Pharmaceutical compounds for treatment of complement-mediated disorders

Abstract

The present disclosure provides compounds, compositions, and methods for treating medical conditions, such as complement-mediated conditions, including complement C1s-mediated conditions.

Description

Technical Field

[0001] Provided herein are pharmaceutical compounds for treating medical disorders, such as complement-mediated disorders, including complement C1-mediated disorders. Background Art

[0002] The complement system is part of the innate immune system. It does not adapt to changes in a subject's life course but is recruited and used by the adaptive immune system. For example, it assists or supplements the ability of antibodies and phagocytes to eliminate pathogens. This complex regulatory pathway allows for a rapid response to pathogenic organisms while protecting host cells from damage. More than 30 proteins and protein fragments make up the complement system. These proteins act through opsonization (enhancing phagocytosis of antigens), chemotaxis (attracting macrophages and neutrophils), cell lysis (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 triggered by antibody-antigen complexes of the IgG and IgM isotypes. The antibody-antigen complex binds to C1, which initiates the cleavage of C4 and C2, generating C3 convertase, which then cleaves C3 into C3a and C3b. C3a interacts with its C3a receptor to recruit leukocytes, while C3b binds to the C3 convertase to form C5 convertase. C5 convertase cleaves C5 into C5a and C5b. Similar to C3a, C5a interacts with its C5a receptor to recruit leukocytes, but C5b interacts with C6, C7, and C8, and together with these proteins, C8 forms a cylindrical membrane attack complex (MAC), which causes cell swelling and rupture. These immune responses can be inhibited by preventing C1 from binding to the antibody-antigen complex.

[0004] In view of the array of serious diseases mediated by malfunction of the complement system, there clearly exists a medical need to provide pharmaceutically acceptable compounds, methods, compositions, and methods of manufacture for inhibiting the complement system in patients in need thereof.

[0005] The present disclosure also provides compounds, uses, compositions, combinations and methods that inhibit C1s (complement C1 esterase) and thus can treat conditions 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), cellular disorders or abnormalities that adversely affect the ability of cells to participate in or respond to normal complement activity (including, for example, the classical complement pathway), or complement-mediated responses that are undesirable to medical treatments such as surgery or other medical procedures or drug or biopharmaceutical administration, blood transfusion or other allogeneic tissue or fluid administration. In some embodiments, the active compound can act as an inhibitor 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 the compounds of the present disclosure exhibit advantageous properties over other C1s inhibitors (e.g., compounds described in WO 2020 / 198062 and WO 2022 / 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., relative to other proteases, such as MASP-2), and / or improved metabolic stability. The present disclosure is also based in part on the unexpected discovery that, for example, the compounds of the present disclosure exhibit improved selectivity for C1s relative to other proteases (e.g., MASP-2) compared to the compounds described in WO 2019 / 231935.

[0008] In one aspect, the present disclosure provides a compound of formula (I):

[0009]

[0010] or a pharmaceutically acceptable salt thereof, wherein all variables are as defined herein.

[0011] In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound disclosed herein (e.g., any of Formula (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.

[0012] In another aspect, the present disclosure provides a method for treating a disorder mediated by complement C1 esterase (C1s), comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein (e.g., any of Formula (I), (I'), (II), (IIA), (III), (IIIA), (IV), (IVA), (V), (VA), (VB), (VC), (VI), (VIA), (VIB), (VIC), and (VII), and compounds of Table 1), or a pharmaceutically acceptable salt thereof.

[0013] In another aspect, the present disclosure provides a compound disclosed herein (e.g., any of Formula (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, for use in treating a C1s-mediated disorder.

[0014] In another aspect, the present disclosure provides use of a compound disclosed herein (e.g., any of Formula (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 treating a C1s-mediated disorder.

[0015] definition

[0016] Compounds are described using standard nomenclature. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0017] The terms "one" and "an" do not represent a quantitative limitation, but rather represent the presence of at least one of the items mentioned. The term "or" means "and / or". Unless otherwise indicated herein, the enumeration of numerical ranges is intended only to be used as a shorthand method for individually referring to each individual value falling within the range, and each individual value is incorporated into the specification as if it were individually enumerated herein. The endpoints of all ranges are included within the range and are independently combinable. Unless otherwise indicated herein or clearly contradicted by the context, all methods described herein can be performed in a suitable order. The use of examples or exemplary language (e.g., "such as") is intended only to be illustrative and does not constitute a limitation on the scope of the invention.

[0018] The term "alkoxy" as used herein refers to a -OR group, where R is alkyl as defined herein.

[0019] As used herein, the term "alkyl" refers to a branched or straight-chain monovalent saturated aliphatic group that, when unsubstituted, contains only C and H. The unit value 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 unit value of the 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, the alkyl group may contain, for example, 1-8, 1-6, 1-4, or 1-2 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.

[0020] As used herein, the term "alkylene" refers to a divalent group obtained by removing a hydrogen atom from a carbon atom of an alkyl group. The divalence of the 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.

[0021] The term "amino" as used herein refers to a monovalent group of formula -NH 2 . "Optionally substituted amino" as used herein refers to an amino group in which one or both hydrogen atoms are independently replaced with substituents as defined herein.

[0022] As used herein, the term "aryl" refers to any monocyclic or fused bicyclic or polycyclic ring system containing only carbon atoms in the ring, which has aromatic characteristics in terms of the distribution of electrons throughout the ring system, for example, phenyl, naphthyl or phenanthrenyl. Aryl can have, for example, 6-16, 6-14 or 6-10 carbon ring atoms (e.g., C6-C 16 、C6-C 14 、C6-C 10 、C6、C 10 、C 14 or C 16 ).

[0023] As used herein, the term "arylene" refers to a divalent group obtained by removing a hydrogen atom from an aryl carbon atom. The divalence of the arylene group does not include the optional substituents on the arylene group. Phenylene is a non-limiting example of an arylene group.

[0024] The term "aryloxy" as used herein refers to a -OR group where R is aryl as defined herein.

[0025] As used herein, the term "carbocyclyl" refers to a monovalent, saturated (i.e., cycloalkyl) or unsaturated, non-aromatic group (e.g., cycloalkenyl, which contains at least one carbon-carbon double bond and no carbon-carbon triple bonds) that, when unsubstituted, contains only C and H and can be monocyclic, bicyclic, or polycyclic (e.g., tricyclic). A carbocyclyl group can have, for example, 3-14 carbon atoms (e.g., C3-C4, C3-C5, C3-C6, C3-C7, C3-C8, or C3-C 14 Carbocyclyl). 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 carbon atoms bridge two non-adjacent members of a monocyclic ring, such as bicyclo[2.2.1]heptyl.

[0026] The term "halo" as used herein refers to a fluoro (fluoro; F), chloro (chloro; Cl), bromo (bromo; Br), or iodo (iodo; I) group.

[0027] As used herein, the term "heteroaryl" refers to a monocyclic, bicyclic, or polycyclic aromatic ring monocyclic, bicyclic, or polycyclic group containing 1, 2, 3, or 4 heteroatoms selected from N, O, S, B, and P (e.g., 1-4, 1-3, or 1 or 2 heteroatoms selected from N, O, and S) as ring atoms, with the remaining ring atoms being carbon. In some embodiments, the 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 (e.g., 1-4, 1-3, or 1 or 2 heteroatoms selected from N, O, and S) as ring atoms, with the remaining ring atoms being carbon. In some embodiments, the heteroaryl group is a monocyclic aromatic ring having 5 or 6 ring atoms (i.e., a 5- or 6-membered heteroaryl group). In some embodiments, it is a bicyclic aromatic ring system having 8 to 10 ring atoms (i.e., an 8- to 10-membered bicyclic heteroaryl group). Examples of heteroaryl groups include, but are not limited to, pyridyl, imidazolyl, imidazopyridyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, furanyl, 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, benzothienyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, tetrahydrofuranyl, and furopyridinyl.

[0028] The term "heteroaryloxy" as used herein refers to a monovalent group of formula -OR, wherein R is heteroaryl as defined herein.

[0029] As used herein, the term "heterocyclyl" 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 or P (e.g., 1-4, 1-3, or 1 or 2 heteroatoms selected from N, O and S) as ring atoms, 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, polycyclic (e.g., tricyclic) 10- to 18-membered ring systems, which may include bridged ring systems when bicyclic or polycyclic. In some embodiments, the heterocyclyl contains 3-16 ring atoms (i.e., 3- to 16-membered heterocyclyl), such as 3-12 ring atoms (i.e., 3- to 12-membered heterocyclyl) or 4-10 ring atoms (i.e., 4- to 10-membered heterocyclyl). Examples of saturated heterocyclic 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); 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 heterocyclic groups include, but are not limited to, dihydrothiophenyl, dihydropyranyl, dihydrofuranyl, and dihydrothiazolyl. Other examples of heterocyclic groups include, but are not limited to, pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl, pyrazolidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, thiazolidinyl, dihydrothiophenyl, 2,3-dihydro-benzo[1,4]dioxanyl, indolinyl, isoindolinyl, dihydrobenzothiophenyl, dihydrobenzofuranyl, isochromanyl, chromanyl, 1,2-dihydroquinolinyl, 1,2,3,4-tetrahydro-isoquinolinyl, 1, 2,3,4-tetrahydro-quinolinyl, 2,3,4,4a,9,9a-hexahydro-1H-3-aza-fluorenyl, 5,6,7-trihydro-1,2,4-triazolo[3,4-a]isoquinolinyl, 3,4-dihydro-2H-benzo[1,4]oxazinyl, benzo[1,4]dioxanyl, 2,3-dihydro-1H-1λ-benzo[d]isothiazol-6-yl, dihydropyranyl, dihydrofuranyl and dihydrothiazolyl. "Bicyclic heterocyclyl" includes radicals 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 radicals 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.

[0030] The term "heterocyclyloxy" as used herein refers to a monovalent group of formula -OR, wherein R is a heterocyclyl group as defined herein.

[0031] As used herein, the term "oxo" refers to a =0 group.

[0032] As used herein, the term "substituted" means that any one or more hydrogens on a designated atom or group are replaced with a moiety as defined herein or selected from a designated group of moieties, provided that the normal valence of the designated atom is not exceeded and the resulting compound is stable. For example, when the substituent is an oxo (i.e., =O), two hydrogens on the atom are replaced. For example, a pyridyl group substituted with an oxo is a pyridone. Only when the combination of substituents and / or variables produces a stable compound or a useful synthetic intermediate is it allowed. As used herein, the phrase "optionally substituted X" is intended to be equivalent to "X, wherein X is optionally substituted" (e.g., "alkyl, wherein the alkyl is optionally substituted"). It is not intended to mean that feature "X" (e.g., alkyl) itself is optional. As used herein, the term "optionally substituted" refers to having 0, 1 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).

[0033] Alkyl, alkylene, alkoxy, amino, carbocyclyl, aryl, arylene, aryloxy, heteroaryl, and heterocyclyl groups may be substituted with carbocyclyl (e.g., cycloalkyl); aryl; heteroaryl; heterocyclyl; halo; OR, wherein R is H, alkyl, carbocyclyl (e.g., cycloalkyl), aryl, heteroaryl, or heterocyclyl; SR, wherein R is H, alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl; CN; NO2; N3; NRR'; wherein each of R and R' is independently H, alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl; S02R, wherein R is H, alkyl, or aryl; S02NRR', wherein each of R and R' is independently H, alkyl, or aryl; SOR, wherein R is H, alkyl, or aryl; or P(O)(OR)2, wherein each R is independently H or alkyl. Amino, aryl, carbocyclyl, heteroaryl, and heterocyclyl groups may also be substituted with alkyl groups. Alkyl, alkylene, carbocyclyl and heterocyclyl can also be replaced by oxo or =NR, wherein R is H or alkyl.Alkyl and alkylene can also be replaced by spirocyclic carbocycle (for example spirocyclic cycloalkyl) or spirocyclic heterocyclyl.In some embodiments, substituent is further replaced by one or more substituents as described herein.For example, C1 alkyl, i.e. methyl, can be replaced by oxo to form formyl and further replaced by -OH or -NR2 to form carboxyl or amide.

[0034] As used herein, the term "complement-mediated disorder" refers to a disorder in which the amount or activity of complement is sufficient to cause the disorder in an individual.

[0035] As used herein, a compound having "complement C1 esterase (C1s) inhibitory activity" is one that exhibits an IC of less than 100 nM. 50 Compounds of the invention as determined using the human complement C1s enzyme assay described in Example 3 herein.

[0036] The term "pharmaceutical composition" as used herein 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 dosage amount suitable for administration in a treatment regimen that, when administered to a relevant population, shows a statistically significant probability of achieving a predetermined therapeutic effect. In certain embodiments, the pharmaceutical composition can be specially formulated for administration in solid or liquid form, including those suitable for oral administration, such as a drench (aqueous or non-aqueous solution or suspension), tablet or capsule; and parenteral administration, such as by subcutaneous, intramuscular or intravenous injection.

[0037] As used herein, the term "pharmaceutically acceptable salt" represents salts of the compounds that are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reaction, and the like, within the scope of sound medical judgment and 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, (P.H. Stahl and C.G. Wermuth, eds.), Wiley-VCH, 2008. These salts may be acid addition salts involving inorganic or organic acids. These salts may be prepared in situ during the final isolation and purification of the compounds described herein, or separately by reacting the free base groups with a suitable acid.

[0038] 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, emollients, emulsifiers, diluents, film-forming or coating agents, flavorings, fragrances, glidants, lubricants, preservatives, printing inks, adsorbents, suspending or dispersing agents, sweeteners, or water of hydration. Those of ordinary skill in the art are familiar with a variety of agents and materials that can be used as excipients.

[0039] As used herein, the term "subject" can be a human, non-human primate or other non-human mammal, such as, but not limited to, dogs, cats, horses, cows, pigs, goats, monkeys, rats, mice and sheep. In a preferred embodiment, the subject is a human.

[0040] As used herein and as is well known in the art, "treating" a condition or "treating" various diseases and disorders is a method for obtaining a beneficial or desired result, such as a clinical result. Beneficial or desired results can include, but are not limited to, alleviation of one or more symptoms or conditions; a reduction in the extent of the disease, disorder, or condition; stabilization of the state of the disease, disorder, or condition (i.e., not worsening); delay or slowing of the progression of the disease, disorder, or condition; improvement or alleviation of the disease, disorder, or condition; and remission (whether partial or complete), whether detectable or undetectable. "Remission" of a disease, disorder, or condition means that the extent and / or undesirable clinical manifestations 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.

[0041] A "therapeutically effective amount" or "effective amount" of an active compound pharmaceutical composition of the present disclosure refers to an amount effective to provide a therapeutic benefit when administered to a subject, such as an improvement in symptoms or a reduction or alleviation of the disease itself. In one embodiment, a therapeutically effective amount is an amount sufficient to prevent a significant increase in, or to significantly reduce, the detectable level of hemolysis in a patient's blood, serum, or tissue. DETAILED DESCRIPTION

[0042] Active compound

[0043] The present disclosure provides compounds and salts that can be used to treat disorders mediated by the complement cascade (e.g., disorders mediated by C1s). In some embodiments, the compounds of the present disclosure are described by formula (I'):

[0044]

[0045] or a pharmaceutically acceptable salt thereof, wherein

[0046] R 1 and R 1’ Each of is independently H or an optionally substituted C1-C6 alkyl;

[0047] X is CR 3 or N;

[0048] X' is CR 4 or N;

[0049] 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;

[0050] R3 and R 4 Each of is independently H, halo or optionally substituted C1-C6 alkyl;

[0051] L 1 is a bond; NH; NHC(O); NHC(O)O; NHC(O)NH or NHS(O)2;

[0052] L 2 is a bond or an optionally substituted C1-C6 alkylene group;

[0053] L 3 is a bond, NH, NHC(O), C(O), O, S(O)2CH2; B is a halogen, an optionally substituted C6-C 14 Aryl; optionally substituted C3-C 14 carbocyclyl; optionally substituted 5- to 14-membered heterocyclyl; or optionally substituted 5- to 10-membered heteroaryl; and

[0054] Y is

[0055] in

[0056] Y 1 O, S, NR d , where each R d are independently absent, H or C1-C6 alkyl;

[0057] Y 1’ O, S, NR d or C(R d )2;

[0058] Y 2 and Y 3 Each of NR e or C(R e )2, where each R e are 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 two R e Combine to form oxo;

[0059] Y 4 、Y 4’ 、Y 10 and Y 13 Each of which is independently CR e or N;

[0060] Y 5 、Y 6 and Y 7Each of which is independently O, S, NR f or C(R f )2, where each R f are independently absent; H; optionally substituted C1-C6 alkyl; halo; or N(R g )2; or two R f Combine to form oxo;

[0061] Y 8 and Y 9 Each of which is independently C(R f )2 or NR f ;

[0062] Y 11 and Y 12 Each of NR e 、C(R e )2, S or O;

[0063] each are independently a single bond or a double bond;

[0064] Each of R, R', R" and R'" is independently absent, H, optionally substituted C1-C6 alkyl, halo or N(R g )2; or

[0065] Two R's combine to form an oxo group; or

[0066] Two R's combine to form oxo; and

[0067] q is 0 or 1.

[0068] In some embodiments, the compounds of the present disclosure are compounds of formula (I):

[0069]

[0070] or a pharmaceutically acceptable salt thereof, wherein all variables are as defined in formula (I'), provided that at least one of the following is true:

[0071] (i)-L 1 -L 2 -L 3 - Not combined to form

[0072] (ii)R 2 Not a C1-C6 alkyl group,

[0073] (iii) B does not

[0074] (iv)R 1 and R 1’ At least one of them is not H;

[0075] (v) X is N;

[0076] (vi)X ’ CR 4 ,and

[0077] (vii) Y does not

[0078] In some embodiments, R 1 is H. In some embodiments, R 1 is an optionally substituted C1-C6 alkyl. 1 In some embodiments, R 1 is CH2OH.

[0079] In some embodiments, R 1’ is H. In some embodiments, R 1’ is an optionally substituted C1-C6 alkyl. 1 In some embodiments, R 1 is CH2OH.

[0080] In some embodiments, X is CR 3 In some embodiments, X is CH. In some embodiments, X is CCH3. In some embodiments, X is N.

[0081] 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.

[0082] 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.

[0083] In some embodiments, R 2is optionally substituted phenyl, for example, phenyl optionally substituted by 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 for In some embodiments, R 2 for In some embodiments, R 2 for In some embodiments, R 2 for In some embodiments, R 2 for In some embodiments, R 2 for In some embodiments, R 2 for In some embodiments, R 2 for In some embodiments, R 2 for In some embodiments, R 2 for In some embodiments, R 2 for In some embodiments, R 2 for In some embodiments, R 2 for In some embodiments, R 2 for In some embodiments, R 2 for In some embodiments, R 2 for In some embodiments, R 2 for In some embodiments, R 2 for In some embodiments, R 2 for In some embodiments, R 2 for In some embodiments, R 2 for In some embodiments, R 2 for In some embodiments, R 2 for In some embodiments, R 2 for In some embodiments, R 2 for In some embodiments, R 2 for In some embodiments, R 2 for In some embodiments, R 2 for In some embodiments, R 2 for In some embodiments, R 2 for In some embodiments, R 2 for In some embodiments, R 2 for In some embodiments, R 2 for In some embodiments, R 2 for In some embodiments, R 2 for In some embodiments, R 2 for In some embodiments, R 2 for In some embodiments, R 2 for In some embodiments, R 2 for In some embodiments, R 2 for In some embodiments, R 2 for In some embodiments, R 2 for In some embodiments, R 2 for In some embodiments, R 2 for In some embodiments, R 2 for In some embodiments, R 2 for In some embodiments, R 2 for In some embodiments, R 2 for In some embodiments, R 2 for In some embodiments, R 2 for In some embodiments, R 2 for In some embodiments, R 2 for

[0084] In some embodiments, R 2 is an optionally substituted (4- to 10-membered heterocyclyl)oxy. 2 for

[0085] In some embodiments, R 2 is an optionally substituted 4- to 10-membered heterocyclyl. 2 for In some embodiments, R 2 for In some embodiments, R 2 for In some embodiments, R 2 for In some embodiments, R 2 for In some embodiments, R 2 for In some embodiments, R 2 for In some embodiments, R 2 for In some embodiments, R 2 for In some embodiments, R 2 for In some embodiments, R 2 for In some embodiments, R 2 for In some embodiments, R 2 for In some embodiments, R 2 for In some embodiments, R 2 for In some embodiments, R 2 for In some embodiments, R 2 for In some embodiments, R 2 for In some embodiments, R 2 for In some embodiments, R2 for

[0086] In some embodiments, R 2 is an optionally substituted 5- to 10-membered heteroaryl. 2 for In some embodiments, R 2 for In some embodiments, R 2 for In some embodiments, R 2 for In some embodiments, R 2 for In some embodiments, R 2 for In some embodiments, R 2 for In some embodiments, R 2 for In some embodiments, R 2 for In some embodiments, R 2 for In some embodiments, R 2 for In some embodiments, R 2 for In some embodiments, R 2 for

[0087] In some embodiments, R 2 is an optionally substituted C3-C8 carbocyclyl. 2 is an optionally substituted C3-C8 cycloalkyl. 2 for In some embodiments, R 2 for In some embodiments, R 2 is an optionally substituted C3-C8 cycloalkenyl. 2 for

[0088] In some embodiments, R 2 is H. In some embodiments, R 2 In some embodiments, R 2 is CH3. In some embodiments, R 2 It is CH(CH3)2.

[0089] In some embodiments, L 1 In some embodiments, L 1 In some embodiments, L 1 is NHS(O)2. 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.

[0090] In some embodiments, L 2 In some embodiments, L 2 is an optionally substituted C1-C6 alkylene. 2 In some embodiments, L 2 is -CH2-. In some embodiments, L 2 is -(CH2)2-. In some embodiments, L 2 is -(CH2)3-. In some embodiments, L 2 is -(CH2)4-. In some embodiments, L 2 is -(CH2)5-. In some embodiments, L 2 for In some embodiments, L 2 for In some embodiments, L 2 for In some embodiments, L 2 for In some embodiments, L 2 for

[0091] In some embodiments, L 3 In some embodiments, L 3 In some embodiments, L 3 is NHC(O). In some embodiments, L 3 is C(O). In some embodiments, L 3 Is 0. In some embodiments, L 3 It is SO2CH2.

[0092] In some embodiments, B is halo, such as Br.

[0093] In some embodiments, B is an optionally substituted C6-C 14 aryl or optionally substituted 5- to 10-membered heteroaryl.

[0094] In some embodiments, the compound is of formula (II):

[0095]

[0096] or a pharmaceutically acceptable salt thereof, wherein X 1 CR 9 or N; R 5 、R 6 and R 9 Each of R is independently selected from H, halo, CN, SF5, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, S(O)(NH)CH3, S(O)2CH3 and S(O)(NCN)CH3; 7 and R 8 Each of the above is independently H, halogen, 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, provided that R 7 and R 8 At most one of them is an 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; or R 7 and R 8 Together with the atoms to which they are attached, they form an optionally substituted 5- to 6-membered heterocyclyl, an optionally substituted 5- to 10-membered heteroaryl, or an optionally substituted C6-C 14 Aryl; or R 5 and A are combined to form an optionally substituted C1-C2 alkylene group; R 6 and R 9 Combine to form (C2-C6 alkylene) (C6-C 14 arylene) (C2-C6 alkylene), and each of R5, R7 and R8 is H; and all other variables are defined as in formula (I).

[0097] In some embodiments, the compound is of Formula (IIA):

[0098]

[0099] or a pharmaceutically acceptable salt thereof, wherein all variables are defined as in formula (II).

[0100] In some embodiments, X 1 CR 9 In some embodiments, X 1 For CH.

[0101] In some embodiments, R 8 For H.

[0102] In some embodiments, R 7 is an optionally substituted C6-C 14 In some embodiments, R 7 is an optionally substituted phenyl. 7 for In some embodiments, R 7 for In some embodiments, R 7 for In some embodiments, R 7 for In some embodiments, R 7 for In some embodiments, R 7 for In some embodiments, R 7 for In some embodiments, R 7 for In some embodiments, R 7 for

[0103] In some embodiments, R 7 is an optionally substituted 5- to 10-membered heteroaryl. 7 for In some embodiments, R 7 for In some embodiments, R 7 for In some embodiments, R 7 for In some embodiments, R 7 for In some embodiments, R 7 for In some embodiments, R 7 for In some embodiments, R 7 for In some embodiments, R 7 for

[0104] In some embodiments, R 7 is an optionally substituted (5- to 10-membered heteroaryl)oxyl. 7 for In some embodiments, R 7 for

[0105] In some embodiments, R 7 is an optionally substituted (4- to 10-membered heterocyclyl)oxy. 7 for In some embodiments, R 7 for In some embodiments, R 7 for In some embodiments, R 7 for

[0106] In some embodiments, R 7 is an optionally substituted C3-C8 cycloalkyl. 7 for

[0107] In some embodiments, R 7 is an optionally substituted 4- to 10-membered heterocyclyl. 7 for In some embodiments, R 7 for

[0108] In some embodiments, R 8 is an optionally substituted C6-C 14 Aryl, such as optionally substituted phenyl. In some embodiments, R 8 for In some embodiments, R 8 for

[0109] In some embodiments, R 8 is an optionally substituted 5- to 10-membered heteroaryl. 8 for In some embodiments, R 8 for In some embodiments, R 8 for

[0110] In some embodiments, R 7 For H.

[0111] In some embodiments, R 5 is H. In some embodiments, R 5 is an optionally substituted C1-C6 alkoxy group. 5 is OCH3. In some embodiments, R 5 In some embodiments, R 5 For F.

[0112] In some embodiments, R 6 is H. In some embodiments, R 6 is an optionally substituted C1-C6 alkoxy group. 6 is OCH3. In some embodiments, R 6 In some embodiments, R 6 For F.

[0113] In some embodiments, R 6 and R 9 Combine 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

[0114] In some embodiments, B is In some embodiments, B is In some embodiments, B is In some embodiments, B is In some embodiments, B is In some embodiments, B is In some embodiments, B is In some embodiments, B is In some embodiments, B is In some embodiments, B is In some embodiments, B is In some embodiments, B is In some embodiments, B is In some embodiments, B is

[0115] In some embodiments, the compound is of formula (III):

[0116]

[0117] where X 2 O; C(Rh )2, where each R h are independently hydrogen, halogen or optionally substituted C1-C6 alkyl, or two R h Combine to form oxo; S(O)2 or NR h ; m is selected from 0, 1, 2, 3, 4 and 5; n is selected from 0, 1, 2, 3 and 4; and R 10 and R 11 Each of wherein 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 in Formula (I).

[0118] In some embodiments, the compound is of formula (IIIA):

[0119]

[0120] or a pharmaceutically acceptable salt thereof, wherein all variables are defined as in formula (III).

[0121] In some embodiments, the compound is of formula (IV):

[0122]

[0123] where X 2 O; C(R h )2, where each R h are independently hydrogen, halogen or optionally substituted C1-C6 alkyl, or two R h Combined to form oxo; S(O)2 or NR h ; m is selected from 0, 1, 2, 3, 4 and 5; n is selected from 0, 1, 2, 3 and 4; and R 10 and R 11 Each of wherein 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 in Formula (I).

[0124] In some embodiments, the compound is of Formula (IVA):

[0125]

[0126] or a pharmaceutically acceptable salt thereof.

[0127] In some embodiments, X 2 Is O. In some embodiments, X 2 C(R a ) 2. In some embodiments, X 2In some embodiments, X 2 In some embodiments, X 2 It is S(O)2.

[0128] In some embodiments, B is In some embodiments, B is In some embodiments, B is In some embodiments, B is In some embodiments, B is In some embodiments, B is In some embodiments, B is In some embodiments, B is In some embodiments, B is In some embodiments, B is In some embodiments, B is

[0129] In some embodiments, B is an optionally substituted 5- to 10-membered heteroaryl. In some embodiments, B is In some embodiments, B is In some embodiments, B is In some embodiments, B is In some embodiments, B is In some embodiments, B is In some embodiments, B is In some embodiments, B is In some embodiments, B is In some embodiments, B is In some embodiments, B is In some embodiments, B is In some embodiments, B is In some embodiments, B is In some embodiments, B is In some embodiments, B is In some embodiments, B is In some embodiments, B is In some embodiments, B is In some embodiments, B is In some embodiments, B is In some embodiments, B is In some embodiments, B is In some embodiments, B is In some embodiments, B is In some embodiments, B is In some embodiments, B is In some embodiments, B is In some embodiments, B is In some embodiments, B is In some embodiments, B is In some embodiments, B is In some embodiments, B is

[0130] In some embodiments, B is an optionally substituted C3-C 14 carbocyclyl or optionally substituted 5- to 14-membered heterocyclyl.

[0131] In some embodiments, the compound is of Formula (V):

[0132]

[0133] or a pharmaceutically acceptable salt thereof, wherein X 3 and X 4 Each of is independently a bond; O; S; C(R i )2, where each R i are independently H, OH, halogen, optionally substituted C1-C6 alkyl or optionally substituted C1-C6 alkoxy, or two R i Combined to form oxo; NR j , where R j is H or C1-C6 alkyl; or SO2; X 5 CH, CR 13 or N; X 6 CH, CR 12 or N; o is selected from 0, 1, 2 and 3; p is selected from 0, 1 and 2; R 12 and R 13 Each of wherein 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 in Formula (I).

[0134] In some embodiments, the compound is of Formula (VA):

[0135]

[0136] or a pharmaceutically acceptable salt thereof, wherein all variables are as defined in formula (V).

[0137] In some embodiments, the compound is of Formula (VB):

[0138]

[0139] or a pharmaceutically acceptable salt thereof, wherein all variables are as defined in formula (V).

[0140] In some embodiments, the compound is of formula (VC):

[0141]

[0142] or a pharmaceutically acceptable salt thereof, wherein all variables are as defined in formula (V).

[0143] In some embodiments, the compound is of formula (VI):

[0144]

[0145] or a pharmaceutically acceptable salt thereof, wherein X 3 and X 4 Each of is independently a bond; O; S; C(R i )2, where each R i are independently H, OH, halogen, optionally substituted C1-C6 alkyl or optionally substituted C1-C6 alkoxy, or two R i Combined to form oxo; NR j , where R j is H or C1-C6 alkyl; or SO2; X 5 CH, CR 13 or N; X 6 CH, CR 12 or N; o is selected from 0, 1, 2 and 3; p is selected from 0, 1 and 2; R 12 and R 13 Each of wherein 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 in Formula (I).

[0146] In some embodiments, the compound is of formula (VIA):

[0147]

[0148] or a pharmaceutically acceptable salt thereof, wherein all variables are as defined in formula (V).

[0149] In some embodiments, the compound is of Formula (VIB):

[0150]

[0151] or a pharmaceutically acceptable salt thereof, wherein all variables are defined as in formula (VI).

[0152] In some embodiments, the compound is of Formula (VIC):

[0153]

[0154] or a pharmaceutically acceptable salt thereof, wherein all variables are defined as in formula (VI).

[0155] In some embodiments, X 3 In some embodiments, X 3 Is O. In some embodiments, X 3 C(R i ) 2. In some embodiments, X 3 In some embodiments, X 3 For S.

[0156] In some embodiments, X 4 In some embodiments, X 4 Is O. In some embodiments, X 4 C(R i ) 2. In some embodiments, X 3 In some embodiments, X 4 For S.

[0157] In some embodiments, B is In some embodiments, B is In some embodiments, B is In some embodiments, B is In some embodiments, B is In some embodiments, B is In some embodiments, B is In some embodiments, B is

[0158] In some embodiments, B is an optionally substituted C3-C 14 In some embodiments, B is an optionally substituted C3-C8 cycloalkyl. In some embodiments, B is In some embodiments, B is In some embodiments, B is In some embodiments, B is

[0159] In some embodiments, B is an optionally substituted 5- to 14-membered heterocyclyl. In some embodiments, B is In some embodiments, B is In some embodiments, B is In some embodiments, B is In some embodiments, B is In some embodiments, B is In some embodiments, B is In some embodiments, B is In some embodiments, B is

[0160] In some embodiments, Y is For example In some embodiments, Y 2 is N. In some embodiments, Y 2 CR e In some embodiments, Y 2 In some embodiments, Y 3 is N. In some embodiments, Y 3 CR e In some embodiments, Y 3 In some embodiments, Y 1 NR d In some embodiments, Y 1 In some embodiments, Y 1 For S.

[0161] In some embodiments, the compound is of formula (VII):

[0162]

[0163] or a pharmaceutically acceptable salt thereof.

[0164] In some embodiments, Y is In some embodiments, Y 1 is S. In some embodiments, Y 2 NR e In some embodiments, Y 2 In some embodiments, Y 2 C(R e ) 2. In some embodiments, Y 2 is CH2. In some embodiments, Y 3 NR e In some embodiments, Y 3 In some embodiments, Y 3 C(R e ) 2. In some embodiments, Y3 For CH2.

[0165] In some embodiments, R is H. In some embodiments, R' is H.

[0166] In some embodiments, Y is In some embodiments, Y is In some embodiments, Y is In some embodiments, Y is In some embodiments, Y is In some embodiments, Y is

[0167] In another aspect, the present disclosure provides a compound of Table 1, or a pharmaceutically acceptable salt thereof.

[0168] In some embodiments of any of the aspects provided herein, the compounds of the present disclosure have complement C1 esterase (C1s) inhibitory activity.

[0169] 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).

[0170] In some embodiments, the compound of the present disclosure is a compound of Table 1.

[0171] Pharmaceutical composition

[0172] The pharmaceutical compositions of the present disclosure contain one or more of the compounds disclosed herein (e.g., one or more of Formula (I), (I'), (II), (IIA), (III), (IIIA), (IV), (IVA), (V), (VA), (VB), (VC), (VI), (VIA), (VIB), (VIC), and (VII), and compounds of Table 1) as therapeutic compounds. 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, the pharmaceutical composition for treating cancer contains one or more of the compounds disclosed herein (e.g., one or more of Formula (I), (I'), (II), (IIA), (III), (IIIA), (IV), (IVA), (V), (VA), (VB), (VC), (VI), (VIA), (VIB), (VIC), and (VII), and compounds of Table 1) and can be formulated and / or administered with or without other therapeutic agents for a particular condition. Examples of such therapeutic agents (second therapeutic agents) are described herein.

[0173] The compounds disclosed herein (e.g., compounds of Formula (I), (I'), (II), (IIA), (III), (IIIA), (IV), (IVA), (V), (VA), (VB), (VC), (VI), (VIA), (VIB), (VIC), and (VII), and Table 1) can be used in free base form or in salt form. All forms are within the scope of the present disclosure.

[0174] Exemplary routes of administration for the 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, the compounds of the present disclosure (e.g., Formula (I), (I'), (II), (IIA), (III), (IIIA), (IV), (IVA), (V), (VA), (VB), (VC), (VI), (VIA), (VIB), (VIC), or (VII), or compounds of Table 1) are formulated for oral administration.

[0175] Formulations for oral administration

[0176] The pharmaceutical compositions of the present disclosure include those formulated for oral administration ("oral dosage forms"). Oral dosage forms can be in the form of, for example, tablets, capsules, liquid solutions or suspensions, powders, or liquid or solid crystals, containing a mixture of the active ingredient and non-toxic pharmaceutically acceptable excipients. These excipients can be, for example, inert diluents or fillers; granulating agents and disintegrants; binders; and lubricants, glidants, and anti-adherents (e.g., magnesium stearate, zinc stearate, stearic acid, silicon dioxide, hydrogenated vegetable oil, or talc). Other pharmaceutically acceptable excipients can be colorants, flavorings, plasticizers, wetting agents, buffers, and the like.

[0177] 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 as soft gelatin capsules in which the active ingredient is mixed with water or an oil medium. Powders, granules and pills may be prepared using the ingredients mentioned above under tablets and capsules in a conventional manner using, for example, a mixer, fluidized bed apparatus or spray drying equipment.

[0178] Liquid forms into which the disclosed compounds and compositions 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.

[0179] Formulations for parenteral administration

[0180] The pharmaceutical compositions of the present disclosure can be administered in a pharmaceutically acceptable parenteral (e.g., intravenous, intramuscular, subcutaneous or similar) formulation as described herein. The pharmaceutical composition can also be administered parenterally in a dosage form or formulation containing a conventional, non-toxic pharmaceutically acceptable carrier and adjuvant. Specifically, formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions, which may contain antioxidants, buffers, antibacterial agents, and solutes that make the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions that may include suspending agents and thickening agents. For example, to prepare such a composition, the compound of the present disclosure can be dissolved or suspended in a liquid vehicle that is acceptable to parenteral administration. Acceptable vehicles and solvents that can be used are water; water adjusted to a suitable pH by adding an appropriate amount of hydrochloric acid, sodium hydroxide, or a suitable buffer; 1,3-butanediol; Ringer's solution; and isotonic sodium chloride solution. The aqueous formulation 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), the entire contents of which are incorporated herein by reference.

[0181] Parenteral formulations can be any of the five general types of preparations identified by USP-NF as suitable for parenteral administration:

[0182] (1) “Drug injection”: a liquid preparation, which is a drug substance (e.g., a compound of the present disclosure) or a solution thereof;

[0183] (2) "Injectable drug": a drug substance (e.g., a compound of the present disclosure) as a dry solid that is to be combined with an appropriate sterile vehicle for parenteral administration as a pharmaceutical injection;

[0184] (3) “Drug injectable emulsion”: a liquid formulation of a drug substance (e.g., a compound of the present disclosure) dissolved or dispersed in a suitable emulsion medium;

[0185] (4) "Drug injectable suspension": a liquid formulation of a drug substance (e.g., a compound of the present disclosure) suspended in a suitable liquid medium; and

[0186] (5) "Drug substance for injectable suspension": a drug substance (eg, a compound of the present disclosure) as a dry solid to be combined with an appropriate sterile vehicle for parenteral administration as a pharmaceutical injectable suspension.

[0187] Exemplary formulations for parenteral administration include solutions of compounds prepared in water appropriately mixed with surfactants such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycol, DMSO, and mixtures thereof containing or not containing alcohol, as well as in oil. Under normal storage and use conditions, these preparations may contain preservatives to prevent microbial growth. For selecting and preparing suitable formulations, conventional procedures and ingredients are described in, for example, Remington: The Science and Practice of Pharmacy, 23rd edition, compiled by Adejare, Academic Press (2020) and The United States Pharmacopeia and National Formulary (USP-NF 2021, 1-3 phases) published in 2021.

[0188] The formulation for parenteral administration can, for example, contain sterile water, saline, polyalkylene glycols (e.g., polyethylene glycol), oils of plant origin, or hydrogenated naphthalene. Biocompatible, biodegradable lactide polymers, lactide / glycolide copolymers, or polyoxyethylene-polyoxypropylene copolymers can be used to control the release of the compound. Other potentially useful parenteral delivery systems for the compound include ethylene-vinyl acetate copolymer particles, osmotic pumps, implantable infusion systems, and liposomes. The formulation for inhalation can contain, for example, lactose, or can be an aqueous solution containing, for example, polyoxyethylene-9-lauryl ether, glycocholate, and deoxycholate, or can be an oily solution for use in the form of nasal drops or as a gel.

[0189] The dosage of the compounds described herein (e.g., compounds of Formula (I), (I'), (II), (IIA), (III), (IIIA), (IV), (IVA), (V), (VA), (VB), (VC), (VI), (VIA), (VIB), (VIC), and (VII), and compounds of Table 1) and / or compositions comprising the compounds described herein may depend on a number of factors, such as the pharmacodynamic properties of the compound; the mode of administration; the age, health condition, and weight of the recipient; the nature and extent of the symptoms; the frequency of treatment and the type of concurrent treatment, if any; and the clearance rate of the compound in the subject to be treated. One skilled in the art can determine the appropriate dosage based on the above factors. In general, satisfactory results are obtained when the compounds described herein are administered to humans at a daily dose of, for example, 0.05 mg to 3000 mg (measured in solid form). For example, the dosage range may be 10-1000 mg (e.g., 50-800 mg).

[0190] Alternatively, the patient's weight can be used to calculate the dosage. For example, the dosage of the compound or its pharmaceutical composition administered to the patient can be 0.1-100 mg / kg. The dosage form containing a compound disclosed herein ((such as 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) can be, for example, once a day (QD), twice a day (BID), three times a day (TID), four times a day (QID), once every other day (Q2D), once every three days (Q3D) or any dosing schedule as needed is used.

[0191] Use of active compounds for the treatment of selected conditions

[0192] In one aspect, an effective amount of an active compound described herein (e.g., any of Formula (I), (I'), (II), (IIA), (III), (IIIA), (IV), (IVA), (V), (VA), (VB), (VC), (VI), (VIA), (VIB), (VIC), and (VII), and compounds of 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-related disorder or a disorder associated with the alternative complement pathway, a cellular disorder or abnormality that adversely affects the ability of a cell to participate in or respond to normal complement activity, or a complement-mediated response that is undesirable to a medical treatment such as surgery or other medical procedure or drug or biopharmaceutical administration, blood transfusion or other allogeneic tissue or fluid administration.

[0193] In some embodiments, the condition is an autoimmune disease. In some embodiments, the condition is cancer. In some embodiments, the condition is an infectious disease. In some embodiments, the condition is an inflammatory disease. In some embodiments, the condition is a blood disease. In some embodiments, the condition is ischemia-reperfusion injury. In some embodiments, the condition is an eye disease. In some embodiments, the condition is a kidney disease. In some embodiments, the condition is transplant rejection. In some embodiments, the condition is antibody-mediated transplant rejection, such as acute antibody-mediated rejection. In some embodiments, the condition is a vascular disease. In some embodiments, the condition is a vasculitic condition. In some embodiments, the condition is a neurodegenerative disorder, such as a tauopathy.

[0194] In some embodiments, the condition is a central nervous system (CNS) medical condition or a peripheral nervous system condition involving complement activation. In some embodiments, the condition is an acquired brain or spinal cord injury. In some embodiments, the condition is ischemic reperfusion injury. In some embodiments, the condition is a stroke. In some embodiments, the condition is a traumatic brain injury (TBI). In some embodiments, the condition is a spinal cord injury (SCI).

[0195] In some embodiments, the disorder is a neuroinflammatory disorder.

[0196] 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 neurological paraneoplastic syndrome, such as 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 (involving 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, such as temporal arteritis. In some embodiments, the neuroinflammatory disorder is arachnoiditis. In some embodiments, the neuroinflammatory disorder is Kinsbourne syndrome. In some embodiments, the neuroinflammatory disease is opsoclonus myoclonus syndrome (OMS). In some embodiments, the neuroinflammatory disease is Saint Vitus Dance or Sydenham's chorea (SD).

[0197] In some embodiments, the disease is Alzheimer's disease (AD). AD has two hallmark pathological features: beta-amyloid (Aβ) plaques and neurofibrillary tangles containing hyperphosphorylated tau protein. Recent studies have shown that complement is involved in the pathogenesis of AD, including genome-wide association studies that confirmed single nucleotide polymorphisms (SNPs) associated with the risk of late-onset AD in genes encoding complement proteins clusterin (CLU) and CR1 (CR1). See Carpanini et al., Therapeutic Inhibition of the Complement System in Diseases of the Central Nervous System, Front. Immunol., March 4, 2019. Biomarker studies also identify complement proteins and activation products in plasma and / or CSF, which can distinguish AD from controls and predict the risk of progression to AD.

[0198] In some embodiments, the condition is frontotemporal dementia. In some embodiments, the condition is Pick's disease. In some embodiments, the condition is sporadic frontotemporal dementia, such as frontotemporal dementia with Parkinsonism associated with chromosome 17. In some embodiments, progressive supranuclear palsy (PSP). In some embodiments, corticobasal degeneration (CBD). In some embodiments, the condition is subacute sclerosing panencephalitis.

[0199] In some embodiments, the disease is amyotrophic lateral sclerosis (ALS). ALS is caused by the progressive loss of upper and lower (α) motor neurons, leading to denervation of the neuromuscular junction of 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 ALS postmortem tissue; C3 activation fragments and TCC in pathological areas; C4d and TCC staining of degenerating neurons and glial cells in the ALS motor cortex and spinal cord, and upregulation of C5aR1 in pathological areas. Even early in the disease process, C3d and C4d have been found on oligodendrocytes and degenerating 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 motor nerve end plates in the intercostal muscles of ALS donors. See Carpanini et al., Therapeutic Inhibition of the Complement System in Diseases of the Central Nervous System, Front. Immunol., Mar. 4, 2019.

[0200] In some embodiments, the condition is Parkinson's disease (PD). PD is characterized by the loss of dopamine neurons and the deposition of the protein α-synuclein in the substantia nigra, forming Lewy bodies, the pathological hallmark of the disease. Patients present with resting tremor, bradykinesia, and rigidity. Complement activation is associated with α-synuclein and Lewy bodies in Parkinson's disease; in vitro studies have shown that the disease-associated splice variant α-synuclein 112 (but not the full-length protein) causes complement activation. In vivo, the localization of C3d, C4d, C7, and C9 in Lewy bodies has been reported. Recently, iC3b and C9 have been reported to be deposited in Lewy bodies and melanized neurons, and iC3b immunoreactivity has been shown to increase with normal aging and is further elevated in PD compared to age-matched controls. In addition, a correlation has been shown between the C3 / Aβ42 or FH / Aβ42 ratio in CSF and the severity of motor and cognitive symptoms in Parkinson's disease. See Carpanini et al., Therapeutic Inhibition of the Complement System in Diseases of the Central Nervous System, Front. Immunol., Mar. 4, 2019. In some embodiments, the subject to be treated suffers from Parkinson's disease with dementia (PDD).

[0201] In some embodiments, the disease is Huntington's disease (HD). HD is an autosomal dominant neurodegenerative disease characterized by progressive motor symptoms, mental disorders and dementia. It is caused by the expansion of a three-base pair (CAG) repeat sequence in exon 1 of the HTT gene (39-121 repeats relative to the normal range of 8-39 repeats), which is translated into a polyglutamine tract at the N-terminus of the protein. This leads to polyglutamine length-dependent misfolding and accumulation of huntingtin in the striatum and cortex (layers 3, 5 and 6), followed by neuronal loss in these areas, spreading to the hippocampus. It has been shown that neurons, astrocytes and myelin in the HD caudate and striatum are immunoreactive to new epitopes in C1q, C4, C3 and iC3b and TCC. The expression of mRNA encoding the early complement components C1q (c-chain), C1r, C3, and C4, the complement regulatory factors C1INH, Clusterin, MCP, DAF, and CD59, and the complement receptors C3a and C5a has been shown to be upregulated in the HD striatum. See Carpanini et al., Therapeutic Inhibition of the Complement System in Diseases of the Central Nervous System, Front. Immunol., Mar 4, 2019.

[0202] In some embodiments, the condition is argyrophilic grain dementia. In some embodiments, the condition is British amyloid angiopathy. In some embodiments, the condition is cerebral amyloid angiopathy. In some embodiments, the condition is Creutzfeldt-Jakob disease. In some embodiments, the condition is dementia pugilistica. In some embodiments, the condition is diffuse neurofibrillary tangles with calcifications. In some embodiments, the condition is Down's syndrome. In some embodiments, the condition is frontotemporal lobar degeneration. In some embodiments, the condition is Gerstmann-Straussler-Scheinker disease. In some embodiments, the condition is Hallervorden-Spatz disease. In some embodiments, the condition is inclusion body myositis. In some embodiments, the condition is multiple system atrophy (MSA). In some embodiments, the condition is myotonic dystrophy. In some embodiments, the condition is Niemann-Pick disease type C. In some embodiments, the condition is non-Guam motor neuron disease with neurofibrillary tangles. In some embodiments, the condition is postencephalitic Parkinson's disease. In some embodiments, the condition is prion protein cerebral amyloid angiopathy. In some embodiments, the condition is progressive subcortical gliomatosis. In some embodiments, the condition is progressive supranuclear palsy. In some embodiments, the condition is subacute sclerosing panencephalitis. In some embodiments, the condition is pure tangle dementia. In some embodiments, the condition is multi-infarct dementia. In some embodiments, the condition is ischemic stroke. In some embodiments, the condition is chronic traumatic encephalopathy (CTE).

[0203] In some embodiments, the condition is hereditary motor and sensory neuropathy (HMSN). In some embodiments, HMSN is Charcot-Marie-Tooth (CMT) disease. In some embodiments, HSMN is Charcot-Marie-Tooth disease type 1A or 1B. In some embodiments, HSMN is Charcot-Marie-Tooth disease type 2. In some embodiments, HSMN is Dejerine-Sottas disease (Charcot-Marie-Tooth disease type 3). In some embodiments, HSMN is Refsum disease. In some embodiments, HSMN is Charcot-Marie-Tooth disease with pyramidal features. In some embodiments, HSMN is Charcot-Marie-Tooth disease type 6. In some embodiments, HSMN is HMSN plus retinitis pigmentosa.

[0204] In some embodiments, the condition is Churg-Strauss syndrome. In some embodiments, the condition is peripheral arterial disease (PAD). In some embodiments, the condition is myasthenia gravis, such as myasthenia gravis involving the CNS. In some embodiments, the condition is dementia with Lewy bodies. In some embodiments, the condition is a prion disease. In some embodiments, the condition is Behçet's disease. In some embodiments, the condition is congenital myasthenia. In some embodiments, the condition is subacute sclerosing panencephalitis (SSPE).

[0205] In some embodiments, the disorder is a demyelinating disease. In some embodiments, the disorder is a demyelinating myelin-destroying disease. In some embodiments, the disorder is a demyelinating leukodystrophy disease.

[0206] In some embodiments, the demyelinating myelin destruction disease is multiple sclerosis (MS). Multiple sclerosis (MS) is the most common cause of neurological dysfunction in young people of Northern European Caucasian descent, with a lifetime risk of approximately one in four hundred. C3 has been shown to deposit in the brains of MS patients. T cell clones (TCCs) have been shown to be associated with capillary endothelial cells, primarily located within plaques and adjacent white matter. C activation has also been shown to localize to areas of active myelin destruction, with TCCs specifically deposited in such areas. C3d deposition has been shown to be associated with short fragments of damaged myelin in low-activity demyelinating plaques, and C3d provides evidence for C's contribution to disease progression and 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.

[0207] In some embodiments, the demyelinating myelin-destroying disease is neuromyelitis optica (NMO). Neuromyelitis optica (NMO) is an inflammatory demyelinating disease that primarily affects the optic nerve and spinal cord. Traditionally considered a variant of MS, it has recently been redefined based on new criteria using a combination of phenotypic subtyping and the newly developed disease biomarker NMO-immunoglobulin G (IgG), which has a reported sensitivity of 58-76% and a specificity of 85–99% for NMO. Patients with NMO have higher levels of C3a and anti-C1q antibodies than healthy controls. C3a levels correlate with disease activity, neurological impairment, and aquaporin-4 IgG. Nytrova et al. J Neuroimmunol. 2014 Sep 15;274(1-2):185-91.

[0208] In some embodiments, the demyelinating myelin destructive disease is neuromyelitis optica spectrum disorder (NMOSD). In some embodiments, the demyelinating myelin destructive disease is idiopathic inflammatory demyelinating disease (IIDD). In some embodiments, the demyelinating myelin destructive disease is anti-NMDA receptor encephalitis. In some embodiments, the demyelinating myelin destructive disease is acute disseminated encephalomyelitis. In some embodiments, the demyelinating myelin destructive disease is anti-MOG autoimmune encephalomyelitis. In some embodiments, the demyelinating myelin destructive disease is chronic relapsing inflammatory optic neuritis (CRION). In some embodiments, the demyelinating myelin destructive disease is acute disseminated encephalomyelitis (ADEM). In some embodiments, the demyelinating myelin destructive disease is immune-mediated encephalomyelitis. In some embodiments, the demyelinating myelin destructive disease is progressive multifocal leukoencephalopathy (PML). In some embodiments, the demyelinating myelin destructive disease is McDonalds-positive multiple sclerosis. In some embodiments, the demyelinating myelin destructive disease is acute hemorrhagic leukoencephalitis. In some embodiments, the demyelinating myelin destructive disease is Rasmussen's Encephalitis. In some embodiments, the demyelinating myelin destructive disease is Marburg multiple sclerosis. In some embodiments, the demyelinating myelin destructive disease is pseudotumescent or tumescent multiple sclerosis. In some embodiments, the demyelinating myelin destructive disease is Balo's concentric sclerosis. In some embodiments, the demyelinating myelin destructive disease is diffuse myelin destructive sclerosis. In some embodiments, the demyelinating myelin destructive disease is isolated sclerosis. In some embodiments, the demyelinating myelin destructive disease is multiple sclerosis with cavitary lesions. In some embodiments, the demyelinating myelin destructive disease is spinal cortical multiple sclerosis (MCMS). In some embodiments, the demyelinating myelin destructive disease is atypical optic spinal multiple sclerosis. In some embodiments, the demyelinating myelin-destroying disease is simple spinal multiple sclerosis. In some embodiments, the demyelinating myelin-destroying disease is HLA DRB3*02:02 multiple sclerosis. In some embodiments, the demyelinating myelin-destroying cell disease is autoimmune GFAP astrocytopathy. In some embodiments, the demyelinating myelin-destroying disease is chronic inflammatory demyelinating polyneuropathy (CIDP). In some embodiments, the demyelinating myelin-destroying disease is Guillain–Barré syndrome (acute or chronic). In some embodiments, the demyelinating myelin-destroying disease is progressive inflammatory neuropathy.In some embodiments, the demyelinating myelin destructive disease is Lewis-Sumner Syndrome. In some embodiments, the demyelinating myelin destructive disease is combined central and peripheral demyelination (CCPD). In some embodiments, the demyelinating myelin destructive disease is Bickerstaff brainstem encephalitis. In some embodiments, the demyelinating myelin destructive disease is Fisher syndrome. In some embodiments, the demyelinating myelin destructive disease is trigeminal neuralgia. In some embodiments, the demyelinating myelin destructive disease is NMDAR anti-NMDA receptor encephalitis. In some embodiments, the demyelinating myelin destructive disease is primary progressive MS (PPMS). In some embodiments, the demyelinating myelin destructive disease is OPA1 variant multiple sclerosis. In some embodiments, the demyelinating myelin destructive disease is KIR4.1 multiple sclerosis. In some embodiments, the demyelinating myelin-destroying disease is aquaporin-associated multiple sclerosis. In some embodiments, the demyelinating myelin-destroying disease is chronic cerebrospinal venous insufficiency (CCSVI or CCVI). In some embodiments, the demyelinating myelin-destroying disease is diffuse sclerosis. In some embodiments, the demyelinating myelin-destroying disease is Schilder's disease.

[0209] In certain aspects, the condition to be treated is a demyelinating leukodystrophy disease. In some embodiments, the demyelinating leukodystrophy disease is myelitis. In some embodiments, the demyelinating leukodystrophy disease is central pontine myelinolysis (CPM). In some embodiments, the demyelinating leukodystrophy disease is extrapontine myelinolysis. In some embodiments, the demyelinating leukodystrophy disease is tabes dorsalis (tabesdorsalis). In some embodiments, the demyelinating leukodystrophy disease is progressive multifocal leukoencephalopathy. In some embodiments, the demyelinating leukodystrophy disease is white matter ablative leukoencephalopathy. In some embodiments, the demyelinating leukodystrophy disease is leukoencephalopathy with axonal spheroids. In some embodiments, the demyelinating leukodystrophy disease is reversible posterior leukoencephalopathy syndrome. In some embodiments, the demyelinating leukodystrophy disease is megalencephalic leukodystrophy with subcortical cysts. In some embodiments, the demyelinating leukodystrophy disease is megalencephalic leukodystrophy 1 with subcortical cysts. In some embodiments, the demyelinating leukodystrophy disease is hypertensive leukodystrophy. In some embodiments, the demyelinating leukodystrophy disease is metachromatic leukodystrophy. In some embodiments, the demyelinating leukodystrophy disease is Krabbe disease. In some embodiments, the demyelinating leukodystrophy disease is Canavan disease. In some embodiments, the demyelinating leukodystrophy disease is X-linked adrenoleukodystrophy. In some embodiments, the demyelinating leukodystrophy disease is Alexander disease. In some embodiments, the demyelinating leukodystrophy disease is cerebrotendinous xanthomatosis. In some embodiments, the demyelinating leukodystrophy disease is Pelizaeus–Merzbacher disease. In some embodiments, the demyelinating leukodystrophy disease is Refsum disease.

[0210] 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.

[0211] 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.

[0212] 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.

[0213] In certain aspects, the condition 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 a hereditary neuropathy with a tendency to compressive paralysis. In some embodiments, the demyelinating disease of the peripheral nervous system is a copper deficiency-related condition (e.g., peripheral neuropathy, myelopathy, or rare optic neuropathy).

[0214] In some embodiments, an effective amount of an active compound described herein, or a pharmaceutically acceptable salt thereof, is used to treat transverse myelitis.

[0215] In certain aspects, the condition to be treated is peripheral neuropathy. In some embodiments, the peripheral neuropathy is mononeuropathy. In some embodiments, the neuropathy is polyneuropathy. In some embodiments, the polyneuropathy is distal axonopathy, diabetic neuropathy, demyelinating polyneuropathy, small fiber peripheral neuropathy, multiple mononeuritis, multiple polyneuritis, autonomic neuropathy, or neuritis.

[0216] 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.

[0217] In some embodiments, an effective amount of an active compound as 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, Behcet's disease ( disease), Kawasaki disease, Berger's disease, and "limited" granulomatosis with polyangiitis.

[0218] In some embodiments, an active compound as 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 an arteritis. In some embodiments, the arteritis is giant cell arteritis. In some embodiments, the arteritis is Takayasu arteritis. In some embodiments, the arteritis is temporal arteritis. In some embodiments, the arteritis is polyarteritis nodosa.

[0219] 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 type I MPGN. In some embodiments, the MPGN is type II MPGN. In some embodiments, the MPGN is type III MPGN. 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 C4 deposit disorder.

[0220] 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, such as type I (Goodpasture syndrome), type II, or type III rapidly progressive glomerulonephritis.

[0221] In some embodiments, a method for treating paroxysmal nocturnal hemoglobinuria (PNH) is provided, comprising administering to a subject an effective amount of a compound disclosed herein (e.g., any of Formula (I), (I'), (II), (IIA), (III), (IIIA), (IV), (IVA), (V), (VA), (VB), (VC), (VI), (VIA), (VIB), (VIC), and (VII), and compounds of Table 1), or a pharmaceutically acceptable salt thereof, optionally in the form of a pharmaceutically acceptable composition.

[0222] 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 of Formula (I), (I'), (II), (IIA), (III), (IIIA), (IV), (IVA), (V), (VA), (VB), (VC), (VI), (VIA), (VIB), (VIC), and (VII), and compounds of Table 1), or a pharmaceutically acceptable salt thereof, optionally in the form of a pharmaceutically acceptable composition. Mutations in the SERPING1 gene cause hereditary angioedema types I and II. Hereditary angioedema is a condition characterized by recurring episodes of severe swelling (angioedema). The most common areas of the body where swelling occurs are the extremities, face, intestines, and airways. The SERPING1 gene provides instructions for making the C1 inhibitor protein, which is important for controlling inflammation. C1 inhibitor blocks the activity of certain proteins that promote inflammation. Mutations that cause hereditary angioedema type I result in low levels of C1 inhibitor in the blood, while mutations that cause type II result in the production of dysfunctional C1 inhibitor. Without adequate levels of functional C1 inhibitor, excess amounts of a protein fragment (peptide) called bradykinin are produced. Bradykinin promotes inflammation by increasing the leakage of fluid through blood vessel walls into body tissues. Excess fluid accumulation in body tissues causes swelling in individuals with hereditary angioedema types I and II.

[0223] In some embodiments, a method for treating cold agglutinin disease (CAD) is provided, comprising administering to a subject an effective amount of a compound disclosed herein (e.g., any of Formula (I), (I'), (II), (IIA), (III), (IIIA), (IV), (IVA), (V), (VA), (VB), (VC), (VI), (VIA), (VIB), (VIC), and (VII), and compounds of Table 1), or a pharmaceutically acceptable salt thereof, optionally in the form of a pharmaceutically acceptable composition. CAD is a rare autoimmune hemolytic condition with potentially severe acute and chronic consequences that is driven by C1 activation of the classical complement pathway.

[0224] In some embodiments, a method for treating atypical hemolytic uremic syndrome (aHUS) is provided, comprising administering to a subject an effective amount of a compound disclosed herein (e.g., any of Formula (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 the form of a pharmaceutically acceptable composition. Atypical hemolytic uremic syndrome is a disease that primarily affects kidney function. Atypical hemolytic uremic syndrome can occur at any age and causes abnormal blood clots (thrombi) to form in the small blood vessels of the kidneys. If these clots restrict or block blood flow, serious medical problems can result. Atypical hemolytic uremic syndrome is characterized by three main features related to abnormal coagulation: hemolytic anemia, thrombocytopenia, and kidney failure.

[0225] In another embodiment, a method for treating wet or dry age-related macular degeneration (AMD) in a subject is provided, comprising administering to the subject an effective amount of a compound disclosed herein (e.g., any one of Formula (I), (I'), (II), (IIA), (III), (IIIA), (IV), (IVA), (V), (VA), (VB), (VC), (VI), (VIA), (VIB), (VIC), and (VII), and compounds of Table 1), or a pharmaceutically acceptable salt thereof, optionally in the form of a pharmaceutically acceptable composition. In another embodiment, a method for treating rheumatoid arthritis in a subject is provided, comprising administering to the subject an effective amount of a compound disclosed herein (e.g., any one of Formula (I), (I'), (II), (IIA), (III), (IIIA), (IV), (IVA), (V), (VA), (VB), (VC), (VI), (VIA), (VIB), (VIC), and (VII), and compounds of Table 1), or a pharmaceutically acceptable salt thereof, optionally in the form of a pharmaceutically acceptable composition.

[0226] In another embodiment, a method for treating multiple sclerosis in a subject is provided, comprising administering to the subject an effective amount of a compound disclosed herein (e.g., any of Formula (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 the form of a pharmaceutically acceptable composition.

[0227] The active compounds disclosed herein, or pharmaceutically acceptable salts thereof, can also be used in combination (in the same or different dosage forms) or in alternating administration with a second pharmaceutical agent to improve or reduce the side effects of the second pharmaceutical agent.

[0228] For example, in some embodiments, the active compounds can be used in combination with adoptive cell transfer therapy to reduce inflammatory responses associated with such therapy, eg, cytokine-mediated responses such as cytokine response syndrome.

[0229] In some embodiments, the adoptive cell transfer therapy is chimeric antigen receptor T cells (CAR T) or dendritic cells for the treatment of hematological or solid tumors, such as B cell-related hematological cancers.

[0230] 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.

[0231] In some embodiments, the adoptive cell transfer therapy is a non-engineered T cell therapy in which the T cells have been activated and / or expanded to one or more viral or tumor antigens. In some embodiments, the associated inflammatory response is a cytokine-mediated response.

[0232] In some embodiments, the second pharmaceutical agent is a cell that has been transformed to express a protein, wherein the protein in the subject is mutated or otherwise has impaired function. In some embodiments, the transformed cell comprises a CRISPR gene.

[0233] Another embodiment is provided that 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 the form of a pharmaceutically acceptable composition, to treat an ocular, pulmonary, gastrointestinal, or other condition.

[0234] 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 compounds of Table 1) can be used to treat or prevent a complement-mediated disorder in a subject. As an example, the present disclosure includes methods for treating or preventing a complement-associated disorder induced by an antibody-antigen interaction, a component of an immune or autoimmune disorder, or by ischemic injury. The present disclosure also provides methods for reducing inflammation or immune responses (including autoimmune responses) mediated or influenced by the classical complement pathway.

[0235] In some embodiments, the condition is selected from fatty liver and conditions derived from fatty liver, such as non-alcoholic steatohepatitis (NASH), liver inflammation, cirrhosis, and liver failure. In some embodiments of the present disclosure, a method of treating fatty liver disease in a subject is provided by administering an effective amount of an active compound as 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.

[0236] In another embodiment, an active compound as 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 an immune response prior to or during surgery or other medical procedures. A non-limiting example is use in connection with acute or chronic graft versus host disease, a common complication resulting from organ transplantation, allogeneic tissue transplantation, and can also occur as a result of blood transfusions.

[0237] In some embodiments, the present disclosure provides a method of treating dermatomyositis by administering to a subject in need thereof an effective amount of an active compound as 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.

[0238] In some embodiments, the present disclosure provides a method of treating amyotrophic lateral sclerosis by administering to a subject in need thereof an effective amount of an active compound as 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.

[0239] In some embodiments, the present disclosure provides a method 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 as 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.

[0240] In another embodiment, a method of treating or preventing a cytokine or inflammatory response in response to administration of a drug or biotherapeutic (e.g., CAR T cell therapy or monoclonal antibody therapy) in a subject is provided by administering an effective amount of an active compound as 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. Various types of cytokine or inflammatory responses may occur in response to a variety of factors, such as the administration of a biotherapeutic.

[0241] 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 results in cytokine release). Symptoms of cytokine release syndrome range from fever, headache, and rash to bronchospasm, hypotension, and even cardiac arrest. Severe cytokine release syndrome is described as a cytokine storm and may be fatal.

[0242] Fatal cytokine storms have been observed in response to 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. "Invivo 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.

[0243] Also contemplated herein are the use of an active compound as 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, for mediating adverse immune responses in a patient receiving a bispecific T cell engager (BiTE). Bispecific T cell engagers direct T cells to target and bind to specific antigens on the surface of cancer cells. For example, blinatumomab (Amgen), a BiTE, was recently approved as a second-line therapy for Philadelphia chromosome-negative relapsed or refractory acute lymphoblastic leukemia. Blinatumomab is administered by continuous intravenous infusion in 4-week cycles. The use of BiTE agents has been associated with adverse immune responses, including cytokine release syndrome. The most significantly elevated cytokines 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).

[0244] In another embodiment, the condition is episcleritis, idiopathic episcleritis, anterior episcleritis, or posterior episcleritis. In some embodiments, the condition is idiopathic anterior uveitis, HLA-B27-associated uveitis, herpes keratouveitis, Posner Schlossman syndrome, Fuch's heterochromic iridocyclitis, or cytomegalovirus anterior uveitis.

[0245] In some embodiments, the present disclosure provides a method of treating IC-MPGN by administering to a subject in need thereof an effective amount of an active compound as 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.

[0246] 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 as 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.

[0247] In some embodiments, the present disclosure provides a method of treating hereditary angioedema (HAE) by administering to a subject in need thereof an effective amount of an active compound as 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.

[0248] In some embodiments, the present disclosure provides a method of treating cold agglutinin disease (CAD) by administering to a subject in need thereof an effective amount of an active compound as 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.

[0249] 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 as 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.

[0250] In some embodiments, the present disclosure provides a method of treating age-related macular degeneration (AMD) by administering to a subject in need thereof an effective amount of an active compound as 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.

[0251] In some embodiments, the present disclosure provides a method of treating rheumatoid arthritis by administering to a subject in need thereof an effective amount of an active compound as 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.

[0252] In some embodiments, the present disclosure provides a method of treating multiple sclerosis by administering to a subject in need thereof an effective amount of an active compound as 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.

[0253] In some embodiments, the present disclosure provides a method of treating myasthenia gravis by administering to a subject in need thereof an effective amount of an active compound as 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.

[0254] 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 as 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.

[0255] In another embodiment, the present disclosure provides a method of treating a condition as described below, including: vitritis, sarcoidosis, syphilis, tuberculosis, or Lyme disease; retinal vasculitis, Eales disease, tuberculosis, syphilis, or toxoplasmosis; optic neuritis, viral retinitis, or acute retinal necrosis; varicella zoster virus, herpes simplex virus, cytomegalovirus, Epstein-Barr virus, lichen planus, or dengue-related diseases (e.g., hemorrhagic dengue); masquerade syndrome, contact dermatitis, trauma-induced inflammation, UVB-induced inflammation, eczema, granuloma annulare, or acne, by administering to a subject in need thereof an effective amount of an active compound as 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.

[0256] In another embodiment, the condition is selected from the group consisting of acute myocardial infarction, aneurysm, cardiopulmonary bypass, dilated cardiomyopathy, complement activation during cardiopulmonary bypass surgery, coronary artery disease, restenosis after stent placement, or percutaneous transluminal coronary angioplasty (PTCA); antibody-mediated transplant rejection, anaphylactic shock, allergic reaction, allograft, humoral and vascular transplant rejection, graft dysfunction, graft-versus-host disease, Graves' disease, adverse drug reaction, or chronic allograft vasculopathy; allergic bronchopulmonary aspergillosis, allergic neuritis, drug hypersensitivity, radiation-induced lung injury, eosinophilic pneumonia, radiographic contrast allergy, bronchiolitis obliterans, or interstitial lung disease combined parkinsonian dementia, sporadic frontotemporal dementia, frontotemporal dementia with Parkinsonism linked to chromosome 17, frontotemporal lobar degeneration, pure tangle dementia, cerebral amyloid angiopathy, cerebrovascular disorders, 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 Parkinson's disease, subacute sclerosing panencephalitis, non-Guam motor neuron disease with neurofibrillary tangles, neurogenesis, and diffuse neurofibrillary tangles with calcifications.

[0257] In some embodiments, the disorder is selected from the group consisting of atopic dermatitis, dermatitis, dermatomyositis bullous pemphigoid, scleroderma, scleroderma myositis, psoriatic arthritis, pemphigus vulgaris, discoid lupus erythematosus, cutaneous lupus, pernio lupus erythematosus, or lupus erythematosus-lichen planus overlap syndrome; cryoglobulin vasculitis, mesenteric / intestinal vascular disorders, peripheral vascular disorders, anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), IL-2-induced vascular leak syndrome, immune complex vasculitis, angioedema, low platelets (HELLP) syndrome, sickle cell disease, platelet refractoriness, red cell casts, and vasculitis. casts), or classic or infectious hemolytic uremic syndrome (tHUS); hematuria, hemorrhagic shock, drug-induced thrombocytopenia, autoimmune hemolytic anemia (AIHA), azotemia, vascular and / or lymphangiitis, coronary artery rotational atherectomy, or delayed hemolytic transfusion reaction; British amyloid angiopathy, Burger's disease, bullous pemphigoid, C1q nephropathy, cancer, and catastrophic antiphospholipid syndrome. In some embodiments, the disorder is an autoimmune hemolytic anemia, such as warm autoimmune hemolytic anemia.

[0258] In another embodiment, the condition is selected from the group consisting of wet (exudative) AMD, dry (non-exudative) AMD, chorioretinal degeneration, choroidal neovascularization (CNV), choroiditis, loss of RPE function, vision loss (including loss of visual acuity or visual field), vision loss due to AMD, light-induced retinal damage, retinal degeneration, retinal detachment, retinal dysfunction, retinal neovascularization (RNV), retinopathy of prematurity, pathological myopia, or RPE degeneration; pseudophakic bullous keratopathy, symptomatic macular degeneration-related conditions, optic nerve degeneration, photoreceptor degeneration, cone degeneration, photoreceptor cell loss, pars planitis, scleritis, proliferative vitreoretinopathy, or formation of ocular drusen; chronic urticaria, Chargar-Strauss syndrome, cold agglutinin disease (CAD), corticobasal degeneration (CBD), cryoglobulinemia, cyclitis, damage of the Bruch's membrane, or ocular drusen formation. Bruch's membrane), Degos' disease, diabetic vasculopathy, elevated liver enzymes, endotoxemia, epidermolysis bullosa or acquired epidermolysis bullosa; primary mixed cryoglobulinemia, elevated blood urea nitrogen (BUN), focal segmental glomerulosclerosis, Gerstmann-Straussler-Schenck disease, giant cell arteritis, gout, Hallervorden-Spatz disease, Hashimoto's thyroiditis thyroiditis), Henoch-Schonlein purpura nephritis or abnormal urine residue; hepatitis, hepatitis A, hepatitis B, hepatitis C or human immunodeficiency virus (HIV), more generally a viral infection, for example selected from the families Flaviviridae, Retroviruses, Coronaviridae, Poxviridae, Adenoviridae, Herpesviridae, Caliciviridae, Reoviridae, Picornaviridae, Togaviridae, Orthomyxoviridae, Rhabdoviridae, or Hepadnaviridae; Neisseria meningitidis meningitidis), Shiga toxin-producing Escherichia coli-associated hemolytic uremic syndrome (STEC-HUS), hemolytic uremic syndrome (HUS);Streptococcus and post-streptococcal glomerulonephritis;

[0259] In yet another embodiment, the disorder is selected from the group consisting of: hyperlipidemia, hypertension, hypoalbuminemia, hypovolemic shock, hypocomplementary urticarial vasculitis syndrome, hypophosphastasis, hypovolemic shock, idiopathic pneumonia syndrome, or idiopathic pulmonary fibrosis; inclusion body myositis, intestinal ischemia, iridocyclitis, iritis, juvenile chronic arthritis, Kawasaki disease (arteritis), or lipiduria; membranoproliferative glomerulonephritis (MPGN) I, microscopic polyangiitis, mixed cryoglobulinemia, type A molybdenum cofactor deficiency (MoCD), pancreatitis, sebaceous laminitis, Pick's disease, polyarteritis nodosa (PAN), progressive subcortical gliomatosis, proteinuria, renal Decreased glomerular filtration rate (GFR), or renovascular disorder; 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, spondyloarthropathies, 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).

[0260] In some embodiments, an active compound as 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, can be used to treat a condition selected from the group consisting of autoimmune oophoritis, endometriosis, autoimmune orchitis, Ord's thyroiditis, autoimmune bowel disease, 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 dolorosa (Dercum's disease), adult Still's disease, onset Still's disease), ankylosing spondylitis, CREST syndrome, drug-induced lupus, eosinophilic fasciitis (Shulman's syndrome), Felty syndrome, IgG4-related disease, mixed connective tissue disease (MCTD), relapsing rheumatic disease (Hench-Rosenberg syndrome), Parry-Romberg syndrome, Parsonage-Turner syndrome, relapsing polychondritis (Meyenburg-Altherr-Uehlinger syndrome), retroperitoneal fibrosis, rheumatic fever, Schnitzler syndrome, fibromyalgia, neuromyotonia (Isaac's disease), paraneoplastic degeneration, autoimmune inner ear disease, Meniere's disease, interstitial cystitis, autoimmune pancreatitis, Zika virus-related disorders, chikungunya virusvirus-related diseases, subacute bacterial endocarditis (SBE), IgA nephropathy, IgA vasculitis, polymyalgia rheumatica, rheumatoid vasculitis, alopecia areata, autoimmune progesterone dermatitis, dermatitis herpetiformis, erythema nodosum, pemphigoid gestationis, hidradenitis suppurativa, lichen sclerosus, linear IgA disease (LAD), localized scleroderma, myositis, acute lichen varicocele, vitiligo, post-myocardial infarction syndrome (Dressler syndrome), postpericardiotomy syndrome, autoimmune retinopathy, Cogan syndrome, Graves' ophthalmopathy, woody conjunctivitis, Mooren's ulcer, opsoclonus-myoclonus syndrome, optic neuritis, retino-cochlear cerebrovascular disease (Susac syndrome), sympathetic ophthalmia, Tolosa-Hunt syndrome, interstitial lung disease, antisynthetase syndrome, Addison's disease disease), autoimmune polyendocrine syndrome (APS) type I, autoimmune polyendocrine syndrome (APS) type II, autoimmune polyendocrine syndrome (APS) type III, disseminated sclerosis (multiple sclerosis, type II), rapidly progressive glomerulonephritis (RPGN), juvenile rheumatoid arthritis, enthesitis-related arthritis, reactive arthritis (Reiter's syndrome), autoimmune hepatitis or lupus-like 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, Balo's concentric sclerosis (Schilders' disease), Bickerstaff's encephalitis, chronic inflammatory demyelinating polyneuropathy, idiopathic inflammatory demyelinating disease, Lambert-Eaton myasthenic syndrome, Oshtoran syndrome, pediatric autoimmune neuropsychiatric disorders associated with streptococci (PANDAS), progressive inflammatory neuropathy, restless legs syndrome, stiff-person syndrome, Sydenhem syndrome, transverse myelitis, lupus vasculitis, leukocytoclastic vasculitis, microscopic polyangiitis, polymyositis, and ocular ischemia-reperfusion injury.

[0261] Examples of ocular conditions that can be treated according to the compositions and methods disclosed herein include amoebic keratitis, fungal keratitis, bacterial keratitis, viral keratitis, onchocercal keratitis, bacterial keratoconjunctivitis, viral keratoconjunctivitis, corneal dystrophic diseases, Fuchs' endothelial dystrophy, Sjogren's syndrome, Stevens-Johnson syndrome, and keratitis. syndrome), autoimmune dry eye, environmental dry eye, corneal neovascular disease, prevention and treatment of corneal transplant rejection, 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.

[0262] In yet another embodiment, the disorder is selected from glaucoma, diabetic retinopathy, blistering skin diseases (including bullous pemphigoid, pemphigus, and epidermolysis bullosa), ocular cicatricial pemphigoid, uveitis, adult macular degeneration, diabetic retinopathy, retinitis pigmentosa, macular edema, diabetic macular edema, Behçet's uveitis, multifocal choroiditis, Vogt-Koyanagi-Harada syndrome, intermediate uveitis, birdshot retinochorioditis, sympathetic ophthalmia, ocular cicatricial pemphigoid, pemphigus ocular, non-arteritic ischemic optic neuropathy, postoperative inflammation, and retinal vein occlusion, and central retinal vein occlusion (CVRO).

[0263] In some embodiments, a method of treating an autoimmune blistering disease in a subject is provided, comprising administering an effective amount of an active compound as 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.

[0264] In some embodiments, a method of treating bullous pemphigoid in a subject is provided, comprising administering an effective amount of an active compound as 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.

[0265] 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 useful for treating diseases and disorders related to fatty acid metabolism, including obesity and other metabolic disorders.

[0266] In some embodiments, a method of treating geographic atrophy in a subject is provided, comprising administering an effective amount of an active compound as 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.

[0267] Conditions that can be treated or prevented by an active compound as 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, but are not limited to, hereditary angioedema, capillary leak syndrome, hemolytic uremic syndrome (HUS), neurological disorders, Guillain-Barré Syndrome, central nervous system diseases, and the like. other neurodegenerative conditions, glomerulonephritis (including membranoproliferative glomerulonephritis), SLE nephritis, proliferative nephritis, liver fibrosis, tissue regeneration and nerve regeneration, or Barraquer-Simons syndrome; inflammatory effects of sepsis, systemic inflammatory response syndrome (SIRS), disorders of inappropriate or adverse complement activation, interleukin-2 induced toxicity during IL-2 therapy, inflammatory disorders, inflammation of 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 conditions, balloon angioplasty, atherosclerosis, post-pump syndrome in cardiopulmonary bypass or renal shunt, renal ischemia, mesenteric artery reperfusion after aortic reconstruction, antiphospholipid syndrome, autoimmune heart disease, ischemic reperfusion injury, obesity or diabetes; Alzheimer's dementia, stroke, schizophrenia, traumatic brain injury, trauma, Parkinson's disease, epilepsy, transplant rejection, prevention of miscarriage, biomaterial reaction (e.g., in hemodialysis, implants), hyperacute allograft rejection, xenograft rejection, transplantation, psoriasis, burns, thermal injury, including burns or frostbite, or crush injuries; asthma, allergies, acute respiratory distress syndrome (ARDS) RDS), cystic fibrosis, adult respiratory distress syndrome, dyspnea, hemoptysis, chronic obstructive pulmonary disease (COPD), emphysema, pulmonary embolism and infarction, pneumonia, fibrous dust diseases, inert dusts and minerals (e.g., silica, coal dust, beryllium, and asbestos), pulmonary fibrosis, organic dust diseases, chemical injury (due to irritant gases and chemicals such as chlorine, phosgene, sulfur dioxide, hydrogen sulfide, nitrogen dioxide, ammonia, and hydrochloric acid), smoke injury, thermal injury (e.g., burns, frostbite), bronchoconstriction, hypersensitivity pneumonitis, parasitic diseases, Goodpasture's syndrome (anti-glomerular basement membrane nephritis), pulmonary vasculitis, pauci-immune vasculitis, and immune complex-associated inflammation.

[0268] In some embodiments, a method of treating sickle cell disease in a subject is provided, comprising administering an effective amount of an active compound as 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.

[0269] In some embodiments, a method of treating immune thrombocytopenic purpura (ITP), thrombotic thrombocytopenic purpura (TTP), or idiopathic thrombocytopenic purpura (ITP) in a subject is provided, comprising administering an effective amount of an active compound as 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. In some embodiments, a method of treating immune thrombocytopenic purpura (ITP).

[0270] In some embodiments, a method of treating ANCA-vasculitis in a subject is provided, comprising administering an effective amount of an active compound as 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.

[0271] In some embodiments, a method of treating IgA nephropathy in a subject is provided, comprising administering an effective amount of an active compound as 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.

[0272] In some embodiments, a method of treating rapidly progressive glomerulonephritis (RPGN) in a subject is provided, comprising administering an effective amount of an active compound as 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.

[0273] In some embodiments, a method of treating lupus nephritis in a subject is provided, comprising administering an effective amount of an active compound as 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.

[0274] In some embodiments, a method of treating hemorrhagic dengue in a subject is provided, comprising administering an effective amount of an active compound as 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.

[0275] In another alternative embodiment, an active compound as 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 an autoimmune disorder. The complement pathway enhances the ability of antibodies and phagocytes to clear microorganisms and damaged cells from the body. It is part of the innate immune system and is an essential process in healthy individuals. Inhibiting the complement pathway reduces the body's immune system response. Therefore, one object of the present disclosure is to treat an autoimmune disorder by administering an effective dose of an active compound as 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.

[0276] In some embodiments, the autoimmune disorder is caused by the activity of the complement system. In some embodiments, the autoimmune disorder is caused by the activity of the alternative complement pathway. In some embodiments, the autoimmune disorder is caused by the activity of the classical complement pathway. In another embodiment, the autoimmune disorder is caused by a mechanism of action not directly related to the complement system, such as excessive proliferation of T lymphocytes or excessive production of cytokines.

[0277] 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, Crohn's disease, and terminal ileitis), diabetes, multiple sclerosis, pernicious anemia, psoriasis, rheumatoid arthritis, sarcoidosis, and scleroderma.

[0278] In some embodiments, an active compound as 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 lupus. Non-limiting examples of lupus include lupus erythematosus, cutaneous lupus erythematosus, discoid lupus erythematosus, perniolar lupus erythematosus, and lupus erythematosus-lichen planus overlap syndrome.

[0279] Systemic lupus erythematosus (SLE) is a common disease that includes both systemic and dermatological symptoms. Systemic forms of the disease can have skin manifestations as well as systemic manifestations. However, there are also some forms of the disease that only involve the skin without systemic involvement. For example, SLE is an inflammatory disease of unknown etiology that occurs primarily in women and is characterized by joint symptoms, butterfly rash, recurrent pleurisy, pericarditis, systemic adenopathy, splenomegaly, and CNS (central nervous system) involvement and progressive renal failure. The serum of most patients (over 98%) contains antinuclear antibodies, including anti-DNA antibodies. High titers of anti-DNA antibodies are essentially specific for SLE. The conventional treatment of this disease is the administration of corticosteroids or immunosuppressants.

[0280] There are three forms of cutaneous lupus: chronic cutaneous lupus (also known as discoid lupus erythematosus or DLE), subacute cutaneous lupus, and acute cutaneous lupus. DLE is a disfiguring, chronic condition that primarily affects the skin, with well-defined macules and plaques that appear with erythema, clogged hair follicles, scaling, dilated capillaries, and atrophy. The condition is often triggered by light exposure, with early lesions appearing as erythematous, round, scaly papules 5 to 10 mm in diameter that show clogged hair follicles. DLE lesions most commonly appear on the cheeks, nose, scalp, and ears, but can also be more widespread on the upper trunk, extensor surfaces of the limbs, and oral mucosa. If left untreated, the central lesions atrophy and leave scars. Unlike SLE, antibodies to double-stranded DNA (e.g., DNA binding tests) are almost always absent in DLE.

[0281] Diabetes can refer to type 1 or type 2 diabetes. In some embodiments, an effective dose of an active compound as 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 provided to treat type 1 diabetes patients. In some embodiments, an effective dose of an active compound as 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 provided to treat type 2 diabetes patients. Type 1 diabetes is an autoimmune disease. Autoimmune diseases occur when the body's system for fighting infection (the immune system) attacks a part of the body. In the case of type 1 diabetes, the pancreas produces little or no insulin.

[0282] In some embodiments, the complement-mediated disease or disorder comprises transplant rejection. In some embodiments, the complement-mediated disease or disorder is antibody-mediated transplant rejection.

[0283] In certain aspects, an active compound as 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. Targeted cancers suitable 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, but are not limited to, estrogen receptor-positive cancers, HER2-negative advanced breast cancer, advanced 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 cancer and ovarian cancer, as well as lung and bronchial cancer, colon adenocarcinoma, rectal adenocarcinoma, central nervous system germ cell tumors, teratomas, estrogen receptor-negative breast cancer, estrogen receptor-positive breast cancer, familial testicular germ cell tumors, HER2-negative breast cancer, HER2-positive breast cancer, male breast cancer, immature ovarian teratoma, mature ovarian teratoma, monoblastic and highly specific ovarian teratomas, progesterone receptor-negative breast cancer, progesterone receptor-positive breast cancer, recurrent breast cancer, recurrent colon cancer, recurrent extragonadal germ cell tumor, recurrent extragonadal non-seminomatous germ cell tumor, recurrent extragonadal seminoma, recurrent malignant testicular germ cell tumor, recurrent melanoma, recurrent ovarian germ cell tumor, recurrent rectal cancer, stage III extragonadal non-seminomatous germ cell tumor, stage III extragonadal seminoma, stage III malignant testicular germ cell tumor, stage III ovarian germ cell tumor, stage IV breast cancer, stage IV colon cancer, stage IV extragonadal non-seminomatous germ cell tumor, stage IV extragonadal seminoma, stage IV melanoma, stage IV ovarian germ cell tumor, stage IV rectal cancer, immature testicular teratoma, mature testicular teratoma. In certain embodiments, targeted cancers include estrogen receptor-positive, HER2-negative advanced breast cancer, advanced 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, vaginal, and ovarian cancers, as well as lung and bronchial cancers, metastatic colorectal cancer, and CDK4-mutated or amplified metastatic melanoma.or cisplatin-refractory, unresectable germ cell tumors, lung cancer, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, skin or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, 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, urethra cancer, penile cancer, prostate cancer, bladder cancer, kidney or ureter cancer, renal cell carcinoma, renal pelvis cancer, neoplasms of the central nervous system (CNS), primary CNS lymphoma, spinal axis tumors, brainstem glioma, pituitary adenoma, fibrosarcoma, myxosarcoma, chondrosarcoma, osteosarcoma, chordoma, malignant fibrosarcoma Hemangiosarcoma, angiosarcoma, lymphangiosarcoma, mesothelioma, leiomyosarcoma, rhabdomyosarcoma, squamous cell carcinoma; epidermoid carcinoma, malignant skin adnexal tumor, adenocarcinoma, hepatocellular carcinoma, renal cell carcinoma, adrenal adenoma, bile duct carcinoma, transitional cell carcinoma, choriocarcinoma, seminoma, embryonal cell carcinoma, degenerative glioma; glioblastoma multiforme, neuroblastoma, medulloblastoma, malignant meningioma, malignant neurilemoma, neurofibrosarcoma, parathyroid carcinoma, medullary thyroid carcinoma, bronchial carcinoid, pheochromocytoma, pancreatic islet cell carcinoma, malignant carcinoid, malignant paraganglioma, melanoma, Merkel cell carcinoma cell) neoplasms, cystosarcoma phyllodes, salivary gland cancer, thymic cancer, bladder cancer and Wilms tumor, blood disorders or hematological malignancies, including but not limited to bone marrow disorders, lymphoid disorders, leukemias, lymphomas, myelodysplastic syndromes (MDS), myeloproliferative disorders (MPD), mast cell disorders and myeloma (e.g., multiple myeloma), among which T-cell or NK-cell lymphomas, such as but not limited to: peripheral T-cell lymphoma; anaplastic large cell lymphoma, such as anaplastic lymphoma kinase (ALK)-positive, ALK-negative anaplastic large cell lymphoma or primary cutaneous anaplastic large cell lymphoma; angioimmunoblastic lymphoma; cutaneous T-cell lymphoma,Examples include mycosis fungoides, Sézary syndrome, primary cutaneous degenerative 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-sized 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, such as lymphoma arising after solid organ or bone marrow transplantation; T-cell prolymphocytic leukemia; T-cell large granular lymphocytic leukemia; NK-cell chronic lymphoproliferative disorder; aggressive NK-cell leukemia; systemic EBV+ T-cell lymphoproliferative disorder of childhood (associated with chronic active EBV infection); vaccinia-like lymphoma; adult T-cell leukemia / lymphoma; enteropathy-associated T-cell lymphoma; hepatosplenic T-cell lymphoma; or subcutaneous lipitis-like T-cell lymphoma.

[0284] In some embodiments, the methods described herein can be used to treat a subject, such as a human, having a lymphoma or a lymphocyte or myeloproliferative disorder or abnormality. For example, the methods described herein can be administered to a subject having Hodgkin lymphoma or non-Hodgkin lymphoma. For example, the subject can have a non-Hodgkin lymphoma, such as, but not limited to: AIDS-related lymphoma; anaplastic large cell lymphoma; angioimmunoblastic lymphoma; blastic NK cell lymphoma; Burkitt's lymphoma; 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 T-cell lymphoma; pediatric lymphoma; peripheral T-cell lymphoma; primary central nervous system lymphoma; T-cell leukemia; transformed lymphoma; therapy-related T-cell lymphoma; or Waldenstrom's macroglobulinemia (WM) Hodgkin lymphoma, such as, but not limited to, tuberous sclerosis classical Hodgkin lymphoma (CHL); mixed cellularity CHL; lymphocyte-depleted CHL; lymphocyte-rich CHL; lymphocyte-predominant Hodgkin lymphoma; or nodular lymphocyte-predominant HL, specific B-cell lymphomas or proliferative disorders, such as, but not limited to, multiple myeloma; diffuse large B-cell lymphoma; follicular lymphoma; mucosa-associated lymphoid tissue lymphoma (MALT); small cell Lymphocytic lymphoma; mediastinal large B-cell lymphoma; nodular 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 variant; lymphoplasmacytic lymphoma; heavy chain disorders, e.g., alpha heavy chain disease, gamma heavy chain disease, mu heavy chain disease; plasma cell myeloma; solitary plasmacytoma of bone; extraskeletal plasmacytoma cytoma; primary cutaneous follicle-centered lymphoma; T-cell / histiocyte-rich large B-cell lymphoma; DLBCL associated with chronic inflammation; Epstein-Barr virus (EBV)+ DLBCL of the elderly; primary mediastinal (thymic) large B-cell lymphoma; primary cutaneous DLBCL, leg type; ALK+ large B-cell lymphoma; plasmablastic lymphoma; HHV8-associated multicentric large B-cell lymphoma; Castleman's disease; B-cell lymphoma, unclassifiable, with features intermediate between those of diffuse large B-cell lymphoma;or B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and classical Hodgkin lymphoma, leukemia, e.g., acute or chronic leukemia of lymphocytic or myeloid origin, such as, 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 (a subtype of AML); large granular lymphocytic leukemia; or adult T-cell chronic leukemia. In some embodiments, the patient has acute myeloid leukemia, such as undifferentiated AML (M0); myeloblastic leukemia (M1; with / without minimal cell maturation); myeloblastic leukemia (M2; with cell 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, HP V-positive malignancies (such as cervical cancer and certain head and neck cancers), MYC-amplified tumors (such as Burkitt's lymphoma), and triple-negative breast cancer; certain sarcomas, certain non-small cell lung cancers, certain melanomas, certain pancreatic cancers, certain leukemias, certain lymphomas, certain brain cancers, certain colon cancers, certain prostate cancers, certain ovarian cancers, certain uterine cancers, certain thyroid cancers and other endocrine tissue cancers, certain salivary gland cancers, certain thymic cancers, certain kidney cancers, certain bladder cancers, and certain testicular cancers.

[0285] In certain aspects, an active compound as 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, can be used to preserve an organ or blood product or to prevent damage to an organ or blood product. For example, an active compound as 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, can be used to prevent damage to an organ, tissue, cell product, or blood product harvested for transplantation. In some embodiments, the organ is 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.

[0286] In some embodiments, an active compound as 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, prevents or delays the onset of at least one symptom of a complement-mediated disease or condition in a subject. In some embodiments, an active compound as 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 condition in a subject. 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, kidney disease, transplant rejection, eye disease, vascular disease, or vasculitis. Symptoms can be neurological symptoms, such as impaired cognitive function, memory impairment, loss of motor function, etc. Symptoms can also be the activity of C1s protein in cells, tissues, or body fluids of an individual. Symptoms can also be the degree of complement activation in cells, tissues, or body fluids of an individual.

[0287] In some embodiments, administration of an active compound as 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 modulates complement activation in a cell, tissue, or body fluid of the subject. In some embodiments, administration of an active compound as 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 inhibits complement activation in a cell, tissue, or body fluid of the subject. For example, in some embodiments, an active compound as 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 a monotherapy or combination therapy to a subject having a complement-mediated disease or disorder, inhibits complement activation in the subject 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 subject prior to treatment with the compound described herein.

[0288] In some embodiments, an active compound as 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 deposition of C3 on red blood cells; for example, in some embodiments, an active compound as 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 deposition of C3b, iC3b, etc. on red blood cells (RBCs). In some embodiments, an active compound as 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 lysis of erythrocytes.

[0289] In some embodiments, an active compound as 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 deposition of C3 on platelets; for example, in some embodiments, an active compound as 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 deposition of C3b, iC3b, etc. on platelets.

[0290] In some embodiments, administration of an active compound as 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, results in a result selected from the group consisting of: (a) reduced complement activation; (b) improved cognitive function; (c) reduced neuronal loss; (d) reduced levels of phosphorylated Tau protein 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 thrombosis; (v) Improved coagulation; (w) Improved renal function; (x) Reduced antibody-mediated complement activation; (y) Reduced autoantibody-mediated complement activation; (z) Improved anemia; (aa) Reduced demyelination; (ab) Increased eosinophilia (ac) reduction in C3 deposition on erythrocytes (e.g., reduction in C3b, iC3b, etc. deposition on RBCs); and (ad) reduction in C3 deposition on platelets (e.g., reduction in C3b, iC3b, etc. deposition on platelets); and (ae) reduction in anaphylatoxin production; (af) reduction in autoantibody-mediated blister formation; (ag) reduction in autoantibody-induced pruritus; (ah) reduction in autoantibody-induced erythema; (ai) reduction in autoantibody-mediated skin erosions; (aj) reduction in erythrocyte destruction due to transfusion reactions; (ak) reduction in erythrocyte lysis due to alloantibodies; (al) reduction in hemolysis due to transfusion reactions; and (am) reduction in alloantibody-mediated hemolysis. (an) reduction in platelet lysis; (ao) reduction in platelet lysis due to transfusion reactions; (ap) reduction in mast cell activation; (aq) reduction in vascular permeability; (ar) reduction in edema; (as) reduction in complement deposition on graft endothelium; (at) reduction in anaphylatoxin production in graft endothelium; (au) reduction in dermal-epidermal junction separation; (av) reduction in anaphylatoxin production in the dermal-epidermal junction; (aw) reduction in alloantibody-mediated complement activation in graft endothelium; (ax) reduction in antibody-mediated loss of the neuromuscular junction; (ay) reduction in complement activation at the neuromuscular junction; (az) reduction in anaphylatoxin production at the neuromuscular junction;(ba) reduction in complement deposition at the neuromuscular junction; (bb) reduction in paralysis; (bc) reduction in numbness; (bd) increase in bladder control; (be) increase in bowel control; (bf) reduction in mortality associated with the autoantibody; and (bg) reduction in morbidity associated with the autoantibody.

[0291] In some embodiments, an active compound as 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 at one or more doses to a subject having a complement-mediated disease or disorder, is effective to achieve 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% of one or more of the following outcomes compared to the level or extent of the outcome in the subject prior to treatment with the active compound or salt thereof. , at least about 90% or greater reduction in: (a) complement activation; (b) cognitive decline; (c) neuronal loss; (d) levels of phosphorylated Tau protein in neurons; (e) glial cell activation; (f) lymphocyte infiltration; (g) macrophage infiltration; (h) antibody deposition, (i) glial cell loss; (j) oligodendrocyte loss; (k) dendritic cell infiltration; (l) neutrophil infiltration; (m) erythrocyte lysis; (n) erythrocyte phagocytosis; (o) platelet phagocytosis; (p) platelet lysis; (q) graft rejection; I macrophage-mediated phagocytosis; (s) visual loss; (t) antibody-mediated complement activation; (u) autoantibody-mediated complement activation; (v) demyelination; (w) eosinophilia.

[0292] In some embodiments, an active compound as 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 a subject having a complement-mediated disease or condition, is effective to achieve 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 in one or more of the following outcomes: a) cognitive function; b) graft survival; c) vision; d) motor control; e) thrombosis; f) coagulation; g) renal function; and h) hematocrit (red blood cell count), as compared to the level or extent of the outcome in the subject prior to treatment with the active compound or salt thereof.

[0293] In some embodiments, administration of an active compound as 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 reduces complement activation in the subject. For example, in some embodiments, an active compound as 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 a subject having a complement-mediated disease or disorder, reduces complement activation in the subject 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 subject prior to treatment with the active compound or salt thereof.

[0294] In some embodiments, administration of an active compound as 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 a subject. 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 a subject having a complement-mediated disease or condition, improves cognitive function in the subject 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 subject's cognitive function prior to treatment with the active compound or a salt thereof.

[0295] In some embodiments, administration of an active compound as 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 the rate of decline in cognitive function in a subject. 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 condition, 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 prior to treatment with the active compound or salt thereof.

[0296] In some embodiments, administration of an active compound as 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 reduces neuronal loss in the subject. 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 a subject having a complement-mediated disease or disorder, reduces neuronal loss in the subject 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 subject prior to treatment with the active compound or salt thereof.

[0297] In some embodiments, administration of an active compound as 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 reduces the level of phosphorylated Tau protein in the subject. 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 a subject having a complement-mediated disease or disorder, reduces phosphorylated Tau protein in the subject 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 phosphorylated Tau protein in the subject prior to treatment with the active compound or salt thereof.

[0298] In some embodiments, administration of an active compound as 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 reduces glial activation in the subject. 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 a subject having a complement-mediated disease or condition, reduces glial cell activation in the subject 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 subject prior to treatment with the active compound or salt thereof. In some embodiments, the glial cells are astrocytes or microglia.

[0299] In some embodiments, administration of an active compound as 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, or a composition thereof, to a subject reduces lymphocyte infiltration in the subject. 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 a subject having a complement-mediated disease or disorder, reduces lymphocyte infiltration in the subject 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 subject prior to treatment with the active compound or salt thereof.

[0300] In some embodiments, administration of an active compound as 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, or a composition thereof, to a subject reduces macrophage infiltration in the subject. 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 a subject having a complement-mediated disease or disorder, reduces macrophage infiltration in the subject 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 macrophage infiltration in the subject prior to treatment with the active compound or salt thereof.

[0301] In some embodiments, administration of an active compound as 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 reduces deposition of antibodies in the subject. 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 a subject having a complement-mediated disease or disorder, reduces deposition of an antibody in the subject 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 deposition of the antibody in the subject prior to treatment with the active compound or salt thereof.

[0302] In some embodiments, administration of an active compound as 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 reduces anaphylatoxin (e.g., C3a, C4a, C5a) production in the subject. 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 a subject having a complement-mediated disease or disorder, reduces anaphylatoxin production in the subject 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 subject prior to treatment with the active compound or salt thereof.

[0303] The present disclosure provides the 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, 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 of Table 1), or a salt thereof, and a pharmaceutically acceptable excipient for treating a subject suffering from a complement-mediated disease or disorder. In some embodiments, the present disclosure provides the 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, for treating a subject suffering from a complement-mediated disease or condition. In some embodiments, the present disclosure provides the 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 a subject suffering from a complement-mediated disease or condition.

[0304] Example

[0305] The following examples are illustrative only and should not be construed as limiting the scope of the present disclosure in any way, as many variations and equivalents will become apparent to those skilled in the art after reading this disclosure. The contents of all references, patents, and patent applications cited throughout this application are expressly incorporated herein by reference.

[0306] Example 1. Non-limiting synthetic examples of compounds disclosed herein

[0307] The following schemes are non-limiting examples of methods for making compounds of the present disclosure. The skilled artisan will recognize that various modifications can be made to make analogs or otherwise prepare the compounds.

[0308] abbreviation

[0309]

[0310]

[0311] General approach

[0312] All non-aqueous reactions were carried out under dry argon or nitrogen atmosphere using anhydrous solvents. Reaction progress and the purity of the target compounds were determined using one of the 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.

[0313] LC Method A

[0314] Instrument: Waters Acquity Ultra Performance LC

[0315] Column: ACQUITY UPLC BEH C18 2.1′50mm, 1.7mm

[0316] Column temperature: 40°C

[0317] Mobile phase: Solvent A: H2O + 0.05% FA; Solvent B: CH3CN + 0.05% FA

[0318] Flow rate: 0.8 mL / min

[0319] Gradient: 0.24 min @ 15% B, 3.5 min gradient (15-85% B), then 0.5 min @ 85% B.

[0320] Detection: UV (210-410 nm) and MS (SQ in ES+ mode)

[0321] 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)

[0322]

[0323] Step 1: tert-Butyl 2-(5-((2,4-dimethoxybenzyl)amino)-2-(methylthio)-6-oxopyrimidin-1(6H)-yl)acetate

[0324] 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) under N atmosphere were added rac-BINAP (373 mg, 0.60 mmol), CsCO (1.95 g, 5.99 mmol) and Pd(OAc) (67 mg, 0.30 mmol), 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) + .

[0325] Step 2: tert-Butyl 2-(5-((2,4-dimethoxybenzyl)amino)-6-oxo-2-phenylpyrimidin-1(6H)-yl)acetate

[0326] 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) under an N atmosphere was added copper ((thiophene-2-carbonyl)oxy) (344 mg, 1.80 mmol) and Pd(PPh) (95 mg, 0.082 mmol). The mixture was degassed three times under an N atmosphere and stirred overnight at 55° C. in a sealed tube. The reaction mixture was diluted with EtOAc and filtered. The filtrate was 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, 0-24% 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) + .

[0327] Step 3: 2-(5-amino-6-oxo-2-phenylpyrimidin-1(6H)-yl)acetic acid

[0328] 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 hours. 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) + .

[0329] 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

[0330] 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 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 light yellow oil. LC / MS (ESI) m / z: 475 (M+H) + .

[0331] Step 5: tert-Butyl 2-((2-(6-oxo-2-phenyl-5-(3-phenylpropionamido)pyrimidin-1(6H)-yl)acetamido)methyl)-1H-pyrrolo[3,2-c]pyridine-1-carboxylate

[0332] To a mixture of 3-phenylpropionic 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 N2 atmosphere, and the mixture was stirred at room temperature for 30 minutes. 2-((2-(5-amino-6-oxo-2-phenylpyrimidin-1(6H)-yl)acetamido)methyl)-1H-pyrrolo[3,2-c]pyridine-1-carboxylic acid tert-butyl ester (50 mg, 0.11 mmol) was added to the stirred 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 Na2SO4, 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-phenylpropionamido)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) + .

[0333] 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)

[0334] To a solution of tert-butyl 2-((2-(6-oxo-2-phenyl-5-(3-phenylpropionamido)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. 1 HNMR (400MHz, CD3OD) δ8.92(d,J=3.3Hz,2H),8.24(d,J=6.4Hz,1H),7.72(d,J=6.2Hz,1H),7.56–7.50(m,3H),7.47–7.42(m,2H),7.2 6(d,J=4.6Hz,4H),7.17(dd,J=9.0,4.8Hz,1H),6.74(s,1H),4.67(s,2H),4.59(s,2H),3.01(t,J=7.6Hz,2H),2.81(t,J=7.6Hz,2H). LC / MS(ESI)m / z:507(M+H)+ . RT (Method A): 1.14 min.

[0335] The following compounds were prepared based on steps 5-6 in Scheme 1:

[0336]

[0337]

[0338]

[0339] a Only step 5.

[0340] 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)

[0341]

[0342] Step 1: 2-(5-((2,4-dimethoxybenzyl)amino)-6-oxo-2-phenylpyrimidin-1(6H)-yl)acetic acid

[0343] 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 / H2O / THF (40 mL, 2 / 1 / 1) was added NaOH (1.3 g, 34.4 mmol) under N2 atmosphere and the reaction mixture was stirred at 50°C for 2 hours. The mixture was acidified to pH~3 with 1N aqueous HCl and extracted twice with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, 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) + .

[0344] 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

[0345] 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 N2 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 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 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) + .

[0346] Step 3: N-((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)-2-(5-amino-6-oxo-2-phenylpyrimidin-1(6H)-yl)acetamide hydrochloride

[0347] 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 N2 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) + .

[0348] 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)

[0349] 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) under N atmosphere was added DIPEA (41 mg, 0.032 mmol) and HATU (33 mg, 0.090 mmol), 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. 1 H-NMR (400MHz, CD3OD) δ9.02(s,1H),8.90(s,1H),8.44(s,1H),8.21(d,J=6.1Hz,1H),8.00–7.97(m,2H),7.66(d,J=6.2Hz,1H), 7.56(dd,J=7.6,6.1Hz,3H),7.48–7.42(m,4H),7.23(t,J=7.4Hz,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 min.

[0350] 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)

[0351]

[0352] 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) under an N atmosphere were added DIPEA (36 mg, 0.27 mmol) and HATU (31 mg, 0.090 mmol), and the reaction mixture was stirred at room temperature for 1 hour. To the mixture were added LiOH (4.8 mg, 0.20 mmol), MeOH (0.5 mL), and water (0.1 mL), and the mixture was stirred at room temperature for 6 hours. The mixture was diluted with EtOAc and washed with saturated aqueous NaHCO solution 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. 1 H NMR (400MHz, CD3OD) δ8.73 (s, 1H), 8.12 (d, J = 5.9Hz, 1H), 7.47 (d, J = 6.8Hz, 3H),7.44–7.38(m,3H),7.23(t,J=7.9Hz,4H),7.16(t,J=7.2Hz,1H),7.07(s ,1H),6.50(s,1H),5.24(q,J=6.8Hz,1H),4.60(t,J=13.5Hz,2H),3.17(t,J= 7.0Hz, 2H), 2.74 (t, J = 7.6Hz, 2H), 2.02–1.94 (m, 2H), 1.55 (d, J = 6.9Hz, 3H). LC / MS(ESI)m / z:507(M+H) + . RT (Method A): 1.41 min.

[0353] The following compounds were prepared based on Scheme 3:

[0354]

[0355]

[0356]

[0357] a Only step 1. b The intermediate formed by the coupling reaction is isolated prior to deprotection. c Use HBTU instead of HATU.

[0358] 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)

[0359]

[0360] Step 1: (4-Azidobutyloxy)benzene

[0361] To a solution of (4-bromobutoxy)benzene (200 mg, 0.88 mmol) in DMF (3 mL) was added NaN3 (112 mg, 1.75 mmol) at 0 ° C under N2 atmosphere and the mixture was stirred at 50 ° C for 16 hours. 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, 0-8% 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) + .

[0362] Step 2: 4-Phenoxybutan-1-amine

[0363] To a solution of (4-azidobutyloxy)benzene (150 mg, 0.78 mmol) in MeOH (3 mL) was added Pd / C (20 mg, 10% wt.), the mixture was degassed three times under a N2 atmosphere and stirred under a H2 balloon at 25°C overnight. 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) + .

[0364] Step 3: tert-Butyl 2-(2-(methylthio)-6-oxo-5-((4-phenoxybutyl)amino)pyrimidin-1(6H)-yl)acetate

[0365] 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) under N₂ atmosphere were added Cs₂CO₃ (494 mg, 1.46 mmol), rac-BINAP (94.3 mg, 0.15 mmol), and Pd(OAc)₂ (17 mg, 0.07 mmol). The reaction mixture was degassed three times under N₂ 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 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-(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) + .

[0366] Step 4: tert-Butyl 2-(6-oxo-5-((4-phenoxybutyl)amino)-2-phenylpyrimidin-1(6H)-yl)acetate

[0367] 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) under N2 atmosphere were added ((thiophene-2-carbonyl)oxy)copper (100 mg, 0.53 mmol) and Pd(PPh3)4 (55 mg, 0.05 mmol). 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) + .

[0368] Step 5: 2-(6-oxo-5-((4-phenoxybutyl)amino)-2-phenylpyrimidin-1(6H)-yl)acetic acid

[0369] 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) + .

[0370] 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)

[0371] 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) under N atmosphere was added DIPEA (49 mg, 0.36 mmol) and PyBop (33 mg, 0.06 mmol), and the reaction mixture was stirred at room temperature for 2 hours. 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 (400MHz, CD3OD) δ8.73 (s, 1H), 8.12 (d, J = 5.9Hz, 1H), 7.49 (s, 1H), 7.47 (d,J=1.7Hz,2H),7.45(d,J=4.8Hz,1H),7.42(d,J=5.5Hz,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,2 H), 4.55 (s, 2H), 4.05 (d, J = 5.8Hz, 2H), 3.27 (s, 2H), 1.90 (d, J = 2.9Hz, 4H). LC / MS(ESI)m / z:523(M+H) + . RT (Method A): 1.41 min.

[0372] The following compounds were prepared based on steps 3-6 of Scheme 4:

[0373]

[0374]

[0375]

[0376]

[0377]

[0378] a In step 6, HBTU was used instead of PyBOP. b In step 6, HATU was used instead of PyBOP. c Only steps 4-6. d The intermediate obtained from step 4 was deprotected with NaOH.

[0379] 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)

[0380]

[0381] Step 1: 4-(4-Phenoxyphenyl)butyric acid

[0382] 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 three times under a N2 atmosphere, and the mixture was stirred under a H2 balloon at 70°C for 5 hours. 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) + .

[0383] 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)

[0384] 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 hours. 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 (400MHz, CD3OD) δ8.92(s,1H),8.73(s,1H),8.12(d,J=5.9Hz,1H),7.52(d ,J=8.1Hz,3H),7.43(t,J=5.5Hz,3H),7.34–7.30(m,2H),7.22(d,J=8.5Hz,2H) ,7.07(t,J=7.4Hz,1H),6.93(dd,J=14.5,8.1Hz,4H),6.52(s,1H),4.67(s,2H) ,4.55(s,2H),2.70(t,J=7.6Hz,2H),2.53(t,J=7.3Hz,2H),2.04–2.00(m,2H). LC / MS(ESI)m / z:613(M+H) + . RT (Method A): 1.68 min.

[0385] 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)

[0386]

[0387] Step 1: N-methoxy-N-methyl-4-(4-phenoxyphenyl)butanamide

[0388] 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 N2 atmosphere and the reaction mixture was stirred at room temperature for 2 hours. The mixture was diluted with EtOAc, washed with saturated aqueous NH4Cl solution 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) + .

[0389] Step 2: 4-(4-phenoxyphenyl)butyraldehyde

[0390] 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, 1 N in THF) dropwise under N2 atmosphere at -78 ° C and the mixture was stirred at -78 ° C for 1 hour. The mixture was quenched with saturated aqueous potassium sodium tartrate solution 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, 0-20% 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) + .

[0391] 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)

[0392] 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) was added NaBHCN (20 mg, 0.32 mmol) under N atmosphere, and the reaction mixture was stirred at 50° C. for 1 hour. 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 (400MHz, CD3OD) δ8.97(s,1H),8.26(d,J=6.5Hz,1H),7.79(d,J=6.5Hz,1H),7.49( t,J=5.9Hz,3H),7.45–7.40(m,2H),7.30(t,J=7.9Hz,2H),7.19(d,J=8.4Hz,2H),7.14 (s,1H),7.06(t,J=7.4Hz,1H),6.91(dd,J=16.2,8.2Hz,4H),6.81(s,1H),4.63(d,J=1 3.1Hz, 4H), 3.20 (t, J = 6.4Hz, 2H), 2.67 (t, J = 7.0Hz, 2H), 1.74 (dt, J = 8.4, 4.9Hz, 4H). LC / MS(ESI)m / z:599(M+H) + . RT (Method A): 1.94 min.

[0393] 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)

[0394]

[0395] Step 1: 4-Oxo-4-(4-phenoxyphenyl)butanoic acid

[0396] To a mixture of diphenyl ether (5.0 g, 29.4 mmol) and dihydrofuran-2,5-dione (2.9 g, 29.4 mmol) in DCM (50 mL) was added AlCl₃ (5.9 g, 44.1 mmol) at 0°C under N₂ atmosphere and the mixture was stirred at room temperature overnight. The mixture was acidified to pH~3 with 1N aqueous HCl solution 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 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) + .

[0397] 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)

[0398] 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 hours. The mixture was diluted with EtOAc, washed with saturated aqueous NH4Cl solution 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. 1 HNMR (400MHz, CD3OD) δ8.91(s,1H),8.75(s,1H),8.14(d,J=5.9Hz,1H),8.04(d,J=8.8Hz,2H),7.53(d,J=8.3Hz,3H),7.46–7.41(m,5H),7.24(d, J=7.4Hz,1H),7.09(d,J=7.8Hz,2H),7.02(d,J=8.8Hz,2H),6.54(s,1H),4.68(s,2H),4.56(s,2H),3.41(t,J=6.4Hz,2H),2.92(t,J=6.4Hz,2H). LC / MS(ESI)m / z:627(M+H)+ . RT (Method A): 1.59 min.

[0399] 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)

[0400]

[0401] Step 1: Methyl 2-(6-oxo-2,5-diphenylpyrimidin-1(6H)-yl)acetate

[0402] 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. The reaction mixture was degassed three times under N atmosphere and stirred at 80° C. for 1 hour. 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) + .

[0403] Step 2: 2-(6-oxo-2,5-diphenylpyrimidin-1(6H)-yl)acetic acid

[0404] To a solution of methyl 2-(6-oxo-2,5-diphenylpyrimidin-1(6H)-yl)acetate (39 mg, 0.15 mmol) in MeOH / THF / H2O (4 mL, 2 / 1 / 1) was added LiOH·H2O (15 mg, 0.30 mmol) under N2 atmosphere and the reaction mixture was stirred at room temperature for 2 hours. The mixture was acidified to pH~3 with 1N aqueous HCl solution and extracted twice with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, 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) + .

[0405] Step 3: N-((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)-2-(6-oxo-2,5-diphenylpyrimidin-1(6H)-yl)acetamide (Compound 25)

[0406] 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) under N2 atmosphere was added DIPEA (78 mg, 0.55 mmol) and HATU (54 mg, 0.14 mmol), and the reaction mixture was stirred at room temperature for 1 hour. 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 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 (400MHz, CD3OD) δ8.68(s,1H),8.52(s,1H),8.45–8.41(m,1H),8.23(d,J=7.2Hz,2H),8.10(d,J=6.5Hz,1H),7.76(d,J=7.1Hz,2H), 7.48(dd,J=9.5,5.3Hz,3H),7.43(d,J=7.3Hz,1H),7.33(t,J=7.3Hz,1H),7.27(d,J=7.8Hz,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 min.

[0407] 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)

[0408]

[0409] Step 1: Dibenzo[b,d]furan-3-carbaldehyde

[0410] 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 N2 atmosphere at -78 ° C. The reaction mixture was slowly warmed to 0 ° C and stirred for 10 minutes. Then, the reaction mixture was cooled to -78 ° C. DMF (266 mg, 3.64 mmol) was added to the above mixture. The resulting mixture was stirred at -78 ° C for 1 hour. The reaction mixture was quenched with saturated NH4Cl aqueous solution 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-carboxaldehyde (30 mg, 12.6% yield) as a white solid. 1 H NMR (400MHz, CDCl3) δ10.14(s,1H),8.11–8.02(m,3H),7.91(dd,J=7.9,1.3Hz,1H),7.65–7.55(m,2H),7.42(dd,J=11.6,4.3Hz,1H).

[0411] 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)

[0412] 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) was added NaBHCN (12 mg, 0.19 mmol) under N atmosphere and the reaction mixture was stirred at 50° C. for 2 hours. 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. 1H NMR (400MHz, CD3OD) δ8.82(d,J=5.7Hz,1H),8.51(s,1H),8.17(t,J=6.8Hz,1H),8.03–7.96(m,2H),7.64(d,J=5.8Hz, 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=6.2Hz,1H),4.66–4.57(m,6H). LC / MS(ESI)m / z:555(M+H) + . RT (Method A): 1.61 min.

[0413] The following compounds were prepared based on Scheme 8:

[0414]

[0415]

[0416]

[0417] a Only step 2. b Step 2 was carried out using NaBH3CN in MeOH in the presence of MgSO4.

[0418] Compound 178 can be prepared based on Step 2 in Scheme 8:

[0419]

[0420] 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)

[0421]

[0422] 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) under N2 atmosphere was added DIPEA (65 mg, 0.5 mmol) and the reaction mixture was stirred at room temperature for 2 hours. The mixture was purified by preparative HPLC to give Compound 29 (4.8 mg, 8.7% yield) as a white solid. 1HNMR(400MHz,CD3OD)δ9.08(s,1H),8.77(s,1H),8.14(d,J=6.0Hz,1H),8.07(d,J=8.5Hz,2H),7.83(d,J=8.5Hz,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 min.

[0423] Compound 31 was prepared based on Scheme 9:

[0424]

[0425] 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)

[0426]

[0427] Step 1: 2-Bromo-4,5,6,7-tetrahydrobenzo[d]thiazole (2)

[0428] To a solution of CuBr2 (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 under N2 atmosphere at 40 ° C. for 10 minutes. 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 hours. The mixture was quenched with 0.5N HCl aqueous solution and extracted twice with EtOAc. The combined organic layers were washed with saturated NaHCO3 aqueous solution, brine, dried over anhydrous Na2SO4, 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 light yellow oil. LC / MS (ESI) m / z: 218 (M+H) + .

[0429] Step 2: 2-(tributylstannyl)-4,5,6,7-tetrahydrobenzo[d]thiazole (3)

[0430] To a solution of 2-bromo-4,5,6,7-tetrahydrobenzo[d]thiazole (77 mg, 0.35 mmol) in THF (3 mL) was added n-BuLi (0.6 mL, 0.40 mmol, 2.5 M) dropwise under N2 atmosphere at -78 ° C and the reaction mixture was stirred at -78 ° C for 30 minutes. Tributyl chlorotin (104 mg, 0.32 mmol) was added to the mixture and the mixture was stirred at -78 ° C to room temperature for 1.5 hours. The mixture was concentrated to dryness (15 ° C) under reduced pressure. The residue was dissolved in hexane and the reaction mixture was stirred at room temperature for 5 minutes. The mixture was filtered through celite and the filtrate was concentrated to dryness (15 ° C) under reduced pressure to give 2-(tributyltinyl)-4,5,6,7-tetrahydrobenzo[d]thiazole (150 mg, 99.2% yield) as a light yellow oil, which was used directly in the next reaction without further purification.

[0431] Step 3: Methyl 2-(6-oxo-2-phenyl-5-(4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)pyrimidin-1(6H)-yl)acetate (4)

[0432] 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) under N2 atmosphere at 0°C were added AcOK (47 mg, 0.48 mmol) and Pd(PPh3)4 (28 mg, 0.024 mmol) and the mixture was stirred at 120°C for 3 hours. 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 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, 33.0% yield) as a yellow solid. 1 H NMR(400MHz,CD3OD)δ9.37(s,1H),8.38(dd,J=7.7,1.8Hz,2H),7.51(t,J=6.3Hz ,3H),5.28(s,2H),3.80(s,3H),2.88(dd,J=13.5,5.7Hz,4H),1.98–1.90(m,4H). LC / MS(ESI)m / z:382(M+H) + .

[0433] Step 4: 2-(6-Oxo-2-phenyl-5-(4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)pyrimidin-1(6H)-yl)acetic acid (5)

[0434] 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·H₂O (13 mg, 0.31 mmol) in water (1 mL), and the mixture was stirred at room temperature for 1 hour. The mixture was acidified to pH ~3 with 1N aqueous HCl 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 to afford 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) + .

[0435] 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)

[0436] 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) under N atmosphere were added DIPEA (31 mg, 0.27 mmol) and HBTU (35 mg, 0.082 mmol) and the reaction mixture was stirred at room temperature for 1 hour. 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. 1H NMR (400MHz, CD3OD) δ9.34(s,1H),8.48(s,1H),8.31–8.28(m,2H),8.05(d,J=6.1Hz,1H),7.42–7.37(m ,1H),7.33–7.29(m,3H),6.53(s,1H),5.23(s,2H),4.64(s,2H),2.85–2.80(m,4H),1.94–1.87(m,4H). LC / MS(ESI)m / z:497(M+H) + . RT (Method A): 1.53 min.

[0437] 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)

[0438]

[0439] 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)

[0440] 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) at room temperature was added NaBHCN (74 mg, 1.14 mmol) 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) + .

[0441] 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)

[0442] 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 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-((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) + .

[0443] 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)

[0444] 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) was added DIPEA (87 mg, 0.66 mmol) and HATU (50 mg, 0.13 mmol) under N2 atmosphere, and the reaction mixture was stirred at room temperature for 2 hours. 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. 1HNMR(400MHz,CD3OD)δ8.75(d,J=0.8Hz,1H),8.12(d,J=6.0Hz,1H),7.85–7.7 7(m,2H),7.52–7.43(m,4H),7.39(dd,J=11.2,4.5Hz,4H),7.29(s,1H),7.19(t ,J=7.4Hz,1H),7.04(dd,J=8.6,1.0Hz,2H),6.99–6.95(m,2H),6.53(d,J=8.3H z, 1H), 4.62 (s, 2H), 4.55 (s, 2H), 3.66 (t, J = 6.1Hz, 2H), 3.43 (t, J = 6.1Hz, 2H). LC / MS(ESI)m / z:614(M+H) + . RT (Method A): 1.38 min.

[0445] 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)

[0446]

[0447] 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) was added DIPEA (73 mg, 0.54 mmol) and HATU (36 mg, 0.09 mmol) under N atmosphere, and the reaction mixture was stirred at room temperature for 2 hours. 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. 1H NMR (400MHz, CD3OD) δ8.72(s,1H),8.53(d,J=1.5Hz,1H),8.10(d,J=6.1Hz,1H),8.05( d,J=7.2Hz,1H),8.00(dd,J=8.7,1.9Hz,1H),7.63(d,J=3.2Hz,1H),7.61(d,J=2.8Hz, 1H),7.54(d,J=7.2Hz,1H),7.49–7.45(m,4H),7.38(dd,J=8.9,6.0Hz,3H),7.34(s,1H ), 6.56 (s, 1H), 4.63 (s, 2H), 4.57 (s, 2H), 3.74 (t, J = 5.9Hz, 2H), 3.51 (t, J = 6.1Hz, 2H). LC / MS(ESI)m / z:612(M+H) + . RT (Method A): 1.33 min.

[0448] Compound 36 was prepared based on Scheme 12:

[0449]

[0450] 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)

[0451]

[0452] Step 1: tert-Butyldimethyl(3-(4-(methylthio)phenyl)propoxy)silane (2)

[0453] To a solution of 3-(4-(methylthio)phenyl)propan-1-ol (260 mg, 1.43 mmol) in DCM (3 mL) was 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 hours. 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.

[0454] Step 2: tert-Butyldimethyl(3-(4-(methylsulfonyl)phenyl)propoxy)silane (3)

[0455] 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 N₂ atmosphere, and the reaction mixture was stirred at room temperature for 2 hours. The mixture was diluted with DCM, quenched with saturated aqueous Na₂SO₃, 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, 0–50% EtOAc in PE) to afford tert-butyldimethyl(3-(4-(methylsulfonyl)phenyl)propoxy)silane (100 mg, 89.7% yield) as a white solid.

[0456] Step 3: 3-(4-(Methylsulfonyl)phenyl)propan-1-ol (4)

[0457] 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 an N atmosphere for 2 hours. 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 HNMR (400MHz, CDCl3) δ7.80 (s, 1H), 7.78 (s, 1H), 7.34 (d, J = 7.9Hz, 2H), 3.62 (t, J = 6.2Hz, 2H), 2.98 (s, 3H), 2.75 (t, J = 7.7Hz, 2H), 1.88–1.81 (m, 2H).

[0458] Step 4: 3-(4-(Methylsulfonyl)phenyl)propanal (5)

[0459] To a solution of 3-(4-(methylsulfonyl)phenyl)propan-1-ol (58 mg, 0.27 mmol) in DCM (2 mL) was added Dess-Martin periodinane (172 mg, 0.41 mmol) under N₂ atmosphere, and the reaction mixture was stirred at room temperature for 2 hours. The mixture was diluted with DCM, quenched with saturated aqueous Na₂S₂O₃, 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 (DCM:MeOH = 20:1) to give 3-(4-(methylsulfonyl)phenyl)propanal (55 mg, 94.5% yield) as a white solid.

[0460] 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)

[0461] 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) was added 3-(4-(methylsulfonyl)phenyl)propanal (57 mg, 0.27 mmol) and NaBHCN (23 mg, 0.36 mmol) under N atmosphere and the reaction mixture was stirred at 50° C. for 2 hours. 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 (400MHz, CD3OD) δ8.74(s,1H),8.13(d,J=5.9Hz,1H),7.88(d,J=8.3Hz,2H),7.46(ddd,J=20.6,15.3,7.7Hz,8H),7.11 (s,1H),6.52(s,1H),4.62(s,2H),4.55(s,2H),3.23(t,J=6.9Hz,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) + .

[0462] 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)

[0463]

[0464] Step 1: tert-Butyl 2-(5-((3-(4-methoxyphenyl)propyl)amino)-6-oxo-2-phenylpyrimidin-1(6H)-yl)acetate

[0465] 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, and the reaction mixture was purged with nitrogen for 3 minutes. The reaction mixture was stirred at 120° C. under microwave irradiation for 10 minutes. 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) + .

[0466] Step 2: 2-(5-((3-(4-methoxyphenyl)propyl)amino)-6-oxo-2-phenylpyrimidin-1(6H)-yl)acetic acid

[0467] 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 and the reaction was stirred at rt for 1 hr. Excess TFA was evaporated, and MeOH containing 1 M HCl 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) + .

[0468] 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)

[0469] 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 rt for 30 minutes. Water (30 mL) was added to the reaction mixture and the solid was filtered. The solid was dissolved in DCM and dried over anhydrous NaSO, 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 (0.007 g, 40% yield) as an off-white solid. 1H NMR (400MHz, MeOD-CDCl3) δ8.71(s,1H),8.12(d,J=5.8Hz,1H),7.51–7.42(m,3H),7.38(dd,J=11.9,6.7Hz,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=7.0Hz,2H),2.71(t,J=7.5Hz,2H),2.05–1.93(m,2H),1.28(s,1H). LC / MS(ESI)m / z:523(M+H) + . RT (Method A): 1.45 min.

[0470] The following compounds were prepared based on Scheme 14:

[0471]

[0472]

[0473]

[0474]

[0475]

[0476]

[0477]

[0478]

[0479]

[0480]

[0481] a Step 1 was carried out with Pd 2 (dba) 3 and XantPhos in 1,4-dioxane in the presence of Cs 2 CO 3 , step 2 was carried out with TFA in THF / MeOH / H 2 O or DCM (for compounds 236, 244 and 245), and in step 3 HATU was used instead of TBTU. b Step 1 was carried out with Pd 2 (dba) 3 and XantPhos in the presence of Cs 2 CO 3 in DMF, step 2 was carried out with TFA in DCM, and in step 3 HATU was used instead of TBTU. c Step 1 was carried out with Pd 2 (dba) 3 and XantPhos in 1,4-dioxane in the presence of Cs 2 CO 3 , step 2 was carried out with NaOH in THF / MeOH / H 2 O, and in step 3 HATU was used instead of TBTU. d Step 2 in MeOH / H2O. e Step 1 was carried out with LiOH.H2O in THF.MeOH, step 2 was carried out with LiOH in THF.MeOH, and HATU was used instead of TBTU in step 3.

[0482] Compound 181 was prepared based on Scheme 14:

[0483]

[0484] 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)

[0485]

[0486] Step 1: 3-(4-Fluorophenyl)propan-1-ol (2)

[0487] 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 hour. The mixture was quenched by adding MeOH dropwise 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 (400MHz, CDCl3) δ7.07(dd,J=7.9,5.8Hz,2H),6.89(t,J=8.6Hz,2H),3.58(t,J=6.4Hz,2H),2.60(t,J=7.7Hz,2H),1.83–1.75(m,2H).

[0488] Step 2: 3-(4-Fluorophenyl)propanal (3)

[0489] 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 N2 atmosphere and the reaction mixture was stirred at room temperature for 2 hours. 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 (400MHz, CDCl3) δ9.74 (s, 1H), 7.07 (dd, J = 7.8, 5.5Hz, 2H), 6.91 (d, J = 8.6Hz, 2H), 2.86 (t, J = 7.4Hz, 2H), 2.69 (t, J = 7.4Hz, 2H).

[0490] 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)

[0491] 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) at 0° C. under N atmosphere was added NaBHCN (60 mg, 0.96 mmol) 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 (400MHz, CD3OD) δ8.70(s,1H),8.10(d,J=5.6Hz,1H),7.46(t,J=7.0Hz,3H),7.40(d,J=6.1Hz,3H),7.23(t,J=6.2Hz,2H),7.08(s ,1H),6.99(t,J=8.1Hz,2H),6.47(s,1H),4.62(s,2H),4.54(s,2H),3.18(t,J=6.9Hz,2H),2.74(t,J=7.3Hz,2H),2.03–1.94(m,2H). LC / MS(ESI)m / z:511(M+H) + . RT (Method A): 1.56 min.

[0492] Compound 88 was prepared based on Scheme 15:

[0493]

[0494] 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)

[0495]

[0496] Step 1: 4-(3-Hydroxypropyl)benzonitrile

[0497] To a mixture of 3-(4-bromophenyl)propan-1-ol (2.0 g, 9.35 mmol) and Zn(CN)2 (2.2 g, 18.70 mmol) in DMF (20 mL) was added Pd(PPh3)4 (1.1 g, 0.94 mmol) at 0°C under an N2 atmosphere. The mixture was degassed three times under an N2 atmosphere and stirred at 110°C overnight. 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, 0-25% 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) + .

[0498] Step 2: 4-(3-Oxopropyl)benzonitrile

[0499] 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 hours at 0° C. Silica gel was added to the mixture and stirred at 0° C. for 0.5 hours, 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.

[0500] 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)

[0501] 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 N atmosphere, and the reaction mixture was stirred at 50° C. for 1 hour. 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). 1H NMR (400MHz, CD3OD) δ8.87(s,1H),8.47(s,1H),8.20(d,J=6.2Hz,1H),7.65(d,J=8.2Hz,3H),7.50–7.40(m,7H),7. 11(s,1H),6.68(s,1H),4.64(s,2H),4.59(s,2H),3.21(t,J=6.8Hz,2H),2.85(t,J=7.6Hz,2H),2.08–1.85(m,2H). LC / MS(ESI)m / z:518(M+H) + . RT (Method A): 1.29 min.

[0502] 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)

[0503]

[0504] Step 1: N-[[1-(phenylsulfonyl)pyrrolo[3,2-c]pyridin-2-yl]methyl]-2-[5-[(2,4-dimethoxyphenyl)methylamino]-6-oxo-2-phenyl-pyrimidin-1-yl]acetamide

[0505] 2-[5-[(2,4-Dimethoxyphenyl)methylamino]-6-oxo-2-phenyl-pyrimidin-1-yl]acetic acid (1 g, 2.529 mmol), [1-(phenylsulfonyl)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 rt for 30 minutes. Water (30 mL) was added to the reaction mixture, and the solid was filtered. The solid was dissolved in DCM and dried over anhydrous NaSO, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0-5% MeOH in DCM) to give N-[[1-(phenylsulfonyl)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) + .

[0506] Step 2: 2-(5-Amino-6-oxo-2-phenyl-pyrimidin-1-yl)-N-[[1-(phenylsulfonyl)pyrrolo[3,2-c]pyridin-2-yl]methyl]acetamide

[0507] 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 hr. The excess reagent was evaporated to complete dryness and the crude material was washed with saturated NaHCO 3 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-(phenylsulfonyl)pyrrolo[3,2-c]pyridin-2-yl]methyl]acetamide (0.1 g, 90% yield) as an off-white solid. LC / MS (ESI) m / z: 515 (M+H) + .

[0508] 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)

[0509] 2-(5-amino-6-oxo-2-phenyl-pyrimidin-1-yl)-N-[[1-(phenylsulfonyl)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 and stirred at rt 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 and stirred at 50 ° C for 30 minutes. The solvent was evaporated and extracted with DCM. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0-3% MeOH in DCM) to afford compound 49 (2 mg, 17.85% yield). 1H NMR (400MHz, MeOD-CDCl3) δ8.83 (d, J = 5.0Hz, 1H), 8.62 (s, 1H), 8.43 (s, 3H), 8. 02(s,1H),7.41(t,J=8.2Hz,3H),7.36–7.28(m,3H),7.21–7.10(m,2H),6.83(t d,J=13.1,7.7Hz,3H),6.39(s,1H),4.57(s,2H),4.52(s,1H),4.45(s,2H),2.5 6(s,1H),2.13(s,1H),2.03–1.87(m,3H),1.64(s,3H),1.41(d,J=11.8Hz,1H). LC / MS(ESI)m / z:577(M+H) + . RT (Method A): 1.87 min.

[0510] The following compounds were prepared based on Step 3 in Scheme 17:

[0511]

[0512]

[0513] 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)

[0514]

[0515] Step 1: Methyl 4-(2,4-difluorophenoxy)benzoate (2)

[0516] 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 stirred under an O atmosphere at room temperature 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 light yellow oil. 1H NMR (400MHz, CDCl3) δ7.98 (d, J = 8.9Hz, 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) + .

[0517] Step 2: 4-(2,4-difluorophenoxy)benzoic acid (3)

[0518] 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·H2O (450 g, 10.72 mmol) and the mixture was stirred at room temperature for 4 hours. The mixture was acidified to pH ~3 with 1N aqueous HCl 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 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) + .

[0519] 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)

[0520] 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) under N₂ atmosphere were added TCFH (440 mg, 1.57 mmol) and NMI (130 mg, 1.57 mmol), and the reaction mixture was stirred at room temperature for 1 hour. The mixture was diluted with DCM, washed with 10% 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, 0-4% 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) + .

[0521] 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)

[0522] 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) 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 Na2SO4, 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. 1 H NMR (400MHz, DMSO-d6) δ11.34(s,1H),9.48(s,1H),8.83–8.71(m,3H),8.11(d,J=5.6Hz,1H),8.04–7.97(m,2H),7.59–7.52(m,4 H),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=5.5Hz,2H). LC / MS(ESI)m / z:607(M+H) + . RT (Method A): 1.73 min.

[0523] The following compounds were prepared based on steps 3 and 4 in Scheme 18:

[0524]

[0525]

[0526]

[0527]

[0528]

[0529]

[0530] a LiOH was used instead of NaOMe for deprotection.b The intermediate from the coupling reaction was not isolated prior to deprotection. c Step 4 was performed with NaOH in DMSO.

[0531] Compounds 163 and 173 were prepared based on steps 3 and 4 in Scheme 18:

[0532]

[0533] 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)

[0534]

[0535] Step 1: (Cyano(phenyl)methyl)glycine benzyl ester hydrochloride (2)

[0536] To a solution of glycine benzyl ester (8.5 g, 51.5 mmol) in DCM (15 mL) was added benzaldehyde (5.5 g, 51.5 mmol) in portions, followed by the dropwise addition of TMSCN (5.61 g, 56.7 mmol) at room temperature over 10 minutes. 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 HCl aqueous solution was added dropwise at 0 ° C. The precipitate formed was collected by filtration, washed with PE, and dried under vacuum to give (cyano (phenyl) methyl) glycine benzyl ester hydrochloride (6.5 g, 46.4% yield) as a white solid. LC / MS (ESI) m / z: 281 (M + H) + .

[0537] Step 2: Benzyl 2-(3,5-dichloro-2-oxo-6-phenylpyrazin-1(2H)-yl)acetate (3)

[0538] To a solution of (cyano(phenyl)methyl)glycine benzyl ester hydrochloride (6.5 g, 23.2 mmol) in chlorobenzene (65 mL) was added oxalyl chloride (12.0 g, 92.9 mmol) under N2 atmosphere and the reaction mixture was stirred at 100 ° C for 16 hours. 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 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) + .

[0539] Step 3: Benzyl 2-(5-chloro-3-((2,4-dimethoxybenzyl)amino)-2-oxo-6-phenylpyrazin-1(2H)-yl)acetate (4)

[0540] To a solution of 2-(3,5-dichloro-2-oxo-6-phenylpyrazin-1(2H)-yl)benzyl acetate (6.0 g, 15.5 mmol) in EtOAc (60 mL) was added 2,4-dimethoxybenzylamine (3.87 g, 23.3 mmol) under N2 atmosphere and the reaction mixture was stirred at 80 ° C for 2 hours. 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 2-(5-chloro-3-((2,4-dimethoxybenzyl)amino)-2-oxo-6-phenylpyrazin-1(2H)-yl)benzyl acetate (7.5 g, 93.8% yield) as a light yellow solid. LC / MS (ESI) m / z: 520 (M+H) + .

[0541] Step 4: 2-(3-((2,4-dimethoxybenzyl)amino)-2-oxo-6-phenylpyrazin-1(2H)-yl)acetic acid (5)

[0542] 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, wt. 10%), the mixture was degassed ten times under a N atmosphere and stirred at 40° C. under a H balloon for 16 hours. 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) + .

[0543] Step 5: Methyl 2-(3-((2,4-dimethoxybenzyl)amino)-2-oxo-6-phenylpyrazin-1(2H)-yl)acetate (6)

[0544] 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 TMSCHN2 (4.1 mL, 8.23 ​​mmol) at 0°C under N2 atmosphere and the reaction mixture was stirred at room temperature for 2 hours. 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 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 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) + .

[0545] Step 6: Methyl 2-(3-amino-2-oxo-6-phenylpyrazin-1(2H)-yl)acetate (7)

[0546] 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 hours. 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) + .

[0547] Step 7: Methyl 2-(3-(([1,1'-biphenyl]-4-ylmethyl)amino)-2-oxo-6-phenylpyrazin-1(2H)-yl)acetate (8)

[0548] To a solution of 2-(3-amino-2-oxo-6-phenylpyrazine-1(2H)-yl)acetic acid methyl ester (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 N2 atmosphere and the reaction mixture was stirred at 80 ° C for 16 hours. The mixture was cooled to 0 ° C and NaBH (OAc) 3 (327 mg, 1.55 mmol) was added. The resulting mixture was stirred at 0 ° C to rt for 1 hour. The mixture was quenched with saturated NH4Cl aqueous solution 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, 0-25% 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) + .

[0549] Step 8: 2-(3-(([1,1'-biphenyl]-4-ylmethyl)amino)-2-oxo-6-phenylpyrazin-1(2H)-yl)acetic acid (9)

[0550] 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·H2O (4.4 mg, 0.11 mmol), and the mixture was stirred at room temperature for 2 hours. The mixture was acidified to pH ~3 with 1N aqueous HCl 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 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) + .

[0551] 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)

[0552] 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) under N2 atmosphere were added DIPEA (47 mg, 0.36 mmol) and HATU (34 mg, 0.09 mmol), and the reaction mixture was stirred at room temperature for 2 hours. The mixture was diluted with EtOAc, washed with saturated aqueous NH4Cl solution 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. 1 H NMR (400MHz, DMSO-d6) δ11.31(s,1H),8.74(s,1H),8.64(s,1H),8.12(d,J=5.2Hz,1H),7.90(s,1H),7.62(dd,J=13.2, 8.0Hz, 4H), 7.45 (t, J = 8.3Hz, 5H), 7.35 (d, J = 9.3Hz, 6H), 6.66 (s, 1H), 6.31 (s, 1H), 4.58 (d, J = 5.3Hz, 2H), 4.41 (s, 4H). LC / MS(ESI)m / z:541(M+H) + . RT (Method A): 1.81 min.

[0553] 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)

[0554]

[0555] Step 1: (R)-tert-Butyl 2-(2-(methylthio)-6-oxo-5-((1-(4-phenoxyphenyl)ethyl)amino)pyrimidin-1(6H)-yl)acetate (2)

[0556] 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) at 0° C. under N atmosphere, Pd(OAc) (65 mg, 0.29 mmol), CsCO (1.89 g, 5.75 mmol), and BINAP (360 mg, 0.58 mmol) were added and the mixture was stirred at 120° C. 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 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) + .

[0557] Step 2: tert-Butyl 2-(6-oxo-5-((1-(4-phenoxyphenyl)ethyl)amino)-2-phenylpyrimidin-1(6H)-yl)acetate (3)

[0558] To a mixture of tert-butyl 1-2-(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(PPh 3 ) 4 (199 mg, 0.17 mmol) at room temperature and the mixture was stirred under N 2 atmosphere at 80° C. for 2 hours. The mixture was quenched with saturated aqueous NaHCO 3 solution and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4 , 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) + .

[0559] Step 3: 2-(6-Oxo-5-((1-(4-phenoxyphenyl)ethyl)amino)-2-phenylpyrimidin-1(6H)-yl)acetic acid (4)

[0560] To a solution of tert-butyl 1-2-(6-oxo-5-((1-(4-phenoxyphenyl)ethyl)amino)-2-phenylpyrimidin-1(6H)-yl)acetate (220 mg, 0.44 mmol) in MeOH / THF / H2O (2 mL, 2 / 1 / 1) was added LiOH·H2O (56 mg, 1.32 mmol) under N2 atmosphere and the reaction mixture was stirred at room temperature for 2 hours. The mixture was acidified to pH~3 with 1N aqueous HCl and extracted twice with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give 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) + .

[0561] 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)

[0562] To a mixture of p-2-(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) at 0° C. under N 2 atmosphere, DIPEA (53 mg, 0.40 mmol) and HATU (34 mg, 0.09 mmol) were added and the mixture was stirred at room temperature for 2 hours. The mixture was quenched with saturated aqueous NH 4 Cl solution and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4 , 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, 2.3% yield) as a white solid. 1 H NMR (400MHz, CD3OD) δ8.75(s,1H),8.13(d,J=5.3Hz,1H),7.43(d,J=6.4Hz,1H),7.37(d,J=7.0Hz,1H),7.33(s,1H),7.0 9(s,1H),6.96(s,1H),6.88(s,1H),6.52(s,1H),4.62(s,1H),4.55(s,1H),4.50(d,J=5.1Hz,1H),1.59(d,J=5.9Hz,1H). LC / MS(ESI)m / z:571(M+H) +. RT (Method A): 1.76 min.

[0563] 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)

[0564]

[0565] Step 1: Methyl 2-(2-oxo-3-((4-phenoxybenzyl)amino)-6-phenylpyrazin-1(2H)-yl)acetate (2)

[0566] 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 N2 atmosphere and the reaction mixture was stirred at 80 ° C for 16 hours. NaBH(OAc)3 (327 mg, 1.55 mmol) was added to the mixture and the resulting mixture was stirred at 80 ° C for 1 hour. 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, 0-25% 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) + .

[0567] Step 2: 2-(2-Oxo-3-((4-phenoxybenzyl)amino)-6-phenylpyrazin-1(2H)-yl)acetic acid (3)

[0568] 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) was added LiOH·H2O (2.6 mg, 0.06 mmol) and the mixture was stirred at room temperature for 2 hours. The mixture was acidified to pH ~3 with 1N aqueous HCl 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 to give 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) + .

[0569] 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)

[0570] 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) under N atmosphere was added DIPEA (36 mg, 0.30 mmol) and HATU (27 mg, 0.08 mmol), and the reaction mixture was stirred at room temperature for 2 hours. 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. 1 H NMR (400MHz, CD3OD) δ8.90(s,1H),8.46(s,1H),8.22(d,J=4.9Hz,1H),7.69(d,J=6.3Hz,1H),7.41–7.30(m,8H),7. 09(t,J=7.9Hz,1H),6.97(dd,J=19.3,12.1Hz,4H),6.73(d,J=16.3Hz,2H),4.62(s,2H),4.58(s,2H),4.56(s,2H). LC / MS(ESI)m / z:557(M+H) + . RT (Method A): 1.27 min.

[0571] 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)

[0572]

[0573] Step 1: 4-(Fluoromethoxy)benzaldehyde (2)

[0574] To a mixture of 4-hydroxybenzaldehyde (700 mg, 5.73 mmol) and iodomethane (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 in a sealed tube at room temperature. 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 light yellow oil. 1 H NMR (400MHz, CDCl3) δ9.94 (s, 1H), 7.92–7.85 (m, 2H), 7.20 (d, J = 8.6Hz, 2H), 5.85 (s, 1H), 5.72 (s, 1H). LC / MS(ESI)m / z:155(M+H) + .

[0575] Step 2: Methyl (E)-3-(4-(fluoromethoxy)phenyl)acrylate (3)

[0576] To a solution of 4-(fluoromethoxy)benzaldehyde (750 mg, 4.87 mmol) in THF (15 mL) was added 2-(triphenyl-λ)-benzaldehyde under N2 atmosphere. 5 -phosphinyl)acetic acid methyl ester (4.83 g, 14.44 mmol) was added 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 (400MHz, CDCl3) δ7.65(d,J=15.8Hz,1H),7.50(d,J=7.9Hz,2H),7.08(d, J=7.9Hz,2H),6.35(d,J=16.0Hz,1H),5.80(s,1H),5.66(s,1H),3.80(s,3H). LC / MS(ESI)m / z:211(M+H) + .

[0577] Step 3: (E)-3-(4-(Fluoromethoxy)phenyl)prop-2-en-1-ol (4)

[0578] To a solution of (E)-methyl 3-(4-(fluoromethoxy)phenyl)acrylate (400 mg, 1.90 mmol) in THF (8 mL) was added dropwise LiAlH (9.5 mL, 9.50 mmol, 1 M) under N atmosphere at -20 ° C and the reaction mixture was stirred at -20 ° C for 2 hours. The mixture was quenched with Na SO .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 Na SO , 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. 1 H NMR (400MHz, CDCl3) δ7.35 (d, J = 7.4Hz, 2H), 7.03 (d, J = 7.5Hz, 2H), 6.58 (d, J = 15.8Hz, 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) + .

[0579] Step 4: (E)-3-(4-(Fluoromethoxy)phenyl)acrolein (5)

[0580] To a solution of (E)-3-(4-(fluoromethoxy)phenyl)prop-2-en-1-ol (230 mg, 1.26 mmol) in DCM (10 mL) at 0°C was added Dess-Martin periodinane (1.49 g, 3.51 mmol) and NaHCO (294 mg, 3.50 mmol), and the reaction mixture was stirred at room temperature for 1 hour. 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 give the title compound (123 mg, 54.1% yield) as a white solid. 1 H NMR (400MHz, CDCl3) δ9.68(d,J=7.5Hz,1H),7.56(d,J=7.8Hz,2H),7.44(d,J=16.0H z, 1H), 7.13 (d, J = 7.8Hz, 2H), 6.64 (dd, J = 15.9, 7.6Hz, 1H), 5.75 (d, J = 54.0Hz, 2H). LC / MS(ESI)m / z:181(M+H) + .

[0581] 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)

[0582] To a solution of (E)-3-(4-(fluoromethoxy)phenyl)propenal (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 N atmosphere and the reaction mixture was stirred at 55° C. for 1 hour. Another portion of (E)-3-(4-(fluoromethoxy)phenyl)propenal (14 mg, 0.078 mmol) and NaBHCN (7 mg, 0.11 mmol) was then added to the mixture and the resulting mixture was stirred at 55° C. overnight. The mixture was quenched with saturated aqueous NH4Cl and extracted twice with DCM. 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=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) + .

[0583] 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)

[0584] 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) was added Pd / C (5 mg, 10% wt.), the mixture was degassed three times under an N atmosphere and stirred under a H balloon at room temperature for 10 minutes. 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 (400MHz, CD3OD) δ8.78(s,1H),8.15(d,J=6.0Hz,1H),7.50-7.45(m,4H),7.42–7.38(m,2H),7.21(d,J=8.5Hz,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=6.9Hz,2H),2.73(t,J=7.6Hz,2H),2.01–1.95(m,2H). LC / MS(ESI)m / z:541(M+H) + . RT (method a): 1.49 min.

[0585] 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)

[0586]

[0587] Step 1: N-(tert-Butyl)-1-chloromethanesulfonamide (2)

[0588] 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) at 0° C. was added chloromethanesulfonyl chloride (500 mg, 3.37 mmol), and the mixture was stirred at room temperature for 2 hours. The mixture was diluted with EtOAc, washed with 1M aqueous HCl solution and brine, dried over anhydrous Na 2 SO 4 , 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) + .

[0589] 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)

[0590] 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) at 0° C. was added K CO (142 mg, 1.02 mmol) and N-(tert-butyl)-1-chloromethanesulfonamide (64 mg, 0.34 mmol) and the mixture was stirred at room temperature for 2 hours. The mixture was diluted with EtOAc, washed with saturated aqueous NaHCO and brine, dried over anhydrous Na SO, 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) + .

[0591] Step 3: 2-(2-(4-((N-(tert-butyl)sulfamoyl)methoxy)phenyl)-6-oxo-5-((3-phenylpropyl)amino)pyrimidin-1(6H)-yl)acetic acid (4)

[0592] 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 hours. The mixture was acidified to pH ˜3 with 1N aqueous HCl and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4 , filtered and concentrated to dryness under reduced pressure to give 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) + .

[0593] 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)

[0594] 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) at 0° C., DIPEA (107 mg, 0.80 mmol) and HATU (95 mg, 0.24 mmol) were added, and the mixture was stirred at room temperature for 2 hours. The mixture was diluted with EtOAc, washed with saturated aqueous NaHCO 3 solution and brine, dried over anhydrous Na 2 SO 4 , 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) + .

[0595] 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)

[0596] 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 under N atmosphere at room temperature 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. 1H NMR (400MHz, DMSO-d6) δ11.32(s,1H),8.74(s,1H),8.70(t,J=5.7Hz,1H),8.11(d,J=5.7H z,1H),7.43(d,J=8.7Hz,2H),7.35–7.26(m,4H),7.24(d,J=6.7Hz,3H),7.20–7.17(m,1H), 7.13(d,J=8.8Hz,2H),7.08(s,1H),6.36(s,1H),5.48(t,J=5.9Hz,1H),5.11(s,2H),4.50( s, 2H), 4.43 (d, J = 5.4Hz, 2H), 3.12–3.06 (m, 2H), 2.67 (t, J = 7.6Hz, 2H), 1.93–1.85 (m, 2H). LC / MS(ESI)m / z:602(M+H) + . RT (Method A): 1.32 min.

[0597] Compounds 131 and 139 were prepared based on the procedure described in Scheme 23.

[0598]

[0599] 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)

[0600]

[0601] Step 1: tert-Butyl 2-(2-(4-(ethoxy(methyl)phosphoryl)phenyl)-6-oxo-5-((3-phenylpropyl)amino)pyrimidin-1(6H)-yl)acetate (2)

[0602] 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 diethyl methylphosphinate (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 a 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 Na SO , 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) + .

[0603] Step 2: 2-(2-(4-(ethoxy(methyl)phosphoryl)phenyl)-6-oxo-5-((3-phenylpropyl)amino)pyrimidin-1(6H)-yl)acetic acid (3)

[0604] 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 hours. The reaction mixture was concentrated to dryness under reduced pressure to give the title compound as a yellow solid (80 mg, 97.8% yield), which was used directly in the next step without further purification. LC / MS (ESI) m / z: 470 (M+H) + .

[0605] 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)

[0606] 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) under N2 atmosphere were added DIPEA (41 mg, 0.32 mmol) and HATU (61 mg, 0.16 mol), and the reaction mixture was stirred at room temperature for 2 hours. 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) + .

[0607] 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)

[0608] 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 (400MHz, DMSO) δ12.29-11.96(m,1H),9.30–8.83(m,1H),8.74(s,1H),8.09(d,J=5.7Hz ,1H),7.69(d,J=7.6Hz,2H),7.40-7.32(m,3H),7.32–7.27(m,2H),7.25(d,J=6.9Hz,2H),7. 21–7.16(m,1H),7.08(s,1H),6.34(s,1H),5.47(t,J=5.8Hz,1H),4.51(s,2H),4.36(s,2H) ,3.10(dd,J=13.1,6.6Hz,2H),2.67(t,J=7.7Hz,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 min.

[0609] Compounds 132 and 140 were prepared based on the procedure described in Scheme 24.

[0610]

[0611]

[0612] 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)

[0613]

[0614] Step 1: tert-Butyl 2-(2-(4-(methylsulfonyl)phenyl)-6-oxo-5-((3-phenylpropyl)amino)pyrimidin-1(6H)-yl)acetate (2)

[0615] 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 hour. The mixture was diluted with DCM, 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, 0-40% 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) + .

[0616] Step 2: 2-(2-(4-(methylsulfonyl)phenyl)-6-oxo-5-((3-phenylpropyl)amino)pyrimidin-1(6H)-yl)acetic acid (3)

[0617] 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) at 0° C. under N₂ atmosphere and the reaction mixture was stirred at room temperature for 2 hours. 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) + .

[0618] 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)

[0619] 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) under N2 atmosphere was added DIPEA (51 mg, 0.40 mmol) and HATU (45 mg, 0.12 mol), 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(400MHz,DMSO-d6)δ11.32(s,1H),8.76–8.71(m,2H),8.11(d,J=5.6Hz,1H),7 .97(d,J=8.4Hz,2H),7.75(d,J=8.4Hz,2H),7.33–7.23(m,5H),7.18(t,J=7.0Hz, 1H),7.12(s,1H),6.33(s,1H),5.69(t,J=6.0Hz,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 = 7.7Hz, 2H), 1.93–1.86 (m, 2H). LC / MS(ESI)m / z:571(M+H) + . RT (Method A): 1.42 min.

[0620] 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)

[0621]

[0622] Step 1: (Isocyanatomethyl)cyclohexane (2)

[0623] To a solution of cyclohexylmethylamine (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) under N2 atmosphere at 0°C and the mixture was stirred at room temperature for 1 hour. 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.

[0624] 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)

[0625] 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) was added (isocyanatomethyl)cyclohexane (22 mg, 0.16 mmol) and DIPEA (16 mg, 0.12 mmol) under N2 atmosphere, and the reaction mixture was stirred at room temperature for 2 hours. 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. 1 H NMR (400MHz, CD3OD) δ8.81(s,1H),8.30(d,J=6.0Hz,1H),7.66(d,J=6.0Hz,1H),7.52–7.47(m,3H),7.42(t,J=7.4Hz,3H),6.70(s,1H),4.67(s ,2H),4.64(s,2H),3.28(d,J=6.9Hz,2H),1.86(d,J=12.5Hz,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 min.

[0626] Compound 79 was prepared based on step 2 in Scheme 26:

[0627]

[0628] Scheme 27. Synthesis of N-((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)-2-(5-phenyl-2-((3-phenylpropyl)amino)-75-pyridin-4-yl)acetamide (Compound 80)

[0629]

[0630] Step 1: Ethyl 2-(2-chloropyridin-4-yl)acetate (2)

[0631] 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 hour. 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 hours. The mixture was quenched with saturated NH4Cl aqueous solution 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) + .

[0632] Step 2: Ethyl 2-(2-((tert-Butoxycarbonyl)amino)pyridin-4-yl)acetate (3)

[0633] To a mixture of ethyl 2-(2-chloropyridin-4-yl)acetate (1.5 g, 7.5 mmol) and NH2Boc (2.6 g, 22.6 mmol) in THF (20 mL) under N2 atmosphere were added Cs2CO3 (3.68 g, 11.3 mmol), Xant-Phos (218 mg, 0.4 mmol) and Pd2(dba)3 (173 mg, 0.2 mmol), the mixture was degassed ten times under N2 atmosphere and stirred overnight at 75°C under N2 atmosphere. The reaction 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, 0-20% 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) + .

[0634] Step 3: Ethyl 2-(5-bromo-2-((tert-butoxycarbonyl)amino)pyridin-4-yl)acetate (4)

[0635] 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 hours. The mixture was diluted with EtOAc, washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (silica gel, 0-20% 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) + .

[0636] Step 4: Ethyl 2-(2-((tert-Butoxycarbonyl)amino)-5-phenylpyridin-4-yl)acetate (5)

[0637] 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 H2O (1.5 mL) under N2 atmosphere were added Na2CO3 (666 mg, 9.6 mmol) and Pd(PPh3)4 (242 mg, 0.21 mmol), the mixture was degassed ten times under N2 atmosphere and stirred overnight at 80°C under N2 atmosphere. The reaction 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, 0-20% 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) + .

[0638] Step 5: Ethyl 2-(2-amino-5-phenylpyridin-4-yl)acetate hydrochloride (6)

[0639] 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 hours. 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) + .

[0640] Step 6: Ethyl 2-(5-phenyl-2-((3-phenylpropyl)amino)pyridin-4-yl)acetate (7)

[0641] 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 NaBH3CN (196 mg, 2.34 mmol) under N2 atmosphere and the reaction mixture was stirred at 50 ° C for 2 hours. 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, 0-80% 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) + .

[0642] Step 7: 2-(5-phenyl-2-((3-phenylpropyl)amino)pyridin-4-yl)acetic acid (8)

[0643] 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·H2O (27 mg, 0.64 mmol) and the reaction mixture was stirred at 25°C for 2 hours. The mixture was acidified to pH ~6 with 1N aqueous HCl and extracted twice with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, 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) + .

[0644] 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)

[0645] 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) under N2 atmosphere was added DIPEA (179 mg, 1.38 mmol) and HATU (131 mg, 0.35 mmol), and the reaction mixture was stirred at room temperature for 2 hours. The mixture was diluted with EtOAc, washed with saturated aqueous NH4Cl solution 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. 1 H NMR (400MHz, CD3OD) δ8.69(s,1H),8.10(d,J=5.8Hz,1H),7.76(s,1H),7.36(d,J=5.8Hz,1H),7.27-7.23(m,7H),7.21–7.1 5(m,3H),6.48(s,1H),6.42(s,1H),4.45(s,2H),3.49(s,2H),3.26(d,J=7.0Hz,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 min.

[0646] 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)

[0647]

[0648] Step 1: 1-(2-(tert-Butoxy)-2-oxoethyl)-6-oxo-2-phenyl-1,6-dihydropyrimidine-5-carboxylic acid (2)

[0649] 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·H O (23 mg, 0.56 mmol) and the reaction mixture was stirred at -5°C for 2 hours. The mixture was acidified to pH ˜3 with 1N aqueous HCl and extracted twice with EtOAc. The combined organic layers were dried over anhydrous Na SO , filtered, and concentrated to dryness under reduced pressure to give 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) + .

[0650] Step 2: tert-Butyl 2-(5-((2-aminophenyl)carbamoyl)-6-oxo-2-phenylpyrimidin-1(6H)-yl)acetate (3)

[0651] 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 N2 atmosphere, and the reaction mixture was stirred at room temperature for 2 hours. The mixture was diluted with EtOAc, washed with saturated aqueous NH4Cl solution 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) + .

[0652] Step 3: 2-(5-(1H-benzo[d]pyridin-2-yl)-6-oxo-2-phenylpyrimidin-1(6H)-yl)acetic acid (4)

[0653] 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. in a CEM microwave reactor for 2 hours. The mixture was filtered, and the filter cake was dried under vacuum to give the title compound as a white solid (30 mg, 45.5% yield). LC / MS (ESI) m / z: 347 (M+H) + .

[0654] 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)

[0655] 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) under N atmosphere were added DIPEA (70 mg, 0.54 mmol) and HATU (51 mg, 0.14 mmol), and the reaction mixture was stirred at room temperature for 2 hours. 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 (400MHz, CD3OD) δ9.43(s,1H),8.46(s,1H),8.32(d,J=7.3Hz,2H),8.05(d,J=6.2Hz,1H),7.70–7. 66(m,2H),7.39(d,J=7.3Hz,1H),7.31(dt,J=7.2,4.3Hz,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 min.

[0656] Compounds 81 and 425 were prepared based on Scheme 28:

[0657]

[0658]

[0659] a Only steps 2-4. b Only step 4.

[0660] 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)-dibenzohexane-12-carboxamide (Compound 83)

[0661]

[0662] Step 1: 1,4(1,4)-diphenylhexane-1 2 -Methyl formate (2)

[0663] In N2 atmosphere, 0℃ to 1 2 -Bromo-1,4(1,4)-diphenylheterocyclohexane (100 mg, 0.35 mmol) was added to a mixture of 1,4-dioxane (15 mL) with Pd(dppf)Cl2 (25.4 mg, 0.035 mmol). 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 Na2SO4, 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) + .

[0664] Step 2: 1,4(1,4)-diphenylhexane-1 2 -Formic acid (3)

[0665] To a solution of 1,4(1,4)-dibenzohexane-12-carboxylic acid methyl ester (57 mg, 0.21 mmol) in THF / MeOH / H2O (6 mL, 4 / 1 / 1) was added LiOH·H2O (26.5 mg, 0.69 mmol) under N2 atmosphere and the reaction mixture was stirred at 60°C overnight. The mixture was acidified to pH~3 with 1N aqueous HCl solution and extracted twice with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, 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) + .

[0666] 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)-dibenzohexane-1 2 -Formamide (Compound 83)

[0667] To a mixture of 1,4(1,4)-dibenzohexane-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 N atmosphere, and the reaction mixture was stirred at room temperature for 2 hours. The mixture was diluted with EtOAc, washed with saturated aqueous NH4Cl solution 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, 6.7% yield) as a white solid. 1 H NMR (400MHz, CD3OD) δ8.74(s,1H),7.50(t,J=6.1Hz,3H),7.43(t,J=7.3Hz,4H),6.93–6.73(m,3H),6.71 (d,J=5.1Hz,2H),6.62(s,2H),6.38(d,J=8.0Hz,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 min.

[0668] Scheme 30. Synthesis of N-((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)-2-(5-((3-(4-(N-cyano-S-methylsulfonylimino)phenyl)propyl)amino)-6-oxo-2-phenylpyrimidin-1(6H)-yl)acetamide (Compound 84)

[0669]

[0670] Step 1: (E)-N-((4-(3-((tert-butyldimethylsilyl)oxy)propyl)phenyl)(methyl)-14-sulfanylidene)cyanamide (2)

[0671] To a solution of tert-butyldimethyl(3-(4-(methylthio)phenyl)propoxy)silane (150 mg, 0.51 mol) in MeCN (2 mL) was added NHCN (28 mg, 0.67 mmol), t-BuOK (0.6 mL, 1.18 mmol) and NBS (135 mg, 0.76 mmol) under N atmosphere and the mixture was stirred at room temperature for 3 hours. 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) + .

[0672] Step 2: N-((4-(3-((tert-butyldimethylsilyl)oxy)propyl)phenyl)(methyl)(oxo)-16-sulfanylidene)cyanamide (2)

[0673] 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 H2O (0.3 mL) was added K2CO3 (148 mg, 1.07 mmol) and m-CPBA (92 mg, 0.53 mmol) under N2 atmosphere, and the reaction mixture was stirred at room temperature overnight. The mixture was diluted with EtOAc, washed with aqueous Na2S2O3 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 the title compound (85 mg, 67.6% yield) as a colorless oil. LC / MS (ESI) m / z: 353 (M+H) + .

[0674] Step 3: N-((4-(3-Hydroxypropyl)phenyl)(methyl)(oxo)-16-sulfanylidene)cyanamide (3)

[0675] 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 hour. The mixture was diluted with EtOAc, washed with 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) + .

[0676] Step 4: N-(methyl(oxo)(4-(3-oxopropyl)phenyl)-16-sulfanylidene)cyanamide (4)

[0677] 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 3 (100 mg, 0.62 mmol) and TEA (98 mg, 0.97 mmol) at 0° C. and the mixture was stirred under N 2 atmosphere at room temperature for 2 hours. The mixture was diluted with water and extracted twice with DCM. The combined organic layers were washed with aqueous Na 2 S 2 O 3 solution, dried over anhydrous Na 2 SO 4 , 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) + .

[0678] Step 5: N-((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)-2-(5-((3-(4-(N-cyano-S-methylsulfonylimino)phenyl)propyl)amino)-6-oxo-2-phenylpyrimidin-1(6H)-yl)acetamide (Compound 84)

[0679] 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) at 0° C. was added NaBH 3 CN (12 mg, 0.19 mol) and the reaction mixture was stirred at 50° C. for 4 hours. 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. 1 H NMR (400MHz, CD3OD) δ8.77(s,1H),8.15(d,J=6.0Hz,1H),7.98(d,J=8.5Hz,2H),7.63(d,J=8.4Hz,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=6.8Hz,2H),2.96–2.90(m,2H),2.10–2.02(m,2H). LC / MS(ESI)m / z:595(M+H) + . RT (Method A): 1.02min.

[0680] 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)

[0681]

[0682] Step 1: Methyl 2-(2-methyl-3-nitrophenyl)acetate (2)

[0683] 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) and refluxed for 18 hours at room temperature. The reaction mixture was cooled to room temperature and added to a 20% sodium carbonate solution (100 mL). The reactants were 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 obtain the title product (1.9 g, 91.0%) as a colorless oil, which was used directly in the next step without further purification.

[0684] Step 2: Methyl 2-(3-amino-2-methylphenyl)acetate (2)

[0685] 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.), the mixture was degassed three times under a 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 as a yellow solid (0.78 g, 49% yield), which was used directly in the next step without further purification. LC / MS (ESI) m / z: 180 (M+H) + .

[0686] Step 3: Methyl 2-(3-amino-6-bromo-2-methylphenyl)acetate (3)

[0687] To a solution of methyl 2-(3-amino-2-methylphenyl)acetate (0.78 g, 4.4 mmol) in CH3CN (3 mL) was added N-bromosuccinimide (0.78 g, 4.4 mmol) at room temperature. After 2 hours, the reaction mixture was concentrated and the residue was partitioned between dichloromethane and water. The organic layer was washed with an aqueous Na2S2O3 solution, 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 (0.86 g, 76% yield) as a white solid. LC / MS (ESI) m / z: 258 (M+H) + .

[0688] Step 4: Methyl 2-(4-amino-3-methyl-[1,1'-biphenyl]-2-yl)acetate (4)

[0689] 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) under N2 atmosphere at 25°C were added K3PO4 (1.3 g, 5.94 mmol) and Pd(PPh3)4 (110 mg, 0.096 mmol) and the reaction mixture was degassed three times under N2 atmosphere and stirred at 100°C. After 1 hour, 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, 0-10% EtOAc in PE) to give the title compound (460 mg, 91% yield) as a colorless solid. LC / MS (ESI) m / z: 256 (M+H) + .

[0690] Step 5: Methyl 2-(3-methyl-4-((3-phenylpropyl)amino)-[1,1'-biphenyl]-2-yl)acetate (5)

[0691] 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 NaBH3CN (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) + .

[0692] Step 6: 2-(3-Methyl-4-((3-phenylpropyl)amino)-[1,1'-biphenyl]-2-yl)acetic acid (6)

[0693] 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 / H2O (6 mL, 4 / 1 / 1) was added LiOH·H2O (9.5 mg, 0.225 mmol) under N2 atmosphere and the reaction mixture was stirred at 100°C overnight. The mixture was acidified to pH~3 with 1N aqueous HCl solution and extracted twice with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, 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) + .

[0694] 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)

[0695] 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) under N2 atmosphere were added DIPEA (36 mg, 0.28 mmol) and HATU (25.6 mg, 0.068 mol), and the reaction mixture was stirred at room temperature for 2 hours. The mixture was diluted with EtOAc, washed with saturated aqueous NH4Cl solution 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. 1 H NMR (400MHz, DMSO) δ11.31(s,1H),8.74(s,1H),8.29(t,J=5.7Hz,1H),8.12(d,J= 5.6Hz,1H),7.35–7.24(m,10H),7.19(t,J=7.0Hz,1H),6.88(d,J=8.3Hz,1H),6.50 (d,J=8.4Hz,1H),6.36(s,1H),4.86(t,J=5.5Hz,1H),4.44(d,J=5.6Hz,2H),3.45 (s,2H),3.15–3.08(m,2H),2.71(t,J=7.6Hz,2H),1.98(s,3H),1.96–1.89(m,2H). LC / MS(ESI)m / z:489(M+H) + . RT (Method A): 1.92 min.

[0696] 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)

[0697]

[0698] Step 1: tert-Butyl 2-(2-(4-(oxetan-3-yloxy)phenyl)-6-oxo-5-((3-phenylpropyl)amino)pyrimidin-1(6H)-yl)acetate (2)

[0699] 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 3-oxetane-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 light yellow solid. LC / MS (ESI) m / z: 492 (M+H) + .

[0700] Step 2: 2-(2-(4-(oxetan-3-yloxy)phenyl)-6-oxo-5-((3-phenylpropyl)amino)pyrimidin-1(6H)-yl)acetic acid (3)

[0701] 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 hours. The mixture was concentrated, diluted with EtOAc, washed with saturated aqueous NaHCO 3 solution, dried over anhydrous Na 2 SO 4 , 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.

[0702] 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)

[0703] 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) under N atmosphere was added DIPEA (36.8 mg, 0.285 mmol) and HATU (32 mg, 0.084 mol), and the reaction mixture was stirred at room temperature for 2 hours. The mixture was diluted with EtOAc, washed with saturated aqueous NH4Cl solution 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, 18.4% yield) as a white solid. 1 H NMR (400MHz, CD3OD) δ8.74(s,1H),8.13(d,J=5.9Hz,1H),7.43–7.39(m,2H),7.30–7.14(m,5H),7.06(s,1H),6.72(d,J=8.7Hz,2H),6.50(s,1H), 5.18(t,J=5.4Hz,1H),4.95(t,J=6.6Hz,2H),4.63(t,J=6.0Hz,4H),4.54 (s,2H),3.17(t,J=6.9Hz,2H),2.74(t,J=7.6Hz,2H),2.02–1.90(m,2H). LC / MS(ESI)m / z:564(M+H) + . RT (Method A): 1.37 min.

[0704] 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)

[0705]

[0706] Step 1: tert-Butyl 2-(2-(methylsulfonyl)-6-oxo-5-((3-phenylpropyl)amino)pyrimidin-1(6H)-yl)acetate (2)

[0707] 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) at 0° C. was added m-CPBA (44 mg, 0.36 mmol) and the mixture was stirred at room temperature for 3 hours. The mixture was quenched with aqueous Na2S2O3 and washed twice with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, 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) + .

[0708] 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)

[0709] 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 hours. Tert-butyl 2-(2-(methylsulfonyl)-6-oxo-5-((3-phenylpropyl)amino)pyrimidin-1(6H)-yl)acetate (50 mg, 0.12 mmol) was then added to DMF (1 mL) 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) + .

[0710] 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)

[0711] 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) + .

[0712] 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)

[0713] 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 N atmosphere and the reaction mixture was stirred at room temperature for 1 hour. 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 (400MHz, CD3OD) δ8.71(d,J=0.8Hz,1H),8.10(d,J=5.8Hz,1H),7.38(d,J=5.8Hz,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=5.6Hz,1H),4.89(d,J=16.0Hz,1H),4.79(t,J=5.2Hz,1H),4.73(d,J=16.0 Hz,1H),4.57(dd,J=9.2,4.4Hz,3H),3.99(dd,J=9.9,6.0Hz,1H),3.96–3.91(m,1H),3.91–3.86(m,1H),3.83(dd,J=9.9 ,5.2Hz,1H),3.51(t,J=8.1Hz,1H),3.42(s,3H),3.04(t,J=7.0Hz,2H),2.74–2.69(m,2H),1.95(dd,J=15.0,7.2Hz,2H). LC / MS(ESI)m / z:575(M+H) + . RT (Method A): 1.30 min.

[0714] 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)

[0715]

[0716] Step 1: Diethoxyphosphorylmethyl 4-chlorobenzenesulfonate (2)

[0717] 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 for 17 hours at N2 and 25 ° C. The mixture was diluted with H2O 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 (3.2 g, 78% yield) as a yellow oil. LC / MS (ESI) (m / z): 343 (M+H) + .

[0718] Step 2: tert-Butyl 2-(2-(4-((diethoxyphosphoryl)methoxy)phenyl)-6-oxo-5-((3-phenylpropyl)amino)pyrimidin-1(6H)-yl)acetate (3)

[0719] 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 N2 at 25°C for 3 hours. The mixture was diluted with H2O 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 (40 mg, 30% yield) as a white solid. LC / MS (ESI) (m / z): 586 (M+H) + .

[0720] Step 3: 2-(2-(4-((diethoxyphosphoryl)methoxy)phenyl)-5-(hex-5-en-1-ylamino)-6-oxopyrimidin-1(6H)-yl)acetic acid (4)

[0721] 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) was added. The mixture was stirred at 25° C. for 1 hour. 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) + .

[0722] 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)

[0723] 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) were 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. 1 H NMR (400MHz, CD3OD) δ8.72(d,J=0.9Hz,1H),8.11(d,J=5.8Hz,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=10.0Hz,2H),4.27–4.18(m,4H),3.16(t,J=7.0Hz ,2H),2.79–2.69(m,2H),2.04–1.93(m,2H),1.35(t,J=7.1Hz,6H).LC / MS(ESI)(m / z):659(M+H) + . RT (Method A): 1.53 min.

[0724] 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)

[0725]

[0726] Step 1: 3-(4-Bromophenyl)propanal (2)

[0727] 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 hour. Silica gel was added and the mixture was stirred at room temperature for 0.5 hours. 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.

[0728] 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)

[0729] 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 NaBH3CN (134 mg, 2.1 mmol) under N2 atmosphere and the reaction mixture was stirred at 50 ° C. overnight. The mixture was diluted with EtOAc, 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 (40 mg, 26.3% yield) as a white solid. LC / MS (ESI) m / z: 571 (M+H) + .

[0730] 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)

[0731] 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 diethyl methylphosphite (48 mg, 0.35 mmol) in DMF (2 mL) was 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 in a CEM microwave reactor at 130 ° C. for 30 minutes. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na SO, 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) + .

[0732] 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)

[0733] 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) was added LiOH.HO (4 mg, 0.09 mmol) 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 (400MHz, CD3OD) δ8.95 (s, 1H), 8.36 (s, 1H), 8.23 ​​(d, J = 6.6Hz, 1H), 7.83 (d,J=6.5Hz,1H),7.70(m,2H),7.53–7.47(m,3H),7.44(d,J=7.5Hz,2H),7.2 4(d,J=6.4Hz,2H),7.14(s,1H),6.86(s,1H),4.63(d,J=6.3Hz,4H),3.19(t ,J=6.7Hz,2H),2.75(t,J=7.7Hz,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 min.

[0734] 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)

[0735]

[0736] Step 1: (3R,3aR,6R,6aS)-6-((tert-butyldiphenylsilyl)oxy)hexahydrofuro[3,2-b]furan-3-ol (2)

[0737] 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) at 0°C was added TBDPSCl (33.9 g, 123.2 mmol) and imidazole (21.0 g, 308.2 mmol) and the mixture was stirred at room temperature for 4 hours. 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. 1HNMR(400MHz, CDCl3)δ7.78–7.73(m,2H),7.70–7.66(m,2H),7.47–7.38(m,6H),4.35( d,J=5.2Hz,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) + .

[0738] Step 2: tert-Butyl(((3R,3aS,6R,6aR)-6-methoxyhexahydrofuro[3,2-b]furan-3-yl)oxy)diphenylsilane (3)

[0739] 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 mixture was stirred at 0 ° C for 0.5 hours. To the mixture was added iodomethane (2.8 g, 19.5 mmol) at 0 ° C and the resulting mixture was stirred at room temperature for 3 hours. 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) + .

[0740] Step 3: (3R,3aR,6R,6aR)-6-methoxyhexahydrofuro[3,2-b]furan-3-ol (4)

[0741] 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 HNMR (400MHz, CDCl3) δ4.57(t,J=4.8Hz,1H),4.51(t,J=5.2Hz,1H),4.27(q,J =5.9Hz,1H),4.07(m,1H),4.01–3.92(m,2H),3.73–3.65(m,2H),3.47(s,3H).

[0742] Step 4: (3R,3aR,6R,6aR)-3-(allyloxy)-6-methoxyhexahydrofuro[3,2-b]furan (5)

[0743] 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) under N2 atmosphere, followed by 3-iodoprop-1-ene (1.3 g, 7.5 mmol), 2,6-di-tert-butylpyridine (1.4 g, 7.5 mmol) and the mixture was stirred at 30 ° C for 16 hours. 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, 0-15% MeOH in DCM) to give the title compound (320 mg, 85.3% yield) as a yellow oil. 1 H NMR(400MHz, CDCl3)δ5.93(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).

[0744] Step 5: 3-(((3R,3aR,6R,6aR)-6-methoxyhexahydrofuro[3,2-b]furan-3-yl)oxy)propan-1-ol (6)

[0745] 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 dropwise BH .THF (1.1 mL, 1.1 mmol) at 0° C. and the reaction was stirred at 0° C. for 2.5 hours. NaOH (1.0 mL, 10 M in water) and H O (1.0 mL, 30 wt.%) were added to the mixture at 0° C. The resulting mixture was stirred at room temperature for 0.5 hours. Water was added to the mixture 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, 0-10% MeOH in DCM) to give the title compound (120 mg, 68.8% yield) as a colorless oil. 1 H NMR (400MHz, CDCl3) δ4.62(m,2H),4.06(t,J=7.2Hz,3H),3.92(m,2H),3.78–3.65(m,5H),3.46(s,3H),1.83(m,2H).

[0746] Step 6: 3-(((3R,3aR,6R,6aR)-6-methoxyhexahydrofuro[3,2-b]furan-3-yl)oxy)propanal (7)

[0747] 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 hours. The mixture was quenched with aqueous Na2S2O3 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, 0-20% MeOH in DCM) to give the title compound (60 mg, 79.3% yield) as a yellow oil.

[0748] 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)

[0749] 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) was added NaBHCN (15 mg, 0.24 mmol) under N atmosphere and the reaction mixture was stirred at 50° C. for 16 hours. 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 (400MHz, CD3OD) δ8.71(s,1H),8.11(d,J=5.8Hz,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 min.

[0750] Scheme 37. N-((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)-2-(6-oxo-2-(4-(pentafluoro-λ 6 Synthesis of 5-((3-phenylpropyl)amino)pyrimidin-1(6H)-yl)acetamide (Compound 96)

[0751]

[0752] Step 1: 4,4,5,5-tetramethyl-2-(4-(pentafluoro-λ 6 -sulfanyl)phenyl)-1,3,2-dioxaborolane (2)

[0753] Under N2 atmosphere, (4-bromophenyl)pentafluoro-λ 6-sulfane (500 mg, 1.78 mmol) and Pin2B2 (1.8 g, 7.12 mmol) were added to a mixture of 1,4-dioxane (1 mL) with Pd(PPh3)2Cl2 (385 mg, 0.55 mmol) and KOAc (524 mg, 5.34 mmol). The reaction mixture was degassed three times under a N2 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 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) + .

[0754] Step 2: (4-(pentafluoro-λ 6 -sulfanyl)phenyl)boronic acid (3)

[0755] To a solution of 4,4,5,5-tetramethyl-2-(4-(pentafluoro-λ-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 hours. 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.

[0756] Step 3: tert-Butyl 2-(2-(methylthio)-6-oxo-5-((3-phenylpropyl)amino)pyrimidin-1(6H)-yl)acetate (3)

[0757] 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) was added CsCO (974 mg, 2.99 mmol), BINAP (187 mg, 0.3 mmol) and Pd(OAc) (34 mg, 0.15 mmol) under N2 atmosphere. The reaction mixture was degassed three times under N2 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 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 (170 mg, 29.3% yield) as a brown oil. LC / MS (ESI) m / z: 390 (M+H) + .

[0758] Step 4: 2-(6-oxo-2-(4-(pentafluoro-λ 6 -sulfanyl)phenyl)-5-((3-phenylpropyl)amino)pyrimidin-1(6H)-yl)acetate (4)

[0759] Under N2 atmosphere, 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 6 To a mixture of ((thiophene-2-carbonyl)oxy)copper (185 mg, 0.044 mmol) and Pd(PPh3)4 (51 mg, 0.044 mmol) in THF (3 mL) was added 2-((thiophene-2-carbonyl)oxy)copper) (185 mg, 0.044 mmol) and Pd(PPh3)4 (51 mg, 0.044 mmol), and the reaction mixture was degassed three times under an 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 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) + .

[0760] Step 5: 2-(6-oxo-2-(4-(pentafluoro-λ 6 -sulfanyl)phenyl)-5-((3-phenylpropyl)amino)pyrimidin-1(6H)-yl)acetate (5)

[0761] 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 N2 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) + .

[0762] 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)

[0763] 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) under N₂ atmosphere were added DIPEA (50 mg, 0.38 mmol) and HATU (35 mg, 0.09 mmol), and the reaction mixture was stirred at room temperature for 2 hours. 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 preparative TLC (DCM:MeOH=15:1) to give compound 96 (1.2 mg, yield 2.2%) as a yellow solid. 1 H NMR (400MHz, CD3OD) δ8.75(s,1H),8.14(d,J=5.7Hz,1H),7.80(d,J=8.8Hz,2H),7.67(d,J=8.2Hz,2H),7.47(d,J=5.1Hz,1H),7.30–7. 21(m,4H),7.17(d,J=7.0Hz,1H),6.56(s,1H),4.58(d,J=16.9Hz,4H),3.19(t,J=7.0Hz,2H),2.75(t,J=7.7Hz,2H),2.05–1.91(m,2H). LC / MS(ESI)m / z:619(M+H) + . RT (Method A): 1.89 min.

[0764] 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)

[0765]

[0766] Step 1: 3-(4-iodophenoxy)oxetane (2)

[0767] To a mixture of 4-methylbenzenesulfonic acid oxetane-3-ester (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) at 0°C under an N atmosphere and the reaction mixture was degassed three times under an N atmosphere 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 (400MHz, CDCl3) δ7.57–7.53(m,2H), 6.49–6.46(m,2H), 5.18–5.12(m,1H), 4.95(t,J=6.9Hz,2H), 4.75–4.71(m,2H).

[0768] Step 2: 3-(4-(Oxetane-3-yloxy)phenyl)prop-2-yn-1-ol (3)

[0769] 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) under N₂ atmosphere were added CuI (49 mg, 0.25 mmol) and Pd(PPh₃)₂Cl₂ (178 mg, 0.25 mmol). The mixture was degassed ten times under N₂ atmosphere and stirred at room temperature under N₂ atmosphere for 2 hours. The reaction 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 the title compound (426 mg, 80.8% yield) as a yellow solid. 1 H NMR (400MHz, CDCl3) δ7.36 (d, J = 7.7Hz, 2H), 6.63 (d, J = 7.7Hz, 2H), 5.24–5.17 (m, 1H), 4.97 (t, J = 6.4Hz, 2H), 4.75 (t, J = 5.7Hz, 2H), 4.48 (s, 2H).

[0770] Step 3: 3-(4-(Oxetane-3-yloxy)phenyl)propan-1-ol (4)

[0771] To a solution of 3-(4-(oxetan-3-yloxy)phenyl)prop-2-yn-1-ol (426 mg, 2.01 mmol) in MeOH (4 mL) was added Pd / C (40 mg, 10 wt.%), the mixture was degassed three times under a N atmosphere and stirred under a H balloon at room temperature overnight. The mixture was filtered, and the filtrate was concentrated to dryness to give the title compound (390 mg, 58.9% yield) as a yellow oil, which was used directly in the next step without further purification.

[0772] Step 4: 3-(4-(Oxetane-3-yloxy)phenyl)propanal (5)

[0773] To a solution of 3-(4-(oxetan-3-yloxy)phenyl)propan-1-ol (90 mg, 0.43 mmol) in DCM (2 mL) was added DMP (275 mg, 0.65 mmol) under an N atmosphere, and the reaction mixture was stirred at room temperature for 2 hours. The mixture was diluted with EtOAc, washed with aqueous NaHCO and brine, dried over anhydrous NaSO, filtered, and concentrated to dryness under reduced pressure. The residue was purified by preparative TLC (PE:EtOAc = 10:1) to give the title compound (49 mg, 53.2% yield). 1 HNMR(400MHz, CDCl3)δ9.83(t,J=1.4Hz,1H),7.40(s,1H),7.37(s,1H),6.78(s,1H),6.75(s,1 H), 5.03 (s, 3H), 4.98 (s, 1H), 4.82 (s, 1H), 2.93 (t, J = 7.4Hz, 2H), 2.78 (dd, J = 10.6, 3.4Hz, 2H).

[0774] Step 5: N-((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)-2-(5-((3-(4-(oxetan-3-yloxy)phenyl)propyl)amino)-6-oxo-2-phenylpyrimidin-1(6H)-yl)acetamide (Compound 103)

[0775] To a mixture of 3-(4-(oxetan-3-yloxy)phenyl)propanal (30 mg, 0.14 mmol) and N-((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)-2-(5-amino-6-oxo-2-phenylpyrimidin-1(6H)-yl)acetamide hydrochloride (26 mg, 0.07 mol) in MeOH (2 mL) was added MgSO (60 mg, 0.49 mmol) and NaBHCN (120 mg, 1.9 mmol) under N atmosphere and the reaction mixture was stirred at 50 ° C. for 2 hours. 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 HPLC to give Compound 103 (1 mg, 2.5% yield) as a white solid. 1 H NMR (400MHz, CD3OD) δ8.85(s,1H),8.19(d,J=6.2Hz,1H),7.61(d,J=6.0Hz,1H),7.48( d,J=7.2Hz,3H),7.41(dd,J=6.6,2.9Hz,2H),7.26(d,J=8.6Hz,1H),7.16–7.07(m,2H) ,6.78(d,J=8.6Hz,1H),6.66(d,J=6.4Hz,2H),4.70–4.65(m,4H),4.58(s,4H),4.06(d ,J=5.9Hz...

Claims

1. A compound of formula (I): or a pharmaceutically acceptable salt thereof, in R 1 and R 1 'Each of which is independently H or an optionally substituted C1-C6 alkyl; X is CR 3 or N; X ’ 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, or optionally substituted (4- to 10-membered heterocyclyl)oxy, or optionally substituted (5- to 9-membered heteroaryl)oxy; R 3 and R 4 Each of 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; L 2 is a bond or an optionally substituted C1-C6 alkylene group; L 3 for bonds, NH, NHC(O), C(O), O, S(O)2CH2; B is halogen, optionally substituted C6-C 14 Aryl, optionally substituted C3-C 14 carbocyclyl, optionally substituted 5- to 14-membered heterocyclyl; or optionally substituted 5- to 10-membered heteroaryl; and Y is in Y 1 O, S, NR d , where each R d are independently absent, H or C1-C6 alkyl; Y 1’ O, S, NR d or C(R d )2; Y 2 and Y 3 Each of which is independently NR e or C(R e )2, where each R e are 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 two R e Combine to form oxo; Y 4 , Y 4’ , Y 10 and Y 13 Each of which is independently CR e or N; Y 5 , Y 6 and Y 7 Each of which is independently O, S, NR f or C(R f )2, where each R f are independently absent; H; optionally substituted C1-C6 alkyl; halo; or N(R g )2; or two R f Combine to form oxo; Y 8 and Y 9 Each of which is independently C(R f )2 or NR f ; Y 11 and Y 12 Each of which is independently NR e , C(R e )2, S or O; each 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 Two R's combine to form oxo; or Two R's combine to form oxo; and q is 0 or 1; The premise is that at least one of the following is true: (i)-L 1 -L 2 -L 3 - Not combined to form (ii) R 2 Not a C1-C6 alkyl group, (iii) B does not (iv) R 1 and R 1’ At least one of is not H; (v) X is N; (vi)X ’ CR 4 ,and (vii) Y does not 2. The compound of claim 1, wherein R 1 For H.

3. The compound according to claim 1 or 2, wherein R 1 ' is H or methyl.

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

5. The compound of claim 4, wherein X is CCH3.

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

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

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

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

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

11. The compound of claim 10, wherein R 2 It is phenyl optionally substituted by one or more substituents independently selected from halogen; 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.

12. The compound of claim 10, wherein R 2 for 13. A compound as claimed in any one of claims 1 to 9, wherein R 2 is an optionally substituted (4- to 10-membered heterocyclyl)oxy group.

14. The compound of claim 13, wherein R 2 for 15. A compound as claimed in any one of claims 1 to 9, wherein R 2 is an optionally substituted 4- to 10-membered heterocyclic group.

16. The compound of claim 15, wherein R 2 for 17. A compound as described in any one of claims 1 to 9, wherein R 2 is an optionally substituted 5- to 10-membered heteroaryl group.

18. The compound of claim 17, wherein R 2 for 19. A compound as described in any one of claims 1 to 9, wherein R 2 is an optionally substituted C3-C8 cycloalkyl group.

20. The compound of claim 19, wherein R 2 for 21. A compound as described in any one of claims 1 to 9, wherein R 2 It is an optionally substituted C3-C8 cycloalkenyl group.

22. The compound of claim 21, wherein R 2 for 23. A compound as described in any one of claims 1 to 9, wherein R 2 For H.

24. A compound as described in any one of claims 1 to 9, wherein R 2 For CH3.

25. The compound of any one of claims 1 to 24, wherein L 1 is the key.

26. A compound as described in any one of claims 1 to 24, wherein L 1 For NH.

27. A compound as described in any one of claims 1 to 24, wherein L 1 It is NHC(O).

28. A compound as described in any one of claims 1 to 27, wherein L 2 is the key.

29. The compound of any one of claims 1 to 27, wherein L 2 is an optionally substituted C1-C6 alkylene group.

30. The compound of claim 29, wherein L 2 are –CH2–, –(CH2)2–, –(CH2)3–, –(CH2)4–, –(CH2)5–, 31. A compound as described in any one of claims 1 to 30, wherein L 3 is the key.

32. A compound as described in any one of claims 1 to 30, wherein L 3 It is NHC(O).

33. A compound as described in any one of claims 1 to 30, wherein L 3 is C(O).

34. A compound as described in any one of claims 1 to 30, wherein L 3 is O.

35. A compound as described in any one of claims 1 to 34, wherein B is an optionally substituted C6-C 14 aryl or optionally substituted 5- to 10-membered heteroaryl.

36. The compound of claim 35, wherein the compound is of formula (II): or a pharmaceutically acceptable salt thereof, wherein X 1 CR 9 or N; R 5 , R 6 and R 9 Each of which is independently selected from H, halo, CN, SF5, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, S(O)(NH)CH3, S(O)2CH3, and S(O)(NCN)CH3; and R 7 and R 8 Each of the above is independently H, halogen, 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, provided that R 7 and R 8 No more than one of them is an 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; or R 7 and R 8 Together with the atoms to which they are attached, they form an optionally substituted 5- to 6-membered heterocyclyl, an optionally substituted 5- to 10-membered heteroaryl, or an optionally substituted C6-C 14 aryl; or R 5 and A are combined to form an optionally substituted C1-C2 alkylene group; R 6 and R 9 Combine to form (C2-C6 alkylene) (C6-C 14 arylene) (C2-C6 alkylene), and each of R5, R7 and R8 is H.

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

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

39. A compound as described in any one of claims 36 to 38, wherein R 8 For H.

40. A compound as described in any one of claims 36 to 39, wherein R 7 is an optionally substituted phenyl group.

41. The compound of claim 40, wherein R 7 for 42. A compound as described in any one of claims 36 to 39, wherein R 7 is an optionally substituted 5- to 10-membered heteroaryl group.

43. The compound of claim 42, wherein R 7 for 44. A compound as described in any one of claims 36 to 39, wherein R 7 is an optionally substituted (5- to 10-membered heteroaryl)oxy group.

45. The compound of claim 44, wherein R 7 for 46. ​​A compound as described in any one of claims 36 to 39, wherein R 7 is an optionally substituted (4- to 10-membered heterocyclyl)oxy group.

47. The compound of claim 46, wherein R 7 for 48. A compound as described in any one of claims 36 to 39, wherein R 7 is an optionally substituted C3-C8 cycloalkyl group.

49. The compound of claim 48, wherein R 7 for 50. A compound as described in any one of claims 36 to 39, wherein R 7 is an optionally substituted 4- to 10-membered heterocyclic group.

51. The compound of claim 50, wherein R 7 for 52. A compound as described in any one of claims 36 to 38, wherein R 8 is an optionally substituted phenyl group.

53. The compound of claim 52, wherein R 8 for 54. A compound as described in any one of claims 36 to 38, wherein R 8 is an optionally substituted 5- to 10-membered heteroaryl group.

55. The compound of claim 54, wherein R 8 for 56. A compound as described in any one of claims 36 to 39 and 52 to 55, wherein R 7 For H.

57. A compound as described in any one of claims 36 to 56, wherein R 6 For H.

58. A compound as described in any one of claims 36 to 56, wherein R 6 is an optionally substituted C1-C6 alkoxy group.

59. The compound of claim 56, wherein R 6 It is OCH3.

60. A compound as described in any one of claims 36 to 56, wherein R 6 It is a halogen group.

61. The compound of claim 60, wherein R 6 For F.

62. A compound as described in any one of claims 36 to 61, wherein R 5 For H.

63. A compound as described in any one of claims 36 to 38, wherein R 6 and R 9 Combine to form (C2-C6 alkylene) (C6-C 14 arylene) (C2-C6 alkylene), and each of R5, R7 and R8 is H.

64. The compound of claim 63, wherein B is 65. The compound of claim 64, wherein B is 66. The compound of claim 35, wherein the compound is of formula (III): or a pharmaceutically acceptable salt thereof, wherein X 2 O; C(R h )2, where each R h are independently hydrogen, halogen or optionally substituted C1-C6 alkyl, or two R h Combine to form oxo; S(O)2 or NR h ; 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 are independently halo, CN, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy or optionally substituted C3-C8 cycloalkyl.

67. The compound of claim 35, wherein the compound is of formula (IV): or a pharmaceutically acceptable salt thereof, wherein X 2 O; C(R h )2, where each R h are independently hydrogen, halogen or optionally substituted C1-C6 alkyl, or two R h Combine to form oxo; S(O)2 or NR h ; 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 are independently halo, CN, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy or optionally substituted C3-C8 cycloalkyl.

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

69. The compound of claim 66, wherein B is 70. The compound of claim 35, wherein B is an optionally substituted 5- to 10-membered heteroaryl.

71. The compound of claim 70, wherein B is 72. A compound as described in any one of claims 1 to 34, wherein B is an optionally substituted C3-C 14 carbocyclyl or optionally substituted 5- to 14-membered heterocyclyl.

73. The compound of claim 72, wherein the compound is of formula (V): or a pharmaceutically acceptable salt thereof, wherein X 3 and X 4 Each of the following is independently a bond; O; S; C(R d )2, where each R d are independently H, OH, halogen, optionally substituted C1-C6 alkyl or optionally substituted C1-C6 alkoxy, or two R d Combine to form oxo; NR e , where R e is H or C1-C6 alkyl; or SO2; X 5 CH, CR 13 or N; X 6 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 are independently halo, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy or optionally substituted C3-C8 cycloalkyl.

74. The compound of claim 72, wherein the compound is of formula (VI): or a pharmaceutically acceptable salt thereof, wherein X 3 and X 4 Each of the following is independently a bond; O; S; C(R i )2, where each R i are independently H, OH, halogen, optionally substituted C1-C6 alkyl or optionally substituted C1-C6 alkoxy, or two R i Combine to form oxo; NR j , where R j is H or C1-C6 alkyl; or SO2; X 5 CH, CR 13 or N; X 6 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 are independently halo, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy or optionally substituted C3-C8 cycloalkyl.

75. The compound of claim 73 or 74, wherein X 3 It is O, S or CF2.

76. A compound as described in any one of claims 73 to 75, wherein X 4 is the key.

77. The compound of claim 73, wherein B is 78. The compound of claim 74, wherein B is 79. A compound as described in any one of claims 1 to 34, wherein B is an optionally substituted C3-C 14 Carbocyclic group.

80. The compound of claim 79, wherein B is 81. The compound of any one of claims 1 to 34, wherein B is an optionally substituted 5- to 14-membered heterocyclyl.

82. The compound of claim 81, wherein B is 83. A compound as described in any one of claims 1 to 82, wherein Y is 84. The compound of claim 83, wherein Y is 85. The compound of claim 84, wherein Y 2 is N or CH.

86. The compound of claim 84 or 85, wherein Y 3 It is N or CH.

87. The compound of any one of claims 84 to 86, wherein Y 1 NH or S.

88. The compound of claim 83, wherein Y is 89. The compound of claim 88, wherein Y 1 For S.

90. The compound of claim 88 or 89, wherein Y 2 is NH or CH2.

91. The compound of any one of claims 88 to 90, wherein Y 3 is NH or CH2.

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

93. The compound of any one of claims 1 to 82, wherein Y is 94. A compound of Table 1 or a pharmaceutically acceptable salt thereof.

95. The compound of any one of claims 1 to 94 having complement C1 esterase (C1s) inhibitory activity.

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

97. A method of treating a C1s-mediated disorder comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I'): or a pharmaceutically acceptable salt thereof, in R 1 and R 1 'Each of which is independently H or an optionally substituted C1-C6 alkyl; X is CR 3 or N; X ’ CR 4 or N; R 2 is H, optionally substituted C1-C6 alkyl, optionally substituted C6-C 14 aryl, optionally substituted 5- to 10-membered heteroaryl, optionally substituted C3-C8 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; R 3 and R 4 Each of 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; L 2 is a bond or an optionally substituted C1-C6 alkylene group; L 3 for bonds, NH, NHC(O), C(O), O, S(O)2CH2; B is halogen, optionally substituted C6-C 14 Aryl; optionally substituted C3-C 14 carbocyclyl; optionally substituted 5- to 14-membered heterocyclyl; or optionally substituted 5- to 10-membered heteroaryl; and Y is in Y 1 O, S, NR d , where each R d are independently absent, H or C1-C6 alkyl; Y 1’ O, S, NR d or C(R d )2; Y 2 and Y 3 Each of which is independently NR e or C(R e )2, where each R e are 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 two R e Combine to form oxo; Y 4 , Y 4’ , Y 10 and Y 13 Each of which is independently CR e or N; Y 5 , Y 6 and Y 7 Each of which is independently O, S, NR f or C(R f )2, where each R f are independently absent; H; optionally substituted C1-C6 alkyl; halo; or N(R g )2; or two R f Combine to form oxo; Y 8 and Y 9 Each of which is independently C(R f )2 or NR f ; Y 11 and Y 12 Each of which is independently NR e , C(R e )2, S or O; each 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 Two R's combine to form oxo; or Two R's combine to form oxo; and q is 0 or 1; 98. The method of claim 97, wherein the compound is a compound as described in any one of claims 1 to 94, or a pharmaceutically acceptable salt thereof.

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

100. The method of claim 98 or 99, wherein the condition is acute antibody-mediated rejection, amyotrophic lateral sclerosis, autoimmune blistering 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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