WO2025207595A1 - Modulators of mannan-binding lectin-associated protease - Google Patents

Abstract

Provided herein are modulators of MASP represented by Formula (I); and pharmaceutically acceptable salts thereof. Also provided are pharmaceutical compositions comprising the compounds of Formula (I) and uses for treating conditions associate with modulation of MASP.

Description

125994-02220 MODULATORS OF MANNAN-BINDING LECTIN-ASSOCIATED PROTEASE R^ELATED A^PPLICATIONS [0001] This application claims the benefit of priority to U.S. Provisional Application No. 63/569,397, filed March 25, 2024, the entire contents of which are incorporated herein by reference. B^ACKGROUND [0002] Mannan-binding lectin-associated serine proteases (MASPs) are plasma proteins involved in activation of the lectin and alternative complement pathways. When the complex of MASP-1, MASP-2, and certain lectin-like pattern recognition proteins, including mannan- binding lectin, ficolins and collectins, encounter a stimulatory signal, the MASP-1 zymogen is activated by autolytic cleavage. MASP-1 then activates the MASP-2 zymogen proteolytically. MASP-2 then proteolytically activates the complement C2 zymogen and cleaves complement C4, leading to formation of the C3 convertase C2b4b of the lectin pathway. MASP-3 activates the alternative complement pathway by cleaving the zymogen of complement factor D. Three types of MASPs (MASP-1, MASP-2, and MASP-3) are complexed with MBL and ficolins in serum. MASP-1 and MASP-2 are known to contribute to complement activation, while MASP-3 is key for the conversion of profactor D to the active factor D thereby bridging the lectin and alternative pathways. MASP-3 is associated with pattern-recognition molecules as a homodimer and can be activated by MASP-1, MASP-2 and other MASP-3 molecules when these are bound to an activating surface. [0003] Inhibitors of MASP-2 and MASP-3 have gained attention for their therapeutic utility in treating various lectin-mediated disorders, including those associated with the alternative pathway of the complement system. See e.g., Int J Mol Sci. 2024 Feb; 25(3): 1566. However, the need remains for small molecule-based therapeutics which target the MASP pathway. S^UMMARY [0004] Provided herein are small molecule inhibitors of MASP-2 and/or MASP-3. Such molecules include compounds represented by Formula I: 1 ^{ME152554612v.1} 125994-02220 and pharmaceutically acceptable salts thereof, wherein X, R¹, R², R³, R^2’, R^3’, R⁴, R⁵, R⁶, R⁷, R⁸ and q are as described herein. Also provided are pharmaceutical compositions comprising the compounds of Formula I as well as their use for treating conditions associated with the inhibition of MASP-2 and/or MASP-3. D^ETAILED D^ESCRIPTION 1. General Description of Compounds [0005] In one of Formula I: or a pharmaceutically acceptable salt thereof, wherein X is N or CH; R¹ is selected from hydrogen, halo, (C1-C4)alkyl, halo(C1-C4)alkyl, (C1-C4)alkoxy, halo(C₁-C₄)alkoxy, and cyano; R², R^2’, R³, R^3’, R⁵, R⁶, and R⁸ are each independently selected from hydrogen, (C1- C4)alkyl, and halo(C1-C4)alkyl; or R^2’ and R^3’ together with the carbon atom to which they are attached form =O; R⁴ is hydrogen or (C₁-C₄)alkyl; R⁷ is selected from cycloalkyl, heteroaryl, heterocyclyl, and phenyl, each of which being optionally substituted; and q is 0, 1, 2, or 3. 2. Definitions [0006] When used in connection to describe a chemical group that may have multiple points of attachment, a hyphen (-) designates the point of attachment of that group to the variable to which it is defined. For example, -NR^aR^b means that the point of attachment for this group occurs on the nitrogen atom. 2 ^{ME152554612v.1} 125994-02220 [0007] The terms “halo” and “halogen” as used herein refer to an atom selected from fluorine (fluoro, F), chlorine (chloro, Cl), bromine (bromo, Br), and iodine (iodo, I). [0008] The term “alkyl” means saturated straight-chain or branched monovalent hydrocarbon radical. Unless otherwise specified, an alkyl group typically has 1-6 carbon atoms, i.e., (C1-C6)alkyl. As used herein, a “(C1-C6)alkyl” group means a radical having from 1 to 6 carbon atoms in a linear or branched arrangement. [0009] “Alkoxy” means an alkyl radical attached through an oxygen linking atom, represented by –O-alkyl. For example, “(C1-C4)alkoxy” includes methoxy, ethoxy, propoxy, and butoxy. [0010] Unless otherwise specified, the term “heteroaryl” refers to a 5- to 12-membered aromatic radical containing 1-4 heteroatoms selected from N, O, and S. In some instances, nitrogen atoms in a heteroaryl may be quaternized. A heteroaryl group may be mono- or bi- cyclic. Monocyclic heteroaryl includes, for example, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, etc. Bi-cyclic heteroaryls include groups in which a monocyclic heteroaryl ring is fused to one or more aryl or heteroaryl rings. Nonlimiting examples include indolyl, benzooxazolyl, benzooxodiazolyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, quinazolinyl, quinoxalinyl, pyrrolopyridinyl, pyrrolopyrimidinyl, pyrrolopyridinyl, thienopyridinyl, thienopyrimidinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. It will be understood that when specified, optional substituents on a heteroaryl group may be present on any substitutable position and, include, e.g., the position at which the heteroaryl is attached. [0011] Unless otherwise specified, the term “heterocyclyl” means a 4- to 12-membered saturated or partially unsaturated heterocyclic ring containing 1 to 4 heteroatoms independently selected from N, O, and S. A heterocyclyl ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure. A heterocyclyl group may be mono- or bicyclic. Examples of monocyclic saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothienyl, terahydropyranyl, pyrrolidinyl, pyrrolidonyl, piperidinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, morpholinyl, dihydrofuranyl, dihydropyranyl, dihydropyridinyl, tetrahydropyridinyl, dihydropyrimidinyl, tetrahydropyrimidinyl, dihydrooxadizolyl, and dihydroisoxazolyl. Bi-cyclic heterocyclyl groups include, e.g., unsaturated heterocyclic radicals fused to another unsaturated heterocyclic radical, cycloalkyl, aryl, or heteroaryl ring, such as for example, benzodioxolyl, dihydrobenzodioxinyl, dihydrobenzofuranyl, and the 3 ^{ME152554612v.1} 125994-02220 like. It will be understood that when specified, optional substituents on a heterocyclyl group may be present on any substitutable position and, include, e.g., the position at which the heterocyclyl is attached. [0012] The term “spiro” refers to two rings that shares one ring atom (e.g., carbon). [0013] The term “fused” refers to two rings that share two adjacent ring atoms with one another. [0014] The term “bridged” refers to two rings that share three ring atoms with one another. [0015] The term “aryl” refers to an aromatic carbocyclic single ring or two fused ring system containing 6 to 10 carbon atoms. Examples include phenyl, indanyl, tetrahydronaphthalene, and naphthyl. In one aspect, the aryl is phenyl. [0016] The term “cycloalkyl” refers to a saturated cyclic aliphatic monocyclic or bicyclic ring system, as described herein, having from, unless otherwise specified, 3 to 10 carbon ring atoms. Monocyclic cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, and cyclooctyl. It will be understood that when specified, optional substituents on a cycloalkyl or cycloaliphatic group may be present on any substitutable position and, include, e.g., the position at which the cycloalkyl group is attached. [0017] The term “optionally substituted” means that one or more hydrogens of the designated moiety may be replaced with a suitable substituent. Unless otherwise indicated, an “optionally substituted” group may have a suitable substituent at each substitutable position of the group as valency permits. Optional substituents include, but are not limited to, one or more groups selected from cyano (–CN), halo, imino (=NH), nitro (–NO₂), oxo (=O), – C(O)Rⁱ, –C(O)ORⁱ, –C(O)NRⁱⁱRⁱⁱⁱ, –C(O)SRⁱ, –C(NRⁱ)NRⁱⁱRⁱⁱⁱ, –C(S)Rⁱ, –C(S)ORⁱ, – C(S)NRⁱⁱRⁱⁱⁱ, –ORⁱ, –OC(O)Rⁱ, –OC(O)ORⁱ, –OC(O)NRⁱⁱRⁱⁱⁱ, –OC(O)SRⁱ, –OC(NRⁱ)NRⁱⁱRⁱⁱⁱ, –OC(S)Rⁱ, –OC(S)ORⁱ, –OC(S)NRⁱⁱRⁱⁱⁱ, –OP(O)(ORⁱⁱ)ORⁱⁱⁱ, –OS(O)Rⁱ, –OS(O)₂Rⁱ, – OS(O)NRⁱⁱRⁱⁱⁱ, –OS(O)₂NRⁱⁱRⁱⁱⁱ, –NRⁱⁱRⁱⁱⁱ, –NRⁱC(O)R^iv, –NRⁱC(O)OR^iv, –NRⁱC(O)NRⁱⁱRⁱⁱⁱ, – NR^aC(O)SR^iv, –NRⁱC(NR^iv)NRⁱⁱRⁱⁱⁱ, –NRⁱC(S)R^iv, –NRⁱC(S)OR^iv, –NRⁱC(S)NRⁱⁱRⁱⁱⁱ, – NRⁱS(O)R^iv, –NRⁱS(O)2R^iv, –NRⁱS(O)NRⁱⁱRⁱⁱⁱ, –NRⁱS(O)2NRⁱⁱR^iv, –SRⁱ, –S(O)Rⁱ, –S(O)2Rⁱ, – S(O)NRⁱⁱR^iv, –S(O)₂NRⁱⁱR^iv, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl, wherein said alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl are each further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q^a, wherein each Rⁱ, Rⁱⁱ, Rⁱⁱⁱ, and R^iv is independently alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or 4 ^{ME152554612v.1} 125994-02220 heterocyclyl, each of which is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q^a or Rⁱⁱ and Rⁱⁱⁱ together with the N atom to which they are attached form heterocyclyl optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q^a, wherein each Q^a is independently selected from cyano, halo, imino, nitro, oxo, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, C6-14 aryl, heteroaryl, heterocyclyl, –C(O)R^v, –C(O)OR^v, –C(O)NR^viR^vii, –C(O)SR^v, –C(NR^v)NR^viR^vii, – C(S)R^v, –C(S)OR^v, –C(S)NR^viR^vii, –OR^v, –OC(O)R^v, –OC(O)OR^v, –OC(O)NR^viR^vii, – OC(O)SR^v, –OC(NR^v)NR^viR^vii, –OC(S)R^v, –OC(S)OR^v, –OC(S)NR^viR^vii, –OP(O)(OR^v)OR^vi, –OS(O)R^v, –OS(O)2R^v, –OS(O)NR^viR^vii, –OS(O)2NR^vR^vii, –NR^viR^vii, –NR^vC(O)R^viii, – NR^eC(O)OR^vi, –NR^vC(O)NR^viR^vii, –NR^vC(O)SR^vi, –NR^vC(NR^viii)NR^viR^vii, –NR^vC(S)R^viii, – NR^vC(S)OR^vi, –NR^vC(S)NR^viR^vii, –NR^vS(O)R^viii, –NR^vS(O)2R^viii, –NR^vS(O)NR^viR^vii, – NR^vS(O)2NR^viR^vii, –SR^v, –S(O)R^v, –S(O)2R^v, –S(O)NR^viR^vii, and –S(O)2NR^viR^vii; wherein each R^v, R^vi, R^vii, and R^viii is independently alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, or heterocyclyl; or (iii) R^vi and R^viii together with the N atom to which they are attached form heterocyclyl. [0018] When a described compound is named or depicted by structure without indicating a particular geometric isomer form, it is to be understood that the name or structure encompasses one geometric isomer free of other geometric isomers, mixtures of geometric isomers, or mixtures of all geometric isomers. [0019] Where the stereochemistry of a described compound is named or depicted by structure, the named or depicted stereoisomer is at least 60%, 70%, 80%, 90%, 99% or 99.9% by weight pure relative to all of the other stereoisomers. Percent by weight pure relative to all of the other stereoisomers is the ratio of the weight of one stereoisomer over the weight of the other stereoisomers. [0020] Unless otherwise stated, all tautomeric forms of the compounds described herein are within the scope of the invention. [0021] The compounds described herein may be present in the form of pharmaceutically acceptable salts. For use in medicines, the salts of the compounds of the invention refer to non-toxic “pharmaceutically acceptable salts.” Pharmaceutically acceptable salt forms include pharmaceutically acceptable acidic/anionic or basic/cationic salts such as e.g., ammonium salts, alkali metal salts (such as sodium and potassium salts), alkaline earth metal salts (such as magnesium and calcium salts), and ammonium salts (such as tetrabutylammonium, trimethylammonium, tributylammonium, triisopropylammonium, and N,N-diisopropylethylammonium). 5 ^{ME152554612v.1} 125994-02220 [0022] The term “pharmaceutically acceptable carrier” refers to a non-toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated. Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the compositions described herein include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat. [0023] The terms “subject” and “patient” may be used interchangeably, and means a mammal in need of treatment, e.g., companion animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, pigs, horses, sheep, goats and the like) and laboratory animals (e.g., rats, mice, guinea pigs and the like). Typically, the subject is a human in need of treatment. [0024] The term “inhibit,” “inhibition” or “inhibiting” includes a decrease in the baseline activity of a biological activity or process. [0025] As used herein, the terms “treatment,” “treat,” and “treating” refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease or disorder, or one or more symptoms thereof, as described herein. In some embodiments, treatment may be administered after one or more symptoms have developed, i.e., therapeutic treatment. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and/or in light of exposure to a particular organism, or other susceptibility factors), i.e., prophylactic treatment. Treatment may also be continued after symptoms have resolved, for example to prevent or delay their recurrence. [0026] The term “effective amount” or “therapeutically effective amount” includes an amount of the compound described herein that will elicit a biological or medical response of a subject, for example, the reduction or inhibition of enzyme or protein activity related to a a bacterial infection, amelioration of symptoms of a bacterial infection, or the slowing or delaying of progression of a bacterial infection. In one aspect, a therapeutically effective amount refers to a dosage of from about 0.01 to about 100 mg/kg body weight/day. [0027] The terms "administer," "administering" or "administration" include any method of delivery of a pharmaceutical composition or agent into a subject's system or to a particular 6 ^{ME152554612v.1} 125994-02220 region in or on a subject. In certain embodiments of the invention, an agent is administered intravenously, intramuscularly, subcutaneously, intradermally, intranasally, orally, transcutaneously, or mucosally. In a preferred embodiment, an agent is administered intravenously. In another preferred embodiment, an agent is administered orally. Administering an agent can be performed by a number of people working in concert. Administering an agent includes, for example, prescribing an agent to be administered to a subject and/or providing instructions, directly or through another, to take a specific agent, either by self-delivery, e.g., as by oral delivery, subcutaneous delivery, intravenous delivery through a central line, etc.; or for delivery by a trained professional, e.g., intravenous delivery, intramuscular delivery, intratumoral delivery, etc. 3. Description of Exemplary Compounds [0028] In a first embodiment, the present disclosure provides a compound of Formula I: or a pharmaceutically acceptable salt thereof, wherein the variables are as described above. [0029] In a second embodiment, X in the compound of Formula I, or a pharmaceutically acceptable salt thereof, is CH, wherein the remaining variables are as described above for Formula I. [0030] In a third embodiment, R^2’ in the compound of Formula I, or a pharmaceutically acceptable salt thereof, is hydrogen and R^3’ is halo(C₁-C₄)alkyl, wherein the remaining variables are as described above for Formula I or the second embodiment. Alternatively, as part of a third embodiment, R^2’ in the compound of Formula I, or a pharmaceutically acceptable salt thereof, is hydrogen and R^3’ is CF3, wherein the remaining variables are as described above for Formula I or the second embodiment. [0031] In a fourth embodiment, R^2’ and R^3’ in the compound of Formula I, or a pharmaceutically acceptable salt thereof, together with the carbon atom to which they are attached form =O, wherein the remaining variables are as described above for Formula I or the second embodiment. [0032] In a fifth embodiment, R¹ in the compound of Formula I, or a pharmaceutically acceptable salt thereof, is selected from hydrogen, halo, (C₁-C₄)alkyl, and (C₁-C₄)alkoxy, wherein the remaining variables are as described above for Formula I or any one of the 7 ^{ME152554612v.1} 125994-02220 second to fourth embodiments. Alternatively, as part of a fifth embodiment, R¹ in the compound of Formula I, or a pharmaceutically acceptable salt thereof, is selected from OCH₃, CH₃, and fluoro, wherein the remaining variables are as described above for Formula I or any one of the second to fourth embodiments. [0033] In a sixth embodiment, R⁴ in the compound of Formula I, or a pharmaceutically acceptable salt thereof, is hydrogen or CH₃, wherein the remaining variables are as described above for Formula I or any one of the second to fifth embodiments. [0034] In a seventh embodiment, R² and R³ in the compound of Formula I, or a pharmaceutically acceptable salt thereof, are each independently selected from hydrogen and (C₁-C₄)alkyl, wherein the remaining variables are as described above for Formula I or any one of the second to sixth embodiments. Alternatively, as part of a seventh embodiment, R² and R³ in the compound of Formula I, or a pharmaceutically acceptable salt thereof, are each independently selected from hydrogen and CH₃, wherein the remaining variables are as described above for Formula I or any one of the second to sixth embodiments. Alternatively, as part of a seventh embodiment, R² and R³ in the compound of Formula I, or a pharmaceutically acceptable salt thereof, are each hydrogen, wherein the remaining variables are as described above for Formula I or any one of the second to sixth embodiments. [0035] In an eighth embodiment, R⁵ and R⁶ in the compound of Formula I, or a pharmaceutically acceptable salt thereof, are each independently selected from hydrogen and (C₁-C₄)alkyl, wherein the remaining variables are as described above for Formula I or any one of the second to seventh embodiments. Alternatively, as part of an eighth embodiment, R⁵ and R⁶ in the compound of Formula I, or a pharmaceutically acceptable salt thereof, are each independently selected from hydrogen and CH₃, wherein the remaining variables are as described above for Formula I or any one of the second to seventh embodiments. In another alternative, as part of an eighth embodiment, R⁵ and R⁶ in the compound of Formula I, or a pharmaceutically acceptable salt thereof, are each hydrogen, wherein the remaining variables are as described above for Formula I or any one of the second to seventh embodiments. [0036] In a ninth embodiment, q in the compound of Formula I, or a pharmaceutically acceptable salt thereof, is 0, 1, or 2, wherein the remaining variables are as described above for Formula I or any one of the second to eighth embodiments. [0037] In a tenth embodiment, R⁷ in the compound of Formula I, or a pharmaceutically acceptable salt thereof, is selected from (C3-C7)cycloalkyl, 5- to 7-membered heteroaryl, 4- to 10-membered heterocyclyl, and phenyl, each of which are optionally substituted, wherein the remaining variables are as described above for Formula I or any one of the second to ninth 8 ^{ME152554612v.1} 125994-02220 embodiments. Alternatively, as part of a tenth embodiment, R⁷ in the compound of Formula I, or a pharmaceutically acceptable salt thereof, is selected from cyclopentyl, cyclopropyl, cyclohexyl, pyridinyl, phenyl, pyrrolidinyl, pyrimidinyl, piperidinyl, spiro[3.3]heptanyl, bicyclo[1.1.1]pentanyl, and indolinyl, each of which are optionally substituted, wherein the remaining variables are as described above for Formula I or any one of the second to ninth embodiments. [0038] In an eleventh embodiment, the optional substituents for R⁷ in the compound of Formula I, or a pharmaceutically acceptable salt thereof, are selected from (C1-C4)alkyl, halo(C1-C4)alkyl, cyano, phenyl, -(C1-C4)alkylphenyl, 5- to 7-membered heteroaryl, -(C1- C₄)alkyl[5- to 7-membered heteroaryl], 4- to 7-membered heterocyclyl, (C₁-C₄)alkyl[4- to 7- membered heterocyclyl], (C3-C6)cycloalkyl, -(C1-C4)alkyl(C3-C6)cycloalkyl, oxo, -OR^a, - NR^aR^b, -C(O)R^a, -C(O)OR^a, -(C1-C4)alkylNR^aR^b, -NR^aC(O)R^c, -(C1-C4)alkylNR^aC(O)R^c, - C(O)NR^aR^c, -(C₁-C₄)alkylC(O)NR^aR^c, -NR^aS(O)₂R^c, -(C₁-C₄)alkylNR^aS(O)₂R^c, -NR^aS(O)R^c, -(C1-C4)alkylNR^aS(O)R^c, S(O)2R^c, S(O)R^c, -(C1-C4)alkylS(O)2R^c, and -(C1-C4)alkylS(O)R^c, wherein said phenyl, 5- to 7-membered heteroaryl, 4- to 7-membered heterocyclyl, and (C3- C₆)cycloalkyl are each optionally substituted with one or more groups selected from halo, (C₁-C₄)alkyl, halo(C₁-C₄)alkyl, cyano, phenyl, -(C₁-C₄)alkylphenyl, 5- to 7-membered heteroaryl, -(C1-C4)alkyl[5- to 7-membered heteroaryl], 4- to 7-membered heterocyclyl, (C1- C4)alkyl[4- to 7-membered heterocyclyl], -hydroxy(C1-C4)alkylphenyl, (C3-C6)cycloalkyl, - (C₁-C₄)alkyl(C₃-C₆)cycloalkyl, oxo, -OR^a1, -NR^a1R^c1, -C(O)R^a1, -C(O)OR^a1, -(C₁- C4)alkylNR^a1R^b1, -NR^a1C(O)R^c1, -(C1-C4)alkylNR^a1C(O)R^c1, -C(O)NR^a1R^c1, -(C1- C4)alkylC(O)NR^a1R^c1, -NR^a1S(O)2R^c1, -(C1-C4)alkylNR^a1S(O)2R^c1, -NR^a1S(O)R^c1, -(C1- C₄)alkylNR^a1S(O)R^c1, S(O)₂R^c1, and S(O)R^c1; and R^a, R^a1, R^b, R^b1, R^c, and R^c1 are each independently selected from hydrogen, (C1- C4)alkyl, halo(C1-C4)alkyl, cyano(C1-C4)alkyl, hydroxy(C1-C4)alkyl, (C1-C4)alkoxy, halo(C1- C₄)alkoxy, cyano, oxo, phenyl, -(C₁-C₄)alkylphenyl, 4- to 7-membered heterocyclyl, -(C₁- C₄)alkyl[4- to 7-membered heterocyclyl], 5- to 7-membered heteroaryl, -(C₁-C₄)alkyl[5- to 7- membered heteroaryl], (C3-C6)cycloalkyl, and -(C1-C4)alkyl(C3-C6)cycloalkyl, wherein - said (C1-C4)alkyl and said (C1-C4)alkyl of -(C1-C4)alkylphenyl, hydroxy(C1- C₄)alkyl, -(C₁-C₄)alkyl[4- to 7-membered heterocyclyl], -(C₁-C₄)alkyl[5- to 7-membered heteroaryl], and -(C1-C4)alkyl(C3-C6)cycloalkyl for R^a or R^b are each optionally substituted with one or more groups selected from halo, (C1-C4)alkyl, halo(C1-C4)alkyl, (C1-C4)alkoxy, halo(C₁-C₄)alkoxy, hydroxy, -(C₁-C₄)alkoxyO(C₁-C₄)alkyl, (C₃-C₆)cycloalkyl, 4- to 7- membered heterocyclyl, 5- to 7-membered heteroaryl, and phenyl; 9 ^{ME152554612v.1} 125994-02220 - said (C3-C6)cycloalkyl for R^a or R^b is optionally substituted with one or more groups selected from halo, (C1-C4)alkyl, halo(C1-C4)alkyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy, hydroxy, -(C₁-C₄)alkoxyO(C₁-C₄)alkyl, (C₃-C₆)cycloalkyl, 4- to 7-membered heterocyclyl, 5- to 7-membered heteroaryl, and phenyl; . - said 4- to 7-membered heterocyclyl, and 5- to 7-membered heteroaryl for R^c is optionally substituted with (C₁-C₄)alkyl; and - said phenyl of R^c is optionally substituted with (C₁-C₄)alkoxyO(C₁-C₄)alkyl, wherein the remaining variables are as described above for Formula I or any one of the second to tenth embodiments. Alternatively, as part of an eleventh embodiment, the optional substituents for R⁷ in the compound of Formula I, or a pharmaceutically acceptable salt thereof, are selected from (C1-C4)alkyl, -(C1-C4)alkylphenyl, phenyl, 5- to 7-membered heteoaryl, oxo, -OR^a, -NR^aR^b, -NR^aC(O)R^c, -C(O)NR^aR^c, and -NR^aS(O)2R^c, wherein said phenyl is optionally substituted with one or more groups selected from -OR^a1, -hydroxy(C₁- C4)alkylphenyl, and -NR^a1S(O)2R^c1, and wherein said 5- to 7-membered heteoaryl is optionally substituted with one or more -NR^a1R^c1; R^a and R^b are each independently selected from hydrogen, (C₁-C₄)alkyl, hydroxy(C₁- C₄)alkyl, phenyl, -(C₁-C₄)alkylphenyl, -(C₁-C₄)alkyl[4- to 7-membered heterocyclyl], and (C3-C6)cycloalkyl, wherein said (C1-C4)alkyl of -(C1-C4)alkylphenyl is optionally substituted with one or more groups selected from halo and (C3-C6)cycloalkyl, wherein said (C3- C₆)cycloalkyl for R^a or R^b is optionally substituted with phenyl, and wherein said (C₁- C4)alkyl of hydroxy(C1-C4)alkyl is optionally substituted with phenyl; R^c is selected from cyano(C1-C4)alkyl, phenyl, -(C1-C4)alkylphenyl, (C3- C₆)cycloalkyl, -(C₁-C₄)alkyl(C₃-C₆)cycloalkyl, 5- to 7-membered heteroaryl, 4- to 7- membered heterocyclyl, and -(C1-C4)alkyl[4- to 7-membered heterocyclyl], wherein said phenyl and said phenyl of -(C1-C4)alkylphenyl are each optionally substituted with one or more groups selected from halo, (C₁-C₄)alkyl, halo(C₁-C₄)alkyl, (C₁-C₄)alkoxy, halo(C₁- C₄)alkoxy, and -(C₁-C₄)alkoxyO(C₁-C₄)alkyl, and wherein said 5- to 7-membered heteroaryl and 4- to 7-membered heterocyclyl are each optionally substituted with one or more (C1- C4)alkyl; and R^a1 is selected from phenyl and hydrogen; and R^c1 is selected from hydrogen, phenyl, and (C3-C6)cycloalkyl optionally substituted with phenyl, wherein the remaining variables are as described above for Formula I or any one of the second to tenth embodiments. In another alternative, as part of an eleventh embodiment, the optional substituents for R⁷ are selected from (C1-C4)alkyl, -(C1- 10 ^{ME152554612v.1} 125994-02220 C4)alkylphenyl, phenyl, pyridinyl, oxo, -OR^a, -NR^aR^b, -NR^aC(O)R^c, -C(O)NR^aR^c, and - NR^aS(O)2R^c, wherein said phenyl is optionally substituted with one or more groups selected from -OR^a1, -hydroxy(C₁-C₄)alkylphenyl, and -NR^a1S(O)₂R^c1, and wherein said pyridinyl is optionally substituted with one or more -NR^a1R^c1; R^a and R^b are each independently selected from hydrogen, (C1-C4)alkyl, hydroxy(C1- C₄)alkyl, phenyl, -(C₁-C₄)alkylphenyl, -(C₁-C₄)alkyl[piperidinyl], -(C₁- C₄)alkyl[tetrahydropyranyl], and cyclopropyl, wherein said (C₁-C₄)alkyl of -(C₁- C4)alkylphenyl is optionally substituted with one or more groups selected from halo and cyclopropyl, wherein said cyclopropyl for R^a or R^b is optionally substituted with phenyl, and wherein said (C₁-C₄)alkyl of hydroxy(C₁-C₄)alkyl is optionally substituted with phenyl; R^c is selected from cyano(C1-C4)alkyl, phenyl, -(C1-C4)alkylphenyl, cyclopropyl, cyclohexyl, cyclopentyl, -(C1-C4)alkyl[cyclohexyl], -(C1-C4)alkyl[cyclopropyl], pyrazolyl, tetrahydropyranyl, morpholinyl, piperazinyl, piperidinyl, and -(C₁- C4)alkyl[tetrahydropyranyl], -(C1-C4)alkyl[piperidinyl], wherein said phenyl and said phenyl of -(C1-C4)alkylphenyl are each optionally substituted with one or more groups selected from halo, (C₁-C₄)alkyl, halo(C₁-C₄)alkyl, (C₁-C₄)alkoxy, halo(C₁-C₄)alkoxy, and -(C₁- C₄)alkoxyO(C₁-C₄)alkyl, and wherein said pyrazolyl, tetrahydropyranyl, morpholinyl, and piperazinyl are each optionally substituted with one or more (C1-C4)alkyl; and R^a1 is selected from phenyl and hydrogen; and R^c1 is selected from hydrogen, phenyl, and cyclopropyl optionally substituted with phenyl, wherein the remaining variables are as described above for Formula I or any one of the second to tenth embodiments. [0039] In a twelfth embodiment, R⁷ in the compound of Formula I, or a pharmaceutically acceptable salt thereof, is selected from 11 ^{ME152554612v.1} 125994-02220 12 ^{ME152554612v.1} 125994-02220 , , , , 13 ^{ME152554612v.1} 125994-02220 , , , , , , and , wherein the remaining variables are as described above for Formula I or any one of the second to eleventh embodiments. [0040] Specific examples of compounds are provided in the EXEMPLIFICATION. Pharmaceutically acceptable salts as well as the neutral forms of these compounds are included herein. 14 ^{ME152554612v.1} 125994-02220 4. Uses, Formulation and Administration [0041] The compounds and pharmaceutically acceptable salts of the compounds described herein can be used to treat diseases or disorders associated with MASP e.g., a MASP-2 and/or MASP-3 associated disease or disorder. Also provided is the use of a compound or a pharmaceutically acceptable salt of a compound described herein for use in treating a disease or disorder associated with MASP e.g., a MASP-2 and/or MASP-3 associated disease or disorder. Also provided is the use of a compound or a pharmaceutically acceptable salt of a compound described herein for the manufacture of a medicament for treating a disease or disorder associated with MASP e.g., a MASP-2 and/or MASP-3 associated disease or disorder. [0042] In some aspects, the disease or disorder associated with MASP include e.g., thrombotic microangiopathy (TMA), a renal condition, an inflammatory reaction resulting from tissue or organ transplantation, an ischemia reperfusion injury, a complication associated with diabetes, a cardiovascular disease or disorder, an inflammatory gastrointestinal disorder, a pulmonary disorder, an ophthalmic disease or disorder, disseminated intravascular coagulation, graft-versus-host disease, veno-occlusive disease and diffuse alveolar hemorrhage. [0043] In other aspects, the disease or disorder associated with MASP include e.g., paroxysmal nocturnal hemoglobinuria (PNH), age-related macular degeneration (AMD), ischemia-reperfusion injury, arthritis, disseminated intravascular coagulation, thrombotic microangiopathy (including hemolytic uremic syndrome (HUS), atypical hemolytic uremic syndrome (aHUS) and thrombotic thrombocytopenic purpura (TTP), cold agglutinin disease (CAD), asthma, dense deposit disease, pauci-immune necrotizing crescentic glomerulonephritis, traumatic brain injury, aspiration pneumonia, endophthalmitis, neuromyelitis optica, Behcet's disease, multiple sclerosis, Guillain Barre Syndrome, Alzheimer's disease, Amylotrophic lateral sclerosis (ALS), lupus nephritis, systemic lupus erythematosus (SLE), Diabetic Date Recue/Date Received 2021-06-14 retinopathy, Uveitis, Chronic obstructive pulmonary disease (COPD), C3 glomerulopathy, transplant rejection, Graft-versus-host disease (GVHD), hemodialysis, sepsis, Systemic inflammatory response syndrome (SIRS), CD55-deficient protein-losing enteropathy (CHAPLE disease), Acute Respiratory Distress Syndrome (ARDS), sickle cell disease, ANCA vasculitis, Anti- phospholipid syndrome, Atherosclerosis, IgA Nephropathy and Myasthenia Gravis. [0044] According to other aspects, the present disclosure provides pharmaceutically acceptable compositions comprising a compound or a pharmaceutically acceptable salt 15 ^{ME152554612v.1} 125994-02220 thereof described herein; and a pharmaceutically acceptable carrier. These compositions can be used to treat one or more of the conditions recited above. [0045] Compositions described herein may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. Liquid dosage forms, injectable preparations, solid dispersion forms, and dosage forms for topical or transdermal administration of a compound are included herein. [0046] The amount of provided compounds that may be combined with carrier materials to produce a composition in a single dosage form will vary depending upon the patient to be treated and the particular mode of administration. [0047] It should also be understood that a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, the judgment of the treating physician, and the severity of the particular disease being treated. The amount of a provided compound in the composition will also depend upon the particular compound in the composition. E^{XEMPLIFICATION} [0048] As depicted in the Examples below, in certain exemplary embodiments, compounds are prepared according to the following general procedures. It will be appreciated that, although the general methods depict the synthesis of certain compounds herein, the following general methods, and other methods known to one of ordinary skill in the art, can be applied to all compounds and subclasses and species of each of these compounds, as described herein. Abbreviations DMF = N,N-dimethylformamide MeOH = methanol EtOH = ethanol t-BuOH = tert-butanol DCM = dichloromethane DMSO = dimethylsulfoxide MeCN = acetonitrile 16 ^{ME152554612v.1} 125994-02220 THF = tetrahydrofuran Hex = hexanes 1,2-DCE = 1,2-dichloroethane Py = pyridine DIPEA = N,N-diisopropylethylamine DMAP = 4-(dimethylamino)pyridine NMI = N-methylimidazole TFA = trifluoroacetic acid TFAA = trifluoroacetic anhydride NBS = N-bromosuccinimide NIS = N-iodosuccinimide TCFH = N,N,N’,N’-tetramethylchloroformamidinium hexafluorophosphate HATU = hexafluorophosphate azabenzotriazole tetramethyl uronium HBTU = hexafluorophosphate benzotriazole tetramethyl uronium EDCI = 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide HOBt = hydroxybenzotriazole PyBOP = benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate SEM-Cl = 2-(trimethylsilyl)ethoxymethyl chloride SEM = 2-(trimethylsilyl)ethoxymethyl Boc₂O = di-tert-butyl decarbonate Boc = tert-butyloxycarbonyl Trt-Cl = trityl chloride Trt = trityl PMB = para-methoxy benzyl Bn = benzyl QPhos = pentaphenyl(di-tert-butylphosphino)ferrocene Pd(dppf)Cl₂ = [1,1’-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) Pd(dppf)Cl2·CH2Cl2 = [1,1’-Bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane B₂Pin₂ = bis(pinacolato)diboron LiHMDS = lithium bis(trimethylsilyl)amide SFC = supercritical fluid chromatography LC-MS = liquid chromatography-mass spectrometry NMR = nuclear magnetic resonance 17 ^{ME152554612v.1} 125994-02220 h = hour min = minute rt = room temperature MASP-2 = mannan-binding lectin serine protease 2 MASP-3 = mannan-binding lectin serine protease 3 EXAMPLES [0049] Example 1: N-(4-(2-amino-1H-imidazol-4-yl)benzyl)benzamide. Int-1 [0050] A solution of 2-nitroimidazole (5 g, 44.2 mmol, 1.0 eq) in THF (50 mL) was treated with NaH (1.06 g, 44.2 mmol, 1.0 eq) for 2 min at 0 °C followed by the portion-wise addition of [2-(chloromethoxy)ethyl]trimethylsilane (7.82 mL, 7.37 g, 44.2 mmol, 1.0 eq) at 0 °C. The ice bath was removed, and the reaction was stirred for 2.5 h at rt. The reaction was cooled to 0 °C and quenched by the addition of sat. NH₄Cl. The resulting mixture was extracted 3x with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4), filtered, and concentrated under reduced pressure to afford 2-nitro-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-imidazole (7.5 g, 70% yield) as a yellow oil: ¹H NMR 18 ^{ME152554612v.1} 125994-02220 (400 MHz, DMSO-d6) δ 7.87 (d, J = 1.2 Hz, 1H), 7.29 (d, J = 1.1 Hz, 1H), 5.78 (s, 2H), 3.69 – 3.61 (m, 2H), 0.92 (dd, J = 8.5, 7.5 Hz, 2H), 0.00 (s, 9H). Int-2 [0051] A mixture of 2-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (20 g, 82.19 mmol, 1.0 eq) and NBS (36.57 g, 205.48 mmol, 2.5 eq) in DMF (200 mL) was stirred for 2 h at 55 °C. The reaction was cooled to rt, quenched with H₂O and sat. NaHCO₃, then diluted with EtOAc. The layers were separated, and the aqueous layer was extracted 2x with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4), filtered, and concentrated under reduced pressure. The resultant material was purified by flash chromatography eluting with hexanes/EtOAc (10% EtOAc) to give 4-bromo-2-nitro-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-imidazole (10.03 g, 36% yield) as a yellow solid: LC-MS, ES⁺: m/z 321.95 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d6) δ 8.56 (s, 3H), 8.14 (s, 1H), 7.93 (d, J = 8.1 Hz, 2H), 7.72 – 7.42 (m, 2H), 4.04 (q, J = 6.0 Hz, 2H). Int-3 [0052] A solution of 4-bromo-2-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (10 g, 31.03 mmol, 1.0 eq) in H₂O (50 mL) and DMF (100 mL) was treated with tert-butylN- {[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl}carbamate (11.38 g, 34.14 mmol, 1.1 eq) at 25 °C under a nitrogen atmosphere. K2CO3 (8.58 g, 62.07 mmol, 2.0 eq) and Pd(PPh3)4 (1.79 g, 1.55 mmol, 0.05 eq) were added portion-wise at 25 °C. The reaction was stirred for 1 h at 100 °C. The reaction was cooled to rt and diluted with EtOAc. The layers were separated and the aqueous layer was extracted 2x with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4), filtered, and concentrated under reduced pressure. The resultant material was purified by reverse phase flash chromatography on a C18 column eluting with H2O/MeCN (10% MeCN → 50% MeCN) to give tert-butyl (4-(2-nitro- 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)benzyl)carbamate (7 g, 50% yield) as a yellow solid: LC-MS, ES⁺: m/z 449 [M+H]⁺; ¹H NMR (300 MHz, CHLOROFORM-d) δ 7.81 (d, J = 8.3 Hz, 2H), 7.56 (s, 1H), 7.35 (d, J = 8.5 Hz, 2H), 5.82 (s, 2H), 4.35 (br d, J = 5.7 Hz, 2H), 3.61 - 3.83 (m, 2H), 1.47 - 1.48 (m, 9H), 0.97 - 1.05 (m, 2H), 0.03 (s, 9H). Int-4 [0053] A solution of tert-butyl (4-(2-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- imidazol-4-yl)benzyl)carbamate (12 g, 26.75 mmol, 1.0 eq) in HCl (20 mL, 80 mmol of a 4M solution in 1,4-dioxane) was stirred at room temperate for 2 h. The precipitate was collected by filtration and washed with EtOAc to afford (4-(2-nitro-1H-imidazol-4- yl)phenyl)methanamine hydrochloride (5.01 g, 74% yield) as a yellow solid: LC-MS, ES⁺: 19 ^{ME152554612v.1} 125994-02220 m/z 219.21 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d6) δ 8.56 (s, 3H), 8.14 (s, 1H), 8.05 – 7.69 (m, 2H), 7.69 – 7.35 (m, 2H), 4.04 (q, J = 6.0 Hz, 2H). Int-5 [0054] The general procedure for amide coupling using HBTU: [0055] To a stirred solution of (4-(2-nitro-1H-imidazol-4-yl)phenyl)methanamine (50 mg, 0.23 mmol, 1.0 eq) and benzoic acid (28.0 mg, 0.23 mmol, 1.0 eq) in DMF (0.5 mL) were added HBTU (104.3 mg, 0.28 mmol, 1.2 eq) and DIPEA (118.5 mg, 0.93 mmol, 4.0 eq) portion-wise at 0 °C. The ice bath was removed, and the reaction was stirred for 1 h at rt. The reaction mixture was purified by reverse phase flash chromatography on a C18 column eluting with H₂O/MeCN (30% MeCN → 80% MeCN) to give N-(4-(2-nitro-1H-imidazol-4- yl)benzyl)benzamide (35 mg, 47% yield) as a white solid: LC-MS, ES-: m/z 321.05 [M-H]-. Example 1 [0056] The general procedure for nitro reduction using Fe: [0057] A solution of N-(4-(2-nitro-1H-imidazol-4-yl)benzyl)benzamide (70 mg, 0.22 mmol, 1.0 eq) in EtOH (1.0 mL) and H2O (0.5 mL) was treated with Fe powder (48.5 mg, 0.89 mmol, 4.0 eq) and NH₄Cl (46.5 mg, 0.89 mmol, 4.0 eq) at rt. The reaction mixture was stirred at 80 °C for 1 h. The resulting mixture was filtered, the filter cake was washed with MeOH, and the filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC on a Xselect CSH C18 OBD Column (30 x 150 mm, 5 µM) eluting with H₂O/MeCN (10% MeCN → 35% MeCN containing 0.05% TFA) to give N-(4-(2- amino-1H-imidazol-4-yl)benzyl)benzamide; trifluoroacetic acid (31.7 mg, 36% yield) as a white solid: LC-MS, ES⁺: m/z 293.00 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d6) δ 12.75 (s, 1H), 12.05 (s, 1H),9.09 (s, 1H), 7.98 – 7.83 (m, 2H), 7.60 (d, J = 8.2 Hz, 2H), 7.58 – 7.44 (m, 5H), 7.38 (d, J = 8.5 Hz, 3H), 4.49 (d, J = 5.9 Hz, 2H). [0058] Examples 2, 3, 4, 13, and 16 were prepared from Int-4 and the corresponding carboxylic acid according to the procedure for the synthesis of Example 1. The carboxylic acid used to prepare example 16 was prepared according to the procedure in J. Org. Chem.1989, 54, 1815. [0059] Example 6: (1S,2R)-N-(4-(2-amino-1H-imidazol-4-yl)benzyl)-2- phenylcyclopropane-1-carboxamide. 20 ^{ME152554612v.1} 125994-02220 Scheme 2 Int-6 [0060] The general procedure for amide coupling using HATU: [0061] HATU (38 mg, 0.1 mmol, 1.1 eq) was added to a solution of (1S,2R)-2- phenylcyclopropane-1-carboxylic acid (16.3 mg, 0.1 mmol, 1.1 eq) in DMF (0.1 mL) and the reaction stirred for 1 min at rt. A solution of Int-4 (20 mg, 0.092 mmol, 1 eq) and DIPEA (36 µL 0.184, 2 eq) in DMF (0.55 mL) was added followed by additional DIPEA (18 µL, 0.092 mmol, 1 eq). The reaction was stirred for 3h at rt. NaHCO3 (39 mg) was added to the reaction and the mixture was stirred vigorously for 30min. The reaction was filtered through a cotton plug and the solvent was removed under reduced pressure. The resultant crude material was purified by flash chromatography eluting with hexanes/EtOAc (0% EtOAc → 50% EtOAc) to give (1S,2R)-N-(4-(2-nitro-1H-imidazol-4-yl)benzyl)-2-phenylcyclopropane-1- carboxamide (26.3 mg, 79% yield) as a yellow solid: LC-MS, ES⁺: m/z 363.2 [M+H]⁺. Example 6 [0062] A mixture of (1S,2R)-N-(4-(2-nitro-1H-imidazol-4-yl)benzyl)-2- phenylcyclopropane-1-carboxamide (26.3 mg, 0.0726 mmol, 1.0 eq) and catalytic 5% Pt/C (5 mg) in EtOAc (0.55 mL) was cooled in an cold water bath maintaining the temperature between 5 °C to 10 °C. The reaction was evacuated and backfilled with H2 (3x) and stirred under an atmosphere of H₂ for 50 min. The reaction was flushed with N₂ then diluted with MeOH and filtered through a syringe filter (0.45 µm PTFE filter), rinsing with MeOH. The filtrate was concentrated under reduced pressure, and the residue purified flash chromatography eluting with DCM/MeOH (0% MeOH → 10% MeOH) to give (1S,2R)-N- (4-(2-amino-1H-imidazol-4-yl)benzyl)-2-phenylcyclopropane-1-carboxamide (2.7 mg, 11% yield) as a pale yellow residue: LC-MS, ES⁺: m/z 333.2 [M+H]⁺; ¹H NMR (300 MHz, METHANOL-d4) δ ppm 7.38 (d, J = 8.3 Hz, 2H), 7.13 - 7.27 (m, 5H), 7.08 (s, 1H), 7.01 (d, J 21 ^{ME152554612v.1} 125994-02220 = 8.3 Hz, 2H), 4.25 - 4.36 (m, 1H), 4.05 - 4.18 (m, 1H), 2.44 - 2.57 (m, 1H), 2.13 (ddd, J = 9.4, 7.9, 5.8 Hz, 1H), 1.71 (dt, J = 7.2, 5.5 Hz, 1H), 1.19 - 1.34 (m, 2H). [0063] Examples 5 and 7 were prepared from Int-4 and the corresponding carboxylic acid according to the procedure for the synthesis of Example 6. [0064] Example 9: (1R,2S)-N-(4-(2-amino-1H-imidazol-4-yl)benzyl)-2-(4- phenoxyphenyl)cyclopropane-1-carboxamide. Int-7 [0065] SM-4 was synthesized according to the procedure in J. Am. Chem. Soc. 2022, 144, 2062. [0066] Lithium hydroxide (178 mg, 7.44 mmol, 5.0 eq) was added to a solution of ethyl 2-(4-phenoxyphenyl)cyclopropane-1-carboxylate (420 mg, 1.49 mmol, 1.0 eq) in THF (3.0 mL), MeOH (3.0 mL), and H₂O (1.0 mL) and the reaction was stirred at rt for 1 h. The reaction was acidified to ~pH=2 with concentrated HCl. The reaction was diluted with water and EtOAc. The layers were separated, and the aqueous layer was extracted 2x with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude material was purified reverse phase flash chromatography on a C18 column eluting with H2O/MeCN (40% MeCN → 60% MeCN) to give impure 2-(4-phenoxyphenyl)cyclopropane-1-carboxylic acid (400 mg) as a yellow oil that was used without further purification: LC-MS, ES⁺: m/z 255.10 [M+H]⁺. 22 ^{ME152554612v.1} 125994-02220 Int-8 [0067] To a stirred solution of 2-(4-phenoxyphenyl)cyclopropane-1-carboxylic acid (440 mg 1.73 mmol, 1.0 eq) and (R)-2-amino-2-phenylethan-1-ol (285 mg, 2.08 mmol, 1.2 eq) in DMF (5.0 mL) were added HBTU (984 mg, 2.60 mmol, 1.5 eq) and DIPEA (671 mg, 5.19 mmol, 3.0 eq). The reaction was stirred at rt for 1 h. The reaction mixture was purified by reverse phase flash chromatography on a C18 column eluting with H₂O/MeCN (40% MeCN → 65% MeCN) to give (1R,2S)-N-((R)-2-hydroxy-1-phenylethyl)-2-(4- phenoxyphenyl)cyclopropane-1-carboxamide (100 mg, 16% yield over 2 steps) as a yellow oil: LC-MS, ES-: m/z 374.20 [M+H]⁺. Int-9 [0068] A solution of (1R,2S)-N-((R)-2-hydroxy-1-phenylethyl)-2-(4- phenoxyphenyl)cyclopropane-1-carboxamide (100 mg, 0.27 mmol, 1.0 eq) and NaOH (43 mg, 1.07 mmol, 4.0 eq) in EtOH (2.0 mL) was stirred at 80 °C for 16 h. The reaction was acidified to ~pH=2 with concentrated HCl. The reaction was diluted with water and EtOAc. The layers were separated and the aqueous layer was extracted 2x with EtOAc. The combined organic layers were washed with brine, dried (Na₂SO₄), filtered, and concentrated under reduced pressure. The crude material was purified reverse phase flash chromatography on a C18 column eluting with H2O/MeCN (40% MeCN → 60% MeCN) to give impure (1R,2S)-2-(4-phenoxyphenyl)cyclopropane-1-carboxylic acid (70 mg) as a yellow oil that was used without further purification: LC-MS, ES⁺: m/z 255.25 [M+H]⁺. [0069] The synthesis of Example 9 was completed from Int-9 and Int-4 according to the general procedure for amide coupling using HATU, followed by the general procedure for nitro reduction using Fe. [0070] Example 8 was prepared from 1-phenoxy-3-vinylbenzene according to the procedure for the synthesis of Example 9. [0071] Example 10: (1R,2S)-N-(4-(2-amino-1H-imidazol-4-yl)benzyl)-2-(4-((S)-1- hydroxy-1-phenylethyl)phenyl)cyclopropane-1-carboxamide. 23 ^{ME152554612v.1} 125994-02220 Scheme 4 Int-10 and Int-11 [0072] SM-5 was synthesized according to the procedure in J. Am. Chem. Soc. 2018, 140, 6645. [0073] Di-n-butylmagnesium (8.0 mL, 8.09 mmol, 1.5 eq of a 1.0M solution in n- heptane) was added dropwise to a solution of (1R,2S)-2-(4-bromophenyl)cyclopropane-1- carboxylic acid (1.3 g, 5.39 mmol, 1.0 eq) in THF at -20 °C. The reaction was stirred for 5 min at -20 °C, whereupon n-butyllithium (4.3 mL, 10.78 mmol, 2.0 eq of a 2.5M solution in hexanes) was added dropwise. The reaction was stirred for 1 h at -20 °C. Acetophenone (0.78 g, 6.47 mmol, 1.2 eq) was added and the reaction was stirred at rt for 1 h. The reaction was quenched by the addition of sat. NH4Cl and diluted with EtOAc. The layers were separated and the aqueous layer was extracted 2x with EtOAc. The combined organic layers were washed with brine, dried (Na₂SO₄), filtered, and concentrated under reduced pressure. The crude material was purified reverse phase flash chromatography on a C18 column eluting with H₂O/MeCN (30% MeCN → 60% MeCN) to give (1R,2S)-2-(4-((S)-1-hydroxy-1- phenylethyl)phenyl)cyclopropane-1-carboxylic acid (487 mg, 32% yield) as a yellow oil: LC- MS, ES⁺: m/z 281.10 [M+H]⁺, and (1R,2S)-2-(4-((R)-1-hydroxy-1- phenylethyl)phenyl)cyclopropane-1-carboxylic acid (800 mg, 53% yield) as a yellow oil: LC- MS, ES⁺: m/z 281.05 [M+H]⁺. [0074] The synthesis of Example 10 was completed from Int-10 and Int-4 according to the general procedure for amide coupling using HBTU, followed by the general procedure for nitro reduction using Fe. [0075] Example 11 was prepared from Int-11 and Int-4 according to the procedure for the synthesis of Example 10. [0076] Example 14: (1S,3R)-N-(4-(2-amino-1H-imidazol-4-yl)benzyl)-3- hydroxycyclopentane-1-carboxamide. 24 ^{ME152554612v.1} 125994-02220 Scheme 5 Int-12 [0077] HATU (38 mg, 0.1 mmol) was added to a solution of (1S,3R)-3- hydroxycyclopentane-1-carboxylic acid (13.1 mg, 0.1 mmol) in DMF (0.1 mL) and the reaction was stirred for 1 min. A solution of Int-4 (20 mg, 0.092 mmol) in DMF (0.55 mL) was added, followed by DIPEA (18 µL, 0.1 mmol), and the reaction was stirred for 3 h. The reaction was quenched with sat. NaHCO3 and diluted with EtOAc. The layers were separated, and the aqueous layer was extracted 2x with EtOAc. The combined organic layers were washed with H₂O, dried (MgSO₄), filtered, and concentrated under reduced pressure. Desired product was detected in the remaining aqueous layer. MeOH was added to the aqueous layer and the resultant precipitate was filtered and the filtrate was concentrated under reduced pressure. The residue was added to the EtOAc extracts and purified by flash chromatography eluting with DCM/MeOH (0% MeOH → 20% MeOH) to give (1S,3R)-3-hydroxy-N-(4-(2- nitro-1H-imidazol-4-yl)benzyl)cyclopentane-1-carboxamide (18 mg, 59% yield over 2 steps) as a yellow solid: LC-MS, ES⁺: m/z 331.1 [M+H]⁺. Example 14 [0078] A mixture of (1S,3R)-3-hydroxy-N-(4-(2-nitro-1H-imidazol-4- yl)benzyl)cyclopentane-1-carboxamide (8 mg, 0.0242 mmol) in MeOH (4 mL) was evacuated and backfilled with N_2(g) 3x. 10% Pd/C (1 mg) was added and the reaction evacuated and backfilled with H2(g) 3x and stirred under an atmosphere of H2 for 90 min. The reaction was filtered through a 0.45 µm PTFE syringe filter and concentrated under reduced pressure. The residue was purified by reverse phase HPLC eluting with H₂O/MeCN (0% MeCN → 60% MeCN containing 0.1% formic acid) to give (1S,3R)-N-(4-(2-amino-1H- imidazol-4-yl)benzyl)-3-hydroxycyclopentane-1-carboxamide (2.2 mg, 30% yield) as a pale yellow solid: LC-MS, ES⁺: m/z 301.3 [M+H]⁺; ¹H NMR (300 MHz, METHANOL-d₄) δ ppm 25 ^{ME152554612v.1} 125994-02220 7.53 (d, J = 8.3 Hz, 2H), 7.35 (d, J = 8.5 Hz, 2H), 7.11 (s, 1H), 4.38 (s, 2H), 4.18 - 4.28 (m, 1H), 2.72 - 2.86 (m, 1H), 2.03 - 2.19 (m, 1H), 1.89 - 2.00 (m, 2H), 1.66 - 1.87 (m, 3H). [0079] Example 15: N-(4-(2-amino-1H-imidazol-4-yl)benzyl)-1- (phenylamino)cyclopropane-1-carboxamide. Scheme 6 Int-13 [0080] The general procedure for amide coupling using TCFH-NMI: [0081] To a stirred mixture of Int-4 (200 mg, 0.57 mmol, 1.0 eq) and TCFH (241.6 mg, 0.86 mmol, 1.5 eq) in MeCN (6.0 mL) were added 1-(phenylamino)cyclopropane-1- carboxylic acid (131.7 mg, 0.69 mmol, 1.2 eq) and NMI (117.8 mg, 1.44 mmol, 2.5 eq) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred for 2 h at room temperature under nitrogen atmosphere. The reaction was purified by reverse phase flash chromatography on a C18 column eluting with H₂O/MeCN (30% MeCN → 80% MeCN) to give N-(4-(2-nitro-1H-imidazol-4-yl)benzyl)-1-(phenylamino)cyclopropane-1- carboxamide (200 mg, 67% yield) as a yellow solid: LC-MS, ES⁺: m/z 378.40 [M+H]⁺. [0082] The synthesis of Example 15 was completed according to the general procedure for nitro reduction using Fe. [0083] Examples 12 and 17 were prepared from Int-4 and the corresponding carboxylic acid according to the procedure for the synthesis of Example 15. [0084] Example 18: N¹-(4-(2-amino-1H-imidazol-4-yl)benzyl)-N²-phenylcyclopropane- 1,2-dicarboxamide. 26 ^{ME152554612v.1} 125994-02220 Scheme 7 Int-14 [0085] A solution of 2-(methoxycarbonyl)cyclopropane-1-carboxylic acid (500 mg, 3.47 mmol, 1.0 eq), aniline (323 mg, 3.47 mmol, 1.0 eq), HBTU (1.84 g, 4.86 mmol, 1.4 eq) and DIPEA (2.4 mL, 13.88 mmol, 4.0 eq) in DMF (10.0 mL) was stirred for 1 h at rt. The reaction was partitioned between H2O and EtOAc. The layers were separated and the aqueous layer was extracted 2x with EtOAc. The combined organic layers were washed with brine, dried (Na₂SO₄), filtered, and concentrated under reduced pressure. The crude material was purified reverse phase flash chromatography on a C18 column eluting with H2O/MeCN (30% MeCN → 60% MeCN) to give methyl 2-(phenylcarbamoyl)cyclopropane-1-carboxylate (200 mg, 26% yield) as a yellow solid: LC-MS, ES⁺: m/z 219.24 [M+H]⁺. Int-15 [0086] Lithium hydroxide (110 mg, 4.6 mmol, 5.0 eq) was added to a solution of methyl 2-(phenylcarbamoyl)cyclopropane-1-carboxylate (200 mg, 0.92 mmol, 1.0 eq) in THF (4.0 mL), MeOH (1.0 mL), and H2O (1.0 mL) and the reaction was stirred at rt for 1 h. The reaction was acidified to ~pH=3 with 1M HCl. The reaction was diluted with water and EtOAc. The layers were separated and the aqueous layer was extracted 2x with EtOAc. The combined organic layers were washed with brine, dried (Na₂SO₄), filtered, and concentrated under reduced pressure. The crude material was purified reverse phase flash chromatography on a C18 column eluting with H₂O/MeCN (30% MeCN → 50% MeCN) to give 2- (phenylcarbamoyl)cyclopropane-1-carboxylic acid (100 mg, 54% yield) as a yellow solid: LC-MS, ES⁺: m/z 206.21 [M+H]⁺. [0087] The synthesis of Example 18 was completed from Int-15 and Int-4 according to the general procedure for amide coupling using HBTU, followed by the general procedure for nitro reduction using Fe. [0088] Example 19: N-(4-(2-amino-1H-imidazol-4-yl)benzyl)-1-(6-aminopyridin-3- yl)cyclopropane-1-carboxamide. 27 ^{ME152554612v.1} 125994-02220 Scheme 9 Int-16 [0089] A solution of 1-(6-chloropyridin-3-yl)cyclopropane-1-carboxylic acid (500 mg, 2.53 mmol, 1.0 eq) in 1,4-dioxane (5.0 mL) was treated with Cs₂CO₃ (2.47 g, 7.59 mmol, 3.0 eq), Pd-PEPPSI-IHept-Cl (493 mg, 0.50 mmol, 0.2 eq, CAS No. 1814936-54-3), and PMB- NH2 (382 mg, 2.78 mmol, 1.1 eq) at rt. The reaction mixture was stirred at 100 °C for 1 h. The reaction was diluted with H₂O and EtOAc. The layers were separated and the aqueous layer was extracted 2x with EtOAc. The combined organic layers were washed with H₂O, dried (Na2SO4), filtered and concentrated under reduced pressure. The crude material was purified reverse phase flash chromatography on a C18 column eluting with H2O/MeCN (40% MeCN → 80% MeCN) to give 1-(6-((4-methoxybenzyl)amino)pyridin-3-yl)cyclopropane-1- carboxylic acid (350 mg, 46% yield) as a yellow solid: LC-MS, ES⁺: m/z 299.00 [M+H]⁺. Int-17 [0090] Int-17 was synthesized from Int-16 and Int-4 according to the general procedure for amide coupling using HBTU, followed by the general procedure for nitro reduction using Fe. Example 19 [0091] A solution of N-(4-(2-amino-1H-imidazol-4-yl)benzyl)-1-(6-((4- methoxybenzyl)amino)pyridin-3-yl)cyclopropane-1-carboxamide (120 mg, 0.26 mmol, 1.0 eq) in TFA (3.0 mL) was stirredfor 2 h at rt.The resulting mixture was concentrated under reduced pressure to afford the crude product. The crude product was purified by Prep-HPLC with the following conditions (Column: Xselect CSH C18 OBD Column 30*150mm 5μm; Mobile Phase A: Water (0.05% TFA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 2% B to 20% B in7min; Wave Length: 254nm/220nm; RT1(min): 6.2) to afford N- (4-(2-amino-1H-imidazol-4-yl)benzyl)-1-(6-aminopyridin-3-yl)cyclopropane-1-carboxamide 28 ^{ME152554612v.1} 125994-02220 trifluoroacetate (23.6 mg, 20 % yield) as an orange solid: LC-MS, ES⁺: m/z 349.10 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d6) δ 13.12 (s, 1H), 12.28 (s, 1H), 7.95 (d, J = 2.1 Hz, 1H), 7.89 (dd, J = 9.1, 2.2 Hz, 1H), 7.81 (t, J = 6.0 Hz, 1H), 7.70 (s, 2H), 7.59 – 7.53 (m, 2H), 7.36 (s, 1H), 7.24 (d, J = 8.1 Hz, 2H), 6.95 (d, J = 9.1 Hz, 1H), 4.22 (d, J = 6.0 Hz, 2H), 1.36 (q, J = 3.8 Hz, 2H), 1.02 (q, J = 3.9 Hz, 2H). [0092] Example 20: N-(4-(2-amino-1H-imidazol-4-yl)benzyl)-1-(6-((1- phenylcyclopropyl)amino)pyridin-3-yl)cyclopropane-1-carboxamide. Int-18 [0093] To a solution of 5-bromo-2-fluoropyridine (5.0 g, 28.4 mmol, 1.0 eq) and 1- phenylcyclopropan-1-amine (7.2 g, 42.6 mmol, 1.5 eq) in DMSO (20 mL) was added K2CO3 (11.8 g, 85.2 mmol, 3.0 eq). The resulting mixture was stirred for 16 h at 120 °C. The reaction was quenched with H₂O and diluted with EtOAc. The layers were separated and the aqueous layer was extracted 2x with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude material was purified by reverse phase flash chromatography on a C18 column eluting with H2O/MeCN (40% MeCN → 60% MeCN) to give 5-bromo-N-(1-phenylcyclopropyl)pyridin- 2-amine (850 mg, 10% yield) as a colorless oil: LC-MS, ES⁺: m/z 289.00 [M+H]⁺. Int-19 [0094] To a solution of 5-bromo-N-(1-phenylcyclopropyl)pyridin-2-amine (850 mg, 2.94 mmol, 1.0 eq) in THF (10 mL) was added (1-(methoxycarbonyl)cyclopropyl)zinc(II) bromide 29 ^{ME152554612v.1} 125994-02220 (3.6 g, 14.7 mmol, 5.0 eq), Q-Phos (418 mg, 0.59 mmol, 0.2 eq), and Pd(dba)2 (169 mg, 0.29 mmol, 0.1 eq). The reaction mixture was stirred at rt for 1 h. The reaction was quenched with sat. NH₄Cl and extracted 3x with EtOAc. The combined organic layers were washed with H2O, dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude material was purified by reverse phase flash chromatography on a C18 column eluting with H₂O/MeCN (30% MeCN → 60% MeCN) to give methyl 1-(6-((1- phenylcyclopropyl)amino)pyridin-3-yl)cyclopropane-1-carboxylate (720 mg, 79% yield) as a yellow oil: LC-MS, ES⁺: m/z 309.15 [M+H]⁺. Int-20 [0095] The general procedure for ester hydrolysis using MeOH/THF/H₂O as the solvent: [0096] A solution of methyl 1-(6-((1-phenylcyclopropyl)amino)pyridin-3- yl)cyclopropane-1-carboxylate (200 mg, 0.65 mmol, 1.0 eq) and LiOH (78 mg, 3.25 mmol, 5.0 eq) in MeOH (2.0 mL), THF (2.0 mL), and H₂O (1.0 mL) was stirred for 1 h at rt. The reaction was acidified to ~pH=2 with concentrated HCl. The reaction was diluted with water and EtOAc. The layers were separated, and the aqueous layer was extracted 2x with EtOAc. The combined organic layers were washed with brine, dried (Na₂SO₄), filtered, and concentrated under reduced pressure. The crude material was purified reverse phase flash chromatography on a C18 column eluting with H2O/MeCN (30% MeCN → 60% MeCN) to give 1-(6-((1-phenylcyclopropyl)amino)pyridin-3-yl)cyclopropane-1-carboxylic acid (70 mg, 37% yield) as a yellow oil: LC-MS, ES⁺: m/z 295.10 [M+H]⁺. [0097] The synthesis of Example 20 was completed according to the general procedure for amide coupling using HBTU (coupling with Int-4), followed by the general procedure for nitro reduction using Fe. [0098] Example 22: N-(4-(2-amino-1H-imidazol-4-yl)benzyl)-2-(5-phenoxy-6- (phenylsulfonamido)pyridin-3-yl)acetamide. 30 ^{ME152554612v.1} 125994-02220 Scheme 11 Int-21 [0099] A solution of 5-bromo-3-fluoro-2-nitropyridine (2.0 g, 9.1 mmol, 1.0 eq) in MeCN (20 mL) was treated with phenol (937 mg, 9.9 mmol, 1.1 eq) and Cs2CO3 (8.85 g, 27.2 mmol, 3.0 eq) at rt. The reaction mixture was stirred at rt for 16 h. The reaction was quenched with H₂O and diluted with EtOAc. The aqueous layer was extracted 2x with EtOAc. The combined organic layers were washed with H₂O, dried (Na₂SO₄), filtered, and concentrated under reduced pressure. The crude material was purified by flash chromatography eluting with hexanes/EtOAc (5:1) to afford 5-bromo-2-nitro-3- phenoxypyridine (2.1 g, 79% yield) as a yellow solid: LC-MS, ES⁺: m/z 296.01 [M+H]⁺. Int-22 [00100] To a solution of 5-bromo-2-nitro-3-phenoxypyridine (2.2 g, 7.46 mmol, 1.0 eq) in THF (22 mL) was added tert-butyl 2-(bromozincio)acetate (2.3 g, 8.95 mmol, 1.2 eq), Pd(dba)2 (214 mg, 0.37 mmol, 0.05 eq), Q-Phos (528 mg, 0.75 mmol, 0.1 eq). The reaction mixture was stirred at 65 °C for 1 h. The reaction was quenched with sat. NH4Cl and extracted 3x with EtOAc. The combined organic layers were washed with H₂O, dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude material was purified by reverse phase flash chromatography on a C18 column eluting with H2O/MeCN (10% MeCN → 50% MeCN) to give tert-butyl 2-(6-nitro-5-phenoxypyridin-3-yl)acetate (1.9 g, 77% yield) as a yellow solid: LC-MS, ES⁺: m/z 331.15 [M+H]⁺. Int-23 [00101] A solution of tert-butyl 2-(6-nitro-5-phenoxypyridin-3-yl)acetate (1.4 g, 4.2 mmol, 1.0 eq) in EtOH (7.0 mL) and H₂O (7.0 mL) was treated with Fe powder (947 mg, 31 ^{ME152554612v.1} 125994-02220 17.0 mmol, 4.0 eq) and NH4Cl (907 mg, 17.0- mmol, 4.0 eq) at rt. The reaction mixture was stirred at 80 °C for 1 h. The resulting mixture was filtered, the filter cake was washed with MeOH, and the filtrate was concentrated under reduced pressure to give tert-butyl 2-(6- amino-5-phenoxypyridin-3-yl)acetate (700 mg, 55% yield) as a yellow solid: LC-MS, ES⁺: m/z 301.05 [M+H]⁺. Int-24 [00102] A solution of tert-butyl 2-(6-amino-5-phenoxypyridin-3-yl)acetate (500 mg, 1.67 mmol, 1.0 eq), DMAP (4.1 mg, 0.033 mmol, 0.02 eq) and benzenesulfonyl chloride (323 mg, 1.83 mmol, 1.1 eq) in pyridine (5.0 mL) was stirred for 1 h at 40 °C. The resulting mixture was concentrated under reduced pressure. The crude material was purified by reverse phase flash chromatography on a C18 column eluting with H2O/MeCN (40% MeCN → 80% MeCN) to give tert-butyl 2-(5-phenoxy-6-(phenylsulfonamido)pyridin-3-yl)acetate (270 mg, 37% yield) as a white solid: LC-MS, ES⁺: m/z 441.25 [M+H]⁺. Int-25 [00103] A solution of tert-butyl 2-(5-phenoxy-6-(phenylsulfonamido)pyridin-3-yl)acetate (270 mg, 0.61 mmol, 1.0 eq) in HCl (5.0 mL of a 4M solution in 1,4-dioxane) was stirred for 1 h at rt. The resulting mixture was concentrated under reduced pressure to afford 2-(5- phenoxy-6-(phenylsulfonamido)pyridin-3-yl)acetic acid (200 mg, 85% yield) as a white solid: LC-MS, ES⁺: m/z 385.00 [M+H]⁺. [00104] The synthesis of Example 22 was completed according to the general procedure for amide coupling using HBTU (coupling with Int-4), followed by the general procedure for nitro reduction using Fe. [00105] Example 25: N-(4-(2-amino-1H-imidazol-4-yl)benzyl)-2-(5-phenoxypyridin-3- yl)acetamide. 32 ^{ME152554612v.1} 125994-02220 Int-26 [00106] A solution of 3-bromo-5-fluoropyridine (1 g, 5.68 mmol, 1.0 eq), phenol (803 mg, 8.53 mmol, 1.5 eq) and Cs₂CO₃ (3.70 g, 11.36 mmol, 2.0 eq) in MeCN (10 mL) was stirred at 80 °C overnight under nitrogen. The reaction was diluted with EtOAc and washed with brine (2x) The organic layer was dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude material was purified by reverse phase flash chromatography on a C18 column eluting with H₂O/MeCN (50% MeCN → 70% MeCN) to give 3-bromo-5-phenoxypyridine (500 mg, 35% yield) as a yellow oil: LC-MS, ES⁺: m/z 249.85 [M+H]⁺. [00107] The synthesis of Example 25 was completed according to the procedure for the synthesis of Example 1. [00108] Example 26: N-(4-(2-amino-1H-imidazol-4-yl)benzyl)-2-(6- (benzylamino)pyridin-3-yl)acetamide. [00109] To a solution of 5-bromo-2-fluoropyridine (100 mg, 0.57 mmol, 1.0 eq) and benzylamine (60.9 mg, 0.57 mmol, 1.0 eq) in DMF (1.0 mL) was added K2CO3 (235.6 mg, 1.71 mmol, 3.0 eq) in portion-wise at 0 °C. The resulting mixture was stirred for additional 1 h at 120 °C. The reaction was purified by reverse phase flash chromatography on a C18 column eluting with H2O/MeCN (40% MeCN → 70% MeCN) to give N-benzyl-5- bromopyridin-2-amine (70 mg, 47% yield) as a white solid: LC-MS, ES⁺: m/z 262.95 [M+H]⁺. 33 ^{ME152554612v.1} 125994-02220 Int-28 [00110] The general procedure for Negishi coupling: [00111] To a solution of N-benzyl-5-bromopyridin-2-amine (100 mg, 0.38 mmol, 1.0 eq) in THF (1.0 mL) was added tert-butyl 2-(bromozincio)acetate (395.9 mg, 1.52 mmol, 4.0 eq), Q-Phos (26.9 mg, 0.038 mmol, 0.1 eq), and Pd(dba)2 (21.9 mg, 0.038 mmol, 0.1 eq). The reaction mixture was stirred at 65 °C for 1 h. The reaction was quenched with sat. NH₄Cl and extracted 3x with EtOAc. The combined organic layers were washed with H₂O, dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude material was purified by reverse phase flash chromatography on a C18 column eluting with H2O/MeCN (70% MeCN → 90% MeCN) to give tert-butyl 2-(6-(benzylamino)pyridin-3-yl)acetate (30 mg, 26% yield) as a yellow solid: LC-MS, ES⁺: m/z 299.15 [M+H]⁺. Int-29 [00112] The general procedure for tert-butyl ester cleavage using TFA: [00113] A solution of tert-butyl 2-(6-(benzylamino)pyridin-3-yl)acetate (100 mg, 0.36 mmol, 1.0 eq) and TFA (7.6 mg, 0.072 mmol, 0.2 equiv) in DCM (1.0 mL) was stirred for1 h at rt. The reaction was concentrated under reduced pressure to give 2-(6- (benzylamino)pyridin-3-yl)acetic acid (60 mg, 74% yield) as a yellow solid: LC-MS, ES⁺: m/z 243.10 [M+H]⁺. [00114] The synthesis of Example 26 was completed according to the procedure for the synthesis of Example 1. [00115] Example 21 was prepared from 5-bromo-3-fluoro-2-nitropyridine according to the procedure for the synthesis of Example 26, with the following exceptions: The nucleophilic aromatic substitution step was performed at rt utilizing Cs₂CO₃ as the base, and MeCN as the solvent. The amide coupling with Int-4 was performed utilizing the general procedure for amide coupling using HATU. [00116] Examples 23, 24, and 27 were prepared from the corresponding amino- or alkoxy- aryl bromide according to the procedure for the synthesis of Example 26. [00117] Example 31 was prepared from the corresponding amino aryl bromide (prepared as in J. Am. Chem. Soc. 2004, 126, 12226) according to the procedure for the synthesis of Example 26. [00118] Examples 30, 37, 38, 40, and 42 were prepared from SM-10 and the corresponding amine according to the procedure for the synthesis of Example 26. 34 ^{ME152554612v.1} 125994-02220 [00119] Example 32 was prepared from SM-10 and the corresponding benzyl amine according to the procedure for the synthesis of Examples 26, with the exception that the nucleophilic aromatic substitution step was performed at 150 °C. [00120] Example 43 was prepared from 3-bromo-6-fluoro-2-methylpyridine and the corresponding amine according to the procedure for the synthesis of Example 26. [00121] Example 29: N-(4-(2-amino-1H-imidazol-4-yl)benzyl)-2-(6-((1- phenylethyl)amino)pyridin-3-yl)acetamide. [00122] Int-30 was prepared from the corresponding aryl bromide according to the procedure for the synthesis of Example 26. Example 29 isomer 1 and Example 29 isomer 2 [00123] The crude N-(4-(2-amino-1H-imidazol-4-yl)benzyl)-2-(6-((1- phenylethyl)amino)pyridin-3-yl)acetamide (60 mg, 0.145 mmol) was purified by Prep-HPLC with the following conditions (Column: CHIRALPAK IK 2*25 cm, 5 μm; Mobile Phase A: Hex(0.5% 2M NH3-MeOH)--HPLC, Mobile Phase B: MeOH: DCM=11--HPLC; Flow rate: 20 mL/min; Gradient: isocratic 35; Wave Length: 220/254 nm; RT1(min): 16.93; RT2(min): 21.58; Sample Solvent: MeOH: DCM=1: 1-HPLC; Injection Volume: 0.5 mL; Number Of Runs: 4) to afford N-(4-(2-amino-1H-imidazol-4-yl)benzyl)-2-(6-((1- phenylethyl)amino)pyridin-3-yl)acetamide isomer 1 (25.3 mg, 42%) as a white solid and N- (4-(2-amino-1H-imidazol-4-yl)benzyl)-2-(6-((1-phenylethyl)amino)pyridin-3-yl)acetamide isomer 2 (25.4 mg, 42% yield) as a white solid. [00124] Data for Example 29 isomer 1: LC-MS, ES⁺: m/z 427.10 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d6) δ 10.69 (s, 1H), 8.34 (t, J = 5.9 Hz, 1H), 7.77 (d, J = 2.3 Hz, 1H), 7.55 – 7.45 (m, 2H), 7.40 – 7.33 (m, 2H), 7.32 – 7.21 (m, 3H), 7.20 – 7.07 (m, 3H), 6.94 (s, 1H), 35 ^{ME152554612v.1} 125994-02220 6.81 (d, J = 7.8 Hz, 1H), 6.41 (d, J = 8.5 Hz, 1H), 5.37 (s, 2H), 4.96 (p, J = 7.1 Hz, 1H), 4.18 (d, J = 5.8 Hz, 2H), 3.23 (s, 2H), 1.40 (d, J = 6.9 Hz, 3H). [00125] Data for Example 29 isomer 2: LC-MS, ES⁺: m/z 427.10 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d6) δ 10.80 (s, 1H), 8.35 (t, J = 5.9 Hz, 1H), 7.77 (d, J = 2.3 Hz, 1H), 7.50 (d, J = 8.0 Hz, 2H), 7.36 (d, J = 7.2 Hz, 2H), 7.31 – 7.22 (m, 3H), 7.15 (dd, J = 18.9, 7.7 Hz, 3H), 6.97 (s, 1H), 6.81 (d, J = 7.9 Hz, 1H), 6.41 (d, J = 8.5 Hz, 1H), 5.51 (s, 2H), 4.96 (p, J = 7.2 Hz, 1H), 4.19 (d, J = 5.8 Hz, 2H), 3.23 (s, 2H), 1.40 (d, J = 6.9 Hz, 3H). [00126] Examples 33 isomer 1, 33 isomer 2, 36 isomer 1, and 36 isomer 2 were prepared from SM-10 and the corresponding benzyl alcohol according to the procedure for the synthesis of Examples 29 isomer 1 and 29 isomer 2. [00127] Examples 34 isomer 1, 34 isomer 2, 35 isomer 1, and 35 isomer 2 were prepared from SM-10 and the corresponding benzyl amine according to the procedure for the synthesis of Examples 29 isomer 1 and 29 isomer 2, with the exception that the nucleophilic aromatic substitution step was performed at 150 °C. [00128] Example 39: N-(4-(2-amino-1H-imidazol-4-yl)benzyl)-2-(4-((1-(1- methylpiperidin-4-yl)ethyl)amino)phenyl)acetamide. 36 ^{ME152554612v.1} 125994-02220 Scheme 15 Int-31 [00129] Int-31 was prepared from tert-butyl 4-(1-aminoethyl)piperidine-1-carboxylate according to the first two steps of the synthesis of Example 26. Int-32 [00130] The general procedure for ester deprotection using Me₃SnOH: [00131] To a solution of tert-butyl 4-(1-((5-(2-(tert-butoxy)-2-oxoethyl)pyridin-2- yl)amino)ethyl)piperidine-1-carboxylate (630 mg, 1.5 mmol, 1.0 eq) in 1,2-DCE (20 mL) was added Me₃SnOH (2.44 g, 13.5 mmol, 9.0 eq) portion-wise at rt under nitrogen. The reaction mixture was heated at reflux for 20 h under a nitrogen atmosphere. The reaction was cooled to rt and diluted with EtOAc and quenched with brine. The layers were separated, and the aqueous layer was extracted 2x with EtOAc. The combined organic layers were dried (Na₂SO₄), filtered, and concentrated under reduced pressure. The crude material was purified by reverse phase flash chromatography on a C18 column eluting with H2O/MeCN (30% MeCN → 70% MeCN) to give 2-(6-((1-(1-(tert-butoxycarbonyl)piperidin-4- yl)ethyl)amino)pyridin-3-yl)acetic acid (460 mg, 84% yield) as a light brown solid: LC-MS, ES⁺: m/z 364.1 [M+H]⁺. 37 ^{ME152554612v.1} 125994-02220 Int-33 [00132] Int-33 was prepared from 2-(6-((1-(1-(tert-butoxycarbonyl)piperidin-4- yl)ethyl)amino)pyridin-3-yl)acetic acid according to the general procedure for amide coupling using HBTU. Int-34 [00133] The general procedure for Boc deprotection with TFA: [00134] TFA (5.0 mL) was added to a solution of tert-butyl 4-(1-((4-(2-((4-(2-nitro-1H- imidazol-4-yl)benzyl)amino)-2-oxoethyl)phenyl)amino)ethyl)piperidine-1-carboxylate (630 mg, 1.1 mmol, 1.0 eq) in DCM (5.0 mL) and the reaction was stirred for 3 h at rt under a nitrogen atmosphere room temperature for 3h under nitrogen atmosphere. The solvent was removed under reduced pressure and the residue was dissolved in MeOH (10 mL) and basified to pH 9 with a solution of NaOH in MeOH. The solvent was removed under reduced pressure and the residue was dissolved in THF (20 mL). The mixture was filtered, rinsing with THF (2 x 2 mL) and the filtrate was concentrated under reduced pressure to give N-(4- (2-nitro-1H-imidazol-4-yl)benzyl)-2-(4-((1-(piperidin-4-yl)ethyl)amino)phenyl)acetamide (480 mg, 94% yield) as a brown solid: LC-MS, ES⁺: m/z 464.10 [M+H]⁺. Int-35 [00135] Sodium cyanoborohydride (650 mg, 10.35 mmol, 10.0 eq) was added portion-wise to a solution of N-(4-(2-nitro-1H-imidazol-4-yl)benzyl)-2-(4-((1-(piperidin-4- yl)ethyl)amino)phenyl)acetamide (480 mg, 1.04 mmol, 1.0 eq) and formaldehyde (311 mg, 10.36 mmol, 10.0 eq) in MeOH (10.0 mL). The reaction was stirred for 4 h under a nitrogen atmosphere. The solvent was removed under reduced pressure and the crude material was purified by reverse-phase flash chromatography on a C18 column eluting with H₂O/MeCN (40% MeCN → 90% MeCN, containing 0.1% TFA) to give 2-(4-((1-(1-methylpiperidin-4- yl)ethyl)amino)phenyl)-N-(4-(2-nitro-1H-imidazol-4-yl)benzyl)acetamide (179 mg, 36% yield) as a yellow solid: LC-MS, ES⁺: m/z 478.50 [M+H]⁺. Example 39 [00136] The general procedure for nitro reduction using tetrahydroxydiboron: [00137] A solution of 4,4’-bipyridine (2.6 mg, 0.017 mmol, 0.05 eq) in DMF (2.0 mL) was added dropwise to a solution of 2-(4-((1-(1-methylpiperidin-4-yl)ethyl)amino)phenyl)-N-(4- (2-nitro-1H-imidazol-4-yl)benzyl)acetamide (159 mg, 0.33 mmol, 1.0 eq) and tetrahydroxydiboron (90 mg, 1.00 mmol, 3.0 eq) in DMF (6.0) mL at 10 °C. The reaction was warmed to rt and stirred for 20 min. The solvent was removed under reduced pressure and the residue was purified by reverse-phase flash chromatography on a C18 column eluting with 38 ^{ME152554612v.1} 125994-02220 H2O/MeCN (5% MeCN → 95% MeCN, containing 0.1% TFA) to give an impure material. This material was purified further by prep-HPLC with the following conditions (Column: Xselect CSH C18 OBD Column 19*250mm 5μm; Mobile Phase A: Water(0.05% TFA), Mobile Phase B: MeOH; Flow rate: 30 mL/min mL/min; Gradient: 11% B to 28% B in 8 min; Wave Length: 254nm/220nm nm; RT1(min): 7; Number Of Runs: 6) to afford N-(4-(2- amino-1H-imidazol-4-yl)benzyl)-2-(4-((1-(1-methylpiperidin-4- yl)ethyl)amino)phenyl)acetamide (30.7 mg, 14% yield) as an off-white solid: LC-MS, ES⁺: m/z 448.30 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 13.35 (s, 1H), 12.42 (s, 1H), 9.63 (s, 1H), 8.8-8.40 (m, 2H),7.84-7.70 (m, 4H),7.69-7.46 (m, 2H),7.38 (s, 1H),7.36-7.24 (m, 2H),7.15-6.96 (m, 1H), 4.28 (s, 2H), 3.54-3.40 (m, 4H), 3.03-2.80 (m, 2H),2.74 (s, 3H), 2.05- 1.97 (m, 2H),1.95-1.65 (s, 1H),1.59-1.36(m, 2H),1.35 (s, 1H),1.21-1.10 (d, J = 6.4Hz, 3H). [00138] Example 41 was prepared from tert-butyl 4-(1-(methylamino)ethyl)piperidine- 1-carboxylate according to the procedure for the synthesis of Example 39. [00139] Example 44: N-(4-(2-amino-5-methyl-1H-imidazol-4-yl)benzyl)-2-(6- (benzylamino)pyridin-3-yl)acetamide. Int-36 [00140] To a mixture of 5-methyl-1H-imidazole (15 g, 183 mmol, 1.0 eq) and Et3N (76 mL, 548 mmol, 3.0 eq) in DCM (500 mL) was added triphenylmethyl chloride (76 g, 274 mmol, 1.5 eq) portion-wise at 0 °C. The resulting mixture was stirred at rt for 8 h. The precipitated solids were collected by filtration, washed with DCM, and dried under vacuum to give 5-methyl-1-trityl-1H-imidazole (13 g, 22% yield) as a white solid: LC-MS, ES⁺: m/z 325.10 [M+H]⁺. 39 ^{ME152554612v.1} 125994-02220 Int-37 [00141] n-Butyllithium (13.6 mL, 33.9 mmol, 1.0 eq of a 2.5M solution in hexanes) was added dropwise to a solution of 5-methyl-1-trityl-1H-imidazole (11 g, 33.9 mmol, 1.0 eq) in THF (200 mL) at 0 °C, and the reaction was stirred for 3 h at 0 °C. The reaction was warmed to rt and isopropyl nitrate (5.3 g, 50.9 mmol, 1.5 eq) was added dropwise. The reaction was stirred for 2 h at rt then cooled to 0 °C. H₂O (5.0 mL) was added dropwise over 1 min at 0 °C. The reaction was concentrated under reduced pressure to remove the THF. The residue was dissolved in MeOH (80 mL) and HCl (20 mL of a 2M aqueous solution) was added dropwise over 5 min at 0 °C. The reaction was concentrated under reduced pressure to remove MeOH, and the resultant acidic mixture was adjusted to pH ~8 with the careful addition of sat. Na2CO3. The mixture was extracted 3x with EtOAc and the organic layer was discarded. The pH of the aqueous phase was adjusted to ~4 by the addition of sat. KHSO4 and extracted 4x with DCM. The combined organic layers were dried (Na₂SO₄), filtered, and concentrated under reduced pressure to give 4-methyl-2-nitro-1H-imidazole (500 mg, 12 yield%) as a yellow solid: LC-MS, ES⁺: m/z 128.15 [M+H]⁺. Int-38 [00142] N-iodosuccinimide (425 mg, 1.89 mmol, 1.2 eq) was added to a solution of 5- methyl-2-nitro-1H-imidazole (200 mg, 1.57 mmol, 1.0 eq) in DCM (3.0 mL), and the reaction was stirred at rt for 1 h. The reaction was quenched with brine and diluted with EtOAc. The layers were separated and the organic layer was extracted 2x with EtOAc. The combined organic layers were dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude material was purified by reverse phase flash chromatography on a C18 column eluting with H₂O/MeCN (40% MeCN → 70% MeCN) to give 4-iodo-5-methyl-2- nitro-1H-imidazole (160 mg, 40% yield) as a yellow solid: LC-MS, ES⁺: m/z 254.00 [M+H]⁺. [00143] The synthesis of Example 44 was completed according to the synthesis of Example 1 (Suzuki coupling with SM-2, Boc deprotection with HCl in 1,4-dioxane, amide coupling with Int-29, and nitro reduction with Fe). [00144] Example 45: 5-(2-((4-(2-amino-1H-imidazol-4-yl)benzyl)amino)-3,3,3- trifluoropropyl)-N-benzylpyridin-2-amine. 40 ^{ME152554612v.1} 125994-02220 Scheme 17 Int-39 [00145] A solution of 2-(6-(benzylamino)pyridin-3-yl)acetic acid (450 mg, 1.9 mmol, 1.0 eq) and CF3CO2Na (505 mg, 3.7 mmol, 2.0 eq) in trifluoroacetic anhydride (5.0 mL) was stirred at 80 °C for 2 h. The reaction was cooled to 0 °C and carefully quenched with H₂O. The resulting mixture was extracted 2x with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography on a C18 column eluting with H₂O/MeCN (10% MeCN → 50% MeCN) to give 3-(6-(benzylamino)pyridin-3-yl)-1,1,1- trifluoropropan-2-one (200 mg, 37% yield) as a yellow solid: LC-MS, ES⁺: m/z 295.05 [M+H]⁺. Int-40 [00146] Ti(Oi-Pr)₄ (115.9 mg, 0.41 mmol, 0.5 eq) was added to a solution of 3-(6- (benzylamino)pyridin-3-yl)-1,1,1-trifluoropropan-2-one (240 mg, 0.82 mmol, 1.0 eq) and Int- 4 (178 mg, 0.82 mmol, 1.0 eq) in 1,2-DCE (3.0 mL) and the reaction was heated at 65 °C overnight. The reaction was cooled to rt and NaBH₃CN (103 mg, 1.63 mmol, 2.0 eq) was added portion-wise. Upon complete addition of NaBH3CN the reaction was carefully quenched with sat. NH₄Cl. The reaction was extracted 3x with EtOAc. The combined organic layers were washed with brine, dried (Na₂SO₄), filtered, and concentrated under reduced pressure. The crude material was purified by flash chromatography eluting with hexanes/EtOAc (33% EtOAc) to give N-benzyl-5-(3,3,3-trifluoro-2-((4-(2-nitro-1H-imidazol- 4-yl)benzyl)amino)propyl)pyridin-2-amine (100 mg, 25% yield) as a yellow oil: LC-MS, ES⁺: m/z 497.35 [M+H]⁺. [00147] Example 45 was completed according to the general procedure for nitro reduction using tetrahydroxydiboron. [00148] Example 46: (rac)-N-(4-(2-amino-1H-imidazol-4-yl)benzyl)-2-(3-phenylindolin- 5-yl)acetamide. 41 ^{ME152554612v.1} 125994-02220 Scheme 19 Int-41 [00149] A solution of (4-bromophenyl)hydrazine (5.0 g, 26.7 mmol, 1.0 eq) and phenylacetaldehyde (3.2 g, 26.7 mmol, 1.0 eq) in EtOH (70 mL) was stirred under N₂ at 90 °C for 12 h. The reaction was concentrated and partitioned between H₂O and DCM. The layers were separated, and the aqueous layer was extracted 2x with DCM. The combined organic layers were washed with brine, dried (Na₂SO₄), filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with hexanes/EtOAc (25% EtOAc) to give 5-bromo-3-phenyl-1H-indole (2.8 g, 31% yield) as a grey solid: LC-MS, ES-: m/z 269.95 [M-H]- Int-42 [00150] A solution of 5-bromo-3-phenyl-1H-indole (1.5 g, 5.5 mmol, 1.0 eq) and Et3SiH (3.2 g, 27.6 mmol, 5.0 eq) in TFA (9 mL) was stirred at 50 °C for 12 h. The mixture was carefully basified to pH 9 with saturated Na₂CO₃ (aq.). The resulting mixture was extracted 3x with DCM. The combined organic layers were washed with brine, dried (Na₂SO₄), filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with hexanes/EtOAc (20% EtOAc) to give 5-bromo-3- phenylindoline (1.5 g, 99% yield) as a yellow oil: LC-MS, ES⁺: m/z 273.90 [M+H]⁺. Int-43 [00151] A solution of 5-bromo-3-phenylindoline (1.5 g, 5.5 mmol, 1.0 eq) and di-tert- butyl dicarbonate (3.6 g, 16.4 mmol, 3.0 eq) in tert-butanol (50 mL) was stirred at 50 °C for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by flash chromatography eluting with hexanes/EtOAc (10% EtOAc) to give tert-butyl 5- bromo-3-phenylindoline-1-carboxylate (2.0 g, 78% yield) as a red solid: LC-MS, ES⁺: m/z 375.80 [M+H]⁺. [00152] The synthesis of Example 46 was completed according to the procedure for the synthesis of Example 26. [00153] Example 52: N-(4-(2-amino-1H-imidazol-4-yl)benzyl)-2-(4-((tetrahydro-2H- pyran)-4-sulfonamido)phenyl)acetamide. 42 ^{ME152554612v.1} 125994-02220 Int-44 [00154] Int-44 was prepared from 2-(4-((tert-butoxycarbonyl)amino)phenyl)acetic acid and Int-4 according to the general procedure for amide coupling using HBTU, followed by the general procedure for Boc deprotection with TFA. Int-45 [00155] Triethylamine (47 µL, 0.42 mmol, 3.0 eq) was added dropwise to a solution of 2- (4-aminophenyl)-N-(4-(2-nitro-1H-imidazol-4-yl)benzyl)acetamide (50 mg, 0.14 mmol, 1.0 eq) and tetrahydro-2H-pyran-4-sulfonyl chloride (31.5 mg, 0.17 mmol, 1.2 eq) in DCM (0.5 mL) at 0 °C. The reaction was warmed to rt and stirred for 1 h. The mixture was purified by reverse-phase flash chromatography on a C18 column eluting with H₂O/MeCN (40% MeCN → 80% MeCN) to give N-(4-(2-nitro-1H-imidazol-4-yl)benzyl)-2-(4-((tetrahydro-2H-pyran)- 4-sulfonamido)phenyl)acetamide (25 mg, 35% yield) as a white solid: LC-MS, ES⁺: m/z 498.10 [M+H]⁺. [00156] The synthesis of Example 52 was completed according to the general procedure for nitro reduction using Fe. [00157] Example 65 was prepared from Int-44 and the corresponding sulfonyl chloride according to the procedure for the synthesis of Example 52. [00158] Example 53: N-(4-(2-amino-1H-imidazol-4-yl)benzyl)-2-(4- ((phenylmethyl)sulfonamido)phenyl)acetamide. 43 ^{ME152554612v.1} 125994-02220 Scheme 20 Int-46 [00159] The general procedure for sulfonamide formation using pyridine: [00160] Pyridine (34 µL, 0.43 mmol, 3.0 eq) was added dropwise to a solution of 2-(4- aminophenyl)-N-(4-(2-nitro-1H-imidazol-4-yl)benzyl)acetamide (50 mg, 0.14 mmol, 1.0 eq) and phenylmethanesulfonyl chloride (27.1 mg, 0.14 mmol, 1.0 eq) in DCM (0.5 mL) at 0 °C. The reaction was warmed to rt and stirred for 1 h. The mixture was concentrated under reduced pressure and the residue was purified by reverse-phase flash chromatography on a C18 column eluting with H₂O/MeCN (40% MeCN → 70% MeCN) to give N-(4-(2-nitro-1H- imidazol-4-yl)benzyl)-2-(4-((phenylmethyl)sulfonamido)phenyl)acetamide (25 mg, 35% yield) as a white solid: LC-MS, ES⁺: m/z 504.25 [M+H]⁺. [00161] The synthesis of Example 53 was completed according to the general procedure for nitro reduction using Fe. [00162] Examples 50, 51, 54, 59, 63, 64, 66, and 67 were prepared from Int-44 and the corresponding sulfonyl chloride according to the procedure for the synthesis of Example 53. [00163] Example 55: N-(4-(2-amino-1H-imidazol-4-yl)benzyl)-2-(4-((1-methyl-1H- pyrazole)-4-sulfonamido)phenyl)acetamide. 44 ^{ME152554612v.1} 125994-02220 Int-47 [00164] DIPEA (149 µL, 0.86 mmol, 3.0 eq) was added to a solution of 2-(4- aminophenyl)-N-(4-(2-nitro-1H-imidazol-4-yl)benzyl)acetamide (100 mg, 0.29 mmol, 1.0 eq) in DCM (2.0 mL) and the reaction was stirred at rt for 2 h. The solvent was removed under reduced pressure and the crude material was purified by reverse-phase flash chromatography on a C18 column eluting with H₂O/MeCN (30% MeCN → 60% MeCN) to give 2-(4-((1- methyl-1H-pyrazole)-4-sulfonamido)phenyl)-N-(4-(2-nitro-1H-imidazol-4- yl)benzyl)acetamide (60 mg, 43% yield) as a yellow solid: LC-MS, ES⁺: m/z 494.20 [M+H]⁺. [00165] The synthesis of Example 55 was completed according to the general procedure for nitro reduction using Fe. [00166] Example 58 was prepared from Int-44 and the corresponding sulfonyl chloride according to the procedure for the synthesis of Example 55. [00167] Example 56: N-(4-(2-amino-1H-imidazol-4-yl)benzyl)-2-(4- (phenylsulfonamido)phenyl)acetamide. Int-48 [00168] The general procedure for sulfonamide or amide formation from sulfonyl or acyl chlorides: [00169] Sulfonyl chloride (425 µL, 3.33 mmol, 1.1 eq) was added dropwise to a mixture of methyl 2-(4-aminophenyl)acetate (500 mg, 3.03 mmol, 1 eq), DMAP (28 mg, 0.303 mmol, 0.1 eq), and DIPEA (1.08 mL, 6.05 mmol, 2.0 eq) in DCM (1.0 mL) at 0 °C. 45 ^{ME152554612v.1} 125994-02220 The reaction was warmed to rt and the DCM was evaporated under a stream of N2. Pyridine (2 mL) was added, and the reaction heated at 45 °C for 5 h. The reaction was concentrated under reduced pressure and the residue purified by flash chromatography eluting with hexanes/EtOAc (0% EtOAc → 70% EtOAc) to give methyl 2-(4- (phenylsulfonamido)phenyl)acetate (768 mg, 2.51 mmol, 83% yield): LC-MS, ES⁺: m/z 306.09 [M+H]⁺; ¹H NMR (300 MHz, METHANOL-d₄) δ ppm 7.70 - 7.78 (m, 2H), 7.51 - 7.59 (m, 1H), 7.41 - 7.50 (m, 2H), 7.09 - 7.15 (m, 2H), 7.00 - 7.06 (m, 2H), 3.65 (s, 3H), 3.55 (s, 2H). Int-49 [00170] The general procedure for ester hydrolysis: [00171] LiOH (180 mg, 7.53 mmol, 3 eq) was added to a solution of methyl 2-(4- (phenylsulfonamido)phenyl)acetate (768 mg, 2.51 mmol, 1 eq) in THF/H2O (4.0 mL of a 1.4:1 mixture) and the reaction was heated at 35 °C for 2 h. The reaction was cooled to rt and stirred for an additional 40 min. The reaction was washed 3x with EtOAc and the aqueous layer was acidified with 6M HCl(aq) (1.75 mL). The aqueous layer was extracted 2x with EtOAc. The combined organic layers were washed 2x with H₂O, dried (MgSO₄), filtered, and concentrated under reduced pressure to give crude 2-(4-(phenylsulfonamido)phenyl)acetic acid (710 mg, 97% yield) which was used without further purification: LC-MS, ES⁺: m/z 292.04 [M+H]⁺. Int-50 [00172] The general procedure for amide coupling using PyBOP: [00173] Int-4 (75 mg, 0.34 mmol, 1.0 eq) was added to a mixture of 2-(4- (phenylsulfonamido)phenyl)acetic acid (110.1 mg, 0.38 mmol, 1.1 eq), PyBOP (196.7 mg, 0.38 mmol, 1.1 eq) and DIPEA (184 µL, 1.03 mmol, 3.0 eq) in MeCN (1.0 mL). DMF (1.5 mL) was added for solubility, and the reaction was stirred overnight. The reaction was quenched by the careful addition of solid NaHCO₃ (100 mg) and the reaction stirred for 30 min. The solvent was removed under reduced pressure and the residue purified by flash chromatography eluting with DCM/MeOH (0% MeOH → 10% MeOH) to give N-(4-(2- nitro-1H-imidazol-4-yl)benzyl)-2-(4-(phenylsulfonamido)phenyl)acetamide that was contaminated with the phosphoramide derived from PyBOP. This material was used in the next step without further purification: LC-MS, ES⁺: m/z 492.08 [M+H]⁺. Example 56 [00174] Fe powder (152.4 mg, 2.73 mmol, 8.0 eq) and NH₄Cl (146 mg, 2.73 mmol, 8.0 eq) were added to a solution of crude N-(4-(2-nitro-1H-imidazol-4-yl)benzyl)-2-(4- 46 ^{ME152554612v.1} 125994-02220 (phenylsulfonamido)phenyl)acetamide (167.7 mg, 0.34 mmol, 1.0 eq) in EtOH/H2O (5 mL of a 2:1 mixture) and the reaction was stirred at 80 °C for 20 min. The reaction was cooled to rt and filtered through celite, rinsing with MeOH. The filtrate was concentrated under reduced pressure to give a white solid which was purified by reverse-phase prep HPLC on a C18 column eluting with H2O/MeCN (5% MeCN → 75% MeCN containing 0.1% formic acid) to give N-(4-(2-amino-1H-imidazol-4-yl)benzyl)-2-(4-(phenylsulfonamido)phenyl)acetamide (21.6 mg, 13% yield over 2 steps) as a white solid: LC-MS, ES⁺: m/z 462.34 [M+H]⁺; ¹H NMR (300 MHz, METHANOL-d4) δ ppm 7.68 - 7.78 (m, 2H), 7.39 - 7.58 (m, 5H), 7.29 (d, J = 8.7 Hz, 2H), 7.09 - 7.19 (m, 3H), 6.99 - 7.08 (m, 2H), 4.36 (s, 2H), 3.46 (s, 2H). [00175] Example 48 was prepared according to the procedure for the synthesis of Example 55. [00176] Examples 47, 48, 56, 59, 60, and 61 were prepared according to the procedure for the synthesis of Example 55, with the exception that the sulfonamide or amide formation was run in pyridine as the solvent. [00177] Example 91 was prepared from ethyl 2-(6-aminopyridin-3-yl)acetate and 4-(2- methoxyethoxy)benzenesulfonyl chloride according to the procedure for the synthesis of Example 55, with the following exceptions: The ethyl ester hydrolysis required a temperature of 45 °C. The amide coupling was run in DMF as the sole solvent. [00178] Example 28: N-(4-(2-amino-1H-imidazol-4-yl)benzyl)-2-(5-phenethylpyridin-3- yl)acetamide. Scheme 23 Int-51 [00179] A mixture of methyl 2-(5-bromopyridin-3-yl)acetate (400 mg, 1.74 mmol, 1.0 eq), phenethylboronic acid (521.5 mg, 3.48 mmol, 2.0 eq), K₂CO₃ (480.6 mg, 3.48 mmol, 2.0 eq), and Pd(dppf)Cl2 (121 mg, 0.17 mmol, 0.1 eq) were in 1,4-dioxane (5.0 mL) and H2O (0.5 mL) was stirred and the reaction vessel was flushed with nitrogen. The reaction was stirred at 105 °C for 18 h. The solvent was removed under reduced pressure and the crude material was 47 ^{ME152554612v.1} 125994-02220 purified by flash chromatography eluting with DCM/MeOH (0% MeOH → 15% MeOH) to give methyl 2-(5-phenethylpyridin-3-yl)acetate (175.5 mg, 40% yield): LC-MS, ES⁺: m/z 256.09 [M+H]⁺. [00180] The synthesis of Example 28 was completed according to the procedure for the synthesis of Example 55, beginning with the general procedure for ester hydrolysis. [00181] Example 68: N-(4-(2-amino-1H-imidazol-4-yl)-2-methylbenzyl)-2-(4- (phenylsulfonamido)phenyl)acetamide. Int-52 [00182] Int-52 was prepared from Int-49 and (4-bromo-2-methylphenyl)methanamine according to the general procedure for amide coupling using PyBOP. Int-53 [00183] A mixture of N-(4-bromo-2-methylbenzyl)-2-(4- (phenylsulfonamido)phenyl)acetamide (169 mg, 0.36 mmol, 1.0 eq), KOAc (75 mg, 0.76 mmol, 2.1 eq), bis(pinacolato)diboron (193 mg, 0.76 mmol, 2.1 eq), and Pd(dppf)Cl2 (24 mg, 0.036 mmol, 0.1 eq) were dissolved in 1,4-dioxane/DMSO (3.3 mL of a 10:1 mixture), and the reaction was heated at 105 °C for 4 h. The solvent was removed under reduced pressure and the crude material was purified by flash chromatography eluting with hexanes/EtOAc (0% EtOAc → 65% EtOAc) to give N-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 48 ^{ME152554612v.1} 125994-02220 2-yl)benzyl)-2-(4-(phenylsulfonamido)phenyl)acetamide (122.7 mg, 66% yield): LC-MS, ES⁺: m/z 521.17 [M+H]⁺; ¹H NMR (300 MHz, METHANOL-d4) δ ppm 7.69 - 7.78 (m, 2H), 7.38 - 7.60 (m, 5H), 7.13 - 7.20 (m, 2H), 7.01 - 7.11 (m, 3H), 4.33 (s, 2H), 3.44 (s, 2H), 2.20 (s, 3H), 1.33 (s, 12H). Int-54 [00184] A mixture of 4-bromo-2-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- imidazole (152 mg, 0.47 mmol, 2.0 eq), N-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzyl)-2-(4-(phenylsulfonamido)phenyl)acetamide (122.7 mg, 0.24 mmol, 1.0 eq), K2CO3 (65.2 mg, 0.47 mmol, 2.0 eq), and Pd(dppf)Cl2 (26.3 mg, 0.036 mmol, 0.15 eq) in 1,4-dioxane (3.0 mL) and H₂O (0.3 mL) was stirred and the reaction vessel was flushed with nitrogen. The reaction was stirred at 105 °C for 19 h. The solvent was removed under reduced pressure and the crude material was purified by flash chromatography eluting with DCM/MeOH (0% MeOH → 10% MeOH) to give N-(2-methyl-4-(2-nitro-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)benzyl)-2-(4- (phenylsulfonamido)phenyl)acetamide (28.9 mg, 19% yield): LC-MS, ES⁺: m/z 636.07 [M+H]⁺; ¹H NMR (300 MHz, METHANOL-d₄) δ ppm 7.96 (s, 1 H), 7.71 - 7.78 (m, 2H), 7.65 (s, 1H), 7.50 - 7.61 (m, 2H), 7.40 - 7.49 (m, 2H), 7.14 - 7.22 (m, 3H), 7.01 - 7.07 (m, 2H), 5.80 (s, 2H), 4.35 (d, J = 5.48 Hz, 2H), 3.64 - 3.77 (m, 2H), 3.46 (s, 2H), 2.27 (s, 3H), - 0.02 (s, 9H). Int-55 [00185] A mixture of N-(2-methyl-4-(2-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- imidazol-4-yl)benzyl)-2-(4-(phenylsulfonamido)phenyl)acetamide (28.9 mg, 0.045 mmol, 1.0 eq) and H₂O (10 µL) in HCl (4 mL of a solution in 1,4-dioxane) was heated at 40 °C for 45 min. The solvent was removed under reduced pressure to give crude N-(2-methyl-4-(2-nitro- 1H-imidazol-4-yl)benzyl)-2-(4-(phenylsulfonamido)phenyl)acetamide, which was used without further purification: LC-MS, ES⁺: m/z 506.03 [M+H]⁺. [00186] The synthesis of Example 68 was completed according to the general procedure for nitro reduction using Fe. [00187] Example 70 was prepared from (4-bromo-3-methoxyphenyl)methanamine according to the procedure for the synthesis of Example 68. [00188] Example 69: N-(4-(2-amino-1H-imidazol-4-yl)-2-fluorobenzyl)-2-(4- (phenylsulfonamido)phenyl)acetamide. 49 ^{ME152554612v.1} 125994-02220 Scheme-25 Int-56 [00189] A mixture of 4-bromo-2-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- imidazole (784 mg, 2.43 mmol, 2.0 eq), (4-(aminomethyl)-3-fluorophenyl)boronic acid, hydrochloride (250 mg, 1.22 mmol, 1.0 eq), K2CO3 (505 mg, 3.65 mmol, 3.0 eq), and Pd(dppf)Cl2 (89.0 mg, 0.12 mmol, 0.10 eq) in 1,4-dioxane (10.0 mL) and H2O (1.0 mL) was stirred and the reaction vessel was flushed with nitrogen. The reaction was stirred at 105 °C for 19 h. The solvent was removed under reduced pressure and the crude material was purified by flash chromatography eluting with DCM/MeOH (0% MeOH → 10% MeOH) to give (2-fluoro-4-(2-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4- yl)phenyl)methanamine (13.5 mg, 3% yield): LC-MS, ES⁺: m/z 367.11 [M+H]⁺. [00190] The synthesis of Example 69 was completed according to the general procedure for amide coupling using PyBOP then according to the procedure for the synthesis of Example 68. [00191] Example 99 was prepared from Int-56 and 2-(4-((4-(3- methoxypropoxy)phenyl)sulfonamido)phenyl)acetic acid (prepared according to the procedure for the synthesis of Int-49) according to the procedure for the synthesis of Example 69. [00192] Example 71: N-((5-(2-amino-1H-imidazol-4-yl)pyridin-2-yl)methyl)-2-(4-((4- methoxyphenyl)sulfonamido)phenyl)acetamide. 50 ^{ME152554612v.1} 125994-02220 Scheme 26 Int-57 [00193] 2-(4-((4-methoxyphenyl)sulfonamido)phenyl)acetic acid was prepared from methyl 2-(4-aminophenyl)acetate and 4-methoxybenzenesulfonyl chloride according to the first two steps in the synthesis of Example 55. (5-bromopyridin-2-yl)methanamine, hydrochloride was coupled with 2-(4-((4-methoxyphenyl)sulfonamido)phenyl)acetic acid according to the general procedure for amide coupling using PyBOP to give N-((5- bromopyridin-2-yl)methyl)-2-(4-((4-methoxyphenyl)sulfonamido)phenyl)acetamide. Int-58 [00194] A mixture of N-((5-bromopyridin-2-yl)methyl)-2-(4-((4- methoxyphenyl)sulfonamido)phenyl)acetamide (486 mg, 0.99 mmol, 1.0 eq), KOAc (207.5 mg, 2.11 mmol, 2.1 eq), bis(pinacolato)diboron (536 mg, 2.11 mmol, 2.1 eq), and Pd(dppf)Cl2 (77 mg, 0.099 mmol, 0.1 eq) were dissolved in 1,4-dioxane/DMSO (5.5 mL of a 10:1 mixture), and the reaction was heated at 105 °C for 5 h. The solvent was removed under reduced pressure and the residue was partitioned between brine and EtOAc. The layers were separated and the aqueous layer was extracted 2x with EtOAc. The combined organic layers were dried (Na₂SO₄), filtered, and concentrated to give a solid that was triturated with hexanes. The resultant solid was collected via filtration and rinsed with hexanes to give crude (6-((2-(4-((4-methoxyphenyl)sulfonamido)phenyl)acetamido)methyl)pyridin-3-yl)boronic acid that was used without further purification: LC-MS, ES⁺: m/z 456.03 [M+H]⁺. [00195] Example 71 was completed according to the procedure for the synthesis of Example 68. [00196] Example 74: N-(4-(2-amino-1H-imidazol-4-yl)benzyl)-N-methyl-2-(4-(N- methylphenylsulfonamido)phenyl)acetamide. 51 ^{ME152554612v.1} 125994-02220 Scheme 27 Int-59 [00197] The general procedure for Suzuki coupling using Pd(dppf)Cl₂·CH₂Cl₂: [00198] A mixture of tert-butyl methyl(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzyl)carbamate (500 mg, 1.44 mmol, 1.0 eq), Int-2 (465 mg, 1.44 mmol, 1.0 eq), Pd(dppf)Cl₂·CH₂Cl₂ (118 mg, 0.14 mmol, 0.1 eq), and Na₂CO₃ (306 mg, 2.89 mmol, 2.0 eq) in 1,4-dioxane (5.0 mL) and H2O (1.0 mL) was stirred for 1 h at 100 °C. The reaction was filtered, rinsing with 1,4-dioxne. The filtrate was concentrated under reduced pressure and the residue was purified by reverse phase flash chromatography on a C18 column eluting with H₂O/MeCN (40% MeCN → 70% MeCN) to give tert-butyl methyl(4-(2-nitro-1H-imidazol- 4-yl)benzyl)carbamate (240 mg, 50% yield) as a yellow oil: LC-MS, ES⁺: m/z 331.10 [M+H]⁺. [00199] The synthesis of Example 74 was completed according to the general procedure for Boc deprotection with TFA, followed by the general procedure for amide coupling using HBTU [coupling with 2-(4-(N-methylphenylsulfonamido)phenyl)acetic acid], and the general procedure for nitro reduction using Fe. [00200] 2-(4-(N-methylphenylsulfonamido)phenyl)acetic acid was synthesized from methyl 2-(4-(methylamino)phenyl)acetate and benzenesulfonyl chloride according to the procedure for the first two steps in the synthesis of Example 55. [00201] Example 72 was synthesized from Int-4 and 2-(4-(N- methylphenylsulfonamido)phenyl)acetic acid according to the procedure for the synthesis of Example 74. [00202] Example 73 was synthesized from Int-59 and Int-49 according to the procedure for the synthesis of Example 74. [00203] Example 75 was synthesized from tert-butyl (R)-(1-(4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)phenyl)ethyl)carbamate according to the procedure for the synthesis of example 74, with the following exception: the general procedure for amide coupling using TCFH-NMI was used for the amide coupling. [00204] Example 76 was synthesized from tert-butyl (S)-(1-(4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)phenyl)ethyl)carbamate according to the procedure for the synthesis of 52 ^{ME152554612v.1} 125994-02220 Example 74, with the following exception: the general procedure for amide coupling using TCFH-NMI was used for the amide coupling. [00205] Example 78: (R)-N-(4-(2-amino-1H-imidazol-4-yl)benzyl)-2-(4- (phenylsulfonamido)phenyl)propenamide. Int-60 [00206] To a solution of (R)-2-(4-nitrophenyl)propanoic acid (2 g, 10.25 mmol, 1.0 eq) and Boc2O (2.2 g, 10.25 mmol, 1.0 eq) in t-BuOH (30 mL) was added DMAP (1.9 g, 15.37 mmol, 1.5 eq). The resulting mixture was stirred overnight at rt. The reaction mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography on a C18 column eluting with H2O/MeCN (40% MeCN → 80% MeCN) to give tert-butyl (R)-2-(4-nitrophenyl)propanoate (530 mg, 41% yield) as a colorless oil: LC- MS, ES⁺: m/z 252.10 [M+H]⁺. Int-61 [00207] Int-61 was prepared according to the general procedure for nitro reduction using Fe. Int-62 [00208] The general procedure for sulfonamide formation using triethylamine. [00209] Triethylamine (661 µL, 4.5 mmol, 3.0 eq) was added dropwise to a solution of tert-butyl (R)-2-(4-aminophenyl)propanoate (350 mg, 1.6 mmol, 1.0 eq) and benzenesulfonyl chloride (335 mg, 1.9 mmol, 1.2 eq) in DCM (12 mL) and the reaction was stirred for 16 h at rt. The reaction was concentrated under reduced pressure, and the crude material was purified 53 ^{ME152554612v.1} 125994-02220 by flash chromatography eluting with hexanes/EtOAc (8:1) to give tert-butyl (R)-2-(4- (phenylsulfonamido)phenyl)propanoate (360 mg, 62% yield) as a yellow solid: LC-MS, ES⁺: m/z 384.20 [M+H]⁺. [00210] The synthesis of Example 78 was completed according to the general procedure for tert-butyl ester cleavage using TFA, followed by the general procedure for amide coupling using HBTU (coupling with Int-4), and the general procedure for nitro reduction using tetrahydroxydiboron. [00211] Example 77 was prepared according to the procedure for the synthesis of Example 78. [00212] Example 79: N-(4-(2-amino-1H-imidazol-4-yl)benzyl)-2-(6- ((cyclopropylmethyl)sulfonamido)pyridin-3-yl)acetamide. [00213] Example 79 was prepared from ethyl 2-(6-aminopyridin-3-yl)acetate and the corresponding sulfonyl chloride according to the general procedure for sulfonamide formation using triethylamine, followed by the general procedure for ester hydrolysis using MeOH/THF/H₂O as the solvent, the general procedure for amide coupling using EDCI (coupling with Int-4), and the general procedure for nitro reduction using Fe. [00214] Examples 80, 81, 82, and 83 were prepared according to the procedure for the synthesis of Example 79. [00215] Example 84: N-(4-(2-amino-1H-imidazol-4-yl)benzyl)-2-(6-(piperidine-4- sulfonamido)pyridin-3-yl)acetamide. [00216] Example 79 was prepared from ethyl 2-(6-aminopyridin-3-yl)acetate and the corresponding sulfonyl chloride according to the general procedure for sulfonamide formation using triethylamine, followed by the general procedure for ester hydrolysis using MeOH/THF/H₂O as the solvent, the general procedure for amide coupling using HBTU (coupling with Int-4), the general procedure for tert-butyl ester cleavage using TFA, and the general procedure for nitro reduction using Fe. 54 ^{ME152554612v.1} 125994-02220 [00217] Example 85: N-(4-(2-amino-1H-imidazol-4-yl)benzyl)-2-(6-((piperidin-4- ylmethyl)sulfonamido)pyridin-3-yl)acetamide. [00218] Int-63 was prepared from ethyl 2-(6-aminopyridin-3-yl)acetate and the corresponding sulfonyl chloride according to the general procedure for sulfonamide formation using triethylamine, followed by the general procedure for ester hydrolysis using MeOH/THF/H₂O as the solvent, and the general procedure for amide coupling using HBTU (coupling with Int-4). Int-64 [00219] A solution of benzyl 4-((N-(5-(2-((4-(2-nitro-1H-imidazol-4-yl)benzyl)amino)-2- oxoethyl)pyridin-2-yl)sulfamoyl)methyl)piperidine-1-carboxylate (100 mg, 0.15 mmol, 1.0 eq) in TFA (1.0 mL) was stirred for 8 h at 60 °C. The reaction was concentrated under reduced pressure to give N-(4-(2-nitro-1H-imidazol-4-yl)benzyl)-2-(6-((piperidin-4- ylmethyl)sulfonamido)pyridin-3-yl)acetamide, trifluoroacetate (60 mg, 63% yield) as a yellow solid: LC-MS, ES⁺: m/z 514.40 [M+H]⁺. [00220] The synthesis of Example 85 was completed according to the general procedure for nitro reduction using Fe. [00221] Example 86: N-(4-(2-amino-1H-imidazol-4-yl)benzyl)-2-(6-((1-methyl-1H- pyrazole)-4-sulfonamido)pyridin-3-yl)acetamide. 55 ^{ME152554612v.1} 125994-02220 [00222] Example 86 was prepared from SM-20 and the corresponding sulfonyl chloride according to the general procedure for sulfonamide formation using pyridine, followed by the general procedure for ester hydrolysis, the general procedure for amide coupling using HBTU (coupling with Int-4), and the general procedure for nitro reduction using Fe. [00223] Example 87: N-(4-(2-amino-1H-imidazol-4-yl)benzyl)-2-(6- (phenylsulfonamido)pyridin-3-yl)acetamide. Int-65 [00224] Benzenesulfonyl chloride (0.38 mL, 3.0 mmol, 1.0 eq) was added carefully dropwise to a solution of methyl 2-(6-aminopyridin-3-yl)acetate (500 mg, 3.0 mmol, 1.0 eq) in pyridine (30 mL) and the reaction was stirred for 24 h. LC-MS analysis of the crude reaction mixture indicated that the starting aminopyridine remained. Additional benzenesulfonyl chloride (0.38 mL, 3.0 mmol, 1.0 eq) was added and the reaction was stirred for 4 h. The solvent was removed under reduced pressure. The resultant orange gum was purified by flash chromatography eluting with hexanes/EtOAc (5% EtOAc → 100% EtOAc) to give methyl 2-(6-(phenylsulfonamido)pyridin-3-yl)acetate (608 mg, 2.0 mmol, 66% yield) as a pale yellow solid: LC-MS, ES⁺: m/z 307.0 [M+H]⁺; ¹H NMR (300 MHz, DMSO- d6) δ 7.94 (d, J = 1.7 Hz, 1H), 7.80-7.90 (m, 2H), 7.50-7.70 (m, 4H), 7.12 (d, J = 8.7 Hz, 1H), 3.59-3.61 (m, 5H). 56 ^{ME152554612v.1} 125994-02220 Int-66 [00225] LiOH (6.55 mL of a 1M solution in H2O, 6.55 mmol, 3.3 eq) was added to a solution of methyl 2-(6-(phenylsulfonamido)pyridin-3-yl)acetate (608 mg, 2.0 mmol, 1.0 eq) in THF (6.6 mL) and the reaction was stirred for 1 h at rt. The reaction was diluted with H2O (10 mL) and the pH was carefully adjusted to 5 with 1M HCl(aq). The reaction was extracted 3x with EtOAc. Solid NaCl was added to the aqueous layer until saturated and the aqueous layer was extracted a further 3x with EtOAc. The combined organic layers were dried (MgSO4), filtered, and concentrated to give 2-(6-(phenylsulfonamido)pyridin-3-yl)acetic acid (188 mg, 32% yield) as a yellow amorphous solid: LC-MS, ES⁺: m/z 293.9 [M+H]⁺; ¹H NMR (300 MHz, DMSO-d6) δ 12.10 (br s, 2H), 7.80-7.92 (m, 3H), 7.49-7.65 (m, 4H), 7.12 (d, J = 8.7 Hz), 3.49 (s, 2H). Int-67 [00226] Triethylamine (0.1 mL, 0.72mmol, 5.0 eq) was added to a mixture of 2-(6- (phenylsulfonamido)pyridin-3-yl)acetic acid (42 mg, 0.14 mmol, 1.0 eq) , Int-4 (40.3 mg, 0.16 mmol, 1.1 eq), and PyBOP (82.3 mg, 0.16 mmol, 1.1 eq) in DMF (1.8 mL) and the reaction was stirred for 30 min at rt. The solvent was removed under reduced pressure and the crude material was purified by reverse phase flash chromatography on a C18 column eluting with H2O/MeCN (10% MeCN → 100% MeCN) to give N-(4-(2-nitro-1H-imidazol-4- yl)benzyl)-2-(6-(phenylsulfonamido)pyridin-3-yl)acetamide (23.2 mg, 33% yield) as a yellow amorphous solid: LC-MS, ES⁺: m/z 493.20 [M+H]⁺; ¹H NMR (300 MHz, DMSO-d6) δ 14.62 (br s, 1H), 8.53 (t, J = 5.8 Hz, 1H), 8.00 (br s, 1H), 7.85-7.94 (m, 3H), 7.80 (d, J = 8.3 Hz, 2H), 7.51-7.65 (m, 4H), 7.26 (d, J = 8.3 Hz, 2H), 7.13 (d, J = 8.7 Hz, 1H), 4.26 (d, J = 5.7 Hz, 2H), 3.40 (s, 2H). [00227] The synthesis of Example 87 was completed according to the general procedure for nitro reduction using Fe. [00228] Example 88: N-(4-(2-amino-1H-imidazol-4-yl)benzyl)-2-(6-((4- isopropylphenyl)sulfonamido)pyridin-3-yl)acetamide. [00229] Example 88 was prepared from SM-20 and Int-4 according to the general procedure for amide coupling using HBTU, followed by the general procedure for 57 ^{ME152554612v.1} 125994-02220 sulfonamide formation (with the corresponding sulfonyl chloride) using pyridine, and the general procedure for nitro reduction using Fe. [00230] Examples 89, 90, 92, 93, 94, 95, and 96 were prepared according to the procedure for the synthesis of Example 88. [00231] Example 97: N-(4-(2-amino-1H-imidazol-4-yl)-3-methylbenzyl)-2-(6- (phenylsulfonamido)pyridin-3-yl)acetamide. Int-68 [00232] A mixture of 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzaldehyde (500 mg, 2.03 mmol, 1.0 eq), Int-2 (786 mg, 2.44 mmol, 1.2 eq), Cs2CO3 (2.0 g, 6.10 mmol, 3.0 eq), and Pd(dppf)Cl₂·CH₂Cl₂ (166 mg, 0.20 mmol, 0.1 eq) in 1,4- dioxane (5.0 mL) and H₂O (1.0 mL) was heated at 100 °C for 2 h. The reaction was filtered, rinsing with DCM, and the filtrate was concentrated under reduced pressure. The crude material was purified by reverse phase flash chromatography on a C18 column eluting with H₂O/MeCN (50% MeCN → 70% MeCN) to give 3-methyl-4-(2-nitro-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)benzaldehyde (390 mg, 53% yield) as a yellow oil: LC-MS, ES⁺: m/z 360.05 [M+H]⁺. Int-69 [00233] To a solution of 3-methyl-4-(2-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- imidazol-4-yl)benzaldehyde (360 mg, 1.0 mmol, 1.0 eq) and tert-butyl carbamate (350 mg, 3.0 mmol, 3.0 eq) in MeCN (3.0 mL) and DCM (1.0 mL) were added TFA (152 µL, 2.0 mmol, 2.0 eq) and triethylsilane (477 µL, 3.0 mmol, 3.0 eq) and the reaction was stirred for 2 h at rt. The reaction was concentrated under reduced pressure and the residue was purified by 58 ^{ME152554612v.1} 125994-02220 reverse phase flash chromatography on a C18 column eluting with H2O/MeCN (60% MeCN → 80% MeCN) to give tert-butyl (3-methyl-4-(2-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)- 1H-imidazol-4-yl)benzyl)carbamate (334 mg, 73% yield) as a yellow oil: LC-MS, ES⁺: m/z 461.15 [M+H]⁺. [00234] Int-70 was synthesized from SM-22 according to the procedure for the synthesis of Int-49 (Scheme 22). [00235] The synthesis of Example 97 was completed from Int-69 and Int-70 according to the general procedure for amide coupling using HBTU and the general procedure for nitro reduction using Fe. [00236] Example 98 was prepared from (4-formyl-2-methoxyphenyl)boronic acid, Int- 2, and 2-(6-((4-isopropylphenyl)sulfonamido)pyridin-3-yl)acetic acid according to the procedure for the synthesis of Example 97. [00237] Example 101: N-(4-(2-amino-1H-imidazol-4-yl)benzyl)-2-(6-((4- methylpiperazine)-1-sulfonamido)pyridin-3-yl)acetamide. Int-71 [00238] 4-Methylpiperazine-1-sulfonyl chloride (575 mg, 2.88 mmol, 2.0 eq) was added portion-wise to a solution of ethyl 2-(6-aminopyridin-3-yl)acetate (260 mg, 1.44 mmol, 1.0 eq) in Et₃N (2.0 mL) and the reaction was irradiated with microwave radiation at 100 °C for 3 h. The reaction was cooled to rt and the solvent was removed under reduced pressure. The 59 ^{ME152554612v.1} 125994-02220 crude material was purified by reverse phase flash chromatography on a C18 column eluting with H2O/MeCN (30% MeCN → 80% MeCN, containing 10 mM NH4HCO3) to give ethyl 2- (6-((4-methylpiperazine)-1-sulfonamido)pyridin-3-yl)acetate (295 mg, 60% yield) as a yellow oil: LC-MS, ES⁺: m/z 343.00 [M+H]⁺. Int-72 [00239] To a solution of ethyl 2-(6-((4-methylpiperazine)-1-sulfonamido)pyridin-3- yl)acetate (295 mg, 0.86 mmol, 1.0 eq) in 1,2-DCE (2.0 mL) was added Me₃SnOH (780 g, 4.31 mmol, 5.0 eq) portion-wise at rt under nitrogen. The reaction mixture was heated at 65 °C for 8 h under a nitrogen atmosphere. The reaction was cooled to rt and concentrated under reduced pressure. The crude material was purified by reverse phase flash chromatography on a C18 column eluting with H2O/MeCN (20% MeCN → 50% MeCN, containing 0.1% TFA) to give 2-(6-((4-methylpiperazine)-1-sulfonamido)pyridin-3-yl)acetic acid (140 mg, 47% yield) as a yellow oil: LC-MS, ES⁺: m/z 315.00 [M+H]⁺. Int-73 [00240] The general procedure for amide coupling using EDCI: [00241] EDCI (100 mg, 0.64 mmol, 1.5 eq) and DIPEA (225 µL, 0.50 mmol, 1.1 eq) were added to a mixture of 2-(6-((4-methylpiperazine)-1-sulfonamido)pyridin-3-yl)acetic acid and HOBt (87 mg, 0.64 mmol, 1.5 eq) in DMF (2.0 mL). Int-4 (110 mg, 0.50 mmol, 1.1 eq) was added and the reaction was stirred for 6 h at rt. The reaction was purified by reverse phase flash chromatography on a C18 column eluting with H₂O/MeCN (20% MeCN → 70% MeCN,) to give 2-(6-((4-methylpiperazine)-1-sulfonamido)pyridin-3-yl)-N-(4-(2-nitro-1H- imidazol-4-yl)benzyl)acetamide (130 mg, 56% yield) as a yellow oil: LC-MS, ES⁺: m/z 515.00 [M+H]⁺. [00242] The synthesis of Example 101 was completed according to the general procedure for nitro reduction using Fe. [00243] Example 100 was prepared according to the procedure for the synthesis of Example 101. [00244] Example 102: N-(4-(2-amino-1H-imidazol-4-yl)benzyl)-2-(2- (phenylsulfonamido)pyrimidin-5-yl)acetamide. 60 ^{ME152554612v.1} 125994-02220 [00245] Example 102 was prepared from 5-bromopyrimidin-2-amine and (2-(tert- butoxy)-2-oxoethyl)zinc(II) bromide according to the general procedure for Negishi coupling, followed by the general procedure for sulfonamide formation using pyridine (coupling with benzenesulfonyl chloride), the general procedure for tert-butyl ester cleavage using TFA, the general procedure for amide formation using EDCI (coupling with Int-4), and the general procedure for nitro reduction using Fe. [00246] Example 104 was prepared from 5-bromo-6-methylpyridin-2-amine according to the procedure for the synthesis of Example 102. [00247] Example 105 was prepared from 5-bromo-6-methoxypyridin-2-amine according to the procedure for the synthesis of Example 102. [00248] Example 103: N-(4-(2-amino-1H-imidazol-4-yl)benzyl)-2-(5- (phenylsulfonamido)pyrimidin-2-yl)acetamide. Int-74 [00249] A mixture of ethyl 2-(5-bromopyrimidin-2-yl)acetate (500 mg, 2.0 mmol, 1.0 eq), benzenefulfonamide (962 mg, 6.1 mmol, 3.0 eq), CuI (194 mg, 1.0 mmol, 0.5 eq), 1,2- dimethylethylenediamine (90 mg, 1.0 mmol, 0.5 eq), and K₂CO₃ (705 mg, 5.1 mmol, 2.5 eq) in MeCN (8.0 mL) were heated at 70 °C for 12 h under a nitrogen atmosphere. The reaction was cooled to 0 °C and carefully quenched by the addition of 2M HCl (4.0 mL). The resulting mixture was extracted 3x with EtOAc. The combined organic layers were washed with brine, dried (Na₂SO₄), filtered, and concentrated under reduced pressure. The crude material was purified by reverse phase flash chromatography on a C18 column eluting with H2O/MeCN (40% MeCN → 70% MeCN,) to give ethyl 2-(5-(phenylsulfonamido)pyrimidin- 2-yl)acetate (500 mg, 76% yield) as a dark green oil: LC-MS, ES⁺: m/z 320.05 [M+H]⁺. 61 ^{ME152554612v.1} 125994-02220 [00250] The synthesis of Example 103 was completed according to the general procedure for ester hydrolysis, followed by the general procedure for amide coupling using HOBt (coupling with Int-4), and the general procedure for nitro reduction using Fe. [00251] Example 106: N-(4-(2-amino-1H-imidazol-4-yl)benzyl)-2-(4- (phenylsulfonamido)piperidin-1-yl)acetamide. Int-75 [00252] To a solution of ethyl 2-(4-amino-1-piperidyl)acetate;dihydrochloride (204 mg, 0.79 mmol, 1.0 eq) in DCM (6 mL) was added benzenesulfonyl chloride (0.12 mL, 0.94 mmol, 1.2 eq), DIPEA (0.55 mL, 3.15 mmol, 4.0 eq) and DMAP (9.62 mg, 0.08 mmol, 0.1 eq). The reaction mixture was stirred for 2 h then the solvent was removed under reduced pressure. The crude material was purified by flash chromatography eluting with hexanes/EtOAc (0% EtOAc → 70% EtOAc) to give ethyl 2-(4- (phenylsulfonamido)piperidin-1-yl)acetate (139.7 mg, 54% yield) as a colorless oil: LC-MS, ES⁺: m/z 327 [M+H]⁺. Int-76 [00253] To a solution of 2-(4-(phenylsulfonamido)piperidin-1-yl)acetate (139.7 mg, 0.43 mmol, 1.0 eq) in THF (2 mL) and water (2 mL) was added LiOH (26.7 mg, 1.07 mmol, 2.5 eq). The reaction mixture was stirred overnight, then 1M HCl (1.07 mL, 1.07 mmol, 2.5 eq) was added and the reaction was concentrated under reduced pressure. The resultant material was purified by reverse phase flash chromatography on a C18Aq column eluting with H2O/MeCN (0% MeCN → 100% MeCN) to give 2-(4-(phenylsulfonamido)piperidin-1- yl)acetic acid (92.8 mg, 73% yield) as a white solid: LC-MS, ES⁺: m/z 299 [M+H]⁺. [00254] Example 106 was prepared from Int-4 and Int-76 according to the procedure for the synthesis of Example 1. 62 ^{ME152554612v.1} 125994-02220 [00255] Examples 108 and 109 were prepared from ethyl 2-((1r,4r)-4- aminocyclohexyl)acetate according to the procedure for the synthesis of Example 106. [00256] Example 110 was prepared from ethyl 2-(6-aminospiro[3.3]heptan-2-yl)acetate according to the procedure for the synthesis of Example 106. [00257] Example 107: N-(4-(2-amino-1H-imidazol-4-yl)benzyl)-2-(2-oxo-4- (phenylsulfonamido)piperidin-1-yl)acetamide. Int-77 [00258] A solution of 4-aminopiperidin-2-one trifluoroacetate (200 mg, 0.88 mmol, 1.0 eq), Boc₂O (210 mg, 0.97 mmol, 1.1 eq) and Na₂CO₃ (372 mg, 3.51 mmol, 4.0 eq) in THF (2.0 mL) /H₂O (2.0 mL) was stirred at rt for 1 h. The resulting mixture was concentrated under reduced pressure. The crude material was purified by reverse phase flash chromatography on a C18 column eluting with H₂O/MeCN (50% MeCN → 70% MeCN,) to give tert-butyl (2-oxopiperidin-4-yl)carbamate (166 mg, 88% yield) as a white solid: LC-MS, ES⁺: m/z 215.15 [M+H]⁺. 63 ^{ME152554612v.1} 125994-02220 Int-78 [00259] LiHMDS (0.76 mL, 0.76 mmol, 1.2 eq of a 1.0M solution in THF) was added dropwise to a solution of tert-butyl (2-oxopiperidin-4-yl)carbamate (135 mg, 0.63 mmol, 1.0 eq) in THF (3.0 mL) at 0 °C. The reaction was stirred for 30 min at 0 °C, whereupon ethyl bromoacetate (70 µL, 0.63 mmol, 1.0 eq) portion-wise over 1 h at 0 °C. The rection was warmed to rt and stirred for 1 h. The reaction was quenched with sat. NH₄Cl and diluted with EtOAc. The aqueous layer was extracted 2x with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude material was purified by reverse phase flash chromatography on a C18 column eluting with H₂O/MeCN (60% MeCN → 80% MeCN,) to give ethyl 2-(4-((tert- butoxycarbonyl)amino)-2-oxopiperidin-1-yl)acetate (139 mg, 74% yield) as a white solid: LC-MS, ES⁺: m/z 299.10 [M+H]⁺. [00260] The synthesis of Int-79 was completed according to the general procedure for ester hydrolysis using MeOH/THF/H2O as the solvent, followed by the general procedure for amide coupling using HBTU (coupling with Int-4), the general procedure for Boc deprotection using TFA, the general procedure for sulfonamide formation using triethylamine (coupling with benzenesulfonyl chloride), and the general procedure for nitro reduction using Fe. Example 107 isomer 1 and Example 107 isomer 2 [00261] Crude racemic N-(4-(2-amino-1H-imidazol-4-yl)benzyl)-2-(2-oxo-4- (phenylsulfonamido)piperidin-1-yl)acetamide (50 mg, 0.104 mmol) was purified by Prep- HPLC under the following conditions (Column: CHIRALPAKIK3; Mobile Phase A: MTBE (0.2%DEA):(EtOH: DCM=1:1) = 50:50; Flow rate: 1mL/min; Gradient: isocratic) to afford Example 107 isomer 1 (8.2 mg, 16% yield) as a white solid and Example 107 isomer 2 (9.3 mg, 21% yield). [00262] Data for Example 107 isomer 1: ¹H NMR (400 MHz, Methanol-d4): δ 7.89 (d, J = 7.6 Hz, 2H), 7.59 (dt, J = 15.2, 7.4 Hz, 3H), 7.50 (d, J = 7.9 Hz, 2H), 7.26 (d, J = 7.9 Hz, 2H), 6.93 (s, 1H), 4.36 (s, 2H), 4.03 (q, J = 16.3 Hz, 2H), 3.65 (t, J = 8.2 Hz, 1H), 3.36 (t, J = 6.0 Hz, 2H), 2.50 (dd, J = 17.5, 5.5 Hz, 1H), 2.22 (dd, J = 17.3, 8.1 Hz, 1H), 1.96 (d, J = 14.0 Hz, 1H), 1.82 (dt, J = 13.5, 7.5 Hz, 1H); LC-MS, ES⁺: m/z 483.20 [M+H]⁺. [00263] Data for Example 107 isomer 2: ¹H NMR (400 MHz, Methanol-d4): δ 7.96 – 7.78 (m, 2H), 7.74 – 7.53 (m, 3H), 7.51 (dd, J = 8.2, 2.3 Hz, 2H), 7.25 (d, J = 8.2 Hz, 2H), 6.92 (s, 1H), 4.36 (s, 2H), 4.03 (q, J = 16.3 Hz, 2H), 3.66 (tdd, J = 8.7, 5.5, 3.2 Hz, 1H), 3.36 (h, J = 64 ^{ME152554612v.1} 125994-02220 5.9, 5.2 Hz, 2H), 2.56 – 2.43 (m, 1H), 2.21 (dd, J = 17.4, 8.1 Hz, 1H), 2.03 – 1.89 (m, 1H), 1.87 – 1.76 (m, 1H); LC-MS, ES⁺: m/z 483.15 [M+H]⁺. [00264] Example 111: N-(4-(2-amino-1H-imidazol-4-yl)benzyl)-2-(3- (phenylsulfonamido)bicyclo[1.1.1]pentan-1-yl)acetamide. Int-80 [00265] A solution of ethyl 2-(3-((tert-butoxycarbonyl)amino)bicyclo[1.1.1]pentan-1- yl)acetate (320 mg, 1.2 mmol, 1.0 eq) in HCl (3.0 mL of a 4M solution in 1,4-dioxane) was stirred at rt for 1 h. The solvent was removed under reduced pressure and the resultant solid was triturated with hexanes. The solid was collected via filtration, rinsing with hexanes to give ethyl 2-(3-aminobicyclo[1.1.1]pentan-1-yl)acetate, hydrochloride (180 mg, 74% yield) as a white solid: LC-MS, ES⁺: m/z 170.20 [M+H]⁺. Int-81 [00266] Triethylamine (484 µL, 3.5 mmol, 3.6 eq) was added to a mixture of ethyl 2-(3- aminobicyclo[1.1.1]pentan-1-yl)acetate, hydrochloride (196 mg, 0.96 mmol, 1.0 eq) and benzenesulfonyl chloride (205 mg, 1.2 mmol, 1.2 eq) in DCM (3.0 mL) and the reaction was stirred for 1 h at rt. The reaction was quenched with H2O and diluted with DCM. The layers were separated and the aqueous layer was extracted 2x with DCM. The combined organic layers were dried (Na₂SO₄), filtered, and concentrated under reduced pressure. The crude material was purified by reverse phase flash chromatography on a C18 column eluting with H2O/MeCN (40% MeCN → 70% MeCN,) to give ethyl 2-(3- (phenylsulfonamido)bicyclo[1.1.1]pentan-1-yl)acetate (210 mg, 71% yield) as a yellow solid: LC-MS, ES⁺: m/z 307.95 [M+H]⁺. [00267] The synthesis of Example 111 was completed according to the general procedure for ester hydrolysis, followed by the general procedure for amide coupling with HBTU (coupling with Int-4), and the general procedure for nitro reduction using Fe. 65 ^{ME152554612v.1} 125994-02220 Characterization data for examples are shown in Table 1. Table 1 66 ^{ME152554612v.1} 125994-02220 67 ^{ME152554612v.1} 125994-02220 68 ^{ME152554612v.1} 125994-02220 69 ^{ME152554612v.1} 125994-02220 70 ^{ME152554612v.1} 125994-02220 71 ^{ME152554612v.1} 125994-02220 72 ^{ME152554612v.1} 125994-02220 73 ^{ME152554612v.1} 125994-02220 74 ^{ME152554612v.1} 125994-02220 75 ^{ME152554612v.1} 125994-02220 76 ^{ME152554612v.1} 125994-02220 77 ^{ME152554612v.1} 125994-02220 78 ^{ME152554612v.1} 125994-02220 79 ^{ME152554612v.1} 125994-02220 80 ^{ME152554612v.1} 125994-02220 81 ^{ME152554612v.1} 125994-02220 82 ^{ME152554612v.1} 125994-02220 83 ^{ME152554612v.1} 125994-02220 84 ^{ME152554612v.1} 125994-02220 85 ^{ME152554612v.1} 125994-02220 86 ^{ME152554612v.1} 125994-02220 87 ^{ME152554612v.1} 125994-02220 88 ^{ME152554612v.1} 125994-02220 89 ^{ME152554612v.1} 125994-02220 90 ^{ME152554612v.1} 125994-02220 91 ^{ME152554612v.1} 125994-02220 92 ^{ME152554612v.1} 125994-02220 93 ^{ME152554612v.1} 125994-02220 94 ^{ME152554612v.1} 125994-02220 95 ^{ME152554612v.1} 125994-02220 96 ^{ME152554612v.1} 125994-02220 97 ^{ME152554612v.1} 125994-02220 98 ^{ME152554612v.1} 125994-02220 99 ^{ME152554612v.1} 125994-02220 100 ^{ME152554612v.1} 125994-02220 101 ^{ME152554612v.1} 125994-02220 102 ^{ME152554612v.1} 125994-02220 103 ^{ME152554612v.1} 125994-02220 104 ^{ME152554612v.1} 125994-02220 105 ^{ME152554612v.1} 125994-02220 ASSAY [00268] MASP-2 assay. Compounds to be tested for inhibition of MASP-2 were dissolved and 2-fold serially diluted in DMSO, then 0.5 µl/well was transferred into assay plates using a ViaFlow 96/384 (Integra Biosciences, Hudson, NH) equipped with a 12.5-µl, 384-well pipetting head. To each well was added 25 µl of 800 µM (2X) Z-Lys-SBzl and 200 µM DTNB in assay buffer, which consisted of 50 mM HEPES pH 7.5, 150 mM NaCl, and 0.005% Triton X-100. Reactions were initiated by addition of 25 µl of 1.8 nM (2X) MASP-2 (CCP1-CCP2-SP construct). Reactions at ambient temperature (22^oC) were monitored at 1- min intervals for 1 hour at 412 nm with a Spectramax Plus 384 plate reader (Molecular Devices, San Jose, CA). One hundred percent inhibition (MIN) was measured in wells containing 50 µM nafamostat mesylate. To correct for test compound interference (Shapiro et al 2009) a duplicate set of wells was used in which the enzyme was replaced with 34 µM N- acetyl-L-cysteine to produce approximately the same absorbance as the enzyme reactions. The substrate Km was obtained by varying the Z-Lys-SBzl concentration, measuring the initial rate of the reaction, and fitting the initial rate versus substrate concentration data to the Michaelis-Menten equation by nonlinear regression. The K_m for Z-Lys-SBzl was estimated at 1.36 mM under assay conditions. 106 M^{E152554612v.1} 125994-02220 [00269] MASP-3 assay. The MASP-3 assay was performed as above, except that the final Z-Lys-SBzl and MASP-3 concentrations were 50 µM and 0.4 nM, respectively. The Km for Z-Lys-SBzl was estimated at 88 µM under assay conditions. [00270] IC50 calculation. Percent inhibition at each inhibitor concentration was calculated using the formula % inhibition = 100(1- (X - MIN)/(MAX – MIN)), where X, MAX and MIN are the absorbances at the 1-hour time point in the presence of the inhibitor, in the absence of inhibitor, and in the presence of nafamostat, respectively. IC₅₀s were calculated from % inhibition data using nonlinear regression and the formula: % inhibition = 100[I]ⁿ/(IC50ⁿ + [I]ⁿ), where [I] is the inhibitor concentration and n is the Hill coefficient. The Excel plug-in XLfit (IDBS, Boston, MA) was used to perform nonlinear regression with equation 205. Table 2 107 ^{ME152554612v.1} 125994-02220 108 ^{ME152554612v.1} 125994-02220 109 ^{ME152554612v.1} 125994-02220 110 ^{ME152554612v.1} 125994-02220 [00271] The contents of all references (including literature references, issued patents, published patent applications, and co-pending patent applications) cited throughout this application are hereby expressly incorporated herein in their entireties by reference. Unless otherwise defined, all technical and scientific terms used herein are accorded the meaning commonly known to one with ordinary skill in the art. 111 ^{ME152554612v.1}

Claims

125994-02220 Listing of Claims 1. A compound having the Formula I: or a pharmaceutically acceptable salt thereof, wherein X is N or CH; R¹ is selected from hydrogen, halo, (C1-C4)alkyl, halo(C1-C4)alkyl, (C1-C4)alkoxy, halo(C₁-C₄)alkoxy, and cyano; R², R^2’, R³, R^3’, R⁵, R⁶, and R⁸ are each independently selected from hydrogen, (C₁- C4)alkyl, and halo(C1-C4)alkyl; or R^2’ and R^3’ together with the carbon atom to which they are attached form =O; R⁴ is hydrogen or (C₁-C₄)alkyl; R⁷ is selected from cycloalkyl, heteroaryl, heterocyclyl, and phenyl, each of which being optionally substituted; and q is 0, 1, 2, or 3. 2. The compound of Claim 1, or a pharmaceutically acceptable salt thereof, wherein X is CH. 3. The compound of Claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R^2’ is hydrogen and R^3’ is halo(C₁-C₄)alkyl. 4. The compound of any one of Claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein R^2’ is hydrogen and R^3’ is CF3. 5. The compound of Claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R^2’ and R^3’ together with the carbon atom to which they are attached form =O. 6. The compound of any one of Claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein R¹ is selected from hydrogen, halo, (C1-C4)alkyl, and (C1-C4)alkoxy. 112 ^{ME152554612v.1} 125994-02220 7. The compound of any one of Claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R¹ is selected from OCH₃, CH₃, and fluoro. 8. The compound of any one of Claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein R⁴ is hydrogen or CH₃. 9. The compound of any one of Claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein R² and R³ are each independently selected from hydrogen and CH3. 10. The compound of any one of Claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein R² and R³ are each hydrogen. 11. The compound of any one of Claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein R⁵ and R⁶ are each independently selected from hydrogen and (C1-C4)alkyl. 12. The compound of any one of Claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein R⁵ and R⁶ are each independently selected from hydrogen and CH3. 13. The compound of any one of Claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein R⁵ and R⁶ are each hydrogen. 14. The compound of any one of Claims 1 to 13, or a pharmaceutically acceptable salt thereof, wherein q is 0, 1, or 2. 15. The compound of any one of Claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein R⁷ is selected from (C₃-C₇)cycloalkyl, 5- to 7-membered heteroaryl, 4- to 10-membered heterocyclyl, and phenyl, each of which are optionally substituted. 16. The compound of any one of Claims 1 to 15, or a pharmaceutically acceptable salt thereof, wherein R⁷ is selected from cyclopentyl, cyclopropyl, cyclohexyl, pyridinyl, phenyl, pyrrolidinyl, pyrimidinyl, piperidinyl, spiro[3.3]heptanyl, bicyclo[1.1.1]pentanyl, and indolinyl, each of which are optionally substituted. 113 ^{ME152554612v.1} 125994-02220 17. The compound of any one of Claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein the optional substituents for R⁷ are selected from (C1-C4)alkyl, halo(C1- C₄)alkyl, cyano, phenyl, -(C₁-C₄)alkylphenyl, 5- to 7-membered heteroaryl, -(C₁-C₄)alkyl[5- to 7-membered heteroaryl], 4- to 7-membered heterocyclyl, (C1-C4)alkyl[4- to 7-membered heterocyclyl], (C3-C6)cycloalkyl, -(C1-C4)alkyl(C3-C6)cycloalkyl, oxo, -OR^a, -NR^aR^b, - C(O)R^a, -C(O)OR^a, -(C₁-C₄)alkylNR^aR^b, -NR^aC(O)R^c, -(C₁-C₄)alkylNR^aC(O)R^c, - C(O)NR^aR^c, -(C₁-C₄)alkylC(O)NR^aR^c, -NR^aS(O)₂R^c, -(C₁-C₄)alkylNR^aS(O)₂R^c, -NR^aS(O)R^c, -(C1-C4)alkylNR^aS(O)R^c, S(O)2R^c, S(O)R^c, -(C1-C4)alkylS(O)2R^c, and -(C1-C4)alkylS(O)R^c, wherein said phenyl, 5- to 7-membered heteroaryl, 4- to 7-membered heterocyclyl, and (C3- C₆)cycloalkyl are each optionally substituted with one or more groups selected from halo, (C1-C4)alkyl, halo(C1-C4)alkyl, cyano, phenyl, -(C1-C4)alkylphenyl, 5- to 7-membered heteroaryl, -(C1-C4)alkyl[5- to 7-membered heteroaryl], 4- to 7-membered heterocyclyl, (C1- C₄)alkyl[4- to 7-membered heterocyclyl], -hydroxy(C₁-C₄)alkylphenyl, (C₃-C₆)cycloalkyl, - (C1-C4)alkyl(C3-C6)cycloalkyl, oxo, -OR^a1, -NR^a1R^c1, -C(O)R^a1, -C(O)OR^a1, -(C1- C4)alkylNR^a1R^b1, -NR^a1C(O)R^c1, -(C1-C4)alkylNR^a1C(O)R^c1, -C(O)NR^a1R^c1, -(C1- C₄)alkylC(O)NR^a1R^c1, -NR^a1S(O)₂R^c1, -(C₁-C₄)alkylNR^a1S(O)₂R^c1, -NR^a1S(O)R^c1, -(C₁- C₄)alkylNR^a1S(O)R^c1, S(O)₂R^c1, and S(O)R^c1; and R^a, R^a1, R^b, R^b1, R^c, and R^c1 are each independently selected from hydrogen, (C1- C4)alkyl, halo(C1-C4)alkyl, cyano(C1-C4)alkyl, hydroxy(C1-C4)alkyl, (C1-C4)alkoxy, halo(C1- C₄)alkoxy, cyano, oxo, phenyl, -(C₁-C₄)alkylphenyl, 4- to 7-membered heterocyclyl, -(C₁- C4)alkyl[4- to 7-membered heterocyclyl], 5- to 7-membered heteroaryl, -(C1-C4)alkyl[5- to 7- membered heteroaryl], (C3-C6)cycloalkyl, and -(C1-C4)alkyl(C3-C6)cycloalkyl, wherein - said (C₁-C₄)alkyl and said (C₁-C₄)alkyl of -(C₁-C₄)alkylphenyl, hydroxy(C₁- C4)alkyl, -(C1-C4)alkyl[4- to 7-membered heterocyclyl], -(C1-C4)alkyl[5- to 7-membered heteroaryl], and -(C1-C4)alkyl(C3-C6)cycloalkyl for R^a or R^b are each optionally substituted with one or more groups selected from halo, (C₁-C₄)alkyl, halo(C₁-C₄)alkyl, (C₁-C₄)alkoxy, halo(C₁-C₄)alkoxy, hydroxy, -(C₁-C₄)alkoxyO(C₁-C₄)alkyl, (C₃-C₆)cycloalkyl, 4- to 7- membered heterocyclyl, 5- to 7-membered heteroaryl, and phenyl; - said (C3-C6)cycloalkyl for R^a or R^b is optionally substituted with one or more groups selected from halo, (C₁-C₄)alkyl, halo(C₁-C₄)alkyl, (C₁-C₄)alkoxy, halo(C₁-C₄)alkoxy, hydroxy, -(C1-C4)alkoxyO(C1-C4)alkyl, (C3-C6)cycloalkyl, 4- to 7-membered heterocyclyl, 5- to 7-membered heteroaryl, and phenyl; . - said 4- to 7-membered heterocyclyl, and 5- to 7-membered heteroaryl for R^c is optionally substituted with (C1-C4)alkyl; and 114 ^{ME152554612v.1} 125994-02220 - said phenyl of R^c is optionally substituted with (C1-C4)alkoxyO(C1-C4)alkyl. 18. The compound of any one of Claims 1 to 17, or a pharmaceutically acceptable salt thereof, wherein the optional substituents for R⁷ are selected from (C1-C4)alkyl, -(C1- C4)alkylphenyl, phenyl, 5- to 7-membered heteoaryl, oxo, -OR^a, -NR^aR^b, -NR^aC(O)R^c, - C(O)NR^aR^c, and -NR^aS(O)₂R^c, wherein said phenyl is optionally substituted with one or more groups selected from -OR^a1, -hydroxy(C₁-C₄)alkylphenyl, and -NR^a1S(O)₂R^c1, and wherein said 5- to 7-membered heteoaryl is optionally substituted with one or more -NR^a1R^c1; R^a and R^b are each independently selected from hydrogen, (C1-C4)alkyl, hydroxy(C1- C₄)alkyl, phenyl, -(C₁-C₄)alkylphenyl, -(C₁-C₄)alkyl[4- to 7-membered heterocyclyl], and (C3-C6)cycloalkyl, wherein said (C1-C4)alkyl of -(C1-C4)alkylphenyl is optionally substituted with one or more groups selected from halo and (C3-C6)cycloalkyl, wherein said (C3- C₆)cycloalkyl for R^a or R^b is optionally substituted with phenyl, and wherein said (C₁- C4)alkyl of hydroxy(C1-C4)alkyl is optionally substituted with phenyl; R^c is selected from cyano(C1-C4)alkyl, phenyl, -(C1-C4)alkylphenyl, (C3- C₆)cycloalkyl, -(C₁-C₄)alkyl(C₃-C₆)cycloalkyl, 5- to 7-membered heteroaryl, 4- to 7- membered heterocyclyl, and -(C₁-C₄)alkyl[4- to 7-membered heterocyclyl], wherein said phenyl and said phenyl of -(C1-C4)alkylphenyl are each optionally substituted with one or more groups selected from halo, (C1-C4)alkyl, halo(C1-C4)alkyl, (C1-C4)alkoxy, halo(C1- C₄)alkoxy, and -(C₁-C₄)alkoxyO(C₁-C₄)alkyl, and wherein said 5- to 7-membered heteroaryl and 4- to 7-membered heterocyclyl are each optionally substituted with one or more (C1- C4)alkyl; and R^a1 is selected from phenyl and hydrogen; and R^c1 is selected from hydrogen, phenyl, and (C3-C6)cycloalkyl optionally substituted with phenyl. 19. The compound of any one of Claims 1 to 18, or a pharmaceutically acceptable salt thereof, wherein the optional substituents for R⁷ are selected from (C1-C4)alkyl, -(C1- C4)alkylphenyl, phenyl, pyridinyl, oxo, -OR^a, -NR^aR^b, -NR^aC(O)R^c, -C(O)NR^aR^c, and - NR^aS(O)₂R^c, wherein said phenyl is optionally substituted with one or more groups selected from -OR^a1, -hydroxy(C1-C4)alkylphenyl, and -NR^a1S(O)2R^c1, and wherein said pyridinyl is optionally substituted with one or more -NR^a1R^c1; R^a and R^b are each independently selected from hydrogen, (C₁-C₄)alkyl, hydroxy(C₁- C4)alkyl, phenyl, -(C1-C4)alkylphenyl, -(C1-C4)alkyl[piperidinyl], -(C1- 115 ^{ME152554612v.1} 125994-02220 C4)alkyl[tetrahydropyranyl], and cyclopropyl, wherein said (C1-C4)alkyl of -(C1- C4)alkylphenyl is optionally substituted with one or more groups selected from halo and cyclopropyl, wherein said cyclopropyl for R^a or R^b is optionally substituted with phenyl, and wherein said (C1-C4)alkyl of hydroxy(C1-C4)alkyl is optionally substituted with phenyl; R^c is selected from cyano(C1-C4)alkyl, phenyl, -(C1-C4)alkylphenyl, cyclopropyl, cyclohexyl, cyclopentyl, -(C₁-C₄)alkyl[cyclohexyl], -(C₁-C₄)alkyl[cyclopropyl], pyrazolyl, tetrahydropyranyl, morpholinyl, piperazinyl, piperidinyl, and -(C₁- C4)alkyl[tetrahydropyranyl], -(C1-C4)alkyl[piperidinyl], wherein said phenyl and said phenyl of -(C1-C4)alkylphenyl are each optionally substituted with one or more groups selected from halo, (C₁-C₄)alkyl, halo(C₁-C₄)alkyl, (C₁-C₄)alkoxy, halo(C₁-C₄)alkoxy, and -(C₁- C4)alkoxyO(C1-C4)alkyl, and wherein said pyrazolyl, tetrahydropyranyl, morpholinyl, and piperazinyl are each optionally substituted with one or more (C1-C4)alkyl; and R^a1 is selected from phenyl and hydrogen; and R^c1 is selected from hydrogen, phenyl, and cyclopropyl optionally substituted with phenyl. 20. The compound of any one of Claims 1 to 19, or a pharmaceutically acceptable salt thereof, wherein R⁷ is selected from , , , , 116 ^{ME152554612v.1} 125994-02220 , 117 ^{ME152554612v.1} 125994-02220 118 ^{ME152554612v.1} 125994-02220 . 21. The compound of Claim 1, wherein the compound is selected from any of those in Table 1; or a pharmaceutically acceptable salt thereof. 22. A pharmaceutical composition comprising a compound of any one of Claims 1 to 21, or a pharmaceutically acceptable salt thereof. 119 ^{ME152554612v.1} 125994-02220 23. The pharmaceutical composition of Claim 22, wherein the composition further comprises a pharmaceutically acceptable excipient. 24. A method of treating a condition responsive to the inhibition of MASP-2 and/or MASP-3 in a subject comprising administering to the subject a therapeutically effective amount of a compound of any one of Claims 1 to 21, or a pharmaceutically acceptable salt thereof 25. The method of Claim 24, wherein the condition is selected from thrombotic microangiopathy (TMA), a renal condition, an inflammatory reaction resulting from tissue or organ transplantation, an ischemia reperfusion injury, a complication associated with diabetes, a cardiovascular disease or disorder, an inflammatory gastrointestinal disorder, a pulmonary disorder, an ophthalmic disease or disorder, disseminated intravascular coagulation, graft-versus-host disease, veno-occlusive disease and diffuse alveolar hemorrhage. 120 ^{ME152554612v.1}