Complement inhibition

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 INHIBITIONCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] 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

[0002] 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

[0003] 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.

[0004] 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 methodsthereof. 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 Rdor Reor 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.

[0005] 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.

[0006] 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.

[0007] 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 Rais independently selected from halogen, — CN, Ral, -ORal, and -NRalRa2, wherein each of Raland Ra2is independently R’ ; a is 0, 1, 2, 3, 4 or 5;L1is 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 Rbis independently selected from halogen, -CN, -Lb-C(O)ORbl, -Lb-C(O)NRblRb2, -Lb-Rbl, -Lb-ORbl, -Lb-NRblRb2, -Lb-C(O)Rbl, -Lb-C(O)N(Rbl)S(O)2Rb2, -Lb-S(O)2N(Rbl)C(O)Rb2, -Lb-S(O)2NRblRb2, -Lb-S(O)(NRbl)Rb2, or -Lb-S(O)2Rbl, wherein each of Rbland Rb2is independently R’, and Lbis 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, oxygenRcis -LC-C(O)OH or a bioisostere thereof, -Lc-C(O)ORcl, -Lc-C(O)NRclRc2, -Lc-Rcl, -Lc-ORcl, -Lc-NRclRc2, -Lc-C(O)Rcl, -Lc-C(O)N(Rcl)S(O)2Rc2, -Lc-S(O)2N(Rcl)C(O)Rc2, -Lc-S(O)2NRclRc2, -Lc-S(O)(NRcl)Rc2, -LC-S(O)2RCI, halogen, -CN, -Lc-P(O)(ORcl)(ORc2), -Lc-OP(O)(ORcl)(ORc2), or -Lc-BRclRc2, wherein each of Rcland Rc2is independently R’ or -N(R’)2, and Lcis a covalent bond or optionally substituted -CH2-; each Rdis independently selected from halogen, -CN, Rdl, -ORdl, and -NRdlRd2, wherein each of Rdland Rd2is independently R’; d is 0, 1, or 2; each Reis independently selected from halogen, -CN, Rel, -ORel, and -NRelRe2, wherein each of Reland Re2is 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-C6heteroaliphatic 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.

[0008] In some embodiments, as described in the Examples, an occurrence of Rdor an occurrence Reis an amino group. In some embodiments, an occurrence of Rdis -NRdlRd2or an occurrence Reis — NRelRe2, wherein each of each of

[0009] 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.

[0010] 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.

[0011] 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 aprovided compound (e.g., a compound of formula I or a pharmaceutically acceptable salt thereof).

[0012] 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).

[0013] 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.

[0014] 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 nocturnalhemoglobinuria. 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.

[0016] 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)).

[0017] 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.

[0018] 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.

[0019] 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.

[0020] 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).

[0021] 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.

[0022] 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 someembodiments, 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

[0024] 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.

[0025] 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.

[0026] 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.

[0027] Alkenyl: As used herein, the term “alkenyl” refers to an aliphatic group, as defined herein, having one or more double bonds.

[0028] 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).

[0029] Alkynyl: As used herein, the term “alkynyl” refers to an aliphatic group, as defined herein, having one or more triple bonds.

[0030] 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.

[0031] 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.

[0032] 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).

[0033] 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 attackcomplex (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.

[0034] 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.

[0035] 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 someembodiments, 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.

[0036] 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.

[0037] 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.

[0038] 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.

[0039] 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.

[0040] 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.

[0041] 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 agentmay 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.

[0042] Local complement activation: As used herein, the term “local complement activation” refers to complement activation that occurs outside the vascular system.

[0043] 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.

[0044] 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.

[0045] 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.

[0046] 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 mustbe “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.

[0047] 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 usingcounterions 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.

[0048] 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, 3rdedition, 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.

[0049] 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.

[0050] 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.

[0051] 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.

[0052] 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.

[0053] 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.

[0054] 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.

[0055] 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 thesame 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.

[0056] 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(RO)C(O)N(RO)2; -N(RO)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(RO)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)O4SRO, -SC(S)SR°; -(CH2)(MSC(O)R°; -(CH2)O 4C(O)N(RO)2; -C(S)N(RO)2; -C(S)SR°; -SC(S)SR°, -(CH2)^4OC(O)N(RO)2; -C(O)N(OR°)R°; -C(O)C(O)R°; -C(O)CH2C(O)RO; -C(NOR°)R°; -(CH2)(MSSR0; -(CH2)O-4S(O)2RO; -(CH2)(MS(O)2OR0; -(CH2)O ^OS(O)2RO; -S(O)2N(R°)2; -(CH2)(MS(O)R0; -N(RO)S(O)2N(R°)2; - N(R°)S(O)2R°; -N(ORO)R°; -C(NH)N(RO)2; -Si(R°)3; -OSi(R°)3; -P(R°)2; -P(OR°)2; -OP(R°)2;-OP(OR°)2; -N(R°)P(RO)2; -B(RO)2; -OB(RO)2; -P(O)(RO)2; -OP(O)(RO)2; -N(RO)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.

[0057] 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.

[0058] 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.

[0059] 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.

[0060] Suitable substituents on a substitutable nitrogen arc -Rf, -NRf2, -C(O)Rf, -C(O)ORf, - C(O)C(O)Rt, -C(O)CH2C(O)Rt, -S(O)2Rf, -S(O)2NRf2, -C(S)NR%, -QNWNR^, or -N(Rt)S(O)2Rt; 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.

[0061] 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 heteroatomsindependently selected from nitrogen, oxygen, and sulfur.

[0062] 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.

[0063] 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.

[0064] 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.

[0065] 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.

[0066] 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.

[0067] 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.

[0068] 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, atherapeutically 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.

[0069] 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.

[0070] 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

[0071] Technologies of the present disclosure may be understood more readily by reference to the following detailed description of certain embodiments.I. Complement System

[0072] 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.

[0073] 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.

[0074] 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.

[0075] 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.

[0076] 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 aC3 convertase described above.

[0077] 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

[0078] 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 improvedby 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., L1as described herein)-Ring 2 (e.g., an optionally substituted nitrogen-containing optionally substituted non-aromatic ring which is bonded to L12through 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.

[0079] 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.

[0080] 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, anamino 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 Rdor Re.

[0081] 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.

[0082] In some embodiments, a provided compound is a compound of formula I or a salt thereof, wherein each variable is independently as described herein.

[0083] Certain useful embodiments for various variables, and various compounds, are described below as examples.Ring A

[0084] 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.

[0085] 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 optionallysubstituted 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, RingA is optionally substituted H a

[0086] 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.Ra

[0087] In some embodiments, each Rais independently selected from halogen, — CN, Ral, -ORal, and -NRalRa2, wherein each of Raland Ra2is independently R as described herein. In some embodiments, Rais -H. In some embodiments, Rais not -H. In some embodiments, Rais halogen. In some embodiments, Rais -CN. In some embodiments, Rais Ral. In some embodiments, Rais -ORal. In some embodiments, Rais -NRalRa2. In some embodiments, Rais -NHRal. In some embodiments, each Rais independently Ralor -ORal, wherein Ralis as described herein.

[0088] In some embodiments, Ralis R as described herein. In some embodiments, Ralis — H. In some embodiments, Ralis not hydrogen. In some embodiments, Ralis optionally substituted C1-6 aliphatic. In some embodiments, Ralis optionally substituted C1-6 alkyl. In some embodiments, Ralis optionally substituted -CH2-C1-6 aliphatic. In some embodiments, Ralis optionally substituted -CH2-C36 cycloalkyl. In some embodiments, Ralis optionally substituted -CH2-C36 cyclopropyl. In some embodiments, Ralis optionally substituted C3-10 cycloaliphatic. In some embodiments, Ralis optionally substituted C3-7 cycloaliphatic. In some embodiments, Ralis optionally substituted C3-6 cycloaliphatic. In some embodiments, Ralis optionally substituted C3-10 cycloalkyl. In some embodiments, Ralis optionally substituted C3-7 cycloalkyl. In some embodiments, Ralis optionally substituted C3-6 cycloalkyl. In some embodiments, Ralis optionally substituted cyclopropyl. In some embodiments, Ralis optionally substituted cyclobutyl. In some embodiments, Ralis optionally substituted cyclopentyl. In some embodiments, Ralis optionally substituted cyclohexyl. In some embodiments, Ralis substituted. In some embodiments, Ralis unsubstituted.

[0089] In some embodiments, Ra2is R as described herein. In some embodiments, Ra2is — H. In some embodiments, Ra2is not hydrogen. In some embodiments, Ra2is optionally substituted C1-6 aliphatic. Insome embodiments, Ra2is optionally substituted C1-6 alkyl. In some embodiments, Ra2is optionally substituted -CH2-C1-6 aliphatic. In some embodiments, Ra2is optionally substituted -CH2-C3-6 cycloalkyl.In some embodiments, Ra2is optionally substituted -CH2-C36 cyclopropyl. In some embodiments, Raland Ra2arc R and arc taken together to form a ring as described herein.

[0090] In some embodiments, Rais R1as described herein. In some embodiments, Rais R2as described herein. In some embodiments, Rais R3as described herein. For example, in some embodiments, Rais -OMe. In some embodiments, Rais methyl. In some embodiments, Rais -H.

[0091] In some embodiments,wherein each of R1, R2and R3is independently Ra. Certain embodiments of each of R1, R2and R3are independently described below.L1

[0092] In some embodiments, L1is optionally substituted -CH2-. In some embodiments, L1is -Chhin some embodiments, L1is substituted -CH2-. In some embodiments, L1is -CDi— . In some embodiments, L12is L1as described herein.

[0093] Ring B

[0094] 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.

[0096] In some embodiments, Ring B is saturated. In some embodiments, Ring B is partially unsaturated.

[0097] 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 nitrogenatom, 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

[0098] 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 a4-8 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 thenitrogen 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.

[0099] 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 substitutedIn some embodiments, Ring B is optionallyIn some embodiments. Ring B is optionally substitutedembodiments, 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 substitutedsome embodiments, Ring B is optionallysubstituted

[0100] 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,omewherein each variable is independently as described herein.independently as described herein. In some embodiments,wherein eachvaiiable is independently as described herein. In some embodiments,wherein each variable is independently as described herein. In some embodiments,

[0102] 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 issome embodiments,some embodiments,embodiments, i

[0103] 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.Rb

[0104] In some embodiments, Rbis hydrogen. In some embodiments, Rbis not hydrogen. In some embodiments, Rbis R6as described herein. In some embodiments, Rbis R6as described herein. In some embodiments, an occurrence of Rbis R6as described herein, and an occurrence of Rbis R6as described herein. In some embodiments, Rbis R4as described herein.

[0105] In some embodiments, Rbis halogen. In some embodiments, Rbis -F. In some embodiments, Rbis -Cl. In some embodiments, Rbis -Br. In some embodiments, Rbis -I. In some embodiments, each Rbis independently halogen. In some embodiments, each Rbis -F.

[0106] In some embodiments, Rbis -CN.

[0107] In some embodiments, Rbis -Lb— C(O)ORbl, wherein Rblis as described herein.

[0108] In some embodiments, Rbis -Lb-C(O)NRblRb2, wherein each of Rbland Rb2is independently as described herein. In some embodiments, Rbis -Lb— C(O)NHRblwherein Rblis as described herein.

[0109] In some embodiments, Rbis -Lb-Rbl. In some embodiments, Rbis -Rblwherein Rblis R. In some embodiments, Rbis -Rblwherein Rblis optionally substituted C1-6 aliphatic. In some embodiments, Rbis optionally substituted C1-6 alkyl. In some embodiments, Rbis C1-6 alkyl. In some embodiments, Rbis Ci e haloalkyl. In some embodiments, Rbis -CF3. In some embodiments, Rbis -H. In some embodiments, Rbis optionally substituted C3-10 cycloaliphatic. In some embodiments, Rbis optionally substituted C3-6 cycloalkyl. In some embodiments, Rbis optionally substituted cyclopropyl. In some embodiments, Rbis cyclopropyl. In some embodiments, Rbis optionally substituted 3-7 membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, Rbis optionally substituted 3-7 membered heterocyclyl having one heteroatom independently selected from nitrogen, oxygen and sulfur. In some embodiments, Rbis optionally substituted 4-membered heterocyclyl having one heteroatom independently selected from nitrogen, oxygen and sulfur. In some embodiments, Rbis optionally substituted,

[0110] In some embodiments, Rbis -Lb-ORbl. In some embodiments, Rbis -Lb-ORbl, wherein Rblis R as described herein. In some embodiments, Rbis -Lb-ORbl, wherein Rblis optionally substituted C1-6 aliphatic. In some embodiments, Rbis -Lb-ORbl, wherein Rblis optionally substituted Cue alkyl. In some embodiments, Rblis methyl. In some embodiments, Rblis ethyl. In some embodiments, Rblis -CH2-C3 e cycloalkyl. In some embodiments, Rblis -CH2-cyclopropyl. In some embodiments, Lbis a covalent bond. In some embodiments, Rbis -OCH3. In some embodiments, Rbis -O-CH2-cyclopropyl. In some embodiments, Rbis -OEt.

[0111] In some embodiments, Rbis -Lb-NRblRb2wherein each of Rbland Rb2is independently as described herein. In some embodiments, Rbis -Lb— NHRblwherein Rblis as described herein.

[0112] In some embodiments, Rbis -Lb— C(O)Rblwherein Rblis as described herein.

[0113] In some embodiments, Rbis -Lb-C(O)N(Rbl)S(O)2Rb2wherein each of Rbland Rb2is independently as described herein. In some embodiments, Rbis -Lb-C(O)NHS(O)2Rb2wherein Rb2is as described herein.

[0114] In some embodiments, Rbis -Lb-S(O)2N(Rbl)C(O)Rb2wherein each of Rbland Rb2is independently as described herein. In some embodiments, Rbis — Lh— S(O)2NHC(O)Rb2wherein Rb2is as described herein.

[0115] In some embodiments, Rbis -Lb-S(O)2NRblRb2wherein each of Rbland Rb2is independently as described herein. In some embodiments, Rbis -Lb-S(O)2NHRblwherein Rblis as described herein.

[0116] In some embodiments, Rbis -Lb-S(O)(NRbl)Rb2wherein each of Rbland Rb2is independently as described herein. In some embodiments, Rbis -Lb— S(O)(NH)Rb2wherein and Rb2is as described herein.

[0117] In some embodiments, Rbis -Lb— S(O)2Rbl, wherein Rblis as described herein. In some embodiments, Rbis -S(O)2Rbl, wherein Rblis as described herein. For example, in some embodiments, Rblis -R wherein R is as described herein. In some embodiments, Rblis -R wherein R is not -H. In some embodiments, Rblis optionally substituted C1-6 aliphatic. In some embodiments, Rblis ethyl.

[0118] In some embodiments, an occurrence of Rbis trans relative to Ring C. In some embodiments, an occurrence of Rbis cis relative to Ring C.

[0119] In some embodiments, Rblis R as described herein. In some embodiments, Rblis — H. In some embodiments, Rblis not hydrogen. In some embodiments, Rblis optionally substituted C1-6 aliphatic. In some embodiments, Rblis optionally substituted C1-6 alkyl. In some embodiments, Rblis optionally substituted -CH2-C1-6 aliphatic. In some embodiments, Rblis optionally substituted -CH2-C36 cycloalkyl. In some embodiments, Rblis optionally substituted -CH2-C36 cyclopropyl.

[0120] In some embodiments, Rb2is R as described herein. In some embodiments, Rb2is — H. In some embodiments, Rb2is not hydrogen. In some embodiments, Rb2is optionally substituted C1-6 aliphatic. In some embodiments, Rb2is optionally substituted C1-6 alkyl. In some embodiments, Rb2is optionally substituted -CH2-C1-6 aliphatic. In some embodiments, Rb2is optionally substituted -CH2-C36 cycloalkyl. In some embodiments, Rb2is optionally substituted -CH2-C36 cyclopropyl. In some embodiments, RblandRb2are R and are taken together to form a ring as described herein.

[0121] As described herein, two groups that are R or can be R, e.g., two Rbgroups, may be taken together to form an optionally substituted ring as described herein. In some embodiments, two Rbgroups 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.

[0122] For example, in some embodiments, two Rbgroups 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 isnitrogen. 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 Rbgroups arc taken together with the carbon atom to which they arc attached to form optionally substituted. In some embodiments, two Rbgroups are taken together with the carbon atom to which they are attached to form. In some embodiments, two Rbgroups are taken together with the carbon atom to which they are attached to form. In some embodiments, two Rbgroups are taken together with the carbon atom to which they are attached to form optionally substituted. jnsome embodiments, two Rbgroups are taken together with the carbon atom to which they are attached to form. In some embodiments, two Rbgroups are taken together with the carbon atom to which they ar e attached to form. In some embodiments, two Rbgroups are taken together with the carbon atom to which they are attached to formLb

[0123] In some embodiments, Lbis a covalent bond. In some embodiments, Lbis optionally substituted -CHi-. In some embodiments, Lbis -CH2-.Ring C

[0124] 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.

[0125] In some embodiments, Ring C is substituted. In some embodiments, Ring C is unsubstituted.

[0126] 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.

[0127] In some embodiments. Ring C is monocyclic. In some embodiments, Ring C is bicyclic. In someembodiments, 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 Rc.

[0128] In some embodiments. Ring C is saturated. In some embodiments, Ring C is partially unsaturated. In some embodiments, Ring C is aromatic.

[0129] 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.

[0130] In some embodiments, Ring C is optionally substituted. In some embodiments, Ring C isoptionally substitutedIn some embodiments, Ring C is optionally substituted. In some embodiments, Ring C is optionally substitutedIn some embodiments, Ring C is optionally substitutedIn some embodiments, Ring C is optionally substitutedembodiments, Ring C is optionally substitutedIn some embodiments, Ring C is optionallyO substituted. In some embodiments, Ring C is optionally substituted.In some embodiments,Ring C is optionally substituted. In some embodiments, Ring C is optionally substitutedIn some embodiments, Ring C is optionally substitutedIn some embodiments,Ring C is optionally substitutedembodiments, it isIn some embodiments, it isIn some embodiments, it is. In some embodiments, it isIn some embodiments, it isIn some embodiments,Rk<“>^(Rd)dRC\xN\xRd

[0132] In some embodiments, (Re XSJk is XXx.zXr'- . I n some embodiments, Rdcomprises a H-bond donor, e.g., -NH2, -OH, etc., which can form a H-bond with the ring nitrogen atom.

[0133] In some embodiments,is R4as described herein. In some embodiments, R4is substituted with R5and one or two R5. In some embodiments, at least one R5is -N(R51)2as described herein. In some embodiments, Reis R5as described herein, wherein R5is -N(R5I)2as described herein. In some embodiments, Rdis R5as described herein, wherein R5is -N(R51)2as described herein.Rc

[0134] As those skilled in the art reading the present disclosure will appreciate, various groups may be utilized for Rc. 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.

[0135] In some embodiments, Rcis or comprises an acidic group or a bioisostere thereof. In some embodiments, Rcis or comprises an acidic group. In some embodiments, Rcis or comprises a group that can be converted (e.g., through metabolism) to an acidic group or a bioisostere thereof. In some embodiments, Rcis R5as described herein, hi some embodiments, Rcis -Lc— C(O)OH or a bioisostere thereof, -Lc-C(O)ORcl, -Lc-C(O)NRclRc2, -Lc-C(O)N(Rcl)S(O)2Rc2, -LC-S(O)2N(RC1)C(O)RC2, -LC-S(O)2NRC1RC2, -Lc-S(O)(NRcl)Rc2, -LC-S(O)2RCI, -CN, -LC-P(O)(ORC1)(ORC2), -LC-OP(O)(ORC1)(ORC2), or -Lc-BRclRc2. In some embodiments, Rcis -LC-C(O)OH or a bioisostere thereof, -Lc-C(O)ORcl, -Lc-C(O)NRclRc2, -LC-C(O)N(RC1)S(O)2RC2, -LC-S(O)2N(RC1)C(O)RC2, -LC-S(O)2NRC1RC2, -LC-S(O)(NRC1)RC2, -LC-S(O)2RC1, -CN, -Lc-P(O)(ORcl)(ORc2), or -Lc-OP(O)(ORcl)(ORc2). In some embodiments, Rcis -LC-C(O)OH or a bioisostere thereof, -Lc-C(O)ORcl, -Lc-C(O)NRclRc2, -Lc-C(O)N(Rcl)S(O)2Rc2, -Lc-S(O)2N(Rcl)C(O)Rc2,-Lc-S(O)2NRclRc2, -LC-S(O)(NRC1)RC2, -LC-S(O)2RC1, -LC-P(O)(ORC1)(ORC2), or -Lc-0P(0)(0Rcl)(0Rc2).

[0136] In some embodiments, Rcis — Lc— C(O)OH or a bioisostere thereof. In some embodiments, Rcis -C(O)OH or a bioisostere thereof. In some embodiments, Rcis — C(O)OH.

[0137] In some embodiments, Rcis — Lc— C(O)ORclwherein Rclis independently as described herein.

[0138] In some embodiments, Rcis — Lc— C(O)NRclRc2wherein each of Rcland Rc2is independently as described herein. In some embodiments, Rcis -Lc-C(O)NHRclwherein Rclis independently as described herein.

[0139] In some embodiments, Rcis — Lc— Rclwherein Rclis independently as described herein. In some embodiments, Rcis Rclas described herein. In some embodiments, Rclis R’ as described herein. In some embodiments, Rclis — N(R’)2wherein each R’ is independently as described herein. In some embodiments, Rclis -N(R)2wherein each R is independently as described herein. In some embodiments, Rcis 5-6 membered heteroaryl having 1-4 ring nitrogen atoms and 0 or 1 ring oxygen or sulfur atom. In some embodiments, Rcis optionally substituted tetrazolyl. In some embodiments, Rcis tetrazolyl.

[0140] In some embodiments, Rcis — Lc— ORclwherein Rclis independently as described herein.

[0141] In some embodiments, Rcis — Lc— NRclRc2wherein each of Rcland Rc2is independently as described herein. In some embodiments, Rcis -Lc— NHRclwherein Rclis independently as described herein.

[0142] In some embodiments, Rcis -Lc-C(O)Rclwherein Rclis independently as described herein.

[0143] In some embodiments, Rcis -Lc-C(O)N(Rcl)S(O)2Rc2wherein each of Rcland Rc2is independently as described herein. In some embodiments, Rcis -Lc-C(O)NHS(O)2Rc2wherein Rc2is independently as described herein.

[0144] In some embodiments, Rcis -Lc-S(O)2N(Rcl)C(O)Rc2wherein each of Rcland Rc2is independently as described herein. In some embodiments, Rcis — Lc— S(O)2NHC(O)Rc2wherein Rc2is independently as described herein.

[0145] In some embodiments, Rcis -Lc-S(O)2NRclRc2wherein each of Rcland Rc2is independently as described herein. In some embodiments, Rcis -Lc-S(O)2NHRclwherein Rclis independently as described herein.

[0146] In some embodiments, Rcis -Lc-S(O)(NRcl)Rc2wherein each of Rcland Rc2is independently as described herein. In some embodiments, Rcis -Lc— S(O)(NH)Rc2wherein Rc2is independently as described herein.

[0147] In some embodiments, Rcis -LL-S(O)2Rclwherein Rclis independently as described herein.

[0148] In some embodiments, Rcis halogen. In some embodiments, Rcis -F. In some embodiments, Rcis -Cl. In some embodiments, Rcis — Br. In some embodiments, Rcis -I.

[0149] In some embodiments, Rcis — CN.

[0150] In some embodiments, Rcis — Lc— P(O)(ORcl)(ORc2) wherein each of Rcland Rc2is independently as described herein. In some embodiments, each of Rcland Rc2is -H.|00151 | In some embodiments, Rcis -Lc-OP(O)(ORcl)(ORc2) wherein each of Rcland Rc2isindependently as described herein. In some embodiments, each of Rcland Rc2is -H.

[0152] In some embodiments, Rcis — Lc— BRclRc2wherein each of Rcland Rc2is independently as described herein.

[0153] In some embodiments, Rclis R’ as described herein. In some embodiments, Rclis -N(R’)2 wherein each R' is independently as described herein. In some embodiments, Rclis R as described herein. In some embodiments, Rclis -H. In some embodiments, Rclis not hydrogen. In some embodiments, Rclis optionally substituted C1-6 aliphatic. In some embodiments, Rclis optionally substituted C1-6 alkyl. In some embodiments, Rclis optionally substituted -CH 2— Ci 6 aliphatic. In some embodiments, Rclis optionally substituted -CH2-C36 cycloalkyl. In some embodiments, Rclis optionally substituted -CH2-C36 cyclopropyl.

[0154] In some embodiments, Rc2is R' as described herein. In some embodiments, Rc2is -N(R')2 wherein each R’ is independently as described herein. In some embodiments, Rc2is R as described herein. In some embodiments, Rc2is -H. In some embodiments, Rc2is not hydrogen. In some embodiments, Rc2is optionally substituted Ci 6 aliphatic. In some embodiments, Rc2is optionally substituted Ci 6 alkyl. In some embodiments, Rc2is optionally substituted -CH 2— CM aliphatic. In some embodiments, Rc2is optionally substituted -CH2-C36 cycloalkyl. In some embodiments, Rc2is optionally substituted -CH2-C36 cyclopropyl. In some embodiments, Rcland Rc2are R and arc taken together to form a ring as described herein.Lc

[0155] In some embodiments, Lcis a covalent bond. In some embodiments, Lcis optionally substituted -CH2-. In some embodiments, Lcis -CH2-. d

[0156] 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.Rd

[0157] In some embodiments, Rdis 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.

[0158] In some embodiments, Rdis -CN.

[0159] In some embodiments, Rdis Rdlas described herein.

[0160] In some embodiments, Rdis -ORdlwherein Rdlis as described herein. In some embodiments, Rdis R as described herein.

[0161] In some embodiments, Rdis -NRdlRd2wherein each of Rdland Rd2is independently as described herein. In some embodiments, Rdis — NHRdlwherein Rdlis as described herein. In some embodiments, Rdlis -H. In some embodiments, Rdlis not — H. In some embodiments, Rdlis optionally substituted C1-6 aliphatic. In some embodiments, Rdlis optionally substituted C1-6 alkyl. In some embodiments, Rdlis optionally substituted CM aliphatic. In some embodiments, Rdlis optionally substituted CM alkyl. In someembodiments, Rdlis optionally substituted C1-3 aliphatic. In some embodiments, Rdlis optionally substituted C1-3 alkyl. In some embodiments, Rdlis optionally substituted Cm aliphatic. In some embodiments, Rdlis optionally substituted C1-2 alkyl. In some embodiments, Rdlis optionally substituted methyl. In some embodiments, Rdlis unsubstituted aliphatic or alkyl as described herein. In some embodiments, Rdlis substituted aliphatic or alkyl, wherein each substituent is independently halogen. In some embodiments, Rdlis substituted aliphatic or alkyl, wherein each substituent is -F. For example, in some embodiments, Rdlis methyl. In some embodiments, Rdlis ethyl. In some embodiments, Rdbeing a secondary amine provides various benefits as described herein (e.g., permeability, melanin binding, PK, etc.). In some embodiments, d is not 0 and Rdis -NRdlRd2, or e is not 0 and Reis — NRelRe2. In some embodiments, Rdis -NH2. In some embodiments, Rdis -NHMe. In some embodiments, Rdis -NHEt. In some embodiments, Rdis at a position next to Rc. In some embodiments, Rdis at a position next to a position that is next to Rc(e.g., Rc— C-C-Rd). In some embodiments, Rdlis -CD3. In some embodiments, Rdis -NHCD3.

[0162] In some embodiments, Rdlis R’ as described herein. In some embodiments, Rdlis R. In some embodiments, Rdlis — C(O)R. In some embodiments, Rdlis -C(O)CHj. In some embodiments, Rdlis -S(O)?R. In some embodiments, Rdlis -S(O)2 CH3. In some embodiments, Rdis — NHAc. In some embodiments, Rdis -NHSlOhCH;.

[0163] In some embodiments, Rdlcomprises a H-bond donor group. In some embodiments, Rdlcomprises -NH2. In some embodiments, Rdlcomprises -C(O)NH2. In some embodiments, Rdlcomprises -OH. In some embodiments, the ring atom next to the carbon atom to which Rdis attached is -N=, and the H-bond donor in Rdlcan form a H-bond with the -N=.

[0164] In some embodiments, Rdlis R as described herein. In some embodiments, Rdlis — H. In some embodiments, Rdlis not hydrogen. In some embodiments, Rdlis optionally substituted C1-6 aliphatic. In some embodiments, Rdlis optionally substituted C1-6 alkyl. In some embodiments, Rdlis optionally substituted -CH2-C1-6 aliphatic. In some embodiments, Rdlis optionally substituted -CH2-C36 cycloalkyl. In some embodiments, Rdlis optionally substituted -CH2-C36 cyclopropyl. In some embodiments, Rdlis optionally substituted 3-10 membered cycloaliphatic. In some embodiments, Rdlis optionally substituted cyclobutyl. In some embodiments, Rdlis optionally substituted cyclopropyl. In some embodiments, Rdlis optionally substituted 3-10 membered heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, Rdlis optionally substituted oxetane. In some embodiments, Rdlis optionally substituted 5-10 membered heteroaryl having 1-6 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0165] In some embodiments, Rd2is R as described herein. In some embodiments, Rd2is — H. In some embodiments, Rd2is not hydrogen. In some embodiments, Rd2is optionally substituted C1-6 aliphatic. In some embodiments, Rd2is optionally substituted C1-6 alkyl. In some embodiments, Rd2is optionally substituted -CH2-C1-6 aliphatic. In some embodiments, Rd2is optionally substituted -CH2-C36 cycloalkyl. In some embodiments, Rd2is optionally substituted -CH2-C36 cyclopropyl. In some embodiments, Rd2isoptionally substituted 3-10 membered cycloaliphatic. In some embodiments, Rd2is optionally substituted cyclobutyl. In some embodiments, Rd2is optionally substituted cyclopropyl. In some embodiments, Rd2is optionally substituted 3-10 membered heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, Rd2is optionally substituted oxctanc. In some embodiments, Rd2is optionally substituted 5-10 membered heteroaryl having 1-6 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, Rd2is -CDj.

[0166] In some embodiments, Rdland Rd2are R and are taken together to form a ring as described herein. For example, in some embodiments, Rdland Rd2are 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

[0167] In some embodiments, e is 0. In some embodiments, e is 1. In some embodiments, e is 2.Re

[0168] In some embodiments, Reis 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.

[0169] In some embodiments, Reis Relas described herein. In some embodiments, Reis R as described herein.

[0170] In some embodiments, Rcis -CN.

[0171] In some embodiments, Reis -ORclwherein Relis as described herein.

[0172] In some embodiments, Reis — NRelRe2wherein each of Reland Re2is independently as described herein. In some embodiments, Reis — NHRelwherein Relis as described herein. In some embodiments, Relis -H. In some embodiments, Relis not — H. In some embodiments, Relis optionally substituted C1-6 aliphatic. In some embodiments, Relis optionally substituted C1-6 alkyl. In some embodiments, Relis optionally substituted C1-4 aliphatic. In some embodiments, Rclis optionally substituted CM alkyl. In some embodiments, Relis optionally substituted C1-3 aliphatic. In some embodiments, Relis optionally substitutedC1-3 alkyl. In some embodiments, Relis optionally substituted C1-2 aliphatic. In some embodiments, Relis optionally substituted C1 2 alkyl. In some embodiments, Relis optionally substituted methyl. In some embodiments, Relis unsubstituted aliphatic or alkyl as described herein. In some embodiments, Relis substituted aliphatic or alkyl, wherein each substituent is independently halogen. In some embodiments, Relis substituted aliphatic or alkyl, wherein each substituent is -F. For example, in some embodiments, Relis methyl. In some embodiments, RL Iis ethyl. In some embodiments, Rebeing a secondary amine provides various benefits as described herein (e.g., permeability, melanin binding, PK, etc.). In some embodiments, Reis -NH2. In some embodiments, Reis — NHMe. In some embodiments, Reis -NHEt. In some embodiments, Reis at a position next to Rc. In some embodiments, Reis at a position next to a position that is next to Rc(e.g., Rc-C-C-Re).

[0173] In some embodiments, Relis R' as described herein. In some embodiments, Relis R. In some embodiments, Relis -C(O)R. In some embodiments, Relis -C(O)CH ;. In some embodiments, Relis -S(O)2R. In some embodiments, Relis -SlOhCH,. In some embodiments, Relis -CD3.

[0174] In some embodiments, Relis R as described herein. In some embodiments, Relis — H. In some embodiments, Relis not hydrogen. In some embodiments, Relis optionally substituted Cre aliphatic. In some embodiments, Relis optionally substituted C1-6 alkyl. In some embodiments, Relis optionally substituted -CH2-C1-6 aliphatic. In some embodiments, Relis optionally substituted -CH2-C36 cycloalkyl. In some embodiments, Relis optionally substituted -CH2-C3-6 cyclopropyl. In some embodiments, RL Iis optionally substituted 3-10 membered cycloaliphatic. In some embodiments, Relis optionally substituted cyclobutyl. In some embodiments, Relis optionally substituted cyclopropyl. In some embodiments, Relis optionally substituted 3-10 membered heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, Relis optionally substituted oxetane. In some embodiments, Relis optionally substituted 5-10 membered heteroaryl having 1-6 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, Reis -NHAc. In some embodiments, Reis -NHS(O)2CH3.

[0175] In some embodiments, Re2is R as described herein. In some embodiments, Re2is — H. In some embodiments, Re2is not hydrogen. In some embodiments, Re2is optionally substituted C1-6 aliphatic. In some embodiments, Re2is optionally substituted C1-6 alkyl. In some embodiments, Re2is optionally substituted -CH2-C1-6 aliphatic. In some embodiments, Re2is optionally substituted -CH2-C36 cycloalkyl. In some embodiments, Re2is optionally substituted -CH2-C36 cyclopropyl. In some embodiments, Reland Re2are R and are taken together to form a ring as described herein. In some embodiments, Re2is optionally substituted 3-10 membered cycloaliphatic. In some embodiments, Re2is optionally substituted cyclobutyl. In some embodiments, Re2is optionally substituted cyclopropyl. In some embodiments, Re2is optionally substituted 3-10 membered heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, Re2is optionally substituted oxetane. In some embodiments, Re2is optionally substituted 5-10 membered heteroaryl having 1-6 heteroatoms independently selected fromnitrogen, oxygen and sulfur. In some embodiments, Re2is -CD3.

[0176] In some embodiments, Rdand Reare R and are taken together with their intervening atom(s) to form a ring as described herein. In some embodiments, one of Rdland Rd2and one of Reland Re2are R and arc taken together with then' intervening atom(s) to form a ring as described herein. In some embodiments, Rdland Relare R and are taken together with their intervening atom(s) to form a ring as described herein. In some embodiments, Rd2and Re2are R and are taken together with their intervening atom(s) to form a ring as described herein. In some embodiments, Reland Re2are R and are taken together to form a ring as described herein. For example, in some embodiments, Reland Re2are 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'

[0177] 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

[0178] 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 someembodiments, 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 oneheteroatom 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<

[0179] In some embodiments, two groups that are R or can be R (e.g., Ra, Ral, Ra2, Rb, Rbl, Rb2, Rc, Rcl, Rc2, Rd, Rdl, Rd2, Re, Rel, Re2, 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.

[0180] In some embodiments, a group that can be R, e.g., Ra, Ral, Ra2, Rb, Rbl, Rb2, R\ Rcl, Rc2, Rd, Rdl, Rd2, Rc, Rel, Re2, R’, etc., is R as described herein. Those skilled in the art appreciate that embodimentsdescribed 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.

[0181] 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.

[0182] 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.

[0183] 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.

[0184] In some embodiments, a provided compounds has the structure of formula I-a:or a salt thereof, wherein each variable is independently described herein.

[0185] In some embodiments, a provided compounds has the structure of formula I-a-1:I-a-1or a salt thereof, wherein each variable is independently described herein.

[0186] 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.

[0187] In some embodiments, a provided compounds has the structure of formula I-b:or a salt thereof, wherein each variable is independently described herein.

[0188] 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.

[0189] 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.

[0190] In some embodiments, a provided compounds has the structure of formula I-c:or a salt thereof, wherein each variable is independently described herein.

[0191] 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.

[0192] 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.

[0193] In some embodiments, a provided compounds has the structure of formula I-d:or a salt thereof, wherein each variable is independently described herein.

[0194] 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.

[0195] 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.

[0196] 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.

[0197] In some embodiments, a provided compounds has the structure of formula I-e:or a salt thereof, wherein each variable is independently described herein.

[0198] 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.

[0199] 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.

[0200] 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.

[0201] 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.

[0202] 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.

[0203] 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.

[0204] In some embodiments, a provided compounds has the structure of formula I-g:or a salt thereof, wherein each variable is independently described herein.

[0205] 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.

[0206] 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.

[0207] 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 Rbgroups 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, Rcis -NRclRc2wherein each of Rcland Rc2is independently as described herein. In some embodiments, Reis -NHRclwherein Relis as described herein. In some embodiments, Relis optionally substituted CM aliphatic. In some embodiments, Relis optionally substituted Ci 4 aliphatic. In some embodiments, Relis optionally substituted C1-2 aliphatic. In some embodiments, Relis optionally substituted C1-6 alkyl. In some embodiments, Relis optionally substituted CM alkyl. In some embodiments, Relis optionally substituted C1-2 alkyl. In some embodiments, Relis not substituted. In some embodiments, R1is substituted and each substituent is independently halogen. In some embodiments, Relis methyl. In some embodiments, Rclis ethyl. In some embodiments, Reis -NH(CHIn some embodiments, Reland Re2are R and are taken together to form a ring as described herein. For example, in some embodiments, Reland Re2are 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 selectedfrom 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, Reis optionally substituted. In some embodiments, Reis

[0208] In some embodiments, a provided compounds has the structure of formula I-h:or a salt thereof, wherein each variable is independently described herein.

[0209] 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.

[0210] In some embodiments, a provided compounds has the structure of formula I-h-2:I-h-2or 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.

[0212] In some embodiments, m is 1 and n is 1. In some embodiments, Rcis -COOH. In some embodiments, Rdis -NRd1Rd2wherein each of Rdland Rd2is independently as described herein. In some embodiments, Reis -NRd1Rd2wherein each of Reland Re2is independently as described herein.

[0213] 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;R1is 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)pC1-C6 alkyl, -CH2NHC(O)C1-C4 alkyl or -OCH2C(O)R7; p is 0, 1, or 2;R2is hydrogen, C1-C6 alkyl, C1-C6 alkoxy, hydroxy C1-C6 alkyl, or halogen;R3is hydrogen, halogen, cyano, C1-C4 alkyl, halo C1-C4 alkyl, -CH2C(O)R7;R4is 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 R5and 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 R5are 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 R51is independently R6’ ;R4is hydrogen, C1-C4 alkyl, or hydroxy C1-C4 alkyl;R5is -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)2or 5- membered heteroaryl having 1-4 ring nitrogen atoms and 0 or 1 ring oxygen or sulfur atom; each R6is 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 R6on a carbon atom are taken together to form =0, or two R6on 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 R6are 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; orR4and one R6are taken together to form C2-C4 alkylene; t is 0, 1, 2, 3 or 4;R6is 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:R6and R6are 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 substituentsindependently selected from halogen, C1-C4 alkyl, halo C1-C4 alkyl, C1-C4 alkoxy, hydroxyl, and oxo;R7is hydroxyl, Ci-C4 alkoxy, amino, or mono- or di-Ci-C4 alkylamino; each R8is 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;R9is 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; andR10is 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.

[0214] In some embodiments, R4is substituted with R5and one or two R5’. In some embodiments, R4is substituted with R5and one or two R5', wherein R5is -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)2or 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(R5I)2, wherein each R51is independently as described herein.

[0215] 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.

[0216] In some embodiments, R1is 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, R1is 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, R1is 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, R1is 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, R1is 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- C6alkyl, -CH2NHC(O)CI-C4alkyl or -OCH2C(O)R7.

[0217] In some embodiments, R1is hydrogen. In some embodiments, R1is halogen. In some embodiments, R1is hydroxy. In some embodiments, R1is C1-C6alkyl. In some embodiments, R1is C2-C6alkenyl. In some embodiments, R1is C3-C6cycloalkyl. In some embodiments, R1is C3-C5cycloalkyl. In some embodiments, R1is cyclopropyl.

[0218] In some embodiments, R1is halo C1-C6 alkyl.

[0219] In some embodiments, R1is hydroxy C1-C6alkyl. In some embodiments, R1is amino C1-C6alkyl. In some embodiments, R1is C1-C6alkoxy C1-C6alkyl. In some embodiments, R1is C1-C6alkoxy C1- C6 alkoxy. In some embodiments, R1is C3-C6 cycloalkyl C1-C6 alkoxy.

[0220] In some embodiments, R1is halo C1-C6 alkoxy. In some embodiments, R1is halo C1-C4 alkoxy. In some embodiments, R1is halo C1-C2 alkoxy. In some embodiments, R1is halo C1-C2 alkoxy. In some embodiments, R1is –OCHF2.

[0221] In some embodiments, R1is −S(O)pC1-C6 alkyl. In some embodiments, R1is −SC1-C6 alkyl. In some embodiments, R1is −S(O)C1-C6 alkyl. In some embodiments, R1is −CH2NHC(O)C1-C4 alkyl. In some embodiments, R1is −OCH2C(O)R7.

[0222] In some embodiments, R1is C1-C6 alkoxy.

[0223] 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, R1is C1-C6 alkoxy. In some embodiments, R1is −O−CH3.

[0224] In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2.

[0225] In some embodiments, R1is −SC1-C6 alkyl. In some embodiments, R1is −S(O)C1-C6 alkyl. In some embodiments, R1is −S(O)2C1-C6 alkyl.

[0226] In some embodiments, R2is hydrogen, C1-C6 alkyl, C1-C6 alkoxy, hydroxy C1-C6 alkyl, or halogen.

[0227] In some embodiments, R2is hydrogen.

[0228] In some embodiments, R2is C1-C6alkyl. In some embodiments, R2is methyl. In some embodiments, R2is ethyl.

[0229] In some embodiments, R2is C1-C6alkoxy. In some embodiments, R2is hydroxy C1-C6alkyl. In some embodiments, R2is halogen. In some embodiments, R2is −F. In some embodiments, R2is −Cl. In some embodiments, R2is −Br. In some embodiments, R2is −I.

[0230] In some embodiments, R3is hydrogen, halogen, cyano, C1-C4alkyl, halo C1-C4alkyl, −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.

[0231] In some embodiments, R3is hydrogen.

[0232] In some embodiments, R3is halogen. In some embodiments, R3is -F. In some embodiments, R3is -Cl. In some embodiments, R3is — Br. In some embodiments, R3is -I. In some embodiments, R3is cyano.

[0233] In some embodiments, R3is C1-C4 alkyl. In some embodiments, R3is C1-C4 alkyl optionally substituted with one hydroxy group. In some embodiments, R3is C1-C4 alkyl substituted with one hydroxy group.

[0234] In some embodiments, R3is halo C1-C4 alkyl. In some embodiments, R3is halo C1-C4 alkyl optionally substituted with one hydroxy group. In some embodiments, R3is halo Cj-C4 alkyl substituted with one hydroxy group. In some embodiments, R3is -CH2C(O)R7.

[0235] In some embodiments, R4is 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 R5and further optionally substituted with one or two R5’. In some embodiments, R4is 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 R5and further substituted with 0 or 1 substituent selected from halogen, C1-C4 alkyl, C1-C4 alkoxy, hydroxy C1-C4 alkyl, hydroxyl, and cyanomethyl.

[0236] In some embodiments, R4is optionally substituted phenyl. In some embodiments, R4is optionally substituted naphthyl. In some embodiments, R4is optionally substituted 1,2,3,4- tetrahydronaphthalenyl. In some embodiments, R4is optionally substituted 5-10 membered heteroaryl. In some embodiments, R4is optionally substituted 5-6 membered heteroaryl. In some embodiments, R4is optionally substituted 9-membered bicyclic heteroaryl. In some embodiments, R4is optionally substituted 10- membered bicyclic heteroaryl. In some embodiments, R4is not substituted with R5. In some embodiments, R4is not substituted with R5. In some embodiments, R4is not substituted with R5or R5’. In some embodiments, R4is substituted with R5. In some embodiments, R4is substituted with R5but no R5’. In some embodiments, R4is substituted with R5. In some embodiments, R4is substituted with one R5. In some embodiments, R4is substituted with two R5. In some embodiments, R4is substituted with R5and R5’. In some embodiments, R4is substituted with one R5and one R5’. In some embodiments, R4is substituted with one R5and two R5’.

[0237] In some embodiments, R4is 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 R5and further substituted with 0 or 1 substituent selected from halogen, C1-C4 alkyl, C1-C4 alkoxy, hydroxy C1-C4 alkyl, hydroxyl, sulfonyl, and cyanomethyl.

[0238] In some embodiments, R4is 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)R8and further substituted with 0 or 1 substituent selected from halogen, C1-C4 alkyl, C1-C4 alkoxy, hydroxy C1-C4 alkyl, hydroxyl, sulfonyl, and cyanomethyl.

[0239] In some embodiments, R4is 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.

[0240] In some embodiments, R4is phenyl. In some embodiments, R4is phenyl substituted with R5and 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, R4is phenyl substituted with R5only. In some embodiments, R4is phenyl substituted with R5and further substituted with one substituent selected from halogen, C1-C4 alkyl, C1-C4 alkoxy, hydroxy C1-C4 alkyl, hydroxyl, and cyanomethyl. In some embodiments, R4is phenyl substituted with -C(O)R8and 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, R4is phenyl substituted with -C(O)R8only. In some embodiments, R4is phenyl substituted with -C(O)R8and further substituted with one substituent selected from halogen, C1-C4 alkyl, C1-C4 alkoxy, hydroxy C1-C4 alkyl, hydroxyl, and cyanomethyl. In some embodiments, R4is 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, R4is phenyl substituted with -COOH only. In some embodiments, R4is 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.

[0241] In some embodiments, R4is naphthyl. In some embodiments, R4is naphthyl substituted with R5and 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, R4is naphthyl substituted with R5only. In some embodiments, R4is naphthyl substituted with R5and further substituted with one substituent selected from halogen, C1-C4 alkyl, C1-C4 alkoxy, hydroxy C1-C4 alkyl, hydroxyl, and cyanomethyl. In some embodiments, R4is naphthyl substituted with -C(O)R8and 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, R4is naphthyl substituted with -C(O)R8only. In some embodiments, R4is naphthyl substituted with — C(O)R8and further substituted with one substituent selected from halogen, C1-C4 alkyl, C1- C4 alkoxy, hydroxy C1-C4 alkyl, hydroxyl, and cyanomethyl. In some embodiments, R4is 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, R4is naphthyl substituted with — COOH only. In some embodiments, R4is 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.

[0242] In some embodiments, R4is tetrahydronaphthalenyl. In some embodiments, R4is tetrahydronaphthalenyl substituted with R5and 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, R4is tetrahydronaphthalenyl substituted with R5only. In some embodiments, R4is tetrahydronaphthalenyl substituted with R5and further substituted with one substituent selected from halogen, C1-C4 alkyl, Cj-C4 alkoxy, hydroxy C1-C4 alkyl, hydroxyl, and cyanomethyl. In some embodiments, R4is tetrahydronaphthalenyl substituted with — C(O)R8and 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, R4is tetrahydronaphthalenyl substituted with -C(O)R8only. In some embodiments, R4is tetrahydronaphthalenyl substituted with — C(O)R8and further substituted with one substituent selected from halogen, C1-C4 alkyl, C1-C4 alkoxy, hydroxy C1-C4 alkyl, hydroxyl, and cyanomethyl. In some embodiments, R4is 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, R4is tetrahydronaphthalenyl substituted with -COOH only. In some embodiments, R4is 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.

[0243] In some embodiments, R4is 5- or 6-membered heteroaryl having 1, 2 or 3 ring heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, R4is 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 R5and 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 R5only. In some embodiments, the heteroaryl is substituted with R5and further substituted with one substituent selected from halogen, C1-C4 alkyl, C1-C4 alkoxy, hydroxy C1-C4 alkyl, hydroxyl, and cyanomethyl. In some embodiments, R4is 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)R8and 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)R8only. In some embodiments, the heteroaryl substituted with -C(O)R8and further substituted with one substituent selected from halogen, C1-C4 alkyl, C1-C4 alkoxy, hydroxy C1-C4 alkyl, hydroxyl, and cyanomethyl. In some embodiments, R4is 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-C4At 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-C4alkyl, C1-C4alkoxy, hydroxy C1-C4alkyl, hydroxyl, and cyanomethyl. In some embodiments, the heteroaryl of R4is 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.

[0244] In some embodiments, the further substituent on R4in addition to R5is 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-C4alkyl. In some embodiments, it is C1-C4alkoxy. In some embodiments, it is hydroxy C1-C4alkyl. In some embodiments, it is hydroxy. In some embodiments, it is cyanomethyl.

[0245] In some embodiments, wherein R4is 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 R5and further optionally substituted with one or two R5’. In some embodiments, R4is phenyl substituted with R5and further optionally substituted with one or two R5’. In some embodiments, wherein R4is phenyl para- substituted (unless otherwise indicated, relative to the atom at which R4is attached to the rest of the compound) with R5and further optionally substituted with one or two R5’. In some embodiments, R4is phenyl meta-substituted with R5and further optionally substituted with one or two R5’. In some embodiments, R4is naphthyl substituted with R5and further optionally substituted with one or two R5’. In some embodiments, R4is 1,2,3,4-tetrahydronaphthalenyl substituted with R5and further optionally substituted with one or two R5’. In some embodiments, R4is 5-membered heteroaryl substituted with R5and further optionally substituted with one or two R5’. In some embodiments, R4is 6-membered heteroaryl substituted with R5and further optionally substituted with one or two R5’. In some embodiments, R4is 6-membered heteroaryl para-substituted with R5and further optionally substituted with one or two R5’. In some embodiments, R4is 6-membered heteroaryl meta-substituted with R5and further optionally substituted with one or two R5’. In some embodiments, a 6-membered heteroaryl is pyridyl. In some embodiments, R4is 9- membered bicyclic heteroaryl substituted with R5and further optionally substituted with one or two R5’. In some embodiments, R4is 10-membered bicyclic heteroaryl substituted with R5and further optionally substituted with one or two R5’.

[0246] In some embodiments, R4is substituted with one R5. In some embodiments, R4is substitutedwith two R5. In some embodiments, a R5is attached to an atom that is boned to an atom to which R5bonds. In some embodiments, a R5is attached to a carbon atom that is boned to an atom to which R5bonds. In some embodiments, a R5is attached to a carbon atom that is boned to a carbon atom to which R5bonds. In some embodiments, R4is or comprises an aromatic ring to which both R5and a R5’ are bonded. In some embodiments, R5and a R5’ are ortho.

[0247] 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.

[0248] 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.

[0249] In some embodiments, R5’ is C1-C4 alkoxy as described herein. In some embodiments, it is methoxy. In some embodiments, it is ethoxy.

[0250] In some embodiments, R5’ is hydroxy C1-C4 alkyl as described herein. In some embodiments, it is −CH2OH. In some embodiments, it is −CH2CH2OH.

[0251] In some embodiments, R5’is hydroxyl.

[0252] In some embodiments, R5’ is R10as described herein. In some embodiments, R10comprises a nitrogen ring atom. In some embodiments, R10is bonded to R4at a nitrogen ring atom.

[0253] In some embodiments, R5’ is −OR6’wherein R6’ is as described herein. In some embodiments, it is −OR10wherein R10is as described herein.

[0254] In some embodiments, R5’ is halo C1-C6 alkyl. In some embodiments, R5’ is C1-C6 alkyl substituted with one or more −F.

[0255] In some embodiments, R5’ is cyano. In some embodiments, R5’ is cyanomethyl.

[0256] In some embodiments, two R5’are taken together to form an optionally substituted ring as described herein. In some embodiments, two R5’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 R5’are taken together to form an optionally substituted 5-6 membered aromatic ring as described herein. In some embodiments, two R5’are taken together to form an optionally substituted 5-membered aromatic ring as described herein. In some embodiments, two R5’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.

[0257] 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)2wherein each R51isindependently as described herein. In some embodiments, R5’ is −NHR51wherein R51is as described herein. In some embodiments, R5’ is −N(CH3)R51wherein R51is as described herein.

[0258] In some embodiments, R5’ is −NHC(O)CH3. In some embodiments, R5’ is −NHC(O)CH2CH3. In some embodiments, R51is −SO2−C1-C6aliphatic, wherein the C1-C6aliphatic is optionally substituted. In some embodiments, R51is −SO2−C1-C6 aliphatic. In some embodiments, R51is −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).

[0259] As described herein, each R51is independently R6’ as described herein.

[0260] In some embodiments, each R51is 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.

[0261] In some embodiments, R51is hydrogen. In some embodiments, R51is optionally substituted C1- C6 aliphatic. In some embodiments, R51is C1-C6 aliphatic. In some embodiments, R51is C1-C6 alkyl. In some embodiments, R51is cyclopropyl. In some embodiments, R51is methyl. In some embodiments, R51is ethyl. In some embodiments, R51is cyclobutyl. In some embodiments, R51is −CH2−cyclopropyl. In some embodiments, R51is substituted C1-C6 aliphatic. In some embodiments, R51is −CH2(CO2H). In some embodiments, R51is substituted C1-C6 alkyl. In some embodiments, R51is (S)−CH(CH3)(CF3). In some embodiments, R51is −CH2CF3. In some embodiments, R51is substituted C3-C6 cycloalkyl. In some embodiments, R51is 3,3-difluorocyclobutyl. In some embodiments, R51is R10as described herein. In some embodiments, R51is −CH2−R10wherein R10is as described herein. In some embodiments, R51is −CH2−CHF2.

[0262] In some embodiments, R51is −C(O)−C1-C6aliphatic, wherein the C1-C6aliphatic is optionally substituted. In some embodiments, R51is −C(O)−C1-C6aliphatic. In some embodiments, R51is −C(O)−C1-C6alkyl. In some embodiments, R51is −C(O)−CH3.

[0263] In some embodiments, R51is −SO2−C1-C6aliphatic. In some embodiments, R51is −SO2−CH3.

[0264] In some embodiments, R4’is hydrogen. In some embodiments, R4’is C1-C4alkyl. In some embodiments, R4’is hydroxy C1-C4alkyl. In some embodiments, R4’and one R6are taken together to formC2-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 someembodiments, the carbon to which R4' is attached has a structure o . In some embodiments, thecarbon to which R4' is attached has a structure o .

[0265] In some embodiments, R5is −C(O) (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.

[0266] In some embodiments, R5is −COOH or a bioisostere thereof.

[0267] In some embodiments, R5is −C(O)R8. In some embodiments, R5is −C(O)OH. In some embodiments, R5is −C(O)R8, wherein R8is C1-C4 alkoxy.

[0268] In some embodiments, R5is −CH2C(O)R8. In some embodiments, R5is −CH2C(O)OH. In some embodiments, R5is −CH2C(O)R8, wherein R8is C1-C4 alkoxy.

[0269] In some embodiments, R5is R9. In some embodiments, R5is −C(O)NHSO2C1-C4alkyl. In some embodiments, R5is −C(O)NHSO2CH3. In some embodiments, R5is −C(O)NHSO2(cyclopropyl). In some embodiments, R5is −SO2NHC(O)C1-C4alkyl. In some embodiments, R5is −SO2N(H)p(C1-C4alkyl)2-p. In some embodiments, R5is −SO2N(C1-C4alkyl)2. In some embodiments, R5is −SO2NH(C1-C4alkyl). In some embodiments, R5is −SO2NH2. In some embodiments, R5is −SO(NH)C1-C4alkyl. In some embodiments, R5is −SO2C1-C4alkyl. In some embodiments, R5is cyano. In some embodiments, R5is halogen. In some embodiments, R5is −F. In some embodiments, R5is −Cl. In some embodiments, R5is −Br. In some embodiments, R5is −I. In some embodiments, R5is hydroxy C1-C4alkyl.

[0270] In some embodiments, R5is −B(R8)2. In some embodiments, R5is −B(R8)2, wherein each R8is independently hydroxy or C1-C4alkoxy. In some embodiments, R5is −B(OH)2. In some embodiments, R5is −B(R8)2, wherein each R8is independently C1-C4alkoxy.

[0271] In some embodiments, R5is 5-membered heteroaryl having 1-4 ring nitrogen atoms and 0 or 1 ring oxygen or sulfur atom. In some embodiments, R5is 5-membered heteroaryl having 1-4 ring nitrogen atoms. In some embodiments, R5is tetrazolyl.

[0272] In some embodiments, each R6is independently hydrogen, halogen, hydroxyl, amino, mono- and di-C1-C6alkylamino, C1-C6alkyl, halo C1-C6alkyl, hydroxy C1-C6alkyl, cyano C1-C6alkyl or C1-C6alkoxy.

[0273] In some embodiments, R6is hydrogen. In some embodiments, R6is not hydrogen. In some embodiments, R6is halogen. In some embodiments, R6is −F. In some embodiments, R6is −Cl. In some embodiments, R6is −Br. In some embodiments, R6is −I. In some embodiments, R6is hydroxy. In some embodiments, R6is amino. In some embodiments, R6is mono- and di-C1-C6alkylamino. In some embodiments, R6is C1-C6alkyl.

[0274] In some embodiments, R6is halo C1-C6 alkyl. In some embodiments, R6is halo C1-C4 alkyl. In some embodiments, R6is −CF3. In some embodiments, R6is −CHF2. In some embodiments, R6is −CH2F.

[0275] In some embodiments, R6is hydroxy C1-C6 alkyl. In some embodiments, R6is hydroxy C1-C4 alkyl. In some embodiments, R6is −CH2OH.

[0276] In some embodiments, R6is cyano C1-C6 alkyl. In some embodiments, R6is cyano C1-C4 alkyl. In some embodiments, R6is C1-C6 alkoxy. In some embodiments, R6is C1-C4 alkoxy.

[0277] In some embodiments, two R6on 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 R4and R4’are attached. In some embodiments, =O is on a carbon at the p-position relative to the carbon to which R4and R4’are attached. In some embodiments, two R6on 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 R6on a carbon atom arn together with the carbon atom to formmembered monocyclic saturated ring having a nitrogen ring atom. In some embodiments, two R6on a carbon atom are taken together with the carbon atom to form a 3-membered monocyclic saturated ring having a sulfur ring atom.

[0278] In some embodiments, two R6are 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 isnitrogen. 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-C4alkyl. In some embodiments, a substituent is halo C1-C4alkyl. In some embodiments, a substituent is C1-C4alkoxy. In some embodiments, a substituent is hydroxy. In some embodiments, a substituent is oxo.

[0279] 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 R6is not hydrogen. In some embodiments, t is 1, 2, 3, or 4, and each R6is 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.

[0280] In some embodiments, R6’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.

[0281] In some embodiments, R6’is hydrogen. In some embodiments, R6’is not hydrogen.

[0282] 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.

[0283] 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-C4alkyl, halo C1-C4alkyl, C1-C4alkoxy, hydroxyl, and oxo, and wherein each nitrogen ring atom of the heterocyclyl is optionally and independently substituted with C1-3acyl, cyano C1-C4alkyl, C3-C6cycloalkyl, 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 C1-3acyl.

[0284] In some embodiments, R6’ is optionally substituted C1-6aliphatic. In some embodiments, R6’ is C1-6aliphatic. In some embodiments, R6’ is C1-C6alkyl optionally substituted as described herein. In some embodiments, R6’ is C1-C6alkyl. In some embodiments, R6’ is C1. In some embodiments, R6’ is C2. In someembodiments, 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, R6’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, R51is −CH2(CO2H).

[0285] 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.

[0286] 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, R6’is −CH2CH=CH2.

[0287] In some embodiments, R6’ is C2-C6 alkynyl optionally substituted as described herein. In some embodiments, R6’ is C2-C6alkynyl. In some embodiments, an alkynyl is a terminal alkynyl group. In some embodiments, R6’is −CH2C≡CH.

[0288] In some embodiments, R6’is −CH2−(hydroxy C1-C4alkyl). In some embodiments, R6’is −CH2CH2OH.

[0289] In some embodiments, R6’is −C(O) −C1-C6aliphatic. In some embodiments, R6’is −C(O)−CH3.

[0290] In some embodiments, R6’is −SO2−C1-C6aliphatic. In some embodiments, R6’is −SO2−CH3.

[0291] In some embodiments, a group (e.g., C1-6aliphatic, C3-C6cycloaliphatic, phenyl, etc.) of R6’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, R6’is C1-6aliphaticsubstituted with one or more −F. In some embodiments, R6’is C1-6alkyl substituted with one or more −F. In some embodiments, R6’is −(CH2)2−F. In some embodiments, R6’is −(CH2)3−F. In some embodiments, R6’is −CH2−CHF2. In some embodiments, R6’is −CH(CH3)−CHF2. In some embodiments, R6’is −CH2−CF3. In some embodiments, R6’is −CH2−CH2−CHF2. In some embodiments, R6’is −CH2−CH2−CF3. In some embodiments, R6’is −CH2−CF2−CH3. In some embodiments, R6’is −CH(CH3)−CH2−CF3. In some embodiments, R6’is C3-C6substituted one or more −F. In some embodiments, R6’is cyclopropyl substituted with −F.

[0292] In some embodiments, a group (e.g., C1-6 aliphatic, C3-C6 cycloaliphatic, phenyl, etc.) of R6’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, R6’is −CH2CH2OCH3.

[0293] In some embodiments, R6’ is R10. In some embodiments, R6’is 3-6 membered heterocyclyl optionally substituted as described herein. In some embodiments, R6’is 3-membered heterocyclyl optionally substituted as described herein. In some embodiments, R6’is 4-membered heterocyclyl optionally substituted as described herein. In some embodiments, R6’is 5-membered heterocyclyl optionally substituted as described herein. In some embodiments, R6’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, R6’is .

[0294] In some embodiments, R6’is 5-6 membered heteroaryl optionally substituted as described herein. In some embodiments, R6’is 5-membered heteroaryl optionally substituted as described herein. In some embodiments, R6’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 someembodiments, .

[0295] Inments, the atom of R10that forms a bond with the nitrogen to which R10is attached is a carbon atom.

[0296] In some embodiments, R6’ is −CH2−C3-C6cycloaliphatic 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-C6cycloalkyl wherein the cycloaliphatic group is optionally substituted as described herein. In some embodiments, R6’ is −CH2−C3-C6cycloaliphatic. In some embodiments, R6’ is −CH2−C3-C6 cycloalkyl. In some embodiments, a cycloalkyl is cyclopropyl. In someembodiments, a cycloalkyl is cyclobutyl. In some embodiments, a cycloalkyl is cyclopentyl. In some embodiments, a cycloalkyl is cyclohexyl.

[0297] In some embodiments, R6’ is −CH2−R10, wherein R10is as described herein.

[0298] In some embodiments, R6’ is −CH2−(hydroxy C1-C4alkyl). In some embodiments, R6’is −CH2CH2OH.

[0299] 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.

[0300] In some embodiments, R6’is −C(O)−C1-C6 aliphatic, wherein the C1-C6 aliphatic is as described herein. In some embodiments, R6’is −C(O)−C1-C6 aliphatic, wherein the C1-C6 aliphatic is optionally substituted as described herein. In some embodiments, R6’is −C(O)−C1-C6 alkyl. In some embodiments, R6’is −C(O)−CH3.

[0301] In some embodiments, R6’is −SO2−C1-C6 aliphatic, wherein the C1-C6 aliphatic is as described herein. In some embodiments, R6’is −SO2−C1-C6 aliphatic, wherein the C1-C6 aliphatic is optionally substituted as described herein. In some embodiments, R6’is −SO2−C1-C6 alkyl. In some embodiments, R6’is −SO2−CH3.

[0302] 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.

[0303] 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.

[0304] In some embodiments, R6’ is −CH2−(mono- and di-C1-C4 alkylamino C1-C4 alkyl).

[0305] In some embodiments, R6and 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-C4alkyl, halo C1-C4alkyl, C1-C4alkoxy, hydroxyl, and oxo.

[0306] In some embodiments, R6and 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-C4alkyl, halo C1-C4alkyl, C1-C4alkoxy, 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. Insome embodiments, a formed ring is 7-membered. In some embodiments, a formed ring is 8-membered.

[0307] 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.

[0308] In some embodiments, R6and R6’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, R6and R6’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, R6and R6’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, R6and R6’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, R6and R6’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-C4alkyl, halo C1-C4alkyl, C1-C4alkoxy, hydroxyl, and oxo. In some embodiments, R6and R6’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-C4alkyl, halo C1-C4alkyl, C1-C4alkoxy, hydroxyl, and oxo. In some embodiments, R6and R6’are taken together with their intervening atoms to form a 5-6 membered monocyclicor 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-C4alkyl, halo C1-C4alkyl, C1-C4alkoxy, hydroxyl, and oxo. In some embodiments, R6and R6’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-C4alkyl, halo C1-C4alkyl, C1-C4alkoxy, hydroxyl, and oxo. In some embodiments, R6and R6’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, R6and R6’are taken together with their intervening atoms to form a 5- 8 membered monocyclic saturated ring having 1 ring nitrogen atom. In some embodiments, R6and R6’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, R6and R6’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, R6and R6’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, R6and R6’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, R6and R6’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, R6and R6’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, R6and R6’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.

[0309] In some embodiments, R7is hydroxy. In some embodiments, R7is C1-C4alkoxy. In some embodiments, R7is amino. In some embodiments, R7is mono-C1-C4alkylamino. In some embodiments, R7is di-C1-C4alkylamino.

[0310] In some embodiments, each R8is independently hydroxyl, C1-C4alkoxy, amino or a 5-7 membered saturated heterocyclyl having 1, 2, or 3 ring heteroatoms independently selected from nitrogen, oxygen and sulfur; or R8is mono- and di-C1-C4alkylamino which is optionally substituted with one or more substituents independently selected from halogen, hydroxy and C1-C4alkyl.

[0311] In some embodiments, R8−OH. In some embodiments, R8is C1-4alkoxy. In some embodiments, R8is methoxy. In some embodiments, R8is ethoxy. In some embodiments, R8is amino. In someembodiments, R8is 5-, 6- or 7-membered saturated heterocyclyl having 1, 2, or 3 ring heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, R8is 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, R8is mono-C1-C4 alkylamino. In some embodiments, R8is 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, R8is di-C1-C4 alkylamino.

[0312] In some embodiments, R8is 5-7 membered saturated heterocyclyl having 1, 2, or 3 ring heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, R8is mono- and di-C1-C4 alkylamino which is optionally substituted with one or more substituents independently selected from halogen, hydroxy and C1-C4 alkyl.

[0313] In some embodiments, R9is 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, R9is 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.

[0314] In some embodiments, R10is optionally substituted 3-6 membered heterocyclyl. In some embodiments, R10is optionally substituted 3-membered heterocyclyl. In some embodiments, R10is optionally substituted 4-membered heterocyclyl. In some embodiments, R10is optionally substituted 5-membered heterocyclyl. In some embodiments, R10is optionally substituted 6-membered heterocyclyl. In some embodiments, R10is optionally substituted 5-membered heteroaryl. In some embodiments, R10is optionally substituted 6-membered heteroaryl. In some embodiments, R10is substituted. In some embodiments, R10is unsubstituted. In some embodiments, R10has one and only one ring heteroatom. In some embodiments, a ring heteroatom is nitrogen. In some embodiments, a ring heteroatom is oxygen.

[0315] In some embodiments, R10is 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, R10is 3-, 4-, 5- or 6-membered heterocyclyl optionally substituted as described herein. In some embodiments, R10is 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 ringatom of heterocyclyl is nitrogen. In some embodiments, each heteroatom ring atom of heteroaryl is nitrogen.

[0316] In some embodiments, R10is optionally substituted 5-6 membered heteroaryl having 1 -3 ring atoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, R10is 5-membered hctcroaryl having 1-3 ring nitrogen atoms substituted with C1-C4 alkyl. In some embodiments, R10is. In some embodiments, R10is optionally substituted 3-6 membered heterocyclyl. In some embodiments, R10is optionally substituted 6-membered heterocyclyl. In some embodiments, R10is. , . In some embodiments, R10is.

[0317] 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 isabout 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, Rdis -NHCDj, and a compound or composition has an isotopic purity for each D independently as described herein. In some embodiments, L1is -CD2-, and a compound or composition has an isotopic purity for each D independently as described herein.

[0318] 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, R6and R6are 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.

[0319] 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.

[0320] 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 Rbis trans relative to Ring C. In some embodiments, an occurrence of Rbis 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.

[0321] 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 Rdand Rebeing -H. In some embodiments, a reference compound is otherwise identical but has each of Rdand Rebeing -H.

[0322] For example, as demonstrated herein, compounds comprising secondary amino groups (e.g., Rdor Re) 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 Rdand Rebeing groups other than amino groups, etc.).

[0323] 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

[0324] 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.

[0325] 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.

[0326] 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.

[0327] 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.

[0328] 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 alyophilized 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.

[0329] 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.

[0330] 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.

[0331] 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.

[0332] 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 .

[0333] 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.

[0334] 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.

[0335] 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.

[0336] 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.

[0337] 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.

[0338] 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.

[0339] 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 rangethat may be determined by medical practitioners based on responses of individual patients.

[0340] 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.

[0341] 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

[0342] 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 forreducing 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.

[0343] 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.

[0344] 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

[0345] 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

[0346] 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.

[0347] 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 opticneuropathy, post-operative inflammation, and retinal vein occlusion.Nervous System Disorders

[0348] 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

[0349] 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

[0350] 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

[0351] 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

[0352] 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.

[0353] 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.

[0354] 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 aregenetically non-identical members of the same species).Ischemia / Reperfusion Injury

[0355] 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.

[0356] 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.

[0357] 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.

[0358] 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

[0359] 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.

[0360] 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.

[0361] 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.

[0362] 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.

[0363] 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.

[0364] 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

[0365] 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.

[0366] In some embodiments, the present disclosure provides technologies for manufacturing compounds and compositions described herein, comprising incorporating Rd, Rc, and / or Ring C as described herein. In some embodiments, a provided technology comprises incorporation of Rdas described herein. In some embodiments, a provided technology comprises incorporation of Reas described herein. In some embodiments, a provided technology comprises incorporation of Ring C as described herein.

[0367] 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.

[0368] 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.

[0369] 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.

[0370] 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.

[0371] 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 accordancewith the present disclosure.

[0372] 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.

[0373] 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 Rais independently selected from halogen, — CN, Ral, -ORal, and -NRalRa2, wherein each of Raland Ra2is independently R’ ; a is 0, 1, 2, 3, 4 or 5;L1is 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 Rbis independently selected from halogen, -CN, -Lb-C(O)ORbl, -Lb-C(O)NRblRb2, -Lb-Rbl, -Lb-ORbl, -Lb-NRblRb2, -Lb-C(O)Rbl, -Lb-C(O)N(Rbl)S(O)2Rb2, -Lb-S(O)2N(Rbl)C(O)Rb2, -Lb-S(O)2NRblRb2, -Lb-S(O)(NRbl)Rb2, or -Lb-S(O)2Rbl, wherein each of Rbland Rb2is independently R’, and Lbis 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-Lc-BRclRc2, wherein each of Rcland Rc2is independently R' or -N(R')2, and Lcis a covalent bond or optionally substituted -CH2-; each Rdis independently selected from halogen, -CN, Rdl, -0Rdl, and -NRdlRd2, wherein each of Rdland Rd2is independently R’; d is 0, 1, or 2; each Reis independently selected from halogen, — CN, Rel, -ORel, and -NRelRe2, wherein each of Reland Re2is 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 H10. 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 Rais independently not -H.13.wherein each of R1, R2and R3is independently Ra.14. The compound of Embodiment 13, wherein R1is -OR.15. The compound of Embodiment 13, wherein R1is -OR, wherein R is optionally substituted C1-io aliphatic.16. The compound of Embodiment 13, wherein R1is -OR, wherein R is optionally substituted C1-6 alkyl.17. The compound of Embodiment 13, wherein R1is -OR, wherein R is C1-6 alkyl.18. The compound of any one of Embodiments 13-17, wherein R1is -OMe.19. The compound of any one of Embodiments 13-17, wherein R1is -OEt.20. The compound of any one of Embodiments 13-15, wherein R1is -OR, wherein R is optionally substituted -CH2-C36 cycloaliphatic.21. The compound of any one of Embodiments 13-15, wherein R1is -OR, wherein R is optionally substituted -CH2-C3-6 cycloalkyl.22. The compound of any one of Embodiments 13-15, wherein R1is -OR, wherein R is -CH2-cyclopropyl.23. The compound of Embodiment 13, wherein R1is -R.24. The compound of Embodiment 23, wherein R1is optionally substituted C1-6 aliphatic.25. The compound of Embodiment 23, wherein R1is optionally substituted C1-6 alkyl.26. The compound of Embodiment 23, wherein R1is optionally substituted C3-6 cycloalkyl.27. The compound of Embodiment 23, wherein R1is optionally substituted C3-6 cyclopropyl.28. The compound of any one of Embodiments 13-27, wherein R2is R.29. The compound of Embodiment 28, wherein R2is optionally substituted C1-6 aliphatic.30. The compound of Embodiment 28, wherein R2is optionally substituted C1-6 alkyl.31. The compound of Embodiment 28, wherein R2is methyl.32. The compound of any one of Embodiments 13-31, wherein R ’ is R.33. The compound of Embodiment 32, wherein R3is -H.34. The compound of any one of the preceding Embodiments, wherein L1is -CH2-.35. The compound of any one of Embodiments 1-33, wherein L1is substituted -CH2-.36. The compound of any one of the preceding Embodiments, wherein Lbis a covalent bond.37. The compound of any one of Embodiments 1-35, wherein Lbis 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 substituted53. The compound of any one of Embodiments 1-37, wherein Ring B is optionally substituted54. The compound of any one of Embodiments 1-37, wherein Ring B is optionally substituted55. The compound of any one of Embodiments 1-37, wherein Ring B is optionally substituted56. The compound of any one of Embodiments 1-37, wherein Ring B is optionally substituted57. The compound of any one of Embodiments 1-37, wherein Ring B is optionally substituted58. The compound of any one of Embodiments 1-37, wherein Ring B is optionally substituted59. The compound of any one of Embodiments 1-37, wherein Ring B is optionally substituted60. The compound of any one of Embodiments 1-37, wherein Ring B is optionally substituted61. 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, whereinwherein 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, whereinwherein 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, whereins , and each of m and n is independently 1 or 2.65. The compound of any one of Embodiments 1-37, whereinof m and n is independently 1 or 2.66. The compound of any one of Embodiments 1-37, wherein67. The compound of any one of Embodiments 1-37, whereinand each of m and n is independently 1 or 2.68. The compound of any one of Embodiments 1-37, wherein69. The compound of any one of Embodiments 1-68, wherein an occurrence of Rbis R.70. The compound of any one of Embodiments 1-68, wherein an occurrence of Rbis optionally substituted C1-6 aliphatic.71. The compound of any one of Embodiments 1-68, wherein an occurrence of Rbis optionally substituted C1-6 alkyl.72. The compound of any one of Embodiments 1-68, wherein an occurrence of Rbis C1-6 alkyl.73. The compound of any one of Embodiments 1-68, wherein an occurrence of Rbis C1-6 haloalkyl.74. The compound of any one of Embodiments 1-68, wherein an occurrence of Rbis -CF3.75. The compound of any one of Embodiments 1-68, wherein an occurrence of Rbis -H.76. The compound of any one of Embodiments 1-68, wherein an occurrence of Rbis optionally substituted C3-10 cycloaliphatic.77. The compound of any one of Embodiments 1-68, wherein an occurrence of Rbis optionally substituted C36 cycloalkyl.78. The compound of any one of Embodiments 1-68, wherein an occurrence of Rbis optionally substituted cyclopropyl.79. The compound of any one of Embodiments 1-68, wherein an occurrence of Rbis cyclopropyl.80. The compound of any one of Embodiments 1-68, wherein an occurrence of Rbis 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 Rbis 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 Rbis 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 Rbis>84. The compound of any one of Embodiments 1-68, wherein an occurrence of Rbis -OR.85. The compound of any one of Embodiments 1-68, wherein an occurrence of Rbis -OR, wherein R is optionally substituted CMO aliphatic.86. The compound of any one of Embodiments 1-68, wherein an occurrence of Rbis -OR, wherein R is optionally substituted CMO aliphatic.87. The compound of any one of Embodiments 1-68, wherein an occurrence of Rbis -OR, wherein R is optionally substituted C1-6 alkyl.88. The compound of any one of Embodiments 1-68, wherein an occurrence of Rbis -OR, wherein R is Cj 6 alkyl.89. The compound of any one of Embodiments 1-68, wherein an occurrence of Rbis -OMe.90. The compound of any one of Embodiments 1-68, wherein an occurrence of Rbis -OEt.91. The compound of any one of Embodiments 1-68, wherein an occurrence of Rbis -OR, wherein R is optionally substituted -CH2-C36 cycloaliphatic.92. The compound of any one of Embodiments 1-68, wherein an occurrence of Rbis -OR, wherein R is optionally substituted -CH2-C36 cycloalkyl.93. The compound of any one of Embodiments 1-68, wherein an occurrence of Rbis -OR, wherein R is -CEE-cyclopropyl.94. The compound of any one of Embodiments 1-68, wherein an occurrence of Rbis -S(O)2Rbl.95. The compound of Embodiment 94, wherein Rblis R.96. The compound of Embodiment 94, wherein Rblis R and is not -H.97. The compound of Embodiment 94, wherein Rblis optionally substituted C1-6 aliphatic.98. The compound of Embodiment 94, wherein Rblis optionally substituted C1-6 alkyl.99. The compound of Embodiment 94, wherein Rblis optionally substituted ethyl.100. The compound of any one of Embodiments 1 -68, wherein an occurrence of Rbis -halogen.101. The compound of any one of Embodiments 1-68, wherein an occurrence of Rbis -F.102. The compound of any one of Embodiments 1-68, wherein each occurrence of Rbis independently halogen.103. The compound of any one of Embodiments 1-68, wherein each occurrence of Rbis -F.104. The compound of any one of Embodiments 1-103, wherein two occurrences of Rbare attached to the same atom.105. The compound of any one of Embodiments 1-103, wherein all occurrences of Rbare attached to the same atom.106. The compound of any one of Embodiments 65-66, wherein the two Rbare 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 Rbare 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 Rbare taken together with the carbon atom to which they are attached to form optionally substituted123. The compound of any one of Embodiments 65-66, wherein the two Rbare taken together with thecarbon atom to which they are attached to form124. The compound of any one of Embodiments 65-66, wherein the two Rbare 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 Rbare 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 Rbis R.127. The compound of any one of Embodiments 67-68, wherein Rbis optionally substituted Cue aliphatic.128. The compound of any one of Embodiments 67-68, wherein Rbis optionally substituted C1-6 alkyl.129. The compound of any one of Embodiments 67-68, wherein Rbis C1-6 alkyl.130. The compound of any one of Embodiments 67-68, wherein Rbis C1-6 haloalkyl.131. The compound of any one of Embodiments 67-68, wherein Rbis -CF3.132. The compound of any one of Embodiments 67-68, wherein Rbis -H.133. The compound of any one of Embodiments 67-68, wherein Rbis optionally substituted C3-10 cycloaliphatic.134. The compound of any one of Embodiments 67-68, wherein Rbis optionally substituted C3-6 cycloalkyl.135. The compound of any one of Embodiments 67-68, wherein Rbis optionally substituted cyclopropyl.136. The compound of any one of Embodiments 67-68, wherein Rbis cyclopropyl.137. The compound of any one of Embodiments 67-68, wherein Rbis 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 Rbis 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 Rbis 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 Rbis141. The compound of any one of Embodiments 67-68, wherein Rbis -OR.142. The compound of any one of Embodiments 67-68, wherein Rbis -OR, wherein R is optionally substituted C1-10 aliphatic.143. The compound of any one of Embodiments 67-68, wherein Rbis -OR, wherein R is optionally substituted C1- 10 aliphatic.144. The compound of any one of Embodiments 67-68, wherein Rbis -OR, wherein R is optionally substituted C1-6 alkyl.145. The compound of any one of Embodiments 67-68, wherein Rbis -OR, wherein R is C1-6 alkyl.146. The compound of any one of Embodiments 67-68, wherein Rbis -OMe.147. The compound of any one of Embodiments 67-68, wherein Rbis -OEt.148. The compound of any one of Embodiments 67-68, wherein Rbis -OR, wherein R is optionally substituted -CH2-C36 cycloaliphatic.149. The compound of any one of Embodiments 67-68, wherein Rbis -OR, wherein R is optionally substituted -CH2-C3 6 cycloalkyl.150. The compound of any one of Embodiments 67-68, wherein Rbis -OR, wherein R is -CH2-cyclopropyl.151. The compound of any one of Embodiments 67-68, wherein Rbis -S(O)2Rbl.152. The compound of Embodiment 151, wherein Rblis R.153. The compound of Embodiment 151, wherein Rblis R and is not -H.154. The compound of Embodiment 151, wherein Rblis optionally substituted C1-6 aliphatic.155. The compound of Embodiment 151, wherein Rblis optionally substituted Ci 6 alkyl.156. The compound of Embodiment 151, wherein Rblis optionally substituted ethyl.157. The compound of any one of Embodiments 67-68, wherein Rbis -halogen.158. The compound of any one of Embodiments 67-68, wherein Rbis -F.159. The compound of any one of the preceding Embodiments, wherein an occurrence of Rbis 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 3181. 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 substituted183. The compound of any one of Embodiments 1 -159, wherein Ring C is optionally substituted184. The compound of any one of Embodiments 1-159, wherein Ring C is optionally substituted185. The compound of any one of Embodiments 1-159, wherein Ring C is optionally substituted186. The compound of any one of Embodiments 1-159, wherein Ring C is optionally substituted187. The compound of any one of Embodiments 1-159, wherein Ring C is optionally substituted188. The compound of any one of Embodiments 1-159, wherein Ring C is optionally substituted189. 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, wherein192. The compound of any one of Embodiments 1-159. wherein193. The compound of any one of Embodiments 1-159. wherein194. The compound of any one of Embodiments 1-159, wherein195. The compound of any one of Embodiments -159, wherein196. The compound of any one of Embodiments -159, wherein197. The compound of any one of Embodiments -159, wherein198. The compound of any one of Embodiments199. The compound of any one of Embodiments 1-198, wherein Rcis -LC-C(O)OH or a bioisostere thereof, -Lc-C(O)ORcl, -Lc-C(O)NRclRc2, -Lc-C(O)N(Rcl)S(O)2Rc2, -Lc-S(O)2N(Rcl)C(O)Rc2,-Lc-S(O)2NRclRc2, -LC-S(O)(NRC1)RC2, -LC-S(O)2RCI, -CN, -Lc-P(O)(ORcl)(ORc2), -Lc-OP(O)(ORcl)(ORc2), or -Lc-BRclRc2.200. The compound of any one of Embodiments 1-198, wherein Rcis -LC-C(O)OH or a bioisostere thereof, -Lc-C(O)ORcl, -Lc-C(O)NRclRc2, -Lc-C(O)N(Rcl)S(O)2Rc2, -Lc-S(O)2N(Rcl)C(O)Rc2, -Lc-S(O)2NRclRc2, -LC-S(O)(NRC1)RC2, -LC-S(O)2RC1, -CN, -LC-P(O)(ORC1)(ORC2), or -Lc-OP(O)(ORcl)(ORc2).201. The compound of any one of Embodiments 1-198, wherein Rcis -LC-C(O)OH or a bioisosterethereof, -Lc-C(O)ORcl, -Lc-C(O)NRclRc2, -Lc-C(O)N(Rcl)S(O)2Rc2, -Lc-S(O)2N(Rcl)C(O)Rc2, -LC-S(O)2NRC1RC2, -LC-S(O)(NRC1)RC2, -LC-S(O)2RC1, -LC-P(O)(ORC1)(ORC2), or -Lc-OP(O)(ORcl)(ORc2).202. The compound of any one of Embodiments 1-198, wherein Rcis -LC-C(O)OH or a bioisostere thereof.203. The compound of any one of Embodiments 1-202, wherein Lcis a covalent bond.204. The compound of any one of Embodiments 1-202, wherein Lcis optionally substituted -CH2-205. The compound of any one of Embodiments 1-198, wherein Rcis -C(O)OH or a bioisostere thereof.206. The compound of any one of Embodiments 1-198, wherein Rcis -C(O)OH.207. The compound of any one of Embodiments 1-198, wherein Rcis -Lc-C(O)ORcl.208. The compound of any one of Embodiments 1-198, wherein Rcis -CH2-C(O)ORcl.209. The compound of any one of Embodiments 1-198, wherein Rcis -C(O)ORcl.210. The compound of any one of Embodiments 207-209, wherein Rclis R.211. The compound of any one of Embodiments 207-209, wherein Rclis optionally substituted C1-6 aliphatic.212. The compound of any one of Embodiments 1-198, wherein Rcis 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 Rcis optionally substituted tetrazolyl.214. The compound of any one of Embodiments 1-198, wherein Rcis tetrazolyl.215. The compound of any one of the preceding Embodiments, wherein Rdis -NRdlRd2.216. The compound of any one of the preceding Embodiments, wherein Rdlis R.217. The compound of any one of the preceding Embodiments, wherein Rdlis -H.218. The compound of any one of Embodiments 1-216, wherein Rdlis optionally substituted C1-6 aliphatic.219. The compound of any one of Embodiments 1-216, wherein Rdlis optionally substituted C1-6 alkyl.220. The compound of any one of Embodiments 1-216, wherein Rdlis optionally substituted C1-4 aliphatic.221. The compound of any one of Embodiments 1-216, wherein Rdlis optionally substituted C1-4 alkyl.222. The compound of any one of Embodiments 1-216, wherein Rdlis optionally substituted Cm aliphatic.223. The compound of any one of Embodiments 1-216, wherein Rdlis optionally substituted Cm alkyl.224. The compound of any one of Embodiments 1-216, wherein Rdlis optionally substituted Cm aliphatic.225. The compound of any one of Embodiments 1-216, wherein Rdlis optionally substituted Cm alkyl.226. The compound of any one of Embodiments 1-216, wherein Rdlis optionally substituted methyl.227. The compound of any one of Embodiments 218-226, wherein Rdlis unsubstituted.228. The compound of any one of Embodiments 218-226, wherein Rdlis substituted.229. The compound of any one of Embodiments 218-226, wherein Rdlis substituted wherein each substituent is independently halogen.230. The compound of any one of Embodiments 218-226, wherein Rdlis substituted wherein each substituent is -F.231. The compound of any one of Embodiments 1-216, wherein Rdlis C1-6 alkyl.232. The compound of any one of Embodiments 1 -216, wherein Rdlis methyl.233. The compound of any one of Embodiments 1-216, wherein Rdlis ethyl.234. The compound of any one of Embodiments 1-233, wherein Rdis -NHRdl.235. The compound of any one of the preceding Embodiments, wherein Rd2is R.236. The compound of any one of the preceding Embodiments, wherein Rd2is -H.237. The compound of any one of Embodiments 1-233, wherein Rd2is optionally substituted C1-6 aliphatic.238. The compound of any one of Embodiments 1-233, wherein Rd2is optionally substituted Ci 6 alkyl.239. The compound of any one of Embodiments 1-233, wherein Rd2is C1-6 alkyl.240. The compound of any one of Embodiments 1-233, wherein Rd2is CM alkyl.241. The compound of any one of Embodiments 1-233, wherein Rd2is methyl.242. The compound of any one of Embodiments 1-233, wherein Rd2is ethyl.243. The compound of any one of Embodiments 1-214, wherein Rdis -NH2.244. The compound of any one of Embodiments 1-214, wherein Rdis -NHMe.245. The compound of any one of Embodiments 1-214, wherein Rdis -NHEt.246. The compound of any one of Embodiments 1-214, wherein Rdis -NRdlRd2, and Rdland Rd2are 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 Rdis optionally substituted.258. The compound of any one of Embodiments 1-214, wherein Rdis.259. The compound of any one of Embodiments 1-214, wherein Rdis -H.260. The compound of any one of Embodiments 1 -190 and 198-259, wherein Reis -NRelRe2.261. The compound of any one of the preceding Embodiments, wherein Relis R.262. The compound of any one of the preceding Embodiments, wherein Relis -H.263. The compound of any one of Embodiments 1-190 and 198-261, wherein Relis optionally substitutedCi -6 aliphatic.264. The compound of any one of Embodiments 1-190 and 198-261, wherein Relis optionally substituted Cj 6 alkyl.265. The compound of any one of Embodiments 1-190 and 198-261, wherein Relis optionally substituted Ci 4 aliphatic.266. The compound of any one of Embodiments 1-190 and 198-261, wherein Relis optionally substituted CM alkyl.267. The compound of any one of Embodiments 1-190 and 198-261, wherein Relis optionally substituted Ci 3 aliphatic.268. The compound of any one of Embodiments 1-190 and 198-261, wherein Relis optionally substituted CM alkyl.269. The compound of any one of Embodiments 1-190 and 198-261, wherein Relis optionally substituted Ci -2 aliphatic.270. The compound of any one of Embodiments 1-190 and 198-261, wherein Relis optionally substituted C1-2 alkyl.271. The compound of any one of Embodiments 1-190 and 198-261, wherein Relis optionally substituted methyl.272. The compound of any one of Embodiments 263-271 , wherein Relis unsubstituted.273. The compound of any one of Embodiments 263-271, wherein Relis substituted.274. The compound of any one of Embodiments 263-271, wherein Relis substituted wherein each substituent is independently halogen.275. The compound of any one of Embodiments 263-271, wherein Relis substituted wherein each substituent is -F.276....

Claims

CLAIMS1 . 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 Rais independently selected from halogen, — CN, Ral, -ORal, and -NRalRa2, wherein each of Raland Ra2is independently R’ ; a is 0, 1, 2, 3, 4 or 5;L1is 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 Rbis independently selected from halogen, -CN, -Lb-C(O)ORbl, -Lb-C(O)NRblRb2, -Lb-Rbl, -Lb-ORbl, -Lb-NRblRb2, -Lb-C(O)Rbl, -Lb-C(O)N(Rbl)S(O)2Rb2, -Lb-S(O)2N(Rbl)C(O)Rb2, -Lb-S(O)2NRblRb2, -Lb-S(O)(NRbl)Rb2, or -Lb-S(O)2Rbl, wherein each of Rbland Rb2is independently R’, and Lbis a covalent bond or optionally substituted -CH2-; b is 0, 1, 2, 3, 4 or 5;Rcis -LC-C(O)OH, wherein Lcis a covalent bond or optionally substituted -CH2-; each Rdis independently -NRdlRd2, wherein each of Rdland Rd2is independently R’ ; d is 0, 1, or 2; each Reis independently selected from halogen, -CN, Rel, -ORel, and -NRelRe2, wherein each of Reland Re2is 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 Rais independently selected from halogen, -CN, Ral, -ORal, and -NRalRa2, wherein each of Raland Ra2is independently R’ ; a is 0, 1, 2, 3, 4 or 5;L1is 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 Rbis independently selected from halogen, -CN, -Lb-C(O)ORbl, -Lb-C(O)NRblRb2, -Lb-Rbl, -Lb-ORbl, -Lb-NRblRb2, -Lb-C(O)Rbl, -Lb-C(O)N(Rbl)S(O)2Rb2, -Lb-S(O)2N(Rbl)C(O)Rb2, -Lb-S(O)2NRblRb2, -Lb-S(O)(NRbl)Rb2, or — Lb-S(O)2Rbl, wherein each of Rbland Rb2is independently R’,and Lbis 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, oxygenRcis -LC-C(O)OH or a bioisostere thereof, -Lc-C(O)ORcl, -Lc-C(O)NRclRc2, -Lc-Rcl, -Lc-ORcl, -Lc-NRclRc2, -Lc-C(O)Rcl, -Lc-C(O)N(Rcl)S(O)2Rc2, -Lc-S(O)2N(Rcl)C(O)Rc2, -Lc-S(O)2NRclRc2, -Lc-S(O)(NRcl)Rc2, -LC-S(O)2RCI, halogen, -CN, -Lc-P(O)(ORcl)(ORc2), -Lc-OP(O)(ORcl)(ORc2), or -Lc-BRclRc2, wherein each of Rcland Rc2is independently R’ or -N(R’)2, and Lcis a covalent bond or optionally substituted -CH2-; each Rdis independently selected from halogen, -CN, Rdl, -ORdl, and -NRdlRd2, wherein each of Rdland Rd2is independently R’; d is 0, 1, or 2; each Reis independently selected from halogen, -CN, Rel, -ORel, and -NRelRe2, wherein each of Reland Re2is 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 , whereinwherein each of R1, R2and R3is independently Ra.

4. The compound of any one of the preceding claims, wherein L1is -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 substituted10. The compound of any one of claims 1-8, wherein Rcis -C(O)OH.

11. The compound of any one of the preceding claims, wherein Rdis -NRdlRd2.

12. The compound of any one of the preceding claims, wherein Rdlis — H.

13. The compound of any one of the preceding claims, wherein Rd2is — H.

14. The compound of any one of claims 1-12, wherein Rd2is optionally substituted C1-6 aliphatic.

15. The compound of any one of claims 1-12, wherein Rd2is methyl.

16. The compound of any one of claims 1-8, wherein Rdis -NRdlRd2, and Rdland Rd2are 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 Reis -NRelRe2or R.

18. The compound of any one of claims 1-10, wherein Rdand Reare taken together with their interveningatom(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; R1is hydrogen, halogen, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C3-C6 cycloalkyl, C1-C6 alkoxy, halo C1-C6alkyl, hydroxy C1-C6alkyl, amino C1-C6alkyl, C1-C6alkoxy C1-C6alkyl, C1-C6alkoxy C1-C6alkoxy, C3-C6cycloalkyl C1-C6alkoxy, halo C1-C6alkoxy, −S(O)pC1-C6alkyl, −CH2NHC(O)C1-C4alkyl or −OCH2C(O)R7; p is 0, 1, or 2; R2is hydrogen, C1-C6alkyl, C1-C6alkoxy, hydroxy C1-C6alkyl, or halogen; R3is hydrogen, halogen, cyano, C1-C4alkyl, halo C1-C4alkyl, −CH2C(O)R7; R4is 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 R5and further optionally substituted with one or two R5’; each R5’ is independently selected from halogen, C1-C4alkyl, C1-C4alkoxy, hydroxy C1-C4alkyl, hydroxyl, R10, −OR6’, −N(R51)2, halo C1-C6alkyl, cyano, and 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-C4alkyl, halo C1-C4alkyl, C1-C4alkoxy, hydroxyl, and oxo; each R51is independently R6’; R4’is hydrogen, C1-C4 alkyl, or hydroxy C1-C4 alkyl; R5is −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-C4alkyl, −B(R8)2or 5- membered heteroaryl having 1-4 ring nitrogen atoms and 0 or 1 ring oxygen or sulfur atom; each R6is independently hydrogen, halogen, hydroxyl, amino, mono- and di-C1-C6alkylamino, C1-C6alkyl, halo C1-C6alkyl, hydroxy C1-C6alkyl, cyano C1-C6alkyl or C1-C6alkoxy, or: two R6on a carbon atom are taken together to form =O, or two R6on 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 R6are 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 R6are taken together to form C2-C4 alkylene; t is 0, 1, 2, 3 or 4; R6’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: R6and 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-C4alkyl, halo C1-C4alkyl, C1-C4alkoxy, hydroxyl, and oxo; R7is hydroxyl, C1-C4alkoxy, amino, or mono- or di-C1-C4alkylamino; each R8is independently hydroxyl, C1-C4alkoxy, 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-C4alkylamino which is optionally substituted with one or more substituents independently selected from halogen, hydroxy and C1-C4alkyl; R9is 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-C4alkyl groups; and R10is 3-6 membered heterocyclyl or 5-6 membered heteroaryl having 1-3 ring atoms independentlyselected 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 Rdas 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., L1as described herein)-Ring 2 (e.g., an optionally substituted nitrogen-containing optionally substituted nonaromatic ring which is bonded to L12through 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 Rdis -NHCD3.

35. The compound of any one of the preceding claims, wherein L1is -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.

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