Pharmaceutical compounds for the treatment of complement-mediated disorders

Abstract

The present disclosure provides compounds, compositions, and methods for treating medical disorders such as complement-mediated disorders, including complement C1s-mediated disorders. The present disclosure provides compounds, compositions, and methods for treating disorders mediated by the complement cascade (including dysfunctional cascades), such as cellular disorders or abnormalities that adversely affect a cell's ability to participate in or respond to normal complement activity, including the classical complement pathway, or unwanted complement-mediated responses to medical treatments, such as surgery or other medical procedures or administration of pharmaceutical or biopharmaceutical drugs, blood transfusions, or administration of other allogeneic tissues or fluids.

Description

[Technical Field]

[0001] Provided herein are pharmaceutical compounds, compositions, and methods for treating medical disorders such as complement-mediated disorders, including complement C1s-mediated disorders. [Background technology]

[0002] The complement system is part of the innate immune system, which does not adapt to changes throughout a subject's lifetime but is recruited and used by the adaptive immune system. For example, it assists or complements the ability of antibodies and phagocytes to eliminate pathogens. This elaborate regulatory pathway allows for a rapid response to pathogenic organisms while protecting host cells from destruction. More than 30 proteins and protein fragments comprise the complement system. These proteins act through opsonization (enhancing phagocytosis of antigens), chemotaxis (attracting macrophages and neutrophils), cytolysis (rupturing the membranes of foreign cells), and agglutination (clustering and binding pathogens together).

[0003] The complement system has three pathways: the classical pathway, the alternative pathway, and the lectin pathway. The classical pathway is initiated by antibody-antigen complexes with antibody isotypes IgG and IgM. The antibody-antigen complex binds to C1, which initiates the cleavage of C4 and C2 to generate C3 convertase, which then splits C3 into C3a and C3b. C3a interacts with its C3a receptor to recruit leukocytes, while C3b binds to C3 convertase to form C5 convertase. C5 convertase cleaves C5 into C5a and C5b. Like C3a, C5a interacts with its C5a receptor to recruit leukocytes, but C5b interacts with C6, C7, C8, and C9. Together, these proteins form the cylindrical membrane attack complex (MAC), which causes cells to swell and rupture. These immune responses can be inhibited by blocking the ability of C1 to bind to the antibody-antigen complex.

[0004] Given the range of serious diseases mediated by dysfunction of the complement system, there is a clear medical need to provide pharmaceutically acceptable compounds, methods, compositions, and methods of manufacture for inhibiting the complement system in patients in need thereof.

[0005] Thus, the present disclosure provides compounds and their uses and compositions for treating disorders resulting from or amplified by a dysfunction of the complement system. The present disclosure also provides compounds, uses, compositions, formulations, and manufacturing processes that can inhibit C1s (complement C1 esterase) and thus treat disorders mediated by C1s. Summary of the Invention

[0006] The present disclosure provides compounds, compositions, and methods for treating disorders mediated by the complement cascade (including dysfunctional cascades), such as cellular disorders or abnormalities that adversely affect a cell's ability to participate in or respond to normal complement activity, including the classical complement pathway, or unwanted complement-mediated responses to medical treatments, such as surgery or other medical procedures or the administration of pharmaceutical or biopharmaceutical drugs, blood transfusions, or the administration of other allogeneic tissues or fluids. In some embodiments, the active compounds may act as inhibitors of the classical complement pathway by inhibiting complement C1s.

[0007] Without wishing to be bound by theory, the present disclosure is based, in part, on the unexpected discovery that compounds of the present disclosure exhibit advantageous properties over other C1s inhibitors (e.g., compounds described in WO2020 / 198062 and WO2022 / 066774), such as improved C1s inhibitory activity, improved classical pathway hemolysis inhibitory activity, improved Caco-2 permeability, improved oral bioavailability, improved C1s selectivity (e.g., over other proteases such as MASP-2), and / or improved metabolic stability. The present disclosure is also based, in part, on the unexpected discovery that compounds of the present disclosure exhibit improved selectivity for C1s over other proteases (e.g., MASP-2), compared to, for example, compounds described in WO2019 / 231935.

[0008] In one aspect, the present disclosure provides a compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof, wherein all variables are as defined herein.

[0009] In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound disclosed herein (e.g., any one of the compounds of Formulas (I), (I'), (II), (IIA), (III), (IIIA), (IV), (IVA), (V), (VA), (VB), (VC), (VI), (VIA), (VIB), (VIC), and (VII), and the compounds of Table 1), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0010] In another aspect, the disclosure provides a method of treating a complement C1 esterase (C1s)-mediated disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein (e.g., any one of the compounds of Formulas (I), (I'), (II), (IIA), (III), (IIIA), (IV), (IVA), (V), (VA), (VB), (VC), (VI), (VIA), (VIB), (VIC), and (VII), and Table 1), or a pharmaceutically acceptable salt thereof.

[0011] In another aspect, the present disclosure provides a compound disclosed herein (e.g., any one of the compounds of formulas (I), (I'), (II), (IIA), (III), (IIIA), (IV), (IVA), (V), (VA), (VB), (VC), (VI), (VIA), (VIB), (VIC), and (VII), and in Table 1), or a pharmaceutically acceptable salt thereof, for use in treating a C1s-mediated disorder.

[0012] In another aspect, the present disclosure provides the use of a compound disclosed herein (e.g., any one of formulas (I), (I'), (II), (IIA), (III), (IIIA), (IV), (IVA), (V), (VA), (VB), (VC), (VI), (VIA), (VIB), (VIC), and (VII), and the compounds of Table 1), or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for use in treating a C1s-mediated disorder.

[0013] definition Compounds are described using standard nomenclature. Unless defined otherwise, all technical and scientific terms have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0014] The terms "a" and "an" do not denote a limitation of quantity, but rather denote the presence of at least one of the referenced items. The term "or" means "and / or." The recitation of ranges of values, unless otherwise indicated herein, is merely intended to serve as a shorthand notation for referring individually to each separate value falling within the range, and each separate value is incorporated herein as if it were individually listed herein. The endpoints of all ranges are included within the range and are independently combinable. All methods described herein can be performed in any suitable order unless otherwise indicated herein or clearly contradicted by context. The use of examples or exemplary language (e.g., "such as") is intended merely as an illustrative example and does not impose a limitation on the scope of the invention.

[0015] The term "alkoxy," as used herein, refers to the -OR radical, where R is alkyl, as defined herein.

[0016] The term "alkyl," as used herein, when unsubstituted, refers to a branched or straight-chain monovalent saturated aliphatic radical containing only C and H. The monovalence of an alkyl group does not include optional substituents on the alkyl group. For example, if an alkyl group is attached to a compound, the monovalence of an alkyl group refers to its attachment to the compound and does not include any additional substituents that may be present on the alkyl group. In some embodiments, an alkyl group can contain, for example, 1 to 8, 1 to 6, 1 to 4, or 1 to 2 carbon atoms (e.g., C1-C8, C1-C6, C1-C4, or C1-C2). Examples include, but are not limited to, methyl, ethyl, isobutyl, sec-butyl, tert-butyl, 2-methylpropyl, and 2,2-dimethylpropyl.

[0017] As used herein, the term "alkylene" refers to a divalent radical obtained by removing a hydrogen atom from a carbon atom of an alkyl group. The divalent nature of an alkylene group does not include optional substituents on the alkylene group. Examples of alkylene groups include, but are not limited to, methylene, ethylene, and n-propylene.

[0018] As used herein, the term "amino" refers to a monovalent radical of formula -NH. As used herein, "optionally substituted amino" refers to an amino group in which one or both hydrogen atoms are independently replaced with a substituent, as defined herein.

[0019] The term "aryl," as used herein, refers to any monocyclic or bicyclic or polycyclic fused ring system containing only carbon atoms in the ring(s), e.g., phenyl, naphthyl, or phenanthryl, which has aromatic properties in terms of electron distribution throughout the ring system. Aryl groups can have, for example, 6 to 16, 6 to 14, or 6 to 10 carbon ring atoms (e.g., C6-C6). 16 , C6~C 14 , C6~C 10 , C6, C 10 , C 14 , or C 16 ).

[0020] As used herein, the term "arylene" refers to a divalent radical obtained by removing a hydrogen atom from a carbon atom of an aryl group. The divalent nature of an arylene group does not include optional substituents on the arylene group. Phenylene is a non-limiting example of an arylene group.

[0021] The term "aryloxy," as used herein, refers to the -OR radical, where R is aryl, as defined herein.

[0022] As used herein, the term "carbocyclyl," when unsubstituted, refers to a monovalent saturated (i.e., cycloalkyl) or unsaturated, non-aromatic group (e.g., cycloalkenyl, containing at least one carbon-carbon double bond and no carbon-carbon triple bonds) that contains only C and H and can be monocyclic, bicyclic, or polycyclic (e.g., tricyclic). A carbocyclyl can be, for example, a cycloalkenyl having 3 to 14 carbons (e.g., C3-C4, C3-C5, C3-C6, C3-C7, C3-C8, or C3-C9). 14 Examples of carbocyclyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclohexenyl, cycloheptenyl, and fluorenyl. The term "carbocyclyl" also includes cyclic groups having bridged polycyclic structures in which one or more carbons bridge two non-adjacent members of a single ring, such as bicyclo[2.2.1]heptyl.

[0023] The term "halo" as used herein refers to a fluorine (fluoro; F), chlorine (chloro; Cl), bromine (bromo; Br), or iodine (iodo; I) radical.

[0024] The term "heteroaryl," as used herein, refers to a monocyclic, bicyclic, or polycyclic group of a monocyclic, bicyclic, or polycyclic aromatic ring containing 1, 2, 3, or 4 heteroatoms selected from N, O, S, B, and P as ring atoms (e.g., 1 to 4, 1 to 3, or 1 or 2 heteroatoms selected from N, O, and S), with the remaining ring atoms being carbon. In some embodiments, a heteroaryl group is a bicyclic or tricyclic ring system containing at least one 5-, 6-, or 7-membered aromatic ring containing 1, 2, 3, or 4 heteroatoms selected from N, O, S, B, or P as ring atoms (e.g., 1 to 4, 1 to 3, or 1 or 2 heteroatoms selected from N, O, and S), with the remaining ring atoms being carbon. In some embodiments, a heteroaryl group is a monocyclic aromatic ring having 5 or 6 ring atoms (i.e., a 5- or 6-membered heteroaryl). In some embodiments, it is a bicyclic aromatic ring system having 8 to 10 ring atoms (ie, an 8- to 10-membered bicyclic heteroaryl). Examples of heteroaryl groups include, but are not limited to, pyridinyl, imidazolyl, imidazopyridinyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, furyl, thienyl, isoxazolyl, thiazolyl, oxadiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, triazolyl, thiadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, tetrahydrofuranyl, and furopyridinyl.

[0025] As used herein, the term "heteroaryloxy" refers to a monovalent radical of formula -OR, where R is heteroaryl, as defined herein.

[0026] The term "heterocyclyl," as used herein, refers to a saturated or unsaturated non-aromatic monocyclic, bicyclic, or polycyclic group containing 1, 2, 3, or 4 heteroatoms selected from N, O, S, B, and P as ring atoms (e.g., 1 to 4, 1 to 3, or 1 or 2 heteroatoms selected from N, O, and S), with the remaining ring atoms being carbon. The term "heterocyclyl" includes, for example, monocyclic 3- to 12-membered rings, bicyclic 5- to 16-membered ring systems, and polycyclic (e.g., tricyclic) 10- to 18-membered ring systems, which, if bicyclic or polycyclic, may include bridged ring systems. In some embodiments, the heterocyclyl group contains 3 to 16 ring atoms (i.e., 3- to 16-membered heterocyclyl), for example, 3 to 12 ring atoms (i.e., 3- to 12-membered heterocyclyl) or 4 to 10 ring atoms (i.e., 4- to 10-membered heterocyclyl). Examples of saturated heterocyclyl groups include saturated 4- to 7-membered monocyclic groups containing 1 to 4 nitrogen atoms (e.g., pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl, azetidinyl, piperazinyl, and pyrazolidinyl), saturated 4- to 6-membered monocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms (e.g., morpholinyl), and saturated 3- to 6-membered monocyclic groups containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms (e.g., thiazolidinyl). Examples of unsaturated non-aromatic heterocyclyl radicals include, but are not limited to, dihydrothienyl, dihydropyranyl, dihydrofuryl, and dihydrothiazolyl.Other examples of heterocyclyl radicals include pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl, pyrazolidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, thiazolidinyl, dihydrothienyl, 2,3-dihydro-benzo[1,4]dioxanyl, indolinyl, isoindolinyl, dihydrobenzothienyl, dihydrobenzofuryl, isochromanyl, chromanyl, 1,2-dihydroquinolyl, 1,2,3,4-tetrahydro-isoquinolyl, 1, Examples of heterocyclic heterocyclic rings include, but are not limited to, 2,3,4-tetrahydroquinolyl, 2,3,4,4a,9,9a-hexahydro-1H-3-aza-fluorenyl, 5,6,7-trihydro-1,2,4-triazolo[3,4-a]isoquinolyl, 3,4-dihydro-2H-benzo[1,4]oxazinyl, benzo[1,4]dioxanyl, 2,3-dihydro-1H-1λ-benzo[d]isothiazol-6-yl, dihydropyranyl, dihydrofuryl, and dihydrothiazolyl. "Bicyclic heterocyclyl" includes groups in which a saturated or unsaturated non-aromatic ring containing 1, 2, 3, or 4 heteroatoms as ring atoms is fused to an aryl group (e.g., phenyl) or a cycloalkyl group. "Bicyclic heterocyclyl" also includes groups in which a heteroaryl group, as defined herein, is fused to a saturated or unsaturated non-aromatic ring containing 0, 1, 2, 3, or 4 heteroatoms as ring atoms.

[0027] As used herein, the term "heterocyclyloxy" refers to a monovalent radical of formula -OR, where R is heterocyclyl, as defined herein.

[0028] The term "oxo" as used herein refers to the ═O radical.

[0029] As used herein, the term "substituted" means that any one or more hydrogens on the specified atom or group have been replaced with a moiety selected from the group of moieties as defined herein or indicated, provided that the normal valence of the specified atom is not exceeded and the resulting compound is stable. For example, when a substituent is oxo (i.e., ═O), two hydrogens on the atom are replaced. For example, a pyridyl group substituted with oxo is a pyridone. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds or useful synthetic intermediates. As used herein, the phrase "optionally substituted X" is intended to be equivalent to "X (where X is optionally substituted)" (e.g., "alkyl (where the alkyl is optionally substituted)"). It is not intended to imply that the feature "X" (e.g., alkyl) itself is optional. As used herein, the term "optionally substituted" refers to having zero, one, or more substituents (e.g., 0-10 substituents, 0-5 substituents, or 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 substituents).

[0030] Alkyl, alkylene, alkoxy, amino, carbocyclyl, aryl, arylene, aryloxy, heteroaryl, and heterocyclyl groups include carbocyclyl (e.g., cycloalkyl), aryl, heteroaryl, heterocyclyl, halo, OR (where R is H, alkyl, carbocyclyl (e.g., cycloalkyl), aryl, heteroaryl, or heterocyclyl), SR (where R is H, alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl), CN, NO, N, NRR ’(wherein each of R and R' is independently H, alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl), SOR (wherein R is H, alkyl, or aryl), S0NR R' (wherein each of R and R' is independently H, alkyl, or aryl), SOR (wherein R is H, alkyl, or aryl), or P(O)(OR) (wherein each R is independently H or alkyl). Amino, aryl, carbocyclyl, heteroaryl, and heterocyclyl groups may also be substituted with alkyl. Alkyl, alkylene, carbocyclyl, and heterocyclyl groups may also be substituted with oxo or =NR (wherein R is H or alkyl). Alkyl and alkylene groups may also be substituted with spirocyclic carbocycles (e.g., spirocyclic cycloalkyls) or spirocyclic heterocyclyls. In some embodiments, substituents are further substituted with one or more substituents described herein. For example, a C1 alkyl group, ie, methyl, may be substituted with oxo to form a formyl group, and may be further substituted with -OH or -NR2 to form a carboxyl or amide group.

[0031] As used herein, the term "complement-mediated disorder" refers to a disorder in which the amount or activity of complement is such that it causes the disorder in an individual.

[0032] As used herein, a compound having "complement C1 esterase (C1s) inhibitory activity" is one that has an IC of less than 100 nM as determined using a human complement C1s enzyme assay such as that described in Example 3 herein. 50 This refers to a compound that exhibits the following.

[0033] As used herein, the term "pharmaceutical composition" refers to one or more active compounds formulated together with one or more pharmaceutically acceptable excipients. In some embodiments, the compounds of the present disclosure are present in a unit dose amount suitable for administration in a treatment regimen that exhibits a statistically significant probability of achieving a predetermined therapeutic effect when administered to a relevant population, for example. In certain embodiments, pharmaceutical compositions may be specially formulated for administration in solid or liquid form, including those adapted for: oral administration, e.g., drenches (aqueous or non-aqueous solutions or suspensions), tablets, or capsules; and parenteral administration, e.g., by subcutaneous, intramuscular, or intravenous injection.

[0034] As used herein, the term "pharmaceutically acceptable salt" refers to a salt of a described compound that is suitable, within the scope of sound medical judgment, for use in contact with the tissues of humans and animals without undue toxicity, irritation, allergic response, etc., and that is commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in Berge et al., J. Pharmaceutical Sciences 66:1-19, 1977, and Handbook of Pharmaceutical Salts: Properties, Selection, and Use, (Eds. P.H. Stahl and C.G. Wermuth), Wiley-VCH, 2008. These salts may be acid addition salts, including inorganic or organic acids. Salts can be prepared in situ during the final isolation and purification of the compounds described herein, or separately by reacting the free base with a suitable acid.

[0035] As used herein, the term "pharmaceutically acceptable excipient" refers to any inactive ingredient (e.g., a vehicle capable of suspending or dissolving an active compound) that is biocompatible and suitable for administration to a subject. Typical excipients include, for example, anti-adherents, antioxidants, binders, coating agents, compression aids, disintegrants, dyes, softeners, emulsifiers, diluents, film-forming or coating agents, flavorings, fragrances, glidants, lubricants, preservatives, printing inks, adsorbents, suspending or dispersing agents, sweeteners, or hydration water. Those skilled in the art are familiar with a variety of agents and materials useful as excipients.

[0036] As used herein, the term "subject" may be a human, a non-human primate, or other non-human mammal such as, but not limited to, a dog, cat, horse, cow, pig, goat, monkey, rat, mouse, and sheep. In a preferred embodiment, the subject is a human.

[0037] As used herein, and as is well understood in the art, "treating" a condition or "treatment" of various diseases and disorders is an approach for obtaining beneficial or desired results, such as clinical results. Beneficial or desired results can include, but are not limited to, alleviation of one or more symptoms or conditions, whether detectable or undetectable; attenuation of the extent of the disease, disorder, or condition; stabilization of the state of the disease, disorder, or condition (i.e., it is not worsening); delaying or slowing the progression of the disease, disorder, or condition; improvement or palliation of the disease, disorder, or condition; and remission (whether partial or complete). "Alleviating" a disease, disorder, or condition means that the extent and / or undesirable clinical signs of the disease, disorder, or condition are reduced and / or the time course of progression is slowed or prolonged compared to the extent or time course in the absence of treatment.

[0038] A "therapeutically effective amount" or "effective amount" of an active compound of the pharmaceutical composition of the present disclosure refers to an amount that, when administered to a subject, is effective to provide a therapeutic benefit, such as amelioration of symptoms or a reduction or diminishment of the disease itself. In one embodiment, a therapeutically effective amount is an amount sufficient to prevent or significantly reduce a significant increase in detectable hemolysis levels in the patient's blood, serum, or tissues. DETAILED DESCRIPTION OF THE INVENTION

[0039] active compound The present disclosure provides compounds and salts useful for treating disorders mediated by the complement cascade (e.g., disorders mediated by C1s). In some embodiments, the compounds of the present disclosure have the formula (I'): [ka] or a pharmaceutically acceptable salt thereof, wherein: R 1 and R 1’ each independently is H or optionally substituted C1-C6 alkyl; X is CR 3 or N, X ’ But, CR 4 or N, R 2 is H, C1-C6 alkyl, optionally substituted C6-C 14 aryl, optionally substituted C3-C8 carbocyclyl, optionally substituted 5- to 10-membered heteroaryl, optionally substituted 4- to 10-membered heterocyclyl, optionally substituted (4- to 10-membered heterocyclyl)oxy, or optionally substituted (5- to 9-membered heteroaryl)oxy; R 3 and R 4 each is independently H, halo, or optionally substituted C1-C6 alkyl; L 1 is a bond, NH, NHC(O), NHC(O)O, NHC(O)NH, or NHS(O)2; L2 is a bond or an optionally substituted C1-C6 alkylene; L 3 is a bond, NH, NHC(O), C(O), O, S(O)2CH2, and B is halo, optionally substituted C6-C 14 Aryl, optionally substituted C-C 14 carbocyclyl, optionally substituted 5- to 14-membered heterocyclyl, or optionally substituted 5- to 10-membered heteroaryl; Y is, [ka] and During the ceremony, Y 1 But O, S, NR d where each R d is independently absent, H, or C1-C6 alkyl; Y 1’ But O, S, NR d , or C(R d )2, Y 2 and Y 3 Each of these independently represents NR e or C(R e )2, where each R e is independently absent, H, optionally substituted C1-C6 alkyl, halo, or N(R g )2, where each R g are independently H or C1-C6 alkyl, or both R e combine to form oxo, Y 4 , Y 4’ , Y 10 , and Y 13 Each of these independently e or N, Y 5 , Y 6 , and Y 7 each independently represents O, S, NR f or C(R f )2, where each R fis independently absent, H, optionally substituted C1-C6 alkyl, halo, or N(R g )2 or both R f combine to form oxo, Y 8 and Y 9 Each of these independently represents C(R f )2 or NR f and Y 11 and Y 12 Each of these independently represents NR e , C(R e )2, S, or O; each [ka] are independently a single bond or a double bond; Each of R, R', R", and R'" is independently absent, H, optionally substituted C1-C6 alkyl, halo, or N(R g )2 or Both R combine to form oxo, or Both R' combine to form oxo, q is 0 or 1.

[0040] In some embodiments, compounds of the present disclosure have formula (I): [ka] or a pharmaceutically acceptable salt thereof, wherein all variables are as defined for formula (I'), except: (i)-L 1 -L 2 -L 3 - is combined, [ka] There is no formation of (ii)R 2 is C1-C6 alkyl, [ka] isn't it, (iii) B is [ka] isn't it, (iv)R 1 and R 1’ At least one of these is not H, (v) X is N; (vi)X ’ But, CR 4 is, and (vii) Y is [ka] isn't it, At least one of the following must be true:

[0041] In some embodiments, R 1 is H. In some embodiments, R 1 is an optionally substituted C1-C6 alkyl. In some embodiments, R 1 is methyl. In some embodiments, R 1 is CH2OH.

[0042] In some embodiments, R 1’ is H. In some embodiments, R 1’ is an optionally substituted C1-C6 alkyl. In some embodiments, R 1 is methyl. In some embodiments, R 1 is CH2OH.

[0043] In some embodiments, X is CR 3 In some embodiments, X is CH. In some embodiments, X is CCH. In some embodiments, X is N.

[0044] In some embodiments, X’ is CR 4 In some embodiments, X' is CH. In some embodiments, X' is CCH3. In some embodiments, X' is N.

[0045] In some embodiments, R 2 is an optionally substituted C6-C 14 aryl, optionally substituted 5- to 10-membered heteroaryl, optionally substituted 4- to 10-membered heterocyclyl, or optionally substituted (4- to 10-membered heterocyclyl)oxy, or optionally substituted (5- to 9-membered heteroaryl)oxy.

[0046] In some embodiments, R 2 is optionally substituted phenyl, e.g., phenyl optionally substituted with one or more substituents independently selected from halo, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted (4- to 10-membered heterocyclyl)oxy, P(O)(OH)CH3, P(O)(OR"')2 (wherein each R"' is independently H or C1-C6 alkyl), S(O)2CH3, optionally substituted 4- to 10-membered heterocyclyl, SF5, S(O)(NCN)CH3, S(O)(NH)CH3, and optionally substituted amino. In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] is.

[0047] In some embodiments, R 2 is an optionally substituted (4- to 10-membered heterocyclyl)oxy. 2 teeth, [ka] is.

[0048] In some embodiments, R 2 is an optionally substituted 4- to 10-membered heterocyclyl. 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] is.

[0049] In some embodiments, R 2 is an optionally substituted 5- to 10-membered heteroaryl. In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] is.

[0050] In some embodiments, R 2 is an optionally substituted C3-C8 carbocyclyl. 2 is an optionally substituted C-C cycloalkyl. In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 is an optionally substituted C-C cycloalkenyl. In some embodiments, R 2 teeth, [ka] is.

[0051] In some embodiments, R 2 is H. In some embodiments, R 2is C1-C6 alkyl. In some embodiments, R 2 is CH3. In some embodiments, R 2 is CH(CH3)2.

[0052] In some embodiments, L 1 is a bond. In some embodiments, L 1 is NH. In some embodiments, L 1 is NHS(O). In some embodiments, L 1 is NHC(O). In some embodiments, L 1 is NHC(O)O. In some embodiments, L 1 is NHC(O)NH.

[0053] In some embodiments, L 2 is a bond. In some embodiments, L 2 is an optionally substituted C1-C6 alkylene. In some embodiments, L 2 is C1-C6 alkylene. 2 is -CH-. In some embodiments, L 2 is —(CH)—. In some embodiments, L 2 is —(CH)—. In some embodiments, L 2 is —(CH)—. In some embodiments, L 2 is —(CH)—. In some embodiments, L 2 teeth, [ka] In some embodiments, L 2 teeth, [ka] In some embodiments, L 2 teeth, [ka] In some embodiments, L 2teeth, [ka] In some embodiments, L 2 teeth, [ka] is.

[0054] In some embodiments, L 3 is a bond. In some embodiments, L 3 is NH. In some embodiments, L 3 is NHC(O). In some embodiments, L 3 is C(O). In some embodiments, L 3 is O. In some embodiments, L 3 is SO2CH2.

[0055] In some embodiments, B is halo, eg, Br.

[0056] In some embodiments, B is an optionally substituted C-C 14 It is aryl or an optionally substituted 5- to 10-membered heteroaryl.

[0057] In some embodiments, the compound has the formula (II): [ka] or a pharmaceutically acceptable salt thereof, wherein X 1 But, CR 9 or N and R 5 , R 6 , and R 9 are each independently selected from H, halo, CN, SF, optionally substituted C-C alkyl, optionally substituted C-C alkoxy, S(O)(NH)CH, S(O)CH, and S(O)(NCN)CH; 7 and R 8each independently is H, halo, CN, SF5, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted amino, S(O)(NH)CH3, S(O)2CH3, S(O)(NCN)CH3, optionally substituted C3-C8 cycloalkyl, optionally substituted C6-C 14 Aryloxy, optionally substituted C6-C 14 aryl, optionally substituted 5- to 10-membered heteroaryl, optionally substituted (5- to 10-membered heteroaryl)oxy, or optionally substituted (4- to 10-membered heterocyclyl)oxy, with the proviso that R 7 and R 8 More than one of C6 to C 14 Aryloxy, optionally substituted C6-C 14 aryl, optionally substituted 5- to 10-membered heteroaryl, optionally substituted (5- to 10-membered heteroaryl)oxy, or optionally substituted (4- to 10-membered heterocyclyl)oxy; or R 7 and R 8 together with the atom to which each is attached, optionally substituted 5- to 6-membered heterocyclyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted C-C 14 Form an aryl or R 5 and A combine to form an optionally substituted C1-C2 alkylene, and R 6 and R 9 are combined to form (C2-C6 alkylene)(C6-C 14 wherein each of R5, R7, and R8 is H, and all other variables are as defined in relation to formula (I).

[0058] In some embodiments, the compound has formula (IIA): [ka] or a pharmaceutically acceptable salt thereof, wherein all variables are as defined in relation to formula (II).

[0059] In some embodiments, X 1 is CR 9 In some embodiments, X 1 is CH.

[0060] In some embodiments, R 8 is H.

[0061] In some embodiments, R 7 is an optionally substituted C6-C 14 In some embodiments, R 7 is optionally substituted phenyl. In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 teeth, [ka] is.

[0062] In some embodiments, R 7 is an optionally substituted 5- to 10-membered heteroaryl. In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 teeth, [ka] is.

[0063] In some embodiments, R 7 is an optionally substituted (5- to 10-membered heteroaryl)oxy. 7 teeth, [ka] In some embodiments, R 7 teeth, [ka] is.

[0064] In some embodiments, R 7 is an optionally substituted (4- to 10-membered heterocyclyl)oxy. 7 teeth, [ka] In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 teeth, [ka] is.

[0065] In some embodiments, R 7 is an optionally substituted C-C cycloalkyl. In some embodiments, R 7 teeth, [ka] is.

[0066] In some embodiments, R 7 is an optionally substituted 4- to 10-membered heterocyclyl. 7 teeth, [ka] In some embodiments, R 7 teeth, [ka] is.

[0067] In some embodiments, R 8 is an optionally substituted C6-C 14 aryl, for example, optionally substituted phenyl. In some embodiments, R 8 teeth, [ka] In some embodiments, R 8 teeth, [ka] is.

[0068] In some embodiments, R 8 is an optionally substituted 5- to 10-membered heteroaryl. In some embodiments, R 8 teeth, [ka] In some embodiments, R 8 teeth, [ka] In some embodiments, R 8 teeth, [ka] is.

[0069] In some embodiments, R 7 is H.

[0070] In some embodiments, R 5 is H. In some embodiments, R 5 is an optionally substituted C1-C6 alkoxy. In some embodiments, R 5 is OCH. In some embodiments, R 5 is halo. In some embodiments, R 5 is F.

[0071] In some embodiments, R 6 is H. In some embodiments, R 6 is an optionally substituted C1-C6 alkoxy. In some embodiments, R 6 is OCH. In some embodiments, R 6 is halo. In some embodiments, R 6 is F.

[0072] In some embodiments, R 6 and R 9 are combined to form (C2-C6 alkylene)(C6-C 14 arylene)(C2-C6 alkylene), and each of R5, R7, and R8 is H. In some embodiments, B is [ka] is.

[0073] In some embodiments, B is [ka] In some embodiments, B is [ka] In some embodiments, B is [ka] In some embodiments, B is [ka] In some embodiments, B is [ka] In some embodiments, B is [ka] In some embodiments, B is [ka] In some embodiments, B is [ka] In some embodiments, B is [ka] In some embodiments, B is [ka] In some embodiments, B is [ka] In some embodiments, B is [ka] In some embodiments, B is [ka] In some embodiments, B is [ka] is.

[0074] In some embodiments, the compound has the formula (III): [ka] wherein X 2 However, O,C(R h )2 (where each R h are independently hydrogen, halo, or optionally substituted C1-C6 alkyl, or both R h combine to form oxo), S(O)2, or NR h wherein m is selected from 0, 1, 2, 3, 4, and 5, n is selected from 0, 1, 2, 3, and 4, and each R 10 and R 11 is independently halo, CN, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, or optionally substituted C3-C8 cycloalkyl, and all other variables are as defined for formula (I).

[0075] In some embodiments, the compound has formula (IIIA): [ka] or a pharmaceutically acceptable salt thereof, wherein all variables are as defined in relation to formula (III).

[0076] In some embodiments, the compound has formula (IV): [ka] wherein X 2 However, O,C(R h )2 (where each R h are independently hydrogen, halo, or optionally substituted C1-C6 alkyl, or both R h combine to form oxo), S(O)2, or NR h wherein m is selected from 0, 1, 2, 3, 4, and 5, n is selected from 0, 1, 2, 3, and 4, and each R 10 and R 11 is independently halo, CN, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, or optionally substituted C3-C8 cycloalkyl, and all other variables are as defined for formula (I).

[0077] In some embodiments, the compound has the formula (IVA): [ka] or a pharmaceutically acceptable salt thereof.

[0078] In some embodiments, X 2 is O. In some embodiments, X 2 is C(R a )2. In some embodiments, X 2 is C(O). In some embodiments, X 2 is CF2. In some embodiments, X 2 is S(O)2.

[0079] In some embodiments, B is [ka] In some embodiments, B is [ka] In some embodiments, B is [ka] In some embodiments, B is [ka] In some embodiments, B is [ka] In some embodiments, B is [ka] In some embodiments, B is [ka] In some embodiments, B is [ka] In some embodiments, B is [ka] In some embodiments, B is [ka] In some embodiments, B is [ka] is.

[0080] In some embodiments, B is an optionally substituted 5-10 membered heteroaryl. [ka] In some embodiments, B is [ka] In some embodiments, B is [ka] In some embodiments, B is [ka] In some embodiments, B is [ka] In some embodiments, B is [ka] In some embodiments, B is [ka] In some embodiments, B is [ka] In some embodiments, B is [ka] In some embodiments, B is [ka] In some embodiments, B is [ka] In some embodiments, B is [ka] In some embodiments, B is [ka] In some embodiments, B is [ka] In some embodiments, B is [ka] In some embodiments, B is [ka] In some embodiments, B is [ka] In some embodiments, B is [ka] In some embodiments, B is [ka] In some embodiments, B is [ka] In some embodiments, B is [ka] In some embodiments, B is [ka] In some embodiments, B is [ka] In some embodiments, B is [ka] In some embodiments, B is [ka] In some embodiments, B is [ka] In some embodiments, B is [ka] In some embodiments, B is [ka] In some embodiments, B is [ka] In some embodiments, B is [ka] In some embodiments, B is [ka] In some embodiments, B is [ka] In some embodiments, B is [ka] is.

[0081] In some embodiments, B is an optionally substituted C-C 14 It is a carbocyclyl or an optionally substituted 5- to 14-membered heterocyclyl.

[0082] In some embodiments, the compound has the formula (V): [ka] or a pharmaceutically acceptable salt thereof, wherein X 3 and X 4 each independently represents a bond, O, S, C(R i )2 (where each R iare independently H, OH, halo, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 alkoxy, or both R i combine to form oxo), NR j (where R j is H or C1-C6 alkyl), or SO2, and X 5 But CH, CR 13 , or N and X 6 But CH, CR 12 or N, o is selected from 0, 1, 2, and 3, p is selected from 0, 1, and 2, and each R 12 and R 13 is independently halo, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, or optionally substituted C3-C8 cycloalkyl, and all other variables are as defined for formula (I).

[0083] In some embodiments, the compound has the formula (VA): [ka] or a pharmaceutically acceptable salt thereof, wherein all variables are as defined in relation to formula (V).

[0084] In some embodiments, the compound has the formula (VB): [ka] or a pharmaceutically acceptable salt thereof, wherein all variables are as defined in relation to formula (V).

[0085] In some embodiments, the compound has the formula (VC): [ka] or a pharmaceutically acceptable salt thereof, wherein all variables are as defined in relation to formula (V).

[0086] In some embodiments, the compound has formula (VI): [ka] or a pharmaceutically acceptable salt thereof, wherein X 3 and X 4 each independently represents a bond, O, S, C(R i )2 (where each R i are independently H, OH, halo, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 alkoxy, or both R i combine to form oxo), NR j (where R j is H or C1-C6 alkyl), or SO2, and X 5 But CH, CR 13 , or N and X 6 But CH, CR 12 or N, o is selected from 0, 1, 2, and 3, p is selected from 0, 1, and 2, and each R 12 and R 13 is independently halo, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, or optionally substituted C3-C8 cycloalkyl, and all other variables are as defined for formula (I).

[0087] In some embodiments, the compound has formula (VIA): [ka] or a pharmaceutically acceptable salt thereof, wherein all variables are as defined in relation to formula (V).

[0088] In some embodiments, the compound has formula (VIB): [ka] or a pharmaceutically acceptable salt thereof, wherein all variables are as defined in relation to formula (VI).

[0089] In some embodiments, the compound has the formula (VIC): [ka] or a pharmaceutically acceptable salt thereof, wherein all variables are as defined in relation to formula (VI).

[0090] In some embodiments, X 3 is a bond. In some embodiments, X 3 is O. In some embodiments, X 3 is C(R i )2. In some embodiments, X 3 is CF2. In some embodiments, X 3 is S.

[0091] In some embodiments, X 4 is a bond. In some embodiments, X 4 is O. In some embodiments, X 4 is C(R i )2. In some embodiments, X 3 is CF2. In some embodiments, X 4 is S.

[0092] In some embodiments, B is [ka] In some embodiments, B is [ka] In some embodiments, B is [ka] In some embodiments, B is [ka] In some embodiments, B is [ka] In some embodiments, B is [ka] In some embodiments, B is [ka] In some embodiments, B is [ka] is.

[0093] In some embodiments, B is an optionally substituted C-C 14 In some embodiments, B is optionally substituted C3-C8 cycloalkyl. In some embodiments, B is [ka] In some embodiments, B is [ka] In some embodiments, B is [ka] In some embodiments, B is [ka] is.

[0094] In some embodiments, B is an optionally substituted 5- to 14-membered heterocyclyl. [ka] In some embodiments, B is [ka] In some embodiments, B is [ka] In some embodiments, B is [ka] In some embodiments, B is [ka] In some embodiments, B is [ka] In some embodiments, B is [ka] In some embodiments, B is [ka] In some embodiments, B is [ka] is.

[0095] In some embodiments, Y is [ka] In some embodiments, Y 2 is N. In some embodiments, Y 2 is CR e In some embodiments, Y 2 is CH. In some embodiments, Y 3 is N. In some embodiments, Y 3 is CRe In some embodiments, Y 3 is CH. In some embodiments, Y 1 is NR d In some embodiments, Y 1 is NH. In some embodiments, Y 1 is S.

[0096] In some embodiments, the compound has formula (VII): [ka] or a pharmaceutically acceptable salt thereof.

[0097] In some embodiments, Y is [ka] In some embodiments, Y 1 is S. In some embodiments, Y 2 is NR e In some embodiments, Y 2 is NH. In some embodiments, Y 2 is C(R e )2. In some embodiments, Y 2 is CH. In some embodiments, Y 3 is NR e In some embodiments, Y 3 is NH. In some embodiments, Y 3 is C(R e )2. In some embodiments, Y 3 is CH2.

[0098] In some embodiments, R is H. In some embodiments, R' is H.

[0099] In some embodiments, Y is [ka] In some embodiments, Y is [ka] In some embodiments, Y is [ka] In some embodiments, Y is [ka] In some embodiments, Y is [ka] In some embodiments, Y is [ka] is.

[0100] In another aspect, the disclosure provides a compound of Table 1, or a pharmaceutically acceptable salt thereof.

[0101] In some embodiments of any of the aspects provided herein, the compounds of the disclosure have complement C1 esterase (C1s) inhibitory activity.

[0102] In some embodiments, the compound of the present disclosure is a compound of formula (II), (IIA), (III), (IIIA), (IV), (IVA), (V), (VA), (VB), (VC), (VI), (VIA), (VIB), (VIC), or (VII).

[0103] In some embodiments, the compound of the disclosure is a compound of Table 1.

[0104] Pharmaceutical Composition The pharmaceutical compositions of the present disclosure contain, as a therapeutic compound, one or more of the compounds disclosed herein (e.g., one or more of the compounds of formulas (I), (I'), (II), (IIA), (III), (IIIA), (IV), (IVA), (V), (VA), (VB), (VC), (VI), (VIA), (VIB), (VIC), and (VII), and in Table 1). In addition to a therapeutically effective amount of the compound, the pharmaceutical composition also contains a pharmaceutically acceptable excipient, which can be formulated by methods known to those skilled in the art. In some embodiments, pharmaceutical compositions for treating cancer contain one or more of the compounds disclosed herein (e.g., one or more of the compounds of Formulae (I), (I'), (II), (IIA), (III), (IIIA), (IV), (IVA), (V), (VA), (VB), (VC), (VI), (VIA), (VIB), (VIC), and (VII), and in Table 1), and may be formulated and / or administered with or without other therapeutic agents for particular conditions. Examples of such therapeutic agents (second therapeutic agents) are described herein.

[0105] The compounds disclosed herein (e.g., compounds of formulas (I), (I'), (II), (IIA), (III), (IIIA), (IV), (IVA), (V), (VA), (VB), (VC), (VI), (VIA), (VIB), (VIC), and (VII), and in Table 1) may be used in their free base form or in their salt form. All forms are within the scope of the present disclosure.

[0106] Exemplary routes of administration of pharmaceutical compositions (or compounds of the compositions) include oral, sublingual, buccal, transdermal, intradermal, intramuscular, parenteral, intravenous, intraarterial, intracranial, subcutaneous, intraorbital, intraventricular, intraspinal, intraperitoneal, intranasal, inhalation, and topical administration. In some embodiments, a compound of the present disclosure (e.g., a compound of Formula (I), (I'), (II), (IIA), (III), (IIIA), (IV), (IVA), (V), (VA), (VB), (VC), (VI), (VIA), (VIB), (VIC), or (VII), or Table 1) is formulated for oral administration.

[0107] Oral dosage forms Pharmaceutical compositions of the present disclosure include those formulated for oral administration ("oral dosage forms"). Oral dosage forms may be, for example, in the form of tablets, capsules, solutions or suspensions, powders, or liquid crystals or solid crystals, containing the active ingredient(s) in a mixture with non-toxic pharmaceutically acceptable excipients. These excipients may be, for example, inert diluents or fillers; granulating and disintegrating agents; binders; and lubricants, glidants, and antiadherents (e.g., magnesium stearate, zinc stearate, stearic acid, silica, hydrogenated vegetable oil, or talc). Other pharmaceutically acceptable excipients may be colorants, flavoring agents, plasticizers, humectants, buffers, etc.

[0108] Pharmaceutical compositions for oral administration may also be presented as chewable tablets, hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, or soft gelatin capsules in which the active ingredient is mixed with water or an oil medium. Powders, granules, and pellets may be prepared using the ingredients described above for tablets and capsules by conventional techniques using, for example, mixers, fluidized bed equipment, or spray drying equipment.

[0109] Liquid forms into which the compounds and compositions of the present disclosure can be incorporated for oral administration include aqueous solutions, suitably flavored syrups, aqueous or oily suspensions, and emulsions flavored with edible oils, as well as elixirs and similar pharmaceutical vehicles.

[0110] Formulations for parenteral administration The pharmaceutical compositions of the present disclosure may be administered in pharmaceutically acceptable parenteral (e.g., intravenous, intramuscular, subcutaneous, etc.) formulations described herein. Pharmaceutical compositions may also be administered parenterally in dosage forms or formulations containing conventional non-toxic pharmaceutically acceptable carriers and adjuvants. In particular, formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions, which may contain antioxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions, which may contain suspending agents and thickening agents. For example, to prepare such compositions, the compounds of the present disclosure may be dissolved or suspended in a parenterally acceptable liquid vehicle. Among acceptable vehicles and solvents that may be used are water; water adjusted to a suitable pH by the addition of an appropriate amount of hydrochloric acid, sodium hydroxide, or a suitable buffer; 1,3-butanediol; Ringer's solution; and isotonic sodium chloride solution. Aqueous formulations may also contain one or more preservatives. Additional information regarding parenteral formulations can be found, for example, in the United States Pharmacopeia-National Formulary (USP-NF), which is incorporated herein by reference in its entirety.

[0111] Parenteral formulations can be any of the five general types of preparations identified by the USP-NF as suitable for parenteral administration: (1) "Drug injection": A liquid preparation containing a drug substance (e.g., a compound of the present disclosure) or a solution thereof; (2) "Injectable drug": A drug substance (e.g., a compound of the present disclosure) as a dry solid to be combined with an appropriate sterile vehicle for parenteral administration as a drug injection; (3) "Emulsion drug injection": a liquid preparation of a drug substance (e.g., a compound of the present disclosure) dissolved or dispersed in a suitable emulsion vehicle; (4) "Suspension drug injection": a liquid preparation of a drug substance (e.g., a compound of the present disclosure) suspended in a suitable liquid medium; and (5) "Drug for suspension injection": A drug substance (e.g., a compound of the present disclosure) as a dry solid to be combined with an appropriate sterile vehicle for parenteral administration as a drug for suspension injection.

[0112] Exemplary formulations for parenteral administration include solutions of compounds prepared in water, suitably mixed with surfactants, such as hydroxypropylcellulose.Dispersions can also be prepared in glycerol, liquid polyethylene glycol, DMSO, and their mixtures, with or without alcohol, and in oil.Under normal storage and use conditions, these preparations may contain preservatives to prevent the growth of microorganisms.Conventional procedures and ingredients for the selection and preparation of suitable formulations can be found, for example, in Remington: The Science and Practice of Pharmacy, 23 rd Ed., Adejare, Ed., Academic Press (2020), and in the United States Pharmacopeia and National Formulary published in 2021 (USP-NF 2021, Issues 1-3).

[0113] Formulations for parenteral administration may contain, for example, sterile water, saline, polyalkylene glycols (e.g., polyethylene glycol), vegetable oils, or hydrogenated naphthalene. Biocompatible, biodegradable lactide polymers, lactide / glycolide copolymers, or polyoxyethylene-polyoxypropylene copolymers may be used to control the release of the compound. Other potentially useful parenteral delivery systems for compounds include ethylene-vinyl acetate copolymer particles, osmotic pumps, implantable infusion systems, and liposomes. Formulations for inhalation may contain, for example, lactose, or may be aqueous solutions containing, for example, polyoxyethylene-9-lauryl ether, glycocholic acid, and deoxycholic acid, or may be oily solutions for administration in the form of nasal drops or as a gel.

[0114] The dosage of a compound described herein (e.g., compounds of Formulas (I), (I'), (II), (IIA), (III), (IIIA), (IV), (IVA), (V), (VA), (VB), (VC), (VI), (VIA), (VIB), (VIC), and (VII), and compounds in Table 1), and / or compositions comprising a compound described herein, can vary depending on many factors, including the pharmacodynamic properties of the compound; the mode of administration; the recipient's age, health, and weight; the nature and extent of symptoms; the frequency of treatment and, if applicable, the type of concomitant treatment; and the clearance rate of the compound in the treated subject. One of ordinary skill in the art can determine the appropriate dosage based on the above factors. In general, satisfactory results may be obtained when the compounds described herein are administered to humans at a daily dosage of, for example, 0.05 mg to 3,000 mg (measured as solid form). For example, the dosage range may be 10 to 1,000 mg (e.g., 50 to 800 mg).

[0115] Alternatively, the dosage can be calculated using the patient's body weight. For example, the dose of the compound or pharmaceutical composition thereof administered to the patient may be 0.1 to 100 mg / kg. Dosage forms containing a compound disclosed herein (e.g., a compound of Formula (I), (I'), (II), (IIA), (III), (IIIA), (IV), (IVA), (V), (VA), (VB), (VC), (VI), (VIA), (VIB), (VIC), or (VII), or a compound in Table 1) can be administered, for example, once daily (QD), twice daily (BID), three times daily (TID), four times daily (QID), once every two days (Q2D), once every three days (Q3D), or any dosing schedule as needed.

[0116] Use of Active Compounds for the Treatment of Selected Disorders In one aspect, an effective amount of an active compound described herein (e.g., any one of the compounds of Formulae (I), (I'), (II), (IIA), (III), (IIIA), (IV), (IVA), (V), (VA), (VB), (VC), (VI), (VIA), (VIB), (VIC), and (VII), and Table 1, or a pharmaceutically acceptable salt thereof) is used to treat a medical disorder that is an inflammatory or immune condition, a disorder mediated by the complement cascade (including a dysfunctional cascade), including a complement-associated disorder or an alternative complement pathway-associated disorder, a cellular disorder or abnormality that adversely affects a cell's ability to participate in or respond to normal complement activity, or an unwanted complement-mediated response to a medical procedure, such as surgery or other medical procedure or administration of a pharmaceutical or biopharmaceutical, a blood transfusion, or administration of other allogeneic tissue or fluid.

[0117] In some embodiments, the disorder is an autoimmune disease. In some embodiments, the disorder is cancer. In some embodiments, the disorder is an infectious disease. In some embodiments, the disorder is an inflammatory disease. In some embodiments, the disorder is a blood disease. In some embodiments, the disorder is ischemia-reperfusion injury. In some embodiments, the disorder is an ocular disease. In some embodiments, the disorder is a kidney disease. In some embodiments, the disorder is transplant rejection. In some embodiments, the disorder is antibody-mediated transplant rejection, e.g., acute antibody-mediated rejection. In some embodiments, the disorder is a vascular disease. In some embodiments, the disorder is a vasculitic disorder. In some embodiments, the disorder is a neurodegenerative disorder, e.g., a tauopathy.

[0118] In some embodiments, the disorder is a central nervous system (CNS) or peripheral nervous system medical disorder involving complement activation. In some embodiments, the disorder is an acquired brain injury or spinal cord injury. In some embodiments, the disorder is ischemia-reperfusion injury. In some embodiments, the disorder is stroke. In some embodiments, the disorder is traumatic brain injury (TBI). In some embodiments, the disorder is spinal cord injury (SCI).

[0119] In some embodiments, the disorder is a neuroinflammatory disorder.

[0120] In some embodiments, the neuroinflammatory disorder is cranial arteritis. In some embodiments, the neuroinflammatory disorder is giant cell arteritis. In some embodiments, the neuroinflammatory disorder is Holmes-Adie syndrome. In some embodiments, the neuroinflammatory disorder is inclusion body myositis (IBM). In some embodiments, the neuroinflammatory disorder is meningitis. In some embodiments, the neuroinflammatory disorder is a paraneoplastic neurological syndrome, e.g., Lambert-Eaton myasthenic syndrome, stiff-person syndrome, encephalomyelitis (inflammation of the brain and spinal cord), myasthenia gravis, cerebellar degeneration, limbic and / or brainstem encephalitis, neuromyotonia, opsoclonus (with eye movements), or sensory neuropathy. In some embodiments, the neuroinflammatory disorder is polymyositis. In some embodiments, the neuroinflammatory disorder is transverse myelitis. In some embodiments, the neuroinflammatory disorder is a vasculitis, e.g., temporal arteritis. In some embodiments, the neuroinflammatory disorder is arachnoiditis. In some embodiments, the neuroinflammatory disorder is Kinsbone syndrome. In some embodiments, the neuroinflammatory disorder is opsoclonus-myoclonus syndrome (OMS). In some embodiments, the neuroinflammatory disorder is chorea or Sydenham's chorea (SD).

[0121] In some embodiments, the disorder is Alzheimer's disease (AD). AD is characterized by two prominent pathologies: amyloid-β (Aβ) plaques and neurofibrillary tangles containing hyperphosphorylated tau. Recent studies, including genome-wide association studies identifying single nucleotide polymorphisms (SNPs) in the genes encoding the complement proteins clusterin (CLU) and CR1 (CR1), associated with risk of late-onset AD, have implicated complement in the pathogenesis of AD. See Carpanini et al., Therapeutic Inhibition of the Complement System in Diseases of the Central Nervous System, Front. Immunol., 04 March 2019. Biomarker studies have also identified complement proteins and activation products in plasma and / or CSF that distinguish AD from controls and predict risk of progression to AD.

[0122] In some embodiments, the disorder is frontotemporal dementia. In some embodiments, the disorder is Pick's disease. In some embodiments, the disorder is sporadic frontotemporal dementia, e.g., frontotemporal dementia with parkinsonism linked to chromosome 17. In some embodiments, progressive supranuclear palsy (PSP). In some embodiments, corticobasal degeneration (CBD). In some embodiments, the disorder is subacute sclerosing panencephalitis.

[0123] In some embodiments, the disorder is amyotrophic lateral sclerosis (ALS). ALS is caused by the progressive loss of upper and lower (alpha) motor neurons, leading to denervation of neuromuscular junctions in the peripheral nervous system, progressive muscle weakness, atrophy, spasticity, respiratory failure, and ultimately paralysis and death. Recent studies have shown increased C1q protein in the motor cortex and spinal cord of postmortem ALS tissue, C3 activation fragments and TCC in pathological areas, C4d and TCC staining of degenerated neurons and glia in the motor cortex and spinal cord of ALS, and upregulation of C5aR1 in pathological areas. In ALS donors, even early in the disease process, C3d and C4d have been found on oligodendroglia and degenerated neurites surrounded by CR4-positive microglia in the spinal cord and motor cortex, and C1q, C3, and TCC have been shown to be present on the motor endplates of intercostal muscles. See Carpanini et al., Therapeutic Inhibition of the Complement System in Diseases of the Central Nervous System, Front. Immunol., 04 March 2019.

[0124] In some embodiments, the disorder is Parkinson's disease (PD). PD is characterized by the loss of dopaminergic neurons in the substantia nigra and the deposition of the protein α-synuclein, which forms Lewy bodies, a pathological hallmark of the disease. Patients exhibit resting tremor, bradykinesia, and rigidity. Complement activation has been associated with α-synuclein and Lewy bodies in Parkinson's disease, and in vitro studies have demonstrated that the disease-associated splice variant α-synuclein 112, rather than the full-length protein, triggers complement activation. In vivo, localization of C3d, C4d, C7, and C9 in Lewy bodies has been reported. More recently, deposition of iC3b and C9 in Lewy bodies and melanized neurons has been reported, and iC3b immunoreactivity has been shown to increase with normal aging, which was further elevated in PD compared to age-matched controls. Furthermore, a correlation has been shown between the ratio of C3 / Aβ42 or FH / Aβ42 in the CSF and the severity of motor and cognitive symptoms of Parkinson's disease. See Carpanini et al., Therapeutic Inhibition of the Complement System in Diseases of the Central Nervous System, Front. Immunol., 04 March 2019. In some embodiments, the subject to be treated has Parkinson's disease with dementia (PDD).

[0125] In some embodiments, the disorder is Huntington's disease (HD). HD is an autosomal dominant, inherited neurodegenerative disorder characterized by progressive motor symptoms, psychiatric impairment, and dementia. It is caused by the expansion of a three-base pair (CAG) repeat (39-121 repeats compared to the normal range of 8-39 repeats) in exon 1 of the HTT gene, which is translated into a polyglutamine tract at the N-terminus of the protein. This leads to length-dependent misfolding of the polyglutamine and accumulation of huntingtin protein in the striatum and cortex (layers 3, 5, and 6), followed by neuronal loss in these regions, which spreads to the hippocampus. Neurons, astrocytes, and myelin sheaths in the caudate nucleus and striatum in HD have been shown to be immunoreactive for C1q, C4, C3, and neoepitopes in iC3b and TCC. Expression of mRNAs encoding the early complement components C1q (c chain), C1r, C3, and C4, the complement regulators C1INH, clusterin, MCP, DAF, and CD59, and the complement receptors C3a and C5a have been shown to be upregulated in the striatum in HD. See Carpanini et al., Therapeutic Inhibition of the Complement System in Diseases of the Central Nervous System, Front. Immunol., 04 March 2019.

[0126] In some embodiments, the disorder is argyrophilic grain dementia. In some embodiments, the disorder is British amyloid angiopathy. In some embodiments, the disorder is cerebral amyloid angiopathy. In some embodiments, the disorder is Creutzfeldt-Jakob disease. In some embodiments, the disorder is dementia pugilistica. In some embodiments, the disorder is diffuse neurofibrillary tangle disease with calcifications. In some embodiments, the disorder is Down syndrome. In some embodiments, the disorder is frontotemporal lobar degeneration. In some embodiments, the disorder is Gerstmann-Straussler-Scheinker disease. In some embodiments, the disorder is Hallervorden-Spatz disease. In some embodiments, the disorder is inclusion body myositis. In some embodiments, the disorder is multiple system atrophy (MSA). In some embodiments, the disorder is myotonic dystrophy. In some embodiments, the disorder is Niemann-Pick disease type C. In some embodiments, the disorder is non-Guam motor neuron disease with neurofibrillary tangles. In some embodiments, the disorder is postencephalitic parkinsonism. In some embodiments, the disorder is prion protein cerebral amyloid angiopathy. In some embodiments, the disorder is progressive subcortical gliosis. In some embodiments, the disorder is progressive supranuclear palsy. In some embodiments, the disorder is subacute sclerosing panencephalitis. In some embodiments, the disorder is neurofibrillary tangle dementia (tangle only dementia). In some embodiments, the disorder is multi-infarct dementia. In some embodiments, the disorder is ischemic stroke. In some embodiments, the disorder is chronic traumatic encephalopathy (CTE).

[0127] In some embodiments, the disorder is hereditary motor and sensory neuropathy (HMSN). In some embodiments, the HMSN is Charcot-Marie-Tooth (CMT) disease. In some embodiments, the HSMN is Charcot-Marie-Tooth disease type 1A or type 1B. In some embodiments, the HSMN is Charcot-Marie-Tooth disease type 2. In some embodiments, the HSMN is Dejerine-Sottas disease (Charcot-Marie-Tooth type 3). In some embodiments, the HSMN is Refsum disease. In some embodiments, the HSMN is Charcot-Marie-Tooth with pyramidal features. In some embodiments, the HSMN is Charcot-Marie-Tooth type 6. In some embodiments, the HSMN is HMSN + retinitis pigmentosa.

[0128] In some embodiments, the disorder is Churg-Strauss syndrome. In some embodiments, the disorder is peripheral arterial disease (PAD). In some embodiments, the disorder is myasthenia gravis, e.g., myasthenia gravis with CNS involvement. In some embodiments, the disorder is dementia with Lewy bodies. In some embodiments, the disorder is a prion disease. In some embodiments, the disorder is Behcet's disease. In some embodiments, the disorder is congenital myasthenia gravis. In some embodiments, the disorder is subacute sclerosing panencephalitis (SSPE).

[0129] In some embodiments, the disorder is a demyelinating disease. In some embodiments, the disorder is a demyelinating myelinoclastic disease. In some embodiments, the disorder is a demyelinating leukodystrophic disease.

[0130] In some embodiments, the demyelinating disease is multiple sclerosis (MS). Multiple sclerosis (MS) is the most common cause of neurological disability in young adults in Northern European Caucasian populations, with an estimated lifetime risk of 1 in 400. C3 has been shown to be deposited in the brains of MS patients. T-cell clones (TCCs) have been shown to associate with capillary endothelial cells, primarily within plaques and adjacent white matter. Localization of activated C3 to areas of active myelin destruction has also been shown, with TCC deposition confined to such areas. C3d has been shown to be deposited in association with short segments of destroyed myelin in plaques with mild active demyelination, providing evidence that C contributes to disease progression as well as acute inflammation. See Ingram et al., Complement in multiple sclerosis: its role in disease and potential as a biomarker. Clin Exp Immunol. 2009 Feb;155(2):128-39.

[0131] In some embodiments, the demyelinating disease is neuromyelitis optica (NMO). NMO is an inflammatory demyelinating disease that primarily affects the optic nerve and spinal cord. It was traditionally considered a variant of MS, but has recently been redefined according to new criteria using a combination of phenotypic subtyping with a newly developed disease biomarker, NMO-immunoglobulin G (IgG), which has a reported sensitivity of 58-76% and specificity of 85-99% for NMO. NMO patients have higher levels of C3a and anti-C1q antibodies than healthy controls. C3a levels correlate with disease activity, neuropathy, and aquaporin-4 IgG. Nytrova et al. J Neuroimmunol. 2014 Sep 15;274(1-2):185-91.

[0132] In some embodiments, the demyelinating myelinating disease is neuromyelitis optica spectrum disorder (NMOSD). In some embodiments, the demyelinating myelinating disease is idiopathic inflammatory demyelinating disease (IIDD). In some embodiments, the demyelinating myelinating disease is anti-NMDA receptor encephalitis. In some embodiments, the demyelinating myelinating disease is acute disseminated encephalomyelitis. In some embodiments, the demyelinating myelinating disease is anti-MOG autoimmune encephalomyelitis. In some embodiments, the demyelinating myelinating disease is chronic relapsing inflammatory optic neuropathy (CRION). In some embodiments, the demyelinating myelinating disease is acute disseminated encephalomyelitis (ADEM). In some embodiments, the demyelinating myelinating disease is immune-mediated encephalomyelitis. In some embodiments, the demyelinating myelinating disease is progressive multifocal leukoencephalopathy (PML). In some embodiments, the demyelinating myelinating disease is McDonalds-positive multiple sclerosis. In some embodiments, the demyelinating myelinating disease is acute hemorrhagic leukoencephalitis. In some embodiments, the demyelinating myelinating disease is Rasmussen's encephalitis. In some embodiments, the demyelinating myelinating disease is Marburg multiple sclerosis. In some embodiments, the demyelinating myelinating disease is pseudotumor-like or mass-like multiple sclerosis. In some embodiments, the demyelinating myelinating disease is Barrow concentric sclerosis. In some embodiments, the demyelinating myelinating disease is diffuse myelinating sclerosis. In some embodiments, the demyelinating myelinating disease is isolated sclerosis. In some embodiments, the demyelinating myelinating disease is cavitary multiple sclerosis. In some embodiments, the demyelinating myelinating disease is myelocortical multiple sclerosis (MCMS). In some embodiments, the demyelinating myelinating disease is atypical optic-spinal multiple sclerosis. In some embodiments, the demyelinating myelinating disease is pure spinal multiple sclerosis. In some embodiments, the demyelinating myelinating disease is HLA DRB3 *02:02 Multiple sclerosis. In some embodiments, the demyelinating myelinating disease is autoimmune GFAP astrocytopathy. In some embodiments, the demyelinating myelinating disease is chronic inflammatory demyelinating polyneuropathy (CIDP). In some embodiments, the demyelinating myelinating disease is Guillain-Barré syndrome (acute or chronic). In some embodiments, the demyelinating myelinating disease is progressive inflammatory neuropathy. In some embodiments, the demyelinating myelinating disease is Lewis-Sumner syndrome. In some embodiments, the demyelinating myelinating disease is combined central-peripheral demyelination (CCPD). In some embodiments, the demyelinating myelinating disease is Bickerstaff brainstem encephalitis. In some embodiments, the demyelinating myelinating disease is Fisher syndrome. In some embodiments, the demyelinating myelinating disease is trigeminal neuralgia. In some embodiments, the demyelinating myelinating disease is NMDAR anti-NMDA receptor encephalitis. In some embodiments, the demyelinating myelinating disease is primary progressive MS (PPMS). In some embodiments, the demyelinating myelinating disease is OPA1 variant multiple sclerosis. In some embodiments, the demyelinating myelinating disease is KIR4.1 multiple sclerosis. In some embodiments, the demyelinating myelinating disease is aquaporin-associated multiple sclerosis. In some embodiments, the demyelinating myelinating disease is chronic cerebrospinal venous insufficiency (CCSVI or CCVI). In some embodiments, the demyelinating myelinating disease is diffuse sclerosis. In some embodiments, the demyelinating myelinating disease is Schilder's disease.

[0133] In certain aspects, the disorder being treated is a demyelinating leukodystrophic disease. In some embodiments, the demyelinating leukodystrophic disease is myelitis. In some embodiments, the demyelinating leukodystrophic disease is central pontine myelinolysis (CPM). In some embodiments, the demyelinating leukodystrophic disease is extrapontine myelinolysis. In some embodiments, the demyelinating leukodystrophic disease is tabes dorsalis. In some embodiments, the demyelinating leukodystrophic disease is progressive multifocal leukoencephalopathy. In some embodiments, the demyelinating leukodystrophic disease is leukoencephalopathy with white matter loss. In some embodiments, the demyelinating leukodystrophic disease is leukoencephalopathy with axonal spheroids. In some embodiments, the demyelinating leukodystrophic disease is reversible posterior leukoencephalopathy syndrome. In some embodiments, the demyelinating leukodystrophic disease is macrocephalic leukoencephalopathy with subcortical cysts. In some embodiments, the demyelinating leukodystrophic disease is macrocephalic leukoencephalopathy with subcortical cysts 1. In some embodiments, the demyelinating leukodystrophic disease is hypertensive leukoencephalopathy. In some embodiments, the demyelinating leukodystrophic disease is metachromatic leukodystrophy. In some embodiments, the demyelinating leukodystrophic disease is Krabbe disease. In some embodiments, the demyelinating leukodystrophic disease is Canavan disease. In some embodiments, the demyelinating leukodystrophic disease is X-linked adrenoleukodystrophy. In some embodiments, the demyelinating leukodystrophic disease is Alexander disease. In some embodiments, the demyelinating leukodystrophic disease is cerebrotendinous xanthomatosis. In some embodiments, the demyelinating leukodystrophic disease is Pelicheus-Merzbacher disease. In some embodiments, the demyelinating leukodystrophic disease is Refsum disease.

[0134] In some embodiments, an effective amount of an active compound described herein, or a pharmaceutically acceptable salt thereof, is used to treat Buerger's disease, also known as thromboangiitis obliterans.

[0135] In some embodiments, an effective amount of an active compound described herein, or a pharmaceutically acceptable salt thereof, is used to treat giant cell arteritis.

[0136] In some embodiments, an effective amount of an active compound described herein, or a pharmaceutically acceptable salt thereof, is used to treat Raynaud's disease.

[0137] In certain aspects, the disorder to be treated is a demyelinating disease of the peripheral nervous system. In some embodiments, the demyelinating disease of the peripheral nervous system is anti-MAG peripheral neuropathy. In some embodiments, the demyelinating disease of the peripheral nervous system is hereditary neuropathy with liability to pressure palsies. In some embodiments, the demyelinating disease of the peripheral nervous system is a copper deficiency-related condition (e.g., peripheral neuropathy, myelopathy, or rarely optic neuropathy).

[0138] In some embodiments, an effective amount of an active compound described herein, or a pharmaceutically acceptable salt thereof, is used to treat transverse myelitis.

[0139] In certain aspects, the disorder to be treated is a peripheral neuropathy. In some embodiments, the peripheral neuropathy is a mononeuropathy. In some embodiments, the neuropathy is a polyneuropathy. In some embodiments, the polyneuropathy is distal axonopathy, diabetic neuropathy, demyelinating polyneuropathy, small fiber peripheral neuropathy, mononeuritis multiplex, polyneuritis multiplex, autonomic neuropathy, or neuritis.

[0140] In some embodiments, an effective amount of an active compound described herein, or a pharmaceutically acceptable salt thereof, is used to treat multifocal motor neuropathy.

[0141] In some embodiments, an effective amount of an active compound described herein, or a pharmaceutically acceptable salt thereof, is used to treat an autoimmune vascular disease. In some embodiments, the autoimmune vascular disease is vasculitis. In some embodiments, vasculitis includes, but is not limited to, autoimmune inflammatory vasculitis, cutaneous small-vessel vasculitis, granulomatosis with polyangiitis, eosinophilic granulomatosis with polyangiitis, Behçet's disease, Kawasaki disease, Buerger's disease, and "limited" granulomatosis with polyangiitis.

[0142] In some embodiments, an active compound described herein (e.g., a compound of Formula (I), (I'), (II), (IIA), (III), (IIIA), (IV), (IVA), (V), (VA), (VB), (VC), (VI), (VIA), (VIB), (VIC), or (VII), or a compound in Table 1), or a salt or composition thereof, is used to treat arteritis. In some embodiments, the arteritis is giant cell arteritis. In some embodiments, the arteritis is Takayasu's arteritis. In some embodiments, the arteritis is temporal arteritis. In some embodiments, the arteritis is polyarteritis nodosa.

[0143] In some embodiments, a method for treating glomerulonephritis is provided. In some embodiments, the glomerulonephritis is membranoproliferative glomerulonephritis (MPGN). In some embodiments, the MPGN is MPGN type I. In some embodiments, the MPGN is MPGN type II. In some embodiments, the MPGN is MPGN type III. In some embodiments, the MPGN is C3 glomerulonephritis (C3G). In some embodiments, the MPGN is dense deposit disease (DDD). In some embodiments, the MPGN is a C4 deposition disorder.

[0144] In some embodiments, the glomerulonephritis is IC-MPGN. In some embodiments, the glomerulonephritis is membranous glomerulonephritis. In some embodiments, the glomerulonephritis is IgA nephropathy. In some embodiments, the glomerulonephritis is post-infectious glomerulonephritis. In some embodiments, the glomerulonephritis is rapidly progressive glomerulonephritis, for example, type I (Goodpasture's syndrome), type II, or type III rapidly progressive glomerulonephritis.

[0145] In some embodiments, a method is provided for treating paroxysmal nocturnal hemoglobinuria (PNH), the method comprising administering to a subject an effective amount of a compound disclosed herein (e.g., any one of the compounds of Formulas (I), (I'), (II), (IIA), (III), (IIIA), (IV), (IVA), (V), (VA), (VB), (VC), (VI), (VIA), (VIB), (VIC), and (VII), and Table 1), or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable composition.

[0146] In some embodiments, a method for treating hereditary angioedema (HAE) is provided, comprising administering to a subject an effective amount of a compound disclosed herein (e.g., any one of Formulas (I), (I'), (II), (IIA), (III), (IIIA), (IV), (IVA), (V), (VA), (VB), (VC), (VI), (VIA), (VIB), (VIC), and (VII), and the compounds in Table 1), or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable composition. Mutations in the SERPING1 gene cause hereditary angioedema types I and II. Hereditary angioedema is a disorder characterized by repeated episodes of severe swelling (angioedema). The most common areas of the body that develop swelling are the limbs, face, intestinal tract, and airways. The SERPING1 gene provides instructions for making the C1 inhibitor protein, which is important in controlling inflammation. C1 inhibitor blocks the activity of certain proteins that promote inflammation. Mutations that cause hereditary angioedema type I lead to reduced levels of C1 inhibitor in the blood, while mutations that cause type II lead to the production of abnormally functioning C1 inhibitor. Without adequate levels of functional C1 inhibitor, excessive amounts of a protein fragment (peptide) called bradykinin are produced. Bradykinin promotes inflammation by increasing fluid leakage through blood vessel walls into body tissues. Excessive accumulation of fluid in body tissues causes the swelling episodes seen in individuals with hereditary angioedema types I and II.

[0147] In some embodiments, methods are provided for the treatment of cold agglutinin disease (CAD), the methods comprising administering to a subject an effective amount of a compound disclosed herein (e.g., any one of Formulas (I), (I'), (II), (IIA), (III), (IIIA), (IV), (IVA), (V), (VA), (VB), (VC), (VI), (VIA), (VIB), (VIC), and (VII), and the compounds of Table 1), or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable composition. CAD is a rare autoimmune hemolytic condition with potentially severe acute and chronic consequences driven by C1 activation of the classical complement pathway.

[0148] In some embodiments, methods are provided for treating atypical hemolytic uremic syndrome (aHUS), comprising administering to a subject an effective amount of a compound disclosed herein (e.g., any one of Formulas (I), (I'), (II), (IIA), (III), (IIIA), (IV), (IVA), (V), (VA), (VB), (VC), (VI), (VIA), (VIB), (VIC), and (VII), and the compounds of Table 1), or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable composition. Atypical hemolytic uremic syndrome is a disease that primarily affects kidney function. Atypical hemolytic uremic syndrome, which can occur at any age, causes the formation of abnormal blood clots (thrombi) in the small blood vessels of the kidneys. These blood clots can cause serious medical problems if they restrict or block blood flow. Atypical hemolytic uremic syndrome is characterized by three major features associated with abnormal coagulation: hemolytic anemia, thrombocytopenia, and renal failure.

[0149] In another embodiment, a method is provided for treating wet or dry age-related macular degeneration (AMD) in a subject, the method comprising administering to the subject an effective amount of a compound disclosed herein (e.g., any one of the compounds of Formulas (I), (I'), (II), (IIA), (III), (IIIA), (IV), (IVA), (V), (VA), (VB), (VC), (VI), (VIA), (VIB), (VIC), and (VII), and Table 1), or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable composition. In another embodiment, a method is provided for treating rheumatoid arthritis in a subject, the method comprising administering to the subject an effective amount of a compound disclosed herein (e.g., any one of Formulas (I), (I'), (II), (IIA), (III), (IIIA), (IV), (IVA), (V), (VA), (VB), (VC), (VI), (VIA), (VIB), (VIC), and (VII), and the compounds of Table 1), or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable composition.

[0150] In another embodiment, a method is provided for treating multiple sclerosis in a subject, the method comprising administering to the subject an effective amount of a compound disclosed herein (e.g., any one of the compounds of Formulas (I), (I'), (II), (IIA), (III), (IIIA), (IV), (IVA), (V), (VA), (VB), (VC), (VI), (VIA), (VIB), (VIC), and (VII), and Table 1), or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable composition.

[0151] The active compounds disclosed herein, or pharmaceutically acceptable salts thereof, are also useful for administration in combination or alternation with a second pharmaceutical agent (in the same or different dosage form) for use in ameliorating or reducing the side effects of the second pharmaceutical agent.

[0152] For example, in some embodiments, the active compounds may be used in conjunction with adoptive cell transfer therapy to reduce inflammatory responses associated with such therapy, e.g., cytokine-mediated responses such as cytokine response syndrome.

[0153] In some embodiments, the adoptive cell transfer therapy is chimeric antigen receptor T cells (CAR T), or dendritic cells, used to treat blood or solid tumors, e.g., B-cell-related blood cancers.

[0154] In some embodiments, the hematological or solid tumor is acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), non-Hodgkin's lymphoma, chronic lymphocytic leukemia (CLL), pancreatic cancer, glioblastoma, or a CD19-expressing cancer.

[0155] In some embodiments, the adoptive cell transfer therapy is a non-engineered T cell therapy in which T cells are activated and / or expanded against one or more viral or tumor antigens, hi some embodiments, the associated inflammatory response is a cytokine-mediated response.

[0156] In some embodiments, the second pharmaceutical agent is a cell transformed to express a protein, where the protein in the subject is mutated or otherwise dysfunctional. In some embodiments, the transformed cell comprises a CRISPR gene.

[0157] Another embodiment is provided which includes administering to a subject an effective amount of an active compound (e.g., a compound of Formula (I), (I'), (II), (IIA), (III), (IIIA), (IV), (IVA), (V), (VA), (VB), (VC), (VI), (VIA), (VIB), (VIC), or (VII), or a compound of Table 1), or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable composition, to treat an ophthalmic disorder, a pulmonary disorder, a gastrointestinal disorder, or other disorder.

[0158] In other embodiments of the present disclosure, the active compounds provided herein (e.g., compounds of Formula (I), (I'), (II), (IIA), (III), (IIIA), (IV), (IVA), (V), (VA), (VB), (VC), (VI), (VIA), (VIB), (VIC), or (VII), or in Table 1) can be used to treat or prevent a subject disorder mediated by complement. By way of example, the present disclosure includes methods for treating or preventing complement-associated disorders induced by antibody-antigen interactions that are components of immune or autoimmune disorders or by ischemic injury. The present disclosure also provides methods for reducing immune responses, including inflammatory or autoimmune responses, when mediated or affected by the classical complement pathway.

[0159] In some embodiments, the disorder is selected from fatty liver and conditions resulting from fatty liver, such as nonalcoholic steatohepatitis (NASH), hepatitis, cirrhosis, and liver failure. Some embodiments of the present disclosure provide a method for treating fatty liver disease in a subject by administering an effective amount of an active compound described herein (e.g., a compound of Formula (I), (I'), (II), (IIA), (III), (IIIA), (IV), (IVA), (V), (VA), (VB), (VC), (VI), (VIA), (VIB), (VIC), or (VII), or a compound of Table 1), or a salt or composition thereof.

[0160] In another embodiment, an active compound described herein (e.g., a compound of Formula (I), (I'), (II), (IIA), (III), (IIIA), (IV), (IVA), (V), (VA), (VB), (VC), (VI), (VIA), (VIB), (VIC), or (VII), or a compound of Table 1), or a salt or composition thereof, is used to modulate the immune response before or during surgery or other medical procedures. One non-limiting example is use in connection with acute or chronic graft-versus-target disease, which is a common complication resulting from organ transplantation, allogeneic tissue transplantation, and can also occur as a result of blood transfusions.

[0161] In some embodiments, the present disclosure provides methods of treating dermatomyositis by administering to a subject in need thereof an effective amount of an active compound described herein (e.g., a compound of Formula (I), (I'), (II), (IIA), (III), (IIIA), (IV), (IVA), (V), (VA), (VB), (VC), (VI), (VIA), (VIB), (VIC), or (VII), or a compound of Table 1), or a salt or composition thereof.

[0162] In some embodiments, the present disclosure provides methods of treating amyotrophic lateral sclerosis by administering to a subject in need thereof an effective amount of an active compound described herein (e.g., a compound of Formula (I), (I'), (II), (IIA), (III), (IIIA), (IV), (IVA), (V), (VA), (VB), (VC), (VI), (VIA), (VIB), (VIC), or (VII), or a compound of Table 1), or a salt or composition thereof.

[0163] In some embodiments, the present disclosure provides methods of treating abdominal aortic aneurysm, hemodialysis complications, hemolytic anemia, or hemodialysis by administering to a subject in need thereof an effective amount of an active compound described herein (e.g., a compound of Formula (I), (I'), (II), (IIA), (III), (IIIA), (IV), (IVA), (V), (VA), (VB), (VC), (VI), (VIA), (VIB), (VIC), or (VII), or a compound of Table 1), or a salt or composition thereof.

[0164] In another embodiment, there is provided a method for treating or preventing a cytokine or inflammatory response in a subject in response to administration of a pharmaceutical or biologic (e.g., CAR T cell therapy or monoclonal antibody therapy) by administering an effective amount of an active compound described herein (e.g., a compound of Formula (I), (I'), (II), (IIA), (III), (IIIA), (IV), (IVA), (V), (VA), (VB), (VC), (VI), (VIA), (VIB), (VIC), or (VII), or a compound in Table 1), or a salt or composition thereof. Various types of cytokine or inflammatory responses can occur in response to several factors, such as the administration of a biologic.

[0165] In some embodiments, the cytokine or inflammatory response is cytokine release syndrome. In some embodiments, the cytokine or inflammatory response is tumor lysis syndrome (which also leads to cytokine release). Symptoms of cytokine release syndrome range from fever, headache, and skin rash to bronchospasm, hypotension, and even cardiac arrest. Severe cytokine release syndrome is described as a cytokine storm and can be fatal.

[0166] Fatal cytokine storms have been observed in response to the infusion of several monoclonal antibody therapeutics. See Abramowicz D, et al., "Release of tumor necrosis factor, interleukin-2, and gamma-interferon in serum after injection of OKT3 monoclonal antibody in kidney transplant recipients," Transplantation (1989) 47(4):606-8; Chatenoud L, et al., "In vivo cell activation following OKT3 administration. Systemic cytokine release and modulation by corticosteroids," Transplantation (1990) 49(4):697-702; and Lim LC, Koh LP, and Tan P. "Fatal cytokine release syndrome with chimeric anti-CD20 monoclonal antibody rituximab in a 71-year-old patient with chronic lymphocytic leukemia," J. Clin Oncol. (1999) 17(6):1962-3.

[0167] Also contemplated herein is the use of an active compound described herein (e.g., a compound of Formula (I), (I'), (II), (IIA), (III), (IIIA), (IV), (IVA), (V), (VA), (VB), (VC), (VI), (VIA), (VIB), (VIC), or (VII), or a salt or composition thereof, to mediate adverse immune responses in patients receiving a bispecific T cell engager (BiTE). Bispecific T cell engagers instruct T cells to target and bind to specific antigens on the surface of cancer cells. For example, the BiTE blinatumomab (Amgen) was recently approved as second-line therapy for Philadelphia chromosome-negative relapsed or refractory acute lymphoblastic leukemia. Blinatumomab is given by intravenous continuous infusion in four-week cycles. The use of BiTE agents has been associated with adverse immune responses, including cytokine release syndrome. The cytokines most significantly elevated in ACT-associated CRS include IL-10, IL-6, and IFN-γ (Klinger et al., Immunopharmacologic response of patients with B-lineage acute lymphoblastic leukemia to continuous infusion of T cell-engaging CD19 / CD3-bispecific BiTE antibody blinatumomab. Blood (2012) 119:6226-6233).

[0168] In another embodiment, the disorder is episcleritis, idiopathic episcleritis, anterior scleritis, or posterior scleritis. In some embodiments, the disorder is idiopathic anterior uveitis, HLA-B27-associated uveitis, herpes keratitis, Posner-Schlossman syndrome, Fuchs iridocyclitis, or cytomegalovirus anterior uveitis.

[0169] In some embodiments, the present disclosure provides methods of treating IC-MPGN by administering to a subject in need thereof an effective amount of an active compound described herein (e.g., a compound of Formula (I), (I'), (II), (IIA), (III), (IIIA), (IV), (IVA), (V), (VA), (VB), (VC), (VI), (VIA), (VIB), (VIC), or (VII), or a compound of Table 1), or a salt or composition thereof.

[0170] In some embodiments, the present disclosure provides a method of treating paroxysmal nocturnal hemoglobinuria (PNH) by administering to a subject in need thereof an effective amount of an active compound described herein (e.g., a compound of Formula (I), (I'), (II), (IIA), (III), (IIIA), (IV), (IVA), (V), (VA), (VB), (VC), (VI), (VIA), (VIB), (VIC), or (VII), or a compound of Table 1), or a salt or composition thereof.

[0171] In some embodiments, the present disclosure provides methods of treating hereditary angioedema (HAE) by administering to a subject in need thereof an effective amount of an active compound described herein (e.g., a compound of Formula (I), (I'), (II), (IIA), (III), (IIIA), (IV), (IVA), (V), (VA), (VB), (VC), (VI), (VIA), (VIB), (VIC), or (VII), or a compound of Table 1), or a salt or composition thereof.

[0172] In some embodiments, the present disclosure provides methods of treating cold agglutinin disease (CAD) by administering to a subject in need thereof an effective amount of an active compound described herein (e.g., a compound of Formula (I), (I'), (II), (IIA), (III), (IIIA), (IV), (IVA), (V), (VA), (VB), (VC), (VI), (VIA), (VIB), (VIC), or (VII), or a compound of Table 1), or a salt or composition thereof.

[0173] In some embodiments, the present disclosure provides a method of treating atypical hemolytic syndrome (aHUS) by administering to a subject in need thereof an effective amount of an active compound described herein (e.g., a compound of Formula (I), (I'), (II), (IIA), (III), (IIIA), (IV), (IVA), (V), (VA), (VB), (VC), (VI), (VIA), (VIB), (VIC), or (VII), or a compound of Table 1), or a salt or composition thereof.

[0174] In some embodiments, the present disclosure provides methods of treating age-related macular degeneration (AMD) by administering to a subject in need thereof an effective amount of an active compound described herein (e.g., a compound of Formula (I), (I'), (II), (IIA), (III), (IIIA), (IV), (IVA), (V), (VA), (VB), (VC), (VI), (VIA), (VIB), (VIC), or (VII), or a compound of Table 1), or a salt or composition thereof.

[0175] In some embodiments, the present disclosure provides methods of treating rheumatoid arthritis by administering to a subject in need thereof an effective amount of an active compound described herein (e.g., a compound of Formula (I), (I'), (II), (IIA), (III), (IIIA), (IV), (IVA), (V), (VA), (VB), (VC), (VI), (VIA), (VIB), (VIC), or (VII), or a compound of Table 1), or a salt or composition thereof.

[0176] In some embodiments, the present disclosure provides methods of treating multiple sclerosis by administering to a subject in need thereof an effective amount of an active compound described herein (e.g., a compound of Formula (I), (I'), (II), (IIA), (III), (IIIA), (IV), (IVA), (V), (VA), (VB), (VC), (VI), (VIA), (VIB), (VIC), or (VII), or a compound of Table 1), or a salt or composition thereof.

[0177] In some embodiments, the present disclosure provides methods of treating myasthenia gravis by administering to a subject in need thereof an effective amount of an active compound described herein (e.g., a compound of Formulas (I), (I'), (II), (IIA), (III), (IIIA), (IV), (IVA), (V), (VA), (VB), (VC), (VI), (VIA), (VIB), (VIC), and (VII), or a compound of Table 1), or a salt or composition thereof.

[0178] In some embodiments, the present disclosure provides a method of treating atypical hemolytic uremic syndrome (aHUS) by administering to a subject in need thereof an effective amount of an active compound described herein (e.g., a compound of Formula (I), (I'), (II), (IIA), (III), (IIIA), (IV), (IVA), (V), (VA), (VB), (VC), (VI), (VIA), (VIB), (VIC), or (VII), or a compound of Table 1), or a salt or composition thereof.

[0179] In another embodiment, the present disclosure provides a method of treating a disorder described below by administering to a subject in need thereof an effective amount of an active compound described herein (e.g., a compound of Formula (I), (I'), (II), (IIA), (III), (IIIA), (IV), (IVA), (V), (VA), (VB), (VC), (VI), (VIA), (VIB), (VIC), or (VII), or a compound of Table 1), or a salt or composition thereof, including: Vitritis, sarcoidosis, syphilis, tuberculosis, or Lyme disease; retinal vasculitis, Eales' disease, tuberculosis, syphilis, or toxoplasmosis; neuroretinitis, viral retinitis, or acute retinal necrosis; varicella-zoster virus, herpes simplex virus, cytomegalovirus, Epstein-Barr virus, lichen planus, or dengue-related disease (e.g., dengue hemorrhagic fever); masked syndrome, contact dermatitis, trauma-induced inflammation, UVB-induced inflammation, eczema, granuloma annulare, or acne.

[0180] In additional embodiments, the disorder is acute myocardial infarction, aneurysm, cardiopulmonary bypass, dilated cardiomyopathy, complement activation during cardiopulmonary bypass, coronary artery disease, restenosis after stent placement or percutaneous transluminal coronary angioplasty (PTCA); antibody-mediated graft rejection, anaphylactic shock, anaphylaxis, allograft, humoral and vascular graft rejection, graft dysfunction, graft-versus-target disease, Graves' disease, adverse drug reaction, or chronic graft vasculopathy; allergic bronchopulmonary aspergillosis, allergic neuritis, drug allergy, radiation-induced lung injury, eosinophilic pneumonia, radiographic contrast allergy, bronchiolitis obliterans, or interstitial pneumonia; parkinsonism-dementia complex, isolated frontotemporal dementia, 17th staining. The present invention is selected from frontotemporal dementia with body-linked parkinsonism, frontotemporal lobar degeneration, neurofibrillary tangle dementia, cerebral amyloid angiopathy, cerebrovascular disease, certain forms of frontotemporal dementia, chronic traumatic encephalopathy (CTE), Parkinson's disease with dementia (PDD), argyrophilic grain dementia, dementia pugilistica, dementia with Lewy bodies (DLB), or multi-infarct dementia; Creutzfeldt-Jakob disease, Huntington's disease, multifocal motor neuropathy (MMN), prion protein cerebral amyloid angiopathy, polymyositis, postencephalitic parkinsonism, subacute sclerosing panencephalitis, non-Guam motor neuron disease with neurofibrillary tangles, neuroregeneration, and diffuse neurofibrillary tangle disease with calcification.

[0181] In some embodiments, the disorder is atopic dermatitis, dermatitis, dermatomyositis bullous pemphigoid, scleroderma, sclerodermatomyositis, psoriatic arthritis, pemphigus vulgaris, discoid lupus erythematosus, cutaneous lupus, chilblain lupus erythematosus, or lupus erythematosus-lichen planus overlap syndrome; cryoglobulinemic vasculitis, mesenteric / intestinal vasculopathy, peripheral vascular disease, antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), IL-2-induced vascular leak syndrome, immune complex vasculopathy, In some embodiments, the disorder is selected from inflammation, angioedema, thrombocytopenia (HELLP) syndrome, sickle cell disease, platelet refractory state, red blood cell casts, or typical or infectious hemolytic uremic syndrome (tHUS); hematuria, hemorrhagic shock, drug-induced thrombocytopenia, autoimmune hemolytic anemia (AIHA), azotemia, vascular and / or lymphatic inflammation, rapid rotation atherectomy, or delayed hemolytic transfusion reaction; British amyloid angiopathy, Buerger's disease, bullous pemphigoid, C1q nephropathy, cancer, and fulminant antiphospholipid syndrome. In some embodiments, the disorder is autoimmune hemolytic anemia, e.g., warm autoimmune hemolytic anemia.

[0182] In another embodiment, the disorder is wet (exudative) AMD, dry (non-exudative) AMD, chorioretinal degeneration, choroidal neovascularization (CNV), choroiditis, loss of RPE function, vision loss (including loss of vision or visual field), vision loss due to AMD, retinal damage due to light exposure, retinal degeneration, retinal detachment, retinal dysfunction, retinal neovascularization (RNV), retinopathy of prematurity, pathological myopia, or RPE degeneration; pseudophakic bullous keratopathy, symptomatic macular degeneration-related disorders, Optic nerve degeneration, photoreceptor degeneration, cone degeneration, photoreceptor cell loss, pars planitis, scleritis, proliferative vitreoretinopathy, or ocular drusen formation; chronic urticaria, Churg-Strauss syndrome, cold agglutinin disease (CAD), corticobasal degeneration (CBD), cryoglobulinemia, cyclitis, damage to Bruch's membrane, Degos disease, diabetic angiopathy, elevated liver enzymes, endotoxemia, epidermolysis bullosa, or epidermolysis bullosa acquisita; essential mixed cryoglobulinemia glomerulonephritis, excessive blood urea nitrogen (BUN), focal segmental glomerulosclerosis, Gerstmann-Straussler-Scheinker disease, giant cell arteritis, gout, Hallervorden-Spatz disease, Hashimoto's thyroiditis, Henoch-Schönlein purpura nephritis, or abnormal urinary sediment; hepatitis, hepatitis A, hepatitis B, hepatitis C, or human immunodeficiency virus (HIV), more commonly a viral infection selected from, for example, Flaviviridae, Retrovirus, Coronaviridae, Poxviridae, Adenoviridae, Herpesviridae, Caliciviridae, Reoviridae, Picornaviridae, Togaviridae, Orthomyxoviridae, Rhabdoviridae, or Hepadnaviridae; meningococcus, Shiga toxin E. coli-associated hemolytic uremic syndrome (STEC-HUS), hemolytic uremic syndrome (HUS); streptococcus, and post-streptococcal glomerulonephritis.

[0183] In further embodiments, the disorder is hyperlipidemia, hypertension, hypoalbuminemia, hypovolemic shock, hypocomplementemic urticarial vasculitis syndrome, hypophosphatasia, hypovolemic shock, idiopathic pneumonia syndrome, or idiopathic pulmonary fibrosis; inclusion body myositis, intestinal ischemia, iridocyclitis, iritis, juvenile chronic arthritis, Kawasaki disease (arteritis), or lipuria; membranoproliferative glomerulonephritis (MPGN) I, microscopic polyangiitis, mixed cryoglobulinemia, molybdenum cofactor deficiency (MoCD) type A, pancreatitis, panniculitis, Pick's disease, polyarteritis nodosa (PAN), progressive subcortical gliosis, proteinuria, reduced glomerular filtration rate (GFR), or renal vascular Diseases selected from multiple organ failure, multiple system atrophy (MSA), myotonic dystrophy, Niemann-Pick disease type C, chronic demyelinating disease, or progressive supranuclear palsy; spinal cord injury, spinal muscular atrophy, spondyloarthropathy, Reiter's syndrome, spontaneous abortion, recurrent abortion, preeclampsia, synucleinopathy, Takayasu's arteritis, postpartum thyroiditis, thyroiditis, type I cryoglobulinemia, type II mixed cryoglobulinemia, type III mixed cryoglobulinemia, ulcerative colitis, uremia, urticaria, venous gas embolism (VGE), or Wegener's granulomatosis; von Hippel-Lindau disease, ocular histoplasmosis, hard drusen, soft drusen, pigment clumping, and loss of photoreceptors and / or retinal pigment epithelium (RPE).

[0184] In some embodiments, an active compound described herein (e.g., a compound of Formula (I), (I'), (II), (IIA), (III), (IIIA), (IV), (IVA), (V), (VA), (VB), (VC), (VI), (VIA), (VIB), (VIC), or (VII), or a compound of Table 1), or a salt or composition thereof, is administered to treat or prevent any of the following conditions: autoimmune oophoritis, endometriosis, autoimmune orchitis, Ord's thyroiditis, autoimmune enteropathy, celiac disease, Hashimoto's encephalopathy, antiphospholipid syndrome (APLS) (Hughes' syndrome), aplastic anemia, autoimmune lymphoproliferative syndrome (Canale-Smith syndrome), autoimmune neutropenia, Evans' syndrome, pernicious anemia, pure red cell aplasia, thrombocytopenia, adipose tissue dysplasia, erythropoietin syndrome, erythroblastosis, erythropoietin syndrome ...dolorosa (Dercam's disease), adult-onset Still's disease, ankylosing spondylitis, CREST syndrome, drug-induced lupus, eosinophilic fasciitis (Shulman's syndrome), Felty's syndrome, IgG4-related disease, mixed connective tissue disease (MCTD), relapsing rheumatoid arthritis (Hench-Rosenberg syndrome), Parry-Romberg syndrome, Parsonage-Turner syndrome, relapsing polychondritis (Meyenburg-Altherr-Uehlinger syndrome), retroperitoneal fibrosis, rheumatic fever, Schnitzler's syndrome, fibromyalgia , neuromyotonia (Isaac's disease), paraneoplastic degeneration, autoimmune inner ear disease, Meniere's disease, interstitial cystitis, autoimmune pancreatitis, Zika virus-related disorders, Chikungunya virus-related disorders, subacute bacterial endocarditis (SBE), IgA nephropathy, IgA vasculitis, polymyalgia rheumatica, rheumatoid vasculitis, alopecia areata, autoimmune progesterone dermatitis, dermatitis herpetiformis, erythema nodosum, pemphigoid of pregnancy, hidradenitis suppurativa, lichen sclerosus, linear IgA disease (LAD), morphea, myositis, acute pityriasis lichenoides varioliformis, vitiligo-post-myocardial infarction syndrome (Dressler's syndrome), pericardiotomy Post-inflammatory syndrome, autoimmune retinopathy, Cogan's syndrome, Graves' ophthalmopathy, lignine conjunctivitis, Mooren's ulcer, opsoclonus-myoclonus syndrome, optic neuritis, retinocochlear cerebrovascular disease (Susac syndrome), sympathetic ophthalmia, Tolosa-Hunt syndrome, interstitial lung disease, antisynthetase syndrome, Addison's disease, autoimmune polyendocrine syndrome (APS) type I, autoimmune polyendocrine syndrome (APS) type II, autoimmune polyendocrine syndrome (APS) type III, disseminated sclerosis (multiple sclerosis, pattern II), rapidly progressive glomerulonephritis (RPGN), juvenile rheumatoid arthritis, adhesion Arthritis-associated arthritis, reactive arthritis (Reiter's syndrome), autoimmune or lupoid hepatitis, primary biliary cirrhosis (PBS), primary sclerosing cholangitis, microscopic colitis, latent lupus (undifferentiated connective tissue disease (UCTD)), acute disseminated encephalomyelitis (ADEM), acute motor axonal neuropathy, anti-(R)-N-methyl-D-aspartate receptor encephalitis, Barrow concentric sclerosis (Schilder's disease), Bickerstaff encephalitis, chronic inflammatory demyelinating polyneuropathy, idiopathic inflammatory demyelinating disease, Lambert-Eaton myasthenic syndrome, Oshtoran syndromesyndrome), pediatric autoimmune neuropsychiatric disorder associated with streptococcus aureus (PANDAS), progressive inflammatory neuropathy, restless legs syndrome, stiff-person syndrome, Sydenham's syndrome, transverse myelitis, lupus vasculitis, leukocytoclastic vasculitis, microscopic polyangiitis, polymyositis, and ocular ischemia-reperfusion injury.

[0185] Examples of ocular disorders that can be treated by the compositions and methods disclosed herein include amebic keratitis, fungal keratitis, bacterial keratitis, viral keratitis, onchocercal keratitis, bacterial keratoconjunctivitis, viral keratoconjunctivitis, corneal dystrophic diseases, Fuchs' endothelial corneal dystrophy, Sjogren's syndrome, Stevens-Johnson syndrome, autoimmune dry eye disease, environmental dry eye disease, corneal neovascularization disease, prevention of corneal transplant rejection, and the like. and treatment of autoimmune uveitis, infectious uveitis, posterior uveitis (including toxoplasmosis), panuveitis, inflammatory diseases of the vitreous or retina, prevention and treatment of endophthalmitis, macular edema, macular degeneration, age-related macular degeneration, proliferative and non-proliferative diabetic retinopathy, hypertensive retinopathy, autoimmune diseases of the retina, primary and metastatic intraocular melanoma, other intraocular metastatic tumors, open-angle glaucoma, angle-closure glaucoma, pigmentary glaucoma, and combinations thereof.

[0186] In further embodiments, the disorder is selected from glaucoma, diabetic retinopathy, bullous skin diseases (including bullous pemphigoid, pemphigus, and epidermolysis bullosa), ocular pemphigoid, uveitis, adult macular degeneration, diabetic retinopathy, retinitis pigmentosa, macular edema, diabetic macular edema, Behcet's uveitis, multifocal choroiditis, Vogt-Koyanagi-Harada syndrome, intermediate uveitis, birdshot chorioretinitis, sympathetic ophthalmia, ocular cicatricial pemphigoid, ocular pemphigoid, non-arteritic ischemic optic neuropathy, postoperative inflammation, and retinal vein occlusion, and central retinal vein occlusion (CVRO).

[0187] In some embodiments, a method is provided for treating an autoimmune bullous disease in a subject, the method comprising administering an effective amount of an active compound described herein (e.g., a compound of Formula (I), (I'), (II), (IIA), (III), (IIIA), (IV), (IVA), (V), (VA), (VB), (VC), (VI), (VIA), (VIB), (VIC), or (VII), or a compound of Table 1), or a salt or composition thereof.

[0188] In some embodiments, a method is provided for treating bullous pemphigoid in a subject, the method comprising administering an effective amount of an active compound described herein (e.g., a compound of Formula (I), (I'), (II), (IIA), (III), (IIIA), (IV), (IVA), (V), (VA), (VB), (VC), (VI), (VIA), (VIB), (VIC), or (VII), or a compound of Table 1), or a salt or composition thereof.

[0189] In some embodiments, the complement-mediated disorder is an ophthalmic disease (e.g., early or neovascular age-related macular degeneration and geographic atrophy), an autoimmune disease (e.g., arthritis or rheumatoid arthritis), a respiratory disease, or a cardiovascular disease. In other embodiments, the compounds of the present disclosure are suitable for use in treating diseases and disorders associated with fatty acid metabolism, including obesity and other metabolic disorders.

[0190] In some embodiments, a method is provided for treating geographic atrophy in a subject, the method comprising administering an effective amount of an active compound described herein (e.g., a compound of Formula (I), (I'), (II), (IIA), (III), (IIIA), (IV), (IVA), (V), (VA), (VB), (VC), (VI), (VIA), (VIB), (VIC), or (VII), or a compound of Table 1), or a salt or composition thereof.

[0191] Disorders that may be treated or prevented by an active compound described herein (e.g., a compound of Formula (I), (I'), (II), (IIA), (III), (IIIA), (IV), (IVA), (V), (VA), (VB), (VC), (VI), (VIA), (VIB), (VIC), or (VII), or a compound of Table 1), or a salt or composition thereof, also include hereditary angioedema, capillary leak syndrome, hemolytic uremic syndrome (HUS), neuropathy, Guillain-Barré syndrome, diseases of the central nervous system and other neurodegenerative conditions, glomerulonephritis (including membranoproliferative glomerulonephritis), SLE nephritis, proliferative nephritis, liver fibrosis, tissue regeneration and nerve regeneration, or Barraquer-Simons syndrome. Syndrome); inflammatory effects of sepsis, systemic inflammatory response syndrome (SIRS), disorders of inappropriate or unwanted complement activation, interleukin-2-induced toxicity during IL-2 therapy, inflammatory disorders, inflammation in autoimmune diseases, systemic lupus erythematosus (SLE), lupus nephritis, arthritis, immune complex disorders and autoimmune diseases, systemic lupus, or lupus erythematosus; ischemia / reperfusion injury (I / R injury), myocardial infarction, myocarditis, post-ischemic reperfusion pathology, balloon angioplasty, atherosclerosis , post-pump syndrome in cardiopulmonary or renal bypass, renal ischemia, mesenteric artery reperfusion after aortic reconstruction, antiphospholipid syndrome, autoimmune heart disease, ischemia-reperfusion injury, obesity, or diabetes; Alzheimer's disease, stroke, schizophrenia, traumatic brain injury, trauma, Parkinson's disease, epilepsy, transplant rejection, prevention of miscarriage, biomaterial reactions (e.g., in hemodialysis, implants), hyperacute allograft rejection, xenograft rejection, transplantation, psoriasis, burn injury, thermal injury including burns or frostbite, or crush injury;Also included are, but are not limited to, asthma, allergies, acute respiratory distress syndrome (ARDS), cystic fibrosis, adult respiratory distress syndrome, dyspnea, hemoptysis, chronic obstructive pulmonary disease (COPD), emphysema, pulmonary embolism and infarction, pneumonia, fibrosing dust diseases, inert dusts and minerals (e.g., silicon, coal dust, beryllium, and asbestos), pulmonary fibrosis, organic dust diseases, chemical injury (due to irritant gases and chemicals, e.g., chlorine, phosgene, sulfur dioxide, hydrogen sulfide, nitrogen dioxide, ammonia, and hydrochloric acid), smoke damage, thermal injury (e.g., burns, freezing), bronchoconstriction, hypersensitivity pneumonitis, parasitic diseases, Goodpasture's syndrome (anti-glomerular basement membrane nephritis), pulmonary vasculitis, microimmune vasculitis, and immune complex-associated inflammation;

[0192] In some embodiments, a method is provided for treating sickle cell disease in a subject, the method comprising administering an effective amount of an active compound described herein (e.g., a compound of Formula (I), (I'), (II), (IIA), (III), (IIIA), (IV), (IVA), (V), (VA), (VB), (VC), (VI), (VIA), (VIB), (VIC), or (VII), or a compound of Table 1), or a salt or composition thereof.

[0193] In some embodiments, methods are provided for treating immune thrombocytopenic purpura (ITP), thrombotic thrombocytopenic purpura (TTP), or idiopathic thrombocytopenic purpura (ITP) in a subject, the methods comprising administering an effective amount of an active compound described herein (e.g., a compound of Formula (I), (I'), (II), (IIA), (III), (IIIA), (IV), (IVA), (V), (VA), (VB), (VC), (VI), (VIA), (VIB), (VIC), or (VII), Table 1), or a salt or composition thereof. In some embodiments, the method is for treating immune thrombocytopenic purpura (ITP).

[0194] In some embodiments, methods are provided for treating ANCA-vasculitis in a subject, the methods comprising administering an effective amount of an active compound described herein (e.g., a compound of Formula (I), (I'), (II), (IIA), (III), (IIIA), (IV), (IVA), (V), (VA), (VB), (VC), (VI), (VIA), (VIB), (VIC), or (VII), or a compound of Table 1), or a salt or composition thereof.

[0195] In some embodiments, a method is provided for treating IgA nephropathy in a subject, the method comprising administering an effective amount of an active compound described herein (e.g., a compound of Formula (I), (I'), (II), (IIA), (III), (IIIA), (IV), (IVA), (V), (VA), (VB), (VC), (VI), (VIA), (VIB), (VIC), or (VII), Table 1), or a salt or composition thereof.

[0196] In some embodiments, a method is provided for treating rapidly progressive glomerulonephritis (RPGN) in a subject, the method comprising administering an effective amount of an active compound described herein (e.g., a compound of Formula (I), (I'), (II), (IIA), (III), (IIIA), (IV), (IVA), (V), (VA), (VB), (VC), (VI), (VIA), (VIB), (VIC), or (VII), or a compound of Table 1), or a salt or composition thereof.

[0197] In some embodiments, a method is provided for treating lupus nephritis in a subject, the method comprising administering an effective amount of an active compound described herein (e.g., a compound of Formula (I), (I'), (II), (IIA), (III), (IIIA), (IV), (IVA), (V), (VA), (VB), (VC), (VI), (VIA), (VIB), (VIC), or (VII), or a compound of Table 1), or a salt or composition thereof.

[0198] In some embodiments, a method is provided for treating hemorrhagic dengue fever in a subject, the method comprising administering an effective amount of an active compound described herein (e.g., a compound of Formula (I), (I'), (II), (IIA), (III), (IIIA), (IV), (IVA), (V), (VA), (VB), (VC), (VI), (VIA), (VIB), (VIC), or (VII), or a compound of Table 1), or a salt or composition thereof.

[0199] In additional alternative embodiments, an active compound described herein (e.g., a compound of Formula (I), (I'), (II), (IIA), (III), (IIIA), (IV), (IVA), (V), (VA), (VB), (VC), (VI), (VIA), (VIB), (VIC), or (VII), Table 1), or a salt or composition thereof, is used in the treatment of an autoimmune disorder. The complement pathway enhances the ability of antibodies and phagocytes to eliminate microorganisms and damaged cells from the body. It is part of the innate immune system and is an essential process in healthy individuals. Inhibition of the complement pathway will reduce the body's immune system response. Accordingly, it is an object of the present disclosure to treat an autoimmune disorder by administering an effective dose of an active compound described herein (e.g., a compound of Formula (I), (I'), (II), (IIA), (III), (IIIA), (IV), (IVA), (V), (VA), (VB), (VC), (VI), (VIA), (VIB), (VIC), or (VII), or a compound of Table 1), or a salt or composition thereof, to a subject in need thereof.

[0200] In some embodiments, the autoimmune disorder is caused by activation of the complement system. In some embodiments, the autoimmune disorder is caused by activation of the alternative complement pathway. In some embodiments, the autoimmune disorder is caused by activation of the classical complement pathway. In other embodiments, the autoimmune disorder is caused by a mechanism not directly related to the complement system, such as hyperproliferation of T lymphocytes or overproduction of cytokines.

[0201] Non-limiting examples of autoimmune disorders include lupus, allograft rejection, autoimmune thyroid diseases (such as Graves' disease and Hashimoto's thyroiditis), autoimmune uveoretinitis, giant cell arteritis, inflammatory bowel disease (including Crohn's disease, ulcerative colitis, regional enteritis, granulomatous enteritis, distal ileitis, regional ileitis, and terminal ileitis), diabetes, multiple sclerosis, pernicious anemia, psoriasis, rheumatoid arthritis, sarcoidosis, and scleroderma.

[0202] In some embodiments, an active compound described herein (e.g., a compound of Formula (I), (I'), (II), (IIA), (III), (IIIA), (IV), (IVA), (V), (VA), (VB), (VC), (VI), (VIA), (VIB), (VIC), or (VII), or a compound in Table 1), or a salt or composition thereof, is used in the treatment of lupus. Non-limiting examples of lupus include lupus erythematosus, cutaneous lupus, discoid lupus erythematosus, chilblain lupus erythematosus, and lupus erythematosus-lichen planus overlap syndrome.

[0203] Lupus erythematosus is a general category of disease that includes both systemic and cutaneous disorders. Systemic forms of the disease can have not only systemic but also cutaneous manifestations. However, forms of the disease that are cutaneous without systemic involvement also exist. For example, SLE is an inflammatory disorder of unknown etiology that occurs predominantly in women and is characterized by joint symptoms, butterfly rash, recurrent pleurisy, pericarditis, generalized lymphadenopathy, splenomegaly, as well as CNS lesions and progressive renal failure. The serum of most patients (>98%) contains antinuclear antibodies, including anti-DNA antibodies. High titers of anti-DNA antibodies are essentially specific for SLE. Traditional treatment for this disease involves the administration of corticosteroids or immunosuppressants.

[0204] Cutaneous lupus exists in three forms: chronic cutaneous lupus (also known as discoid lupus erythematosus or DLE), subacute cutaneous lupus, and acute cutaneous lupus. DLE is a disfiguring chronic disorder primarily affecting the skin, with well-defined macules and erythematous plaques, keratotic plugs, scaling, telangiectasias, and atrophy. The condition is often exacerbated by sun exposure, and initial lesions are erythematous, round, scaly papules 5–10 mm in diameter, displaying keratotic plugs. DLE lesions most commonly appear on the cheeks, nose, scalp, and ears, but they may also appear generalized over the upper trunk, extensor surfaces of the extremities, and oral mucosa. If left untreated, central lesions atrophy and leave scars. Unlike SLE, antibodies to double-stranded DNA (e.g., DNA binding tests) are almost universally absent in DLE.

[0205] Diabetes can refer to either type 1 diabetes or type 2 diabetes. In some embodiments, an active compound described herein (e.g., a compound of Formula (I), (I'), (II), (IIA), (III), (IIIA), (IV), (IVA), (V), (VA), (VB), (VC), (VI), (VIA), (VIB), (VIC), or (VII), or a compound in Table 1), or a salt or composition thereof, is provided in a dose effective to treat a patient with type 1 diabetes. In some embodiments, an active compound described herein (e.g., a compound of Formula (I), (I'), (II), (IIA), (III), (IIIA), (IV), (IVA), (V), (VA), (VB), (VC), (VI), (VIA), (VIB), (VIC), or (VII), or a compound in Table 1), or a salt or composition thereof, is provided in a dose effective to treat a patient with type 2 diabetes. Type 1 diabetes is an autoimmune disease. Autoimmune diseases occur when the body's system that fights infection (the immune system) attacks parts of the body. In type 1 diabetes, the pancreas then produces little or no insulin.

[0206] In some embodiments, the complement-mediated disease or disorder comprises transplant rejection, hi some embodiments, the complement-mediated disease or disorder is antibody-mediated transplant rejection.

[0207] In certain embodiments, an active compound described herein (e.g., a compound of Formula (I), (I'), (II), (IIA), (III), (IIIA), (IV), (IVA), (V), (VA), (VB), (VC), (VI), (VIA), (VIB), (VIC), or (VII), or a compound of Table 1), or a salt or composition thereof, is used to treat a proliferative disorder, including, but not limited to, cancer. Suitable targeted cancers for administration of an active compound described herein (e.g., a compound of Formula (I), (I'), (II), (IIA), (III), (IIIA), (IV), (IVA), (V), (VA), (VB), (VC), (VI), (VIA), (VIB), (VIC), or (VII), or a compound of Table 1), or a salt thereof, include estrogen receptor-positive cancer, HER2-negative advanced breast cancer, late-line metastatic breast cancer, liposarcoma, non-small cell lung cancer, liver cancer, ovarian cancer, glioblastoma, refractory solid tumors, retinoblastoma-positive breast cancer and retinoblastoma-positive endometrial cancer, vaginal and ovarian cancer and lung and bronchial cancer, colon adenocarcinoma, rectal adenocarcinoma, central nervous system germ cell tumor, teratoma, estrogen receptor-negative breast cancer, estrogen receptor-positive breast cancer, familial testicular germ cell tumor. tumor, HER2-negative breast cancer, HER2-positive breast cancer, male breast cancer, ovarian immature teratoma, ovarian mature teratoma, ovarian monodermal and highly restricted teratoma, progesterone receptor-negative breast cancer, progesterone receptor-positive breast cancer, recurrent breast cancer, recurrent colon cancer, recurrent extragonadal germ cell tumor, recurrent extragonadal nonseminomatous germ cell tumor, recurrent extragonadal seminoma, recurrent malignant testicular germ cell tumor, recurrent melanoma, recurrent ovarian germ cell tumor The cancers targeted include, but are not limited to, estrogen receptor-positive, HER2-negative advanced breast cancer, posterior line metastatic breast cancer, liposarcoma, non-small cell lung cancer, liver cancer, ovarian cancer, glioblastoma, refractory solid tumors, retinoblastoma-positive breast cancer and retinoblastoma-positive endometrial cancer,Vaginal and ovarian cancer, lung and bronchial cancer, metastatic colorectal cancer, metastatic melanoma with CDK4 mutation or amplification, or cisplatin-refractory unresectable germ cell tumor, lung cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, anal cancer, stomach cancer, colon cancer, breast cancer, uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, esophageal cancer, small intestine cancer, cancer of the endocrine system, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer Adenocarcinoma, bladder cancer, kidney or ureter cancer, renal cell carcinoma, renal pelvis cancer, tumors of the central nervous system (CNS), primary CNS lymphoma, spinal tumors, brainstem glioma, pituitary adenoma, fibrosarcoma, myxosarcoma, chondrosarcoma, osteosarcoma, chordoma, malignant fibrous histiocytoma, angiosarcoma, lymphangiosarcoma, mesothelioma, leiomyosarcoma, rhabdomyosarcoma, squamous cell carcinoma; epidermoid carcinoma, malignant skin adnexal tumor, adenocarcinoma, hepatocellular carcinoma, renal cell carcinoma, adrenal gland tumor, cholangiocarcinoma, transitional cell carcinoma, choriocarcinoma, seminoma, embryonal cell carcinoma , anaplastic glioma; glioblastoma multiforme, neuroblastoma, medulloblastoma, malignant meningioma, malignant schwannoma, neurofibrosarcoma, parathyroid carcinoma, medullary thyroid carcinoma, bronchial carcinoid, pheochromocytoma, islet cell carcinoma, malignant carcinoid, malignant paraganglioma, melanoma, Merkel cell tumor, cystosarcoma phyllodes, salivary gland carcinoma, thymic carcinoma, bladder carcinoma, and Wilms' tumor, among others, myeloid disorders, lymphoid disorders, leukemia, lymphoma, myelodysplastic syndrome (MDS), myeloproliferative disorders (MPD), mast cell carcinoma, blood disorders or hematologic malignancies, including, but not limited to, cutaneous leukemia, leukemia, and myeloma (e.g., multiple myeloma), including, but not limited to, peripheral T-cell lymphoma; anaplastic large cell lymphoma, e.g., anaplastic lymphoma kinase (ALK)-positive, ALK-negative anaplastic large cell lymphoma, or primary cutaneous anaplastic large cell lymphoma; angioimmunoblastic lymphoma; cutaneous T-cell lymphoma, e.g., mycosis fungoides, Sézary syndrome, primary cutaneous anaplastic large cell lymphoma, primary cutaneous CD30+ T-cell lymphoproliferative disorder; primary cutaneous aggressive epidermotropic CD8+ cytotoxic T-cell lymphoma; primary cutaneous gamma-delta T-cell lymphoma; primary cutaneous small / medium CD4+ T-cell lymphoma,and lymphomatoid papulosis; adult T-cell leukemia / lymphoma (ATLL); blastic NK-cell lymphoma; enteropathy-type T-cell lymphoma; hepatosplenic gamma-delta T-cell lymphoma; lymphoblastic lymphoma; nasal NK / T-cell lymphoma; therapy-related T-cell lymphoma; e.g., lymphomas appearing after solid organ or bone marrow transplant; T-cell prolymphocytic leukemia; T-cell large granular lymphocytic leukemia; chronic NK-cell lymphoproliferative disorder; aggressive NK-cell leukemia; pediatric systemic EBV+ T-cell lymphoproliferative disorder (associated with chronic active EBV infection); vaccinia bullosa-like lymphoma; adult T-cell leukemia / lymphoma; enteropathy-associated T-cell lymphoma; hepatosplenic T-cell lymphoma; or subcutaneous panniculitis-like T-cell lymphoma.

[0208] In some embodiments, the methods described herein can be used to treat subjects, such as humans, with lymphoma or lymphatic or myelogenous proliferation disorders or abnormalities.For example, the methods described herein can be administered to subjects with Hodgkin's lymphoma or non-Hodgkin's lymphoma.For example, the subjects may be treated with, but are not limited to, AIDS-related lymphoma; anaplastic large cell lymphoma; angioimmunoblastic lymphoma; blastic NK-cell lymphoma; Burkitt's lymphoma; Burkitt-like lymphoma (small non-cleaved cell lymphoma); chronic lymphocytic leukemia / small lymphocytic lymphoma; cutaneous T-cell lymphoma; diffuse large B-cell lymphoma; enteropathy-type T-cell lymphoma; follicular lymphoma; hepatosplenic gamma-delta T-cell lymphoma; lymphoblastic lymphoma; mantle cell lymphoma; marginal zone lymphoma; nasal Non-Hodgkin's lymphomas, such as, but not limited to, tuberous sclerosis, classical Hodgkin's lymphoma (CHL); mixed cellularity CHL; lymphopenic CHL; lymphocyte-rich CHL; lymphocyte-predominant Hodgkin's lymphoma; or nodular lymphocyte-predominant HL, including, but not limited to, childhood T-cell lymphoma; childhood lymphoma; peripheral T-cell lymphoma; primary central nervous system lymphoma; T-cell leukemia; transformed lymphoma; therapy-related T-cell lymphoma; or Waldenstrom's macroglobulinemia. Multiple myeloma; diffuse large B-cell lymphoma; follicular lymphoma; mucosa-associated lymphoid tissue lymphoma (MALT); small cell lymphocytic lymphoma; mediastinal large B-cell lymphoma; nodal marginal zone B-cell lymphoma (NMZL); splenic marginal zone lymphoma (SMZL); intravascular large B-cell lymphoma; primary effusion lymphoma; or lymphomatoid granulomatosis; B-cell prolymphocytic leukemia; hairy cell leukemia; splenic lymphoma / leukemia, unclassifiable; splenic diffuse red pulp small B-cell lymphoma; hairy cell leukemia Disease variants; certain B-cell lymphomas or proliferative disorders such as lymphoplasmacytic lymphoma; heavy chain diseases, e.g., alpha heavy chain disease, gamma heavy chain disease, mu heavy chain disease; plasma cell myeloma; solitary bone plasmacytoma; extraskeletal plasmacytoma; primary cutaneous follicle center lymphoma; T-cell / histiocytocyte-rich large B-cell lymphoma; DLBCL associated with chronic inflammation; Epstein-Barr virus (EBV)+ DLBCL in the elderly; primary mediastinal (thymic) large B-cell lymphoma; primary cutaneous DLBCL, leg type;The patient may have an acute or chronic leukemia of lymphocytic or myeloid origin, such as ALK+ large B-cell lymphoma; plasmablastic lymphoma; large B-cell lymphoma arising in HHV8-associated multicentric Castleman disease; or B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and classical Hodgkin lymphoma, leukemia, including, but not limited to, acute lymphoblastic leukemia (ALL); acute myeloid leukemia (AML); chronic lymphocytic leukemia (CLL); chronic myeloid leukemia (CML); juvenile myelomonocytic leukemia (JMML); hairy cell leukemia (HCL); acute promyelocytic leukemia (AML variant); large granular lymphocytic leukemia; or adult T-cell chronic leukemia. In some embodiments, the patient has acute myeloid leukemia, e.g., anaplastic AML (M0); myeloblastic leukemia (M1; with or without minimal cellular maturation); myeloblastic leukemia (M2; with cellular maturation); promyelocytic leukemia (M3 or M3 variant [M3V]); myelomonocytic leukemia (M4 or M4 variant with eosinophilia [M4E]); monocytic leukemia (M5); erythroleukemia (M6); or megakaryoblastic leukemia (M7), small cell lung cancer, retinoblastoma, HPV-positive malignancies such as cervical cancer and certain head and neck cancers, MYC-amplified tumors such as Burkitt's lymphoma. certain categories of sarcoma, certain categories of non-small cell lung cancer, certain categories of melanoma, certain categories of pancreatic cancer, certain categories of leukemia, certain categories of lymphoma, certain categories of brain cancer, certain categories of colon cancer, certain categories of prostate cancer, certain categories of ovarian cancer, certain categories of uterine cancer, certain categories of thyroid and other endocrine tissue cancer, certain categories of salivary gland cancer, certain categories of thymus cancer, certain categories of kidney cancer, certain categories of bladder cancer, and certain categories of testicular cancer;

[0209] In certain embodiments, an active compound described herein (e.g., a compound of Formula (I), (I'), (II), (IIA), (III), (IIIA), (IV), (IVA), (V), (VA), (VB), (VC), (VI), (VIA), (VIB), (VIC), or (VII), or a compound in Table 1), or a salt thereof, can be used to preserve or prevent damage to an organ or blood product. For example, an active compound described herein (e.g., a compound of Formula (I), (I'), (II), (IIA), (III), (IIIA), (IV), (IVA), (V), (VA), (VB), (VC), (VI), (VIA), (VIB), (VIC), or (VII), or a compound in Table 1), or a salt thereof, can be used to prevent damage to an organ, tissue, cell product, or blood product harvested for transplantation. In some embodiments, the organ is the heart, kidney, pancreas, lung, liver, or intestine. In some embodiments, the tissue is derived from the cornea, bone, tendon, muscle, heart valve, nerve, artery or vein, or skin. In some embodiments, the blood product is whole blood, plasma, red blood cells, or reticulocytes.

[0210] In some embodiments, an active compound described herein (e.g., a compound of Formula (I), (I'), (II), (IIA), (III), (IIIA), (IV), (IVA), (V), (VA), (VB), (VC), (VI), (VIA), (VIB), (VIC), or (VII), or a salt or composition thereof, prevents or delays the onset of at least one symptom of a complement-mediated disease or disorder in an individual. In some embodiments, an active compound described herein (e.g., a compound of Formula (I), (I'), (II), (IIA), (III), (IIIA), (IV), (IVA), (V), (VA), (VB), (VC), (VI), (VIA), (VIB), (VIC), or (VII), or a compound of Table 1), or a salt or composition thereof, reduces or eliminates at least one symptom of a complement-mediated disease or disorder in an individual. Examples of symptoms include, but are not limited to, symptoms associated with autoimmune diseases, cancer, blood disorders, infectious diseases, inflammatory diseases, ischemia-reperfusion injury, neurodegenerative diseases, neurodegenerative disorders, renal diseases, transplant rejection, eye diseases, vascular diseases, or vasculitic disorders. Symptoms can also be neurological symptoms, such as cognitive impairment, memory impairment, loss of motor function, etc. Symptoms can also be the activity of C1s protein in an individual's cells, tissues, or fluids. Symptoms can also be the degree of complement activation in an individual's cells, tissues, or fluids.

[0211] In some embodiments, administering an active compound described herein (e.g., a compound of Formula (I), (I'), (II), (IIA), (III), (IIIA), (IV), (IVA), (V), (VA), (VB), (VC), (VI), (VIA), (VIB), (VIC), or (VII), or a compound in Table 1), or a salt or composition thereof, to an individual modulates complement activation in cells, tissues, or fluids of the individual. In some embodiments, administering an active compound described herein (e.g., a compound of Formula (I), (I'), (II), (IIA), (III), (IIIA), (IV), (IVA), (V), (VA), (VB), (VC), (VI), (VIA), (VIB), (VIC), or (VII), or a compound in Table 1), or a salt or composition thereof, to an individual inhibits complement activation in cells, tissues, or fluids of the individual. For example, in some embodiments, an active compound described herein (e.g., a compound of Formula (I), (I'), (II), (IIA), (III), (IIIA), (IV), (IVA), (V), (VA), (VB), (VC), (VI), (VIA), (VIB), (VIC), or (VII), or a compound of Table 1), or a salt or composition thereof, when administered in one or more doses as monotherapy or in combination therapy to an individual having a complement-mediated disease or disorder, inhibits complement activation in the individual by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or more than 90% compared to complement activation in the individual before treatment with a compound described herein.

[0212] In some embodiments, an active compound described herein (e.g., a compound of Formula (I), (I'), (II), (IIA), (III), (IIIA), (IV), (IVA), (V), (VA), (VB), (VC), (VI), (VIA), (VIB), (VIC), or (VII), or a compound in Table 1), or a salt or composition thereof, reduces C3 deposition on red blood cells. For example, in some embodiments, an active compound described herein (e.g., a compound of Formula (I), (I'), (II), (IIA), (III), (IIIA), (IV), (IVA), (V), (VA), (VB), (VC), (VI), (VIA), (VIB), (VIC), or (VII), or a compound in Table 1), or a salt or composition thereof, reduces C3b, iC3b, etc. deposition on RBCs. In some embodiments, an active compound described herein (e.g., a compound of formula (I), (I'), (II), (IIA), (III), (IIIA), (IV), (IVA), (V), (VA), (VB), (VC), (VI), (VIA), (VIB), (VIC), or (VII), or a compound of Table 1), or a salt or composition thereof, inhibits complement-mediated erythrocyte lysis.

[0213] In some embodiments, an active compound described herein (e.g., a compound of Formula (I), (I'), (II), (IIA), (III), (IIIA), (IV), (IVA), (V), (VA), (VB), (VC), (VI), (VIA), (VIB), (VIC), or (VII), or a compound of Table 1), or a salt or composition thereof, reduces C3 deposition on platelets. For example, in some embodiments, an active compound described herein (e.g., a compound of Formula (I), (I'), (II), (IIA), (III), (IIIA), (IV), (IVA), (V), (VA), (VB), (VC), (VI), (VIA), (VIB), (VIC), or (VII), or a compound of Table 1), or a salt or composition thereof, reduces C3b, iC3b, etc. deposition on platelets.

[0214] In some embodiments, administration of an active compound described herein (e.g., a compound of Formula (I), (I'), (II), (IIA), (III), (IIIA), (IV), (IVA), (V), (VA), (VB), (VC), (VI), (VIA), (VIB), (VIC), or (VII), Table 1), or a salt or composition thereof, results in: (a) reduced complement activation; (b) improved cognitive function; (c) reduced neuronal loss; (d) reduced phosphorylated tau levels in neurons; (e) reduced glial cell activation; (f) reduced lymphocyte infiltration. , (g) reduced macrophage infiltration, (h) reduced antibody deposition, (i) reduced glial cell loss, (j) reduced oligodendrocyte loss, (k) reduced dendritic cell infiltration, (l) reduced neutrophil infiltration, (m) reduced erythrocyte lysis, (n) reduced erythrocyte phagocytosis, (o) reduced platelet phagocytosis, (p) reduced platelet lysis, (q) improved graft survival, (r) reduced macrophage-mediated phagocytosis, (s) improved vision, (t) improved motor control, (u) improved thrombus formation, (v) improved coagulation, (w) improved kidney function, (x) reduced antibody-mediated complement activation, (y) reduced autoantibody-mediated complement activation. (z) improvement of anemia, (aa) reduction of demyelination, (ab) reduction of eosinophilia, (ac) reduction of C3 deposition on red blood cells (e.g., reduction of C3b, iC3b, etc. deposition on RBCs), and (ad) reduction of C3 deposition on platelets (e.g., reduction of C3b, iC3b, etc. deposition on platelets), and (ae) reduction of anaphylatoxin toxin production, (af) reduction of autoantibody-mediated blister formation, (ag) reduction of autoantibody-induced pruritus, (ah) reduction of autoantibody-induced lupus erythematosus, (ai) reduction of autoantibody-mediated skin erosion, (aj) reduction of autoantibody-mediated cutaneous erosion due to transfusion reactions. Reduced red blood cell destruction, (ak) reduced red blood cell lysis due to alloantibodies, (al) reduced hemolysis due to transfusion reactions, (am) reduced alloantibody-mediated platelet lysis, (an) reduced platelet lysis due to transfusion reactions, (ao) reduced mast cell activation, (ap) reduced mast cell histamine release, (aq) reduced vascular permeability, (ar) reduced edema, (as) reduced complement deposition on graft endothelium, (at) reduced anaphylatoxin production in graft endothelium, (au) reduced dermal-epidermal junction separation, (av) reduced anaphylatoxin production at the dermal-epidermal junction,(aw) reduced alloantibody-mediated complement activation in graft endothelium, (ax) reduced antibody-mediated loss of neuromuscular junction, (ay) reduced complement activation at the neuromuscular junction, (az) reduced anaphylatoxin production at the neuromuscular junction, (ba) reduced complement deposition at the neuromuscular junction, (bb) reduced paralysis, (bc) reduced anesthesia, (bd) increased bladder control, (be) increased bowel control, (bf) reduced autoantibody-associated mortality, and (bg) reduced autoantibody-associated morbidity.

[0215] In some embodiments, an active compound described herein (e.g., a compound of Formula (I), (I'), (II), (IIA), (III), (IIIA), (IV), (IVA), (V), (VA), (VB), (VC), (VI), (VIA), (VIB), (VIC), or (VII), or a compound of Table 1), or a salt or composition thereof, when administered in one or more doses to an individual having a complement-mediated disease or disorder, can improve or decrease any of the following outcomes: (a) complement activation; (b) cognitive decline; (c) neuronal loss; (d) phosphorylated tau levels in neurons; (e) glial activation; (f) lymphocyte infiltration; (g) macrophage infiltration; (h) antibody deposition, (i) glial cell loss; (j) oligodendrocyte loss; (j) leukemia; (k) or ... (k) dendritic cell infiltration; (l) neutrophil infiltration; (m) erythrocyte lysis; (n) erythrocyte phagocytosis; (o) platelet phagocytosis; (p) platelet lysis; (q) transplant rejection; (l) macrophage-mediated phagocytosis; (s) vision loss; (t) antibody-mediated complement activation; (u) autoantibody-mediated complement activation; (v) demyelination; (w) eosinophilia, compared to the level or extent of the outcome in the individual before treatment with the active compound or salt thereof.

[0216] In some embodiments, an active compound described herein (e.g., a compound of Formula (I), (I'), (II), (IIA), (III), (IIIA), (IV), (IVA), (V), (VA), (VB), (VC), (VI), (VIA), (VIB), (VIC), or (VII), or a compound of Table 1), or a salt or composition thereof, when administered in one or more doses to an individual having a complement-mediated disease or disorder, improves or suppresses the progression of any of the following outcomes: a) cognitive function; b) graft survival; c) visual acuity; d) motor control. e) clot formation; f) coagulation; g) kidney function; and h) hematocrit (red blood cell count) by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or more than 90% improvement compared to the level or degree of outcome in the individual before treatment with the active compound or salt thereof.

[0217] In some embodiments, administering to an individual an active compound described herein (e.g., a compound of Formula (I), (I'), (II), (IIA), (III), (IIIA), (IV), (IVA), (V), (VA), (VB), (VC), (VI), (VIA), (VIB), (VIC), or (VII), or a compound of Table 1), or a salt or composition thereof, reduces complement activation in the individual. For example, in some embodiments, an active compound described herein (e.g., a compound of Formula (I), (I'), (II), (IIA), (III), (IIIA), (IV), (IVA), (V), (VA), (VB), (VC), (VI), (VIA), (VIB), (VIC), or (VII), or a compound of Table 1), or a salt or composition thereof, when administered in one or more doses to an individual having a complement-mediated disease or disorder, reduces complement activation in the individual by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or more than 90% compared to the complement activation in the individual before treatment with the active compound or salt thereof.

[0218] In some embodiments, administering an active compound described herein (e.g., a compound of Formula (I), (I'), (II), (IIA), (III), (IIIA), (IV), (IVA), (V), (VA), (VB), (VC), (VI), (VIA), (VIB), (VIC), or (VII), or a compound of Table 1), or a salt or composition thereof, improves cognitive function in an individual. For example, in some embodiments, an active compound described herein (e.g., a compound of Formula (I), (I'), (II), (IIA), (III), (IIIA), (IV), (IVA), (V), (VA), (VB), (VC), (VI), (VIA), (VIB), (VIC), or (VII), or a compound of Table 1), when administered in one or more doses to an individual having a complement-mediated disease or disorder, improves cognitive function in the individual by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or more than 90% compared to cognitive function in the individual prior to treatment with the active compound or salt thereof.

[0219] In some embodiments, administering an active compound described herein (e.g., a compound of Formula (I), (I'), (II), (IIA), (III), (IIIA), (IV), (IVA), (V), (VA), (VB), (VC), (VI), (VIA), (VIB), (VIC), or (VII), or Table 1), or a salt or composition thereof, reduces the rate of cognitive decline in an individual. For example, in some embodiments, an active compound (e.g., a compound of Formula (I), (I'), (II), (IIA), (III), (IIIA), (IV), (IVA), (V), (VA), (VB), (VC), (VI), (VIA), (VIB), (VIC), or (VII), or a compound of Table 1), or a salt thereof, when administered in one or more doses to an individual having a complement-mediated disease or disorder, reduces the rate of decline in cognitive function in the individual by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or more than 90% compared to the rate of decline in cognitive function in the individual before treatment with the active compound or salt thereof.

[0220] In some embodiments, administering to an individual an active compound described herein (e.g., a compound of Formula (I), (I'), (II), (IIA), (III), (IIIA), (IV), (IVA), (V), (VA), (VB), (VC), (VI), (VIA), (VIB), (VIC), or (VII), or a compound of Table 1), or a salt or composition thereof, reduces neuronal loss in the individual. For example, in some embodiments, an active compound (e.g., a compound of Formula (I), (I'), (II), (IIA), (III), (IIIA), (IV), (IVA), (V), (VA), (VB), (VC), (VI), (VIA), (VIB), (VIC), or (VII), or a compound of Table 1), or a salt thereof, when administered in one or more doses to an individual having a complement-mediated disease or disorder, reduces neuronal loss in the individual by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or more than 90% compared to neuronal loss in the individual before treatment with the active compound or salt thereof.

[0221] In some embodiments, administering to an individual an active compound described herein (e.g., a compound of Formula (I), (I'), (II), (IIA), (III), (IIIA), (IV), (IVA), (V), (VA), (VB), (VC), (VI), (VIA), (VIB), (VIC), or (VII), or a compound of Table 1), or a salt or composition thereof, reduces phosphorylated tau levels in the individual. For example, in some embodiments, an active compound (e.g., a compound of Formula (I), (I'), (II), (IIA), (III), (IIIA), (IV), (IVA), (V), (VA), (VB), (VC), (VI), (VIA), (VIB), (VIC), or (VII), or a compound of Table 1), or a salt thereof, when administered in one or more doses to an individual having a complement-mediated disease or disorder, reduces phosphorylated tau in the individual by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or more than 90% compared to phosphorylated tau levels in the individual before treatment with the active compound or salt thereof.

[0222] In some embodiments, administering to an individual an active compound described herein (e.g., a compound of Formula (I), (I'), (II), (IIA), (III), (IIIA), (IV), (IVA), (V), (VA), (VB), (VC), (VI), (VIA), (VIB), (VIC), or (VII), or a compound of Table 1), or a salt or composition thereof, reduces glial cell activation in the individual. For example, in some embodiments, an active compound (e.g., a compound of Formula (I), (I'), (II), (IIA), (III), (IIIA), (IV), (IVA), (V), (VA), (VB), (VC), (VI), (VIA), (VIB), (VIC), or (VII), or a compound of Table 1), or a salt thereof, when administered in one or more doses to an individual having a complement-mediated disease or disorder, reduces glial activation in the individual by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or more than 90% compared to glial cell activation in the individual before treatment with the active compound or salt thereof. In some embodiments, the glial cells are astrocytes or microglia.

[0223] In some embodiments, administering to an individual an active compound described herein (e.g., a compound of Formula (I), (I'), (II), (IIA), (III), (IIIA), (IV), (IVA), (V), (VA), (VB), (VC), (VI), (VIA), (VIB), (VIC), or (VII), or a compound of Table 1), or a salt or composition thereof, reduces lymphocytic infiltration in the individual. For example, in some embodiments, an active compound (e.g., a compound of Formula (I), (I'), (II), (IIA), (III), (IIIA), (IV), (IVA), (V), (VA), (VB), (VC), (VI), (VIA), (VIB), (VIC), or (VII), or a compound of Table 1), or a salt thereof, when administered in one or more doses to an individual having a complement-mediated disease or disorder, reduces lymphocyte infiltration in the individual by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or more than 90% compared to the lymphocyte infiltration in the individual before treatment with the active compound or salt thereof.

[0224] In some embodiments, administering to an individual an active compound described herein (e.g., a compound of Formula (I), (I'), (II), (IIA), (III), (IIIA), (IV), (IVA), (V), (VA), (VB), (VC), (VI), (VIA), (VIB), (VIC), or (VII), or a compound of Table 1), or a salt or composition thereof, reduces macrophage infiltration in the individual. For example, in some embodiments, an active compound (e.g., a compound of Formula (I), (I'), (II), (IIA), (III), (IIIA), (IV), (IVA), (V), (VA), (VB), (VC), (VI), (VIA), (VIB), (VIC), or (VII), or a compound of Table 1), or a salt thereof, when administered in one or more doses to an individual having a complement-mediated disease or disorder, reduces macrophage infiltration in the individual by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or more than 90% compared to the macrophage infiltration in the individual before treatment with the active compound or salt thereof.

[0225] In some embodiments, administering to an individual an active compound described herein (e.g., (I), (I'), (II), (IIA), (III), (IIIA), (IV), (IVA), (V), (VA), (VB), (VC), (VI), (VIA), (VIB), (VIC), or (VII), or a compound in Table 1), or a salt or composition thereof, reduces antibody deposition in the individual. For example, in some embodiments, an active compound (e.g., a compound of Formula (I), (I'), (II), (IIA), (III), (IIIA), (IV), (IVA), (V), (VA), (VB), (VC), (VI), (VIA), (VIB), (VIC), or (VII), or a compound of Table 1), or a salt thereof, when administered in one or more doses to an individual having a complement-mediated disease or disorder, reduces antibody deposition in the individual by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or more than 90% compared to antibody deposition in the individual before treatment with the active compound or salt thereof.

[0226] In some embodiments, administering an active compound described herein (e.g., a compound of Formula (I), (I'), (II), (IIA), (III), (IIIA), (IV), (IVA), (V), (VA), (VB), (VC), (VI), (VIA), (VIB), (VIC), or (VII), or a compound of Table 1), or a salt or composition thereof, to an individual reduces anaphylatoxin (e.g., C3a, C4a, C5a) production in the individual. For example, in some embodiments, an active compound (e.g., a compound of Formula (I), (I'), (II), (IIA), (III), (IIIA), (IV), (IVA), (V), (VA), (VB), (VC), (VI), (VIA), (VIB), (VIC), or (VII), or a compound of Table 1), or a salt thereof, when administered in one or more doses to an individual having a complement-mediated disease or disorder, reduces anaphylatoxin production in the individual by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or more than 90% compared to the level of anaphylatoxin production in the individual before treatment with the active compound or salt thereof.

[0227] The present disclosure provides use of an active compound of the present disclosure (e.g., a compound of Formula (I), (I'), (II), (IIA), (III), (IIIA), (IV), (IVA), (V), (VA), (VB), (VC), (VI), (VIA), (VIB), (VIC), or (VII), or a compound in Table 1) or a salt thereof, or a pharmaceutical composition comprising an active compound of the present disclosure (e.g., a compound of Formula (I), (I'), (II), (IIA), (III), (IIIA), (IV), (IVA), (V), (VA), (VB), (VC), (VI), (VIA), (VIB), (VIC), or (VII), or a compound in Table 1) or a salt thereof, and a pharmaceutically acceptable excipient, for treating an individual having a complement-mediated disease or disorder. In some embodiments, the present disclosure provides use of an active compound of the present disclosure (e.g., a compound of formula (I), (I'), (II), (IIA), (III), (IIIA), (IV), (IVA), (V), (VA), (VB), (VC), (VI), (VIA), (VIB), (VIC), or (VII), or a compound of Table 1), or a salt thereof, to treat an individual having a complement-mediated disease or disorder. In some embodiments, the present disclosure provides use of a pharmaceutical composition comprising an active compound of the present disclosure (e.g., a compound of Formula (I), (I'), (II), (IIA), (III), (IIIA), (IV), (IVA), (V), (VA), (VB), (VC), (VI), (VIA), (VIB), (VIC), or (VII), or a compound of Table 1), or a salt thereof, and a pharmaceutically acceptable excipient, for treating an individual having a complement-mediated disease or disorder. [Example]

[0228] The following examples are illustrative only and should not be construed as limiting the scope of the disclosure in any way, as numerous variations and equivalents will become apparent to those skilled in the art upon reading this disclosure. The contents of all references, patents, and patent applications cited throughout this application are expressly incorporated herein by reference.

[0229] Example 1. Non-limiting synthesis examples of compounds of the present disclosure The following schemes are non-limiting examples of methods for making the compounds of the present disclosure. Those skilled in the art will recognize that there are various modifications that can be made to make analogs or otherwise prepare the compounds. [Table 3-1] [Table 3-2]

[0230] General method All non-aqueous reactions were carried out under an atmosphere of dry argon or nitrogen gas using anhydrous solvents. Reaction progress and purity of target compounds were determined using one of two liquid chromatography (LC) methods A or B disclosed herein. The structures of starting materials, intermediates, and final products were confirmed by standard analytical techniques, including NMR spectroscopy and mass spectrometry.

[0231] LC method A Equipment:Waters Acquity Ultra Performance LC Column: ACQUITY UPLC BEH C18 2.1'50mm, 1.7mm Column temperature: 40℃ Mobile phase: Solvent A: H2O + 0.05% FA, Solvent B: CH3CN + 0.05% FA Flow rate: 0.8mL / min Gradient: 15% B for 0.24 min, gradient (15-85% B) in 3.5 min, then 85% B for 0.5 min. Detection: UV (210-410 nm) and MS (SQ in ES+ mode)

[0232] Scheme 1. Synthesis of N-(1-(2-(((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)amino)-2-oxoethyl)-6-oxo-2-phenyl-1,6-dihydropyrimidin-5-yl)-3-phenylpropanamide (compound 5) [ka] Step 1: Tert-butyl 2-(5-((2,4-dimethoxybenzyl)amino)-2-(methylthio)-6-oxopyrimidin-1(6H)-yl)acetate To a mixture of tert-butyl 2-(5-bromo-2-(methylthio)-6-oxopyrimidin-1(6H)-yl)acetate (1.0 g, 2.99 mmol) and (2,4-dimethoxyphenyl)methanamine (1.0 g, 5.99 mmol) in toluene (10 mL) was added rac-BINAP (373 mg, 0.60 mmol), CsCO (1.95 g, 5.99 mmol), and Pd(OAc) (67 mg, 0.30 mmol) under N atmosphere, and the mixture was degassed three times under N atmosphere and stirred at 120 °C overnight. The reaction mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous NaSO, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (silica gel, 0-18% EtOAc in PE) to give tert-butyl 2-(5-((2,4-dimethoxybenzyl)amino)-2-(methylthio)-6-oxopyrimidin-1(6H)-yl)acetate (1.06 g, 84.3% yield) as a yellow oil. LC / MS (ESI) m / z: 422 (M+H) + .

[0233] Step 2: Tert-butyl 2-(5-((2,4-dimethoxybenzyl)amino)-6-oxo-2-phenylpyrimidin-1(6H)-yl)acetate To a mixture of tert-butyl 2-(5-((2,4-dimethoxybenzyl)amino)-2-(methylthio)-6-oxopyrimidin-1(6H)-yl)acetate (345 mg, 0.82 mmol) and phenylboronic acid (200 mg, 1.64 mmol) in THF (6 mL) was added ((thiophene-2-carbonyl)oxy)copper (344 mg, 1.80 mmol) and Pd(PPh3)4 (95 mg, 0.082 mmol) under N2 atmosphere. The mixture was degassed three times under N2 atmosphere and stirred in a sealed tube at 55 °C overnight. The reaction mixture was diluted with EtOAc and filtered. The filtrate was washed with saturated aqueous NaHCO3 and brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (silica gel, 0-24% EtOAc in PE) to give tert-butyl 2-(5-((2,4-dimethoxybenzyl)amino)-6-oxo-2-phenylpyrimidin-1(6H)-yl)acetate (310 mg, 83.9% yield) as a yellow oil. LC / MS (ESI) m / z: 452 (M+H) + .

[0234] Step 3: 2-(5-amino-6-oxo-2-phenylpyrimidin-1(6H)-yl)acetic acid To a solution of tert-butyl 2-(5-((2,4-dimethoxybenzyl)amino)-6-oxo-2-phenylpyrimidin-1(6H)-yl)acetate (180 mg, 0.40 mmol) in DCM (5 mL) was added TFA (2 mL) and the reaction mixture was stirred at room temperature for 3 h. The mixture was concentrated to dryness under reduced pressure to give 2-(5-amino-6-oxo-2-phenylpyrimidin-1(6H)-yl)acetic acid (97 mg, crude) as a yellow solid, which was used directly in the next step without further purification. LC / MS (ESI) m / z: 246 (M+H) + .

[0235] Step 4: Tert-butyl 2-((2-(5-amino-6-oxo-2-phenylpyrimidin-1(6H)-yl)acetamido)methyl)-1H-pyrrolo[3,2-c]pyridine-1-carboxylate To a mixture of 2-(5-amino-6-oxo-2-phenylpyrimidin-1(6H)-yl)acetic acid (80 mg, 0.33 mmol) and tert-butyl 2-(aminomethyl)-1H-pyrrolo[3,2-c]pyridine-1-carboxylate (80 mg, 0.33 mmol) in DMF (3 mL) was added DIPEA (251 mg, 1.94 mmol) and T3P (372 mg, 0.58 mmol, 50 wt % in EtOAc) under a N2 atmosphere, and the mixture was stirred overnight at 35° C. The mixture was diluted with EtOAc, washed with saturated aqueous NaHCO3 and brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (silica gel, 0-5% MeOH in DCM) to give tert-butyl 2-((2-(5-amino-6-oxo-2-phenylpyrimidin-1(6H)-yl)acetamido)methyl)-1H-pyrrolo[3,2-c]pyridine-1-carboxylate (80 mg, 51.7% yield) as a pale yellow oil. LC / MS (ESI) m / z: 475 (M+H) + .

[0236] Step 5: Tert-butyl 2-((2-(6-oxo-2-phenyl-5-(3-phenylpropanamido)pyrimidin-1(6H)-yl)acetamido)methyl)-1H-pyrrolo[3,2-c]pyridine-1-carboxylate To a mixture of 3-phenylpropanoic acid (16 mg, 0.11 mmol) and HATU (48 mg, 0.13 mmol) in DMF (3 mL) was added DIPEA (40 mg, 0.31 mmol) under a N atmosphere, and the mixture was stirred at room temperature for 30 minutes. Tert-butyl 2-((2-(5-amino-6-oxo-2-phenylpyrimidin-1(6H)-yl)acetamido)methyl)-1H-pyrrolo[3,2-c]pyridine-1-carboxylate (50 mg, 0.11 mmol) was added to the stirring mixture, and the resulting mixture was stirred at 35° C. overnight. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous NaSO, filtered, and concentrated to dryness under reduced pressure. The residue was purified by preparative TLC (DCM:MeOH=10:1) to give tert-butyl 2-((2-(6-oxo-2-phenyl-5-(3-phenylpropanamido)pyrimidin-1(6H)-yl)acetamido)methyl)-1H-pyrrolo[3,2-c]pyridine-1-carboxylate (30 mg, 57.8% yield) as a yellow oil. LC / MS (ESI) m / z: 607 (M+H) + .

[0237] Step 6: N-(1-(2-(((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)amino)-2-oxoethyl)-6-oxo-2-phenyl-1,6-dihydropyrimidin-5-yl)-3-phenylpropanamide (Compound 5) To a solution of tert-butyl 2-((2-(6-oxo-2-phenyl-5-(3-phenylpropanamido)pyrimidin-1(6H)-yl)acetamido)methyl)-1H-pyrrolo[3,2-c]pyridine-1-carboxylate (30 mg, 0.050 mmol) in DCM (1.5 mL) was added TFA (1.5 mL), and the reaction mixture was stirred at room temperature for 3 hours. The mixture was concentrated to dryness under reduced pressure. The residue was purified by preparative HPLC to give compound 5 (6.7 mg, 26.8% yield) as a white solid. 1H NMR (400 MHz, CD3OD) δ 8.92 (d, J = 3.3 Hz, 2H), 8.24 (d, J = 6.4 Hz, 1H), 7.72 (d, J = 6.2 Hz, 1H), 7.56 - 7.50 (m, 3H), 7.47 - 7.42 (m, 2H), 7.26 (d, J = 4.6 Hz, 4H), 7.17 (dd, J = 9.0, 4.8 Hz, 1H), 6.74 (s, 1H), 4.67 (s, 2H), 4.59 (s, 2H), 3.01 (t, J = 7.6 Hz, 2H), 2.81 (t, J = 7.6 Hz, 2H). LC / MS (ESI) m / z: 507 (M+H) + . RT (Method A): 1.14 minutes.

[0238] The following compounds were prepared based on steps 5-6 of Scheme 1: [Table 4-1] [Table 4-2]

[0239] Scheme 2. Synthesis of N-(1-(2-(((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)amino)-2-oxoethyl)-6-oxo-2-phenyl-1,6-dihydropyrimidin-5-yl)-4-phenoxybenzamide (compound 8) [ka] Step 1: 2-(5-((2,4-dimethoxybenzyl)amino)-6-oxo-2-phenylpyrimidin-1(6H)-yl)acetic acid To a solution of tert-butyl 2-(5-((2,4-dimethoxybenzyl)amino)-6-oxo-2-phenylpyrimidin-1(6H)-yl)acetate (3.9 g, 8.6 mmol) in MeOH / HO / THF (40 mL, 2 / 1 / 1) was added NaOH (1.3 g, 34.4 mmol) under a N atmosphere, and the reaction mixture was stirred at 50 °C for 2 h. The mixture was acidified with 1 N aqueous HCl to pH 3 and extracted twice with EtOAc. The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give 2-(5-((2,4-dimethoxybenzyl)amino)-6-oxo-2-phenylpyrimidin-1(6H)-yl)acetic acid (2.8 g, 82.4% yield) as a yellow solid, which was used directly in the next step without further purification. LC / MS (ESI) m / z: 396 (M+H) +.

[0240] Step 2: N-((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)-2-(5-((2,4-dimethoxybenzyl)amino)-6-oxo-2-phenylpyrimidin-1(6H)-yl)acetamide To a mixture of 2-(5-((2,4-dimethoxybenzyl)amino)-6-oxo-2-phenylpyrimidin-1(6H)-yl)acetic acid (2.0 g, 4.8 mmol) and (1H-pyrrolo[3,2-c]pyridin-2-yl)methanamine (705 mg, 4.8 mmol) in DMF (20 mL) was added DIPEA (2.8 g, 21.5 mmol) and HATU (1.8 g, 4.7 mmol) under a N atmosphere, and the reaction mixture was stirred at room temperature for 2 h. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous NaSO, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (silica gel, 0-10% MeOH in DCM) to give N-((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)-2-(5-((2,4-dimethoxybenzyl)amino)-6-oxo-2-phenylpyrimidin-1(6H)-yl)acetamide (2.3 g, 91.7% yield) as a yellow solid. LC / MS (ESI) m / z: 524 (M+H) + .

[0241] Step 3: N-((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)-2-(5-amino-6-oxo-2-phenylpyrimidin-1(6H)-yl)acetamide hydrochloride A solution of N-((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)-2-(5-((2,4-dimethoxybenzyl)amino)-6-oxo-2-phenylpyrimidin-1(6H)-yl)acetamide (2.3 g, 4.4 mmol) in HCl / 1,4-dioxane (20 mL, 4 M) was stirred at room temperature under a N atmosphere for 2 hours. The reaction mixture was concentrated to dryness under reduced pressure to give N-((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)-2-(5-amino-6-oxo-2-phenylpyrimidin-1(6H)-yl)acetamide hydrochloride (1.6 g, 97.7% yield) as a brown solid, which was used directly in the next step without further purification. LC / MS (ESI) m / z: 375 (M+H) + .

[0242] Step 4: N-(1-(2-(((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)amino)-2-oxoethyl)-6-oxo-2-phenyl-1,6-dihydropyrimidin-5-yl)-4-phenoxybenzamide (compound 8) To a mixture of N-((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)-2-(5-amino-6-oxo-2-phenylpyrimidin-1(6H)-yl)acetamide hydrochloride (30 mg, 0.080 mmol) and 4-phenoxybenzoic acid (17 mg, 0.080 mmol) in DMF (0.8 mL), DIPEA (41 mg, 0.032 mmol) and HATU (33 mg, 0.090 mmol) were added under a N atmosphere, and the reaction mixture was stirred at room temperature for 2 hours. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous NaSO, filtered, and concentrated to dryness under reduced pressure. The residue was purified by preparative TLC (DCM:MeOH=8:1) and further purified by preparative HPLC to give compound 8 (0.8 mg, 1.8% yield) as a white solid. 1H-NMR (400 MHz, CD3OD) δ 9.02 (s, 1H), 8.90 (s, 1H), 8.44 (s, 1H), 8.21 (d, J= 6.1 Hz, 1H), 8.00 - 7.97 (m, 2H), 7.66 (d, J= 6.2 Hz, 1H), 7.56 (dd, J= 7.6, 6.1 Hz, 3H), 7.48 - 7.42 (m, 4H), 7.23 (t, J= 7.4 Hz, 1H), 7.12 - 7.08 (m, 4H), 6.71 (s, 1H), 4.60 (s, 2H), 4.58 (s, 2H). LC / MS (ESI) m / z: 571 (M+H) + . RT (Method A): 1.50 minutes.

[0243] Scheme 3. Synthesis of (S)—N-(1-(1H-pyrrolo[3,2-c]pyridin-2-yl)ethyl)-2-(6-oxo-2-phenyl-5-((3-phenylpropyl)amino)pyrimidin-1(6H)-yl)acetamide (Compound 9) [ka] To a mixture of (S)-1-(1H-pyrrolo[3,2-c]pyridin-2-yl)ethan-1-amine hydrochloride (25 mg, 0.083 mmol) and 2-(6-oxo-2-phenyl-5-((3-phenylpropyl)amino)pyrimidin-1(6H)-yl)acetic acid (25 mg, 0.069 mmol) in DMF (1 mL), DIPEA (36 mg, 0.27 mmol) and HATU (31 mg, 0.090 mmol) were added under a N atmosphere, and the reaction mixture was stirred at room temperature for 1 h. To the mixture, LiOH (4.8 mg, 0.20 mmol), MeOH (0.5 mL), and water (0.1 mL) were added, and the mixture was stirred at room temperature for 6 h. The mixture was diluted with EtOAc, washed with saturated aqueous NaHCO and brine, dried over anhydrous NaSO, filtered, and concentrated to dryness under reduced pressure. The residue was purified by preparative TLC (DCM:MeOH=10:1) and further purified by preparative HPLC to give compound 9 (5.3 mg, yield 15.2%) as a white solid. 1H NMR (400 MHz, CD3OD) δ 8.73 (s, 1H), 8.12 (d, J = 5.9 Hz, 1H), 7.47 (d, J = 6.8 Hz, 3H), 7.44 - 7.38 (m, 3H), 7.23 (t, J = 7.9 Hz, 4H), 7.16 (t, J = 7.2 Hz, 1H), 7.07 (s, 1H), 6.50 (s, 1H), 5.24 (q, J = 6.8 Hz, 1H), 4.60 (t, J = 13.5 Hz, 2H), 3.17 (t, J = 7.0 Hz, 2H), 2.74 (t, J = 7.6 Hz, 2H), 2.02 - 1.94 (m, 2H), 1.55 (d, J = 6.9 Hz, 3H). LC / MS (ESI) m / z: 507 (M+H) + . RT (Method A): 1.41 minutes.

[0244] The following compounds were prepared according to Scheme 3: [Table 5-1] [Table 5-2]

[0245] Scheme 4. Synthesis of N-((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)-2-(6-oxo-5-((4-phenoxybutyl)amino)-2-phenylpyrimidin-1(6H)-yl)acetamide (Compound 11) [ka] Step 1: (4-Azidobutoxy)benzene To a solution of (4-bromobutoxy)benzene (200 mg, 0.88 mmol) in DMF (3 mL) was added NaN (112 mg, 1.75 mmol) under a N atmosphere at 0 °C, and the mixture was stirred at 50 °C for 16 h. The mixture was diluted with water and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NaSO, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (silica gel, 0-8% EtOAc in PE) to give (4-azidobutoxy)benzene (150 mg, 93.0% yield) as a colorless oil. LC / MS (ESI) m / z: 192 (M+H) + .

[0246] Step 2: 4-phenoxybutan-1-amine To a solution of (4-azidobutoxy)benzene (150 mg, 0.78 mmol) in MeOH (3 mL) was added Pd / C (20 mg, 10 wt%), and the mixture was degassed three times under N atmosphere and stirred overnight at 25 °C under a H balloon. The mixture was filtered, and the filtrate was concentrated to dryness to give 4-phenoxybutan-1-amine (120 mg, 99% yield) as a colorless oil, which was used directly in the next step without further purification. LC / MS (ESI) m / z: 166 (M+H). + .

[0247] Step 3: Tert-butyl 2-(2-(methylthio)-6-oxo-5-((4-phenoxybutyl)amino)pyrimidin-1(6H)-yl)acetate To a mixture of 4-phenoxybutan-1-amine (120 mg, 0.73 mmol) and tert-butyl 2-(5-bromo-2-(methylthio)-6-oxopyrimidin-1(6H)-yl)acetate (253 mg, 0.73 mmol) in toluene (3 mL), CsCO (494 mg, 1.46 mmol), rac-BINAP (94.3 mg, 0.15 mmol), and Pd(OAc) (17 mg, 0.07 mmol) were added under N atmosphere. The reaction mixture was degassed three times under N atmosphere and stirred at 120 °C overnight. The mixture was diluted with water and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NaSO, filtered, and concentrated to dryness under reduced pressure. The residue was purified by preparative TLC (PE: EtOAc = 1: 1) to give tert-butyl 2-(2-(methylthio)-6-oxo-5-((4-phenoxybutyl) amino) pyrimidin-1(6H)-yl) acetate (100 mg, 32.8% yield) as a yellow solid. LC / MS (ESI) m / z: 420 (M+H) + .

[0248] Step 4: Tert-butyl 2-(6-oxo-5-((4-phenoxybutyl)amino)-2-phenylpyrimidin-1(6H)-yl)acetate To a mixture of tert-butyl 2-(2-(methylthio)-6-oxo-5-((4-phenoxybutyl)amino)pyrimidin-1(6H)-yl)acetate (100 mg, 0.24 mmol) and phenylboronic acid (58 mg, 0.48 mmol) in THF (2 mL) was added ((thiophene-2-carbonyl)oxy)copper (100 mg, 0.53 mmol) and Pd(PPh3)4 (55 mg, 0.05 mmol) under N2 atmosphere, and the reaction mixture was degassed three times under N2 atmosphere and stirred at 55 °C overnight. The mixture was diluted with water and extracted twice with EtOAc. The combined organic layers were washed with saturated aqueous NaHCO3 and brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was purified by preparative TLC (PE: EtOAc = 1: 1) to give tert-butyl 2-(6-oxo-5-((4-phenoxybutyl)amino)-2-phenylpyrimidin-1(6H)-yl)acetate (30 mg, 28.0% yield) as a yellow solid. LC / MS (ESI) m / z: 450 (M+H) + .

[0249] Step 5: 2-(6-oxo-5-((4-phenoxybutyl)amino)-2-phenylpyrimidin-1(6H)-yl)acetic acid To a solution of tert-butyl 2-(6-oxo-5-((4-phenoxybutyl)amino)-2-phenylpyrimidin-1(6H)-yl)acetate (30 mg, 0.07 mmol) in DCM (2 mL) was added TFA (1 mL), and the mixture was stirred overnight at room temperature under a N atmosphere. The reaction mixture was concentrated to dryness under reduced pressure to give 2-(6-oxo-5-((4-phenoxybutyl)amino)-2-phenylpyrimidin-1(6H)-yl)acetic acid (25 mg, 95.2% yield) as a yellow solid, which was used directly in the next step without further purification. LC / MS (ESI) m / z: 394 (M+H) + .

[0250] Step 6: N-((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)-2-(6-oxo-5-((4-phenoxybutyl)amino)-2-phenylpyrimidin-1(6H)-yl)acetamide (Compound 11) To a mixture of 2-(6-oxo-5-((4-phenoxybutyl)amino)-2-phenylpyrimidin-1(6H)-yl)acetic acid (25 mg, 0.06 mmol) and (1H-pyrrolo[3,2-c]pyridin-2-yl)methanamine (19 mg, 0.12 mmol) in DMF (2 mL) was added DIPEA (49 mg, 0.36 mmol) and PyBop (33 mg, 0.06 mmol) under a N atmosphere, and the reaction mixture was stirred at room temperature for 2 h. The mixture was diluted with EtOAc, washed with saturated aqueous NaHCO and brine, dried over anhydrous NaSO, filtered, and concentrated to dryness under reduced pressure. The residue was purified by preparative TLC (DCM:MeOH = 12:1) and further purified by preparative HPLC to give compound 11 (4.0 mg, 12.1% yield) as a white solid. 1 H NMR (400 MHz, CD3OD) δ 8.73 (s, 1H), 8.12 (d, J= 5.9 Hz, 1H), 7.49 (s, 1H), 7.47 (d, J= 1.7 Hz, 2H), 7.45 (d, J= 4.8 Hz, 1H), 7.42 (d, J= 5.5 Hz, 1H), 7.40 (s, 1H), 7.27 - 7.23 (m, 2H), 7.18 (s, 1H), 6.93 - 6.89 (m, 3H), 6.52 (s, 1H), 4.62 (s, 2H), 4.55 (s, 2H), 4.05 (d, J= 5.8 Hz, 2H), 3.27 (s, 2H), 1.90 (d, J= 2.9 Hz, 4H). LC / MS (ESI) m / z: 523 (M+H) + . RT (Method A): 1.41 minutes.

[0251] The following compounds were prepared according to steps 3-6 of Scheme 4: [Table 6-1] [Table 6-2] [Table 6-3]

[0252] Scheme 5. Synthesis of N-(1-(2-(((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)amino)-2-oxoethyl)-6-oxo-2-phenyl-1,6-dihydropyrimidin-5-yl)-4-(4-phenoxyphenyl)butanamide (compound 18) [ka] Step 1: 4-(4-phenoxyphenyl)butanoic acid To a solution of 4-oxo-4-(4-phenoxyphenyl)butanoic acid (1.0 g, 3.70 mmol) in AcOH (10 mL) was added Pd / C (80 mg, 10 wt%), the mixture was degassed under N atmosphere three times, and the mixture was stirred under a H balloon at 70 °C for 5 h. The mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure to give 4-(4-phenoxyphenyl)butanoic acid (880 mg, 92.8% yield) as a yellow oil, which was used directly in the next step without further purification. LC / MS (ESI) (m / z): 257 (M+H) + .

[0253] Step 2: N-(1-(2-(((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)amino)-2-oxoethyl)-6-oxo-2-phenyl-1,6-dihydropyrimidin-5-yl)-4-(4-phenoxyphenyl)butanamide (compound 18) To a mixture of 4-(4-phenoxyphenyl)butanoic acid (40 mg, 0.15 mmol) and N-((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)-2-(5-amino-6-oxo-2-phenylpyrimidin-1(6H)-yl)acetamide (58 mg, 0.15 mmol) in DMF (2 mL) was added DIPEA (120 mg, 0.90 mmol) and HATU (71 mg, 0.18 mmol) under N atmosphere, and the reaction mixture was stirred at room temperature for 2 h. The mixture was diluted with EtOAc, washed with saturated aqueous NaHCO and brine, dried over anhydrous NaSO, filtered, and concentrated to dryness under reduced pressure. The residue was purified by preparative TLC (DCM:MeOH=10:1) and further purified by preparative HPLC to give compound 18 (10 mg, 10.5% yield) as a white solid. 1 H NMR (400 MHz, CD3OD) δ 8.92 (s, 1H), 8.73 (s, 1H), 8.12 (d, J= 5.9 Hz, 1H), 7.52 (d, J= 8.1 Hz, 3H), 7.43 (t, J= 5.5 Hz, 3H), 7.34 - 7.30 (m, 2H), 7.22 (d, J= 8.5 Hz, 2H), 7.07 (t, J= 7.4 Hz, 1H), 6.93 (dd, J= 14.5, 8.1 Hz, 4H), 6.52 (s, 1H), 4.67 (s, 2H), 4.55 (s, 2H), 2.70 (t, J= 7.6 Hz, 2H), 2.53 (t, J= 7.3 Hz, 2H), 2.04 - 2.00 (m, 2H). LC / MS (ESI) m / z: 613 (M+H) + . RT (Method A): 1.68 minutes.

[0254] Scheme 6. Synthesis of N-((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)-2-(6-oxo-5-((4-(4-phenoxyphenyl)butyl)amino)-2-phenylpyrimidin-1(6H)-yl)acetamide (compound 21) [ka] Step 1: N-Methoxy-N-methyl-4-(4-phenoxyphenyl)butanamide To a mixture of 4-(4-phenoxyphenyl)butanoic acid (300 mg, 1.17 mmol) and N,O-dimethylhydroxylamine (229 mg, 2.34 mmol) in DMF (3 mL) was added DIPEA (907 mg, 7.02 mmol) and HATU (534 mg, 1.40 mmol) under a N atmosphere, and the reaction mixture was stirred at room temperature for 2 h. The mixture was diluted with EtOAc, washed with saturated aqueous NH4Cl and brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (silica gel, 0-35% EtOAc in PE) to give N-methoxy-N-methyl-4-(4-phenoxyphenyl)butanamide (242 mg, 69.1% yield) as a brown oil. LC / MS (ESI) m / z: 300 (M+H) + .

[0255] Step 2: 4-(4-phenoxyphenyl)butanal To a solution of N-methoxy-N-methyl-4-(4-phenoxyphenyl)butanamide (242 mg, 0.81 mmol) in DCM (3 mL) was added DIBAL-H (1.20 mL, 1.22 mmol, 1N in THF) dropwise under a N atmosphere at −78° C., and the mixture was stirred at −78° C. for 1 h. The mixture was quenched with saturated aqueous potassium sodium tartrate and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NaSO, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (silica gel, 0-20% EtOAc in PE) to give 4-(4-phenoxyphenyl)butanal (80 mg, 41.2% yield) as a colorless oil. LC / MS (ESI) m / z: 241 (M+H) + .

[0256] Step 3: N-((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)-2-(6-oxo-5-((4-(4-phenoxyphenyl)butyl)amino)-2-phenylpyrimidin-1(6H)-yl)acetamide (compound 21) To a mixture of N-((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)-2-(5-amino-6-oxo-2-phenylpyrimidin-1(6H)-yl)acetamide (30 mg, 0.08 mmol) and 4-(4-phenoxyphenyl)butanal (38 mg, 0.16 mmol) in MeOH (3 mL), NaBHCN (20 mg, 0.32 mmol) was added under N atmosphere, and the reaction mixture was stirred at 50 °C for 1 h. The mixture was diluted with EtOAc, washed with brine, dried over anhydrous NaSO, filtered, and concentrated to dryness under reduced pressure. The residue was purified by preparative TLC (DCM:MeOH = 15:1) and further purified by preparative HPLC to give compound 21 (12 mg, 25.0% yield) as a white solid. 1 H NMR (400 MHz, CD3OD) δ 8.97 (s, 1H), 8.26 (d, J = 6.5 Hz, 1H), 7.79 (d, J = 6.5 Hz, 1H), 7.49 (t, J = 5.9 Hz, 3H), 7.45 - 7.40 (m, 2H), 7.30 (t, J= 7.9 Hz, 2H), 7.19 (d, J= 8.4 Hz, 2H), 7.14 (s, 1H), 7.06 (t, J = 7.4 Hz, 1H), 6.91 (dd, J = 16.2, 8.2 Hz, 4H), 6.81 (s, 1H), 4.63 (d, J = 13.1 Hz, 4H), 3.20 (t, J = 6.4 Hz, 2H), 2.67 (t, J = 7.0 Hz, 2H), 1.74 (dt, J = 8.4, 4.9 Hz, 4H). LC / MS (ESI) m / z: 599 (M+H) + . RT (Method A): 1.94 minutes.

[0257] Scheme 7. Synthesis of N-(1-(2-(((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)amino)-2-oxoethyl)-6-oxo-2-phenyl-1,6-dihydropyrimidin-5-yl)-4-oxo-4-(4-phenoxyphenyl)butanamide (compound 23) [ka] Step 1: 4-oxo-4-(4-phenoxyphenyl)butanoic acid To a mixture of oxydibenzene (5.0 g, 29.4 mmol) and dihydrofuran-2,5-dione (2.9 g, 29.4 mmol) in DCM (50 mL) was added AlCl (5.9 g, 44.1 mmol) under a N atmosphere at 0 °C, and the mixture was stirred at room temperature overnight. The mixture was acidified with 1 N aqueous HCl to pH 3 and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NaSO, filtered, and concentrated to dryness under reduced pressure to give 4-oxo-4-(4-phenoxyphenyl)butanoic acid (7.8 g, 98.2% yield) as a white solid. LC / MS (ESI) (m / z): 271 (M+H) + .

[0258] Step 2: N-(1-(2-(((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)amino)-2-oxoethyl)-6-oxo-2-phenyl-1,6-dihydropyrimidin-5-yl)-4-oxo-4-(4-phenoxyphenyl)butanamide (compound 23) To a mixture of 4-oxo-4-(4-phenoxyphenyl)butanoic acid (40 mg, 0.15 mmol) and N-((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)-2-(5-amino-6-oxo-2-phenylpyrimidin-1(6H)-yl)acetamide (56 mg, 0.15 mmol) in DMF (2 mL) was added DIPEA (120 mg, 0.90 mmol) and HATU (72 mg, 0.19 mmol) under N atmosphere, and the reaction mixture was stirred at room temperature for 2 h. The mixture was diluted with EtOAc, washed with saturated aqueous NH4Cl and brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was purified by preparative TLC (DCM:MeOH = 10:1) and further purified by preparative HPLC to give compound 23 (4.3 mg, 4.63% yield) as a white solid. 1H NMR (400 MHz, CD3OD) δ 8.91 (s, 1H), 8.75 (s, 1H), 8.14 (d, J = 5.9 Hz, 1H), 8.04 (d, J = 8.8 Hz, 2H), 7.53 (d, J = 8.3 Hz, 3H), 7.46 - 7.41 (m, 5H), 7.24 (d, J = 7.4 Hz, 1H), 7.09 (d, J = 7.8 Hz, 2H), 7.02 (d, J = 8.8 Hz, 2H), 6.54 (s, 1H), 4.68 (s, 2H), 4.56 (s, 2H), 3.41 (t, J = 6.4 Hz, 2H), 2.92 (t, J = 6.4 Hz, 2H). LC / MS (ESI) m / z: 627 (M+H) + . RT (Method A): 1.59 minutes.

[0259] Scheme 7. Synthesis of N-((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)-2-(6-oxo-2,5-diphenylpyrimidin-1(6H)-yl)acetamide (Compound 25) [ka] Step 1: Methyl 2-(6-oxo-2,5-diphenylpyrimidin-1(6H)-yl)acetate To a mixture of methyl 2-(5-bromo-6-oxo-2-phenylpyrimidin-1(6H)-yl)acetate (40 mg, 0.12 mmol) and phenylboronic acid (23 mg, 0.18 mmol) in 1,4-dioxane (1.5 mL) and water (1.5 mL) was added NaCO (32 mg, 0.30 mmol) and Pd(PPh) (15 mg, 0.01 mmol) under N atmosphere, and the reaction mixture was degassed three times under N atmosphere and stirred at 80 °C for 1 h. The mixture was diluted with water and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NaSO, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (silica gel, 0-70% EtOAc in PE) to give methyl 2-(6-oxo-2,5-diphenylpyrimidin-1(6H)-yl)acetate (39 mg, 98.1% yield) as a white solid. LC / MS (ESI) m / z: 321 (M+H) + .

[0260] Step 2: 2-(6-oxo-2,5-diphenylpyrimidin-1(6H)-yl)acetic acid To a solution of methyl 2-(6-oxo-2,5-diphenylpyrimidin-1(6H)-yl)acetate (39 mg, 0.15 mmol) in MeOH / THF / HO (4 mL, 2 / 1 / 1) was added LiOH·HO (15 mg, 0.30 mmol) under a N atmosphere, and the reaction mixture was stirred at room temperature for 2 h. The mixture was acidified to pH ∼3 with 1 N aqueous HCl and extracted twice with EtOAc. The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give 2-(6-oxo-2,5-diphenylpyrimidin-1(6H)-yl)acetic acid (37 mg, 99.2% yield) as a white solid, which was used directly in the next step without further purification. LC / MS (ESI) m / z: 307 (M+H) + .

[0261] Step 3: N-((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)-2-(6-oxo-2,5-diphenylpyrimidin-1(6H)-yl)acetamide (compound 25) To a mixture of 2-(6-oxo-2,5-diphenylpyrimidin-1(6H)-yl)acetic acid (35 mg, 0.11 mmol) and (1H-pyrrolo[3,2-c]pyridin-2-yl)methanamine hydrochloride (20 mg, 0.11 mmol) in DMF (2 mL) was added DIPEA (78 mg, 0.55 mmol) and HATU (54 mg, 0.14 mmol) under a N atmosphere, and the reaction mixture was stirred at room temperature for 1 h. The mixture was diluted with EtOAc, washed with saturated aqueous NaHCO and brine, dried over anhydrous NaSO, filtered, and concentrated to dryness under reduced pressure. The residue was purified by preparative TLC (DCM:MeOH = 10:1) and further purified by preparative HPLC to give compound 25 (1.1 mg, 2.21% yield) as a white solid. 1 H NMR (400 MHz, CD3OD) δ 8.68 (s, 1H), 8.52 (s, 1H), 8.45 - 8.41 (m, 1H), 8.23 ​​(d, J = 7.2 Hz, 2H), 8.10 (d, J = 6.5 Hz, 1H), 7.76 (d, J = 7.1 Hz, 2H), 7.48 (dd, J = 9.5, 5.3 Hz, 3H), 7.43 (d, J = 7.3 Hz, 1H), 7.33 (t, J = 7.3 Hz, 1H), 7.27 (d, J = 7.8 Hz, 2H), 6.64 (s, 1H), 5.08 (s, 2H), 4.64 (s, 2H). LC / MS (ESI) m / z: 436 (M+H) + . RT (Method A): 1.31 minutes.

[0262] Scheme 8. Synthesis of N-((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)-2-(5-((dibenzo[b,d]furan-3-ylmethyl)amino)-6-oxo-2-phenylpyrimidin-1(6H)-yl)acetamide (compound 26) [ka] Step 1: Dibenzo[b,d]furan-3-carbaldehyde To a solution of 3-bromodibenzo[b,d]furan (300 mg, 1.21 mmol) in THF (10 mL) was added n-BuLi (0.8 mL, 2.02 mmol, 2.5 M in hexane) dropwise under a N atmosphere at −78 °C. The reaction mixture was slowly warmed to 0 °C and stirred for 10 min. The reaction mixture was then cooled to −78 °C, and DMF (266 mg, 3.64 mmol) was added to the above mixture. The resulting mixture was stirred at −78 °C for 1 h. The reaction mixture was quenched with saturated aqueous NH4Cl at 0 °C and extracted twice with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (silica gel, 0-20% EtOAc in PE) to give dibenzo[b,d]furan-3-carbaldehyde (30 mg, 12.6% yield) as a white solid. 1 H NMR (400 MHz, CDCl3) δ 10.14 (s, 1H), 8.11 - 8.02 (m, 3H), 7.91 (dd, J = 7.9, 1.3 Hz, 1H), 7.65 - 7.55 (m, 2H), 7.42 (dd, J = 11.6, 4.3 Hz, 1H).

[0263] Step 2: N-((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)-2-(5-((dibenzo[b,d]furan-3-ylmethyl)amino)-6-oxo-2-phenylpyrimidin-1(6H)-yl)acetamide (compound 26) To a mixture of dibenzo[b,d]furan-3-carbaldehyde (30 mg, 0.15 mmol) and N-((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)-2-(5-amino-6-oxo-2-phenylpyrimidin-1(6H)-yl)acetamide hydrochloride (21 mg, 0.05 mmol) in MeOH (5 mL), NaBHCN (12 mg, 0.19 mmol) was added under N atmosphere, and the reaction mixture was stirred at 50 °C for 2 h. The mixture was diluted with EtOAc, washed with brine, dried over anhydrous NaSO, filtered, and concentrated to dryness under reduced pressure. The residue was purified by preparative TLC (DCM:MeOH = 15:1) and further purified by preparative HPLC to give compound 26 (5 mg, 17.6% yield) as a white solid. 1 H NMR (400 MHz, CD3OD) δ 8.82 (d, J = 5.7 Hz, 1H), 8.51 (s, 1H), 8.17 (t, J = 6.8 Hz, 1H), 8.03 - 7.96 (m, 2H), 7.64 (d, J = 5.8 Hz, 1H), 7.60 - 7.54 (m, 2H), 7.48 - 7.41 (m, 5H), 7.39 - 7.33 (m, 3H), 7.08 (s, 1H), 6.63 (d, J = 6.2 Hz, 1H), 4.66 - 4.57 (m, 6H). LC / MS (ESI) m / z: 555 (M+H) + . RT (Method A): 1.61 minutes.

[0264] The following compounds were prepared according to Scheme 8: [Table 7]

[0265] Compound 178 can be prepared according to step 2 of scheme 8: [Table 8] Scheme 9. Synthesis of N-(1-(2-(((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)amino)-2-oxoethyl)-6-oxo-2-phenyl-1,6-dihydropyrimidin-5-yl)-[1,1'-biphenyl]-4-carboxamide (compound 29) [ka] To a mixture of [1,1'-biphenyl]-4-carbonyl chloride (22 mg, 0.1 mmol) and N-((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)-2-(5-amino-6-oxo-2-phenylpyrimidin-1(6H)-yl)acetamide hydrochloride (41 mg, 0.1 mmol) in DMF (0.5 mL), DIPEA (65 mg, 0.5 mmol) was added under N atmosphere, and the reaction mixture was stirred at room temperature for 2 h. The mixture was purified by preparative HPLC to give compound 29 (4.8 mg, 8.7% yield) as a white solid. 1 H NMR (400 MHz, CD3OD) δ 9.08 (s, 1H), 8.77 (s, 1H), 8.14 (d, J = 6.0 Hz, 1H), 8.07 (d, J = 8.5 Hz, 2H), 7.83 (d, J = 8.5 Hz, 2H), 7.75 - 7.70 (m, 2H), 7.60 - 7.56 (m, 2H), 7.55 - 7.52 (m, 1H), 7.50 (s, 1H), 7.49 - 7.40 (m, 5H), 6.56 (s, 1H), 4.74 (s, 2H), 4.58 (s, 2H). LC / MS (ESI) m / z: 555 (M+H) + . RT (Method A): 1.61 minutes.

[0266] Compound 31 was prepared according to Scheme 9: [Table 9]

[0267] Scheme 10. Synthesis of N-((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)-2-(6-oxo-2-phenyl-5-(4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)pyrimidin-1(6H)-yl)acetamide (compound 30) [ka] Step 1: 2-Bromo-4,5,6,7-tetrahydrobenzo[d]thiazole (2) To a solution of CuBr (200 mg, 1.30 mmol) in MeCN (5 mL) was added tert-butyl nitrite (174 mg, 1.69 mmol) dropwise at 40 °C, and the reaction mixture was stirred at 40 °C for 10 min under a N atmosphere. A solution of 4,5,6,7-tetrahydrobenzo[d]thiazol-2-amine (200 mg, 1.30 mmol) in MeCN (5 mL) was added to the mixture, and the resulting mixture was stirred at 40 °C for 2 h. The mixture was quenched with 0.5 N aqueous HCl and extracted twice with EtOAc. The combined organic layers were washed with saturated aqueous NaHCO, brine, dried over anhydrous NaSO, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (silica gel, 0-15% EtOAc in PE) to give 2-bromo-4,5,6,7-tetrahydrobenzo[d]thiazole (174 mg, 61.5% yield) as a pale yellow oil. LC / MS (ESI) m / z: 218 (M+H) + .

[0268] Step 2: 2-(tributylstannyl)-4,5,6,7-tetrahydrobenzo[d]thiazole (3) To a solution of 2-bromo-4,5,6,7-tetrahydrobenzo[d]thiazole (77 mg, 0.35 mmol) in THF (3 mL) at −78°C, n-BuLi (0.6 mL, 0.40 mmol, 2.5 M) was added dropwise under a N atmosphere, and the reaction mixture was stirred at −78°C for 30 min. Tributylchlorostannane (104 mg, 0.32 mmol) was added to the mixture, and the resulting mixture was stirred from −78°C to room temperature for 1.5 h. The mixture was concentrated to dryness under reduced pressure (15°C). The residue was dissolved in hexane, and the reaction mixture was stirred at room temperature for 5 min. The mixture was filtered through diatomaceous earth, and the filtrate was concentrated to dryness under reduced pressure (15°C) to give 2-(tributylstannyl)-4,5,6,7-tetrahydrobenzo[d]thiazole (150 mg, 99.2% yield) as a pale yellow oil, which was used directly in the next reaction without further purification.

[0269] Step 3: Methyl 2-(6-oxo-2-phenyl-5-(4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)pyrimidin-1(6H)-yl)acetate (4) To a mixture of 2-(tributylstannyl)-4,5,6,7-tetrahydrobenzo[d]thiazole (150 mg, 0.35 mmol) and methyl 2-(5-bromo-6-oxo-2-phenylpyrimidin-1(6H)-yl)acetate (77 mg, 0.24 mmol) in 1,4-dioxane (3 mL) was added AcOK (47 mg, 0.48 mmol) and Pd(PPh) (28 mg, 0.024 mmol) under a N atmosphere at 0° C., and the mixture was stirred at 120° C. for 3 h. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous NaSO, filtered, and concentrated to dryness under reduced pressure. The residue was purified by preparative TLC (PE: EtOAc = 5:1) to give methyl 2-(6-oxo-2-phenyl-5-(4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)pyrimidin-1(6H)-yl)acetate (30 mg, yield 33.0%) as a yellow solid. 1H NMR (400 MHz, CD3OD) δ 9.37 (s, 1H), 8.38 (dd, J = 7.7, 1.8 Hz, 2H), 7.51 (t, J = 6.3 Hz, 3H), 5.28 (s, 2H), 3.80 (s, 3H), 2.88 (dd, J = 13.5, 5.7 Hz, 4H), 1.98 - 1.90 (m, 4H). LC / MS (ESI) m / z: 382 (M+H) + .

[0270] Step 4: 2-(6-oxo-2-phenyl-5-(4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)pyrimidin-1(6H)-yl)acetic acid (5) To a solution of methyl 2-(6-oxo-2-phenyl-5-(4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)pyrimidin-1(6H)-yl)acetate (30 mg, 0.079 mmol) in MeOH (2 mL) and THF (1 mL) was added a solution of LiOH·HO (13 mg, 0.31 mmol) in water (1 mL), and the mixture was stirred at room temperature for 1 h. The mixture was acidified with 1 N aqueous HCl to pH 3 and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NaSO, filtered, and concentrated to dryness under reduced pressure to give 2-(6-oxo-2-phenyl-5-(4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)pyrimidin-1(6H)-yl)acetic acid (20 mg, 69.2% yield) as a white solid, which was used directly in the next reaction without further purification. LC / MS (ESI) m / z: 368 (M+H) + .

[0271] Step 5: N-((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)-2-(6-oxo-2-phenyl-5-(4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)pyrimidin-1(6H)-yl)acetamide (Compound 30) To a mixture of 2-(6-oxo-2-phenyl-5-(4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)pyrimidin-1(6H)-yl)acetic acid (20 mg, 0.054 mmol) and ((1H-pyrrolo[3,2-c]pyridin-2-yl)methanamine (12 mg, 0.082 mmol) in DMF (3 mL) was added DIPEA (31 mg, 0.27 mmol) and HBTU (35 mg, 0.082 mmol) under a N atmosphere, and the reaction mixture was stirred at room temperature for 1 h. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous NaSO, filtered, and concentrated to dryness under reduced pressure. The residue was purified by preparative TLC (DCM:MeOH=10:1) and further purified by preparative HPLC to give compound 30 (1.4 mg, 5.2% yield) as a white solid. 1 H NMR (400 MHz, CD3OD) δ 9.34 (s, 1H), 8.48 (s, 1H), 8.31 - 8.28 (m, 2H), 8.05 (d, J = 6.1 Hz, 1H), 7.42 - 7.37 (m, 1H), 7.33 - 7.29 (m, LC / MS (ESI) m / z: 497 (M+H) + . RT (Method A): 1.53 minutes.

[0272] Scheme 11. Synthesis of N-(2-((1-(2-(((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)amino)-2-oxoethyl)-6-oxo-2-phenyl-1,6-dihydropyrimidin-5-yl)amino)ethyl)-4-phenoxybenzamide (compound 33) [ka] Step 1: Tert-butyl (2-((1-(2-(((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)amino)-2-oxoethyl)-6-oxo-2-phenyl-1,6-dihydropyrimidin-5-yl)amino)ethyl)carbamate (2) To a mixture of tert-butyl (2-oxoethyl)carbamate (85 mg, 0.52 mmol) and N-((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)-2-(5-amino-6-oxo-2-phenylpyrimidin-1(6H)-yl)acetamide (50 mg, 0.13 mmol) in MeOH (2 mL), NaBHCN (74 mg, 1.14 mmol) was added at room temperature, and the reaction mixture was stirred at 50° C. for 2 h. The mixture was diluted with EtOAc, washed with saturated aqueous NH4Cl and brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure to give tert-butyl (2-((1-(2-(((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)amino)-2-oxoethyl)-6-oxo-2-phenyl-1,6-dihydropyrimidin-5-yl)amino)ethyl)carbamate (60 mg, 87.0% yield) as a white solid. LC / MS (ESI) m / z: 518 (M+H) + .

[0273] Step 2: N-((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)-2-(5-((2-aminoethyl)amino)-6-oxo-2-phenylpyrimidin-1(6H)-yl)acetamide hydrochloride (3) To a solution of tert-butyl (2-((1-(2-(((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)amino)-2-oxoethyl)-6-oxo-2-phenyl-1,6-dihydropyrimidin-5-yl)amino)ethyl)carbamate (60 mg, 0.12 mmol) in DCM (1 mL) was added HCl / 1,4-dioxane (2 mL, 4 M), and the mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated to dryness under reduced pressure to give N-((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)-2-(5-((2-aminoethyl)amino)-6-oxo-2-phenylpyrimidin-1(6H)-yl)acetamide hydrochloride (50 mg, crude) as a colorless oil, which was used directly in the next step without further purification. LC / MS (ESI) m / z: 418 (M+H) + .

[0274] Step 3: N-(2-((1-(2-(((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)amino)-2-oxoethyl)-6-oxo-2-phenyl-1,6-dihydropyrimidin-5-yl)amino)ethyl)-4-phenoxybenzamide (compound 33) To a mixture of 4-phenoxybenzoic acid (24 mg, 0.11 mmol) and N-((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)-2-(5-((2-aminoethyl)amino)-6-oxo-2-phenylpyrimidin-1(6H)-yl)acetamide hydrochloride (50 mg, 0.11 mmol) in DMF (2 mL), DIPEA (87 mg, 0.66 mmol) and HATU (50 mg, 0.13 mmol) were added under N atmosphere, and the reaction mixture was stirred at room temperature for 2 h. The mixture was concentrated to dryness under reduced pressure. The residue was purified by preparative TLC (DCM:MeOH=7:1) and further purified by preparative HPLC to give compound 33 (2 mg, 3.0% yield) as a white solid. 1H NMR (400 MHz, CD3OD) δ 8.75 (d, J = 0.8 Hz, 1H), 8.12 (d, J = 6.0 Hz, 1H), 7.85 - 7.77 (m, 2H), 7.52 - 7.43 (m, 4H), 7.39 (dd, J = 11.2, 4.5 Hz, 4H), 7.29 (s, 1H), 7.19 (t, J = 7.4 Hz, 1H), 7.04 (dd, J = 8.6, 1.0 Hz, 2H), 6.99 - 6.95 (m, 2H), 6.53 (d, J = 8.3 Hz, 1H), 4.62 (s, 2H), 4.55 (s, 2H), 3.66 (t, J = 6.1 Hz, 2H), 3.43 (t, J = 6.1 Hz, 2H). LC / MS (ESI) m / z: 614 (M+H) + . RT (Method A): 1.38 minutes.

[0275] Scheme 12. Synthesis of N-(2-((1-(2-(((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)amino)-2-oxoethyl)-6-oxo-2-phenyl-1,6-dihydropyrimidin-5-yl)amino)ethyl)dibenzo[b,d]furan-2-carboxamide (compound 35) [ka] To a mixture of dibenzo[b,d]furan-2-carboxylic acid (20 mg, 0.09 mmol) and N-((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)-2-(5-((2-aminoethyl)amino)-6-oxo-2-phenylpyrimidin-1(6H)-yl)acetamide (50 mg, 0.12 mmol) in DMF (2 mL), DIPEA (73 mg, 0.54 mmol) and HATU (36 mg, 0.09 mmol) were added under N atmosphere, and the reaction mixture was stirred at room temperature for 2 h. The mixture was diluted with EtOAc, washed with saturated aqueous NH4Cl and brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was purified by preparative TLC (DCM:MeOH = 10:1) and further purified by preparative HPLC to give compound 35 (11 mg, 19.1% yield) as a white solid. 1 H NMR (400 MHz, CD3OD) δ 8.72 (s, 1H), 8.53 (d, J = 1.5 Hz, 1H), 8.10 (d, J = 6.1 Hz, 1H), 8.05 (d, J = 7.2 Hz, 1H), 8.00 (dd, J = 8.7, 1.9 Hz, 1H), 7.63 (d, J = 3.2 Hz, 1H), 7.61 (d, J = 2.8 Hz, 1H), 7.54 (d, J = 7.2 Hz, 1H), 7.49 - 7.45 (m, 4H), 7.38 (dd, J = 8.9, 6.0 Hz, 3H), 7.34 (s, 1H), 6.56 (s, 1H), 4.63 (s, 2H), 4.57 (s, 2H), 3.74 (t, J = 5.9 Hz, 2H), 3.51 (t, J = 6.1 Hz, 2H). LC / MS (ESI) m / z: 612 (M+H) + . RT (Method A): 1.33 minutes.

[0276] Compound 36 was prepared according to Scheme 12: [Table 10]

[0277] Scheme 13. Synthesis of (S)-7-((4-(4-fluorophenoxy)benzoyl)glycyl)-N-((S)-2-hydroxy-1-(1H-pyrrolo[3,2-c]pyridin-2-yl)ethyl)-1,4-dioxa-7-azaspiro[4.4]nonane-8-carboxamide (compound 42) [ka] Step 1: Tert-butyldimethyl(3-(4-(methylthio)phenyl)propoxy)silane (2) To a solution of 3-(4-(methylthio)phenyl)propan-1-ol (260 mg, 1.43 mmol) in DCM (3 mL) were added TBSCl (323 g, 2.14 mmol) and TEA (554 mg, 4.29 mmol) sequentially at 0 °C, and the mixture was stirred at room temperature for 3 h. The mixture was diluted with water and extracted twice with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash chromatography on silica gel (0-20% EtOAc in PE) to give tert-butyldimethyl(3-(4-(methylthio)phenyl)propoxy)silane (330 mg, 78.0% yield) as a colorless oil.

[0278] Step 2: Tert-butyldimethyl(3-(4-(methylsulfonyl)phenyl)propoxy)silane (3) To a solution of tert-butyldimethyl(3-(4-(methylthio)phenyl)propoxy)silane (100 mg, 0.34 mmol) in DCM (2 mL) was added m-CPBA (233 mg, 1.35 mmol) under a N atmosphere, and the reaction mixture was stirred at room temperature for 2 h. The mixture was diluted with DCM, quenched with saturated aqueous NaSO, washed with saturated aqueous NaHCO and brine, dried over anhydrous NaSO, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (silica gel, 0-50% EtOAc in PE) to give tert-butyldimethyl(3-(4-(methylsulfonyl)phenyl)propoxy)silane (100 mg, 89.7% yield) as a white solid.

[0279] Step 3: 3-(4-(methylsulfonyl)phenyl)propan-1-ol (4) To a solution of tert-butyldimethyl(3-(4-(methylsulfonyl)phenyl)propoxy)silane (100 mg, 0.31 mmol) in THF (2 mL) was added TBAF (1 mL, 1 M in THF), and the mixture was stirred at room temperature under a N atmosphere for 2 h. The reaction mixture was concentrated to dryness under reduced pressure. The residue was purified by preparative TLC (PE: EtOAc = 1:2) to give 3-(4-(methylsulfonyl)phenyl)propan-1-ol (58 mg, 87.9% yield) as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ 7.80 (s, 1H), 7.78 (s, 1H), 7.34 (d, J = 7.9 Hz, 2H), 3.62 (t, J = 6.2 Hz, 2H), 2.98 (s, 3H), 2.75 (t, J = 7.7 Hz, 2H), 1.88 - 1.81 (m, 2H).

[0280] Step 4: 3-(4-(methylsulfonyl)phenyl)propanal (5) To a solution of 3-(4-(methylsulfonyl)phenyl)propan-1-ol (58 mg, 0.27 mmol) in DCM (2 mL) was added Dess-Martin (172 mg, 0.41 mmol) under a N atmosphere, and the reaction mixture was stirred at room temperature for 2 h. The mixture was diluted with DCM, quenched with saturated aqueous NaSO, washed with saturated aqueous NaHCO and brine, dried over anhydrous NaSO, filtered, and concentrated to dryness under reduced pressure. The residue was purified by preparative TLC (DCM:MeOH = 20:1) to give 3-(4-(methylsulfonyl)phenyl)propanal (55 mg, 94.5% yield) as a white solid.

[0281] Step 5: N-((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)-2-(5-((3-(4-(methylsulfonyl)phenyl)propyl)amino)-6-oxo-2-phenylpyrimidin-1(6H)-yl)acetamide (compound 42) To a solution of N-((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)-2-(5-amino-6-oxo-2-phenylpyrimidin-1(6H)-yl)acetamide (34 mg, 0.090 mmol) in MeOH (1 mL) were added 3-(4-(methylsulfonyl)phenyl)propanal (57 mg, 0.27 mmol) and NaBHCN (23 mg, 0.36 mmol) under a N atmosphere, and the reaction mixture was stirred at 50 °C for 2 h. The mixture was concentrated to dryness under reduced pressure, and the residue was purified by preparative HPLC to give compound 42 (1.5 mg, 2.9% yield) as a white solid. 1 H NMR (400 MHz, CD3OD) δ 8.74 (s, 1H), 8.13 (d, J = 5.9 Hz, 1H), 7.88 (d, J = 8.3 Hz, 2H), 7.46 (ddd, J = 20.6, 15.3, 7.7 Hz, 8H), 7.11 (s, 1H), 6.52 (s, 1H), 4.62 (s, 2H), 4.55 (s, 2H), 3.23 (t, J = 6.9 Hz, 2H), 3.10 (s, 3H), 2.92 - 2.85 (m, 2H), 2.09 - 2.00 (m, 2H). LC / MS (ESI) m / z: 571 (M+H) + .

[0282] Scheme 14. Synthesis of N-((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)-2-(5-((3-(4-methoxyphenyl)propyl)amino)-6-oxo-2-phenylpyrimidin-1(6H)-yl)acetamide (compound 45) [ka] Step 1: tert-butyl 2-(5-((3-(4-methoxyphenyl)propyl)amino)-6-oxo-2-phenylpyrimidin-1(6H)-yl)acetate A vial was charged with tert-butyl 2-(5-bromo-6-oxo-2-phenyl-pyrimidin-1-yl)acetate (0.05 g, 0.1369 mmol), 3-(4-methoxyphenyl)propan-1-amine (0.023 g, 0.1369 mmol), cesium carbonate (0.0893 g, 0.2738 mmol), BINAP (0.01705 g, 0.02738 mmol), and palladium acetate (0.003074 g, 0.01369 mmol). Toluene was added thereto, and the reaction mixture was purged with nitrogen for 3 minutes. The reaction mixture was stirred at 120 °C for 10 minutes under microwave irradiation. The crude mixture was purified using flash chromatography (silica gel, 0-50% EtOAc in heptane) to give tert-butyl 2-(5-((3-(4-methoxyphenyl)propyl)amino)-6-oxo-2-phenylpyrimidin-1(6H)-yl)acetate (0.02 g, 37% yield). LC / MS (ESI) m / z: 450 (M+H) +.

[0283] Step 2: 2-(5-((3-(4-methoxyphenyl)propyl)amino)-6-oxo-2-phenylpyrimidin-1(6H)-yl)acetic acid tert-Butyl 2-(5-((3-(4-methoxyphenyl)propyl)amino)-6-oxo-2-phenylpyrimidin-1(6H)-yl)acetate (0.02 g, 0.054 mmol) was dissolved in DCM (3 mL). TFA (3 ML) was added thereto and the reaction was stirred at room temperature for 1 hour. Excess TFA was evaporated, and 1 M HCl in MeOH was added to the crude material and stirred for 5 minutes. Methanol was evaporated to dryness to give 2-(5-((3-(4-methoxyphenyl)propyl)amino)-6-oxo-2-phenylpyrimidin-1(6H)-yl)acetic acid (0.020 g, 96% yield) as a brown solid, which was used in the next step without further purification. LC / MS (ESI) m / z: 394 (M+H) +.

[0284] Step 3: N-((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)-2-(5-((3-(4-methoxyphenyl)propyl)amino)-6-oxo-2-phenylpyrimidin-1(6H)-yl)acetamide (compound 45) 2-[5-[3-(4-Methoxyphenyl)propylamino]-6-oxo-2-phenyl-pyrimidin-1-yl]acetic acid (0.015 g, 0.038 mmol), 1H-pyrrolo[3,2-c]pyridin-2-ylmethanamine hydrochloride (0.0070 g, 0.038 mmol), TBTU (0.025 g, 0.076 mmol), and DIPEA (0.14 mL, 0.076 mmol) were stirred in DMF (5 mL) at room temperature for 30 minutes. Water (30 mL) was added to the reaction mixture, and the solid was filtered. The solid was dissolved in DCM, dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0-5% MeOH in DCM) to give 2-[5-[3-(4-methoxyphenyl)propylamino]-6-oxo-2-phenyl-pyrimidin-1-yl]-N-(1H-pyrrolo[3,2-c]pyridin-2-ylmethyl)acetamide as an off-white solid (0.007 g, 40% yield). 1H NMR (400 MHz, MeOD-CDCl3) δ 8.71 (s, 1H), 8.12 (d, J = 5.8 Hz, 1H), 7.51 - 7.42 (m, 3H), 7.38 (dd, J = 11.9, 6.7 Hz, 3H), 7.17 - 7.07 (m, 3H), 6.89 - 6.81 (m, 2H), 6.47 (s, 1H), 4.61 (s, 2H), 4.56 (s, 2H), 3.79 (s, 3H), 3.16 (t, J = 7.0 Hz, 2H), 2.71 (t, J = 7.5 Hz, 2H), 2.05 - 1.93 (m, 2H), 1.28 (s, 1H). LC / MS (ESI) m / z: 523 (M+H) + . RT (Method A): 1.45 minutes.

[0285] The following compounds were prepared according to Scheme 14: [Table 11-1] [Table 11-2] [Table 11-3] [Table 11-4] [Table 11-5] [Table 11-6] [Table 11-7]

[0286] Compound 181 is prepared according to Scheme 14: [Table 12]

[0287] Scheme 15. Synthesis of N-((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)-2-(5-((3-(4-fluorophenyl)propyl)amino)-6-oxo-2-phenylpyrimidin-1(6H)-yl)acetamide (compound 46) [ka] Step 1: 3-(4-fluorophenyl)propan-1-ol (2) To a solution of 3-(4-fluorophenyl)propanoic acid (900 mg, 5.35 mmol) in THF (10 mL) was added BH3.Me2S (1 mL, 10 mol / L) dropwise at room temperature, and the mixture was stirred at 50 °C for 1 h. The mixture was quenched by the dropwise addition of MeOH at 0 °C. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (silica gel, 0-50% EtOAc in PE) to give 3-(4-fluorophenyl)propan-1-ol (600 mg, 72.8% yield) as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ 7.07 (dd, J = 7.9, 5.8 Hz, 2H), 6.89 (t, J = 8.6 Hz, 2H), 3.58 (t, J = 6.4 Hz, 2H), 2.60 (t, J = 7.7 Hz, 2H), 1.83 - 1.75 (m, 2H).

[0288] Step 2: 3-(4-fluorophenyl)propanal (3) To a solution of 3-(4-fluorophenyl)propan-1-ol (425 mg, 2.76 mmol) in DCM (4 mL) was added PCC (1.1 g, 5.19 mmol) under a N atmosphere, and the reaction mixture was stirred at room temperature for 2 h. The mixture was concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (silica gel, 0-30% EtOAc in PE) to give 3-(4-fluorophenyl)propanal (250 mg, 59.5% yield) as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ 9.74 (s, 1H), 7.07 (dd, J = 7.8, 5.5 Hz, 2H), 6.91 (d, J = 8.6 Hz, 2H), 2.86 (t, J = 7.4 Hz, 2H), 2.69 (t, J = 7.4 Hz, 2H).

[0289] Step 3: N-((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)-2-(5-((3-(4-fluorophenyl)propyl)amino)-6-oxo-2-phenylpyrimidin-1(6H)-yl)acetamide (compound 46) To a mixture of 3-(4-fluorophenyl)propanal (146 mg, 0.96 mmol) and N-((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)-2-(5-amino-6-oxo-2-phenylpyrimidin-1(6H)-yl)acetamide (90 mg, 0.24 mmol) in MeOH (3 mL), NaBHCN (60 mg, 0.96 mmol) was added under a N atmosphere at 0 °C, and the reaction mixture was stirred at 50 °C for 2 h. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous NaSO, filtered, and concentrated to dryness under reduced pressure. The residue was purified by preparative HPLC to give compound 46 (6.2 mg, 5.1% yield) as a white solid. 1 H NMR (400 MHz, CD3OD) δ 8.70 (s, 1H), 8.10 (d, J = 5.6 Hz, 1H), 7.46 (t, J = 7.0 Hz, 3H), 7.40 (d, J = 6.1 Hz, 3H), 7.23 (t, J = 6.2 Hz, 2H), 7.08 (s, 1H), 6.99 (t, J = 8.1 Hz, 2H), 6.47 (s, 1H), 4.62 (s, 2H), 4.54 (s, 2H), 3.18 (t, J = 6.9 Hz, 2H), 2.74 (t, J = 7.3 Hz, 2H), 2.03 - 1.94 (m, 2H).LC / MS (ESI) m / z: 511 (M+H) + . RT (Method A): 1.56 minutes.

[0290] Compound 88 was prepared according to Scheme 15: [Table 13]

[0291] Scheme 16. Synthesis of N-((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)-2-(5-((3-(4-cyanophenyl)propyl)amino)-6-oxo-2-phenylpyrimidin-1(6H)-yl)acetamide (compound 48) [ka]

[0292] Step 1: 4-(3-hydroxypropyl)benzonitrile To a mixture of 3-(4-bromophenyl)propan-1-ol (2.0 g, 9.35 mmol) and Zn(CN) (2.2 g, 18.70 mmol) in DMF (20 mL) was added Pd(PPh) (1.1 g, 0.94 mmol) under N at 0 °C. The mixture was degassed three times under N and stirred at 110 °C overnight. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous NaSO, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (silica gel, 0-25% EtOAc in PE) to give 4-(3-hydroxypropyl)benzonitrile (500 mg, 33.3% yield) as a colorless oil. LC / MS (ESI) m / z: 162 (M+H) + .

[0293] Step 2: 4-(3-oxopropyl)benzonitrile To a solution of 4-(3-hydroxypropyl)benzonitrile (300 mg, 1.86 mmol) in DCM (5 mL) was added PCC (483 mg, 2.23 mmol) at 0° C., and the mixture was stirred for 2 h at 0° C. Silica gel was added to the mixture, which was stirred at 0° C. for 0.5 h, filtered, and concentrated to dryness under reduced pressure to give 4-(3-oxopropyl)benzonitrile (125 mg, 42.2% yield) as a colorless oil, which was used directly in the next step without further purification.

[0294] Step 3: N-((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)-2-(5-((3-(4-cyanophenyl)propyl)amino)-6-oxo-2-phenylpyrimidin-1(6H)-yl)acetamide (compound 48) To a mixture of N-((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)-2-(5-amino-6-oxo-2-phenylpyrimidin-1(6H)-yl)acetamide (30 mg, 0.08 mmol) and 4-(3-oxopropyl)benzonitrile (64 mg, 0.40 mmol) in MeOH (3 mL) was added NaBHCN (40 mg, 0.64 mmol) under a N atmosphere, and the reaction mixture was stirred at 50 °C for 1 h. The mixture was diluted with EtOAc, washed with brine, dried over anhydrous NaSO, filtered, and concentrated to dryness under reduced pressure. The residue was purified by preparative TLC (DCM:MeOH = 10:1) and further purified by preparative HPLC to give compound 48 (2 mg, 4.8% yield) as a white solid. 1 H NMR (400 MHz, CD3OD) δ 8.87 (s, 1H), 8.47 (s, 1H), 8.20 (d, J= 6.2 Hz, 1H), 7.65 (d, J= 8.2 Hz, 3H), 7.50 - 7.40 (m, 7H), 7.11 (s, LC / MS (ESI) m / z: 518 (M+H) + . RT (Method A): 1.29 minutes.

[0295] Scheme 17. Synthesis of N-[6-oxo-1-[2-oxo-2-(1H-pyrrolo[3,2-c]pyridin-2-ylmethylamino)ethyl]-2-phenyl-pyrimidin-5-yl]-4-phenoxy-cyclohexanecarboxamide (compound 49) [ka] Step 1: N-[[1-(benzenesulfonyl)pyrrolo[3,2-c]pyridin-2-yl]methyl]-2-[5-[(2,4-dimethoxyphenyl)methylamino]-6-oxo-2-phenyl-pyrimidin-1-yl]acetamide 2-[5-[(2,4-Dimethoxyphenyl)methylamino]-6-oxo-2-phenyl-pyrimidin-1-yl]acetic acid (1 g, 2.529 mmol), [1-(benzenesulfonyl)pyrrolo[3,2-c]pyridin-2-yl]methanamine (0.7266 g, 2.529 mmol), TBTU (1.657 g, 5.058 mmol), and DIPEA (0.6537 g, 5.058 mmol) were stirred in DMF (20 mL) at room temperature for 30 minutes. Water (30 mL) was added to the reaction mixture, and the solid was filtered. The solid was dissolved in DCM, dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0-5% MeOH in DCM) to give N-[[1-(benzenesulfonyl)pyrrolo[3,2-c]pyridin-2-yl]methyl]-2-[5-[(2,4-dimethoxyphenyl)methylamino]-6-oxo-2-phenyl-pyrimidin-1-yl]acetamide (1.2 g, 71% yield) as a white solid. LC / MS (ESI) m / z: 665 (M+H) + .

[0296] Step 2: 2-(5-amino-6-oxo-2-phenyl-pyrimidin-1-yl)-N-[[1-(benzenesulfonyl)pyrrolo[3,2-c]pyridin-2-yl]methyl]acetamide N-[[1-(benzenesulfonyl)pyrrolo[3,2-c]pyridin-2-yl]methyl]-2-[5-[(2,4-dimethoxyphenyl)methylamino]-6-oxo-2-phenyl-pyrimidin-1-yl]acetamide (0.15 g, 0.2257 mmol) was stirred in TFA at 60 °C for 1 hour. Excess reagent was completely evaporated to dryness, and the crude material was washed with saturated NaHCO and extracted with DCM. The organic layer was dried over sodium sulfate and evaporated to dryness to give 2-(5-amino-6-oxo-2-phenyl-pyrimidin-1-yl)-N-[[1-(benzenesulfonyl)pyrrolo[3,2-c]pyridin-2-yl]methyl]acetamide (0.1 g, 90% yield) as a buff-white solid. LC / MS (ESI) m / z: 515 (M+H) + .

[0297] Step 3: N-[6-oxo-1-[2-oxo-2-(1H-pyrrolo[3,2-c]pyridin-2-ylmethylamino)ethyl]-2-phenyl-pyrimidin-5-yl]-4-phenoxy-cyclohexanecarboxamide (compound 49) 2-(5-amino-6-oxo-2-phenyl-pyrimidin-1-yl)-N-[[1-(benzenesulfonyl)pyrrolo[3,2-c]pyridin-2-yl]methyl]acetamide (0.01 g, 0.01943 mmol) and triethylamine (0.005 mL, 0.03887 mmol) were stirred in DCM (1 mL) at 0 °C for 5 minutes. A solution of 4-phenoxycyclohexanecarbonyl chloride (0.009277 g, 0.03887 mmol) in DCM was added dropwise to the reaction mixture, which was stirred at room temperature for 10 minutes. The solvent was evaporated, and the crude material was dissolved in MeOH (1 mL). Aqueous NaOH solution (5% in water, 0.5 mL) was added thereto, and it was stirred at 50 °C for 30 minutes. The solvent was evaporated, and the mixture was extracted with DCM. The organic layer was dried over anhydrous NaSO, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0-3% MeOH in DCM) to give compound 49 (2 mg, 17.85% yield). 1H NMR (400 MHz, MeOD- CDCl3) δ 8.83 (d, J = 5.0 Hz, 1H), 8.62 (s, 1H), 8.43 (s, 3H), 8.02 (s, 1H), 7.41 (t, J = 8.2 Hz, 3H), 7.36 - 7.28 (m, 3H), 7.21 - 7.10 (m, 2H), 6.83 (td, J = 13.1, 7.7 Hz, 3H), 6.39 (s, 1H), 4.57 (s, 2H), 4.52 (s, 1H), 4.45 (s, 2H), 2.56 (s, 1H), 2.13 (s, 1H), 2.03 - 1.87 (m, 3H), 1.64 (s, 3H), 1.41 (d, J = 11.8 Hz, 1H). LC / MS (ESI) m / z: 577 (M+H) + . RT (Method A): 1.87 minutes.

[0298] The following compounds were prepared according to step 3 of Scheme 17: [Table 14]

[0299] Scheme 18. Synthesis of N-(1-(2-(((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)amino)-2-oxoethyl)-6-oxo-2-phenyl-1,6-dihydropyrimidin-5-yl)-4-(2,4-difluorophenoxy)benzamide (compound 55) [ka] Step 1: Methyl 4-(2,4-difluorophenoxy)benzoate (2) To a mixture of 2,4-difluorophenol (500 mg, 3.85 mmol) and (4-(methoxycarbonyl)phenyl)boronic acid (1.04 g, 5.78 mmol) in DCM (15 mL) was added pyridine (0.84 mL, 7.70 mmol), Cu(OAc) (1.05 g, 5.78 mmol), and 4A molecular sieves (3.0 g) at 0 °C, and the mixture was stirred at room temperature under an O atmosphere overnight. The mixture was filtered, and the filtrate was concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0-4% EtOAc in PE) to give the title compound (790 mg, 77.8% yield) as a pale yellow oil. 1 H NMR (400 MHz, CDCl3) δ 7.98 (d, J = 8.9 Hz, 2H), 7.15 - 7.08 (m, 1H), 6.99 - 6.83 (m, 4H), 3.87 (s, 3H). LC / MS (ESI) m / z: 265 (M+H) + .

[0300] Step 2: 4-(2,4-difluorophenoxy)benzoic acid (3) To a solution of methyl 4-(2,4-difluorophenoxy)benzoate (790 mg, 2.99 mmol) in MeOH (10 mL) and water (4 mL) was added LiOH·HO (450 g, 10.72 mmol), and the mixture was stirred at room temperature for 4 h. The mixture was acidified with 1N aqueous HCl to pH 3 and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NaSO, filtered, and concentrated to dryness under reduced pressure to give the title compound (650 mg, 86.9% yield) as a white solid, which was used directly in the next step without further purification. LC / MS (ESI) m / z: 251 (M+H) + .

[0301] Step 3: 4-(2,4-difluorophenoxy)-N-(6-oxo-1-(2-oxo-2-(((1-(phenylsulfonyl)-1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)amino)ethyl)-2-phenyl-1,6-dihydropyrimidin-5-yl)benzamide (4) To a mixture of 4-(2,4-difluorophenoxy)benzoic acid (200 mg, 0.80 mmol) and 2-(5-amino-6-oxo-2-phenylpyrimidin-1(6H)-yl)-N-((1-(phenylsulfonyl)-1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)acetamide (270 mg, 0.52 mmol) in MeCN (5 mL) was added TCFH (440 mg, 1.57 mmol) and NMI (130 mg, 1.57 mmol) under a N atmosphere, and the reaction mixture was stirred at room temperature for 1 h. The mixture was diluted with DCM, washed with 10% aqueous NaHCO and brine, dried over anhydrous NaSO, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (silica gel, 0-4% MeOH in DCM) to give the title compound (260 mg, 66.3% yield) as a yellow solid. LC / MS (ESI) m / z: 747 (M+H) + .

[0302] Step 4: N-(1-(2-(((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)amino)-2-oxoethyl)-6-oxo-2-phenyl-1,6-dihydropyrimidin-5-yl)-4-(2,4-difluorophenoxy)benzamide (Compound 55) A solution of 4-(2,4-difluorophenoxy)-N-(6-oxo-1-(2-oxo-2-(((1-(phenylsulfonyl)-1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)amino)ethyl)-2-phenyl-1,6-dihydropyrimidin-5-yl)benzamide (260 mg, 0.35 mmol) in MeONa / MeOH solution (7.0 mL, 0.5 M) and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water and extracted twice with DCM. The combined organic layers were washed with brine, dried over anhydrous NaSO, filtered, and concentrated to dryness under reduced pressure. The residue was purified by preparative HPLC to give compound 55 (30 mg, 14.2% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.34 (s, 1H), 9.48 (s, 1H), 8.83 - 8.71 (m, 3H), 8.11 (d, J = 5.6 Hz, 1H), 8.04 - 7.97 (m, 2H), 7.59 - 7.52 (m, 4H), 7.49 - 7.41 (m, 3H), 7.34 - 7.30 (m, 1H), 7.24 - 7.17 (m, 1H), 7.11 - 7.05 (m, 2H), 6.32 (s, 1H), 4.58 (s, 2H), 4.43 (d, J = 5.5 Hz, 2H). LC / MS (ESI) m / z: 607 (M+H) + . RT (Method A): 1.73 minutes.

[0303] The following compounds were prepared according to steps 3 and 4 of Scheme 18: [Table 15-1] [Table 15-2] [Table 15-3] [Table 15-4] [Table 15-5]

[0304] Compounds 163 and 173 are prepared according to steps 3 and 4 of Scheme 18: [Table 16]

[0305] Scheme 19. Synthesis of N-((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)-2-(3-(([1,1'-biphenyl]-4-ylmethyl)amino)-2-oxo-6-phenylpyrazin-1(2H)-yl)acetamide (Compound 60) [ka]

[0306] Step 1: Benzyl(cyano(phenyl)methyl)glycinate hydrochloride (2) To a solution of benzyl glycinate (8.5 g, 51.5 mmol) in DCM (15 mL) was added benzaldehyde (5.5 g, 51.5 mmol) in small portions, followed by the dropwise addition of TMSCN (5.61 g, 56.7 mmol) over 10 minutes at room temperature. The reaction mixture was stirred at room temperature for 4 hours. The mixture was concentrated to dryness under reduced pressure, and the residue was dissolved in EtOAc. The mixture was washed with water, and 10 N aqueous HCl was added dropwise at 0°C. The formed precipitate was collected by filtration, washed with PE, and dried in vacuo to give benzyl (cyano(phenyl)methyl)glycinate hydrochloride (6.5 g, 46.4% yield) as a white solid. LC / MS (ESI) m / z: 281 (M+H) + .

[0307] Step 2: Benzyl 2-(3,5-dichloro-2-oxo-6-phenylpyrazin-1(2H)-yl)acetate (3) To a solution of benzyl (cyano(phenyl)methyl)glycinate hydrochloride (6.5 g, 23.2 mmol) in chlorobenzene (65 mL) was added oxalyl dichloride (12.0 g, 92.9 mmol) under a N atmosphere, and the reaction mixture was stirred at 100 °C for 16 h. The mixture was concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (silica gel, 0-25% EtOAc in PE) to give benzyl 2-(3,5-dichloro-2-oxo-6-phenylpyrazin-1(2H)-yl)acetate (6.17 g, 68.9% yield) as a brown solid. LC / MS (ESI) m / z: 389 (M+H) + .

[0308] Step 3: Benzyl 2-(5-chloro-3-((2,4-dimethoxybenzyl)amino)-2-oxo-6-phenylpyrazin-1(2H)-yl)acetate (4) To a solution of benzyl 2-(3,5-dichloro-2-oxo-6-phenylpyrazin-1(2H)-yl)acetate (6.0 g, 15.5 mmol) in EtOAc (60 mL) was added 2,4-dimethoxybenzylamine (3.87 g, 23.3 mmol) under a N atmosphere, and the reaction mixture was stirred at 80 °C for 2 h. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous NaSO, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (silica gel, 0-50% EtOAc in PE) to give benzyl 2-(5-chloro-3-((2,4-dimethoxybenzyl)amino)-2-oxo-6-phenylpyrazin-1(2H)-yl)acetate (7.5 g, 93.8% yield) as a pale yellow solid. LC / MS (ESI) m / z: 520 (M+H) + .

[0309] Step 4: 2-(3-((2,4-dimethoxybenzyl)amino)-2-oxo-6-phenylpyrazin-1(2H)-yl)acetic acid (5) To a solution of benzyl 2-(5-chloro-3-((2,4-dimethoxybenzyl)amino)-2-oxo-6-phenylpyrazin-1(2H)-yl)acetate (4.7 g, 9.1 mmol) in MeOH (50 mL) was added Pd / C (200 mg, 10% by weight), and the mixture was degassed under N atmosphere 10 times and stirred under a H balloon at 40 °C for 16 h. The mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure to give 2-(3-((2,4-dimethoxybenzyl)amino)-2-oxo-6-phenylpyrazin-1(2H)-yl)acetic acid (2.4 g, 66.7% yield) as a yellow solid, which was used directly in the next step without further purification. LC / MS (ESI) (m / z): 396 (M+H) + .

[0310] Step 5: Methyl 2-(3-((2,4-dimethoxybenzyl)amino)-2-oxo-6-phenylpyrazin-1(2H)-yl)acetate (6) To a solution of 2-(3-((2,4-dimethoxybenzyl)amino)-2-oxo-6-phenylpyrazin-1(2H)-yl)acetic acid (2.5 g, 6.33 mmol) in THF (30 mL) was added TMSCHN (4.1 mL, 8.23 ​​mmol) under N atmosphere at 0 °C, and the reaction mixture was stirred at room temperature for 2 h. The mixture was quenched with ice water and extracted twice with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous NaSO, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (silica gel, 0-30% EtOAc in PE) to give methyl 2-(3-((2,4-dimethoxybenzyl)amino)-2-oxo-6-phenylpyrazin-1(2H)-yl)acetate (850 mg, 32.7% yield) as a brown solid. LC / MS (ESI) m / z: 410 (M+H) + .

[0311] Step 6: Methyl 2-(3-amino-2-oxo-6-phenylpyrazin-1(2H)-yl)acetate (7) To a solution of methyl 2-(3-((2,4-dimethoxybenzyl)amino)-2-oxo-6-phenylpyrazin-1(2H)-yl)acetate (850 mg, 2.08 mmol) in DCM (1 mL) was added TFA (10 mL), and the mixture was stirred at room temperature for 16 h. The mixture was concentrated to dryness, and the residue was dissolved in EtOAc. The mixture was washed with saturated aqueous NaHCO3 and brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure to give methyl 2-(3-amino-2-oxo-6-phenylpyrazin-1(2H)-yl)acetate (520 mg, 96.7% yield) as a brown solid. LC / MS (ESI) m / z: 260 (M+H) + .

[0312] Step 7: Methyl 2-(3-(([1,1'-biphenyl]-4-ylmethyl)amino)-2-oxo-6-phenylpyrazin-1(2H)-yl)acetate (8) To a solution of methyl 2-(3-amino-2-oxo-6-phenylpyrazin-1(2H)-yl)acetate (80 mg, 0.31 mmol) in DCE (3 mL) was added [1,1'-biphenyl]-4-carbaldehyde (224 mg, 1.24 mmol) and AcOH (0.05 mL) under a N atmosphere, and the reaction mixture was stirred at 80 °C for 16 h. The mixture was cooled to 0 °C, and NaBH(OAc) (327 mg, 1.55 mmol) was added. The resulting mixture was stirred from 0 °C to room temperature for 1 h. The mixture was quenched with saturated aqueous NH Cl and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na SO , filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (silica gel, 0-25% EtOAc in PE) to give methyl 2-(3-(([1,1'-biphenyl]-4-ylmethyl)amino)-2-oxo-6-phenylpyrazin-1(2H)-yl)acetate (28 mg, 21.4% yield) as a white solid. LC / MS (ESI) m / z: 426 (M+H) + .

[0313] Step 8: 2-(3-(([1,1'-biphenyl]-4-ylmethyl)amino)-2-oxo-6-phenylpyrazin-1(2H)-yl)acetic acid (9) To a solution of methyl 2-(3-(([1,1'-biphenyl]-4-ylmethyl)amino)-2-oxo-6-phenylpyrazin-1(2H)-yl)acetate (28 mg, 0.07 mmol) in MeOH (3 mL) and water (1 mL) was added LiOH·HO (4.4 mg, 0.11 mmol), and the mixture was stirred at room temperature for 2 h. The mixture was acidified with 1 N aqueous HCl to pH 3 and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NaSO, filtered, and concentrated to dryness under reduced pressure to give 2-(3-(([1,1'-biphenyl]-4-ylmethyl)amino)-2-oxo-6-phenylpyrazin-1(2H)-yl)acetic acid (25 mg, 92.6% yield) as a white solid, which was used directly in the next step without further purification. LC / MS (ESI) m / z: 412 (M+H) + .

[0314] Step 9: N-((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)-2-(3-(([1,1′-biphenyl]-4-ylmethyl)amino)-2-oxo-6-phenylpyrazin-1(2H)-yl)acetamide (Compound 60) To a mixture of 2-(3-(([1,1'-biphenyl]-4-ylmethyl)amino)-2-oxo-6-phenylpyrazin-1(2H)-yl)acetic acid (25 mg, 0.06 mmol) and (1H-pyrrolo[3,2-c]pyridin-2-yl)methanamine hydrochloride (18 mg, 0.12 mmol) in DMF (2 mL), DIPEA (47 mg, 0.36 mmol) and HATU (34 mg, 0.09 mmol) were added under a N atmosphere, and the reaction mixture was stirred at room temperature for 2 h. The mixture was diluted with EtOAc, washed with saturated aqueous NH4Cl and brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was purified by preparative HPLC to give compound 60 (3 mg, 9.1% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.31 (s, 1H), 8.74 (s, 1H), 8.64 (s, 1H), 8.12 (d, J = 5.2 Hz, 1H), 7.90 (s, 1H), 7.62 (dd, J = 13.2, 8.0 Hz, LC / MS (ESI) m / z: 541 (M+H) + . RT (Method A): 1.81 minutes.

[0315] Scheme 20. Synthesis of (R)-N-((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)-2-(6-oxo-5-((1-(4-phenoxyphenyl)ethyl)amino)-2-phenylpyrimidin-1(6H)-yl)acetamide (Compound 61) [ka] Step 1: Tert-butyl (R)-2-(2-(methylthio)-6-oxo-5-((1-(4-phenoxyphenyl)ethyl)amino)pyrimidin-1(6H)-yl)acetate (2) To a mixture of tert-butyl 2-(5-bromo-2-(methylthio)-6-oxopyrimidin-1(6H)-yl)acetate (960 mg, 2.87 mmol) and (R)-1-(4-phenoxyphenyl)ethan-1-amine (1.16 g, 5.44 mmol) in toluene (20 mL), Pd(OAc) (65 mg, 0.29 mmol), CsCO (1.89 g, 5.75 mmol), and BINAP (360 mg, 0.58 mmol) were added under a N atmosphere at 0 °C, and the mixture was stirred at 120 °C for 2 h. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous NaSO, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (silica gel, 0-50% EtOAc in PE) to give the title compound (750 mg, 55.9% yield) as a colorless oil. LC / MS (ESI) (m / z): 468 (M+H) + .

[0316] Step 2: Tert-butyl 2-(6-oxo-5-((1-(4-phenoxyphenyl)ethyl)amino)-2-phenylpyrimidin-1(6H)-yl)acetate (3) To a mixture of tert-butyl I-2-(2-(methylthio)-6-oxo-5-((1-(4-phenoxyphenyl)ethyl)amino)pyrimidin-1(6H)-yl)acetate (400 mg, 0.86 mmol) and phenylboronic acid (209 mg, 1.71 mmol) in THF (5 mL) was added CuTc (360 mg, 1.88 mmol) and Pd(PPh3)4 (199 mg, 0.17 mmol) at room temperature, and the mixture was stirred at 80 °C under a N2 atmosphere for 2 h. The mixture was quenched with saturated aqueous NaHCO3 and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (silica gel, 0-10% MeOH in DCM) to give the title compound (230 mg, 54.1% yield) as a white solid. LC / MS (ESI) m / z: 498 (M+H) + .

[0317] Step 3: 2-(6-oxo-5-((1-(4-phenoxyphenyl)ethyl)amino)-2-phenylpyrimidin-1(6H)-yl)acetic acid (4) To a solution of tert-butyl I-2-(6-oxo-5-((1-(4-phenoxyphenyl)ethyl)amino)-2-phenylpyrimidin-1(6H)-yl)acetate (220 mg, 0.44 mmol) in MeOH / THF / HO (2 mL, 2 / 1 / 1) was added LiOH·HO (56 mg, 1.32 mmol) under a N atmosphere, and the reaction mixture was stirred at room temperature for 2 h. The mixture was acidified with 1N aqueous HCl to pH ∼3 and extracted twice with EtOAc. The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to afford the title compound (153 mg, 77% yield) as a white solid, which was used directly in the next step without further purification. LC / MS (ESI) m / z: 442 (M+H) + .

[0318] Step 4: (R)—N-((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)-2-(6-oxo-5-((1-(4-phenoxyphenyl)ethyl)amino)-2-phenylpyrimidin-1(6H)-yl)acetamide (Compound 61) To a mixture of p2-(6-oxo-5-((1-(4-phenoxyphenyl)ethyl)amino)-2-phenylpyrimidin-1(6H)-yl)acetic acid (60 mg, 0.07 mmol) and (1H-pyrrolo[3,2-c]pyridin-2-yl)methanamine (12 mg, 0.08 mmol) in DMF (1 mL) was added DIPEA (53 mg, 0.40 mmol) and HATU (34 mg, 0.09 mmol) under a N atmosphere at 0 °C, and the mixture was stirred at room temperature for 2 h. The mixture was quenched with saturated aqueous NH4Cl and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was purified by preparative TLC (DCM:MeOH=10:1) and further purified by preparative HPLC to give compound 61 (1.8 mg, yield 2.3%) as a white solid. 1H NMR (400 MHz, CD3OD) δ 8.75 (s, 1H), 8.13 (d, J = 5.3 Hz, 1H), 7.43 (d, J = 6.4 Hz, 1H), 7.37 (d, J = 7.0 Hz, 1H), 7.33 (s, 1H), 7.09 (s, LC / MS (ESI) m / z: 571 (M+H) + . RT (Method A): 1.76 minutes.

[0319] Scheme 21. Synthesis of N-((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)-2-(2-oxo-3-((4-phenoxybenzyl)amino)-6-phenylpyrazin-1(2H)-yl)acetamide (Compound 63) [ka] Step 1: Methyl 2-(2-oxo-3-((4-phenoxybenzyl)amino)-6-phenylpyrazin-1(2H)-yl)acetate (2) To a solution of methyl 2-(3-amino-2-oxo-6-phenylpyrazin-1(2H)-yl)acetate (80 mg, 0.31 mmol) in DCE (3 mL) was added 4-phenoxybenzaldehyde (198 mg, 1.24 mmol) and AcOH (0.05 mL) under a N atmosphere, and the reaction mixture was stirred at 80 °C for 16 h. NaBH(OAc) (327 mg, 1.55 mmol) was added to the mixture, and the resulting mixture was stirred at 80 °C for 1 h. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous NaSO, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (silica gel, 0-25% EtOAc in PE) to give the title compound (18 mg, 13.2% yield) as a white solid. LC / MS (ESI) m / z: 442 (M+H)+ .

[0320] Step 2: 2-(2-oxo-3-((4-phenoxybenzyl)amino)-6-phenylpyrazin-1(2H)-yl)acetic acid (3) To a solution of methyl 2-(2-oxo-3-((4-phenoxybenzyl)amino)-6-phenylpyrazin-1(2H)-yl)acetate (18 mg, 0.04 mmol) in MeOH (2.1 mL) and water (0.7 mL), LiOH·HO (2.6 mg, 0.06 mmol) was added, and the mixture was stirred at room temperature for 2 h. The mixture was acidified with 1N aqueous HCl to pH 3 and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NaSO, filtered, and concentrated to dryness under reduced pressure to afford the title compound (17 mg, 97.7% yield) as a yellow oil, which was used directly in the next step without further purification. LC / MS (ESI) m / z: 428 (M+H) + .

[0321] Step 3: N-((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)-2-(2-oxo-3-((4-phenoxybenzyl)amino)-6-phenylpyrazin-1(2H)-yl)acetamide (Compound 63) To a mixture of 2-(2-oxo-3-((4-phenoxybenzyl)amino)-6-phenylpyrazin-1(2H)-yl)acetic acid (20 mg, 0.05 mmol) and (1H-pyrrolo[3,2-c]pyridin-2-yl)methanamine hydrochloride (14 mg, 0.10 mmol) in DMF (2 mL), DIPEA (36 mg, 0.30 mmol) and HATU (27 mg, 0.08 mmol) were added under a N atmosphere, and the reaction mixture was stirred at room temperature for 2 h. The mixture was diluted with EtOAc, washed with saturated aqueous NH4Cl and brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was purified by preparative HPLC to give compound 63 (1.0 mg, 3.8% yield) as a white solid. 1H NMR (400 MHz, CD3OD) δ 8.90 (s, 1H), 8.46 (s, 1H), 8.22 (d, J= 4.9 Hz, 1H), 7.69 (d, J = 6.3 Hz, 1H), 7.41 - 7.30 (m, 8H), 7.09 (t, J = LC / MS (ESI) m / z: 557 (M+H) + . RT (Method A): 1.27 minutes.

[0322] Scheme 22. Synthesis of N-((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)-2-(5-((3-(4-(fluoromethoxy)phenyl)propyl)amino)-6-oxo-2-phenylpyrimidin-1(6H)-yl)acetamide (Compound 66) [ka] Step 1: 4-(Fluoromethoxy)benzaldehyde (2) To a mixture of 4-hydroxybenzaldehyde (700 mg, 5.73 mmol) and fluoroiodomethane (1.00 g, 6.25 mmol) in MeCN (12 mL) was added CsCO (2.24 g, 6.88 mmol), and the mixture was stirred overnight at room temperature in a sealed tube. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous NaSO, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (silica gel, 0-20% EtOAc in PE) to give the title compound (880 mg, 99.6% yield) as a pale yellow oil. 1 H NMR (400 MHz, CDCl3) δ 9.94 (s, 1H), 7.92 - 7.85 (m, 2H), 7.20 (d, J = 8.6 Hz, 2H), 5.85 (s, 1H), 5.72 (s, 1H). LC / MS (ESI) m / z: 155 (M+H) +.

[0323] Step 2: (E)-3-(4-(fluoromethoxy)phenyl)methyl acrylate (3) To a solution of 4-(fluoromethoxy)benzaldehyde (750 mg, 4.87 mmol) in THF (15 mL) was added methyl 2-(triphenyl-λ 5 -phosphanylidene)acetate (4.83 g, 14.44 mmol) was added under a N atmosphere, and the mixture was stirred at 60 °C overnight. The mixture was concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (silica gel, 0-20% EtOAc in PE) to give the title compound (770 mg, 75.3% yield) as a white solid. 1 H NMR (400 MHz, CDCl3) δ 7.65 (d, J = 15.8 Hz, 1H), 7.50 (d, J = 7.9 Hz, 2H), 7.08 (d, J = 7.9 Hz, 2H), 6.35 (d, J = 16.0 Hz, 1H), 5.80 (s, 1H), 5.66 (s, 1H), 3.80 (s, 3H). LC / MS (ESI) m / z: 211 (M+H) + .

[0324] Step 3: (E)-3-(4-(fluoromethoxy)phenyl)prop-2-en-1-ol (4) To a solution of (E)-methyl 3-(4-(fluoromethoxy)phenyl)acrylate (400 mg, 1.90 mmol) in THF (8 mL) was added LiAlH (9.5 mL, 9.50 mmol, 1 M) dropwise at −20° C. under N atmosphere, and the reaction mixture was stirred at −20° C. for 2 h. The mixture was quenched with NaSO.10H O at 0° C., and the mixture was stirred at room temperature for 10 min. The mixture was filtered, and the filtrate was dried over anhydrous NaSO, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (silica gel, 0-30% EtOAc in PE) to give the title compound (230 mg, 66.3% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.35 (d, J = 7.4 Hz, 2H), 7.03 (d, J = 7.5 Hz, 2H), 6.58 (d, J = 15.8 Hz, 1H), 6.30 (s, 1H), 5.77 (s, 1H), 5.64 (s, 1H), 4.31 (s, 2H). LC / MS (ESI) m / z: 165 (M-OH) + .

[0325] Step 4: (E)-3-(4-(fluoromethoxy)phenyl)acrylaldehyde (5) To a solution of (E)-3-(4-(fluoromethoxy)phenyl)prop-2-en-1-ol (230 mg, 1.26 mmol) in DCM (10 mL) was added Dess-Martin periodinane (1.49 g, 3.51 mmol) and NaHCO (294 mg, 3.50 mmol) at 0 °C, and the reaction mixture was stirred at room temperature for 1 h. The mixture was diluted with DCM, washed with water and brine, dried over anhydrous NaSO, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (silica gel, 0-10% EtOAc in PE) to afford the title compound (123 mg, 54.1% yield) as a white solid. 1 H NMR (400 MHz, CDCl3) δ 9.68 (d, J = 7.5 Hz, 1H), 7.56 (d, J = 7.8 Hz, 2H), 7.44 (d, J = 16.0 Hz, 1H), 7.13 (d, J = 7.8 Hz, 2H), 6.64 (dd, J = 15.9, 7.6 Hz, 1H), 5.75 (d, J = 54.0 Hz, 2H). LC / MS (ESI) m / z: 181 (M+H) + .

[0326] Step 5: (E)—N-((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)-2-(5-((3-(4-(fluoromethoxy)phenyl)allyl)amino)-6-oxo-2-phenylpyrimidin-1(6H)-yl)acetamide (6) To a solution of (E)-3-(4-(fluoromethoxy)phenyl)acrylaldehyde (14 mg, 0.078 mmol) in MeOH (2 mL) was added N-((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)-2-(5-amino-6-oxo-2-phenylpyrimidin-1(6H)-yl)acetamide (20 mg, 0.053 mmol) and NaBHCN (7 mg, 0.11 mmol) under a N atmosphere, and the reaction mixture was stirred at 55 °C for 1 h. Then, another batch of (E)-3-(4-(fluoromethoxy)phenyl)acrylaldehyde (14 mg, 0.078 mmol) and NaBHCN (7 mg, 0.11 mmol) was added to the mixture, and the resulting mixture was stirred at 55 °C overnight. The mixture was quenched with saturated aqueous NHCl and extracted twice with DCM. The combined organic layers were washed with brine, dried over anhydrous NaSO, filtered, and concentrated to dryness under reduced pressure. The residue was purified by preparative TLC (DCM:MeOH=15:1) to give the title compound (15 mg, 52.1% yield) as a pale yellow oil. LC / MS (ESI) m / z: 539 (M+H) + .

[0327] Step 6: N-((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)-2-(5-((3-(4-(fluoromethoxy)phenyl)propyl)amino)-6-oxo-2-phenylpyrimidin-1(6H)-yl)acetamide (Compound 66) To a solution of (E)-N-((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)-2-(5-((3-(4-(fluoromethoxy)phenyl)allyl)amino)-6-oxo-2-phenylpyrimidin-1(6H)-yl)acetamide (15 mg, 0.028 mmol) in MeOH (2 mL), Pd / C (5 mg, 10 wt%) was added, and the mixture was degassed under N atmosphere three times and stirred under a H balloon at room temperature for 10 min. The mixture was filtered, and the filtrate was concentrated to dryness. The residue was purified by preparative HPLC to give compound 66 (0.76 mg, 5.0% yield) as a white solid. 1H NMR (400 MHz, CD3OD) δ 8.78 (s, 1H), 8.15 (d, J = 6.0 Hz, 1H), 7.50 - 7.45 (m, 4H), 7.42 - 7.38 (m, 2H), 7.21 (d, J = 8.5 Hz, 2H), 7.09 (s, 1H), 7.03 - 6.99 (m, 2H), 6.57 (s, 1H), 5.77 (s, 1H), 5.64 (s, 1H), 4.63 (s, 2H), 4.56 (s, 2H), 3.19 (t, J = 6.9 Hz, 2H), 2.73 (t, J = 7.6 Hz, 2H), 2.01 - 1.95 (m, 2H). LC / MS (ESI) m / z: 541 (M+H) + . RT (method a): 1.49 minutes.

[0328] Scheme 23. Synthesis of N-((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)-2-(6-oxo-5-((3-phenylpropyl)amino)-2-(4-(sulfamoylmethoxy)phenyl)pyrimidin-1(6H)-yl)acetamide (Compound 67) [ka] Step 1: N-(tert-butyl)-1-chloromethanesulfonamide (2) To a mixture of 4-methylmorpholine (375 mg, 3.70 mmol) and 2-methylpropan-2-amine (271 mg, 3.70 mmol) in THF (5 mL) was added chloromethanesulfonyl chloride (500 mg, 3.37 mmol) at 0° C., and the mixture was stirred at room temperature for 2 hours. The mixture was diluted with EtOAc, washed with 1 M aqueous HCl and brine, dried over anhydrous NaSO, filtered, and concentrated to dryness under reduced pressure to give the title compound (360 mg, 57.6% yield) as a white solid, which was used directly in the next step without further purification. LC / MS (ESI) m / z: 185 (M+H) + .

[0329] Step 2: Tert-butyl 2-(2-(4-((N-(tert-butyl)sulfamoyl)methoxy)phenyl)-6-oxo-5-((3-phenylpropyl)amino)pyrimidin-1(6H)-yl)acetate (3) To a solution of tert-butyl 2-(2-(4-hydroxyphenyl)-6-oxo-5-((3-phenylpropyl)amino)pyrimidin-1(6H)-yl)acetate (150 mg, 0.34 mmol) in DMF (2 mL) was added K2CO3 (142 mg, 1.02 mmol) and N-(tert-butyl)-1-chloromethanesulfonamide (64 mg, 0.34 mmol) at 0 °C, and the mixture was stirred at room temperature for 2 h. The mixture was diluted with EtOAc, washed with saturated aqueous NaHCO3 and brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (silica gel, 0-60% EtOAc in PE) to give the title compound (120 mg, 59.7% yield) as a yellow solid. LC / MS (ESI) m / z: 585 (M+H) + .

[0330] Step 3: 2-(2-(4-((N-(tert-butyl)sulfamoyl)methoxy)phenyl)-6-oxo-5-((3-phenylpropyl)amino)pyrimidin-1(6H)-yl)acetic acid (4) To a solution of tert-butyl 2-(2-(4-((N-(tert-butyl)sulfamoyl)methoxy)phenyl)-6-oxo-5-((3-phenylpropyl)amino)pyrimidin-1(6H)-yl)acetate (120 mg, 0.20 mmol) in MeOH (1 mL), THF (1 mL), and water (1 mL) was added NaOH (16 mg, 0.40 mmol), and the mixture was stirred at 40° C. for 2 h. The mixture was acidified with 1 N aqueous HCl to pH 3 and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NaSO, filtered, and concentrated to dryness under reduced pressure to afford the title compound (88 mg, 81.2% yield) as a yellow solid, which was used directly in the next step without further purification. LC / MS (ESI) m / z: 529 (M+H) + .

[0331] Step 4: N-((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)-2-(2-(4-((N-(tert-butyl)sulfamoyl)methoxy)phenyl)-6-oxo-5-((3-phenylpropyl)amino)pyrimidin-1(6H)-yl)acetamide (5) To a mixture of 2-(2-(4-((N-(tert-butyl)sulfamoyl)methoxy)phenyl)-6-oxo-5-((3-phenylpropyl)amino)pyrimidin-1(6H)-yl)acetic acid (88 mg, 0.16 mmol) and (1H-pyrrolo[3,2-c]pyridin-2-yl)methanamine (73 mg, 0.48 mmol) in DMF (2 mL) was added DIPEA (107 mg, 0.80 mmol) and HATU (95 mg, 0.24 mmol) at 0 °C, and the mixture was stirred at room temperature for 2 h. The mixture was diluted with EtOAc, washed with saturated aqueous NaHCO and brine, dried over anhydrous NaSO, filtered, and concentrated to dryness under reduced pressure. The residue was purified by preparative TLC (DCM:MeOH = 10:1) to give the title compound (70 mg, 64.2% yield) as a yellow solid. LC / MS (ESI) m / z: 658 (M+H) + .

[0332] Step 5: N-((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)-2-(6-oxo-5-((3-phenylpropyl)amino)-2-(4-(sulfamoylmethoxy)phenyl)pyrimidin-1(6H)-yl)acetamide (Compound 67) To a solution of N-((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)-2-(2-(4-((N-(tert-butyl)sulfamoyl)methoxy)phenyl)-6-oxo-5-((3-phenylpropyl)amino)pyrimidin-1(6H)-yl)acetamide (70 mg, 0.10 mmol) in DCM (1 mL) was added TFA (0.5 mL), and the mixture was stirred at room temperature under a N atmosphere for 1 hour. The reaction mixture was concentrated to dryness under reduced pressure. The residue was purified by preparative HPLC to give compound 67 (13.9 mg, 21.7% yield) as a white solid.1 H NMR (400 MHz, DMSO-d6) δ 11.32 (s, 1H), 8.74 (s, 1H), 8.70 (t, J = 5.7 Hz, 1H), 8.11 (d, J = 5.7 Hz, 1H), 7.43 (d, J = 8.7 Hz, 2H), 7.35 - 7.26 (m, 4H), 7.24 (d, J = 6.7 Hz, 3H), 7.20 - 7.17 (m, 1H), 7.13 (d, J = 8.8 Hz, 2H), 7.08 (s, 1H), 6.36 (s, 1H), 5.48 (t, J = 5.9 Hz, 1H), 5.11 (s, 2H), 4.50 (s, 2H), 4.43 (d, J = 5.4 Hz, 2H), 3.12 - 3.06 (m, 2H), 2.67 (t, J = 7.6 Hz, 2H), 1.93 - 1.85 (m, 2H). LC / MS (ESI) m / z: 602 (M+H) + . RT (Method A): 1.32 minutes.

[0333] Compounds 131 and 139 are prepared according to the procedure set out in Scheme 23. [Table 17]

[0334] Scheme 24. Synthesis of (4-(1-(2-(((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)amino)-2-oxoethyl)-6-oxo-5-((3-phenylpropyl)amino)-1,6-dihydropyrimidin-2-yl)phenyl)(methyl)phosphinic acid (compound 68) [ka] Step 1: Tert-butyl 2-(2-(4-(ethoxy(methyl)phosphoryl)phenyl)-6-oxo-5-((3-phenylpropyl)amino)pyrimidin-1(6H)-yl)acetate (2) To a mixture of tert-butyl 2-(2-(4-bromophenyl)-6-oxo-5-((3-phenylpropyl)amino)pyrimidin-1(6H)-yl)acetate (120 mg, 0.24 mmol) and diethylmethylphosphonite (164 mg, 1.20 mmol) in DMF (3 mL) was added DIPEA (156 mg, 1.2 mmol) followed by Pd(dppf)Cl (17 mg, 0.02 mmol). The reaction mixture was degassed three times under N atmosphere and stirred in a CEM microwave reactor at 130 °C for 30 min. The mixture was diluted with water and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NaSO, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (silica gel, 0-90% EtOAc in PE) to give the title compound (75 mg, 59.3% yield) as a yellow oil. LC / MS (ESI) m / z: 526 (M+H) + .

[0335] Step 2: 2-(2-(4-(ethoxy(methyl)phosphoryl)phenyl)-6-oxo-5-((3-phenylpropyl)amino)pyrimidin-1(6H)-yl)acetic acid (3) To a solution of tert-butyl 2-(2-(4-(ethoxy(methyl)phosphoryl)phenyl)-6-oxo-5-((3-phenylpropyl)amino)pyrimidin-1(6H)-yl)acetate (75 mg, 0.14 mmol) in DCM (3 mL) was added TFA (1 mL) and the reaction mixture was stirred at room temperature for 6 h. The reaction mixture was concentrated to dryness under reduced pressure to give the title compound (80 mg, 97.8% yield) as a yellow solid, which was used directly in the next step without further purification. LC / MS (ESI) m / z: 470 (M+H) + .

[0336] Step 3: Ethyl (4-(1-(2-(((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)amino)-2-oxoethyl)-6-oxo-5-((3-phenylpropyl)amino)-1,6-dihydropyrimidin-2-yl)phenyl)(methyl)phosphinate (4) To a mixture of 2-(2-(4-(ethoxy(methyl)phosphoryl)phenyl)-6-oxo-5-((3-phenylpropyl)amino)pyrimidin-1(6H)-yl)acetic acid (50 mg, 0.106 mol) and (1H-pyrrolo[3,2-c]pyridin-2-yl)methanamine (31 mg, 0.21 mmol) in DMF (2 mL) was added DIPEA (41 mg, 0.32 mmol) and HATU (61 mg, 0.16 mol) under a N atmosphere, and the reaction mixture was stirred at room temperature for 2 h. The mixture was diluted with EtOAc, washed with saturated aqueous NH4Cl and brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (silica gel, 0-100% EtOAc in PE) to give the title compound (45 mg, 70.6% yield) as a yellow oil. LC / MS (ESI) m / z: 599 (M+H) + .

[0337] Step 4: (4-(1-(2-(((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)amino)-2-oxoethyl)-6-oxo-5-((3-phenylpropyl)amino)-1,6-dihydropyrimidin-2-yl)phenyl)(methyl)phosphinic acid (compound 68) To a solution of ethyl (4-(1-(2-(((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)amino)-2-oxoethyl)-6-oxo-5-((3-phenylpropyl)amino)-1,6-dihydropyrimidin-2-yl)phenyl)(methyl)phosphinate (45 mg, 0.08 mmol) in MeOH (2 mL) and water (0.5 mL) was added LiOH·HO (6 mg, 0.15 mmol), and the mixture was stirred at room temperature for 2 h. The mixture was purified by preparative HPLC to give compound 68 (15 mg, 35.0% yield) as a white solid. 1H NMR (400 MHz, DMSO) δ 12.29 - 11.96 (m, 1H), 9.30 - 8.83 (m, 1H), 8.74 (s, 1H), 8.09 (d, J = 5.7 Hz, 1H), 7.69 (d, J = 7.6 Hz, 2H), 7.40 - 7.32 (m, 3H), 7.32 - 7.27 (m, 2H), 7.25 (d, J = 6.9 Hz, 2H), 7.21 - 7.16 (m, 1H), 7.08 (s, 1H), 6.34 (s, 1H), 5.47 (t, J = 5.8 Hz, 1H), 4.51 (s, 2H), 4.36 (s, 2H), 3.10 (dd, J = 13.1, 6.6 Hz, 2H), 2.67 (t, J = 7.7 Hz, 2H), 1.94 - 1.86 (m, 2H), 1.16 - 1.08 (m, 3H). LC / MS (ESI) m / z: 571 (M+H) + . RT (Method A): 1.18 minutes.

[0338] Compounds 132 and 140 are prepared according to the procedure set out in Scheme 24. [Table 18]

[0339] Scheme 25. Synthesis of N-((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)-2-(2-(4-(methylsulfonyl)phenyl)-6-oxo-5-((3-phenylpropyl)amino)pyrimidin-1(6H)-yl)acetamide (Compound 69) [ka] Step 1: Tert-butyl 2-(2-(4-(methylsulfonyl)phenyl)-6-oxo-5-((3-phenylpropyl)amino)pyrimidin-1(6H)-yl)acetate (2) To a mixture of tert-butyl 2-(2-(4-(methylthio)phenyl)-6-oxo-5-((3-phenylpropyl)amino)pyrimidin-1(6H)-yl)acetate (100 mg, 0.22 mol) in DCM (2 mL) was added oxone (396 mg, 0.64 mmol) at 0° C., and the mixture was stirred at room temperature for 1 h. The mixture was diluted with DCM, washed with water and brine, dried over anhydrous NaSO, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (silica gel, 0-40% EtOAc in PE) to give the title compound (70 mg, 62.0% yield) as a yellow solid. LC / MS (ESI) (m / z): 498 (M+H) + .

[0340] Step 2: 2-(2-(4-(methylsulfonyl)phenyl)-6-oxo-5-((3-phenylpropyl)amino)pyrimidin-1(6H)-yl)acetic acid (3) To a solution of tert-butyl 2-(2-(4-(methylsulfonyl)phenyl)-6-oxo-5-((3-phenylpropyl)amino)pyrimidin-1(6H)-yl)acetate (60 mg, 0.12 mmol) in DCM (2 mL) was added TFA (1 mL) under N2 atmosphere at 0°C, and the reaction mixture was stirred at room temperature for 2 h. The mixture was concentrated to dryness under reduced pressure to give the title compound (35 mg, 65.6% yield) as a yellow solid, which was used directly in the next step without further purification. LC / MS (ESI) m / z: 442 (M+H) + .

[0341] Step 3: N-((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)-2-(2-(4-(methylsulfonyl)phenyl)-6-oxo-5-((3-phenylpropyl)amino)pyrimidin-1(6H)-yl)acetamide (Compound 69) To a mixture of 2-(2-(4-(methylsulfonyl)phenyl)-6-oxo-5-((3-phenylpropyl)amino)pyrimidin-1(6H)-yl)acetic acid (35 mg, 0.079 mol) and (1H-pyrrolo[2,3-c]pyridin-2-yl)methanamine (17 mg, 0.12 mmol) in DMF (1 mL) was added DIPEA (51 mg, 0.40 mmol) and HATU (45 mg, 0.12 mol) under a N atmosphere, and the reaction mixture was stirred at room temperature for 30 min. The mixture was diluted with EtOAc, washed with saturated aqueous NH4Cl and brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was purified by preparative HPLC to give compound 69 (2.3 mg, 5.1% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 11.32 (s, 1H), 8.76 - 8.71 (m, 2H), 8.11 (d, J = 5.6 Hz, 1H), 7.97 (d, J = 8.4 Hz, 2H), 7.75 (d, J = 8.4 Hz, 2H), 7.33 - 7.23 (m, 5H), 7.18 (t, J = 7.0 Hz, 1H), 7.12 (s, 1H), 6.33 (s, 1H), 5.69 (t, J = 6.0 Hz, 1H), 4.52 (s, 2H), 4.42 (d, J = 5.5 Hz, 2H), 3.24 (s, 3H), 3.15 - 3.10 (m, 2H), 2.67 (t, J = 7.7 Hz, 2H), 1.93 - 1.86 (m, 2H). LC / MS (ESI) m / z: 571 (M+H) + . RT (Method A): 1.42 minutes.

[0342] Scheme 26. Synthesis of N-((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)-2-(5-(3-(cyclohexylmethyl)ureido)-6-oxo-2-phenylpyrimidin-1(6H)-yl)acetamide (Compound 76) [ka] Step 1: (Isocyanatomethyl)cyclohexane (2) To a solution of cyclohexylmethanamine (113 mg, 1.0 mmol) in DCM (2 mL) was added a solution of bis(trichloromethyl)carbonate (297 mg, 1.0 mmol) in DCM (2 mL) and TEA (303 mg, 3.0 mmol) at 0° C. under a N atmosphere, and the mixture was stirred at room temperature for 1 h. The mixture was concentrated to dryness under reduced pressure to give the title compound (400 mg, crude) as a white solid, which was used directly in the next step without further purification.

[0343] Step 2: N-((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)-2-(5-(3-(cyclohexylmethyl)ureido)-6-oxo-2-phenylpyrimidin-1(6H)-yl)acetamide (Compound 76) To a solution of N-((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)-2-(5-amino-6-oxo-2-phenylpyrimidin-1(6H)-yl)acetamide (30 mg, 0.08 mmol) in DMF (1 mL) were added (isocyanatomethyl)cyclohexane (22 mg, 0.16 mmol) and DIPEA (16 mg, 0.12 mmol) under a N atmosphere, and the reaction mixture was stirred at room temperature for 2 h. The mixture was concentrated to dryness under reduced pressure. The residue was purified by preparative HPLC to give compound 76 (2.3 mg, 5.6% yield) as a white solid. 1H NMR (400 MHz, CD3OD) δ 8.81 (s, 1H), 8.30 (d, J = 6.0 Hz, 1H), 7.66 (d, J = 6.0 Hz, 1H), 7.52 - 7.47 (m, 3H), 7.42 (t, J = 7.4 Hz, 3H), 6.70 (s, 1H), 4.67 (s, 2H), 4.64 (s, 2H), 3.28 (d, J = 6.9 Hz, 2H), 1.86 (d, J = 12.5 Hz, 2H), 1.82 - 1.76 (m, 2H), 1.74 - 1.67 (m, 2H), 1.35 - 1.25 (m, 3H), 1.12 - 1.03 (m, 2H). LC / MS (ESI) m / z: 514 (M+H) + . RT (Method A): 1.20 minutes.

[0344] Compound 79 was prepared according to step 2 of scheme 26: [Table 19]

[0345] Scheme 27. Synthesis of N-((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)-2-(5-phenyl-2-((3-phenylpropyl)amino)pyridin-4-yl)acetamide (Compound 80) [ka] Step 1: Ethyl 2-(2-chloropyridin-4-yl)acetate (2) To a solution of 2-chloro-4-methylpyridine (5.0 g, 39.4 mmol) in THF (50 mL) was added LiHMDS (48 mL, 47.3 mmol, 1 mol / L in THF) dropwise at −78° C., and the mixture was stirred at −78° C. for 1 h. Diethyl carbonate (7.0 g, 59.1 mmol) was added to the mixture at −78° C., and the resulting mixture was stirred at −78° C. for 2 h. The mixture was quenched with saturated aqueous NH4Cl and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0-20% EtOAc in PE) to give the title compound (3.5 g, 44.9% yield) as a yellow oil. LC / MS (ESI) m / z: 200 (M+H) + .

[0346] Step 2: Ethyl 2-(2-((tert-butoxycarbonyl)amino)pyridin-4-yl)acetate (3) To a mixture of ethyl 2-(2-chloropyridin-4-yl)acetate (1.5 g, 7.5 mmol) and NHBoc (2.6 g, 22.6 mmol) in THF (20 mL) was added CsCO (3.68 g, 11.3 mmol), Xant-Phos (218 mg, 0.4 mmol), and Pd(dba) (173 mg, 0.2 mmol) under N atmosphere. The mixture was degassed under N atmosphere 10 times and stirred under N atmosphere at 75 °C overnight. The reaction mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous NaSO, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (silica gel, 0-20% EtOAc in PE) to give the title compound (2.1 g, 99.5% yield) as a white solid. LC / MS (ESI) m / z: 281 (M+H) + .

[0347] Step 3: Ethyl 2-(5-bromo-2-((tert-butoxycarbonyl)amino)pyridin-4-yl)acetate (4) To a solution of ethyl 2-(2-((tert-butoxycarbonyl)amino)pyridin-4-yl)acetate (1.6 g, 5.7 mmol) in THF (20 mL) was added NBS (1.2 g, 6.8 mmol) at 0° C., and the reaction mixture was stirred at room temperature for 2 h. The mixture was diluted with EtOAc, washed with brine, dried over anhydrous NaSO, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (silica gel, 0-20% EtOAc in PE) to give the title compound (725 mg, 36.3% yield) as a white solid. LC / MS (ESI) m / z: 359 / 361 (M+H) + .

[0348] Step 4: Ethyl 2-(2-((tert-butoxycarbonyl)amino)-5-phenylpyridin-4-yl)acetate (5) To a mixture of ethyl 2-(5-bromo-2-((tert-butoxycarbonyl)amino)pyridin-4-yl)acetate (750 mg, 2.1 mmol) and phenylboronic acid (383 mg, 3.2 mmol) in 1,4-dioxane (9 mL) and HO (1.5 mL) was added NaCO (666 mg, 9.6 mmol) and Pd(PPh) (242 mg, 0.21 mmol) under N atmosphere. The mixture was degassed under N atmosphere 10 times and stirred under N atmosphere at 80 °C overnight. The reaction mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous NaSO, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (silica gel, 0-20% EtOAc in PE) to give the title compound (740 mg, 99.2% yield) as a white solid. LC / MS (ESI) m / z: 357 (M+H) + .

[0349] Step 5: Ethyl 2-(2-amino-5-phenylpyridin-4-yl)acetate hydrochloride (6) To a solution of ethyl 2-(2-((tert-butoxycarbonyl)amino)-5-phenylpyridin-4-yl)acetate (740 mg, 2.1 mmol) in DCM (1 mL) was added HCl / 1,4-dioxane (9 mL) and the reaction mixture was stirred at room temperature for 2 h. The mixture was concentrated to dryness under reduced pressure to give the title compound (550 mg, crude) as a white solid, which was used directly in the next step without further purification. LC / MS (ESI) m / z: 257 (M+H) + .

[0350] Step 6: Ethyl 2-(5-phenyl-2-((3-phenylpropyl)amino)pyridin-4-yl)acetate (7) To a mixture of ethyl 2-(2-amino-5-phenylpyridin-4-yl)acetate hydrochloride (114 mg, 0.39 mmol) and 3-phenylpropanal (209 mg, 1.56 mmol) in MeOH (5 mL) was added NaBHCN (196 mg, 2.34 mmol) under a N atmosphere, and the reaction mixture was stirred at 50 °C for 2 h. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous NaSO, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (silica gel, 0-80% EtOAc in PE) to give the title compound (120 mg, 82.2% yield) as a colorless oil. LC / MS (ESI) m / z: 375 (M+H) + .

[0351] Step 7: 2-(5-phenyl-2-((3-phenylpropyl)amino)pyridin-4-yl)acetic acid (8) To a solution of ethyl 2-(5-phenyl-2-((3-phenylpropyl)amino)pyridin-4-yl)acetate (120 mg, 0.32 mmol) in MeOH (3 mL) and water (1 mL) was added LiOH·HO (27 mg, 0.64 mmol), and the reaction mixture was stirred at 25 °C for 2 h. The mixture was acidified with 1 N aqueous HCl to pH 6 and extracted twice with EtOAc. The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated to dryness under reduced pressure to give the title compound (100 mg, 90.1% yield) as a white solid, which was used directly in the next step without further purification. LC / MS (ESI) m / z: 347 (M+H) + .

[0352] Step 8: N-((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)-2-(5-phenyl-2-((3-phenylpropyl)amino)pyridin-4-yl)acetamide (Compound 80) To a mixture of 2-(5-phenyl-2-((3-phenylpropyl)amino)pyridin-4-yl)acetic acid (80 mg, 0.23 mmol) and (1H-pyrrolo[3,2-c]pyridin-2-yl)methanamine hydrochloride (43 mg, 0.46 mmol) in DMF (3 mL), DIPEA (179 mg, 1.38 mmol) and HATU (131 mg, 0.35 mmol) were added under a N atmosphere, and the reaction mixture was stirred at room temperature for 2 h. The mixture was diluted with EtOAc, washed with saturated aqueous NH4Cl and brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was purified by preparative HPLC to give compound 80 (5 mg, 4.5% yield) as a white solid. 1H NMR (400 MHz, CD3OD) δ 8.69 (s, 1H), 8.10 (d, J = 5.8 Hz, 1H), 7.76 (s, 1H), 7.36 (d, J = 5.8 Hz, 1H), 7.27 - 7.23 (m, 7H), 7.21 - 7.15 (m, 3H), 6.48 (s, 1H), 6.42 (s, 1H), 4.45 (s, 2H), 3.49 (s, 2H), 3.26 (d, J = 7.0 Hz, 2H), 2.72 - 2.68 (m, 2H), 1.93 - 1.89 (m, 2H). LC / MS (ESI) m / z: 476 (M+H) + . RT (Method A): 0.86 minutes.

[0353] Scheme 28. Synthesis of 2-(5-(1H-benzo[d]pyridin-2-yl)-6-oxo-2-phenylpyrimidin-1(6H)-yl)-N-((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)acetamide (compound 82) [ka] Step 1: 1-(2-(tert-butoxy)-2-oxoethyl)-6-oxo-2-phenyl-1,6-dihydropyrimidine-5-carboxylic acid (2) To a solution of ethyl 1-(2-(tert-butoxy)-2-oxoethyl)-6-oxo-2-phenyl-1,6-dihydropyrimidine-5-carboxylate (200 mg, 0.56 mmol) in THF (3 mL) and water (1 mL) was added LiOH·HO (23 mg, 0.56 mmol), and the reaction mixture was stirred at −5° C. for 2 h. The mixture was acidified with 1N aqueous HCl to pH 3 and extracted twice with EtOAc. The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated to dryness under reduced pressure to afford the title compound (150 mg, 81.5% yield) as a white solid, which was used directly in the next step without further purification. LC / MS (ESI) m / z: 331 (M+H) + .

[0354] Step 2: Tert-butyl 2-(5-((2-aminophenyl)carbamoyl)-6-oxo-2-phenylpyrimidin-1(6H)-yl)acetate (3) To a mixture of 1-(2-(tert-butoxy)-2-oxoethyl)-6-oxo-2-phenyl-1,6-dihydropyrimidine-5-carboxylic acid (190 mg, 0.58 mmol) and benzene-1,2-diamine (76 mg, 0.70 mmol) in DMF (5 mL) was added DIPEA (450 mg, 3.48 mmol) and HATU (332 mg, 0.87 mmol) under N atmosphere, and the reaction mixture was stirred at room temperature for 2 h. The mixture was diluted with EtOAc, washed with saturated aqueous NH4Cl and brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (silica gel, 0-25% EtOAc in PE) to give the title compound (100 mg, 40.8% yield) as a yellow solid. LC / MS (ESI) m / z: 421 (M+H) + .

[0355] Step 3: 2-(5-(1H-benzo[d]pyridin-2-yl)-6-oxo-2-phenylpyrimidin-1(6H)-yl)acetic acid (4) A solution of tert-butyl 2-(5-((2-aminophenyl)carbamoyl)-6-oxo-2-phenylpyrimidin-1(6H)-yl)acetate (80 mg, 0.20 mmol) in AcOH (2 mL) was stirred at 120° C. for 2 h in a CEM microwave reactor. The mixture was filtered and the filter cake was dried in vacuo to give the title compound (30 mg, 45.5% yield) as a white solid. LC / MS (ESI) m / z: 347 (M+H) + .

[0356] Step 4: 2-(5-(1H-benzo[d]pyridin-2-yl)-6-oxo-2-phenylpyrimidin-1(6H)-yl)-N-((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)acetamide (compound 82) To a mixture of 2-(5-(1H-benzo[d]pyridin-2-yl)-6-oxo-2-phenylpyrimidin-1(6H)-yl)acetic acid (30 mg, 0.09 mmol) and (1H-pyrrolo[3,2-c]pyridin-2-yl)methanamine hydrochloride (25 mg, 0.18 mmol) in DMF (2 mL), DIPEA (70 mg, 0.54 mmol) and HATU (51 mg, 0.14 mmol) were added under a N atmosphere, and the reaction mixture was stirred at room temperature for 2 h. The mixture was diluted with EtOAc, washed with saturated aqueous NH4Cl and brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was purified by preparative HPLC to give compound 82 (3 mg, 7.3% yield) as a white solid. 1 H NMR (400 MHz, CD3OD) δ 9.43 (s, 1H), 8.46 (s, 1H), 8.32 (d, J = 7.3 Hz, 2H), 8.05 (d, J = 6.2 Hz, 1H), 7.70 - 7.66 (m, 2H), 7.39 (d, J = 7.3 Hz, 1H), 7.31 (dt, J = 7.2, 4.3 Hz, 5H), 6.54 (s, 1H), 5.28 (s, 2H), 4.66 (s, 2H).LC / MS (ESI) m / z: 476 (M+H) + . RT (Method A): 1.00 minutes.

[0357] Compounds 81 and 425 were prepared according to Scheme 28: [Table 20]

[0358] Scheme 29. Synthesis of N-(1-(2-(((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)amino)-2-oxoethyl)-6-oxo-2-phenyl-1,6-dihydropyrimidin-5-yl)-1,4(1,4)-dibenzenacyclohexaphane-12-carboxamide (compound 83) [ka]

[0359] Step 1: Methyl 1,4(1,4)-dibenzeneacyclohexaphane-1 2 -carboxylate (2) 1 in 1,4-dioxane (15 mL) 2 To a mixture of 1,4-bromo-1,4(1,4)-dibenzeneacyclohexaphane (100 mg, 0.35 mmol), Pd(dppf)Cl (25.4 mg, 0.035 mmol) was added under a N atmosphere at 0 °C. The mixture was degassed three times under a CO atmosphere and stirred at 80 °C overnight. The mixture was diluted with water and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NaSO, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (silica gel, 0-10% EtOAc in PE) to give the title compound (57 mg, 61% yield) as an off-white solid. LC / MS (ESI) m / z: 267 (M+H) + .

[0360] Step 2: 1,4(1,4)-dibenzeneacyclohexaphane-1 2 -carboxylic acid (3) To a solution of methyl 1,4(1,4)-dibenzeneacyclohexaphane-12-carboxylate (57 mg, 0.21 mmol) in THF / MeOH / HO (6 mL, 4 / 1 / 1) was added LiOH·HO (26.5 mg, 0.69 mmol) under a N atmosphere, and the reaction mixture was stirred at 60 °C overnight. The mixture was acidified with 1 N aqueous HCl to pH 3 and extracted twice with EtOAc. The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the title compound (45 mg, 85% yield) as a white solid, which was used directly in the next step without further purification. LC / MS (ESI) m / z: 253 (M+H) + .

[0361] Step 3: N-(1-(2-(((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)amino)-2-oxoethyl)-6-oxo-2-phenyl-1,6-dihydropyrimidin-5-yl)-1,4(1,4)-dibenzeneacyclohexaphane-1 2 -Carboxamide (compound 83) To a mixture of 1,4(1,4)-dibenzeneacyclohexaphane-12-carboxylic acid (20 mg, 0.079 mmol) and N-((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)-2-(5-amino-6-oxo-2-phenylpyrimidin-1(6H)-yl)acetamide (35.4 mg, 0.095 mmol) in DMF (3 mL) was added DIPEA (51 mg, 0.395 mmol) and HATU (39 mg, 0.11 mol) under a N atmosphere, and the reaction mixture was stirred at room temperature for 2 h. The mixture was diluted with EtOAc, washed with saturated aqueous NH4Cl and brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was purified by preparative TLC (DCM:MeOH=20:1) and further purified by preparative HPLC to give compound 83 (3.2 mg, yield 6.7%) as a white solid. 1 H NMR (400 MHz, CD3OD) δ 8.74 (s, 1H), 7.50 (t, J = 6.1 Hz, 3H), 7.43 (t, J = 7.3 Hz, 4H), 6.93 - 6.73 (m, 3H), 6.71 (d, J = 5.1 Hz, 2H), 6.62 (s, 2H), 6.38 (d, J = 8.0 Hz, 1H), 4.69 (s, 4H), 3.24 - 3.07 (m, 5H), 3.06 - 2.90 (m, 3H). LC / MS (ESI) m / z: 609 (M+H) + . RT (Method A): 1.58 minutes.

[0362] Scheme 30. Synthesis of N-((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)-2-(5-((3-(4-(N-cyano-S-methylsulfonimidoyl)phenyl)propyl)amino)-6-oxo-2-phenylpyrimidin-1(6H)-yl)acetamide (compound 84) [ka] Step 1: (E)-N-((4-(3-((tert-butyldimethylsilyl)oxy)propyl)phenyl)(methyl)-14-sulfanylidene)cyanamide (2) To a solution of tert-butyldimethyl(3-(4-(methylthio)phenyl)propoxy)silane (150 mg, 0.51 mol) in MeCN (2 mL) were added NHCN (28 mg, 0.67 mmol), t-BuOK (0.6 mL, 1.18 mmol), and NBS (135 mg, 0.76 mmol) under a N atmosphere, and the mixture was stirred at room temperature for 3 h. The mixture was diluted with water and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NaSO, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (silica gel, 0-50% EtOAc in PE) to give the title compound (170 mg, 99.4% yield) as a colorless oil. LC / MS (ESI) (m / z): 337 (M+H) + .

[0363] Step 2: N-((4-(3-((tert-butyldimethylsilyl)oxy)propyl)phenyl)(methyl)(oxo)-16-sulfanylidene)cyanamide (2) To a solution of (E)-N-((4-(3-((tert-butyldimethylsilyl)oxy)propyl)phenyl)(methyl)-14-sulfanylidene)cyanamide (120 mg, 0.36 mmol) in EtOH (0.9 mL) and HO (0.3 mL) was added KCO (148 mg, 1.07 mmol) and m-CPBA (92 mg, 0.53 mmol) under a N atmosphere, and the reaction mixture was stirred at room temperature overnight. The mixture was diluted with EtOAc, washed with saturated aqueous NaSO and brine, dried over anhydrous NaSO, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (silica gel, 0-50% EtOAc in PE) to give the title compound (85 mg, 67.6% yield) as a colorless oil. LC / MS (ESI) m / z: 353 (M+H) + .

[0364] Step 3: N-((4-(3-hydroxypropyl)phenyl)(methyl)(oxo)-16-sulfanylidene)cyanamide (3) To a solution of N-((4-(3-((tert-butyldimethylsilyl)oxy)propyl)phenyl)(methyl)(oxo)-16-sulfanylidene)cyanamide (80 mg, 0.23 mmol) in THF (1 mL) was added TBAF (0.7 mL, 0.68 mmol, 1 M) at 0 °C, and the mixture was stirred at room temperature for 1 h. The mixture was diluted with EtOAc, washed with saturated aqueous NH4Cl and brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (silica gel, 0-100% EtOAc in PE) to give the title compound (35 mg, 64.7% yield) as a colorless oil. LC / MS (ESI) m / z: 239 (M+H) + .

[0365] Step 4: N-(methyl(oxo)(4-(3-oxopropyl)phenyl)-16-sulfanylidene)cyanamide (4) To a solution of N-((4-(3-hydroxypropyl)phenyl)(methyl)(oxo)-16-sulfanylidene)cyanamide (35 mg, 0.15 mmol) in DCM (1 mL) was added DMSO (328 mg, 4.19 mmol), Py.SO (100 mg, 0.62 mmol), and TEA (98 mg, 0.97 mmol) at 0 °C, and the mixture was stirred at room temperature under a N atmosphere for 2 h. The mixture was diluted with water and extracted twice with DCM. The combined organic layers were washed with aqueous NaSO, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the title compound (20 mg, 57.1% yield) as a colorless oil, which was used directly in the next step without further purification. LC / MS (ESI) m / z: 237 (M+H) + .

[0366] Step 5: N-((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)-2-(5-((3-(4-(N-cyano-S-methylsulfonimidoyl)phenyl)propyl)amino)-6-oxo-2-phenylpyrimidin-1(6H)-yl)acetamide (Compound 84) To a mixture of N-((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)-2-(5-amino-6-oxo-2-phenylpyrimidin-1(6H)-yl)acetamide (25 mg, 0.067 mol) and N-(methyl(oxo)(4-(3-oxopropyl)phenyl)-16-sulfanylidene)cyanamide (20 mg, 0.084 mmol) in MeOH (1 mL) was added NaBHCN (12 mg, 0.19 mol) at 0 °C, and the reaction mixture was stirred at 50 °C for 4 h. The mixture was concentrated to dryness under reduced pressure. The residue was purified by preparative HPLC to give compound 84 (1.1 mg, 2.8% yield) as a white solid. 1H NMR (400 MHz, CD3OD) δ 8.77 (s, 1H), 8.15 (d, J = 6.0 Hz, 1H), 7.98 (d, J = 8.5 Hz, 2H), 7.63 (d, J = 8.4 Hz, 2H), 7.50 - 7.45 (m, 4H), 7.42 - 7.38 (m, 2H), 7.12 (s, 1H), 6.56 (s, 1H), 4.62 (s, 2H), 4.56 (s, 2H), 3.51 (s, 3H), 3.23 (d, J = 6.8 Hz, 2H), 2.96 - 2.90 (m, 2H), 2.10 - 2.02 (m, 2H). LC / MS (ESI) m / z: 595 (M+H) + . RT (Method A): 1.02 minutes.

[0367] Scheme 31. Synthesis of N-((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)-2-(3-methyl-4-((3-phenylpropyl)amino)-[1,1'-biphenyl]-2-yl)acetamide (compound 85) [ka] Step 1: Methyl 2-(2-methyl-3-nitrophenyl)acetate (2) To a mixture of 2-(2-methyl-3-nitrophenyl)acetic acid (1.95 g, 10 mmol) in MeOH (20 mL) was added sulfuric acid (0.18 g, 0.18 mmol) at room temperature and refluxed for 18 hours. The reaction mixture was cooled to room temperature and added to 20% sodium carbonate solution (100 mL). The reaction product was extracted with dichloromethane (50 mL × 2). The combined organic layers were washed with water (100 mL), dried over sodium sulfate, and concentrated under reduced pressure to give the title product (1.9 g, 91.0%) as a colorless oil, which was used directly in the next step without further purification.

[0368] Step 2: Methyl 2-(3-amino-2-methylphenyl)acetate (2) To a solution of methyl 2-(2-methyl-3-nitrophenyl)acetate (1.9 g, 9 mmol) in MeOH (5 mL) was added Pd / C (20 mg, 10 wt%), and the mixture was degassed three times under N atmosphere and stirred overnight at 25 °C under a H balloon. The mixture was filtered, and the filtrate was concentrated to dryness to give the title compound (0.78 g, 49% yield) as a yellow solid, which was used directly in the next step without further purification. LC / MS (ESI) m / z: 180 (M+H) + .

[0369] Step 3: Methyl 2-(3-amino-6-bromo-2-methylphenyl)acetate (3) To a solution of methyl 2-(3-amino-2-methylphenyl)acetate (0.78 g, 4.4 mmol) in CHCN (3 mL) was added N-bromosuccinimide (0.78 g, 4.4 mmol) at room temperature. After 2 h, the reaction mixture was concentrated, and the residue was partitioned between dichloromethane and water. The organic layer was washed with aqueous NaSO, dried over anhydrous NaSO, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (silica gel, 0-25% EtOAc in PE) to give the title compound (0.86 g, 76% yield) as a white solid. LC / MS (ESI) m / z: 258 (M+H) + .

[0370] Step 4: Methyl 2-(4-amino-3-methyl-[1,1'-biphenyl]-2-yl)acetate (4) To a mixture of methyl 2-(3-amino-6-bromo-2-methylphenyl)acetate (510 mg, 1.98 mmol) and phenylboronic acid (241.6 mg, 1.98 mmol) in water (3 mL) was added KPO (1.3 g, 5.94 mmol) and Pd(PPh) (110 mg, 0.096 mmol) under N at 25 °C. The reaction mixture was degassed three times under N and stirred at 100 °C. After 1 h, the mixture was diluted with water and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NaSO, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (silica gel, 0-10% EtOAc in PE) to give the title compound (460 mg, 91% yield) as a colorless solid. LC / MS (ESI) m / z: 256 (M+H) + .

[0371] Step 5: Methyl 2-(3-methyl-4-((3-phenylpropyl)amino)-[1,1'-biphenyl]-2-yl)acetate (5) To a mixture of methyl 2-(4-amino-3-methyl-[1,1'-biphenyl]-2-yl)acetate (60 mg, 0.23 mmol) and 3-phenylpropanal (94 mg, 0.70 mmol) in MeOH (2 mL) was added NaBHCN (86 mg, 0.70 mmol) at room temperature, and the reaction mixture was stirred at 50°C for 2 hours. The mixture was concentrated to dryness under reduced pressure. The residue was purified by preparative HPLC to give the title compound (23 mg, 26.8% yield) as a yellow oil. LC / MS (ESI) m / z: 374 (M+H) + .

[0372] Step 6: 2-(3-methyl-4-((3-phenylpropyl)amino)-[1,1'-biphenyl]-2-yl)acetic acid (6) To a solution of methyl 2-(3-methyl-4-((3-phenylpropyl)amino)-[1,1'-biphenyl]-2-yl)acetate (28 mg, 0.075 mmol) in THF / MeOH / HO (6 mL, 4 / 1 / 1) was added LiOH·HO (9.5 mg, 0.225 mmol) under a N atmosphere, and the reaction mixture was stirred at 100 °C overnight. The mixture was acidified to pH 3 with 1 N aqueous HCl and extracted twice with EtOAc. The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the title compound (20 mg, 74.0% yield) as a white solid, which was used directly in the next step without further purification. LC / MS (ESI) m / z: 360 (M+H) + .

[0373] Step 7: N-((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)-2-(3-methyl-4-((3-phenylpropyl)amino)-[1,1'-biphenyl]-2-yl)acetamide (Compound 85) To a mixture of 2-(3-methyl-4-((3-phenylpropyl)amino)-[1,1'-biphenyl]-2-yl)acetic acid (20 mg, 0.056 mmol) and (1H-pyrrolo[3,2-c]pyridin-2-yl)methanamine (24.7 mg, 0.168 mmol) in DMF (3 mL), DIPEA (36 mg, 0.28 mmol) and HATU (25.6 mg, 0.068 mol) were added under a N atmosphere, and the reaction mixture was stirred at room temperature for 2 h. The mixture was diluted with EtOAc, washed with saturated aqueous NH4Cl and brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was purified by preparative TLC (DCM:MeOH = 20:1) to give compound 85 (2.4 mg, 8.9% yield) as a white solid. 1H NMR (400 MHz, DMSO) δ 11.31 (s, 1H), 8.74 (s, 1H), 8.29 (t, J = 5.7 Hz, 1H), 8.12 (d, J = 5.6 Hz, 1H), 7.35 - 7.24 (m, 10H), 7.19 (t, J = 7.0 Hz, 1H), 6.88 (d, J = 8.3 Hz, 1H), 6.50 (d, J = 8.4 Hz, 1H), 6.36 (s, 1H), 4.86 (t, J = 5.5 Hz, 1H), 4.44 (d, J = 5.6 Hz, 2H), 3.45 (s, 2H), 3.15 - 3.08 (m, 2H), 2.71 (t, J = 7.6 Hz, 2H), 1.98 (s, 3H), 1.96 - 1.89 (m, 2H). LC / MS (ESI) m / z: 489 (M+H) + . RT (Method A): 1.92 minutes.

[0374] Scheme 32. Synthesis of N-((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)-2-(2-(4-(oxetan-3-yloxy)phenyl)-6-oxo-5-((3-phenylpropyl)amino)pyrimidin-1(6H)-yl)acetamide (compound 86) [ka] Step 1: Tert-butyl 2-(2-(4-(oxetan-3-yloxy)phenyl)-6-oxo-5-((3-phenylpropyl)amino)pyrimidin-1(6H)-yl)acetate (2) To a solution of tert-butyl 2-(2-(4-hydroxyphenyl)-6-oxo-5-((3-phenylpropyl)amino)pyrimidin-1(6H)-yl)acetate (96 mg, 0.22 mmol) and CsCO (0.66 mmol, 215 mg) in DMF (1 mL) was added oxetan-3-yl 4-methylbenzenesulfonate (50.2 mg, 0.22 mmol), and the reaction mixture was stirred at 100 °C for 10 h. The residue was purified by flash chromatography (silica gel, 0-25% EtOAc in PE) to give the title compound (86 mg, 79% yield) as a pale yellow solid. LC / MS (ESI) m / z: 492 (M+H) + .

[0375] Step 2: 2-(2-(4-(oxetan-3-yloxy)phenyl)-6-oxo-5-((3-phenylpropyl)amino)pyrimidin-1(6H)-yl)acetic acid (3) To a solution of tert-butyl 2-(2-(4-(oxetan-3-yloxy)phenyl)-6-oxo-5-((3-phenylpropyl)amino)pyrimidin-1(6H)-yl)acetate (52 mg, 0.11 mmol) in DCM (1 mL) was added TFA (10 mL), and the mixture was stirred at room temperature for 16 h. The mixture was concentrated, diluted with EtOAc, washed with saturated aqueous NaHCO, dried over anhydrous NaSO, filtered, and concentrated to dryness under reduced pressure to give the title compound (41 mg, 85.0% yield) as a brown solid. LC / MS (ESI) m / z: 436 (M+H) + , which was used directly in the next step without further purification.

[0376] Step 3: N-((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)-2-(2-(4-(oxetan-3-yloxy)phenyl)-6-oxo-5-((3-phenylpropyl)amino)pyrimidin-1(6H)-yl)acetamide (compound 86) To a mixture of 2-(2-(4-(oxetan-3-yloxy)phenyl)-6-oxo-5-((3-phenylpropyl)amino)pyrimidin-1(6H)-yl)acetic acid (25 mg, 0.057 mmol) and (1H-pyrrolo[3,2-c]pyridin-2-yl)methanamine (25.1 mg, 0.171 mmol) in DMF (3 mL) was added DIPEA (36.8 mg, 0.285 mmol) and HATU (32 mg, 0.084 mol) under a N atmosphere, and the reaction mixture was stirred at room temperature for 2 h. The mixture was diluted with EtOAc, washed with saturated aqueous NH4Cl and brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was purified by preparative TLC (DCM:MeOH=20:1) and further purified by preparative HPLC to give compound 86 (5.9 mg, yield 18.4%) as a white solid. 1 H NMR (400 MHz, CD3OD) δ 8.74 (s, 1H), 8.13 (d, J = 5.9 Hz, 1H), 7.43 - 7.39 (m, 2H), 7.30 - 7.14 (m, 5H), 7.06 (s, 1H), 6.72 (d, J = 8.7 Hz, 2H), 6.50 (s, 1H), 5.18 (t, J = 5.4 Hz, 1H), 4.95 (t, J = 6.6 Hz, 2H), 4.63 (t, J = 6.0 Hz, 4H), 4.54 (s, 2H), 3.17 (t, J = 6.9 Hz, 2H), 2.74 (t, J = 7.6 Hz, 2H), 2.02 - 1.90 (m, 2H). LC / MS (ESI) m / z: 564 (M+H) + . RT (Method A): 1.37 minutes.

[0377] Scheme 33. Synthesis of N-((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)-2-(2-(((3R,3aR,6R,6aR)-6-methoxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-6-oxo-5-((3-phenylpropyl)amino)pyrimidin-1(6H)-yl)acetamide (compound 87) [ka] Step 1: Tert-butyl 2-(2-(methylsulfonyl)-6-oxo-5-((3-phenylpropyl)amino)pyrimidin-1(6H)-yl)acetate (2) To a solution of tert-butyl 2-(2-(methylsulfonyl)-6-oxo-5-((3-phenylpropyl)amino)pyrimidin-1(6H)-yl)acetate (50 mg, 0.13 mmol) in DCM (3 mL) was added m-CPBA (44 mg, 0.36 mmol) at 0° C., and the mixture was stirred at room temperature for 3 h. The mixture was quenched with aqueous NaSO and extracted twice with DCM. The combined organic layers were washed with brine, dried over anhydrous NaSO, filtered, and concentrated to dryness under reduced pressure to give the title compound (54 mg, 99.8% yield) as a white solid, which was used directly in the next reaction without further purification. LC / MS (ESI) m / z: 422 (M+H) + .

[0378] Step 2: tert-butyl 2-(2-(((3R,3aR,6R,6aR)-6-methoxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-6-oxo-5-((3-phenylpropyl)amino)pyrimidin-1(6H)-yl)acetate (3) To a solution of (3R,3aR,6R,6aR)-6-methoxyhexahydrofuro[3,2-b]furan-3-ol (20 mg, 0.12 mmol) in DMF (3 mL) was added NaH (8.0 mg, 0.20 mmol, 60 wt%) at 0 °C, and the mixture was stirred at 0 °C for 0.5 h. A solution of tert-butyl 2-(2-(methylsulfonyl)-6-oxo-5-((3-phenylpropyl)amino)pyrimidin-1(6H)-yl)acetate (50 mg, 0.12 mmol) in DMF (1 mL) was then added, and the resulting mixture was stirred at room temperature overnight. The mixture was quenched with saturated aqueous NH4Cl and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by preparative TLC (PE: EtOAc = 1: 1) to give the title compound (30 mg, 50.4% yield) as a light oil. LC / MS (ESI) m / z: 502 (M+H) + .

[0379] Step 3: 2-(2-(((3R,3aR,6R,6aR)-6-methoxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-6-oxo-5-((3-phenylpropyl)amino)pyrimidin-1(6H)-yl)acetic acid (4) To a solution of tert-butyl 2-(2-(((3R,3aR,6R,6aR)-6-methoxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-6-oxo-5-((3-phenylpropyl)amino)pyrimidin-1(6H)-yl)acetate (30 mg, 0.060 mmol) in DCM (2 mL) was added TFA (2 mL) and the reaction mixture was stirred at room temperature for 5 hours. The mixture was concentrated to dryness under reduced pressure to give the title compound (25 mg, 94.0% yield) as a yellow solid, which was used directly in the next step without further purification. LC / MS (ESI) m / z: 446 (M+H) + .

[0380] Step 4: N-((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)-2-(2-(((3R,3aR,6R,6aR)-6-methoxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-6-oxo-5-((3-phenylpropyl)amino)pyrimidin-1(6H)-yl)acetamide (Compound 87) To a mixture of 2-(2-(((3R,3aR,6R,6aR)-6-methoxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-6-oxo-5-((3-phenylpropyl)amino)pyrimidin-1(6H)-yl)acetic acid (25 mg, 0.056 mmol) and (1H-pyrrolo[3,2-c]pyridin-2-yl)methanamine hydrochloride (29 mg, 0.16 mmol) in DMF (2 mL) was added DIPEA (36 mg, 0.28 mmol) and HATU (32 mg, 0.084 mmol) under a N atmosphere, and the reaction mixture was stirred at room temperature for 1 h. The mixture was diluted with EtOAc, washed with saturated aqueous NH4Cl and brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was purified by preparative TLC (DCM:MeOH=10:1) and further purified by preparative HPLC to give compound 87 (4.2 mg, yield 13.0%) as a white solid. 1H NMR (400 MHz, CD3OD) δ 8.71 (d, J = 0.8 Hz, 1H), 8.10 (d, J = 5.8 Hz, 1H), 7.38 (d, J = 5.8 Hz, 1H), 7.29 - 7.23 (m, 2H), 7.22 - 7.13 (m, 3H), 6.80 (s, 1H), 6.56 (s, 1H), 5.31 (q, J = 5.6 Hz, 1H), 4.89 (d, J = 16.0 Hz, 1H), 4.79 (t, J = 5.2 Hz, 1H), 4.73 (d, J = 16.0 Hz, 1H), 4.57 (dd, J = 9.2, 4.4 Hz, 3H), 3.99 (dd, J = 9.9, 6.0 Hz, 1H), 3.96 - 3.91 (m, 1H), 3.91 - 3.86 (m, 1H), 3.83 (dd, J = 9.9, 5.2 Hz, 1H), 3.51 (t, J = 8.1 Hz, LC / MS (ESI) m / z: 575 (M+H) + . RT (Method A): 1.30 minutes.

[0381] Scheme 34. Synthesis of diethyl((4-(1-(2-(((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)amino)-2-oxoethyl)-6-oxo-5-((3-phenylpropyl)amino)-1,6-dihydropyrimidin-2-yl)phenoxy)methyl)phosphonate (compound 89) [ka] Step 1: (Diethoxyphosphoryl)methyl 4-chlorobenzenesulfonate (2) To a mixture of diethyl(hydroxymethyl)phosphonate (2 g, 11.9 mmol) in THE (20 mL) was added TEA (1.82 mL, 13.0 mmol). 4-Chlorobenzenesulfonyl chloride (2.7 g, 13.0 mmol) was then added to the mixture at -10 °C. The mixture was stirred under N at 25 °C for 17 hours. The mixture was diluted with H O and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na SO , filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (silica gel, 0-50% EtOAc in PE) to give the title compound (3.2 g, 78% yield) as a yellow oil. LC / MS (ESI) (m / z): 343 (M+H) + .

[0382] Step 2: Tert-butyl 2-(2-(4-((diethoxyphosphoryl)methoxy)phenyl)-6-oxo-5-((3-phenylpropyl)amino)pyrimidin-1(6H)-yl)acetate (3) To a solution of tert-butyl 2-(2-(4-hydroxyphenyl)-6-oxo-5-((3-phenylpropyl)amino)pyrimidin-1(6H)-yl)acetate (100 mg, 0.229 mmol) in DMSO (2 mL) was added t-BuOK (52 mg, 0.45 mmol) and (diethoxyphosphoryl)methyl 4-chlorobenzenesulfonate (95 mg, 0.275 mmol). The mixture was stirred under N at 25 °C for 3 h. The mixture was diluted with H O and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na SO , filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (silica gel, 0-50% EtOAc in PE) to give the title compound (40 mg, 30% yield) as a white solid. LC / MS (ESI) (m / z): 586 (M+H) + .

[0383] Step 3: 2-(2-(4-((diethoxyphosphoryl)methoxy)phenyl)-5-(hex-5-en-1-ylamino)-6-oxopyrimidin-1(6H)-yl)acetic acid (4) To a solution of tert-butyl 2-(2-(4-((diethoxyphosphoryl)methoxy)phenyl)-6-oxo-5-((3-phenylpropyl)amino)pyrimidin-1(6H)-yl)acetate (40 mg, 0.068 mmol) in HCl / dioxane (2 mL, 4 M). The mixture was stirred at 25° C. for 1 h. The mixture was concentrated under reduced pressure to give the title compound (35 mg, 95% yield) as a white solid. LC / MS (ESI) (m / z): 494 (M+H) + .

[0384] Step 4: Diethyl ((4-(1-(2-(((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)amino)-2-oxoethyl)-6-oxo-5-((3-phenylpropyl)amino)-1,6-dihydropyrimidin-2-yl)phenoxy)methyl)phosphonate (Compound 89) To a solution of 2-(2-(4-((diethoxyphosphoryl)methoxy)phenyl)-5-(hex-5-en-1-ylamino)-6-oxopyrimidin-1(6H)-yl)acetic acid (35 mg, 0.065 mmol) in DMF (2 mL) was added HATU (75 mg, 0.098 mmol) and DIEA (0.04 mL, 0.195 mmol), and then (1H-pyrrolo[3,2-c]pyridin-2-yl)methanamine (10 mg, 0.068 mmol) was added to the mixture. The mixture was stirred under N at 25 °C for 0.5 h. The mixture was diluted with EtOAc, dried over anhydrous NaSO, and concentrated to dryness under reduced pressure. The residue was purified by preparative HPLC to give compound 89 (4.6 mg, 10.7% yield) as a white solid. 1H NMR (400 MHz, CD3OD) δ 8.72 (d, J = 0.9 Hz, 1H), 8.11 (d, J = 5.8 Hz, 1H), 7.49 - 7.38 (m, 3H), 7.30 - 7.25 (m, 2H), 7.24 - 7.20 (m, 2H), 7.19 - 7.13 (m, 1H), 7.06 (s, 1H), 7.01 - 6.96 (m, 2H), 6.51 (d, J = 0.6 Hz, 1H), 4.62 (s, 2H), 4.54 (s, 2H), 4.37 (d, J = 10.0 Hz, 2H), 4.27 - 4.18 (m, 4H), 3.16 (t, J = 7.0 Hz, 2H), 2.79 - 2.69 (m, 2H), 2.04 - 1.93 (m, 2H), 1.35 (t, J = 7.1 Hz, 6H). LC / MS (ESI) (m / z): 659 (M+H) + . RT (Method A): 1.53 minutes.

[0385] Scheme 35. Synthesis of (4-(3-((1-(2-(((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)amino)-2-oxoethyl)-6-oxo-2-phenyl-1,6-dihydropyrimidin-5-yl)amino)propyl)phenyl)(methyl)phosphinic acid (compound 91) [ka] Step 1: 3-(4-bromophenyl)propanal (2) To a solution of 3-(4-bromophenyl)propan-1-ol (1.0 g, 4.67 mmol) in DCM (10 mL) was added PCC (1.5 g, 6.96 mmol) at 0° C., and the mixture was stirred at room temperature for 1 h. Silica gel was added, and the mixture was stirred at room temperature for 0.5 h. The mixture was filtered, and the filtrate was concentrated to dryness to give the title compound (620 mg, 62.9% yield) as a colorless oil, which was used directly in the next reaction without further purification.

[0386] Step 2: N-((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)-2-(5-((3-(4-bromophenyl)propyl)amino)-6-oxo-2-phenylpyrimidin-1(6H)-yl)acetamide (3) To a mixture of N-((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)-2-(5-amino-6-oxo-2-phenylpyrimidin-1(6H)-yl)acetamide (100 mg, 0.27 mmol) and 3-(4-bromophenyl)propanal (171 mg, 0.81 mmol) in MeOH (3 mL) was added NaBHCN (134 mg, 2.1 mmol) under N atmosphere, and the reaction mixture was stirred at 50 °C overnight. The mixture was diluted with EtOAc, washed with brine, dried over anhydrous NaSO, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (silica gel, 0-10% MeOH in DCM) to give the title compound (40 mg, 26.3% yield) as a white solid. LC / MS (ESI) m / z: 571 (M+H) + .

[0387] Step 3: Ethyl (4-(3-((1-(2-(((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)amino)-2-oxoethyl)-6-oxo-2-phenyl-1,6-dihydropyrimidin-5-yl)amino)propyl)phenyl)(methyl)phosphinate (4) To a mixture of N-((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)-2-(5-((3-(4-bromophenyl)propyl)amino)-6-oxo-2-phenylpyrimidin-1(6H)-yl)acetamide (40 mg, 0.07 mmol) and diethylmethylphosphonite (48 mg, 0.35 mmol) in DMF (2 mL) were added DIPEA (46 mg, 0.36 mmol) and Pd(dppf)Cl (3 mg, 0.004 mmol) under N atmosphere, and the reaction mixture was stirred at 130 °C for 30 min in a CEM microwave reactor. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous NaSO, filtered, and concentrated to dryness under reduced pressure. The residue was purified by preparative TLC (DCM:MeOH=10:1) to give the title compound (18 mg, 42.9% yield) as a white solid. LC / MS (ESI) m / z: 599 (M+H) + .

[0388] Step 4: (4-(3-((1-(2-(((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)amino)-2-oxoethyl)-6-oxo-2-phenyl-1,6-dihydropyrimidin-5-yl)amino)propyl)phenyl)(methyl)phosphinic acid (compound 91) To a solution of ethyl (4-(3-((1-(2-(((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)amino)-2-oxoethyl)-6-oxo-2-phenyl-1,6-dihydropyrimidin-5-yl)amino)propyl)phenyl)(methyl)phosphinate (18 mg, 0.03 mmol) in MeOH (2 mL) and water (1 mL), LiOH·HO (4 mg, 0.09 mmol) was added, and the reaction mixture was stirred at 25 °C overnight. The reaction mixture was concentrated to dryness under reduced pressure. The residue was purified by preparative HPLC to give compound 91 (2.6 mg, 15.2% yield) as a white solid. 1H NMR (400 MHz, CD3OD) δ 8.95 (s, 1H), 8.36 (s, 1H), 8.23 ​​(d, J = 6.6 Hz, 1H), 7.83 (d, J = 6.5 Hz, 1H), 7.70 (m, 2H), 7.53 - 7.47 (m, 3H), 7.44 (d, J = 7.5 Hz, 2H), 7.24 (d, J = 6.4 Hz, 2H), 7.14 (s, 1H), 6.86 (s, 1H), 4.63 (d, J = 6.3 Hz, 4H), 3.19 (t, J = 6.7 Hz, 2H), 2.75 (t, J = 7.7 Hz, 2H), 2.02 - 1.96 (m, 2H), 1.40 - 1.36 (m, 3H). LC / MS (ESI) m / z: 571 (M+H) + . RT (Method A): 0.80 minutes.

[0389] Scheme 36. Synthesis of N-((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)-2-(5-((3-(((3R,3aR,6R,6aR)-6-methoxyhexahydrofuro[3,2-b]furan-3-yl)oxy)propyl)amino)-6-oxo-2-phenylpyrimidin-1(6H)-yl)acetamide (compound 95) [ka] Step 1: (3R,3aR,6R,6aS)-6-((tert-butyldiphenylsilyl)oxy)hexahydrofuro[3,2-b]furan-3-ol (2) To a solution of (3R,3aR,6R,6aR)-hexahydrofuro[3,2-b]furan-3,6-diol (15.0 g, 102.7 mmol) in DMF (30 mL) were added TBDPSCl (33.9 g, 123.2 mmol) and imidazole (21.0 g, 308.2 mmol) at 0 °C, and the mixture was stirred at room temperature for 4 h. The mixture was diluted with water and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0-20% EtOAc in PE) to give the title compound (13.5 g, 34.2% yield) as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ 7.78 - 7.73 (m, 2H), 7.70 - 7.66 (m, 2H), 7.47 - 7.38 (m, 6H), 4.35 (d, J= 5.2 Hz, 1H), 4.26 - 4.20 (m, 3H), 4.02 (m, 1H), 3.78 - 3.72 (m, 2H), 3.68 - 3.63 (m, 1H). LC / MS (ESI) m / z: 407(M+Na) + .

[0390] Step 2: Tert-butyl(((3R,3aS,6R,6aR)-6-methoxyhexahydrofuro[3,2-b]furan-3-yl)oxy)diphenylsilane (3) To a solution of (3R,3aR,6R,6aS)-6-((tert-butyldiphenylsilyl)oxy)hexahydrofuro[3,2-b]furan-3-ol (5.0 g, 13.0 mmol) in DMF (50 mL) was added NaH (469 mg, 19.5 mmol, 60 wt%) at 0 °C, and the reaction solution was stirred at 0 °C for 0.5 h. Iodomethane (2.8 g, 19.5 mmol) was added to the mixture at 0 °C, and the resulting mixture was stirred at room temperature for 3 h. The mixture was quenched with aqueous NH4Cl and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (silica gel, 0-30% EtOAc in PE) to give the title compound (2.3 g, 44.4% yield) as a colorless oil. LC / MS (ESI) m / z: 421 (M+Na) + .

[0391] Step 3: (3R,3aR,6R,6aR)-6-Methoxyhexahydrofuro[3,2-b]furan-3-ol (4) To a solution of tert-butyl(((3R,3aS,6R,6aR)-6-methoxyhexahydrofuro[3,2-b]furan-3-yl)oxy)diphenylsilane (2.2 g, 5.53 mmol) in THF (25 mL) was added TBAF (1.9 mL, 3.9 mmol), and the reaction mixture was stirred at room temperature overnight. The mixture was diluted with aqueous NH4Cl and extracted twice with CHCl3 / i-PrOH (3 / 1, v / v). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0-15% MeOH in DCM) to give the title compound (700 mg, 79.2% yield) as a white solid. 1 H NMR (400 MHz, CDCl3) δ 4.57 (t, J = 4.8 Hz, 1H), 4.51 (t, J = 5.2 Hz, 1H), 4.27 (q, J = 5.9 Hz, 1H), 4.07 (m, 1H), 4.01 - 3.92 (m, 2H), 3.73 - 3.65 (m, 2H), 3.47 (s, 3H).

[0392] Step 4: (3R,3aR,6R,6aR)-3-(allyloxy)-6-methoxyhexahydrofuro[3,2-b]furan (5) To a solution of (3R,3aR,6R,6aR)-6-methoxyhexahydrofuro[3,2-b]furan-3-ol (300 mg, 1.9 mmol) in DCE (10 mL) was added AgOTf (1.4 g, 5.6 mmol), followed by 3-iodoprop-1-ene (1.3 g, 7.5 mmol) and 2,6-di-tert-butylpyridine (1.4 g, 7.5 mmol), and the mixture was stirred at 30 °C for 16 h under a N atmosphere. The mixture was diluted with water and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NaSO, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0-15% MeOH in DCM) to give the title compound (320 mg, 85.3% yield) as a yellow oil. 1 H NMR (400 MHz, CDCl3) δ 5.93 (m, 1H), 5.29 (m, 1H), 5.20 (m, 1H), 4.58 - 4.53 (m, 2H), 4.19 - 4.14 (m, 1H), 4.07 - 4.02 (m, 4H), 3.96 - 3.91 (m, 1H), 3.72 - 3.67 (m, 2H), 3.45 (s, 3H).

[0393] Step 5: 3-(((3R,3aR,6R,6aR)-6-methoxyhexahydrofuro[3,2-b]furan-3-yl)oxy)propan-1-ol (6) To a solution of (3R,3aR,6R,6aR)-3-(allyloxy)-6-methoxyhexahydrofuro[3,2-b]furan (160 mg, 0.8 mmol) in THF (2 mL) was added BH3.THF (1.1 mL, 1.1 mmol) dropwise at 0 °C, and the reaction was stirred at 0 °C for 2.5 h. To the mixture was added a solution of NaOH (1.0 mL, 10 M in water) and H2O2 (1.0 mL, 30 wt%) sequentially at 0 °C. The resulting mixture was stirred at room temperature for 0.5 h. Water was added to the mixture, and it was extracted twice with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (silica gel, 0-10% MeOH in DCM) to give the title compound (120 mg, 68.8% yield) as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ 4.62 (m, 2H), 4.06 (t, J = 7.2 Hz, 3H), 3.92 (m, 2H), 3.78 - 3.65 (m, 5H), 3.46 (s, 3H), 1.83 (m, 2H).

[0394] Step 6: 3-(((3R,3aR,6R,6aR)-6-methoxyhexahydrofuro[3,2-b]furan-3-yl)oxy)propanal (7) To a solution of 3-(((3R,3aR,6R,6aR)-6-methoxyhexahydrofuro[3,2-b]furan-3-yl)oxy)propan-1-ol (80 mg, 0.37 mmol) in DCM (3 mL) was added DMP (233 mg, 0.55 mmol) at 0 °C, and the mixture was stirred at room temperature for 16 h. The mixture was quenched with aqueous NaSO and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NaSO, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (silica gel, 0-20% MeOH in DCM) to give the title compound (60 mg, 79.3% yield) as a yellow oil.

[0395] Step 7: N-((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)-2-(5-((3-(((3R,3aR,6R,6aR)-6-methoxyhexahydrofuro[3,2-b]furan-3-yl)oxy)propyl)amino)-6-oxo-2-phenylpyrimidin-1(6H)-yl)acetamide (Compound 95) To a mixture of N-((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)-2-(5-amino-6-oxo-2-phenylpyrimidin-1(6H)-yl)acetamide (30 mg, 0.08 mmol) and 3-(((3R,3aR,6R,6aR)-6-methoxyhexahydrofuro[3,2-b]furan-3-yl)oxy)propanal (50 mg, 0.23 mmol) in MeOH (3 mL), NaBHCN (15 mg, 0.24 mmol) was added under a N atmosphere, and the reaction mixture was stirred at 50 °C for 16 h. The mixture was diluted with EtOAc, washed with brine, dried over anhydrous NaSO, filtered, and concentrated to dryness under reduced pressure. The residue was purified by preparative HPLC to give compound 95 (3.2 mg, 7.0% yield) as a white solid. 1 H NMR (400 MHz, CD3OD) δ 8.71 (s, 1H), 8.11 (d, J= 5.8 Hz, 1H), 7.47 (m, 3H), 7.39 (m, 3H), 7.17 (s, 1H), 6.48 (s, 1H), 4.61 (d, J= 7.6 Hz, 4H), 4.54 (s, 2H), 4.07 (m, 1H), 3.98 (m, 3H), 3.78 (m, 1H), 3.68 - 3.59 (m, 3H), 3.42 (s, 3H), 3.29 (s, 2H), 1.98 - 1.90 (m, 2H). LC / MS (ESI) m / z: 575 (M+H) + . RT (Method A): 0.56 minutes.

[0396] Scheme 37. N-((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)-2-(6-oxo-2-(4-(pentafluoro-λ) 6Synthesis of (3-sulfanyl)phenyl)-5-((3-phenylpropyl)amino)pyrimidin-1(6H)-yl)acetamide (Compound 96) [ka] Step 1: 4,4,5,5-tetramethyl-2-(4-(pentafluoro-λ)) 6 -sulfanyl)phenyl)-1,3,2-dioxaborolane(2) (4-Bromophenyl)pentafluoro-λ in 1,4-dioxane (1 mL) 6 To a mixture of -sulfane (500 mg, 1.78 mmol) and Pin2B2 (1.8 g, 7.12 mmol), Pd(PPh3)2Cl2 (385 mg, 0.55 mmol) and KOAc (524 mg, 5.34 mmol) were added under N2 atmosphere. The reaction mixture was degassed under N2 atmosphere three times and stirred at 80 °C overnight. The mixture was diluted with water and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (silica gel, 0-50% EtOAc in PE) to give the title compound (300 mg, 46.1% yield) as a white solid. LC / MS (ESI) m / z: 331 (M+H) + .

[0397] Step 2: (4-(pentafluoro-λ 6 -sulfanyl)phenyl)boronic acid (3) To a solution of 4,4,5,5-tetramethyl-2-(4-(pentafluoro-λ6-sulfanyl)phenyl)-1,3,2-dioxaborolane (300 mg, 0.91 mmol) in THF (3 mL) and water (3 mL) was added NaIO (27 mg, 0.65 mol), and the mixture was stirred at room temperature for 6 h. The mixture was concentrated to dryness under reduced pressure. The residue was purified by preparative HPLC to give the title compound as a white solid.

[0398] Step 3: Tert-butyl 2-(2-(methylthio)-6-oxo-5-((3-phenylpropyl)amino)pyrimidin-1(6H)-yl)acetate (3) To a mixture of tert-butyl 2-(5-bromo-2-(methylthio)-6-oxopyrimidin-1(6H)-yl)acetate (500 mg, 1.49 mmol) and 3-phenylpropan-1-amine (402 mg, 3.0 mmol) in toluene (5 mL), CsCO (974 mg, 2.99 mmol), BINAP (187 mg, 0.3 mmol), and Pd(OAc) (34 mg, 0.15 mmol) were added under N atmosphere. The reaction mixture was degassed three times under N atmosphere and stirred at 120 °C overnight. The mixture was diluted with water and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NaSO, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (silica gel, 0-20% EtOAc in PE) to give the title compound (170 mg, 29.3% yield) as a brown oil. LC / MS (ESI) m / z: 390 (M+H) + .

[0399] Step 4: Tert-butyl 2-(6-oxo-2-(4-pentafluoro-λ) 6 -sulfanyl)phenyl)-5-((3-phenylpropyl)amino)pyrimidin-1(6H)-yl)acetate (4) tert-Butyl 2-(2-(methylthio)-6-oxo-5-((3-phenylpropyl)amino)pyrimidin-1(6H)-yl)acetate (170 mg, 0.44 mmol) and (4-(pentafluoro-λ) 6To a mixture of (thiophene-2-carbonyl)oxy)copper (185 mg, 0.044 mmol) and Pd(PPh3)4 (51 mg, 0.044 mmol) was added under N2 atmosphere. The reaction mixture was degassed under N2 atmosphere three times and stirred at 55 °C overnight. The mixture was diluted with water and extracted twice with EtOAc. The combined organic layers were washed with saturated aqueous NaHCO3 and brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (silica gel, 0-20% EtOAc in PE) to give the title compound (55 mg, 23.5% yield) as a brown oil. LC / MS (ESI) m / z: 546 (M+H) + .

[0400] Step 5: Tert-butyl 2-(6-oxo-2-(4-pentafluoro-λ) 6 -sulfanyl)phenyl)-5-((3-phenylpropyl)amino)pyrimidin-1(6H)-yl)acetate (5) To a solution of tert-butyl 2-(6-oxo-2-phenyl-5-((3-phenylpropyl)amino)pyrimidin-1(6H)-yl)acetate (55 mg, 0.10 mmol) in DCM (5 mL) was added TFA (2.5 mL), and the mixture was stirred at room temperature under a N atmosphere for 4 hours. The reaction mixture was concentrated to dryness under reduced pressure to give the title compound (46 mg, 94.1% yield) as a yellow solid, which was used directly in the next step without further purification. LC / MS (ESI) m / z: 490 (M+H) + .

[0401] Step 6: N-((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)-2-(6-oxo-2-(4-(pentafluoro-λ) 6 -sulfanyl)phenyl)-5-((3-phenylpropyl)amino)pyrimidin-1(6H)-yl)acetamide (Compound 96) To a mixture of (2S,4R)-1-((9,9-dimethyl-9H-fluorene-3-carbonyl)glycyl)-4-(methylsulfonyl)pyrrolidine-2-carboxylic acid (46 mg, 0.09 mmol) and 1-(1-(phenylsulfonyl)-1H-pyrrolo[3,2-c]pyridin-2-yl)ethan-1-amine hydrochloride (35 mg, 0.1 mmol) in DMF (2 mL), DIPEA (50 mg, 0.38 mmol) and HATU (35 mg, 0.09 mmol) were added under N atmosphere, and the reaction mixture was stirred at room temperature for 2 h. The mixture was diluted with EtOAc, washed with saturated aqueous NaHCO and brine, dried over anhydrous NaSO, filtered, and concentrated to dryness under reduced pressure. The residue was purified by preparative TLC (DCM:MeOH=15:1) to give compound 96 (1.2 mg, 2.2% yield) as a yellow solid. 1 H NMR (400 MHz, CD3OD) δ 8.75 (s, 1H), 8.14 (d, J = 5.7 Hz, 1H), 7.80 (d, J = 8.8 Hz, 2H), 7.67 (d, J = 8.2 Hz, 2H), 7.47 (d, J = 5.1 Hz, 1H), 7.30 - 7.21 (m, 4H), 7.17 (d, J = 7.0 Hz, 1H), 6.56 (s, 1H), 4.58 (d, J = 16.9 Hz, 4H), 3.19 (t, J = 7.0 Hz, 2H), 2.75 (t, J = 7.7 Hz, 2H), 2.05 - 1.91 (m, 2H).LC / MS (ESI) m / z: 619 (M+H) + . RT (Method A): 1.89 minutes.

[0402] Scheme 38. Synthesis of N-((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)-2-(5-((3-(4-(oxetan-3-yl-oxy)phenyl)propyl)amino)-6-oxo-2-phenylpyrimidin-1(6H)-yl)acetamide (compound 103) [ka] Step 1: 3-(4-iodophenoxy)oxetane (2) To a mixture of oxetan-3-yl 4-methylbenzenesulfonate (3.0 g, 13.6 mmol) and 4-iodophenol (3.1 mg, 13.6 mmol) in DMF (40 mL) was added CsCO (13.3 g, 40.9 mmol) under N at 0 °C. The reaction mixture was degassed three times under N and stirred at 70 °C overnight. The mixture was diluted with water and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NaSO, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (silica gel, 0-40% EtOAc in PE) to give the title compound (3 g, 79.7% yield) as a white solid. 1 H NMR (400 MHz, CDCl3) δ 7.57 - 7.53 (m, 2H), 6.49 - 6.46 (m, 2H), 5.18 - 5.12 (m, 1H), 4.95 (t, J = 6.9 Hz, 2H), 4.75 - 4.71 (m, 2H).

[0403] Step 2: 3-(4-(oxetan-3-yloxy)phenyl)prop-2-yn-1-ol (3) To a mixture of 3-(4-iodophenoxy)oxetane (713 mg, 2.58 mmol) and prop-2-yn-1-ol (208 mg, 3.85 mmol) in TEA (5 mL) and DMSO (5 mL) was added CuI (49 mg, 0.25 mmol) and Pd(PPh)Cl (178 mg, 0.25 mmol) under N. The mixture was degassed under N for 10 times and stirred at room temperature under N for 2 h. The reaction mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous NaSO, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (silica gel, 0-50% EtOAc in PE) to give the title compound (426 mg, 80.8% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.36 (d, J = 7.7 Hz, 2H), 6.63 (d, J = 7.7 Hz, 2H), 5.24 - 5.17 (m, 1H), 4.97 (t, J = 6.4 Hz, 2H), 4.75 (t, J = 5.7 Hz, 2H), 4.48 (s, 2H).

[0404] Step 3: 3-(4-(oxetan-3-yloxy)phenyl)propan-1-ol (4) To a solution of 3-(4-(oxetan-3-yloxy)phenyl)prop-2-yn-1-ol (426 mg, 2.01 mmol) i...

Claims

1. Formula (I): 【Chemical 1】 or a pharmaceutically acceptable salt thereof, During the ceremony, R １ and R １’ each independently represents H or an optionally substituted C １ ~C ６ is alkyl, X is CR ３ or N, X ’ But, CR ４ or N, R ２ But H, C １ ~C ６ Alkyl, optionally substituted C ６ ~C １４ aryl, optionally substituted C ３ ~C ８ carbocyclyl, optionally substituted 5- to 10-membered heteroaryl, optionally substituted 4- to 10-membered heterocyclyl, or optionally substituted (4- to 10-membered heterocyclyl)oxy, or optionally substituted (5- to 9-membered heteroaryl)oxy; R ３ and R ４ each independently is H, halo, or optionally substituted C １ ~C ６ is alkyl, L １ is a bond, NH, NHC(O), NHC(O)O, NHC(O)NH, or NHS(O) ２ and L ２ is a bond or an optionally substituted C １ ~C ６ is alkylene, L ３ is a bond, NH, NHC(O), C(O), O, S(O) ２ CH ２ and B is halo, optionally substituted C ６ ~C １４ aryl, optionally substituted C ３ ~C １４ carbocyclyl, optionally substituted 5- to 14-membered heterocyclyl, or optionally substituted 5- to 10-membered heteroaryl; Y, 【Chemistry 2】 and During the ceremony, Y １ But O, S, NR ｄ where each R ｄ are independently absent, H, or C １ ~C ６ is alkyl, Y １’ But O, S, NR ｄ , or C(R ｄ ) ２ and Y ２ and Y ３ each independently represents NR ｅ or C(R ｅ ) ２ where each R ｅ is independently absent, H, optionally substituted C １ ~C ６ alkyl, halo, or N(R ｇ ) ２ where each R ｇ are independently H or C １ ~C ６ alkyl, or both R ｅ combine to form oxo, Y ４ , Y ４’ , Y １０ , and Y １３ Each of the above may independently be a CR ｅ or N, Y ５ , Y ６ , and Y ７ each independently represents O, S, NR ｆ or C(R ｆ ) ２ where each R ｆ is independently absent, H, optionally substituted C １ ~C ６ alkyl, halo, or N(R ｇ ) ２ or both R ｆ combine to form oxo, Y ８ and Y ９ each independently represents C(R ｆ ) ２ or NR ｆ and Y １１ and Y １２ each independently represents NR ｅ , C(R ｅ ) ２ , S, or O; each 【Chemistry 3】 are independently a single bond or a double bond; Each of R, R', R'', and R''' is independently absent, H, optionally substituted C １ ~C ６ alkyl, halo, or N(R ｇ ) ２ or Both R combine to form oxo, or both R' combine to form oxo; q is 0 or 1; However, the following: (i)-L １ -L ２ -L ３ - is combined, 【Chemistry 4】 There is no formation of (ii) R ２ But C １ ~C ６ Alkyl, 【Chemistry 5】 isn't it, (iii) B is 【Chemistry 6】 isn't it, (iv) R １ and R １’ At least one of the following is not H: (v) X is N; (vi) X ’ But, CR ４ is, and (vii) Y is 【Chemistry 7】 isn't it, The compound is provided that at least one of the following is true:

2. R １ The compound of claim 1 , wherein is H.

3. R １’ 3. The compound of claim 1 or 2, wherein is H or methyl.

4. X is CR ３ The compound according to any one of claims 1 to 3,

5. X is CCH ３ 5. The compound of claim 4, wherein:

6. The compound according to any one of claims 1 to 3, wherein X is N.

7. X' is CR ４ The compound according to any one of claims 1 to 6,

8. 8. The compound of claim 7, wherein X' is CH.

9. X ’ The compound according to any one of claims 1 to 6, wherein is N.

10. R ２ The compound of any one of claims 1 to 9, wherein is optionally substituted phenyl.

11. R ２ halo, optionally substituted C １ ~C ６ Alkyl, optionally substituted C １ ~C ６ Alkoxy, optionally substituted (4- to 10-membered heterocyclyl)oxy, P(O)(OH)CH ３ , P(O)(OR”') ２ wherein each R''' is independently H or C １ ~C ６ alkyl), S(O) ２ CH ３ , optionally substituted 4- to 10-membered heterocyclyl, SF ５ ,S(O)(NCN)CH ３ ,S(O)(NH)CH ３ 11. The compound of claim 10, wherein the aryl group is phenyl, optionally substituted with one or more substituents independently selected from:

12. R ２ but, 【Chemistry 8】 11. The compound of claim 10, wherein:

13. R ２ The compound of any one of claims 1 to 9, wherein is optionally substituted (4- to 10-membered heterocyclyl)oxy.

14. R ２ but, 【Chemistry 9】 14. The compound of claim 13, wherein:

15. R ２ The compound of any one of claims 1 to 9, wherein is an optionally substituted 4- to 10-membered heterocyclyl.

16. R ２ but, 【Chemistry 10】 16. The compound of claim 15, wherein:

17. R ２ The compound of any one of claims 1 to 9, wherein is an optionally substituted 5- to 10-membered heteroaryl.

18. R ２ but, 【Chemistry 11】 18. The compound of claim 17, wherein:

19. R ２ is optionally substituted C ３ ~C ８ The compound of any one of claims 1 to 9, which is cycloalkyl.

20. R ２ but, 【Chemistry 12】 20. The compound of claim 19, wherein:

21. R ２ is optionally substituted C ３ ~C ８ The compound of any one of claims 1 to 9, which is cycloalkenyl.

22. R ２ but, 【Chemistry 13】 22. The compound of claim 21, wherein:

23. R ２ The compound according to any one of claims 1 to 9, wherein is H.

24. R ２ But CH ３ The compound according to any one of claims 1 to 9,

25. L １ The compound of any one of claims 1 to 24, wherein is a bond.

26. L １ The compound of any one of claims 1 to 24, wherein is NH.

27. L １ The compound according to any one of claims 1 to 24, wherein is NHC(O).

28. L ２ The compound of any one of claims 1 to 27, wherein is a bond.

29. L ２ is optionally substituted C １ ~C ６ The compound of any one of claims 1 to 27, which is alkylene.

30. L ２ が、-CH ２ -、-(CH ２ ) ２ -、-(CH ２ ) ３ -、-(CH ２ ) ４ -、-(CH ２ ) ５ -、 【Chemistry 14】 30. The compound of claim 29, wherein:

31. L ３ The compound of any one of claims 1 to 30, wherein is a bond.

32. L ３ The compound according to any one of claims 1 to 30, wherein is NHC(O).

33. L ３ The compound according to any one of claims 1 to 30, wherein is C(O).

34. L ３ The compound according to any one of claims 1 to 30, wherein is O.

35. B is optionally substituted C ６ ~C １４ The compound of any one of claims 1 to 34, which is aryl or an optionally substituted 5- to 10-membered heteroaryl.

36. The compound has the formula (II): 【Chemistry 15】 or a pharmaceutically acceptable salt thereof, wherein X １ But, CR ９ or N, R ５ , R ６ , and R ９ each independently represents H, halo, CN, SF ５ , optionally substituted C １ ~C ６ Alkyl, optionally substituted C １ ~C ６ Alkoxy, S(O)(NH)CH ３ , S(O) ２ CH ３ , and S(O)(NCN)CH ３ is selected from R ７ and R ８ each independently represents H, halo, CN, SF ５ , optionally substituted C １ ~C ６ Alkyl, optionally substituted C １ ~C ６ Alkoxy, optionally substituted amino, S(O)(NH)CH ３ , S(O) ２ CH ３ ,S(O)(NCN)CH ３ , optionally substituted C ３ ~C ８ Cycloalkyl, optionally substituted C ６ ~C １４ Aryloxy, optionally substituted C ６ ~C １４ aryl, optionally substituted 5- to 10-membered heteroaryl, optionally substituted (5- to 10-membered heteroaryl)oxy, or optionally substituted (4- to 10-membered heterocyclyl)oxy, with the proviso that R ７ and R ８ More than one of C is optionally substituted ６ ~C １４ Aryloxy, optionally substituted C ６ ~C １４ provided that it is not aryl, optionally substituted 5- to 10-membered heteroaryl, optionally substituted (5- to 10-membered heteroaryl)oxy, or optionally substituted (4- to 10-membered heterocyclyl)oxy; or R ７ and R ８ together with the atom to which each is attached, optionally substituted 5- to 6-membered heterocyclyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted C ６ ~C １４ forming an aryl, or R ５ and A in combination with optionally substituted C １ ~C ２ Forming an alkylene R ６ and R ９ are combined to form (C ２ ~C ６ alkylene) (C ６ ~C １４ arylene) (C ２ ~C ６ alkylene), and R ５ , R ７ , and R ８ each of which is H; 36. The compound of claim 35.

37. X １ But, CR ９ 37. The compound of claim 36, wherein:

38. X １ 38. The compound of claim 37, wherein is CH.

39. R ８ The compound of any one of claims 36 to 38, wherein is H.

40. R ７ 40. The compound of any one of claims 36 to 39, wherein is optionally substituted phenyl.

41. R ７ but, 【Chemistry 16】 41. The compound of claim 40, wherein:

42. R ７ 40. The compound of any one of claims 36-39, wherein is an optionally substituted 5- to 10-membered heteroaryl.

43. R ７ but, 【Chemistry 17】 43. The compound of claim 42, wherein:

44. R ７ The compound of any one of claims 36 to 39, wherein is optionally substituted (5- to 10-membered heteroaryl)oxy.

45. R ７ but, 【Chemistry 18】 45. The compound of claim 44, wherein:

46. R ７ The compound of any one of claims 36 to 39, wherein is optionally substituted (4- to 10-membered heterocyclyl)oxy.

47. R ７ but, 【Chemistry 19】 47. The compound of claim 46, wherein:

48. R ７ is optionally substituted C ３ ~C ８ The compound of any one of claims 36 to 39, which is cycloalkyl.

49. R ７ but, 【Chemistry 20】 49. The compound of claim 48, wherein:

50. R ７ The compound of any one of claims 36 to 39, wherein is an optionally substituted 4- to 10-membered heterocyclyl.

51. R ７ but, 【Chemical 21】 51. The compound of claim 50, wherein:

52. R ８ The compound of any one of claims 36 to 38, wherein is optionally substituted phenyl.

53. R ８ but, 【Chemical 22】 53. The compound of claim 52, wherein:

54. R ８ The compound of any one of claims 36-38, wherein is an optionally substituted 5- to 10-membered heteroaryl.

55. R ８ but, 【Chemical 23】 55. The compound of claim 54, wherein:

56. R ７ The compound according to any one of claims 36 to 39 and 52 to 55, wherein is H.

57. R ６ The compound of any one of claims 36 to 56, wherein is H.

58. R ６ is optionally substituted C １ ~C ６ The compound of any one of claims 36 to 56, which is alkoxy.

59. R ６ But OCH ３ 57. The compound of claim 56, wherein:

60. R ６ The compound of any one of claims 36 to 56, wherein is halo.

61. R ６ is F.

62. R ５ The compound of any one of claims 36 to 61, wherein is H.

63. R ６ and R ９ are combined to form (C ２ ~C ６ alkylene) (C ６ ~C １４ arylene) (C ２ ~C ６ alkylene), and R ５ , R ７ , and R ８ The compound of any one of claims 36 to 38, wherein each of

64. B, 【Chemistry 24】 64. The compound of claim 63, wherein:

65. B, 【Chemistry 25】 65. The compound of claim 64, wherein:

66. The compound has the formula (III): 【Chemical 26】 or a pharmaceutically acceptable salt thereof, wherein X ２ But O, C (R ｈ ) ２ (where, each R ｈ are independently hydrogen, halo, or optionally substituted C １ ~C ６ alkyl, or both R ｈ combine to form oxo), S(O) ２ , or NR ｈ and m is selected from 0, 1, 2, 3, 4, and 5; n is selected from 0, 1, 2, 3, and 4; Each R １０ and R １１ are independently selected from halo, CN, optionally substituted C １ ~C ６ Alkyl, optionally substituted C １ ~C ６ Alkoxy, or optionally substituted C ３ ~C ８ is cycloalkyl, 36. The compound of claim 35.

67. The compound has the formula (IV): [Chemical 27] or a pharmaceutically acceptable salt thereof, wherein X ２ But O, C (R ｈ ) ２ (where, each R ｈ are independently hydrogen, halo, or optionally substituted C １ ~C ６ alkyl, or both R ｈ combine to form oxo), S(O) ２ , or NR ｈ and m is selected from 0, 1, 2, 3, 4, and 5; n is selected from 0, 1, 2, 3, and 4; Each R １０ and R １１ are independently selected from halo, CN, optionally substituted C １ ~C ６ Alkyl, optionally substituted C １ ~C ６ Alkoxy, or optionally substituted C ３ ~C ８ is cycloalkyl, 36. The compound of claim 35.

68. X ２ 68. The compound of claim 66 or 67, wherein is O or C(O).

69. B, 【Chemical Formula 28】 67. The compound of claim 66, wherein:

70. 36. The compound of claim 35, wherein B is an optionally substituted 5- to 10-membered heteroaryl.

71. B, 【Chemical Formula 29】 71. The compound of claim 70, wherein:

72. B is optionally substituted C ３ ~C １４ The compound of any one of claims 1 to 34, which is carbocyclyl or an optionally substituted 5- to 14-membered heterocyclyl.

73. The compound has the formula (V): 【Chemistry 30】 or a pharmaceutically acceptable salt thereof, wherein X ３ and X ４ each independently represents a bond, O, S, C(R ｄ ) ２ (where, each R ｄ are independently H, OH, halo, optionally substituted C １ ~C ６ alkyl or optionally substituted C １ ~C ６ Alkoxy, or both R ｄ combine to form oxo), NR ｅ (where R ｅ is H or C １ ~C ６ alkyl), or SO ２ and X ５ But CH, CR １３ , or N, X ６ But CH, CR １２ , or N, o is selected from 0, 1, 2, and 3; p is selected from 0, 1, and 2; Each R １２ and R １３ are independently halo, optionally substituted C １ ~C ６ Alkyl, optionally substituted C １ ~C ６ Alkoxy, or optionally substituted C ３ ~C ８ is cycloalkyl, 73. The compound of claim 72.

74. The compound has the formula (VI): 【Chemical 31】 or a pharmaceutically acceptable salt thereof, wherein X ３ and X ４ each independently represents a bond, O, S, C(R ｉ ) ２ (where, each R ｉ are independently H, OH, halo, optionally substituted C １ ~C ６ alkyl or optionally substituted C １ ~C ６ Alkoxy, or both R ｉ combine to form oxo), NR ｊ (where R ｊ is H or C １ ~C ６ alkyl), or SO ２ and X ５ But CH, CR １３ , or N, X ６ But CH, CR １２ , or N, o is selected from 0, 1, 2, and 3; p is selected from 0, 1, and 2; Each R １２ and R １３ are independently halo, optionally substituted C １ ~C ６ Alkyl, optionally substituted C １ ~C ６ Alkoxy, or optionally substituted C ３ ~C ８ is cycloalkyl, 73. The compound of claim 72.

75. X ３ is O, S, or CF ２ 75. The compound of claim 73 or 74, wherein:

76. X ４ The compound of any one of claims 73 to 75, wherein is a bond.

77. B, 【Chemical 32】 74. The compound of claim 73, wherein:

78. B, 【Chemical 33】 75. The compound of claim 74, wherein:

79. B is optionally substituted C ３ ~C １４ 35. The compound of any one of claims 1 to 34, which is carbocyclyl.

80. B, 【Chemical 34】 80. The compound of claim 79, wherein:

81. The compound of any one of claims 1 to 34, wherein B is an optionally substituted 5- to 14-membered heterocyclyl.

82. B, 【Chemical 35】 82. The compound of claim 81, wherein:

83. Y, 【Chemical 36】 83. The compound according to any one of claims 1 to 82,

84. Y, 【Chemical 37】 84. The compound of claim 83, wherein:

85. Y ２ is N or CH.

86. Y ３ is N or CH.

87. Y １ is NH or S.

88. Y, 【Chemical 38】 84. The compound of claim 83, wherein:

89. Y １ is S.

90. Y ２ is NH or CH ２ 90. The compound of claim 88 or 89, wherein:

91. Y ３ is NH or CH ２ The compound according to any one of claims 88 to 90,

92. 92. The compound of any one of claims 83 to 91, wherein each R is H and / or each R' is H.

93. Y, 【Chemical 39】 83. The compound according to any one of claims 1 to 82,

94. A compound of Table 1, or a pharmaceutically acceptable salt thereof.

95. The compound according to any one of claims 1 to 94, which has complement C1 esterase (C1s) inhibitory activity.

96. 97. A pharmaceutical composition comprising a compound according to any one of claims 1 to 96, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

97. A method for treating a C1s-mediated disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I'): 【Chemistry 40】 or a pharmaceutically acceptable salt thereof, During the ceremony, R １ and R １’ each independently represents H or an optionally substituted C １ ~C ６ is alkyl, X is CR ３ or N, X ’ But, CR ４ or N, R ２ is H, optionally substituted C １ ~C ６ Alkyl, optionally substituted C ６ ~C １４ Aryl, optionally substituted 5- to 10-membered heteroaryl, optionally substituted C ３ ~C ８ carbocyclyl, optionally substituted 4- to 10-membered heterocyclyl, or optionally substituted (4- to 10-membered heterocyclyl)oxy, or optionally substituted (5- to 9-membered heteroaryl)oxy; Each R ３ and R ４ are independently H, halo, or optionally substituted C １ ~C ６ is alkyl, L １ is a bond, NH, NHC(O), NHC(O)O, NHC(O)NH, or NHS(O) ２ and L ２ is a bond or an optionally substituted C １ ~C ６ is alkylene, L ３ is a bond, NH, NHC(O), C(O), O, S(O) ２ CH ２ and B is halo, optionally substituted C ６ ~C １４ aryl, optionally substituted C ３ ~C １４ carbocyclyl, optionally substituted 5- to 14-membered heterocyclyl, or optionally substituted 5- to 10-membered heteroaryl; Y is, 【Chemistry 41】 and During the ceremony, Y １ But O, S, NR ｄ where each R ｄ are independently absent, H, or C １ ~C ６ is alkyl, Y １’ But O, S, NR ｄ , or C(R ｄ ) ２ and Y ２ and Y ３ each independently represents NR ｅ or C(R ｅ ) ２ where each R ｅ is independently absent, H, optionally substituted C １ ~C ６ alkyl, halo, or N(R ｇ ) ２ where each R ｇ are independently H or C １ ~C ６ alkyl, or both R ｅ combine to form oxo, Y ４ , Y ４’ , Y １０ , and Y １３ Each of the above may independently be a CR ｅ or N, Y ５ , Y ６ , and Y ７ each independently represents O, S, NR ｆ or C(R ｆ ) ２ where each R ｆ is independently absent, H, optionally substituted C １ ~C ６ alkyl, halo, or N(R ｇ ) ２ or both R ｆ combine to form oxo, Y ８ and Y ９ each independently represents C(R ｆ ) ２ or NR ｆ and Y １１ and Y １２ each independently represents NR ｅ , C(R ｅ ) ２ , S, or O; each 【Chemistry 42】 are independently a single bond or a double bond; Each of R, R', R'', and R''' is independently absent, H, optionally substituted C １ ~C ６ alkyl, halo, or N(R ｇ ) ２ or Both R combine to form oxo, or both R' combine to form oxo; q is 0 or 1; The method.

98. 98. The method of claim 97, wherein the compound is a compound according to any one of claims 1 to 94 or a pharmaceutically acceptable salt thereof.

99. 99. The method of claim 98, wherein the subject is a human.

100. 100. The method of claim 98 or 99, wherein the disorder is acute antibody-mediated rejection, amyotrophic lateral sclerosis, autoimmune bullous disease, bullous pemphigoid, chronic inflammatory demyelinating polyneuropathy, geographic atrophy, Guillain-Barré syndrome, Huntington's disease, immune thrombocytopenic purpura, lupus nephritis, multifocal motor neuropathy, rheumatoid arthritis, traumatic brain injury, and warm autoimmune hemolytic anemia.

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