-yl}-3-chlorobenzoic acid [01401] A mixture of benzyl 2-(2- xypiperidine-1-carboxylate (5 g, 12.53

mmol) and barium hydroxide (22 g, 128.39 mmol) in Water (15 mL) and isopropanol (40 mL) was stirred at 100 °C for 5h. The mixture was acidified to pH= 6 with HCl (aq.). The resulting mixture was quenched with water and extracted with Ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with Petroleum Ether/Ethyl acetate (10:1) to afford 4-{1-[(benzyloxy)carbonyl]-4-ethoxypiperidin-2-yl}-3-chlorobenzoic acid (4 g, 76.36%yield) as a yellow oil. LCMS: (ESI, m/z): [M+H] ⁺= 418.9 [01402] Step 6: benzyl 2-[2-chloro-4-(methoxycarbonyl)phenyl]-4-ethoxypiperidine-1-carboxylate [01403] A mixture of 4-{1-[(benz

idin-2-yl}-3-chlorobenzoic acid (5 g, 11.96 mmol) and (trimethylsilyl)diazomethane (2 M in THF) (11 mL, 23.92 mmol) in Dichloromethane (45 mL) and methanol (5 mL) was stirred at room temperature for 1h. The resulting mixture was quenched with water and extracted with Ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with Petroleum Ether/Ethyl acetate (9:1) to afford benzyl 2-[2-chloro-4-(methoxycarbonyl)phenyl]-4-ethoxypiperidine-1-carboxylate (4 g, 77.40%yield) as a yellow oil. LCMS: (ESI, m/z): [M+H] ⁺ = 432.9 [01404] Step 7: benzyl 4-ethoxy-2-[4-(methoxycarbonyl)-2-(methylamino)phenyl]piperidine-1- carboxylate [01405] A mixture of benzyl 2-[2-

c o o- - e o yca o y phenyl]-4-ethoxypiperidine-1-carboxylate (1 g, 2.31 mmol) and (SP-4-1)-[1,3-BIs[2,6-bis(1-ethylpropyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazol- 2-ylidene]dichloro(2-methylpyridine)palladium (194 mg, 0.23 mmol) and methanamine hydrochloride (1.55 g, 22.94 mmol) and Cesium Carbonate (9.00 g, 27.61 mmol) in 1,4-dioxane (12 mL) was stirred at 100°C for 12h under nitrogen atmosphere. The resulting mixture was quenched with water and extracted with Ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with Petroleum Ether/Ethyl acetate (10:1) to afford benzyl 4-ethoxy-2-[4- (methoxycarbonyl)-2-(methylamino)phenyl]piperidine-1-carboxylate (600 mg, 60.76%yield) as a Brown yellow oil. LCMS: (ESI, m/z): [M+H] ⁺ = 427.5 [01406] Step 8: methyl 4-(4-ethoxypiperidin-2-yl)-3-(methylamino)benzoate [01407] A mixture of benzyl 4-eth -(methylamino)phenyl]piperidine-1-

carboxylate (4 g, 9.37 mmol) and Pd/C (500 mg) in ethyl acetate (40 mL) was stirred at room temperature for 8 h under hydrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with ethyl ether (3x50 mL). The filtrate was concentrated under reduced pressure to afford methyl 4-(4-ethoxypiperidin- 2-yl)-3-(methylamino)benzoate (1.3 g, 47.41%yield) as a yellow oil. LCMS: (ESI, m/z): [M+H] ⁺ = 293.4 [01408] Step 9: tert-butyl 4-({4-ethoxy-2-[4-(methoxycarbonyl)-2-(methylamino)phenyl]piperidin-1- yl}methyl)-5-methoxy-7-methylindole-1-carboxylate [01409] A mixture of methyl 4-(4

ylamino)benzoate (800 mg, 2.73 mmol) and tert-butyl 4-(chloromethyl)-5-methoxy-7-methylindole-1-carboxylate (882 mg, 2.84 mmol) and Cesium Carbonate (2.6 g, 7.98 mmol) and Potassium iodide (396 mg, 2.38 mmol) in N,N-dimethylformamide (8 mL) was stirred at 50°C for 1 h. The resulting mixture was quenched with water and extracted with Ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with Petroleum Ether/Ethyl acetate (12:1) to afford tert-butyl 4-({4-ethoxy-2-[4- (methoxycarbonyl)-2-(methylamino)phenyl]piperidin-1-yl}methyl)-5-methoxy-7-methylindole-1-carboxylate (900 mg, 58.14%yield) as a white solid. LCMS: (ESI, m/z): [M+H] ⁺ =566.7 [01410] Step 10: tert-butyl 4-{[(2S,4S)-4-ethoxy-2-[4-(methoxycarbonyl)-2- (methylamino)phenyl]piperidin-1-yl]methyl}-5-methoxy-7-methylindole-1-carboxylate & tert-butyl 4- {[(2R,4R)-4-ethoxy-2-[4-(methoxycarbonyl)-2-(methylamino)phenyl]piperidin-1-yl]methyl}-5-methoxy-7- methylindole-1-carboxylate & tert-butyl 4-{[(2R,4S)-4-ethoxy-2-[4-(methoxycarbonyl)-2- (methylamino)phenyl]piperidin-1-yl]methyl}-5-methoxy-7-methylindole-1-carboxylate & tert-butyl 4- {[(2S,4R)-4-ethoxy-2-[4-(methoxycarbonyl)-2-(methylamino)phenyl]piperidin-1-yl]methyl}-5-methoxy-7- methylindole-1-carboxylate [01411] [0141 methyl)-

5-methoxy-7-methylindole-1-carboxylate (900 mg, 0.16 mmol) was applied for further separation by Chiral HPLC with the following condition: [01413] Column: CHIRALPAK ID, 2*25 cm, 5 μm; Mobile Phase A: HEX(0.5% 2M NH3-MeOH), Mobile Phase B: ETOH; Flow rate: 20 mL/min; Gradient (B%): isocratic 7; Wave Length: 220/254 nm; RT1(min): 5.925; RT2(min): 8.602; Sample Solvent: EtOH; Injection Volume: 0.6 mL; Number Of Runs: 46 [01414] Column: CHIRALPAK IG 2*25 cm, 5 μm; Mobile Phase A: HEX(0.5% 2M NH3-MeOH), Mobile Phase B: EtOH; Flow rate: 20 mL/min; Gradient (B%): isocratic 5; Wave Length: 220/254 nm; RT1(min): 7.366; RT2(min): 10.068; Sample Solvent: ETOH; Injection Volume: 0.4 mL; Number Of Runs: 20 [01415] (isomer 1, faster peak) (90 mg, 10% yield) LCMS: (ESI, m/z): [M+H] ⁺ = 566.7. tR = 1.83 min (CHIRALPAK IG-3, 4.6*50mm 3um; HEX(0.1%DEA): EtOH=95: 5; 1.0 mL/min) [01416] (isomer 2, slower peak) (90 mg, 10%yield) LCMS: (ESI, m/z): [M+H] ⁺ = 566.7. tR = 2.46 min (CHIRALPAK IG-3, 4.6*50mm 3um; HEX(0.1%DEA): EtOH=95: 5; 1.0 mL/min) [01417] (isomer 3, faster peak) (140 mg, 15%yield) LCMS: (ESI, m/z): [M+H]⁺ = 566.7. tR = 1.73 min (CHIRALPAK AD-3, 4.6*50mm 3um; Hex(0.1%DEA):EtOH=90:10; 1.0 mL/min) [01418] (isomer 4, slower peak) (140 mg, 15%yield) LCMS: (ESI, m/z): [M+H]⁺ = 566.7. tR = 2.17 min (CHIRALPAK AD-3, 4.6*50mm 3um; Hex(0.1%DEA):EtOH=90:10; 1.0 mL/min) [01419] Step 11: 4-[(2S,4S)-4-ethoxy-1-[(5-methoxy-7-methyl-1H-indol-4-yl)methyl]piperidin-2-yl]-3- (methylamino)benzoic acid & 4-[(2S,4R)-4-ethoxy-1-[(5-methoxy-7-methyl-1H-indol-4-yl)methyl]piperidin- 2-yl]-3-(methylamino)benzoic acid & 4-[(2R,4S)-4-ethoxy-1-[(5-methoxy-7-methyl-1H-indol-4- yl)methyl]piperidin-2-yl]-3-(methylamino)benzoic acid & 4-[(2R,4R)-4-ethoxy-1-[(5-methoxy-7-methyl-1H- indol-4-yl)methyl]piperidin-2-yl]-3-(methylamino)benzoic acid [0 Et

hanol (0.9 mL) and Water (0.3 mL) was stirred at 80 C for 2h. The reaction mixture was acidified to pH = 6 with sat. citric acid solution. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in Water (10 mmol/L Ammonium Bicarbonate), 10% to 50% gradient in 10 min; detector, UV 254 nm to afford the product(44.2 mg, 61.53%yield) as a white solid. LCMS: (ESI, m/z): [M+H]⁺ = 452.2.¹H NMR (400 MHz, DMSO-d6) δ 10.87 (s, 1H), 7.30 – 7.24 (m, 1H), 7.22 – 7.10 (m, 3H), 6.86 (s, 1H), 6.67 (s, 1H), 6.21 – 6.15 (m, 1H), 3.72 – 3.65 (m, 4H), 3.62 (s, 2H), 3.47 – 3.39 (m, 3H), 3.30 – 3.25 (m, 2H), 2.77 (d, J = 4.2 Hz, 3H), 2.45 – 2.41 (m, 3H), 2.31 (s, 1H), 1.73 – 1.62 (m, 2H), 1.55 – 1.47 (m, 1H), 1.20 – 1.12 (m, 3H). [01421] A mixture of isomer 2 (90 mg, 0.15 mmol) and Potassium hydroxide (90 mg, 1.60 mmol) in Ethanol (0.9 mL) and Water (0.3 mL) was stirred at 80°C for 2h. The reaction mixture was acidified to pH = 6 with sat. citric acid solution. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C₁₈ silica gel; mobile phase, Acetonitrile in Water (10 mmol/L Ammonium Bicarbonate), 10% to 50% gradient in 10 min; detector, UV 254 nm to afford the product (49.6 mg, 69.04%yield) as a white solid. LCMS: (ESI, m/z): [M+H] ⁺ = 452.2.¹H NMR (400 MHz, DMSO-d6) δ 10.90 – 10.84 (m, 1H), 7.30 – 7.24 (m, 1H), 7.23 – 7.14 (m, 2H), 7.12 (s, 1H), 6.88 (s, 1H), 6.67 (s, 1H), 6.21 – 6.16 (m, 1H), 3.72 – 3.65 (m, 4H), 3.64 – 3.59 (m, 2H), 3.47 – 3.38 (m, 3H), 3.30 – 3.24 (m, 1H), 2.80 – 2.74 (m, 3H), 2.42 (s, 3H), 2.37 – 2.26 (m, 2H), 1.72 – 1.62 (m, 2H), 1.55 – 1.47 (m, 1H), 1.20 – 1.12 (m, 3H). [01422] A mixture of isomer 3 (140 mg, 0.24 mmol) and Potassium hydroxide (142 mg, 2.53 mmol) in Ethanol (1.2 mL) and Water (0.4 mL) was stirred at 80°C for 2h. The reaction mixture was acidified to pH = 6 with sat. citric acid solution. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C₁₈ silica gel; mobile phase, Acetonitrile in Water (10 mmol/L Ammonium Bicarbonate), 10% to 50% gradient in 10 min; detector, UV 254 nm to afford the product(73.9 mg, 66.13%yield) as a white solid. LCMS: (ESI, m/z): [M+H] ⁺ = 452.2.¹H NMR (400 MHz, DMSO-d₆) δ 10.87 (s, 1H), 7.30 – 7.24 (m, 1H), 7.24 – 7.08 (m, 3H), 6.89 (s, 1H), 6.67 (s, 1H), 6.21 – 6.16 (m, 1H), 3.72 – 3.63 (m, 4H), 3.49 – 3.38 (m, 4H), 3.24 – 3.16 (m, 1H), 2.85 – 2.69 (m, 4H), 2.42 (s, 3H), 2.13 – 1.93 (m, 2H), 1.86 – 1.78 (m, 2H), 1.31 – 1.16 (m, 1H), 1.08 – 1.00 (m, 3H). [01423] A mixture of isomer 4 (140 mg, 0.24 mmol) and Potassium hydroxide (142 mg, 2.53 mmol) in Ethanol (1.2 mL) and Water (0.4 mL) was stirred at 80°C for 2h. The reaction mixture was acidified to pH = 6 with sat. citric acid solution. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C₁₈ silica gel; mobile phase, Acetonitrile in Water (10 mmol/L Ammonium Bicarbonate), 10% to 50% gradient in 10 min; detector, UV 254 nm to afford the product (82.2 mg, 73.56%yield) as a white solid. LCMS: (ESI, m/z): [M+H] ⁺ = 452.2.¹H NMR (400 MHz, DMSO-d₆) δ 10.87 (s, 1H), 7.30 – 7.24 (m, 1H), 7.23 – 7.10 (m, 3H), 6.90 (s, 1H), 6.67 (s, 1H), 6.19 (s, 1H), 3.72 – 3.63 (m, 4H), 3.45 – 3.38 (m, 4H), 3.24 – 3.16 (m, 1H), 2.82 – 2.77 (m, 3H), 2.77 – 2.71 (m, 1H), 2.42 (s, 3H), 2.15 – 1.92 (m, 2H), 1.86 – 1.78 (m, 2H), 1.23 (s, 1H), 1.08 – 1.00 (m, 3H). [01424] Example 77. (S)-3-((2-cyanoethyl)amino)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4- yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzoic acid & (R)-3-((2-cyanoethyl)amino)-4-(2,2-difluoro-7-((5- methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzoic acid.

[ 5-

ene-7-carboxylate [01427] A solution of (2-chloro-4 ronic acid (4.20 g, 19.58 mmol), tert-butyl

2,2-difluoro-6-(trifluoromethanesulfonyloxy)-7-azaspiro[3.5]non-5-ene-7-carboxylate (7.98 g, 19.58 mmol), 1,1'-Bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (1.60 g, 1.95 mmol) and Sodium carbonate (4.15 g, 39.17 mmol) in 1, 4-dioxane (56 mL) and Water (14 mL) was stirred at 90 °C for 1 hour under nitrogen atmosphere. The resulting mixture was quenched with water and extracted with Ethyl acetate. The combined organic layers were washed with brine, dried over Sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with Petroleum Ether/Ethyl acetate (11:1) to afford the title compound (3.8 g, 45.34%yield) as a white solid. LCMS (ESI, m/z): [M+H] ⁺ = 428.1 [01428] Step 2: tert-butyl 6-(2-((2-cyanoethyl)amino)-4-(methoxycarbonyl)phenyl)-2,2-difluoro-7- azaspiro[3.5]non-5-ene-7-carboxylate [01429] A solution of tert-butyl 6

l)phenyl)-2,2-difluoro-7- azaspiro[3.5]non-5-ene-7-carboxylate (1.00 g, 2.33 mmol), 3-aminopropanenitrile (245 mg, 3.50 mmol), RuPhos Pd G3 (195 mg, 0.23 mmol), RuPhos (109 mg, 0.23 mmol) and Cesium Carbonate (2.28 g, 7.01 mmol) in 1,4-dioxane (10 mL) was stirred at 80 °C for 6 hours under nitrogen atmosphere. The resulting mixture was quenched with water and extracted with Ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Sodium sulfate. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with Petroleum Ether/Ethyl acetate (3:1) to afford the title compound (740 mg, 68.61%yield) as a yellow solid. LCMS (ESI, m/z): [M+H] + = 462.2 [01430] Step 3: methyl 3-((2-cyanoethyl)amino)-4-(2,2-difluoro-7-azaspiro[3.5]nonan-6-yl)benzoate [01431] A solution of tert-butyl 6- methoxycarbonyl)phenyl)-2,2-difluoro-7-

azaspiro[3.5]non-5-ene-7-carboxylate (740 mg, 1.60 mmol) in TFA (3 mL) and Dichloromethane (6 mL) was stirred at room temperature for 30 minutes. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in Dichloromethane (6 mL). To the above mixture was added Sodium cyanoborohydride (302 mg, 4.80 mmol), the resulting mixture was stirred at room temperature for additional 1 hour. The resulting mixture was filtered, the filter cake was washed with Dichloromethane. The filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in Water (10mmol/L Ammonium Bicarbonate), 5% to 100% gradient in 30 min; detector, UV 254 nm to afford the title compound (500 mg, 85.81%yield) as a yellow oil. LCMS (ESI, m/z): [M+H] ⁺ =363.4 [01432] Step 4: tert-butyl 4-((6-(2-((2-cyanoethyl)amino)-4-(methoxycarbonyl)phenyl)-2,2-difluoro-7- azaspiro[3.5]nonan-7-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate [01433] A solution of methyl 3-((

, fluoro-7-azaspiro[3.5]nonan-6- yl)benzoate (500 mg, 1.37 mmol), tert-butyl 4-(chloromethyl)-5-methoxy-7-methylindole-1-carboxylate (0.85 g, 2.75 mmol), Cesium Carbonate (1.34 g, 4.12 mmol) and Potassium iodide (342 mg, 2.06 mmol) in N,N- dimethylformamide (10 mL) was stirred at 50 °C for 1 hour. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with water. The resulting mixture was extracted with Ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in Water (10mmol/L Ammonium Bicarbonate), 5% to 100% gradient in 30 min; detector, UV 254 nm to afford the title compound (270 mg, 30.82%yield) as a white solid. LCMS (ESI, m/z): [M+H] ⁺ =637.3 [01434] Step 5: tert-butyl (R)-4-((6-(2-((2-cyanoethyl)amino)-4-(methoxycarbonyl)phenyl)-2,2-difluoro- 7-azaspiro[3.5]nonan-7-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (isomer 1, faster peak) & tert-butyl (S)-4-((6-(2-((2-cyanoethyl)amino)-4-(methoxycarbonyl)phenyl)-2,2-difluoro-7- azaspiro[3.5]nonan-7-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (isomer 2, slower peak) [01435] tert-buty

,2-difluoro-7- azaspiro[3.5]nonan-7-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (270 mg, 0.42 mmol) was applied for further separation by Chiral HPLC with the following condition: Column: CHIRALPAK IB 3*25 cm, 5 μm; Mobile Phase A: HEX(0.5% 2M NH₃-MeOH), Mobile Phase B: (ETOH:Dichloromethane=1:1); Flow rate: 30 mL/min; Gradient: isocratic 10; Wave Length: 220/254 nm; RT1(min): 12.105; RT2(min): 14.549; Sample Solvent: ETOH; Injection Volume: 0.6 mL; Number Of Runs: 12. [01436] tert-butyl (R)-4-((6-(2-((2-cyanoethyl)amino)-4-(methoxycarbonyl)phenyl)-2,2-difluoro-7- azaspiro[3.5]nonan-7-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (isomer 1, faster peak) (120 mg, 44%yield). LCMS (ESI, m/z): [M+H] ⁺ = 637.3. t_R = 3.21 min (CHIRAL Cellulose-SB 4.6*100 mm, 3 um, Hex(0.1%DEA): (EtOH:Dichloromethane=1:1)=90:10, 1.0 mL/min, 254 nm). [01437] tert-butyl (S)-4-((6-(2-((2-cyanoethyl)amino)-4-(methoxycarbonyl)phenyl)-2,2-difluoro-7- azaspiro[3.5]nonan-7-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (isomer 2, slower peak) (120 mg, 44% yield). LCMS (ESI, m/z): [M+H] ⁺ = 637.3. tR = 3.78 min (CHIRAL Cellulose-SB 4.6*100 mm, 3 um), Hex(0.1%DEA): (EtOH:Dichloromethane=1:1)=90:10, 1.0 mL/min, 254 nm). [01438] Step 6: (R)-3-((2-cyanoethyl)amino)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4- yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzoic acid & (S)-3-((2-cyanoethyl)amino)-4-(2,2-difluoro-7-((5- methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzoic acid

[01439] A soluti arbonyl)phenyl)-2,2-

difluoro-7-azaspiro[3.5]nonan-7-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (isomer 1, faster peak) (120 mg, 0.18 mmol) and Potassium trimethylsilanolate (193 mg, 1.50 mmol) in Acetonitrile (6 mL) was stirred at room temperature for 2 hours. The mixture was acidified to pH = 6 with citric acid. The resulting mixture was extracted with Ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in Water (10mmol/L Ammonium Bicarbonate), 5% to 100% gradient in 30 min; detector, UV 254 nm to afford (R)-3-((2-cyanoethyl)amino)-4-(2,2-difluoro-7-((5- methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzoic acid (70.2 mg, 71.28% yield) as a light yellow solid. LCMS (ESI, m/z): [M+H] ⁺ =523.3.¹H NMR (300 MHz, DMSO- d6) δ 12.71 (s, 1H), 10.89 (s, 1H), 7.44 (s, 1H), 7.29 (t, J = 4.0 Hz, 1H), 7.26 (s, 2H), 7.17 (s, 1H), 6.68 (s, 1H), 6.28 (s, 1H), 3.77 - 3.70 (m, 1H), 3.68 (s, 3H), 3.58 - 3.46 (m, 1H), 3.46 - 3.36 (m, 1H), 3.31 - 3.19 (m, 2H), 2.87 - 2.61 (m, 5H), 2.49 - 2.45 (m, 1H), 2.43 (s, 3H), 2.40 - 2.20 (m, 2H), 2.05 - 1.90 (m, 1H), 1.70 - 1.47 (m, 3H). [01440] A solution of tert-butyl (S)-4-((6-(2-((2-cyanoethyl)amino)-4-(methoxycarbonyl)phenyl)-2,2- difluoro-7-azaspiro[3.5]nonan-7-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (isomer 2, slower peak) (120 mg, 0.18 mmol) and Potassium trimethylsilanolate (193 mg, 1.50 mmol) in Acetonitrile (6 mL) was stirred at room temperature for 2 hours. The mixture was acidified to pH = 6 with citric acid. The resulting mixture was extracted with Ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in Water (10mmol/L Ammonium Bicarbonate), 5% to 100% gradient in 30 min; detector, UV 254 nm to afford (S)-3-((2-cyanoethyl)amino)-4-(2,2-difluoro-7-((5- methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzoic acid (66.5 mg, 67.52% yield) as a light yellow solid. LCMS (ESI, m/z): [M+H] ⁺ =523.2.¹H NMR (300 MHz, DMSO- d₆) δ 10.91 (s, 1H), 7.43 (s, 1H), 7.28 (t, J = 2.4 Hz, 1H), 7.25 (s, 2H), 6.68 (s, 1H), 6.28 (s, 1H), 3.77 - 3.69 (m, 1H), 3.68 (s, 3H), 3.56 - 3.46 (m, 1H), 3.46 - 3.40 (m, 1H), 3.31 - 3.21 (m, 2H), 2.87 - 2.56 (m, 5H), 2.48 - 2.45 (m, 1H), 2.43 (s, 3H), 2.39 - 2.20 (m, 2H), 2.05 - 1.91 (m, 1H), 1.70 - 1.47 (m, 3H) [01441] Example 78.4-(6-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-6-azaspiro[2.5]octan-5-yl)-3-((2- methoxyethyl)amino)benzoic acid. [01442] Procedure:

[0

)-6- azaspiro[2.5]octan-6-yl)methyl)-7-methyl-1H-indole-1-carboxylate [01444] A solution of 1,1,2-trimeth

mol) in HCl (0.5M, 12 mL) was stirred at 55°C for 2h. The resulting mixture was extracted with CH2Cl2 (4.5 mL). The combined organic layers were dried over anhydrous Sodium sulfate. The organic layers solution (4 mL) were added tert-butyl 4-((5-(2- amino-4-(methoxycarbonyl)phenyl)-6-azaspiro[2.5]octan-6-yl)methyl)-5-methoxy-7-methyl-1H-indole-1- carboxylate (250 mg, 0.46 mmol) and AcOH (4 mL), then the mixture was stirred at room temperature for 1 hour. Sodium cyanoborohydride (117.75 mg, 1.87 mmol) was added to the solution and stirred for 2h at room temperature. The reaction was poured into water at room temperature. The resulting mixture was extracted with Ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in Water (10 mmol/L Ammonium Bicarbonate), 80% to 100% gradient in 10 min; detector, UV 254 nm. to afford the title compound (45 mg, 16.23%yield) as a colorless solid. LCMS (ESI, m/z): [M+H] ⁺ = 592.5. [01445] Step 2: 4-(6-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-6-azaspiro[2.5]octan-5-yl)-3-((2- methoxyethyl)amino)benzoic acid [01446] A solution of tert-butyl 5-m arbonyl)-2-((2-

methoxyethyl)amino)phenyl)-6-azaspiro[2.5]octan-6-yl)methyl)-7-methyl-1H-indole-1-carboxylate (40 mg, 0.06 mmol) and Potassium hydroxide (45.51 mg, 0.81 mmol) in Ethanol (1.5 mL) and Water (0.5 mL) was stirred at 80°C for 2h. The mixture was acidified to pH < 7 with citric acid. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in Water (10 mmol/L Ammonium Bicarbonate), 25% to 30% gradient in 5 min; detector, UV 254 nm. to afford the title compound (21.4 mg, 66.29% yield) as a white solid. LCMS (ESI, m/z): [M+H] ⁺ = 478.2.¹H NMR (500 MHz, DMSO-d₆) δ 10.94 – 10.84 (m, 1H), 7.27 – 7.23 (m, 1H), 7.17 (s, 3H), 6.68 (s, 1H), 6.39 – 6.33 (m, 1H), 3.74 (d, J = 11.8 Hz, 1H), 3.69 (s, 3H), 3.56 – 3.49 (m, 2H), 3.40 – 3.34 (m, 4H), 3.31 – 3.25 (m, 1H), 3.23 (s, 3H), 2.78 – 2.70 (m, 1H), 2.66 (d, J = 16.8 Hz, 1H), 2.43 (s, 3H), 2.10 (s, 1H), 1.80 (s, 1H), 0.72 – 0.68 (m, 2H), 0.37 (d, J = 10.1 Hz, 1H), 0.27 (d, J = 9.0 Hz, 3H). [01447] Example 79.6-(dimethylamino)-5-[(5R)-6-[(5-methoxy-7-methyl-1H-indol-4-yl)methyl]-6- azaspiro[2.5]octan-5-yl]pyridine-2-carboxylic acid &6-(dimethylamino)-5-[(5S)-6-[(5-methoxy-7-methyl-1H- indol-4-yl)methyl]-6-azaspiro[2.5]octan-5-yl]pyridine-2-carboxylic acid. [01448] Procedure:

[

ate [01450] A mixture of methyl 6-amin

boxylate (500 mg, 2.16 mmol) and Bis(pinacolato)diboron (825 mg, 3.25 mmol) and 1,1’-Bis(diphenylphosphino)ferrocene- palladium(II)dichloride dichloromethane complex (177 mg, 0.22 mmol) and Potassium acetate (637 mg, 6.49 mmol) in 1,4-dioxane (6 mL) was stirred at room temperature for 1h under nitrogen atmosphere. The resulting mixture was quenched with water and extracted with Ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by trituration with Petroleum ether (20 mL). The resulting mixture was filtered, the filter cake was washed with Petroleum ether. The crude product was used in the next step directly without further purification. LCMS (ESI, m/z) [M+H] ⁺ = 279.1 [01451] Step 2: tert-butyl 5-[2-amino-6-(methoxycarbonyl)pyridin-3-yl]-6-azaspiro[2.5]oct-4-ene-6- carboxylate [01452] A mixture of methyl 6-ami ,3,2-dioxaborolan-2-yl)pyridine-2-

carboxylate (700 mg, 2.52 mmol) and tert-butyl 5-(trifluoromethanesulfonyloxy)-6-azaspiro[2.5]oct-4-ene-6- carboxylate (899 mg, 2.52 mmol) and Tetrakis(triphenylphosphine)palladium (290 mg, 0.25 mmol) and Potassium fluoride (292 mg, 5.03 mmol) in 2,2-dimethyloxolane (8 mL) and Water (2 mL) was stirred at 75°C for 1h under nitrogen atmosphere. The resulting mixture was quenched with water and extracted with Ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with Petroleum Ether/Ethyl acetate (1:1) to afford title compound (400 mg, 44.22%yield) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 360.2 [01453] Step 3: tert-butyl 5-[2-(dimethylamino)-6-(methoxycarbonyl)pyridin-3-yl]-6-azaspiro[2.5]oct-4- ene-6-carboxylate [01454] A mixture of tert-butyl 5-[2

yl)pyridin-3-yl]-6-azaspiro[2.5]oct-4-ene- 6-carboxylate (400 mg, 1.11 mmol) and Paraformaldehyde (133 mg, 4.45 mmol) and Sodium cyanoborohydride (209 mg, 3.34 mmol) in THF (1 mL) and HOAc (1 mL) was stirred at 50 °C for 2h. The resulting mixture was quenched with water and extracted with Ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with Petroleum Ether/Ethyl acetate (1:1) to afford the title compound (300 mg, 69.57%yield) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 388.5 [01455] Step 4: methyl 5-{6-azaspiro[2.5]oct-4-en-5-yl}-6-(dimethylamino)pyridine-2-carboxylate

[01456] A mixture of tert-butyl 5-[2-(dimethylamino)-6-(methoxycarbonyl)pyridin-3-yl]-6- azaspiro[2.5]oct-4-ene-6-carboxylate (300 mg, 0.77 mmol) and hydrogen chloride(4.0 M in ethyl acetate) (5 mL) was stirred at room temperature for 1h under air atmosphere. The resulting mixture was concentrated under reduced pressure. The resulting mixture was used in the next step directly without further purification. LCMS (ESI, m/z): [M+H] ⁺ = 288.5 [01457] Step 5: methyl 5-{6-azaspiro[2.5]octan-5-yl}-6-(dimethylamino)pyridine-2-carboxylate [01458] A mixture of methyl 5-{6-a -6-(dimethylamino)pyridine-2-carboxylate

(200 mg) and Sodium cyanoborohydride (65. mg, 1.04 mmol) in Dichloromethane (1.6 mL) and methanol (0.4 mL) was stirred at room temperature for 1h under air atmosphere. The resulting mixture was filtered, the filter cake was washed with Dichloromethane. The filtrate was concentrated under reduced pressure. The resulting mixture was used in the next step directly without further purification. LCMS (ESI, m/z): [M+H] ⁺ = 290.2 [01459] Step 6: tert-butyl 4-({5-[2-(dimethylamino)-6-(methoxycarbonyl)pyridin-3-yl]-6- azaspiro[2.5]octan-6-yl}methyl)-5-methoxy-7-methylindole-1-carboxylate [01460] A mixture of methyl 5-{6-a

(dimethylamino)pyridine-2-carboxylate (200 mg, 0.69 mmol) and tert-butyl 4-(chloromethyl)-5-methoxy-7-methylindole-1-carboxylate (428 mg, 1.38 mmol) and Cesium Carbonate (450 mg, 1.38 mmol) and Potassium iodide (229 mg, 1.38 mmol) in N,N- dimethylformamide (3 mL) was stirred at 50°C for 1h. The resulting mixture was quenched with water and extracted with Ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in Water 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in the title compound (130 mg, 33.43%yield) as a yellow oil. LCMS (ESI, m/z): [M+H] ⁺ = 564.3 [01461] Step 7: tert-butyl 4-{[(5R)-5-[2-(dimethylamino)-6-(methoxycarbonyl)pyridin-3-yl]-6- azaspiro[2.5]octan-6-yl]methyl}-5-methoxy-7-methylindole-1-carboxylate & tert-butyl 4-{[(5S)-5-[2- (dimethylamino)-6-(methoxycarbonyl)pyridin-3-yl]-6-azaspiro[2.5]octan-6-yl]methyl}-5-methoxy-7- methylindole-1-carboxylate [01462] tert-butyl 4-( l]-6-azaspiro[2.5]octan-6-

yl}methyl)-5-methoxy-7-methylindole-1-carboxylate(130 mg, 0.23 mmol) was applied for further separation by Chiral HPLC with the following condition: Column: CHIRALPAK IK 2*25 cm, 5 μm; Mobile Phase A: HEX(0.1% DEA), Mobile Phase B: ETOH; Flow rate: 20 mL/min; Gradient (B%): isocratic 1; Wave Length: 220/254 nm; RT1(min): 7582; RT2(min): 9.441; Sample Solvent: ETOH; Injection Volume: 0.3 mL; Number Of Runs: 26 [01463] (isomer 1, faster peak)(44 mg, 33% yield) LCMS (ESI, m/z): [M+H] ⁺ = 564.3. t_R = 1.55 min (CHIRALPAK IK 2*25 cm, 5 μm), Hex(0.1%DEA): EtOH=98: 2, 1.0 mL/min.254nm. [01464] (isomer 2, slower peak)(43 mg, 33% yield) LCMS (ESI, m/z): [M+H] ⁺ = 564.3. tR = 1.73 min (CHIRALPAK IK 2*25 cm, 5 μm), Hex(0.1%DEA): EtOH=98: 2, 1.0 mL/min.254nm. [01465] Step 8: 6-(dimethylamino)-5-[(5R)-6-[(5-methoxy-7-methyl-1H-indol-4-yl)methyl]-6- azaspiro[2.5]octan-5-yl]pyridine-2-carboxylic acid & 6-(dimethylamino)-5-[(5S)-6-[(5-methoxy-7-methyl- 1H-indol-4-yl)methyl]-6-azaspiro[2.5]octan-5-yl]pyridine-2-carboxylic acid O O N N N N [01466] A mixture of

, , m hydroxide (43 mg, 0.78 mmol) in Ethanol (1 mL) and Water (1 mL) was stirred at 80°C for 1h. The mixture was acidified to pH 6 with citric acid. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in Water (10 mmol/L Ammonium Bicarbonate), 10% to 70% gradient in 30 min; detector, UV 254 nm. This resulted in the title compound (25.1 mg, 71.56%yield) as a white solid. LCMS (ESI, m/z): [M+H] ⁺ = 449.3.¹H NMR (500 MHz, DMSO-d₆) δ 10.83 (s, 1H), 8.22 (d, J = 7.7 Hz, 1H), 7.78 (d, J = 7.7 Hz, 1H), 7.40 – 7.18 (m, 1H), 6.63 (s, 1H), 6.40 – 6.24 (m, 1H), 3.67 (s, 4H), 3.44 – 3.31(m, 2H), 3.25 – 3.08 (m, 1H), 2.82 (s, 6H), 2.79 – 2.56 (m, 1H), 2.40 (s, 3H), 2.31 – 2.18(m, 1H), 2.04 (d, J = 12.2 Hz, 1H), 1.90 – 1.71 (m, 1H), 1.06 (d, J = 13.3 Hz, 1H), 0.74 (d, J = 12.8 Hz, 1H), 0.35 (d, J = 5.1 Hz, 2H), 0.34 – 0.27 (m, 2H). [01467] A mixture of isomer 2, slower peak (43 mg, 0.07 mmol) and Potassium hydroxide (42 mg, 0.76 mmol) in Ethanol (1 mL) and Water (1 mL) was stirred at 80°C for 1h under air atmosphere. The mixture was acidified to pH 6 with citric acid. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in Water (10 mmol/L Ammonium Bicarbonate), 10% to 70% gradient in 30 min; detector, UV 254 nm. This resulted in the title compound (23.4 mg, 68.27%yield) as a white solid. LCMS (ESI, m/z): [M+H] ⁺ = 449.3.¹H NMR (500 MHz, DMSO-d6) δ 10.83 (s, 1H), 8.21 (d, J = 7.7 Hz, 1H), 7.77 (d, J = 7.7 Hz, 1H), 7.40 – 7.18 (m, 1H), 6.62 (s, 1H), 6.40 – 6.24 (m, 1H), 3.68 (s, 2H), 3.68 – 3.63 (m, 2H), 3.29 (d, J = 11.7 Hz, 1H), 3.15 (d, J = 11.7 Hz, 2H), 2.81 (s, 6H), 2.74 (d, J = 10.8 Hz, 1H), 2.40 (s, 3H), 2.31 – 2.18(m, 1H), 2.05 (d, J = 12.2 Hz, 1H), 1.90 – 1.71 (m, 1H), 1.06 (d, J = 13.3 Hz, 1H), 0.74 (d, J = 12.8 Hz, 1H), 0.38 – 0.33 (m, 2H), 0.34 – 0.27 (m, 2H). [01468] Example 80. (R)-3-(dimethylamino)-4-(6-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-6- azaspiro[2.5]octan-5-yl)benzoic acid & (S)-3-(dimethylamino)-4-(6-((5-methoxy-7-methyl-1H-indol-4- yl)methyl)-6-azaspiro[2.5]octan-5-yl)benzoic acid. [01469] Procedure:

[0

[01471] A solution of tert-butyl 5-(4

rophenyl)-6-azaspiro[2.5]oct-4-ene-6- carboxylate (4 g, 10.30 mmol) was treated with hydrogen chloride(4.0 M in ethyl acetate) (40 mL, 160.00 mmol) at room temperature for 1 h. The resulting mixture was concentrated under vacuum. The residue was dissolved in Dichloromethane (45 mL) and MeOH (5 mL). The above mixture was added Sodium cyanoborohydride (8.41 g, 133.90 mmol). The resulting mixture was stirred at room temperature for additional 1h. The resulting mixture was filtered, the filter cake was washed with ethyl acetate. The filtrate was concentrated under reduced pressure to afford the crude title compound (5.1 g) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 291.1 [01472] Step 2: tert-butyl 5-methoxy-4-((5-(4-(methoxycarbonyl)-2-nitrophenyl)-6-azaspiro[2.5]octan-6- yl)methyl)-7-methyl-1H-indole-1-carboxylate [01473] A solution of methyl 3-nitro 5-yl)benzoate hydrochloride (5 g, 15.30

mmol), tert-butyl 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylate (7.97 g, 27.54 mmol) and Triethylamine (9.29 g, 91.80 mmol) in THF (80 mL) was stirred at room temperature for 1h. The above mixture was added STAB (9.73 g, 45.90 mmol) at room temperature. The resulting mixture was stirred at room temperature for overnight. The resulting mixture was diluted with water. The resulting mixture was extracted with Ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with Petroleum Ether/Ethyl acetate (95:5) to afford the title compound (5 g, 57.98% yield) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 564.1 [01474] Step 3: tert-butyl 4-((5-(2-amino-4-(methoxycarbonyl)phenyl)-6-azaspiro[2.5]octan-6- yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate [01475] A solution of tert-butyl 5-m

carbonyl)-2-nitrophenyl)-6- azaspiro[2.5]octan-6-yl)methyl)-7-methyl-1H-indole-1-carboxylate (4 g, 7.09 mmol), Fe (2.38 g, 42.58 mmol) and Ammonium chloride (2.28 g, 42.58 mmol) in Ethanol (30 mL) and Water (10 mL) was stirred at 80°C for 2h. The resulting mixture was filtered, the filter cake was washed with ethyl acetate and water. The resulting mixture was diluted with water. The resulting mixture was extracted with Ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in Water (10 mmol/L Ammonium Bicarbonate), 90% to 100% gradient in 10 min; detector, UV 254 nm. to afford the title compound (2.4 g, 63.37% yield) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 534.3 [01476] Step 4: tert-butyl 4-((5-(2-(dimethylamino)-4-(methoxycarbonyl)phenyl)-6-azaspiro[2.5]octan-6- yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate [01477] A solution of tert-butyl 4-(( rbonyl)phenyl)-6-azaspiro[2.5]octan-6-

yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (250 mg, 0.46 mmol), Paraformaldehyde (140.54 mg, 4.68 mmol) and Sodium cyanoborohydride (147.19 mg, 2.34 mmol) in HOAc (2 mL) and THF (2 mL) was stirred at room temperature for overnight. The resulting mixture was diluted with water. The resulting mixture was extracted with Ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with Petroleum Ether/Ethyl acetate (9:1) to afford the title compound (190 mg, 72.20% yield) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 562.5 [01478] Step 5: tert-butyl (R)-4-((5-(2-(dimethylamino)-4-(methoxycarbonyl)phenyl)-6- azaspiro[2.5]octan-6-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate & tert-butyl (S)-4-((5-(2- (dimethylamino)-4-(methoxycarbonyl)phenyl)-6-azaspiro[2.5]octan-6-yl)methyl)-5-methoxy-7-methyl-1H- indole-1-carboxylate [01479] tert-butyl 4-((5

-azaspiro[2.5]octan-6- yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (180 mg, 0.32 mmol) was applied for further separation by Chiral HPLC with the following condition: Column: Lux 5um Cellulose-412*25 cm, 5 μm; Mobile Phase A: Hex(0.5% 2M NH3-MeOH)--HPLC, Mobile Phase B: EtOH--HPLC; Flow rate: 20 mL/min; Gradient (B%): isocratic 1; Wave Length: 220/254 nm; RT1(min): 6.752; RT2(min): 10.38; Sample Solvent: EtOH--HPLC; Injection Volume: 0.8 mL; Number Of Runs: 7 [01480] (isomer 1, faster peak) (65 mg, 36%yield). LCMS (ESI, m/z): [M+H] ⁺ =562.5. tR = 1.00 min (Lux Cellulose‐44.6*50 mm,3 um), Hex(0.1%DEA): EtOH=98:2, 1.0 mL/min, 254 nm). [01481] (isomer 2, slower peak) (65 mg, 36%yield). LCMS (ESI, m/z): [M+H] ⁺ = 562.5. tR = 1.26 min (Lux Cellulose‐44.6*50 mm,3 um), Hex(0.1%DEA): EtOH=98:2, 1.0 mL/min, 254 nm). [01482] Step 6: (R)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)-3-(3-methoxyazetidin-1-yl)benzoic acid & (S)-4-(2,2-difluoro-7-((5-methoxy-7- methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)-3-(3-methoxyazetidin-1-yl)benzoic acid [01483] A solution of m hydroxide (97.38 mg, 1.74

mmol) in Ethanol (1.5 mL) and Water (0.5 mL) was stirred at 80°C for 2h. The mixture was acidified to pH <7 with citric acid. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in Water (10 mmol/L Ammonium Bicarbonate), 30% to 40% gradient in 5 min; detector, UV 254 nm. to afford the product (39.7 mg, 76.65 %yield) as a white solid. LCMS (ESI, m/z): [M+H] ⁺ =448.2.¹H NMR (400 MHz, DMSO-d6) δ 12.86 (s, 1H), 10.80 (s, 1H), 7.89 (d, J = 8.0 Hz, 1H), 7.80 – 7.75 (m, 1H), 7.73 (d, J = 1.7 Hz, 1H), 7.24 (t, J = 2.8 Hz, 1H), 6.63 (s, 1H), 6.42 – 6.38 (m, 1H), 3.94 (d, J = 10.9 Hz, 1H), 3.70 (s, 3H) , 3.41 (s, 1H), 3.20 (d, J = 11.6 Hz, 1H), 2.74 (d, J = 11.4 Hz, 1H), 2.68 (s, 6H), 2.41 (s, 3H), 2.18 (s, 1H), 2.02 – 1.95 (m, 1H), 1.80 – 1.65 (m, 1H), 0.93 (d, J = 13.2 Hz, 1H), 0.73 (d, J = 12.8 Hz, 1H), 0.39 – 0.24 (m, 4H). [01484] A solution of isomer 2, slower peak (65 mg, 0.11 mmol) and Potassium hydroxide (110 mg, 1.96 mmol) in Ethanol (1.5 mL) and Water (0.5 mL) was stirred at 80°C for 2h. The mixture was acidified to pH <7 with citric acid. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in Water (10 mmol/L Ammonium Bicarbonate), 30% to 40% gradient in 5 min; detector, UV 254 nm. to afford the product (38.9 mg, 75.11% yield) as a white solid. LCMS (ESI, m/z): [M+H] ⁺ =448.2.¹H NMR (400 MHz, DMSO-d6) δ 12.86 (s, 1H), 10.81 (s, 1H), 7.90 (d, J = 8.0 Hz, 1H), 7.78 (d, J = 8.2 Hz, 1H), 7.74 (s, 1H), 7.25 (s, 1H), 6.64 (s, 1H), 6.41 (s, 1H), 3.94 (s, 1H), 3.70 (s, 3H), 3.22 (s, 2H), 2.74 (s, 1H), 2.68 (s, 6H), 2.41 (s, 3H), 2.22 (d, J = 29.4 Hz, 1H), 2.01 (d, J = 11.7 Hz, 1H), 1.81 (s, 1H), 0.94 (d, J = 13.1 Hz, 1H), 0.74 (d, J = 12.7 Hz, 1H), 0.44 – 0.26 (m, 4H). [01485] Example 81.6-(((1R)-1-carbamoylethyl)amino)-5-((6S)-2,2-difluoro-7-((5-methoxy-7-methyl- 1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)pyridine-2-carboxylic acid & 6-(((1S)-1- carbamoylethyl)amino)-5-((6R)-2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)pyridine-2-carboxylic acid & 6-(((1R)-1-carbamoylethyl)amino)-5-((6R)-2,2- difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)pyridine-2-carboxylic acid & 6-(((1S)-1-carbamoylethyl)amino)-5-((6S)-2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4- yl)methyl)-7-azaspiro[3.5]nonan-6-yl)pyridine-2-carboxylic acid.

[01487] Step 1: Methyl 5-bromo-6-((1-carbamoylethyl)amino)pyridine-2-carboxylate [01488] A solution of methyl 5-brom

boxylate (1.00 g, 4.27 mmol), 2- aminopropanamide (1.13 g, 12.82 mmol) and triethylamine (2.60 g, 25.64 mmol) in dimethyl sulfoxide (40 mL) was stirred at 90 °C for 6 hours. The resulting mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with petroleum ether / ethyl acetate (20:80) to afford the title compound (980 mg, 75.91% yield) as a white solid. LCMS (ESI, m/z): [M+H] ⁺ =302.0. [01489] Step 2: Methyl 6-((1-carbamoylethyl)amino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)pyridine-2-carboxylate

[01490] A solution of methyl 5-bromo-6-((1-carbamoylethyl)amino)pyridine-2-carboxylate (600 mg, 1.98 mmol), bis(pinacolato)diboron (7.56 g, 29.79 mmol), potassium acetate (585 mg, 5.96 mmol) and 1,1’- Bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (162 mg, 0.20 mmol,) in 1,4-dioxane (15 mL) was stirred at 70°C for 2 hours under nitrogen atmosphere. The resulting mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The crude product was used in the next step directly without further purification. LCMS (ESI, m/z): [M+H] ⁺ =350.2. [01491] Step 3: tert-butyl 6-(2-((1-carbamoylethyl)amino)-6-(methoxycarbonyl)pyridin-3-yl)-2,2- difluoro-7-azaspiro[3.5]non-5-ene-7-carboxylate [01492] A solution of methyl 6-(( ,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-

yl)pyridine-2-carboxylate (900 mg, 2.57 mmol), tert-butyl 2,2-difluoro-6-(trifluoromethanesulfonyloxy)-7- azaspiro[3.5]non-5-ene-7-carboxylate (1.05 g, 2.57 mmol), sodium carbonate (820 mg, 7.73 mmol) and 1,1’- Bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (255 mg, 0.31 mmol) in 1,4-dioxane (12 mL) and water (3 mL) was stirred at 80°C for 3 hours under nitrogen atmosphere. The resulting mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with petroleum ether / ethyl acetate (30:70) to afford the title compound (950 mg, 76.71%yield) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ =481.3. [01493] Step 4: Methyl 6-((1-carbamoylethyl)amino)-5-(2,2-difluoro-7-azaspiro[3.5]nonan-6-yl)pyridine- 2-carboxylate [01494] A solution of tert-butyl 6

y y )-6-(methoxycarbonyl)pyridin-3-yl)-2,2- difluoro-7-azaspiro[3.5]non-5-ene-7-carboxylate (650 mg, 1.35 mmol) and sodium cyanoborohydride (850 mg, 13.52 mmol) in trifluoroacetic acid (3 mL) and dichloromethane (5 mL) was stirred at room temperature for 3 hours. The resulting mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The crude product was used in the next step directly without further purification. LCMS (ESI, m/z): [M+H] ⁺ =383.1. [01495] Step 5: tert-butyl 4-((6-(2-((1-carbamoylethyl)amino)-6-(methoxycarbonyl)pyridin-3-yl)-2,2- difluoro-7-azaspiro[3.5]nonan-7-yl)methyl)-5-methoxy-7-methylindole-1-carboxylate [01496] A solution of methyl 6-((

,2-difluoro-7-azaspiro[3.5]nonan-6- yl)pyridine-2-carboxylate (380 mg, 0.99 mmol), tert-butyl 4-(chloromethyl)-5-methoxy-7-methylindole-1- carboxylate (615 mg, 1.98 mmol), cesium carbonate (970 mg, 2.97 mmol) and potassium iodide (250 mg, 1.50 mmol) in N,N-dimethylformamide (5 mL) was stirred at room temperature for 4 hours . The resulting mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with petroleum ether / ethyl acetate (55:45) to afford the title compound (470 mg, 72.13%yield) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ =656.3. [01497] Step 6: tert-butyl 4-(((6R)-6-(2-(((1S)-1-carbamoylethyl)amino)-6-(methoxycarbonyl)pyridin-3- yl)-2,2-difluoro-7-azaspiro[3.5]nonan-7-yl)methyl)-5-methoxy-7-methylindole-1-carboxylate & tert-butyl 4- (((6S)-6-(2-(((1R)-1-carbamoylethyl)amino)-6-(methoxycarbonyl)pyridin-3-yl)-2,2-difluoro-7- azaspiro[3.5]nonan-7-yl)methyl)-5-methoxy-7-methylindole-1-carboxylate & tert-butyl 4-(((6R)-6-(2-(((1R)- 1-carbamoylethyl)amino)-6-(methoxycarbonyl)pyridin-3-yl)-2,2-difluoro-7-azaspiro[3.5]nonan-7-yl)methyl)- 5-methoxy-7-methylindole-1-carboxylate & tert-butyl 4-(((6S)-6-(2-(((1S)-1-carbamoylethyl)amino)-6- (methoxycarbonyl)pyridin-3-yl)-2,2-difluoro-7-azaspiro[3.5]nonan-7-yl)methyl)-5-methoxy-7-methylindole- 1-carboxylate [0 ro-7-

azaspiro[3.5]nonan-7-yl)methyl)-5-methoxy-7-methylindole-1-carboxylate (470 mg, 0.72 mmol) was applied for further separation by Chiral SFC with the following conditions: Column: (S, S) Whelk-O14.6*50mm 3.5um; Mobile Phase B: IPA(0.5% 2M NH3-MeOH); Flow rate: 4 mL/min; Gradient (B%): 10% to 50% in 2.0 min, hold 1.0 min at 50%; Wave Length: 220 nm; RT1(min): 1.238; RT2(min): 1.278; RT3(min): 1.360; RT4(min): 1.393; Sample Solvent: EtOH. Injection Volume: 0.4 mL. [01499] Isomer 1, first peak (50 mg, 7.67%yield). LCMS (ESI, m/z): [M+H] ⁺ =656.3. tR = 1.238 min (Chiral SFC (S, S) Whelk-O14.6*50mm 3.5um, Mobile Phase B: IPA (0.5% 2M NH3-MeOH), 4.0 mL/min, 220 nm). [01500] Isomer 2, second peak (40 mg, 6.14%yield). LCMS (ESI, m/z): [M+H] ⁺ =656.3. tR = 1.278 min (Chiral SFC (S, S) Whelk-O14.6*50mm 3.5um, Mobile Phase B: IPA (0.5% 2M NH3-MeOH), 4.0 mL/min, 220 nm). [01501] Isomer 3, third peak (60 mg, 9.21%yield). LCMS (ESI, m/z): [M+H] ⁺ =656.3. tR = 1.360 min (Chiral SFC (S, S) Whelk-O14.6*50mm 3.5um, Mobile Phase B: IPA (0.5% 2M NH3-MeOH), 4.0 mL/min, 220 nm). [01502] Isomer 4, fourth peak (60 mg, 9.21%yield). LCMS (ESI, m/z): [M+H] ⁺ =656.3. tR = 1.393 min (Chiral SFC (S, S) Whelk-O14.6*50mm 3.5um, Mobile Phase B: IPA (0.5% 2M NH3-MeOH), 4.0 mL/min, 220 nm). [01503] Step 7: 6-(((1S)-1-carbamoylethyl)amino)-5-((6S)-2,2-difluoro-7-((5-methoxy-7-methyl-1H- indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)pyridine-2-carboxylic acid & 6-(((1S)-1- carbamoylethyl)amino)-5-((6R)-2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)pyridine-2-carboxylic acid & 6-(((1R)-1-carbamoylethyl)amino)-5-((6R)-2,2- difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)pyridine-2-carboxylic acid & 6-(((1S)-1-carbamoylethyl)amino)-5-((6S)-2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4- yl)methyl)-7-azaspiro[3.5]nonan-6-yl)pyridine-2-carboxylic acid [ mg, 0

.53 mmol) in acetonitrile (1 mL) was stirred at room temperature for 2 hours. The reaction mixture was acidified to pH = 6 with sat. citric acid solution. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in Water (10mmol/L Ammonium Bicarbonate), 5% to 50% gradient in 20 min; detector, UV 220 nm. The resulting mixture was concentrated under reduced pressure. The resulting liquid was dried by lyophilization. This resulted in the product (9.2 mg, 22.28%yield) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ =542.1.¹H NMR (400 MHz, DMSO-d₆) δ 10.88 (s, 1H), 7.77 – 7.67 (m, 1H), 7.63 – 7.50 (m, 2H), 7.26 – 7.21 (m, 2H), 6.98 – 6.93 (m, 1H), 6.69 – 6.65 (m, 1H), 6.40 (s, 1H), 4.55 – 4.47 (m, 1H), 3.73 – 3.59 (m, 5H), 2.77 – 2.71 (m, 1H), 2.69 – 2.52 (m, 2H), 2.46 – 2.37 (m, 5H), 2.34 – 2.24 (m, 2H), 2.02 – 1.93 (m, 1H), 1.64 – 1.58 (m, 1H), 1.57 – 1.47 (m, 2H), 1.36 – 1.21 (m, 4H). [01505] A solution of isomer 2, second peak (40 mg, 0.06 mmol) and potassium trimethylsilanolate (55 mg, 0.43 mmol) in acetonitrile (1 mL) was stirred at room temperature for 2 hours. The reaction mixture was acidified to pH = 6 with sat. citric acid solution. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in Water (10mmol/L Ammonium Bicarbonate), 5% to 50% gradient in 20 min; detector, UV 220 nm. The resulting mixture was concentrated under reduced pressure. The resulting liquid was dried by lyophilization. This resulted in the product (13.9 mg, 42.07%yield) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ =542.1.¹H NMR (400 MHz, DMSO-d₆) δ 10.82 (s, 1H), 8.05 – 7.75 (m, 1H), 7.73 – 7.50 (m, 2H), 7.30 – 7.14 (m, 2H), 6.99 – 6.88 (m, 1H), 6.68 – 6.63 (m, 1H), 6.33 (s, 1H), 4.59 – 4.50 (m, 1H), 3.77 – 3.58 (m, 5H), 2.74 – 2.54 (m, 3H), 2.46 – 2.39 (m, 4H), 2.37 – 2.17 (m, 3H), 2.04 – 1.87 (m, 1H), 1.67 – 1.46 (m, 3H), 1.40 – 1.25 (m, 3H), 1.26 – 1.10 (m, 1H). [01506] A solution of isomer 3, third peak (60 mg, 0.09 mmol) and potassium trimethylsilanolate (82 mg, 0.64 mmol) in acetonitrile (1 mL) was stirred at room temperature for 2 hours. The reaction mixture was acidified to pH = 6 with sat. citric acid solution. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in Water (10mmol/L Ammonium Bicarbonate), 5% to 50% gradient in 20 min; detector, UV 220 nm. The resulting mixture was concentrated under reduced pressure. The resulting liquid was dried by lyophilization. This resulted in the product (20.5 mg, 41.37%yield) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ =542.1.¹H NMR (400 MHz, DMSO-d₆) δ 10.88 (s, 1H), 7.85 – 7.70 (m, 1H), 7.67 – 7.49 (m, 2H), 7.32 – 7.21 (m, 2H), 7.02 – 6.94 (m, 1H), 6.71 – 6.65 (m, 1H), 6.42 (s, 1H), 4.50 (s, 1H), 3.78 – 3.58 (m, 5H), 2.78 – 2.72 (m, 1H), 2.70 – 2.53 (m, 2H), 2.48 – 2.36 (m, 5H), 2.35 – 2.25 (m, 2H), 2.05 – 1.92 (m, 1H), 1.66 – 1.59 (m, 1H), 1.57 – 1.45 (m, 2H), 1.39 – 1.18 (m, 4H). [01507] A solution of isomer 4, fourth peak (60 mg, 0.09 mmol) and potassium trimethylsilanolate (82 mg, 0.64 mmol) in acetonitrile (1 mL) was stirred at room temperature for 2 hours. The reaction mixture was acidified to pH = 6 with sat. citric acid solution. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in Water (10mmol/L Ammonium Bicarbonate), 5% to 50% gradient in 20 min; detector, UV 220 nm. The resulting mixture was concentrated under reduced pressure. The resulting liquid was dried by lyophilization. This resulted in the product (20.6 mg, 41.57%yield) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ =542.1.¹H NMR (400 MHz, DMSO-d6) δ 10.82 (s, 1H), 8.08 – 7.74 (m, 1H), 7.71 – 7.47 (m, 2H), 7.31 – 7.17 (m, 2H), 7.01 – 6.89 (m, 1H), 6.65 (s, 1H), 6.33 (s, 1H), 4.58 – 4.49 (m, 1H), 3.76 – 3.61 (m, 5H), 2.77 – 2.54 (m, 3H), 2.45 – 2.39 (m, 4H), 2.38 – 2.24 (m, 3H), 2.04 – 1.88 (m, 1H), 1.69 – 1.48 (m, 3H), 1.42 – 1.31 (m, 3H), 1.29 – 1.21 (m, 1H). [01508] Example 82.6-[(carbamoylmethyl)amino]-5-[(6S)-2,2-difluoro-7-[(5-methoxy-7-methyl-1H- indol-4-yl) methyl]-7-azaspiro [3.5] nonan-6-yl] pyridine-2-carboxylic acid & 6-[(carbamoylmethyl)amino]- 5-[(6R)-2,2-difluoro-7-[(5-methoxy-7-methyl-1H-indol-4-yl) methyl]-7-azaspiro [3.5] nonan-6-yl] pyridine- 2-carboxylic acid.

F F

-6-

, . , inamid (1.90 g, 25.64 mmol) in DMSO (25 mL) was treated with Triethylamine (4.32 g, 42.73 mmol) at 100 °C for 2 h. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with water. The resulting mixture was extracted with Ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. to afford methyl 5-bromo-6-[(carbamoylmethyl) amino] pyridine-2-carboxylate (1.8 g, 73.11% yield) as a light yellow oil. LCMS (ESI, m/z): [M+H] ⁺ = 288.0 [01512] Step 2: 2-[(carbamoylmethyl)amino]-6-(methoxycarbonyl) pyridin-3-ylboronic acid [01513] A solution of methyl 5-brom amino] pyridine-2-carboxylate (1.2 g, 4.16

mmol), bis(pinacolato)diboron (8.46 g, 33.32 mmol), 1,1 -Bis(diphenylphosphino)ferrocene- palladium(II)dichloride dichloromethane complex (0.34 g, 0.42 mmol) in Dioxane (15 mL) was treated with Potassium acetate (0.82 g, 8.33 mmol) at 100 °C for 1 h under nitrogen. The mixture was allowed to cool down to room temperature. The resulting mixture was filtered, the filter cake was washed with ethyl acetate (3 x 15 mL). The filtrate was concentrated under reduced pressure. The residue was purified by trituration with PE/EA (10/1, 30 mL). The precipitated solids were collected by filtration and washed with PE (3 x 3 mL) to afford 2-[(carbamoylmethyl)amino]-6-(methoxycarbonyl) pyridin-3-ylboronic acid (1.5 g, crude) as a brown solid. LCMS (ESI, m/z): [M+H] ⁺ = 254.1 [01514] Step 3: tert-butyl 6-{2-[(carbamoylmethyl)amino]-6-(methoxycarbonyl) pyridin-3-yl}-2,2- difluoro-7-azaspiro [3.5] non-5-ene-7-carboxylate [01515] A solution of tert-butyl 2

sulfonyloxy)-7-azaspiro [3.5] non-5-ene- 7-carboxylate (1.5 g, 3.68 mmol), 2-[(carbamoylmethyl) amino]-6-(methoxycarbonyl) pyridin-3-ylboronic acid (1.40 g, 5.52 mmol), 1,1’-Bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (0.30 g, 0.37 mmol) in dioxane (15 mL) and Water (3 mL) was treated with Sodium carbonate (0.78 g, 7.36 mmol) at 100 °C for 1.5 h under nitrogen. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with water. The resulting mixture was extracted with Ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by C18 silica gel column chromatography, eluted with CH3CN/Water (1:3) to afford tert-butyl 6-{2- [(carbamoylmethyl)amino]-6-(methoxycarbonyl) pyridin-3-yl}-2,2-difluoro-7-azaspiro [3.5] non-5-ene-7- carboxylate (1.3 g, 75.68% yield) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 467.2 [01516] Step 4: methyl 6-[(carbamoylmethyl) amino]-5-{2,2-difluoro-7-azaspiro [3.5] nonan-6- yl}pyridine-2-carboxylate [01517] A solution of tert-butyl 6 ]-6-(methoxycarbonyl) pyridin-3-yl}-2,2- difluoro-7-azaspiro [3.5] non-5-ene-7-

carboxylate (1.3 g, 2.79 mmol) in trifluoroacetic acid (8 mL) and Dichloromethane (8 mL) was treated with Sodium cyanoborohydride (1.75 g, 27.87 mmol) at 0 °C for 2 h. The resulting mixture was concentrated under reduced pressure. The mixture was neutralized to pH 7 with saturated Sodium bicarbonate (aq.). The resulting mixture was diluted with water. The resulting mixture was extracted with Dichloromethane. The combined organic layers were washed with brine, dried over anhydrous Sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by C18 silica gel column chromatography, eluted with CH3CN/Water (1:4) to afford methyl 6- [(carbamoylmethyl)amino]-5-{2,2-difluoro-7-azaspiro [3.5] nonan-6-yl}pyridine-2-carboxylate (800 mg, 77.93% yield) as a light yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 369.2 [01518] Step 5: tert-butyl 4-{[(6S)-6-{2-[(carbamoylmethyl)amino]-6-(methoxycarbonyl) pyridin-3-yl}- 2,2-difluoro-7-azaspiro [3.5] nonan-7-yl] methyl}-5-methoxy-7-methylindole-1-carboxylate & tert-butyl 4- {[(6R)-6-{2-[(carbamoylmethyl)amino]-6-(methoxycarbonyl) pyridin-3-yl}-2,2-difluoro-7- azaspiro[3.5]nonan-7-yl]methyl}-5-methoxy-7-methylindole-1-carboxylate [01519] A solution o

-azaspiro [3.5]nonan-6-yl} pyridine-2-carboxylate (600 mg, 1.63 mmol), tert-butyl 4-(chloromethyl)-5-methoxy-7-methylindole-1- carboxylate (1.51 g, 4.89 mmol), Potassium iodide (0.41 g, 2.44 mmol) in N,N-dimethylformamide (10 mL) was treated with Cesium Carbonate (2.12 g, 6.52 mmol) at 50 °C for 1.5 h. The resulting mixture was diluted with water. The resulting mixture was extracted with Ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Chiral HPLC with the following conditions: Column: CHIRALPAK IA 2*25 cm, 5 μm; Mobile Phase A: HEX(0.5% 2M NH3-MeOH), Mobile Phase B: EtOH; Flow rate: 20 mL/min; Gradient: isocratic 25; Wave Length: 220/254 nm; RT1(min): 5.596; RT2(min): 6.985; Sample Solvent: ETOH; Injection Volume: 0.3 mL; Number Of Runs: 18 [01520] (isomer 1, faster peak) (75 mg, 7.18% yield, yellow solid). LCMS (ESI, m/z): [M+H] ⁺ = 642.3. t_R = 1.39 min (CHIRALPAK IA 2*25 cm, 5 μm, Hex(0.1%DEA): EtOH=75: 25, 254 nm) [01521] (isomer 2, slower peak) (80 mg, 7.65% yield, yellow solid). LCMS (ESI, m/z): [M+H] ⁺ = 642.3. tR = 1.87 min (CHIRALPAK IA 2*25 cm, 5 μm, Hex(0.1%DEA): EtOH=75: 25, 254 nm) [01522] Step 6: 6-[(carbamoylmethyl)amino]-5-[(6S)-2,2-difluoro-7-[(5-methoxy-7-methyl-1H-indol-4- yl)methyl]-7-azaspiro[3.5]nonan-6-yl]pyridine-2-carboxylic acid & 6-[(carbamoylmethyl)amino]-5-[(6R)- 2,2-difluoro-7-[(5-methoxy-7-methyl-1H-indol-4-yl)methyl]-7-azaspiro[3.5]nonan-6-yl]pyridine-2-carboxylic acid [01523] A solution

2 mL) was treated with Potassium trimethylsilanolate (119.81 mg, 0.94 mmol) at room temperature for 2 h. The mixture was acidified to pH 6 with citric acid. The residue was purified by C18 silica gel column chromatography, eluted with CH3CN/Water(Ammonium Bicarbonate) (1:4) to afford the product (29.5 mg, 46.89% yield, 98.0% purity) as a light yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 528.3.¹H NMR (400 MHz, DMSO-d6) δ 10.86 (s, 1H), 7.93 (s, 1H), 7.56 (s, 1H), 7.46 (s, 1H), 7.23 – 7.15 (m, 2H), 6.98 (s, 1H), 6.66 (s, 1H), 6.29 (d, J = 3.1, 1H), 4.30 (s, 1H), 3.85 (s, 1H), 3.67 (s, 4H), 3.39 (s, 2H), 3.30 (s, 2H), 2.74 – 2.65 (m, 1H), 2.57 (s, 1H), 2.42 (s, 4H), 2.31 – 2.15 (m, 2H), 1.94 (d, J = 29.8 Hz, 1H), 1.71 – 1.58 (m, 1H), 1.51 (d, J = 12.9 Hz, 1H). [01524] A solution of isomer 2, slower peak (80 mg, 0.12 mmol) in Acetonitrile (2 mL) was treated with Potassium trimethylsilanolate (127.80 mg, 1.00 mmol) at room temperature for 2 h. The mixture was acidified to pH 6 with citric acid. The residue was purified by C18 silica gel column chromatography, eluted with CH3CN/Water(Ammonium Bicarbonate) (1:4) to afford the product (23.0 mg, 34.27% yield, 98.3% purity) as a light yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 528.3.¹H NMR (400 MHz, DMSO-d6) δ 10.86 (s, 1H), 7.93 (s, 1H), 7.57 (s, 1H), 7.45 (s, 1H), 7.23 – 7.15 (m, 2H), 6.98 (s, 1H), 6.66 (s, 1H), 6.29 (d, J = 3.1, 1H), 4.30 (s, 1H), 3.85 (s, 1H), 3.67 (s, 5H), 2.76 – 2.54 (m, 2H), 2.42 (s, 5H), 2.31 – 2.15 (m, 3H), 1.94 (d, J = 30.1 Hz, 1H), 1.64 – 1.59 (m, 1H), 1.51 (d, J = 12.8 Hz, 2H). [01525] Example 83.3-[(cyanomethyl)amino]-4-[(6S)-2,2-difluoro-7-[(5-methoxy-7-methyl-1H-indol-4- yl)methyl]-7-azaspiro[3.5]nonan-6-yl]benzoic acid & 3-[(cyanomethyl)amino]-4-[(6R)-2,2-difluoro-7-[(5- methoxy-7-methyl-1H-indol-4-yl)methyl]-7-azaspiro[3.5]nonan-6-yl]benzoic acid.

-7- azaspiro[3.5]nonan-7-yl)methyl]-5-methoxy-7-methylindole-1-carboxylate [01528] A solution of tert-butyl 4

onyl)phenyl)-2,2-difluoro-7- azaspiro[3.5]nonan-7-yl)methyl)-5-methoxy-7-methylindole-1-carboxylate (250 mg, 0.43 mmol), N,N- Diisopropylethylamine (166.01 mg, 1.30 mmol) and iodoacetonitrile (715 mg, 4.28 mmol) in N,N- dimethylformamide (2 mL) was stirred at 60°C for 1h. The resulting mixture was quenched with water and extracted with ethyl acetate. The organic layer washed with brine, dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with Petroleum ether/Ethyl acetate (5:1) to afford the title compound (120 mg, 45.0 % yield) as a white solid. LCMS: (ESI, m/z): 623.3 [M+H] ⁺. [01529] Step 2: methyl 3-((cyanomethyl)amino)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4- yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzoate [01530] A solution of tert-butyl 4 4-(methoxycarbonyl)phenyl)-2,2-

difluoro-7-azaspiro[3.5]nonan-7-yl)methyl)-5-methoxy-7-methylindole-1-carboxylate (400 mg, 0.64 mmol) and 2,6-Lutidine (344 mg, 3.21 mmol), Trimethylsilyl trifluoromethanesulfonate (713 mg , 3.21 mmol) in Dichloromethane (4 mL) was stirred at 0 °C for 1h. The resulting mixture was quenched with water and extracted with ethyl acetate. The organic layer washed with brine, dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in Water (10 mmol/L Ammonium bicarbonate), 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in methyl 3-((cyanomethyl)amino)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)- 7-azaspiro[3.5]nonan-6-yl)benzoate (200 mg, 59.6% yield) as a white solid. LCMS: (ESI, m/z): 523.2 [M+H] +. [01531] Step 3: methyl (R)-3-((cyanomethyl)amino)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4- yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzoate & methyl (S)-3-((cyanomethyl)amino)-4-(2,2-difluoro-7-((5- methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzoate [01532] methyl 3-

, yl-1H-indol-4-yl)methyl)- 7-azaspiro[3.5]nonan-6-yl)benzoate (200 mg) was applied for further separation by Chiral HPLC with the following condition: Column: CHIRALPAK IF 2*25 cm, 5 μm; Mobile Phase A: HEX(0.5% 2M NH3- MeOH), Mobile Phase B: ETOH; Flow rate: 20 mL/min; Gradient (B%): isocratic 30; Wave Length: 220/254 nm; RT1(min): 5.599; RT2(min): 7.743; Sample Solvent: ETOH; Injection Volume: 1.0 mL; Number Of Runs: 14. [01533] Isomer 1, faster peak (120 mg, 37.5%yield) LCMS (ESI, m/z): [M+H]⁺ = 523.4. t_R = 1.06 min (CHIRALPAK IF-34.6*50 mm 3 μm, Hex(0.1%DEA): EtOH=70:30, 1.0 mL/min, 254 nm). [01534] Isomer 2, slower peak (120 mg, 37.5%yield) LCMS (ESI, m/z): [M+H]⁺ = 523.4. t_R = 1.40 min (CHIRALPAK IF-34.6*50 mm 3 μm, Hex(0.1%DEA):EtOH=70:30, 1.0 mL/min, 254 nm). [01535] Step 4: 3-[(cyanomethyl)amino]-4-[(6S)-2,2-difluoro-7-[(5-methoxy-7-methyl-1H-indol-4- yl)methyl]-7-azaspiro[3.5]nonan-6-yl]benzoic acid & 3-[(cyanomethyl)amino]-4-[(6R)-2,2-difluoro-7-[(5- methoxy-7-methyl-1H-indol-4-yl)methyl]-7-azaspiro[3.5]nonan-6-yl]benzoic acid [01536] A solution

esterase (80 mg) in Phosphate Buffer solution (PH=7.2-7.4) (1 mL) was stirred at 35 °C for 5 days under air atmosphere. The resulting mixture was quenched with water and extracted with ethyl acetate. The organic layer washed with brine, dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in Water (10mmol/L Ammonium bicarbonate), 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in the product(27.5 mg, 34.37%yield) as a white solid. LCMS: (ESI, m/z): 509.4 [M+H] ⁺.¹H NMR (300 MHz, DMSO-d6) δ 10.89 (s, 1H), 7.60 – 7.34 (m, 2H), 7.32 (s, 1H), 7.29 – 7.22 (m, 1H), 6.68 (s, 1H), 6.35 – 6.28 (m, 1H), 4.43 – 4.36 (m, 2H), 3.71 (s, 4H), 3.28 (s, 3H), 2.73 – 2.63 (m, 2H), 2.43 (s, 4H), 2.39 – 2.25 (m, 3H), 1.96 (s, 1H), 1.66 – 1.48 (m, 3H). [01537] A solution of the isomer intermediate (80 mg, 0.05 mmol) and pig liver esterase (80 mg) in Phosphate Buffer solution (PH=7.2-7.4) (1 mL) was stirred at 35 °C for 5 days under air atmosphere. The resulting mixture was quenched with water and extracted with ethyl acetate. The organic layer washed with brine, dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in Water (10mmol/L Ammonium bicarbonate), 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in the product (20.7 mg, 25.87%yield) as a white solid. LCMS: (ESI, m/z): 509.4 [M+H] ⁺.¹H NMR (300 MHz, DMSO-d6) δ 10.89 (s, 1H), 7.60 – 7.34 (m, 2H), 7.32 (s, 1H), 7.29 – 7.22 (m, 1H), 6.68 (s, 1H), 6.35 – 6.28 (m, 1H), 4.43 – 4.36 (m, 2H), 3.71 (s, 4H), 3.28 (s, 3H), 2.73 – 2.63 (m, 2H), 2.43 (s, 4H), 2.39 – 2.25 (m, 3H), 1.96 (s, 1H), 1.66 – 1.48 (m, 3H). [01538] Example 84.6-[(carboxymethyl)amino]-5-[(6S)-2,2-difluoro-7-[(5-methoxy-7-methyl-1H-indol- 4-yl)methyl]-7-azaspiro[3.5]nonan-6-yl]pyridine-2-carboxylic acid & 6-[(carboxymethyl)amino]-5-[(6R)-2,2- difluoro-7-[(5-methoxy-7-methyl-1H-indol-4-yl)methyl]-7-azaspiro[3.5]nonan-6-yl]pyridine-2-carboxylic acid.

l]-7- azaspiro [3.5] nonan-6-yl] pyridine-2-carboxylic acid & 6-[(carboxymethyl)amino]-5-[(6R)-2,2-difluoro-7- [(5-methoxy-7-methyl-1H-indol-4-yl) methyl]-7-azaspiro [3.5] nonan-6-yl] pyridine-2-carboxylic acid

, , 06 mmol) in Ethanol (1.2 mL) and Water (0.4 mL) was treated with Potassium hydroxide (34.94 mg, 0.62 mmol) at 80 °C for 2.5 h. The mixture was allowed to cool down to room temperature. The mixture was acidified to pH 6 with citric acid. The residue was purified by C18 silica gel column chromatography, eluted with CH3CN/Water(Ammonium Bicarbonate) (1:3) to afford the product (27.4 mg, 82.0% yield) as a light yellow solid LCMS (ESI, m/z): [M+H] ⁺ = 529.3.¹H NMR (300 MHz, DMSO-d₆) δ 10.87 (s, 1H), 8.00 (s, 1H), 7.59 (s, 1H), 7.26 (s, 2H), 6.66 (s, 1H), 6.32 (s, 1H), 4.36 (s, 1H), 3.97 – 3.78 (m, 2H), 3.72 (s, 1H), 3.68 (s, 4H), 3.39 (d, J = 11.2 Hz, 2H), 3.33 (s, 1H), 2.81 – 2.57 (m, 1H), 2.42 (s, 4H), 2.39 – 2.19 (m, 2H), 2.00 (s, 1H), 1.70 – 1.33 (m, 3H). [01542] A solution of isomer 2, slower peak (40 mg, 0.06 mmol) in Ethanol (1.2 mL) and Water (0.4 mL) was treated with Potassium hydroxide (34.94 mg, 0.62 mmol) at 80 °C for 2.5 h. The mixture was allowed to cool down to room temperature. The mixture was acidified to pH 6 with citric acid. The residue was purified by C18 silica gel column chromatography, eluted with CH₃CN/Water(Ammonium Bicarbonate) (1:3) to afford the product (28.1 mg, 84.5% yield) as a light yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 529.3. ¹H NMR (300 MHz, DMSO-d6) δ 10.87 (s, 1H), 7.97 (s, 1H), 7.57 (s, 1H), 7.25 (s, 2H), 6.66 (s, 1H), 6.33 (s, 1H), 4.32 (s, 1H), 3.68 (s, 6H), 3.44 – 3.25 (m, 3H), 2.82 – 2.55 (m, 1H), 2.42 (s, 4H), 2.39 – 2.24 (m, 2H), 1.98 (s, 1H), 1.72 – 1.39 (m, 3H). [01543] Example 85.3-[(cyanomethyl)amino]-4-[(2S)-1-[(5-methoxy-7-methyl-1H-indol-4- yl)methyl]piperidin-2-yl]benzoic acid & 3-[(cyanomethyl)amino]-4-[(2R)-1-[(5-methoxy-7-methyl-1H-indol- 4-yl)methyl]piperidin-2-yl]benzoic acid.

[01 1-

yl)methyl]-5-methoxy-7-methylindole-1-carboxylate [01546] To a stirred solution of tert-bu

-(methoxycarbonyl)phenyl]piperidin-1- yl}methyl)-5-methoxy-7-methylindole-1-carboxylate (0.8 g, 1.58 mmol) and N,N-diisopropylethylamine (0.62 g, 4.80 mmol) in N,N-dimethylformamide (12 mL) was added iodoacetonitrile (1.32 g, 7.88 mmol) dropwise at room temperature. The resulting mixture was stirred at 80 °C for 2 h under nitrogen atmosphere. The resulting mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with Petroleum ether/Ethyl acetate = 90/10 to afford tert-butyl 4-[(2-{2-[(cyanomethyl)amino]-4- (methoxycarbonyl)phenyl}piperidin-1-yl)methyl]-5-methoxy-7-methylindole-1-carboxylate (540 mg, 62.68% yield) as an off-white solid. LCMS: (ESI, m/z): 547.3 [M+H] ⁺. [01547] Step 2: Methyl 3-[(cyanomethyl)amino]-4-{1-[(5-methoxy-7-methyl-1H-indol-4- yl)methyl]piperidin-2-yl}benzoate

[01548] A solution of tert-butyl 4-[(2-{2-[(cyanomethyl)amino]-4-(methoxycarbonyl)phenyl}piperidin-1- yl)methyl]-5-methoxy-7-methylindole-1-carboxylate (500 mg, 0.99 mmol) and 2,6-Lutidine (527.73 mg, 4.93 mmol) trimethylsilyl trifluoromethanesulfonate (1094.55 mg, 4.93 mmol) in dichloromethane (5 mL) was stirred at 0°C for 1h. The resulting mixture was quenched with water and extracted with Ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in Water (10 mmol/L Ammonium bicarbonate), 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in methyl 3-[(cyanomethyl)amino]-4-{1-[(5-methoxy-7-methyl-1H-indol-4-yl)methyl]piperidin-2-yl}benzoate (320 mg, 72.75% yield) as a white solid. LCMS: (ESI, m/z): 447.2 [M+H] ⁺. [01549] Step 3: methyl (S)-3-((cyanomethyl)amino)-4-(1-((5-methoxy-7-methyl-1H-indol-4- yl)methyl)piperidin-2-yl)benzoate & methyl (R)-3-((cyanomethyl)amino)-4-(1-((5-methoxy-7-methyl-1H- indol-4-yl)methyl)piperidin-2-yl)benzoate [01550] methyl 3-[(cyan

indol-4-yl)methyl]piperidin-2- yl}benzoate (200 mg) was applied for further separation by Chiral HPLC with the following condition: Column: CHIRALPAK IA, 2*25 cm, 5 μm; Mobile Phase A: HEX(0.5% 2M NH3-MeOH), Mobile Phase B: ETOH; Flow rate: 20 mL/min; Gradient (B%): isocratic 30; Wave Length: 220/254 nm; RT1(min): 4.752; RT2(min): 6.926; Sample Solvent: EtOH; Injection Volume: 0.6 mL; Number Of Runs: 20 [01551] Isomer 1, faster peak (70 mg, 35%yield) LCMS (ESI, m/z): [M+H]⁺ = 447.2. tR = 1.13 min (CHIRALPAK IA-34.6*50 mm 3 μm, Hex(0.1%DEA):EtOH=70:30, 1.0 mL/min, 254 nm). [01552] Isomer 2, slower peak (70 mg, 35%yield) LCMS (ESI, m/z): [M+H]⁺ = 447.2. tR = 1.67 min (CHIRALPAK IA-34.6*50 mm 3 μm), Hex(0.1%DEA):EtOH=70:30, 1.0 mL/min, 254 nm). [01553] Step 4: 3-[(cyanomethyl)amino]-4-[(2S)-1-[(5-methoxy-7-methyl-1H-indol-4- yl)methyl]piperidin-2-yl]benzoic acid & 3-[(cyanomethyl)amino]-4-[(2R)-1-[(5-methoxy-7-methyl-1H-indol- 4-yl)methyl]piperidin-2-yl]benzoic acid [01554] A solution of esterase (70 mg) in Phosphate

Buffer solution (PH=7.2-7.4) (1 mL) was stirred at 35 °C for 5 days. The resulting mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in Water (10mmol/L Ammonium bicarbonate), 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in the product ( 10.4 mg, 14.85%yield) as a white solid. LCMS: (ESI, m/z): 433.3 [M+H] ⁺.¹H NMR (300 MHz, DMSO-d6) δ 10.88 (s, 1H), 7.46 – 7.19 (m, 5H), 6.68 (s, 1H), 6.36 – 6.29 (m, 1H), 4.42 – 4.34 (m, 2H), 3.71 (s, 3H), 3.24 (s, 3H), 2.77 (d, J = 11.6 Hz, 1H), 2.43 (s, 3H), 1.92 (d, J = 8.8 Hz, 2H), 1.71 (s, 1H), 1.60 – 1.46 (m, 2H), 1.35 (s, 2H), 1.24 (s, 1H). [01555] A solution of the isomer intermediate (70 mg, 0.11 mmol), pig liver esterase (70 mg) in Phosphate Buffer solution (PH=7.2-7.4) (1 mL) was stirred at 35 °C for 5 days. The resulting mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in Water (10mmol/L Ammonium bicarbonate), 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in the product (14.2 mg, 20.28%yield) as a white solid. LCMS: (ESI, m/z): 433.3 [M+H] ⁺.¹H NMR (300 MHz, DMSO-d6) δ 10.88 (s, 1H), 7.54 – 7.23 (m, 5H), 6.68 (s, 1H), 6.37 – 6.29 (m, 1H), 4.38 (d, J = 5.7 Hz, 2H), 3.71 (s, 4H), 3.24 (s, 3H), 2.82 – 2.72 (m, 1H), 2.43 (s, 3H), 1.94 (s, 2H), 1.71 (s, 1H), 1.61 – 1.46 (m, 2H), 1.35 (s, 2H). EQUIVALENTS [01556] Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to specific embodiments of the present disclosure.

Claims

1 . A compound, wherein the compound has the structure of formula I:

or a salt thereof, wherein:

Ring A is an optionally substituted 5-10 membered aromatic ring having 0-5 heteroatoms independently selected from nitrogen, oxygen and sulfur; each R^a is independently selected from halogen, — CN, R^al, -OR^al, and -NR^alR^a2, wherein each of R^al and R^a2 is independently R’ ; a is 0, 1, 2, 3, 4 or 5;

L¹ is optionally substituted -CH₂-;

Ring B is an optionally substituted 5-10 membered monocyclic, bicyclic or polycyclic, saturated or partially unsaturated ring having, in additional to the nitrogen atom, 0-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; each R^b is independently selected from halogen, -CN, -L^b-C(O)OR^bl , -L^b-C(O)NR^blR^b2, -L^b-R^bl, -L^b-OR^bl, -L^b-NR^blR^b2, -L^b-C(O)R^bl, -L^b-C(O)N(R^bl)S(O)₂R^b2, -L^b-S(O)₂N(R^bl)C(O)R^b2, -L^b-S(O)₂NR^blR^b2, -L^b-S(O)(NR^bl)R^b2, or -L^b-S(O)₂R^bl, wherein each of R^bl and R^b2 is independently R’, and L^b is a covalent bond or optionally substituted -CH₂-; b is 0, 1, 2, 3, 4 or 5;

R^c is -L^C-C(O)OH, wherein L^c is a covalent bond or optionally substituted -CH₂-; each R^d is independently -NR^dlR^d2, wherein each of R^dl and R^d2 is independently R’ ; d is 0, 1, or 2; each R^e is independently selected from halogen, -CN, R^el , -OR^el , and -NR^elR^e2, wherein each of R^el and R^e2 is independently R’ ; e is 0, 1, or 2; each R’ is independently R, -OR, -C(O)R, -C(O)OR, or -S(O)2R; each R is independently hydrogen or an optionally substituted group selected from C1-Cio aliphatic, C1-C6 hctcroaliphatic having 1-3 hctcroatoms independently selected from nitrogen, oxygen and sulfur, 3-10 membered cycloaliphatic, 3-10 membered heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, 6-10 membered aryl, 5-10 membered heteroaryl having 1-6 heteroatoms independently selected from nitrogen, oxygen and sulfur, 6-10 membered aryl-C1-C6 aliphatic, and 5-10 membered heteroaryl having 1-6 heteroatoms-C1-C6 aliphatic wherein each heteroatom is independently selected nitrogen, oxygen and sulfur; or two R groups on the same atom are optionally and independently taken together with the atom to form an optionally substituted 3-10 membered ring having, in addition to the atom, 0-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; or two R groups on two atoms are optionally and independently taken together with their intervening atoms to form an optionally substituted 3-10 membered ring having, in addition to the intervening atoms, 0-4 heteroatoms.

2. A compound, wherein the compound has the structure of formula I:

or a salt thereof, wherein:

Ring A is an optionally substituted 5-10 membered aromatic ring having 0-5 heteroatoms independently selected from nitrogen, oxygen and sulfur; each R^a is independently selected from halogen, -CN, R^al, -OR^al, and -NR^alR^a2, wherein each of R^al and R^a2 is independently R’ ; a is 0, 1, 2, 3, 4 or 5;

L¹ is optionally substituted -CH₂-;

Ring B is an optionally substituted 5-10 membered monocyclic, bicyclic or polycyclic, saturated or partially unsaturated ring having, in additional to the nitrogen atom, 0-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; each R^b is independently selected from halogen, -CN, -L^b-C(O)OR^bl , -L^b-C(O)NR^blR^b2, -L^b-R^bl, -L^b-OR^bl, -L^b-NR^blR^b2, -L^b-C(O)R^bl, -L^b-C(O)N(R^bl)S(O)₂R^b2, -L^b-S(O)₂N(R^bl)C(O)R^b2, -L^b-S(O)₂NR^blR^b2, -L^b-S(O)(NR^bl)R^b2, or — L^b-S(O)₂R^bl , wherein each of R^bl and R^b2 is independently R’, and L^b is a covalent bond or optionally substituted -CH₂-; b is 0, 1 , 2, 3, 4 or 5;

Ring C is an optionally substituted 5-10 membered monocyclic, bicyclic or polycyclic, saturated or partially unsaturated or aromatic ring having 0-4 hctcroatoms independently selected from nitrogen, oxygen

R^c is -L^C-C(O)OH or a bioisostere thereof, -L^c-C(O)OR^cl, -L^c-C(O)NR^clR^c2, -L^c-R^cl, -L^c-OR^cl, -L^c-NR^clR^c2, -L^c-C(O)R^cl, -L^c-C(O)N(R^cl)S(O)₂R^c2, -L^c-S(O)₂N(R^cl)C(O)R^c2, -L^c-S(O)₂NR^clR^c2, -L^c-S(O)(NR^cl)R^c2, -L^C-S(O)₂R^CI, halogen, -CN, -L^c-P(O)(OR^cl)(OR^c2), -L^c-OP(O)(OR^cl)(OR^c2), or -L^c-BR^clR^c2, wherein each of R^cl and R^c2 is independently R’ or -N(R’)₂, and L^c is a covalent bond or optionally substituted -CH₂-; each R^d is independently selected from halogen, -CN, R^dl, -OR^dl, and -NR^dlR^d2, wherein each of R^dl and R^d2 is independently R’; d is 0, 1, or 2; each R^e is independently selected from halogen, -CN, R^el, -OR^el, and -NR^elR^e2, wherein each of R^el and R^e2 is independently R’ ; e is 0, 1, or 2; each R’ is independently R, -OR, -C(O)R, -C(O)OR, or -S(O)₂R; each R is independently hydrogen or an optionally substituted group selected from C1-C10 aliphatic, C1-C6 heteroaliphatic having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, 3-10 membered cycloaliphatic, 3-10 membered heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, 6-10 membered aryl, 5-10 membered heteroaryl having 1-6 heteroatoms independently selected from nitrogen, oxygen and sulfur, 6-10 membered aryl-C1-C6 aliphatic, and 5-10 membered heteroaryl having 1-6 hctcroatoms-C1-Cr, aliphatic wherein each heteroatom is independently selected nitrogen, oxygen and sulfur-; or two R groups on the same atom are optionally and independently taken together with the atom to form an optionally substituted 3-10 membered ring having, in addition to the atom, 0-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; or two R groups on two atoms are optionally and independently taken together with their intervening atoms to form an optionally substituted 3-10 membered ring having, in addition to the intervening atoms, 0-4 heteroatoms. 3. The compound of claim 1 , wherein

wherein each of R¹, R² and R³ is independently R^a.

4. The compound of any one of the preceding claims, wherein L¹ is -CH2-.

5. The compound of any one of claims 1-4, wherein Ring B is 6-membered.

6. The compound of any one of claims 1-4, wherein Ring B is 7-membered.

7. The compound of any one of claims 1-4, wherein Ring B is optionally substituted

10. The compound of any one of claims 1-8, wherein R^c is -C(O)OH.

11. The compound of any one of the preceding claims, wherein R^d is -NR^dlR^d2.

12. The compound of any one of the preceding claims, wherein R^dl is — H.

13. The compound of any one of the preceding claims, wherein R^d2 is — H.

14. The compound of any one of claims 1-12, wherein R^d2 is optionally substituted C1-6 aliphatic.

15. The compound of any one of claims 1-12, wherein R^d2 is methyl.

16. The compound of any one of claims 1-8, wherein R^d is -NR^dlR^d2, and R^dl and R^d2 are taken together with the nitrogen atom to which they are attached to form an optionally substituted 3-10 (e.g., 3, 4, 5, 6, 7, 8,

9, 10, 3-8, 3-7, 3-6, 4-6, 5-6, 5-8, etc.) membered ring having, in addition to the nitrogen atom 0-5 (e.g., 1, 2,

3, 4, 5, 1-5, 1-4, 1-2, etc.) heteroatoms independently selected from nitrogen, oxygen and sulfur.

17. The compound of any one of the preceding claims, wherein R^e is -NR^elR^e2 or R.

18. The compound of any one of claims 1-10, wherein R^d and R^e are taken together with their intervening atom(s) to form an optionally substituted 3-10 membered ring having, in addition to the intervening atom(s), 0-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. 19. The compound of any one of the preceding claims, wherein the compound has the structure of formula I-a, I-a-1, I-a-2, I-b, I-b-1, I-b-2, I-c, I-c-1, I-c-2, I-d, I-d-1, I-d-2, I-d-3, I-e, I-e-1, I-e-2, I-f, I-f-1, I-f- 2, I-f-3, I-g, I-g-1, I-g-2, I-h, I-h-1, I-h-2, I-h-3 or II, or a salt thereof. 20. A compound, wherein the compound has the structure of formula II: , or a salt thereof, wherein: m is 1, or 2;

n is 1, or 2; R¹ is hydrogen, halogen, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C3-C6 cycloalkyl, C1-C6 alkoxy, halo C₁-C₆ alkyl, hydroxy C₁-C₆ alkyl, amino C₁-C₆ alkyl, C₁-C₆ alkoxy C₁-C₆ alkyl, C₁-C₆ alkoxy C₁-C₆ alkoxy, C₃-C₆ cycloalkyl C₁-C₆ alkoxy, halo C₁-C₆ alkoxy, −S(O)_pC₁-C₆ alkyl, −CH₂NHC(O)C₁-C₄ alkyl or −OCH₂C(O)R⁷; p is 0, 1, or 2; R² is hydrogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, hydroxy C₁-C₆ alkyl, or halogen; R³ is hydrogen, halogen, cyano, C₁-C₄ alkyl, halo C₁-C₄ alkyl, −CH₂C(O)R⁷; R⁴ is phenyl, naphthyl, 1,2,3,4-tetrahydronaphthalenyl and 5-10 membered heteroaryl having 1, 2 or 3 ring heteroatoms independently selected from nitrogen, oxygen and sulfur, and wherein the phenyl, naphthyl, 1,2,3,4-tetrahydronaphthalenyl, or heteroaryl is optionally substituted with R⁵ and further optionally substituted with one or two R⁵’; each R⁵’ is independently selected from halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, hydroxy C₁-C₄ alkyl, hydroxyl, R¹⁰, −OR^6’, −N(R⁵¹)₂, halo C₁-C₆ alkyl, cyano, and cyanomethyl; or two R^5’ are taken together with their intervening atoms to form a 4-8 membered monocyclic partially unsaturated or aromatic ring having 1-3 ring atoms independently selected from nitrogen, sulfur and oxygen, wherein the ring is optionally substituted with one or more substituents independently selected from halogen, C₁-C₄ alkyl, halo C₁-C₄ alkyl, C₁-C₄ alkoxy, hydroxyl, and oxo; each R⁵¹ is independently R⁶’; R^4’ is hydrogen, C1-C4 alkyl, or hydroxy C1-C4 alkyl; R⁵ is −C(O)R⁸, −CH2C(O)R⁸, R⁹, −C(O)NHSO2C1-C4alkyl, −SO2NHC(O)C1-C4alkyl, −SO2N(H)p(C1- C₄alkyl)_2-p, −SO(NH)C₁-C₄alkyl, −SO₂C₁-C₄alkyl, cyano, halogen, hydroxy C₁-C₄ alkyl, −B(R⁸)₂ or 5- membered heteroaryl having 1-4 ring nitrogen atoms and 0 or 1 ring oxygen or sulfur atom; each R⁶ is independently hydrogen, halogen, hydroxyl, amino, mono- and di-C₁-C₆ alkylamino, C₁-C₆ alkyl, halo C₁-C₆ alkyl, hydroxy C₁-C₆ alkyl, cyano C₁-C₆ alkyl or C₁-C₆ alkoxy, or: two R⁶ on a carbon atom are taken together to form =O, or two R⁶ on a carbon atom are taken together with the carbon atom to form a 3-membered monocyclic saturated ring having 0-1 ring atoms independently selected from nitrogen, sulfur and oxygen; or two R⁶ are taken together with their intervening atoms to form a 3-8 membered monocyclic saturated or partially unsaturated ring having 0-3 ring atoms independently selected from nitrogen, sulfur and oxygen, wherein the ring is optionally substituted with one or more substituents independently selected from halogen, C1-C4 alkyl, halo C1-C4 alkyl, C1-C4 alkoxy, hydroxyl, and oxo; or R^4’ and one R⁶ are taken together to form C2-C4 alkylene; t is 0, 1, 2, 3 or 4; R^6’ is hydrogen, halogen, C1-C6 aliphatic, R¹⁰, −CH2−C3-C6 cycloaliphatic, −CH2−R¹⁰, −CH2−(hydroxy C1-C4 alkyl), phenyl, −C(O)−C1-C6 aliphatic, −SO2−C1-C6 aliphatic, −CH2−phenyl, −CH2−(amino C1-C4 alkyl), or −CH2−(mono- and di-C1-C4 alkylamino C1-C4 alkyl) wherein each of the C1-C6 aliphatic and phenyl is optionally substituted with one or more substituents independently selected from halogen, C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl or 3-6 membered heterocyclyl having 1-4 ring atoms independently selected from nitrogen, oxygen and sulfur, wherein each of the alkyl, alkoxy, cycloalkyl and heterocyclyl is optionally and independently substituted with one or more substituents independently selected from halogen, C1-C4 alkyl, halo C1-C4 alkyl, C1-C4 alkoxy, hydroxyl, and oxo, and wherein each nitrogen ring atom of the heterocyclyl is optionally and independently substituted with C1-3 acyl, cyano C1-C4 alkyl, C3-C6 cycloalkyl, or 3-6 membered heterocyclyl having 1-4 ring atoms independently selected from nitrogen, oxygen and sulfur wherein each ring nitrogen is optionally and independently substituted with C1-3 acyl; or: R⁶ and R^6’ are taken together with their intervening atoms to form a 3-8 membered monocyclic or bicyclic saturated, partially unsaturated or aromatic ring having 1-3 ring atoms independently selected from nitrogen, sulfur and oxygen, wherein the ring is optionally substituted with one or more substituents independently selected from halogen, C₁-C₄ alkyl, halo C₁-C₄ alkyl, C₁-C₄ alkoxy, hydroxyl, and oxo; R⁷ is hydroxyl, C₁-C₄ alkoxy, amino, or mono- or di-C₁-C₄ alkylamino; each R⁸ is independently hydroxyl, C₁-C₄ alkoxy, amino or a 5-7 membered saturated heterocyclyl having 1, 2, or 3 ring heteroatoms independently selected from nitrogen, oxygen and sulfur; or mono- and di- C₁-C₄ alkylamino which is optionally substituted with one or more substituents independently selected from halogen, hydroxy and C₁-C₄ alkyl; R⁹ is a 5-membered heteroaryl having 1 to 4 ring nitrogen atoms and 0 or 1 ring oxygen or sulfur atom, which heteroaryl is optionally substituted with 0 to 2 C₁-C₄ alkyl groups; and R¹⁰ is 3-6 membered heterocyclyl or 5-6 membered heteroaryl having 1-3 ring atoms independently selected from nitrogen, oxygen and sulfur, wherein the heterocyclyl or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, C1-C4 alkyl, halo C1-C4 alkyl, C1-C4 alkoxy, hydroxyl, and oxo, and wherein each nitrogen ring atom of the heterocyclyl or heteroaryl is optionally and independently substituted with C1-3 acyl, cyano C1-C4 alkyl, C;-C<, cycloalkyl, or 3-6 membered heterocyclyl having 1-4 ring atoms independently selected from nitrogen, oxygen and sulfur.

21. A compound selected from Table C-l, E-l, E-lb, E-lc, or E-ld, or a salt thereof.

22. A compound, wherein the compound has an identical structure as a first compound, wherein the first compound comprises an acidic moiety or a bioisostere thereof, or a moiety that can be converted to an acidic moiety or a bioisostere thereof, wherein the moiety is bonded to a ring, except that an additional amino group is bonded to the ring.

23. The compound of claim 22, wherein the additional amino group is R^d as described in one of the preceding claims.

24. A compound, wherein the compound has an identical structure as a first compound, wherein the first compound comprises an acidic moiety or a bioisostere thereof, or a moiety that can be converted to an acidic moiety or a bioisostere thereof, wherein the moiety is bonded to a ring, except that the ring is replaced with a basic nitrogen-containing 5-10 membered ring.

25. The compound of claim 24, wherein the basic nitrogen-containing 5-10 membered ring is Ring C as described in one of the preceding claims.

26. The compound of any one of claims 22-25, wherein the first compound has the structure of Ring 1 (e.g.. Ring A as described herein such as an optionally substituted heteroaromatic ring)-L¹² (e.g., L¹ as described herein)-Ring 2 (e.g., an optionally substituted nitrogen-containing optionally substituted nonaromatic ring which is bonded to L¹² through the nitrogen atom, Ring B as described herein, etc.)-L²³ (e.g., a covalent bond or optionally substituted -CH2-)-Ring 3 (e.g., an optionally substituted aromatic ring having 0-4 heteroatoms, Ring C as described herein), wherein Ring 3 is bonded to an acidic moiety (e.g., -COOH) or a bioisostere thereof, or a moiety that can be converted (e.g., through metabolism) to an acidic moiety or a bioisostere thereof.

27. The compound of any one of claims 22-26, wherein the first compound is a factor B or complement activation inhibitor.

28. The compound of any one of claims 22-27, wherein the first compound is a compound described generically or specifically in WO 2015/009616, US 9682968, US 10093663, WO 2018/005552, WO 2019/043609, WO 2020/016749, WO 2022/028507, WO 2022/028527, WO 2022/143845, WO 2022/218429, WO 2022/234541, WO 2022/256586, WO 2023/020566, WO 2023/037218, WO 2023/072197, WO 2023/139534, or WO 2023/143293.

29. The compound of any one of the preceding claims, wherein the compound has an IC50 of about or no more than about 1000, 900, 800, 700, 600, 500, 400, 300, 200, 100, 90, 80, 70, 60, 50, 40, 30, 20, or 10 nM as measured in an assay in the Examples.

30. The compound of any one of the preceding claims, wherein the compound has a diastereomeric purity of about or no less than about 90%.

31. The compound of any one of the preceding claims, wherein the compound has an enantiomeric purity of about or no less than about 90%.

32. The compound of any one of the preceding claims, wherein the compound comprises one or more isotopes each of which is not the most abundant isotope.

33. The compound of any one of the preceding claims, wherein the compound comprises one or more D.

34. The compound of any one of the preceding claims, wherein R^d is -NHCD3.

35. The compound of any one of the preceding claims, wherein L¹ is -CD2.

36. The compound of any one of claims 32-35, wherein for each D at a particular position, the isotopic purity is independently about 5%-100% (e.g., about 5%, 10%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or more, or about 5%-100%, 10%-100%, 20%- 100%, 30%-100%, 50%-100%, 80%-100%, 90-100%, 95%-100%, 96%-100%, 97%-100%, 98%-100%, 99%- 100%, 95-99%, 95%-99.5%, 95%-99.9%, etc.)

37. The compound of any one of the preceding claims, wherein the compound has a purity of about or no less than about 90%.

38. The compound of any one of the preceding claims, wherein when administered or delivered to a subject, its concentration at an eye or a portion thereof is about or at least about 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, 90 or 100 fold of plasma concentration.

39. The compound of claim 38, wherein the eye or a portion thereof comprises melanin.

40. The compound of any one of claims 38-39, wherein the eye or a portion thereof is or comprise choroid, BrM, RPE, iris, retina and/or ciliary body.

41. The compound of any one of the preceding claims, wherein the compound provides higher concentration ratios at an eye or a portion thereof over plasma concentration relative to a reference compound.

42. The compound of any one of the preceding claims, wherein the compound provides prolonged ocular exposure compared to a reference compound.

43. The compound of any one of the preceding claims, wherein the compound provides increased melanin binding compared to a reference compound.

44. The compound of any one of the preceding claims, wherein the compound is a pharmaceutically acceptable salt.

45. A pharmaceutical composition that comprises a compound of any one of the preceding claims or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient or diluent.

46. A pharmaceutical composition which delivers a compound of any one of the preceding claims or a pharmaceutically acceptable salt thereof.

47. A method for preparing a compound or composition of any one of the preceding claims.

48. A method for assessing a compound, comprising utilizing an assay described in the Examples.

49. A method of inhibiting a C3 convertase, comprising contacting a C3 convertase with a compound or composition of any one of the preceding claims.

50. A method of modulating complement alternative pathway activity in a subject, wherein the method comprises administering to the subject a therapeutically effective amount of a compound or composition of any one of the preceding claims.

51. A method of treating a disorder or a disease in a subject mediated by complement activation, wherein the method comprises administering to the subject a therapeutically effective amount of a compound or composition of any one of the preceding claims.

52. A method of treating a disorder or a disease in a subject mediated by activation of the complement alternative pathway, wherein the method comprises administering to the subject a therapeutically effective amount of a compound or composition of any one of the preceding claims.

53. The method of any one of claims 49-52, wherein the subject is suffering from a disease or disorder selected from age-related macular degeneration, geographic atrophy, Stargardt’ s disease, diabetic retinopathy, uveitis, glaucoma, retinitis pigmentosa, macular edema, Behcet's uveitis, multifocal choroiditis, Vogt- Koyangi-Harada syndrome, intermediate uveitis, birdshot retino-chorioditis, sympathetic ophthalmia, ocular dicatricial pemphigoid, ocular- pemphigus, nonartertic ischemic optic neuropathy, post-operative inflammation, retinal vein occlusion, neurological disorders, multiple sclerosis, stroke, Creutzfeld- Jacob disease, Guillain Barre Syndrome, spinal cord injury, traumatic brain injury, Alzheimer’s disease, Parkinson's disease, progressive supranuclear palsy, corticobasal syndrome, Pick’s disease, mild cognitive impairment. Huntington’s disease, diabetic neuropathy, neuropathic pain syndromes, fibromyalgia, frontotemporal dementia, dementia with Lewy bodies, multiple system atrophy, leptomeningeal metastasis, amyotrophic lateral sclerosis (ALS), chronic inflammatory demyelinating polyneuropathy (CIDP), neuromyelitis optica (NMO), disorders of inappropriate or undesirable complement activation, hemodialysis complications, graft rejection (e.g., hyperacute allograft rejection, xenograft rejection, interleukin-2 induced toxicity during IL-2 therapy, inflammatory disorders, inflammation of autoimmune diseases, Crohn's disease, acute respiratory distress syndrome (ARDS), myocarditis, postischemic reperfusion conditions, myocardial infarction, balloon angioplasty, post-pump syndrome in cardiopulmonary bypass or renal bypass, atherosclerosis, hemodialysis, renal ischemia, mesenteric artery reperfusion after aortic reconstruction, infectious disease or sepsis, immune complex disorders and autoimmune diseases, rheumatoid arthritis, systemic lupus erythematosus (SLE), SLE nephritis, proliferative nephritis, liver fibrosis, hemolytic anemia, myasthenia gravis, tissue regeneration, neural regeneration, dyspnea, hemoptysis, asthma, chronic obstructive pulmonary disease (COPD), emphysema, pulmonary embolisms and infarcts, pneumonia, fibrogenic dust diseases, pulmonary fibrosis, rhinosinusitis, nasal polyposis, allergy, bronchoconstriction, hypersensitivity pneumonitis, parasitic diseases, Goodpasture's Syndrome, pulmonary vasculitis, pauci-immune vasculitis, thrombotic microangiopathy (TMA), immune complex-associated inflammation, antiphospholipid syndrome, glomerulonephritis, C3 glomerulopathy, IgA nephropathy, cancer, periodontitis, gingivitis, and obesity.

54. The method of claim 53, wherein the condition, disorder or disease is hemolytic anemia, and the subject is suffering from paroxysmal nocturnal hemoglobinuria.

55. The method of claim 53, wherein the condition, disorder or disease is hemolytic anemia, and the subject is suffering from autoimmune hemolytic anemia (c.g., cold agglutinin disease or warm autoimmune hemolytic anemia).

56. The method of any one of claims 49-52, wherein the subject suffers from TMA secondary to atypical hemolytic uremic syndrome.

57. The method of any one of claims 49-52, wherein the subject suffers from TMA secondary to hematopoietic stem cell transplant (HSCT-TMA).

58. The method of any one of claims 49-52, wherein the subject suffers from drug-induced TMA.

59. The method of any one of claims 49-52, wherein the subject suffers from complement activation secondary to administration of another therapeutic or diagnostic agent.

60. The method of any one of claims 49-52, wherein the subject suffers from complement-mediated disorder is complement activation secondary to gene therapy (e.g., gene therapy with a viral vector such as an adeno-associated virus (AAV), adenovirus, or lentivirus vector).

61. The method of any one of claims 49-52, wherein the subject suffers from complement-mediated disorder is complement activation secondary to cell therapy.

62. A method of treating age related macular degeneration, comprising administering to a subject suffering therefrom a therapeutically effective amount of a compound or composition of any one of the preceding claims.

63. The method of claim 62, wherein the age related macular degeneration is intermediate age-related macular degeneration.

64. The method of any one of claims 49-63, wherein another therapeutic agent is administered such that a subject is exposed to the effects of both the compound and the another therapeutic agent.

65. The method of any one of claims 49-64, wherein another therapeutic agent is administered prior to, concurrently with or subsequently to the administration of the compound.

66. The improvement in any one of the preceding claims compared to a reference compound.

67. A compound or composition of any one of claims 1-46 for use in the treatment or prevention of a condition, disease or disorder.

68. A compound or composition of any one of claims 1-46 for use in the method of any one of the preceding claims.

69. Use of a compound or composition of any one of claims 1-46 for the manufacture of a medicament for treating a condition, disease or disorder.

70. Use of a compound or composition of any one of claims 1-46 for the manufacture of a medicament for a method of any one of the preceding claims.

71. A compound, composition, method, improvement or use of any one of Embodiments 1-742.