N-((isoquinolin-6-yl)methyl)-1h-pyrazole-4-carboxamid derivatives as plasma kallikrein inhibitors for the treatment of hereditary angioedema

Abstract

The present invention provides compounds and compositions thereof which are useful as inhibitors of plasma kallikrein and which exhibit desirable characteristics for the same.The present invention provides isoquinoline derivatives of formula (I), wherein CyB is formula (II) or formula (III) as plasma kallikrein (PKa) inhibitors for use in methods of treatment of hereditary angioedema (HAE) or diabetic macular edema (DME). Preferred compounds are e.g. N-((isoquinolin-6-yl)methyl)-1H-pyrazole-4-carboxamide derivatives and similar compounds.

Description

INHIBITORS OF PLASMA KALLIKREINI. BACKGROUND OF THE INVENTION

[0001] Plasma Kallikrein (PKa) is a serine protease zymogen in blood that is converted to its catalytically active form by coagulation factor Xlla, and contributes to the innate inflammatory response and intrinsic cascade of blood coagulation. The mechanisms that lead to the activation of this pathway in vivo include interactions with polyphosphates released from activated platelets and deficiency of Cl inhibitor (Cl -INH), the primary physiological inhibitor of PKa. PKa- mediated cleavage of high-molecular weight kininogen generates the potent vasodilator and pro- inflammatory nonapeptide bradykinin (BK), which activates the bradykinin 2 receptor.Subsequent cleavage of BK by carboxypeptidases generates des-Arg9-BK, which activates the Bl receptor. Both Bl and B2 receptors are expressed by vascular, glial, and neuronal cell types, with the highest levels of retinal expression detected in the ganglion cell layer and inner and outer nuclear layers. Activation of Bl and B2 receptors causes vasodilation and increases vascular permeability.

[0002] PKa is also associated with a number of disorders, such as hereditary angioedema (HAE), an autosomal dominant disease characterized by painful, unpredictable, recurrent attacks of inflammation affecting the hands, feet, face, abdomen, urogenital tract, and the larynx. Prevalence for HAE is uncertain but is estimated to be approximately 1 case per 50,000 persons without known differences among ethnic groups. HAE is caused by deficient (Type I) or dysfunctional (Type II) levels of Cl -INH, which inhibits PKa, bradykinin, and other serine proteases in the blood. Individuals with hereditary angioedema (HAE) are deficient in Cl -INH and consequently undergo excessive bradykinin generation, which in turn cause painful, debilitating, and potentially fatal swelling attacks. If left untreated, HAE can result in a mortality rate as high as 40% primarily due to upper airway obstruction.II. SUMMARY OF THE INVENTION

[0003] The present disclosure is based on, at least in part, the development of a number of compounds which bind to plasma kallikrein and effectively inhibit its activity. Accordingly, provided herein are compounds and uses thereof for targeting plasma kallikrein and / or treating plasma kallikrein-mediated diseases and disorders.

[0004] In some embodiments, the present invention provides a compound of Formula (I): CyB— L'— CyA— L— Cyc(I) or a pharmaceutically acceptable salt thereof, wherein each of CyA, CyB, Cyc, L, and L’ is defined and described in classes and subclasses herein, both singly and in combination. In certain embodiments, the present invention provides compounds of Formulae (I)-(XVI-c), as defined and described in classes and subclasses herein.

[0005] In some embodiments, the present invention provides a compound of Formula (I): CyB— U— CyA— L— Cyc(F)

[0006] or a pharmaceutically acceptable salt thereof, wherein each of CyA, CyB, Cyc, L, and L’ is defined and described in classes and subclasses herein, both singly and in combination.

[0007] In some embodiments, the present invention also provides methods of using compounds of Formulae (I)-(XVI-c).III. DETAILED DESCRIPTION OF CERTAIN EMBODIMENTSA. Definitions

[0008] Compounds of this invention include those described generally above, and are further illustrated by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise indicated. For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75thEd. Additionally, general principles of organic chemistry are described in “Organic Chemistry”, Thomas Sorrell, University Science Books, Sausalito: 1999, and “March’s Advanced Organic Chemistry”, 5thEd., Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference.

[0009] The abbreviations used herein have their conventional meaning within the chemical and biological arts. The chemical structures and formulae set forth herein are constructed according to the standard rules of chemical valency known in the chemical arts.

[0010] The term “aliphatic” or “aliphatic group”, as used herein, means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic hydrocarbon or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic (also referred to herein as “carbocyclyl,” “cycloaliphatic” or “cycloalkyl”), that has a single point of attachment to the rest of the molecule. Unless otherwise specified, aliphatic groups contain 1-6 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms, and in yet other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms. In some embodiments, “cycloaliphatic” (or “carbocyclyl” or “cycloalkyl”) refers to a monocyclic C3-C7 hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.

[0011] The term “heteroatom” means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including, any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized form of any basic nitrogen or; a substitutable nitrogen of a heterocyclic ring, for example N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR+(as in N-substituted pyrrolidinyl)).

[0012] The term “unsaturated,” as used herein, means that a moiety has one or more units of unsaturation.

[0013] The term “alkylene” refers to a bivalent alkyl group. An “alkylene chain” is a polymethylene group, i.e., -(CH2)n-, wherein n is a positive integer, preferably from 1 to 6, from 1 to 4, from 1 to 3, from 1 to 2, or from 2 to 3. A substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group.

[0014] The term “halogen” means F, Cl, Br, or I.

[0015] The term “aryl” refers to monocyclic and bicyclic ring systems having a total of five to 10 ring members, wherein at least one ring in the system is aromatic and wherein each ring inthe system contains three to seven ring members. The term “aryl” may be used interchangeably with the term “aryl ring”. In some embodiments, an 8-10 membered bicyclic aryl group is an optionally substituted naphthyl ring. In certain embodiments of the present invention, “aryl” refers to an aromatic ring system which includes, but not limited to, phenyl, biphenyl, naphthyl, anthracyl and the like, which may bear one or more substituents. Also included within the scope of the term “aryl,” as it is used herein, is a group in which an aromatic ring is fused to one or more non-aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl, and the like.

[0016] The terms “heteroaryl” and “heteroar-” refer to groups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms; having 6, 10, or 14 7t electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms. Heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. The terms “heteroaryl” and “heteroar-”, as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where the radical or point of attachment is on the heteroaromatic ring (or in the case of a bivalent fused heteroarylene ring system, at least one radical or point of attachment is on a heteroaromatic ring). Nonlimiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4 / 7- quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-l,4-oxazin-3(4H)-one. A heteroaryl group may be mono- or bicyclic. The term “heteroaryl” may be used interchangeably with the terms “heteroaryl ring,” “heteroaryl group,” or “heteroaromatic,” any of which terms include rings that are optionally substituted.

[0017] As used herein, the terms “heterocyclyl,” “heterocyclic radical,” and “heterocyclic ring” are used interchangeably and refer to a stable 5- to 7-membered monocyclic or 7-10- membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, preferably one to four, heteroatoms, as defined above. When used in this context in reference to a ring atom, the term “nitrogen” includes a substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 0-3heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen may be N (as in 3,4-dihydro- 2 / / -pyrrolyl), NH (as in pyrrolidinyl), or+NR (as in A-substitutcd pyrrolidinyl).

[0018] A heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure and any of the ring atoms can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothiophenyl pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl. The terms “heterocyclyl,” “heterocyclyl ring,” “heterocyclic group,” “heterocyclic moiety,” and “heterocyclic radical,” are used interchangeably herein, and also include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings, such as indolinyl, 37 / -indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl, where the radical or point of attachment is on the heterocyclyl ring. A heterocyclyl group may be mono- or bicyclic. The term “heterocyclylalkyl” refers to an alkyl group substituted by a heterocyclyl, wherein the alkyl and heterocyclyl portions independently are optionally substituted.

[0019] As used herein, the term “partially unsaturated” refers to a ring moiety that includes at least one double or triple bond. The term “partially unsaturated” is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties, as herein defined.

[0020] As used herein and unless otherwise specified, the suffix “-ene” is used to describe a bivalent group. Thus, any of the terms above can be modified with the suffix “-ene” to describe a bivalent version of that moiety. For example, a bivalent carbocycle is “carbocycylene”, a bivalent aryl ring is “arylene”, a bivalent benzene ring is “phenylene”, a bivalent heterocycle is “heterocyclylene”, a bivalent heteroaryl ring is “heteroarylene”, a bivalent alkyl chain is “alkylene”, a bivalent alkenyl chain is “alkenylene”, a bivalent alkynyl chain is “alkynylene”, and so forth.

[0021] As described herein, compounds of the invention may, when specified, contain “optionally substituted” moieties. In general, the term “substituted,” whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. “Substituted” applies to one or more hydrogens that arein a polycyclic ring system, substituents may, unless otherwise indicated, replace a hydrogen on any individual ring (e.g.,). Unless otherwise indicated, an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds. The term “stable,” as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.

[0022] Suitable monovalent substituents on a substitutable carbon atom of an “optionally substituted” group are independently halogen; -(CH2)o-4R°; -(CFUlo-rOR0; -0(CH2)o-4R°, - 0(CH2)O-4C(0)OR°; -0(CH2)O-40R°; -(CH2)O-4CH(OR°)2; -(CH2)O-4SR°; -(CfUjcwPh, which may be substituted with R°; -(CH2)o-40(CH2)o-iPh which may be substituted with R°; -CH=CHPh, which may be substituted with R°; -(CH2)o-40(CH2)o-i-pyridyl which may be substituted with R°; -NO2; -CN; -N3; -(CH2)O-4N(R°)2; -(CH2)O-4N(R°)C(0)R0; -N(R°)C(S)R°; -(CH2)O- 4N(R°)C(0)NRO2; -N(RO)C(S)NRO2; -(CH2)O-4N(R0)C(0)OR°; -N(R°)N(R°)C(O)R°; - N(R°)N(R°)C(O)NR°2; -N(R°)N(R°)C(O)OR°; -(CH2)O-4C(0)R°; -C(S)R°; -(CH2)O-4C(0)OR°; - (CH2)O-4C(0)SR°; - (CH2)o-4C(0)OSiR°3; -(CH2)o-40C(0)R°; -OC(0)(CH2)o.4SR°, -SC(S)SR°; - (CH2)O-4SC(0)R°; -(CH2)O-4C(0)NR°2; -C(S)NRO2; -C(S)SR°; -SC(S)SR°, -(CH2)O-40C(0)NR°2;-C(O)N(OR°)R°; -C(O)C(O)R°; -C(0)CH2C(0)R°; -C(NOR°)R°; -(CH2)o-4SSR°; -(CH2)o-4S(O)2R°; -(CH2)O-4S(0)2OR°; -(CH2)O-40S(0)2R°; -S(0)2NRO2; - (CH2)o.4S(0)R°; - N(R°)S(O)2NR°2; -N(RO)S(O)2R°; -N(OR°)R°; -C(NH)NRO2; -P(O)2RO; -P(O)RO2; -OP(O)RO2; - OP(O)(OR°)2; SiR°2; -0SiR°3, -(Ci-4 straight or branched alkylene)O-N(R°)2; or -(Ci-4 straight or branched alkylene)C(O)O-N(R°)2, wherein each R° may be substituted as defined below and is independently hydrogen, Ci-6 aliphatic, -CH2Ph, -0(CH2)o-iPh, -CH2-(5-6 membered heteroaryl ring), or a 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R°, taken together with their intervening atom(s), form a 3-12 membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below.

[0023] Suitable monovalent substituents on R° (or the ring formed by taking two independent occurrences of R° together with their intervening atoms), are independently halogen, -(CH2)o-2R*, -(haloR*), -(CH2)o-2OH, -(CH2)o-2OR*, -(CH2)o-2CH(OR*)2; -O(haloR’), - CN, -N3, -(CH2)O-2C(0)R*, -(CH2)O-2C(0)OH, -(CH2)O-2C(0)OR*, -(CH2)O-2SR*, -(CH2)O-2SH, - (CH2)O-2NH2, -(CH2)O-2NHR*, -(CH2)O-2NR*2, -NO2, -SiR*3, -OSiR’i, -C(O)SR* -(Ci-4 straight or branched alkylene)C(O)OR*, or -SSR* wherein each R* is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently selected from Ci-4aliphatic, -CH2Ph, -0(CH2)o-iPh, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on a saturated carbon atom of R° include =0 and =S.

[0024] Suitable divalent substituents on a saturated carbon atom of an “optionally substituted” group include the following: =0, =S, =NNR#2, =NNHC(O)R#, =NNHC(0)0R#, =NNHS(O)2R#, =NR#, =N0R#, -O(C(R#2))2-3O-, or -S(C(R#2))2-3S-, wherein each independent occurrence of R#is selected from hydrogen, Ci-6 aliphatic which may be substituted as defined below, or an unsubstituted 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group include: -O(CR#2)2-3O-, wherein each independent occurrence of R#is selected from hydrogen, Ci-6 aliphatic which may be substituted as defined below, or an unsubstituted 5-6-memberedsaturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0025] Suitable substituents on the aliphatic group of R#include halogen, -R*, - (haloR*), - OH, -OR*, -O(haloR*), -CN, -C(O)OH, -C(O)OR*, -NH2, -NHR*, -NR*2, or -NO2, wherein each R* is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently Ci-4 aliphatic, -CH2Ph, -0(CH2)o-iPh, or a 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0026] Suitable substituents on a substitutable nitrogen of an “optionally substituted” group include -Rf, -NR’h, -C(O)Rf, -C(O)ORf, -C(O)C(O)Rf, -C(O)CH2C(O)Rf, -S(O)2Rf, - S(O)2NRT2, -CfSjNR’h, -C(NH)NR1’2, or -N(Rt)S(O)2Rt; wherein each R?is independently hydrogen, Ci-6 aliphatic which may be substituted as defined below, unsubstituted -OPh, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R', taken together with their intervening atom(s) form an unsubstituted 3-12 membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0027] Suitable substituents on the aliphatic group of R' are independently halogen, -R*, - (haloR*), -OH, -OR*, -O(haloR*), -CN, -C(O)OH, -C(O)OR*, -NH2, -NHR*, -NR*2, or -NO2, wherein each R* is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently Ci-4 aliphatic, -CH2Ph, -0(CH2)o-iPh, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0028] As used herein, the term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference.

[0029] In certain embodiments, the neutral forms of the compounds are regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. In some embodiments, the parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents.

[0030] Unless otherwise stated, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention. Additionally, unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures including the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a13C- or14C-enriched carbon are within the scope of this invention. Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents in accordance with the present invention.

[0031] The term “oxo,” as used herein, means an oxygen that is double bonded to a carbon atom, thereby forming a carbonyl.

[0032] The symbol “ ”, except when used as a bond to depict unknown or mixed stereochemistry, denotes the point of attachment of a chemical moiety to the remainder of a molecule or chemical formula.

[0033] The articles “a” and “an” are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element.

[0034] A “dosing regimen” (or “therapeutic regimen”), as that term is used herein, is a set of unit doses (typically more than one) that are administered individually to a subject, typically separated by periods of time. In some embodiments, a given therapeutic agent has a recommended dosing regimen, which may involve one or more doses. In some embodiments, a dosing regimen comprises a plurality of doses each of which are separated from one another by atime period of the same length; in some embodiments, a dosing regimen comprises a plurality of doses and at least two different time periods separating individual doses.

[0035] As will be understood from context, a “reference” compound is one that is sufficiently similar to a particular compound of interest to permit a relevant comparison. In some embodiments, information about a reference compound is obtained simultaneously with information about a particular compound. In some embodiments, information about a reference compound is historical. In some embodiments, information about a reference compound is stored, for example in a computer-readable medium. In some embodiments, comparison of a particular compound of interest with a reference compound establishes identity with, similarity to, or difference of the particular compound of interest relative to the compound.

[0036] As used herein, the phrase “therapeutic agent” refers to any agent that has a therapeutic effect and / or elicits a desired biological and / or pharmacological effect, when administered to a subject.

[0037] As used herein, the term “therapeutically effective amount” refers to an amount of a therapeutic agent that confers a therapeutic effect on the treated subject, at a reasonable benefit / risk ratio applicable to any medical treatment. The therapeutic effect may be objective (i.e., measurable by some test or marker) or subjective (i.e., subject gives an indication of or feels an effect). In particular, the “therapeutically effective amount” refers to an amount of a therapeutic agent effective to treat, ameliorate, or prevent a desired disease or condition, or to exhibit a detectable therapeutic or preventative effect, such as by ameliorating symptoms associated with the disease, preventing or delaying the onset of the disease, and / or also lessening the severity or frequency of symptoms of the disease. A therapeutically effective amount is commonly administered in a dosing regimen that may comprise multiple unit doses. For any particular therapeutic agent, a therapeutically effective amount (and / or an appropriate unit dose within an effective dosing regimen) may vary, for example, depending on route of administration, on combination with other pharmaceutical agents. Also, the specific therapeutically effective amount (and / or unit dose) for any particular subject may depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific therapeutic agent employed; the specific composition employed; the age, body weight, general health, sex and diet of the subject; the time of administration, route ofadministration, and / or rate of excretion or metabolism of the specific therapeutic agent employed; the duration of the treatment; and like factors as is well known in the medical arts.

[0038] As used herein, the term “treatment” (also “treat” or “treating”) refers to any administration of a substance (e.g., provided compositions) that partially or completely alleviates, ameliorates, relives, inhibits, delays onset of, reduces severity of, and / or reduces incidence of one or more symptoms, features, and / or causes of a particular disease, disorder, and / or condition. Such treatment may be of a subject who does not exhibit signs of the relevant disease, disorder and / or condition and / or of a subject who exhibits only early signs of the disease, disorder, and / or condition. Alternatively or additionally, such treatment may be of a subject who exhibits one or more established signs of the relevant disease, disorder and / or condition. In some embodiments, treatment may be of a subject who has been diagnosed as suffering from the relevant disease, disorder, and / or condition. In some embodiments, treatment may be of a subject known to have one or more susceptibility factors that are statistically correlated with increased risk of development of the relevant disease, disorder, and / or condition.B. Compounds

[0039] In some embodiments, a provided compound is of Formula (I): CyB— L'— CyA— L— Cyc(I) or a pharmaceutically acceptable salt thereof, wherein:CyAis phenylene, a 5- to 6-membered monocyclic heteroarylene having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, a 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclene having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, an 8- to 12-membered bicyclic heteroarylene having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, or an 8- to 10-membered bicyclic arylene, wherein CyAis substituted with 0-4 -RAgroups; each RAis independently selected from oxo, halogen, -CN, -C(O)R, -C(O)2R, -C(O)N(R)2, - NO2, -N(R)2, -N(R)C(O)R, -N(R)C(O)2R, -N(R)S(O)2R, -OR, -OC(O)R, -OC(O)N(R)2, - SR, -S(O)R, -S(O)2R, -S(O)N(R)2, -S(O)2N(R)2, or an optionally substituted group selected from C1-6 aliphatic, phenyl, a 3- to 7-membered saturated or partially unsaturatedmonocyclic carbocyclyl, a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur, or a 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from oxygen, nitrogen or sulfur; each R is independently hydrogen or an optionally substituted Ci-6 aliphatic group;L’ is a covalent bond or an optionally substituted Ci-4 hydrocarbon chain, wherein 1 to 3 methylene units are optionally and independently replaced with -O-, -C(O)-, -NRZ-, -S-, -SO- , -SO2-, -S(NH)(O)-, or cyclopropylene; each Rzis independently selected from hydrogen, -(CH2)o-30R, -(CH2)o-3C(0)OR, or an optionally substituted C1-6 aliphatic group;wherein: each of RB1and RB2is independently hydrogen or an optionally substituted group selected from C1-6 aliphatic or a 3- to 7-membered saturated or partially unsaturated monocyclic carbocycyl;RB3is hydrogen or C1-6 aliphatic;RB4is -N(RX)2; each Rxis independently selected from hydrogen, -C(O)R, -C(O)2R, or optionally substituted C1-6 aliphatic. wherein no more than one of RB1or RB2is hydrogen; orwherein:RB5is hydrogen or Ci-6 aliphatic or an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic carbocycyl;each of RB6and RB7is independently hydrogen or an optionally substituted Ci-6 aliphatic;L is an optionally substituted C1-3 hydrocarbon chain, wherein 1 to 3 methylene units are optionally and independently replaced with -C(O)-, -O-, -NRZ-, -N(NO)- -S-, -SO-, -SO2-, an optionally substituted cyclopropylene, or an optionally substituted 5- to 6-membered saturated or partially unsaturated heterocyclene having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur; andCycis selected from a 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, phenyl, 8- to 10-membered bicyclic aryl, a 7- to 10-membered heteroaryl having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, or a 6- to 12- membered saturated or partially unsaturated fused bicyclic heterocyclyl having 1-4 heteroatoms independently selected from oxygen, nitrogen, or sulfur, wherein Cycis substituted with 0-6 -Lc-Rcgroups; each Lcis independently selected from a covalent bond or an optionally substituted C1-6 hydrocarbon chain, wherein 1 to 3 methylene units are optionally and independently replaced with -C(O)-, -O-, or -NR-; and each Rcis independently selected from oxo, halogen, -CN, -C(O)R, -C(O)2R, -C(O)N(R)2, -NO2, -N(R)2, -N(R)C(O)R, -N(R)C(O)2R, -N(R)S(O)2R, -OR, -OC(O)R, -OC(O)N(R)2, -SR, -S(O)R, -S(O)2R, -S(O)N(R)2, -S(O)2N(R)2, or an optionally substituted group selected from C1-6 aliphatic, phenyl, a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, a 5- or 6-membered heteroaryl having 1-3 heteroatoms selected from oxygen, nitrogen, or sulfur, a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur, a 6- to 12-membered saturated or unsaturated bicyclic heterocyclyl having 1-3 heteroatoms selected from oxygen, nitrogen, or sulfur, a 5- to 12- membered saturated or unsaturated bicyclic carbocyclyl, or a 7- to 10-membered heteroaryl having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur.

[0040] In some embodiments, a provided compound is of Formula (!'):CyB— L'— CyA— L— Cyc(F)or a pharmaceutically acceptable salt thereof, wherein each of CyA, Cyc, L, and L’ is defined and described in classes and subclasses herein, both singly and in combination; and CyBis an optionally substituted 9- to 10-membered heteroaryl having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur.

[0041] It will be understood that, unless otherwise specified or prohibited by the foregoing definition of Formula (I'), embodiments of variables CyA, Cyc, L, and L’ as defined above and described in classes and subclasses herein, also apply to compounds of Formula (I'), both singly and in combination

[0042] In some embodiments, CyAis phenylene, a 5- to 6-membered monocyclic heteroarylene having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, a 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclene having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, an 8- to 12-membered bicyclic heteroarylene having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, or an 8- to 10-membered bicyclic arylene, wherein CyAis substituted with 0-4 -RAgroups.

[0043] In some embodiments, CyAis a 5- to 6-membered monocyclic heteroarylene having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, a 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclene having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, or an 8- to 12-membered bicyclic heteroarylene having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein CyAis substituted with 0-4 -RAgroups. In some embodiments, CyAis 5- to 6-membered monocyclic heteroarylene having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, or an 8- to 12-membered bicyclic heteroarylene having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein CyAis substituted with 0-4 -RAgroups. In some embodiments, CyAis a 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclene having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, or an 8- to 12- membered bicyclic heteroarylene having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein CyAis substituted with 0-4 -RAgroups.

[0044] In some embodiments, CyAis phenylene, wherein CyAis substituted with 0-4 -RAgroups. In some embodiments, CyAis phenylene, wherein CyAis substituted with 0-2 -RAgroups.

[0045] In some embodiments, CyAis a 5- to 6-membered monocyclic heteroarylene having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein CyAis substituted with 0-4 -RAgroups.

[0046] In some embodiments, CyAis a 6-membered monocyclic heteroarylene having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein CyAis substituted with 0-4 -RAgroups. In some embodiments, CyAis a 6-membered monocyclic heteroarylene having 1-3 nitrogen heteroatoms, wherein CyAis substituted with 0-4 RAgroups. In some embodiments, CyAis a pyridinediyl substituted with 0-3 RAgroups. In some embodiments, CyAis a pyrimidinediyl substituted with 0-2 RAgroups. In some embodiments, CyAis a pyridazinediyl substituted with 0-2 RAgroups. In some embodiments, CyAis a pyrazinediyl substituted with 0-2 RAgroups. In some embodiments, CyAis a triazinediyl substituted with 0-1 RAgroups.

[0047] In some embodiments, CyAis a 5-membered monocyclic heteroarylene having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein CyAis substituted with 0-2 -RAgroups. In some embodiments, CyAis thiazolediyl, wherein CyAis substituted with 0-1 -RAgroups. In some embodiments, CyAis an unsubstituted thiadiazol ediyl. In some embodiments, CyAis an unsubstituted oxadiazolediyl. In some embodiments, CyAis an unsubstituted triazolediyl. In some embodiments, CyAis pyrrolediyl, wherein CyAis substituted with 0-2 -RAgroups. In some embodiments, CyAis pyrazolediyl, wherein CyAis substituted with 0-2 -RAgroups. In some embodiments, CyAis imidazolediyl, wherein CyAis substituted with 0-2 -RAgroups. In some embodiments, CyAis unsubstituted pyrazolediyl. In some embodiments, CyAis unsubstituted imidazolediyl.

[0048] In some embodiments, CyAis a 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclene having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, wherein CyAis substituted with 0-4 -RAgroups.

[0049] In some embodiments, CyAis an 8- to 12-membered bicyclic heteroarylene having 1- 4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein CyAis substituted with 0-4 -RAgroups. In some embodiments, CyAis an 8- to 10-membered bicyclic heteroarylene having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein CyAis substituted with 0-4 -RAgroups. In some embodiments, CyAis a 9- to 10-membered bicyclic heteroarylene having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein CyAis substituted with 0-4 -RAgroups.

[0050] In some embodiments, CyAis an 8-membered bicyclic heteroarylene having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein CyAis substituted with 0-4 -RAgroups. In some embodiments, CyAis an 8-membered bicyclic heteroarylene having 1-2 nitrogen heteroatoms, wherein CyAis substituted with 0-4 -RAgroups. In some embodiments, CyAis an 8-membered bicyclic heteroarylene having 2 nitrogen heteroatoms, wherein CyAis substituted with 0-4 -RAgroups.

[0051] In some embodiments, CyAis a 9-membered bicyclic heteroarylene having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein CyAis substituted with 0-4 -RAgroups. In some embodiments, CyAis a 9-membered bicyclic heteroarylene having 1-4 nitrogen heteroatoms, wherein CyAis substituted with 0-4 -RAgroups. In some embodiments, CyAis a 9-membered bicyclic heteroarylene having 2 nitrogen heteroatoms, wherein CyAis substituted with 0-4 -RAgroups. In some embodiments, CyAis a 9- membered bicyclic heteroarylene having 3 nitrogen heteroatoms, wherein CyAis substituted with 0-4 -RAgroups. In some embodiments, CyAis a 9-membered bicyclic heteroarylene having 4 nitrogen heteroatoms, wherein CyAis substituted with 0-4 -RAgroups.

[0052] In some embodiments, CyAis a 10-membered bicyclic heteroarylene having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein CyAis substituted with 0-4 -RAgroups. In some embodiments, CyAis a 10-membered bicyclic heteroarylene having 1-2 nitrogen heteroatoms, wherein CyAis substituted with 0-4 -RAgroups. In some embodiments, CyAis a 10-membered bicyclic heteroarylene having 1 nitrogen heteroatoms, wherein CyAis substituted with 0-4 -RAgroups.

[0053] In some embodiments, CyAis a 7- to 12-membered bicyclic heteroarylene having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein CyAis substituted with 0-4 -RAgroups. In some embodiments, CyAis a 9-membered bicyclic heteroarylene having 3-4 heteroatoms independently selected from oxygen and nitrogen, wherein CyAis substituted with 0-1 -RAgroups. In some embodiments, CyAis a 10-membered bicyclic heteroarylene having 3-4 heteroatoms independently selected from oxygen and nitrogen, wherein CyAis substituted with 0-1 -RAgroups.

[0054] In some embodiments, CyAis selected from the group consisting of:wherein * represents the point of attachment to L’.

[0055] In some embodiments, CyAis selected from the group consisting ofwherein * represents the point of attachment to L’.

[0056] In some embodiments, CyAis selected from the group consisting ofwherein * represents the point of attachment to L’.

[0057] In some embodiments, CyAis selected from the group consisting ofwherein * represents the point of attachment to L’.

[0058] In some embodiments, CyAis selected from the group consisting of:wherein * represents the point of attachment to L’.

[0059] In some embodiments, CyAis:wherein * represents the point of attachment to L’.

[0060] In some embodiments, CyAis phenylene, 5-membered monocyclic heteroarylene having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, a 7- to 10- membered saturated or partially unsaturated bicyclic heterocyclene having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, an 8- to 12-membered bicyclic heteroarylene having 1- 4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, or 8- to 10-membered bicyclic arylene, wherein CyAis substituted with 0-4 -RAgroups.

[0061] In some embodiments, CyAis selected from the group consisting of phenylene, thiazolediyl, pyrimidinediyl, pyridazinediyl, triazinediyl, thiadi azolediyl, oxadiazolediyl, triazolediyl, pyrrolediyl, pyrazolediyl, imidazolediyl, wherein CyAis substituted with 0-4 -RAgroups.

[0062] In some embodiments, CyAis selected from the group consisting of:wherein * represents the point of attachment to L’.

[0063] In some embodiments, CyAis not a 6-membered monocyclic heteroarylene having 1- 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, CyAis not a 6-membered monocyclic heteroarylene having 1-2 nitrogen heteroatoms. In some embodiments, CyAis not a pyridinediyl or pyrazinediyl substituted with 0-3 RAgroups. In some embodiments, CyAis not a pyridinediyl substituted with 0-3 RAgroups. In some embodiments, CyAis a not pyrazinediyl substituted with 0-2 RAgroups. In some embodiments, CyAis notsome embodiments, CyAis not. In some embodiments, CyAis not

[0064] In some embodiments, CyAis phenylene, 6-membered monocyclic heteroarylene having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, a 7- to 10- membered saturated or partially unsaturated bicyclic heterocyclene having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, an 8- to 12-membered bicyclic heteroarylene having 1- 4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, or 8- to 10-membered bicyclic arylene, wherein CyAis substituted with 0-4 -RAgroups.

[0065] In some embodiments, CyAis selected from the group consisting of:

[0066] In some embodiments, CyAis not a 5-membered monocyclic heteroarylene having 1- 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, CyAis not a 5-membered monocyclic heteroarylene having 1 nitrogen and 1 sulfur heteroatoms. In some embodiments, CyAis not a thiazolediyl or pyrazinediyl substituted with 0-3 RAgroups.In some embodiments, CyAis not

[0067] In some embodiments, CyAis substituted with 0 -RAgroups (i.e., CyAis unsubstituted).

[0068] In some embodiments, CyAis phenylene, a 5- to 6-membered monocyclic heteroarylene having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, an 8- to 12-membered bicyclic heteroarylene having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, or an 8- to 10-membered bicyclic arylene, wherein CyAis substituted with 0-4 -RAgroups.

[0069] In some embodiments, CyAis not a 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclene having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur substituted with 0-4 -RAgroups.

[0070] In some embodiments, each RAis independently selected from oxo, halogen, -CN, - C(O)R, -C(O)2R, -C(O)N(R)2, -NO2, -N(R)2, -N(R)C(O)R, -N(R)C(O)2R, -N(R)S(O)2R, -OR, - OC(O)R, -OC(O)N(R)2, -SR, -S(O)R, -S(O)2R, -S(O)N(R)2, -S(O)2N(R)2, or an optionally substituted group selected from C1-6 aliphatic, phenyl, a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur, or a 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from oxygen, nitrogen or sulfur.

[0071] In some embodiments, each RAis independently selected from oxo, halogen, -CN, - C(O)2R, -N(R)2, -OR, -SR, -S(O)R, -S(O)2R, or an optionally substituted group selected from C1-6 aliphatic, a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, or a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur.

[0072] In some embodiments, each RAis independently selected from oxo, halogen, -C(O)2R, -OR, -C(O)N(R)2, or an optionally substituted C1-6 aliphatic.

[0073] In some embodiments, each RAis independently selected from halogen, -OR, or an optionally substituted C1-6 aliphatic. In some embodiments, each RAis independently selected from halogen or an optionally substituted C1-6 aliphatic. In some embodiments, each RAis independently selected from fluorine or methyl.

[0074] In some embodiments, substituents on an optionally substituted RAgroup are independently halogen, -(CH2)o-40R°, or -(CH2)O--IN(R0)2, wherein each R° is independently as defined above and described in classes and subclasses herein. In some such embodiments, each R° is independently hydrogen or methyl. In some such embodiments, each R° is hydrogen.

[0075] It will be appreciated that references herein to embodiments in which “a single instance” of a substituent is defined are not limited to monosubstituted embodiments. For example, “ [i]n some embodiments, a single instance of RAis oxo” includes embodiments in which at least one instance of RAis oxo and which may comprise one or more additional RAgroups as defined herein.

[0076] In some embodiments, a single instance of RAis oxo. In some embodiments, a single instance of RAis halogen. In some embodiments, a single instance of RAis fluorine. In someembodiments, a single instance of RAis chlorine. In some embodiments, a single instance of RAis -CN.

[0077] In some embodiments, a single instance of RAis -C(O)2R. In some embodiments, a single instance of RAis -C(O)2R, wherein R is hydrogen, methyl, or ethyl. In some embodiments, a single instance of RAis -C(O)2H. In some embodiments, a single instance of RAis -C(O)2CHa. In some embodiments, a single instance of RAis -C(O)2CH2CH3. In some embodiments, a single instance of RAis -C(O)N(R)2. In some embodiments, a single instance of RAis -C(O)NH2.

[0078] In some embodiments, a single instance of RAis -N(R)2. In some embodiments, a single instance of RAis -OR.

[0079] In some embodiments, a single instance of RAis Ci-6 aliphatic substituted with halogen. In some embodiments, RAis -CHF2. In some embodiments, RAis -CF3.

[0080] In some embodiments, a single instance of RAis Ci-6 aliphatic substituted with - (CH2)O-40R°, wherein R° is selected from hydrogen or C1-6 aliphatic. In some embodiments, a single instance of RAis -CH2OH. In some embodiments, a single instance of RAis -CH2OCH3. In some embodiments, a single instance of RAis C1-6 aliphatic substituted with -(CH2)o-4N(R°)2, wherein each R° is independently selected from hydrogen or C1-6 aliphatic. In some embodiments, a single instance of RAis -CH2NH2. In some embodiments, a single instance of RAis C1-6 aliphatic substituted with -(CH2)o-4C(0)OR°, wherein R° is selected from hydrogen or 0C 1-6 aliphatic.. In some embodiments, a single instance of RAisjnsome o embodiments, a single instance of RAis

[0081] In some embodiments, a single instance of RAis methyl, ethyl, or propyl. In some embodiments, a single instance of RAis methyl.

[0082] In some embodiments, a single instance of RAis optionally substituted 3- to 7- membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, a single instance of RAis optionally substituted cyclopropyl.

[0083] In some embodiments, a single instance of RAis optionally substituted 3- to 7- membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur. In some embodiments, a single instance of RAis optionally substituted 3- to 7-membered saturated monocyclic heterocyclyl having 1-2heteroatoms selected from oxygen and nitrogen. In some embodiments, a single instance of RAis optionally substituted oxetanyl. In some embodiments, a single instance of RAis oxetanyl optionally substituted with halogen or -(CH2)o-40R°. In some embodiments, a single instance of RAis pyrrolidinyl.

[0084] In some embodiments, each RAis independently selected from halogen, -CN, - C(O)R, -C(O)2R, -C(O)N(R)2, -NO2, -N(R)2, -N(R)C(O)R, -N(R)C(O)2R, -N(R)S(O)2R, -OR, - OC(O)R, -OC(O)N(R)2, -SR, -S(O)R, -S(O)2R, -S(O)N(R)2, -S(O)2N(R)2, or an optionally substituted group selected from C1-6 aliphatic, phenyl, a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur, or a 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from oxygen, nitrogen or sulfur.

[0085] In some embodiments, RAis not oxo.

[0086] In some embodiments, L’ is a covalent bond or an optionally substituted Ci-4 hydrocarbon chain, wherein 1 to 3 methylene units are optionally and independently replaced with -O-, -C(O)-, -NRZ-, -S-, -SO-, -SO2-, -S(NH)(O)-, or cyclopropylene.

[0087] In some embodiments, L’ is a covalent bond. In some embodiments, L’ is an optionally substituted C1-4 hydrocarbon chain, wherein 1 to 3 methylene units are optionally and independently replaced with -O-, -C(O)-, -NRZ-, -S-, -SO-, -SO2-, -S(NH)(O)-, or cyclopropylene.

[0088] In some embodiments, L’ is an optionally substituted C1-4 hydrocarbon chain, wherein 1 to 3 methylene units are optionally and independently replaced with -O-, -C(O)-, - NRZ-, -SO2-. In some embodiments, L’ is an optionally substituted C1-4 hydrocarbon chain, wherein 1 to 3 methylene units are optionally and independently replaced with -C(O)- or -NRZ. In some embodiments, L’ is an optionally substituted C2-4 hydrocarbon chain, wherein 1 methylene unit is replaced with -C(O)-, and 1 or 2 additional methylene units are independently replaced with -NRZ. In some embodiments, L’ is an optionally substituted C3-4 hydrocarbon chain, wherein 1 methylene unit is replaced with -C(O)-, and 1 or 2 additional methylene units are independently replaced with -NRZ. In some embodiments, L’ is an optionally substituted C1-4 hydrocarbon chain, wherein 1 methylene unit is replaced -NRZ. In some embodiments, L’ is an optionally substituted C1-3 hydrocarbon chain, wherein 1 methylene unit is replaced -NRZ.

[0089] In some embodiments, L’ is an optionally substituted C2-4 hydrocarbon chain, wherein 1 methylene unit is replaced with -SO2-, and 1 or 2 additional methylene units are independently replaced with -NRZ. In some embodiments, L’ is an optionally substituted C3-4 hydrocarbon chain, wherein 1 methylene unit is replaced with -SO2-, and 1 or 2 additional methylene units are independently replaced with -NRZ. In some embodiments, L’ is an optionally substituted Ci-4 hydrocarbon chain, wherein 1 methylene unis is optionally and independently replaced with -NRZ-.

[0090] In some embodiments, L’ is optionally substituted with halogen. In some embodiments, L’ is optionally substituted with -(CH2)o-4R°, wherein R° is hydrogen or Ci-6 aliphatic and may be further substituted with halogen. In some embodiments, L’ is optionally substituted with -CF3.

[0091] In some embodiments, L’ is selected from the group consisting of:and 0 , wherein # represents the point of attachment to CyB.

[0092] In some embodiments, L’ is selected from the group consisting of:, wherein # represents the point of attachment to CyB.

[0093] In some embodiments, L’ iswherein # represents the point ofattachment to CyB. In some embodiments, L’ is O , wherein # represents the point of attachment to CyB.

[0094] In some embodiments, L’ is a covalent bond or an optionally substituted C1-4 hydrocarbon chain, wherein 1 to 3 methylene units are optionally and independently replaced with -O-, -NRZ-, -S-, -SO-, -SO2-, -S(NH)(O)-, or cyclopropylene.

[0095] In some embodiments, L’ is a covalent bond or an optionally substituted Ci-4 hydrocarbon chain, wherein 1 to 3 methylene units are optionally and independently replaced with -O-, -C(O)-, -S-, -SO-, -SO2-, -S(NH)(O)-, or cyclopropylene.

[0096] In some embodiments, L’ is selected from the group consisting of:0 , wherein # represents the point of attachment to CyB.

[0097] In some embodiments, L’ is not O , wherein # represents the point of attachment to CyB.

[0098] In some embodiments, L’ is a covalent bond or an optionally substituted C2-4 hydrocarbon chain, wherein 1 to 3 methylene units are optionally and independently replaced with -O-, -C(O)-, -NRZ-, -S-, -SO-, -SO2-, -S(NH)(O)-, or cyclopropylene.

[0099] In some embodiments, L’ is not -O-.

[0100] In some embodiments, CyBis an optionally substituted 9- to 10-membered heteroaryl having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, CyBis an optionally substituted 10-membered heteroaryl having 1 nitrogen heteroatom. In some embodiments, CyBis optionally substituted isoquinolinyl. In some embodiments, CyBis optionally substituted. in some embodiments, CyBis optionally substituted with halogen; -(CH2)o-4R°; -(CH2)o-40R°; or -(CH2)o-4N(R°)2. In some such embodiments, R° is hydrogen or C1-6 aliphatic.

[0101] In some embodiments,some embodiments, CyB, wherein no more than one of RB1orRB2is hydrogen. In some embodiments,wherein RB1is not hydrogen. In some embodiments,, wherein RB2is not hydrogen. In some embodiments,CyBis, wherein RB1and RB2are not hydrogen.

[0102] In some embodiments, RB1is hydrogen or an optionally substituted group selected from C1-6 aliphatic or a 3- to 7-membered saturated or partially unsaturated monocyclic carbocycyl. In some embodiments, RB1is hydrogen or C1-6 aliphatic. In some embodiments, RB1is hydrogen. In some embodiments, RB1is C1-6 aliphatic. In some embodiments, RBiis methyl. In some embodiments, RB1is ethyl. In some embodiments, RB1is methyl, optionally substituted with halogen. In some embodiments, RB1is -CF3. In some embodiments, RB1is an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic carbocycyl. In some embodiments, RB1is an optionally substituted cyclopropyl. In some embodiments, RB1is cyclopropyl. In some embodiments, RB1is cyclopropyl, optionally substituted with -(CH2)O-4R0, wherein R° is hydrogen or Ci-6 aliphatic. In some embodiments, RBiisIn some embodiments, RB1is methyl, ethyl, -CF3, or

[0103] In some embodiments, RB2is hydrogen or an optionally substituted group selected from C1-6 aliphatic or a 3- to 7-membered saturated or partially unsaturated monocyclic carbocycyl. In some embodiments, RB2is hydrogen or C1-6 aliphatic. In some embodiments, RB2is hydrogen. In some embodiments, RB2is C1-6 aliphatic. In some embodiments, RB2is methyl. In some embodiments, RB2is ethyl. In some embodiments, RB2is methyl, optionally substituted with halogen. In some embodiments, RB2is -CF3. In some embodiments, RB2is an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic carbocycyl. In some embodiments, RB2is an optionally substituted cyclopropyl. In some embodiments, RB2iscyclopropyl. In some embodiments, RB2is cyclopropyl, optionally substituted with -(CH2)o-4R°, wherein R° is hydrogen or Ci-6 aliphatic. In some embodiments, RB2is

[0104] In some embodiments, RB1and RB2are the same. In some embodiments, RB1and RB2are different. In some embodiments, RB1is hydrogen and RB2is Ci-6 aliphatic. In some embodiments, RB1is Ci-6 aliphatic and RB2is hydrogen. In some embodiments, RB1and RB2are Ci-6 aliphatic. In some embodiments, RB1is hydrogen and RB2is methyl. In some embodiments, RB1is methyl and RB2is hydrogen. In some embodiments, RB1and RB2are methyl. In some embodiments, RB1is methyl, ethyl, -CF3, orand RB2is hydrogen, methyl, ethyl, -CF3, orIn some embodiments, RB1is hydrogen, methyl, ethyl, -CF3, orand RB2is methyl, ethyl, -CF3, orIn some embodiments, RB1is methyl, ethyl, -CF3, or, and RB2is methyl, ethyl, -.

[0105] Without wishing to be bound by any particular theory, it is believed that the sizes of the RB1and / or RB2groups influence potency without loss of binding efficiency. In some embodiments, it is advantageous for there to be a larger substituent (e.g., a substituent other than hydrogen) at the the RB1and / or RB2position. In some embodiments, it is advantageous for there to be a larger substituent (e.g., a substituent other than hydrogen) at the the RB1position. In some embodiments, it is advantageous for there to be a larger substituent (e.g., a substituent other than hydrogen) at the the RB2position. In some embodiments, it is advantageous for there to be a larger substituent (e.g., a substituent other than hydrogen) at the the RB1and RB2positions.

[0106] The relative size of a group (e.g., in this instance, RB1and RB2) can be determined from the van der Waals surface and / or molecular volume calculated for that group. For a single molecule (i.e., a molecule for which there is a path between any two atoms along covalent bonds), the van der Waals surface is a closed surface, and hence, it contains volume. This volume is called the molecular volume, or van der Waals volume, and is usually given in A3. A straightforward way of calculating A-values on the computer is by numerical integration, i.e., by surrounding the van der Waals envelope with a grid of small bricks and summing up the bricks whose centers are within the van der Waals envelope of the molecule (i.e., are within a van derWaals radius from atom nucleus) (see, for example, Whitley, “Van der Waals surface graphs and molecular shape,” Journal of Mathematical Chemistry (1998) 23:377-397).

[0107] The relative size of a group can also be measured from the “A-value” for a given group. The A-value is a measure of the effective size of a given group. The “A-value” refers to the conformational energies (-G0values) as determined for a substituted cyclohexane and the relative axial-equatorial disposition of the substituent (see Table 1, provided below, and pages 695-697 of Eliel and Wilen, Chapter 11 entitled “Configuration and Confirmation of Cyclic Molecules” of Stereochemistry of Organic Compounds, John Wiley & Sons, Inc., NewYork: 1994, incorporated herein by reference). More detailed tabulations have been compiled by Hirsch, “Table of Conformational Energies”, Top. Stereochem. (1967) 1 : 199; Jensen and Bushweller, “Conformational Preferences in Cyclohexanes and Cyclohexenes”, Adv. Alicycl. Chem. (1971) 3: 139; and Schnieder and Hoppen “Carbon-13 Nuclear Magnetic ResonanceSubstituent-induced Shieldings and Conformational Equilibria in Cyclohexanes”, J. Org. Chem.(1978) 43:3866.Table 1. Exemplary A-values.

[0108] In some embodiments, RB1is selected from a moiety with an A-value that is greater than about 1.0 kcal / mol (e.g., as shown in Table 1). In some embodiments, RB1is selected from a moiety with an A-value that is greater than about 1.5 kcal / mol (e.g., as shown in Table 1). In some embodiments, RB1is selected from a moiety with an A-value that is greater than about 1.70 kcal / mol (e.g., as shown in Table 1). In some embodiments, RB1is selected from a moiety with an A-value that is greater than about 2.0 kcal / mol (e.g., as shown in Table 1). In some embodiments, RB1is selected from a moiety with an A-value that is greater than about 2.25 kcal / mol (e.g., as shown in Table 1). In some embodiments, RB1is selected from a moiety with an A-value that is greater than about 2.5 kcal / mol (e.g., as shown in Table 1). In some embodiments, RB1is selected from a moiety with an A-value that is greater than about 2.75 kcal / mol (e.g., as shown in Table 1). In some embodiments, RB1is selected from a moiety with an A-value that is greater than about 3.0 kcal / mol (e.g., as shown in Table 1). In some embodiments, RB1is selected from a moiety with an A-value that is greater than about 4.0 kcal / mol (e.g., as shown in Table 1).

[0109] In some embodiments, RB1is selected from a moiety with an A-value between about 0.25 and about 5.0 (e.g., as shown in Table 1). In some embodiments, RB1is selected from a moiety with an A-value between about 0.5 and about 5.0 (e.g., as shown in Table 1). In some embodiments, RB1is selected from a moiety with an A-value between about 1.0 and about 5.0 (e.g., as shown in Table 1). In some embodiments, RB1is selected from a moiety with an A- value between about 1.5 and about 5.0 (e.g., as shown in Table 1). In some embodiments, RB1is selected from a moiety with an A-value between about 1.70 and about 5.0 (e.g., as shown in Table 1). In some embodiments, RB1is selected from a moiety with an A-value between about 2.0 and about 5.0 (e.g., as shown in Table 1). In some embodiments, RB1is selected from amoiety with an A-value between about 2.25 and about 5.0 (e.g., as shown in Table 1). In some embodiments, RB1is selected from a moiety with an A-value between about 2.5 and about 5.0 (e.g., as shown in Table 1). In some embodiments, RB1is selected from a moiety with an A- value between about 3.0 and about 5.0 (e.g., as shown in Table 1). In some embodiments, RB1is selected from a moiety with an A-value between about 4.0 and about 5.0 (e.g., as shown in Table 1).

[0110] In some embodiments, RB1is selected from a moiety with an A-value between about 0.25 and about 4.0 (e.g., as shown in Table 1). In some embodiments, RB1is selected from a moiety with an A-value between about 0.25 and about 3.0 (e.g., as shown in Table 1). In some embodiments, RB1is selected from a moiety with an A-value between about 0.25 and about 2.5 (e.g., as shown in Table 1). In some embodiments, RB1is selected from a moiety with an A- value between about 0.25 and about 2.0 (e.g., as shown in Table 1). In some embodiments, RB1is selected from a moiety with an A-value between about 0.5 and about 2.5 (e.g., as shown in Table 1). In some embodiments, RB1is selected from a moiety with an A-value between about 1.0 and about 2.5 (e.g., as shown in Table 1). In some embodiments, RB1is selected from a moiety with an A-value between about 1.0 and about 2.0 (e.g., as shown in Table 1). In some embodiments, RB1is selected from a moiety with an A-value between about 1.5 and about 2.0 (e.g., as shown in Table 1). In some embodiments, RB1is selected from a moiety with an A- value between about 1.5 and about 2.5 (e.g., as shown in Table 1).

[0111] In some embodiments, RB2is selected from a moiety with an A-value that is greater than about 1.0 kcal / mol (e.g., as shown in Table 1). In some embodiments, RB2is selected from a moiety with an A-value that is greater than about 1.5 kcal / mol (e.g., as shown in Table 1). In some embodiments, RB2is selected from a moiety with an A-value that is greater than about 1.70 kcal / mol (e.g., as shown in Table 1). In some embodiments, RB2is selected from a moiety with an A-value that is greater than about 2.0 kcal / mol (e.g., as shown in Table 1). In some embodiments, RB2is selected from a moiety with an A-value that is greater than about 2.25 kcal / mol (e.g., as shown in Table 1). In some embodiments, RB2is selected from a moiety with an A-value that is greater than about 2.5 kcal / mol (e.g., as shown in Table 1). In some embodiments, RB2is selected from a moiety with an A-value that is greater than about 2.75 kcal / mol (e.g., as shown in Table 1). In some embodiments, RB2is selected from a moiety with an A-value that is greater than about 3.0 kcal / mol (e.g., as shown in Table 1). In someembodiments, RB2is selected from a moiety with an A-value that is greater than about 4.0 kcal / mol (e.g., as shown in Table 1).

[0112] In some embodiments, RB2is selected from a moiety with an A-value between about 0.25 and about 5.0 (e.g., as shown in Table 1). In some embodiments, RB2is selected from a moiety with an A-value between about 0.5 and about 5.0 (e.g., as shown in Table 1). In some embodiments, RB2is selected from a moiety with an A-value between about 1.0 and about 5.0 (e.g., as shown in Table 1). In some embodiments, RB2is selected from a moiety with an A- value between about 1.5 and about 5.0 (e.g., as shown in Table 1). In some embodiments, RB2is selected from a moiety with an A-value between about 1.70 and about 5.0 (e.g., as shown in Table 1). In some embodiments, RB2is selected from a moiety with an A-value between about 2.0 and about 5.0 (e.g., as shown in Table 1). In some embodiments, RB2is selected from a moiety with an A-value between about 2.25 and about 5.0 (e.g., as shown in Table 1). In some embodiments, RB2is selected from a moiety with an A-value between about 2.5 and about 5.0 (e.g., as shown in Table 1). In some embodiments, RB2is selected from a moiety with an A- value between about 3.0 and about 5.0 (e.g., as shown in Table 1). In some embodiments, RB2is selected from a moiety with an A-value between about 4.0 and about 5.0 (e.g., as shown in Table 1).

[0113] In some embodiments, RB2is selected from a moiety with an A-value between about 0.25 and about 4.0 (e.g., as shown in Table 1). In some embodiments, RB2is selected from a moiety with an A-value between about 0.25 and about 3.0 (e.g., as shown in Table 1). In some embodiments, RB2is selected from a moiety with an A-value between about 0.25 and about 2.5 (e.g., as shown in Table 1). In some embodiments, RB2is selected from a moiety with an A- value between about 0.25 and about 2.0 (e.g., as shown in Table 1). In some embodiments, RB2is selected from a moiety with an A-value between about 0.5 and about 2.5 (e.g., as shown in Table 1). In some embodiments, RB2is selected from a moiety with an A-value between about 1.0 and about 2.5 (e.g., as shown in Table 1). In some embodiments, RB2is selected from a moiety with an A-value between about 1.0 and about 2.0 (e.g., as shown in Table 1). In some embodiments, RB2is selected from a moiety with an A-value between about 1.5 and about 2.0 (e.g., as shown in Table 1). In some embodiments, RB2is selected from a moiety with an A- value between about 1.5 and about 2.5 (e.g., as shown in Table 1).

[0114] In some embodiments, RB3is hydrogen or Ci-6 aliphatic. In some embodiments, RB3is hydrogen. In some embodiments, RB3is Ci-6 aliphatic. In some embodiments, RB3is methyl, ethyl, or propyl. In some embodiments, RB3is methyl.

[0115] In some embodiments, RB4is -N(Rx)i. In some embodiments, RB4is -NH2. In some embodiments, RB4is -NHRX.

[0116] In some embodiments, each Rxis independently selected from hydrogen, -C(O)R, - C(O)2R, or optionally substituted C1-6 aliphatic. In some embodiments, each Rxis hydrogen. In some embodiments, each Rxis independently selected from -C(O)R, -C(O)2R, or optionally substituted C1-6 aliphatic. In some embodiments, one Rxis hydrogen, and the other is selected from -C(O)R, -C(O)2R, or optionally substituted C1-6 aliphatic.

[0117] In some embodiments, Rxis -C(O)R. In some embodiments, Rxis -C(O)R, wherein R is C1-6 aliphatic. In some embodiments, Rx-C(O)CH3 In some embodiments, Rxis -C(O)2R. In some embodiments, Rxis -C(O)2R, wherein R is optionally substituted C1-6 aliphatic. In some embodiments, Rxis -C(O)2R, wherein R is C1-6 aliphatic optionally substituted with -(CH2)o-4Ph. In some embodiments, Rxis -C(O)2CH2Ph. In some embodiments, Rxis -C(O)2R, wherein R is C1-6 aliphatic. In some embodiments, Rxis -C(O)2R, wherein R is methyl, ethyl, isopropyl, or isobutyl. In some embodiments, Rxis -C(O)2CH2CH3. In some embodiments, Rxis - C(O)C(CH3)2. In some embodiments, Rxis -C(O)CH2C(CH3)2. In some embodiments, Rxis optionally substituted C1-6 aliphatic. In some embodiments, Rxis C1-6 aliphatic. In some embodiments, Rxis methyl, ethyl, or propyl. In some embodiments, Rxis methyl.

[0118] In some embodiments, CyBis selected from the group consisting of:

[0119] In some embodiments, CyBis selected from the group consisting of:

[0121] In some embodiments, CyBis selected from the group consisting of:

[0122]

[0123] In some embodiments,

[0124] In some embodiments, RB5is hydrogen or Ci-6 aliphatic or an optionally substituted3- to 7-membered saturated or partially unsaturated monocyclic carbocycyl. In some embodiments, RB5is hydrogen. In some embodiments, RB3is Ci-6 aliphatic or an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic carbocycyl. In some embodiments, RB5is Ci-6 aliphatic. In some embodiments, RB5is methyl, ethyl, or propyl. In some embodiments, RB5is methyl. In some embodiments, RB5is an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic carbocycyl. In some embodiments, RB3is an optionally substituted cyclopropyl. In some embodiments, RB3is cyclopropyl, optionally substituted with -(CH2)o-4R°, wherein R° is hydrogen or Ci-6 aliphatic. In some embodiments,

[0125] In some embodiments, RB6is hydrogen or an optionally substituted Ci-6 aliphatic. In some embodiments, RB6is hydrogen. In some embodiments, RB6is an optionally substituted Ci-6 aliphatic. In some embodiments, RB6is Ci-6 aliphatic or optionally substituted -(CH2)o-4N(R°)2, wherein each R° is independently hydrogen or Ci-6 aliphatic.

[0126] In some embodiments, RB7is hydrogen or an optionally substituted Ci-6 aliphatic. In some embodiments, RB7is hydrogen. In some embodiments, RB7is an optionally substituted Ci-6 aliphatic. In some embodiments, RB7is Ci-6 aliphatic. In some embodiments, RB7is C1-3aliphatic. In some embodiments, RB7is methyl, ethyl, or propyl. In some embodiments, RB7is methyl.

[0127] In some embodiments, CyBis selected from the group consisting of:

[0128] In some embodiments, L is an optionally substituted C1-3 hydrocarbon chain, wherein 1 to 3 methylene units are optionally and independently replaced with -C(O)-, -O-, -NRZ-, - N(N0)- -S-, -SO-, -SO2-, an optionally substituted cyclopropylene, or an optionally substituted 5- to 6-membered saturated or partially unsaturated heterocyclene, having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur.

[0129] In some embodiments, L is an optionally substituted C1-3 hydrocarbon chain, wherein 1 to 3 methylene units are optionally and independently replaced with -C(O)-, -O-, -NR7-, - N(NO)- -S-, -SO-, -SO2-, an optionally substituted cyclopropylene, or an optionally substituted 5-membered saturated or partially unsaturated heterocyclene, having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur.

[0130] In some embodiments, L is an optionally substituted C1-3 hydrocarbon chain, wherein 1 to 3 methylene units are optionally and independently replaced with -C(O)-, -O-, -NRZ-, - N(N0)- -S-, -SO-, -SO2-, an optionally substituted cyclopropylene, or a 5-membered saturated or partially unsaturated heterocyclene having 1 nitrogen heteroatom, optionally substituted with - (CH2)O-40R0or -OSiR°3, wherein R° is as defined above and described in classes and subclasses herein. In some embodiments, L is an optionally substituted C1-3 hydrocarbon chain, wherein 1 to 3 methylene units are optionally and independently replaced with -C(O)-, -O-, -NR7-, -N(N0)- -S-, -SO-, -SO2-, an optionally substituted cyclopropylene, or a pyrrolidinediyl optionally substituted with -(CH2)o-40R° or -OSiR°3, wherein each R° is independently as defined above and described in classes and subclasses herein. In some such embodiments, each R° is independently hydrogen of C1-6 aliphatic.

[0131] In some embodiments, L is an optionally substituted C1-3 hydrocarbon chain, wherein 1-3 methylene units are optionally and independently replaced with -C(O)-, -O-, -NRZ-, -N(N0)-,-S-, or an optionally substituted cyclopropylene. In some embodiments, L is an optionally substituted C1-3 hydrocarbon chain, wherein 1-3 methylene units are optionally and independently replaced with -C(O)-, -O-, -NRZ-, or -S-.

[0132] In some embodiments, L is an optionally substituted C1-2 hydrocarbon chain, wherein 1 methylene unit is optionally replaced with -C(O)-, -O-, -NRZ-, -N(NO)-, or -S-. In some embodiments, L is an optionally substituted C1-2 hydrocarbon chain, wherein 1 methylene unit is optionally replaced with -C(O)-, -O-, -NRZ-, -N(N0)-, -S-, or an optionally substituted cyclopropylene. In some embodiments, L is an optionally substituted C1-2 hydrocarbon chain, wherein 1 methylene unit is optionally replaced with -C(O)-, -O-, -NRZ-, or -S-. In some embodiments, L is an optionally substituted C1-2 hydrocarbon chain, wherein 1 methylene unit is replaced with -C(O)-, -O-, -NRZ-, -N(N0)-, or -S-.

[0133] In some embodiments, L is an optionally substituted Ci hydrocarbon chain, wherein 1 methylene unit is optionally replaced with -C(O)-, -NRZ-, or -O-. In some embodiments, L is an optionally substituted Ci hydrocarbon chain, wherein 1 methylene unit is optionally replaced with -C(O)-. In some embodiments, L is a Ci hydrocarbon chain, optionally substituted with halogen; -(CH2)o-4R°; -(CH2)o-40R°; -(CH2)o-4C(0)OR°; -(CH2)o-4N(R°)2; or -(CH2)o- 4N(R°)C(O)OR°, wherein each R° is independently hydrogen or C1-6 aliphatic.

[0134] In some embodiments, L is. In some embodiments, L is. In some embodiments, L is a Ci hydrocarbon chain, substituted with halogen. In some embodiments, L is, . In some embodiments, L is a Ci hydrocarbon chain, substituted with -(CH2)o-4R°, wherein R° is hydrogen or C1-6 aliphatic. In some embodiments, L is. In some embodiments, L is, wherein % represents the point of attachment to Cyc. In some embodiments, L is, wherein % represents the point of attachment to Cyc. In some embodiments, L is a Ci hydrocarbon chain, substituted withOH-(CH2)O-40R°, wherein R° is hydrogen or Ci-6 aliphatic. In some embodiments, L is. Insome embodiments, L isIn some embodiments, L is a Ci hydrocarbon chain, substituted with -(CH2)o-4C(0)OR°, wherein R° is hydrogen or Ci-6 aliphatic. In some embodiments, L isIn some embodiments, L isIn some embodiments, L is a Ci hydrocarbon chain, substituted with -(CH2)o-4N(R°)2, wherein each R° is independently hydrogen or C1-6 aliphatic. In some embodiments, L isIn some embodiments, L is aCi hydrocarbon chain, substituted with -(CH2)o-4N(R°)C(0)OR°, wherein R° is hydrogen or Ci-6 aliphatic. In some embodiments,

[0135] In some embodiments, L is an optionally substituted C2 hydrocarbon chain, wherein 1 methylene unit is optionally replaced with -NRZ-, -O-, -N(N0)-, -S-. In some embodiments, L is a C2 hydrocarbon chain optionally substituted with -(CH2)o-4R°, wherein R° is hydrogen or C1-6 aliphatic, and wherein 1 methylene unit is independently replaced with -NRZ-, -O-, -N(N0)-, -S-.

[0136] In some embodiments, L is a C2 hydrocarbon chain optionally substituted with -(CH2)O-4R°, wherein R° is hydrogen or CI-G aliphatic. In some embodiments, L is

[0137] In some embodiments, L is a C2 hydrocarbon chain optionally substituted with -(CH2)O-4R°, wherein R° is hydrogen or Ci-6 aliphatic, and wherein 1 methylene unit is replaced with -O-. In some embodiments, L is, wherein % represents the point of attachment to CycIn some embodiments, L iswherein % represents the point of attachment toCycIn some embodiments, L iswherein % represents the point of attachment toCyc. In some embodiments, L is , wherein % represents the point of attachment toCyc. In some embodiments, L is, wherein % represents the point of attachment toCyc.

[0138] In some embodiments, L is a C2 hydrocarbon chain optionally substituted with - (CH2)O-4R°, wherein R° is hydrogen or C1-6 aliphatic, and wherein 1 methylene unit is replaced with -S-. In some embodiments, L is, wherein % represents the point of attachment to Cyc.

[0139] In some embodiments, L is a C2 hydrocarbon chain optionally substituted with - (CH2)O-4R°, wherein R° is hydrogen or Ci-6 aliphatic, and wherein 1 methylene unit is replaced° N with -N(N0)-. In some embodiments, L is, wherein % represents the point of attachment to Cyc.

[0140] In some embodiments, L is a C2 hydrocarbon chain optionally substituted with - (CH2)O-4R°, wherein R° is hydrogen or C1-6 aliphatic, and wherein 1 methylene unit is replaced with -NRZ-. In some embodiments, L is a C2 hydrocarbon chain optionally substituted with - (CH2)o-4R°, wherein R° is hydrogen or C1-6 aliphatic, and wherein 1 methylene unit is replaced with -NRZ-, wherein Rzis hydrogen, -(CH2)o-3C(0)OR, or an optionally substituted C1-6 aliphatic group. In some embodiments, L is, wherein % represents the point of attachment toCyc. In some embodiments, L is, wherein % represents the point of attachment toCyc. In some embodiments, L iswherein % represents the point of attachment toCyc. In some embodiments,wherein % represents the point of attachment toCyc. In some embodiments, L is, wherein % represents the point of attachment°^N to CycIn some embodiments, L iswherein % represents the point of attachment toCyr. In some embodiments, L is , wherein % represents the point of attachment to i H r | 7 %Cy In some embodiments, L is i , wherein % represents the point of attachment to Cyc.

[0141] In some embodiments, L is an optionally substituted C3 hydrocarbon chain, wherein 1 or 2 methylene units are optionally and independently replaced with -C(O)-, -NRZ-, or -O-. In some embodiments, L is an optionally substituted C3 hydrocarbon chain, wherein 1 or 2 methylene units are optionally and independently replaced with -C(O)- or -NRZ-. In some embodiments, L is a C3 hydrocarbon chain optionally substituted with -(CH2)o-4R°, wherein R° is hydrogen or C1-6 aliphatic and may be further substituted with halogen, wherein 1 or 2 methylene units are optionally and independently replaced with -C(O)- or -NRZ-. In some embodiments, LOis H , wherein % represents the point of attachment to Cyc. In some embodiments,OL is i , wherein % represents the point of attachment to Cyc. In some embodiments,L isCF3 , wherein % represents the point of attachment to Cyc.

[0142] In some embodiments, L is optionally substituted , wherein % representsthe point of attachment to Cyc. In some embodiments, L is optionally substitutedwherein % represents the point of attachment to Cyc. In some embodiments,optionally substituted with -(CH2)o-40R° or -OSiR°3, wherein % represents the point ofattachment to Cyc. In some embodiments, L is optionally substituted , wherein %represents the point of attachment to Cy In some embodiments, L is optionally substituted with -(CH2)o-40R° or -OSiR°3, wherein % represents the point of attachment to Cyc.In some embodiments,wherein % represents the point of attachment to Cyc.In some embodiments,, wherein % represents the point of attachment to Cyc.NH26 pIn some embodiments, L is not , wherein % represents the point of attachment to Cy . pIn some embodiments, L is not , wherein % represents the point of attachment to Cy

[0143] In some embodiments, L is selected from the group consisting of:wherein % represents the point of attachment to Cyc.

[0144] In some embodiments, L is selected from the group consisting of:wherein % represents the point of attachment to Cyc.

[0145] In some embodiments, L is selected from the group consisting of:

[0146] In some embodiments, L is an optionally substituted C1-3 hydrocarbon chain, wherein 1 to 3 methylene units are optionally and independently replaced with -C(O)-, -O-, -NRZ-, - N(N0)- -S-, -SO-, an optionally substituted cyclopropylene, or an optionally substituted 5- to 6-membered saturated or partially unsaturated heterocyclene, having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur.

[0147] In some embodiments, L is not -NHS(O)2-%, wherein % represents the point of attachment to Cyc.

[0148] In some embodiments, each Rzis independently selected from hydrogen, -(CH2)o- 3OR, -(CH2)O-3C(0)OR, or an optionally substituted C1-6 aliphatic group. In some embodiments, Rzis hydrogen. In some embodiments, Rzis selected from -(CH2)o-30R, -(CH2)o-3C(0)OR, or an optionally substituted C1-6 aliphatic group. In some embodiments, Rzis -(CH2)o-30R. In some embodiments, Rzis -(CH2)o-3C(0)OR. In some embodiments, Rzis -C(O)OH. In some embodiments, Rzis -C(O)OCH3. In some embodiments, Rzis -C(O)OCH2CH3. In some embodiments, Rzis an optionally substituted C1-6 aliphatic group. In some embodiments, Rzis a Ci-6 aliphatic group optionally substituted with halogen. In some embodiments, Rzis -CH2CF3. In some embodiments, Rzis a C1-6 aliphatic group. In some embodiments, Rzis methyl, ethyl, or propyl. In some embodiments, Rzis methyl.

[0149] In some embodiments, Cycis selected from a 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, phenyl, 8- to 10- membered bicyclic aryl, a 7- to 10-membered heteroaryl having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, or a 6- to 12- membered saturated or partially unsaturated fused bicyclic heterocyclyl having 1-4 heteroatoms independently selected from oxygen, nitrogen, or sulfur, wherein Cycis substituted with 0-6 -Lc-Rcgroups.

[0150] In some embodiments, Cycis phenyl, wherein Cycis substituted with 0-5 -Lc-Rcgroups.

[0151] In some embodiments, Cycis 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein Cycis substituted with 0-6 - Lc-Rcgroups. In some embodiments, Cycis 5-membered heteroaryl having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein Cycis substituted with 0-6 - Lc-Rcgroups. In some embodiments, Cycis 5-membered heteroaryl having 1-2 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein Cycis substituted with 0-6 - Lc-Rcgroups. In some embodiments, Cycis 5-membered heteroaryl having 1 nitrogen heteroatom and 1 sulfur heteroatom, wherein Cycis substituted with 0-4 -Lc-Rcgroups. In some embodiments, Cycis 5-membered heteroaryl having 2 nitrogen heteroatoms, wherein Cycissubstituted with 0-4 -Lc-Rcgroups. In some embodiments, Cycis pyrazolyl or thiazolyl, wherein Cycis substituted with 0-4 -Lc-Rcgroups. In some embodiments, Cycis pyrazolyl, wherein Cycis substituted with 0-4 -Lc-Rcgroups. In some embodiments, Cycis thiazolyl, wherein Cycis substituted with 0-4 -Lc-Rcgroups.

[0152] In some embodiments, Cycis 6-membered heteroaryl having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein Cycis substituted with 0-6 - Lc-Rcgroups. In some embodiments, Cycis 6-membered heteroaryl having 1-3 nitrogen heteroatoms, wherein Cycis substituted with 0-6 -Lc-Rcgroups. In some embodiments, Cycis 6-membered heteroaryl having 1-2 nitrogen heteroatoms, wherein Cycis substituted with 0-6 - Lc-Rcgroups.

[0153] In some embodiments, Cycis pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl, wherein Cycis substituted with 0-4 -Lc-Rcgroups. In some embodiments, Cycis pyridinyl, wherein Cycis substituted with 0-4 -Lc-Rcgroups. In some embodiments, Cycis pyrimidinyl, wherein Cycis substituted with 0-3 -Lc-Rcgroups. In some embodiments, Cycis pyrazinyl, wherein Cycis substituted with 0-3 -Lc-Rcgroups. In some embodiments, Cycis pyridazinyl, wherein Cycis substituted with 0-3 -Lc-Rcgroups.

[0154] In some embodiments, Cycis selected from the group consisting of:

[0155] In some embodiments, Cycis not

[0156] In some embodiments, Cycis an 8- to 10-membered bicyclic aryl, wherein Cycis substituted with 0-6 -Lc-Rcgroups. In some embodiments, Cycis an 8-membered bicyclic aryl,wherein Cycis substituted with 0-6 -Lc-Rcgroups. In some embodiments, Cycis a 9-membered bicyclic aryl, wherein Cycis substituted with 0-6 -Lc-Rcgroups. In some embodiments, Cycis a 10-membered bicyclic aryl, wherein Cycis substituted with 0-6 -Lc-Rcgroups.

[0157] In some embodiments, Cycis indazolyl, benzotriazolyl, naphthalenyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, tetrahydro-2 / / -benzo[ / >][l,4]oxazinyl, or dihydro-2 / / - benzo[Z>][l,4]oxazinonyl, substituted with 0-6 -Lc-Rcgroups.

[0158] In some embodiments, Cycis indazolyl, substituted with 0-5 -Lc-Rcgroups. In some embodiments, Cycis benzotriazolyl, substituted with 0-4 -Lc-Rcgroups.

[0159] In some embodiments, Cycis naphthalenyl, substituted with 0-6 -Lc-Rcgroups. In some embodiments, Cycis quinolinyl, substituted with 0-6 -Lc-Rcgroups. In some embodiments, Cycis isoquinolinyl, substituted with 0-6 -Lc-Rcgroups. In some embodiments, Cycis quinoxalinyl, substituted with 0-5 -Lc-Rcgroups. In some embodiments, Cycis quinazolinyl, substituted with 0-5 -Lc-Rcgroups. In some embodiments, Cycis tctrahydro-2 / / - benzo[Z>][l,4]oxazinyl, substituted with 0-6 -Lc-Rcgroups. In some embodiments, Cycis dihydro-277-benzo[£>][l,4]oxazinonyl, substituted with 0-6 -Lc-Rcgroups.

[0160] In some embodiments, Cycis a 7- to 10-membered heteroaryl having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein Cycis substituted with 0-6 - Lc-Rcgroups. In some embodiments, Cycis a 9- to 10-membered heteroaryl having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein Cycis substituted with 0-6 -Lc-Rcgroups.

[0161] In some embodiments, Cycis a 9-membered heteroaryl having 1-4 nitrogen heteroatoms, wherein Cycis substituted with 0-6 -Lc-Rcgroups. In some embodiments, Cycis a 9-membered heteroaryl having 1-4 nitrogen heteroatoms, wherein Cycis substituted with 0-6 - Lc-Rcgroups. In some embodiments, Cycis a 9-membered heteroaryl having 2-3 nitrogen heteroatoms, wherein Cycis substituted with 0-6 -Lc-Rcgroups. In some embodiments, Cycis a 9-membered heteroaryl having 1 nitrogen heteroatom, wherein Cycis substituted with 0-6 -Lc- Rcgroups. In some embodiments, Cycis a 9-membered heteroaryl having 2 nitrogen heteroatoms, wherein Cycis substituted with 0-6 -Lc-Rcgroups. In some embodiments, Cycis a 9-membered heteroaryl having 3 nitrogen heteroatoms, wherein Cycis substituted with 0-6 -Lc- Rcgroups. In some embodiments, Cycis a 9-membered heteroaryl having 4 nitrogen heteroatoms, wherein Cycis substituted with 0-6 -Lc-Rcgroups. In some embodiments, Cycis a9-membered heteroaryl having 1 oxygen heteroatom, wherein Cycis substituted with 0-6 -Lc-Rcgroups. In some embodiments, Cycis a 9-membered heteroaryl having 1 sulfur heteroatom, wherein Cycis substituted with 0-6 -Lc-Rcgroups. In some embodiments, Cycis a 9-membered heteroaryl having 1 nitrogen and 1 sulfur heteroatoms, wherein Cycis substituted with 0-6 -Lc- Rcgroups. In some embodiments, Cycis a 9-membered heteroaryl having 1 nitrogen and 1 oxygen heteroatoms, wherein Cycis substituted with 0-6 -Lc-Rcgroups.

[0162] In some embodiments, Cycis a 10-membered heteroaryl having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein Cycis substituted with 0-6 - Lc-Rcgroups. In some embodiments, Cycis a 10-membered heteroaryl having 1-2 nitrogen heteroatoms, wherein Cycis substituted with 0-6 -Lc-Rcgroups. In some embodiments, Cycis a10-membered heteroaryl having 1 nitrogen heteroatom, wherein Cycis substituted with 0-6 -Lc- Rcgroups. In some embodiments, Cycis a 10-membered heteroaryl having 2 nitrogen heteroatoms, wherein Cycis substituted with 0-6 -Lc-Rcgroups.

[0163] In some embodiments, Cycis imidazopyridinyl, pyrazolopyridinyl, indazolyl, pyrrolopyridinyl, benzoimidazolyl, triazolopyridinyl, imidazopyridazinyl, imidazopyrimidinyl, imidazopyrimidinonyl, benzotri azolyl, triazolopyrimidinyl, triazolopyridazinyl, benzothiophenyl, benzothiozolyl, thienopyridinyl, benzofuranyl, benzooxazolyl, pyrazolopyrimidinyl, imidazopyrazinyl, quinolinyl, isoquinolinyl, quinazolinyl, naphthyridinyl, wherein Cycis substituted with 0-6 -Lc-Rcgroups.

[0164] In some embodiments, Cycis imidazopyridinyl, wherein Cycis substituted with 0-5 - Lc-Rcgroups. In some embodiments, Cycis pyrazolopyridinyl, wherein Cycis substituted with 0-5 -Lc-Rcgroups. In some embodiments, Cycis indazolyl, wherein Cycis substituted with 0-5 -Lc-Rcgroups. In some embodiments, Cycis pyrrolopyridinyl, wherein Cycis substituted with 0-5 -Lc-Rcgroups. In some embodiments, Cycis benzoimidazolyl, wherein Cycis substituted with 0-5 -Lc-Rcgroups. In some embodiments, Cycis triazolopyridinyl, wherein Cycis substituted with 0-4 -Lc-Rcgroups. In some embodiments, Cycis imidazopyridazinyl, wherein Cycis substituted with 0-4 -Lc-Rcgroups. In some embodiments, Cycis imidazopyrimidinyl, wherein Cycis substituted with 0-4 -Lc-Rcgroups. In some embodiments, Cycis imidazopyrimidinonyl, wherein Cycis substituted with 0-4 -Lc-Rcgroups. In some embodiments, Cycis benzotriazolyl, wherein Cycis substituted with 0-4 -Lc-Rcgroups. In some embodiments, Cycis triazolopyrimidinyl, wherein Cycis substituted with 0-3 -Lc-Rcgroups. .In some embodiments, Cycis triazolopyridazinyl, wherein Cycis substituted with 0-3 -Lc-Rcgroups. In some embodiments, Cycis benzothiophenyl, wherein Cycis substituted with 0-5 -Lc- Rcgroups. In some embodiments, Cycis benzothiozolyl, wherein Cycis substituted with 0-4 - Lc-Rcgroups. In some embodiments, Cycis thienopyridinyl, wherein Cycis substituted with 0-4 -Lc-Rcgroups. In some embodiments, Cycis benzofuranyl, wherein Cycis substituted with 0-5 -Lc-Rcgroups. In some embodiments, Cycis benzooxazolyl, wherein Cycis substituted with 0-4 -Lc-Rcgroups. In some embodiments, Cycis pyrazolopyrimidinyl, wherein Cycis substituted with 0-4 -Lc-Rcgroups. In some embodiments, Cycis imidazopyrazinyl, wherein Cycis substituted with 0-4 -Lc-Rcgroups.

[0165] In some embodiments, Cycis quinolinyl, wherein Cycis substituted with 0-6 -Lc-Rcgroups. In some embodiments, Cycis isoquinolinyl, wherein Cycis substituted with 0-6 -Lc-Rcgroups. In some embodiments, Cycis quinazolinyl, wherein Cycis substituted with 0-5 -Lc-Rcgroups. In some embodiments, Cycis naphthyridinyl, wherein Cycis substituted with 0-5 -Lc- Rcgroups.

[0166] In some embodiments, Cycis selected from the group consisting of:

[0167] In some embodiments, Cycis selected from the group consisting of:

[0168] In some embodiments, Cycis selected from the group consisting of:

[0169] In some embodiments,

[0170] In some embodiments, Cycis selected from a 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, phenyl, 8- to 10- membered bicyclic aryl, or a 6- to 12- membered saturated or partially unsaturated fused bicyclicheterocyclyl having 1-4 heteroatoms independently selected from oxygen, nitrogen, or sulfur, wherein Cycis substituted with 0-6 -Lc-Rcgroups.

[0171] In some embodiments, Cycis not T(LC-RC)C-5

[0172] In some embodiments, Cycis pyrazolopyridinyl, indazolyl, pyrrol opyridinyl, benzoimidazolyl, triazolopyridinyl, imidazopyridazinyl, imidazopyrimidinyl, imidazopyrimidinonyl, benzotri azolyl, triazolopyrimidinyl, triazolopyridazinyl, benzothiophenyl, benzothiozolyl, thienopyridinyl, benzofuranyl, benzooxazolyl, pyrazolopyrimidinyl, imidazopyrazinyl, wherein Cycis substituted with 0-6 -Lc-Rcgroups.

[0173] In some embodiments, Cycis not imidazopyridinyl substituted with 0-6 -Lc-Rcgroups.

[0174] In some embodiments, Cycis selected from the group consisting of:

[0175] In some embodiments, each Lcis independently selected from a covalent bond or an optionally substituted Ci-6 hydrocarbon chain, wherein 1 to 3 methylene units are optionally and independently replaced with -C(O)-, -O-, or -NR-.

[0176] In some embodiments, a single instance of Lcis a covalent bond. In some embodiments, a single instance of Lcis an optionally substituted Ci-6 hydrocarbon chain, wherein 1 to 3 methylene units are optionally and independently replaced with -C(O)-, -O-, or -NR-. In some embodiments, a single instance of Lcis an optionally substituted Ci-6 hydrocarbon chain, wherein 1 to 3 methylene units are optionally and independently replaced with -O- or -NR-.

[0177] In some embodiments, Lcis optionally substituted with -(CH2)o-4R°, wherein R° is independently as defined above and described in classes and subclasses herein. In some such embodiments, R° is hydrogen or Ci-6 aliphatic.

[0178] In some embodiments, a single instance of Lcis selected from the group consisting of: *-NH-, *-NCHs-, *-O-, *-CH2-, *-CH2C(CH3)2-, *-CH2CH2-, *-CH2C(O)N(CH3)-, *-CH2C(O)N(CH3)CH2-, *-CF2-, *-CH(CH3)-, *-OCH2-, *-OCF2-, *-OC(CH3)2-, *-CH2C(O)-, *-OCH2C(O)-, *-CH2C(O)NH-,*-CH2C(O)NHCH2-,*-N(CH3)C(O)-, *-C(CH2CH3)-, *-C(CHCH3)-, *-C(FCH3)-, wherein * represents the point of attachment to Cyc.

[0179] In some embodiments, a single instance of Lciswherein * represents the point of attachment to Cyc. In some embodiments, a single instance of Lcis *-NCH3-, wherein * represents the point of attachment to Cyc. In some embodiments, a single instance of Lcis *-O-, wherein * represents the point of attachment to Cyc. In some embodiments, a single instance of Lcis *-CH2-, wherein * represents the point of attachment to Cyc. In some embodiments, a single instance of Lcis *-CH2C(CH3)2-, wherein * represents the point of attachment to Cyc. In some embodiments, a single instance of Lcis *-CH2CH2-, wherein * represents the point of attachment to Cyc. In some embodiments, a single instance of Lcis *-CH2C(O)N(CH3)-, wherein * represents the point of attachment to Cyc. In some embodiments, a single instance of Lcis *-CH2C(O)N(CH3)CH2-, wherein * represents the point of attachment to Cyc. In some embodiments, a single instance of Lcis *-CF2-, wherein * represents the point of attachment to Cyc. In some embodiments, a single instance of Lcis *-CH(CH3)-, wherein * represents the point of attachment to Cyc. In some embodiments, a single instance of Lcis *-OCH2-, wherein * represents the point of attachment to Cyc. In some embodiments, a single instance of Lcis *- OCF2-, wherein * represents the point of attachment to Cyc. In some embodiments, a single instance of Lcis *-OC(CH3)2-, wherein * represents the point of attachment to Cyc. In some embodiments, a single instance of Lcis *-CH2C(O)-, wherein * represents the point ofattachment to Cyc. In some embodiments, a single instance of Lcis *-OCH2C(O)-, wherein * represents the point of attachment to Cyc. In some embodiments, a single instance of Lcis *-CH2C(0)NH-, wherein * represents the point of attachment to Cyc. In some embodiments, a single instance of Lcis *-CH2C(O)NHCH2-, wherein * represents the point of attachment to Cyc. In some embodiments, a single instance of Lcis *-N(CH3)C(0)-, wherein * represents the point of attachment to Cyc. In some embodiments, a single instance of Lcis *-C(CH2CH3)-, wherein * represents the point of attachment to Cyc. In some embodiments, a single instance of Lcis *-C(CHCH3)-, wherein * represents the point of attachment to Cyc. In some embodiments, a single instance of Lcis *-C(FCH3)-, wherein * represents the point of attachment to Cyc.

[0180] In some embodiments, each Rcis independently selected from oxo, halogen, -CN, - C(O)R, -C(O)2R, -C(O)N(R)2, -NO2, -N(R)2, -N(R)C(O)R, -N(R)C(O)2R, -N(R)S(O)2R, -OR, -OC(O)R, -OC(O)N(R)2, -SR, -S(O)R, -S(O)2R, -S(O)N(R)2, -S(O)2N(R)2, or an optionally substituted group selected from C1-6 aliphatic, phenyl, a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, a 5- or 6-membered heteroaryl having 1-3 heteroatoms selected from oxygen, nitrogen, or sulfur; a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur; a 6- to 12-membered saturated or unsaturated bicyclic heterocyclyl having 1-3 heteroatoms selected from oxygen, nitrogen, or sulfur; a 5- to 12- membered saturated or unsaturated bicyclic carbocyclyl; or a 7- to 10-membered heteroaryl having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur.

[0181] In some embodiments, each Rcis independently selected from oxo, halogen, -CN, - C(O)2R, -C(O)N(R)2, or an optionally substituted group selected from C1-6 aliphatic, phenyl, a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, a 5- or 6-membered heteroaryl having 1-3 heteroatoms selected from oxygen, nitrogen, or sulfur; a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur; a 6- to 12-membered saturated or unsaturated bicyclic heterocyclyl having 1-3 heteroatoms selected from oxygen, nitrogen, or sulfur; a 5- to 12- membered saturated or unsaturated bicyclic carbocyclyl; or a 7- to 10-membered heteroaryl having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur.

[0182] In some embodiments, a single instance of Rcis selected from oxo, halogen, -CN, -C(O)2R, -OR, or an optionally substituted group selected from C1-6 aliphatic, a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, a 5- or 6-membered heteroaryl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur, a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur, or a 6- to 12-membered saturated or unsaturated bicyclic heterocyclyl having 1-3 heteroatoms selected from oxygen, nitrogen, or sulfur.

[0183] In some embodiments, a single instance of Rcis oxo. In some embodiments, a single instance of Rcis halogen. In some embodiments, a single instance of Rcis fluorine. In some embodiments, a single instance of Rcis chlorine. In some embodiments, a single instance of Rcis bromine. In some embodiments, a single instance of Rcis -CN. In some embodiments, a single instance of Rcis -C(O)2R. In some embodiments, a single instance of Rcis -COOH. In some embodiments, a single instance of Rcis -C(O)OCH3. In some embodiments, a single instance of Rcis -C(O)OCH2CH3. In some embodiments, a single instance of Rcis -OR. In some embodiments, a single instance of Rcis -OH. In some embodiments, a single instance of Rcis -OMe. In some embodiments, a single instance of Rcis -C(O)N(R)2. In some embodiments, a single instance of Rcis -C(O)NH2. In some embodiments, a single instance of Rcis -C(O)NHCH3. In some embodiments, a single instance of Rcis -C(O)N(CH3)2. In some embodiments, a single instance of Rcis -C(O)N(CH2CH3)2.

[0184] In some embodiments, a single instance of Rcis an optionally substituted Ci-6 aliphatic. In some embodiments, a single instance of Rcis Ci-6 aliphatic optionally substituted with halogen. In some embodiments, a single instance of Rcis Ci-6 aliphatic optionally substituted with fluorine. In some embodiments, a single instance of Rcis -CF3. In some embodiments, a single instance of Rcis -CHF2. In some embodiments, a single instance of Rcis methyl. In some embodiments, a single instance of Rcis ethyl. In some embodiments, a single instance of Rcis isopropyl. In some embodiments, a single instance of Rcis -CHCHCH3. In some embodiments, a single instance of Rcis -CHC(CH3)2. In some embodiments, a single instance of Rcis butyl. In some embodiments, a single instance of Rcis n-butyl.

[0185] In some embodiments, a single instance of Rcis an optionally substituted phenyl. In some embodiments, a single instance of Rcis phenyl.

[0186] In some embodiments, a single instance of Rcis an optionally substituted 3- to 7- membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, a single instance of Rcis an optionally substituted cyclopropyl. In some embodiments, a singleinstance of Rcis cyclopropyl, optionally substituted with -(CH2)o-4R°, -(CH2)o-4N(R°)C(0)R°, or-(CH2)O-4N(R°)C(0)OR°; wherein R° is hydrogen or Ci-6 aliphatic (e.g., methyl). In some embodiments, a single instance of Rcis cyclopropyl. In some embodiments, a single instance ofRcis. In some embodiments, a single instance of Rcis. In some embodiments, a single instance of Rcis. In some embodiments, a single instance of Rcis. In H ? some embodiments, a single instance of Rcis A . In some embodiments, a single instance of RcisIn some embodiments, Cycis substituted with 1-6 -Lc-Rcgroups, wherein a single instance of Rcis cyclopropyl.

[0187] In some embodiments, a single instance of Rcis an optionally substituted 5- or 6- membered heteroaryl having 1-3 heteroatoms selected from oxygen, nitrogen, or sulfur. In some embodiments, a single instance of Rcis an optionally substituted 5- or 6-membered heteroaryl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur.

[0188] In some embodiments, a single instance of Rcis an optionally substituted 5- membered heteroaryl having 1-3 heteroatoms selected from oxygen, nitrogen, or sulfur. In some embodiments, a single instance of Rcis an optionally substituted 5-membered heteroaryl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur. In some embodiments, a single instance of Rcis an optionally substituted 5-membered heteroaryl having 2 nitrogen heteroatoms. In some embodiments, a single instance of Rcis an optionally substituted pyrazolyl. In some embodiments, a single instance of Rcis pyrazolyl, optionally substituted with -(CH2)O-4R°; wherein R° is Ci-6 aliphatic (e.g., methyl or cyclopropyl). In some embodiments, a single instance of Rcis an optionally substituted imidazolyl. In some embodiments, a single instance of Rcis imidazolyl, optionally substituted with -(CH2)o-4R°; wherein R° is Ci-6 aliphatic (e.g., methyl or cyclopropyl).

[0189] In some embodiments, a single instance of Rcis an optionally substituted 5- membered heteroaryl having 1 nitrogen heteroatom and 1 sulfur heteroatom. In some embodiments, a single instance of Rcis an optionally substituted thiazolyl. In some embodiments, a single instance of Rcis thiazolyl. In some embodiments, a single instance of Rcis an optionally substituted 5-membered heteroaryl having 1 nitrogen heteroatom and 1 oxygenheteroatom. In some embodiments, a single instance of Rcis an optionally substituted oxazolyl. In some embodiments, a single instance of Rcis oxazolyl.

[0190] In some embodiments, a single instance of Rcis an optionally substituted 5- membered heteroaryl having 3 heteroatoms selected from oxygen, nitrogen, or sulfur. In some embodiments, a single instance of Rcis an optionally substituted 5-membered heteroaryl having 2 nitrogen heteroatoms and 1 oxygen heteroatom. In some embodiments, a single instance of Rcis an optionally substituted oxadiazolyl. In some embodiments, a single instance of Rcis oxadiazolyl, optionally substituted with -(CH2)o-4R°; wherein R° is Ci-6 aliphatic (e.g., methyl or cyclopropyl). In some embodiments, a single instance of Rcis oxadiazolyl.

[0191] In some embodiments, a single instance of Rcis an optionally substituted 5- membered heteroaryl having 2 nitrogen heteroatoms and 1 sulfur heteroatom. In some embodiments, a single instance of Rcis an optionally substituted thiadiazolyl. In some embodiments, a single instance of Rcis thiadiazolyl, optionally substituted with -(CH2)o-4R°; wherein R° is Ci-6 aliphatic (e.g., methyl or cyclopropyl). In some embodiments, a single instance of Rcis thiadiazolyl.

[0192] In some embodiments, a single instance of Rcis an optionally substituted 5- membered heteroaryl having 3 nitrogen heteroatoms. In some embodiments, a single instance of Rcis an optionally substituted triazolyl. In some embodiments, a single instance of Rcis triazolyl, optionally substituted with -(CH2)o-4R°; wherein R° is Ci-6 aliphatic (e.g., methyl or cyclopropyl). In some embodiments, a single instance of Rcis triazolyl.

[0193] In some embodiments, a single instance of Rcis an optionally substituted 6- membered heteroaryl having 1-3 heteroatoms selected from oxygen, nitrogen, or sulfur. In some embodiments, a single instance of Rcis an optionally substituted 6-membered heteroaryl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur. In some embodiments, a single instance of Rcis an optionally substituted 6-membered heteroaryl having 1 nitrogen heteroatom. In some embodiments, a single instance of Rcis an optionally substituted pyridinyl. In some embodiments, a single instance of Rcis pyridinyl, optionally substituted with halogen or -(CH2)o- 4R0; wherein R° is C1-6 aliphatic (e.g., methyl or cyclopropyl). In some embodiments, a single instance of Rcis an optionally substituted pyridinonyl. In some embodiments, a single instance of Rcis pyridinonyl, optionally substituted with halogen or -(CH2)o-4R°; wherein R° is C1-6aliphatic (e.g., methyl, ethyl, or cyclopropyl), wherein R° may be further substituted with halogen (e.g., fluorine). In some embodiments, a single instance of Rcis pyridinonyl.

[0194] In some embodiments, a single instance of Rcis an optionally substituted pyrimidinyl. In some embodiments, a single instance of Rcis pyrimidinyl. In some embodiments, a single instance of Rcis an optionally substituted pyrazinyl. In some embodiments, a single instance of Rcis pyrazinyl.

[0195] In some embodiments, a single instance of Rcis an optionally substituted 6- membered heteroaryl having 2 nitrogen heteroatoms.

[0196] In some embodiments, a single instance of Rcis selected from the group consisting

[0197] In some embodiments, a single instance of Rcis an optionally substituted 3- to 7- membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur.

[0198] In some embodiments, a single instance of Rcis an optionally substituted 4- to 6- membered saturated or partially unsaturated monocyclic heterocyclyl having 1 nitrogen heteroatom. In some embodiments, a single instance of Rcis an optionally substituted 4- membered saturated or partially unsaturated monocyclic heterocyclyl having 1 nitrogen heteroatom. In some embodiments, a single instance of Rcis an optionally substitutedazetidinyl. In some embodiments, a single instance of R is x . In some embodiments, asingle instance of Rcis an optionally substituted 5-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 nitrogen heteroatom. In some embodiments, a single instance of Rcis an optionally substituted pyrrolidinyl. In some embodiments, a single instance of Rcis pyrrolidinyl, optionally substituted with -(CH2)o-4R°; wherein R° is Ci-6 aliphatic (e.g., methyl).In some embodiments, a single instance of Rcis. In some embodiments, a single instance of Rcis an optionally substituted pyrrolidinonyl. In some embodiments, a single instance of Rcsome embodiments, a single instance of Rcis an optionally substituted 5- to 6-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 nitrogen heteroatom. In some embodiments, a single instance of Rcis an optionally substituted piperidinyl. In some embodiments, a single instance of RcisIn some embodiments, a single instance of Rcis an optionally substituted piperidinonyl. In some embodiments, a single instance of Rcis

[0199] In some embodiments, a single instance of Rcis an optionally substituted 4- membered saturated or partially unsaturated monocyclic heterocyclyl having 1 heteroatom selected from oxygen, nitrogen, or sulfur. In some embodiments, a single instance of Rcis an optionally substituted 4-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 oxygen heteroatom. In some embodiments, a single instance of Rcis an optionally substituted oxetanyl. In some embodiments, a single instance of Rcis oxetanyl, optionally substituted with halogen or -(CH2)o-40R°, wherein R° is hydrogen or Ci-6 aliphatic (e.g., methyl).In some embodiments, a single instance of RcisIn some embodiments, a single instance

[0200] In some embodiments, a single instance of Rcis an optionally substituted 5- membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur. In some embodiments, a single instance of Rcis an optionally substituted 5-membered saturated or partially unsaturated monocyclic heterocyclylhaving 1 nitrogen heteroatom and 1 oxygen heteroatom. In some embodiments, a single instance of Rcis an optionally substituted oxazolidinonyl. In some embodiments, a single instance of Rc

[0201] In some embodiments, a single instance of Rcis an optionally substituted 6- membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur. In some embodiments, a single instance of Rcis an optionally substituted 6-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 nitrogen heteroatom and 1 oxygen heteroatom. In some embodiments, a single instance of Rcis an optionally substituted morpholinyl. In some embodiments, a single instance of Rcis. In some embodiments, a single instance of R is an optionally substitutedmorpholinonyl. In some embodiments, a single instance of Rcis o

[0202] In some embodiments, a single instance of Rcis an optionally substituted 6- to 12- membered saturated or unsaturated bicyclic heterocyclyl having 1-3 heteroatoms selected from oxygen, nitrogen, or sulfur. In some embodiments, a single instance of Rcis an optionally substituted 6-membered saturated or unsaturated bicyclic heterocyclyl having 1-3 heteroatoms selected from oxygen, nitrogen, or sulfur. In some embodiments, a single instance of Rcis an optionally substituted 6-membered saturated or unsaturated bicyclic heterocyclyl having 1 nitrogen heteroatom.

[0203] In some embodiments, a single instance of Rcis an optionally substituted azabicyclo[3.1.0]hexanyl. In some embodiments, a single instance of Rcis azabicyclo[3.1.0]hexanyl, optionally substituted with halogen, -(CH2)o-4R°, -(CH2)o-40R°,-(CH2)O-4C(0)OR°; wherein R° is hydrogen or Ci-6 aliphatic (e g., methyl), wherein R° may be further substituted with halogen (e.g., fluorine).

[0204] In some embodiments, a single instance of RcisIn some embodiments, a single instance of Rcis. In some embodiments, a single instance of Rcis ’In some embodiments, a single instance of RcisNO^F insome embodiments, a singleHinstance of Rcis H . In some embodiments, a single instance of Rcis. In some embodiments, a single instance of Rcis. In some embodiments, a single instance of Rcis. In some embodiments, a single instance of Rc. In some embodiments, a single instance of Rc. In some embodiments, a single instance of Rcis. ,some embodiments, a single instance of Rcis. In some embodiments, a single instance

[0205] In some embodiments, a single instance of Rcis an optionally substituted 7- membered saturated or unsaturated bicyclic heterocyclyl having 1-3 heteroatoms selected from oxygen, nitrogen, or sulfur. In some embodiments, a single instance of Rcis an optionally substituted 7-membered saturated or unsaturated bicyclic heterocyclyl having 1 nitrogen heteroatom.

[0206] In some embodiments, a single instance of Rcis an optionally substituted 3- azabicyclo[3.1.1]heptanyl. In some embodiments, a single instance of R is

[0207] In some embodiments, a single instance of Rcis an optionally substituted 5- to 12- membered saturated or unsaturated bicyclic carbocyclyl. In some embodiments, a single instance of Rcis an optionally substituted 5- membered saturated or unsaturated bicyclic carbocyclyl. In some embodiments, a single instance of Rcis an optionally substituted 5- membered saturated bicyclic carbocyclyl. In some embodiments, a single instance of Rcis bicycle[l. l.l]pentanyl. In some embodiments, a single instance of Rcis

[0208] In some embodiments, a single instance of Rcis an optionally substituted 7- to 10- membered heteroaryl having 1-4 heteroatoms independently selected from oxygen, nitrogen, andsulfur. In some embodiments, a single instance of Rcis an optionally substituted 9-membered heteroaryl having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, a single instance of Rcis an optionally substituted 9-membered heteroaryl having 2 nitrogen heteroatoms. In some embodiments, a single instance of Rcis an optionally substituted imidazopyridinyl. In some embodiments, a single instance of Rcis

[0209] In some embodiments, a provided compound is of Formula (Il-a) or (Il-b):or a pharmaceutically acceptable salt thereof, wherein each of CyA, Cyc, L, L’, RB1, RB2, RB3, RB4, RB5, RB6, and RB7is defined and described in classes and subclasses herein, both singly and in combination.

[0210] It will be understood that, unless otherwise specified or prohibited by the foregoing definition of Formula (Il-a) and (Il-b), embodiments of variables CyA, Cyc, L, L’, RB1, RB2, RB3, RB4, RB5, RB6, and RB7as defined above and described in classes and subclasses herein, also apply to compounds of Formula (Il-a) and (Il-b), both singly and in combination.

[0211] In some embodiments, a provided compound is of Formula (Ill-a), (Ill-b), (III-c), or(Ill-d):or a pharmaceutically acceptable salt thereof,wherein each of CyA, Cyc, L, L’, RB1, RB2, RB3, and RB4is defined and described in classes and subclasses herein, both singly and in combination.

[0212] It will be understood that, unless otherwise specified or prohibited by the foregoing definitions of Formulae (Ill-a), (Ill-b), (III-c), and (Ill-d) embodiments of variables CyA, Cyc, L, L’, RB1, RB2, RB3, and RB4as defined above and described in classes and subclasses herein, also apply to compounds of Formulae (Ill-a), (Ill-b), (III-c), and (Ill-d) both singly and in combination.

[0213] In some embodiments, a provided compound is of Formula (III-a-1), (III-a-2), or (III- a-3):(III-a-3) or a pharmaceutically acceptable salt thereof, wherein each of CyA, Cyc, L, L’, RB2, RB4, and Rxis defined and described in classes and subclasses herein, both singly and in combination.

[0214] It will be understood that, unless otherwise specified or prohibited by the foregoing definitions of Formulae (III-a-1), (III-a-2), and (III-a-3), embodiments of variables CyA, Cyc, L, L’, RB2, RB4, and Rxas defined above and described in classes and subclasses herein, also apply to compounds of Formulae (III-a-1), (III-a-2), and (III-a-3), both singly and in combination.

[0215] In some embodiments, a provided compound is of Formula (III-b-1), (III-b-2), or (III- b-3):(III-b-1) (III-b-2)(III-b-3) or a pharmaceutically acceptable salt thereof, wherein each of CyA, Cyc, L, L’, RB1, RB4, and Rxis defined and described in classes and subclasses herein, both singly and in combination.

[0216] It will be understood that, unless otherwise specified or prohibited by the foregoing definitions of Formulae (III-b-1), (III-b-2), and (III-b-3), embodiments of variables CyA, Cyc, L, L’, RB1, RB4, and Rxas defined above and described in classes and subclasses herein, also apply to compounds of Formulae (III-b-1), (III-b-2), and (III-b-3), both singly and in combination.

[0217] In some embodiments, a provided compound is of Formula (IV), (IV-a), (IV-b), or(IV-c):(IV-b) (IV-c) or a pharmaceutically acceptable salt thereof, wherein each of CyA, Cyc, L, L’, RB3, RB4, and Rxis defined and described in classes and subclasses herein, both singly and in combination.

[0218] It will be understood that, unless otherwise specified or prohibited by the foregoing definitions of Formulae (IV), (IV-a), (IV-b), and (IV-c), embodiments of variables CyA, Cyc, L, L’, RB3, RB4, and Rxas defined above and described in classes and subclasses herein, also apply to compounds of Formulae Formula (IV), (IV-a), (IV-b), and (IV-c), both singly and in combination.

[0219] In some embodiments, a provided compound is of Formula (V-a), (V-b), or (V-c):(V-c) or a pharmaceutically acceptable salt thereof, wherein each of Cyc, L, L’, RB1, RB2, and RAis defined and described in classes and subclasses herein, both singly and in combination.

[0220] It will be understood that, unless otherwise specified or prohibited by the foregoing definition of Formula (V-a), (V-b), and (V-c), embodiments of variables Cyc, L, L’, RB1, RB2, and RAas defined above and described in classes and subclasses herein, also apply to compounds of Formula (V-a), (V-b), and (V-c), both singly and in combination.

[0221] In some embodiments, a provided compound is of Formula (Vl-a), (Vl-b), or (VI-c):(VI-c) or a pharmaceutically acceptable salt thereof,wherein each of Cyc, L, L’, RB1, RB2, and RAis defined and described in classes and subclasses herein, both singly and in combination.

[0222] It will be understood that, unless otherwise specified or prohibited by the foregoing definitions of Formulae (Vl-a), (Vl-b), and (VI-c), embodiments of variables Cyc, L, L’, RB1, RB2, and RAas defined above and described in classes and subclasses herein, also apply to compounds of Formulae (Vl-a), (Vl-b), and (VI-c), both singly and in combination.

[0223] In some embodiments, a provided compound is of Formula (Vll-a), (Vll-b), or (VII- c):(VII-c) or a pharmaceutically acceptable salt thereof, wherein each of Cyc, L, L’, RB1, RB2, and RAis defined and described in classes and subclasses herein, both singly and in combination.

[0224] It will be understood that, unless otherwise specified or prohibited by the foregoing definitions of Formulae (Vll-a), (Vll-b), and (VII-c), embodiments of variables Cyc, L, L’, RB1, RB2, and RAas defined above and described in classes and subclasses herein, also apply to compounds of Formulae (Vll-a), (Vll-b), and (VII-c), both singly and in combination.

[0225] In some embodiments, a provided compound is of Formula (Vlll-a), (VIILb), or (VIII-c):(VIII-c) or a pharmaceutically acceptable salt thereof, wherein each of CyA, Cyc, L, RB1, and RB2is defined and described in classes and subclasses herein, both singly and in combination.

[0226] It will be understood that, unless otherwise specified or prohibited by the foregoing definitions of Formulae (VIII-a), (VIII-b), and (VIII-c), embodiments of variables CyA, Cyc, L, RB1, and RB2as defined above and described in classes and subclasses herein, also apply to compounds of Formulae (VIII-a), (VIII-b), and (VIII-c), both singly and in combination.

[0227] In some embodiments, a provided compound is of Formula (IX-a), (IX-b), or (IX-c):(IX-c) or a pharmaceutically acceptable salt thereof, wherein each of CyA, Cyc, L, RB1, and RB2is defined and described in classes and subclasses herein, both singly and in combination.

[0228] It will be understood that, unless otherwise specified or prohibited by the foregoing definitions of Formulae (IX-a), (IX-b), and (IX-c), embodiments of variables CyA, Cyc, L, RB1, and RB2as defined above and described in classes and subclasses herein, also apply to compounds of Formulae (IX-a), (IX-b), and (IX-c), both singly and in combination.

[0229] In some embodiments, a provided compound is of Formula (X-a), (X-b), or (X-c):or a pharmaceutically acceptable salt thereof, wherein each of CyA, Cyc, L’, RB1, and RB2is defined and described in classes and subclasses herein, both singly and in combination. It will be understood that the connection between CyAand Cycin each of Formula (X-a), (X-b), and (X-c) is a methylene.

[0230] It will be understood that, unless otherwise specified or prohibited by the foregoing definitions of Formulae (X-a), (X-b), and (X-c), embodiments of variables CyA, Cyc, L’, RB1, and RB2as defined above and described in classes and subclasses herein, also apply to compounds of Formulae (X-a), (X-b), and (X-c), both singly and in combination.

[0231] In some embodiments, a provided compound is of Formula (Xl-a), (Xl-b), or (XI-c):or a pharmaceutically acceptable salt thereof,wherein each of CyA, Cyc, L’, RB1, and RB2is defined and described in classes and subclasses herein, both singly and in combination.

[0232] It will be understood that, unless otherwise specified or prohibited by the foregoing definitions of Formulae (Xl-a), (Xl-b), and (XI-c), embodiments of variables CyA, Cyc, L’, RB1, and RB2as defined above and described in classes and subclasses herein, also apply to compounds of Formulae (Xl-a), (Xl-b), and (XI-c), both singly and in combination.

[0233] In some embodiments, a provided compound is of Formula (Xll-a), (Xll-b), or (XII- c):(XII-c) or a pharmaceutically acceptable salt thereof, wherein each of CyA, L, L’, RB1, RB2, Lc, and Rcis defined and described in classes and subclasses herein, both singly and in combination.

[0234] It will be understood that, unless otherwise specified or prohibited by the foregoing definitions of Formulae (Xll-a), (Xll-b), and (XII-c), embodiments of variables CyA, L, L’, RB1, RB2, Lc, and Rcas defined above and described in classes and subclasses herein, also apply to compounds of Formulae (Xll-a), (Xll-b), and (XII-c), both singly and in combination.

[0235] In some embodiments, a provided compound is of Formula (Xlll-a), (XIILb), or (XIII-c):(XIILa) (Xlll-b)or a pharmaceutically acceptable salt thereof, wherein each of CyA, L, L’, RB1, RB2, Lc, and Rcis defined and described in classes and subclasses herein, both singly and in combination.

[0236] It will be understood that, unless otherwise specified or prohibited by the foregoing definitions of Formulae (XIILa), (Xlll-b), and (XIII-c), embodiments of variables CyA, L, L’, RB1, RB2, LC, and Rcas defined above and described in classes and subclasses herein, also apply to compounds of Formulae (Xlll-a), (Xlll-b), and (XIII-c), both singly and in combination.

[0237] In some embodiments, a provided compound is of Formula (XlV-a), (XlV-b), or (XIV-c):(XIV-c) or a pharmaceutically acceptable salt thereof, wherein each of CyA, L, L’, RB1, RB2, Lc, and Rcis defined and described in classes and subclasses herein, both singly and in combination.

[0238] It will be understood that, unless otherwise specified or prohibited by the foregoing definitions of Formulae (XlV-a), (XlV-b), and (XIV-c), embodiments of variables CyA, L, L’,RB1, RB2, Lc, and Rcas defined above and described in classes and subclasses herein, also apply to compounds of Formulae (XlV-a), (XlV-b), and (XIV-c), both singly and in combination.

[0239] In some embodiments, a provided compound is of Formula (XV-a), (XV-b), or (XV- c):(XV-c) or a pharmaceutically acceptable salt thereof, wherein each of CyA, L, L’, RB1, RB2, Lc, and Rcis defined and described in classes and subclasses herein, both singly and in combination.

[0240] It will be understood that, unless otherwise specified or prohibited by the foregoing definitions of Formulae (XV-a), (XV-b), and (XV-c), embodiments of variables CyA, L, L’, RB1, RB2, LC, and Rcas defined above and described in classes and subclasses herein, also apply to compounds of Formulae (XV-a), (XV-b), and (XV-c), both singly and in combination.

[0241] In some embodiments, a provided compound is of Formula (XVI-a), (XVI-b), or (XVI-c):(XVI-a)(XVI-c) or a pharmaceutically acceptable salt thereof, wherein each of CyA, L, L’, RB1, RB2, Lc, and Rcis defined and described in classes and subclasses herein, both singly and in combination.

[0242] It will be understood that, unless otherwise specified or prohibited by the foregoing definitions of Formulae (XVI-a), (XVI-b), and (XVI-c), embodiments of variables CyA, L, L’, RB1, RB2, LC, and Rcas defined above and described in classes and subclasses herein, also apply to compounds of Formulae (XVI-a), (XVI-b), and (XVI-c), both singly and in combination.

[0243] In some embodiments, a compound is 2-((2S,4R)-4-amino-l-(6-chloroimidazo[l,2- a]pyridine-2-carbonyl)pyrrolidin-2-yl)-N-((l-amino-5,7-dimethylisoquinolin-6- yl)methyl)thiazole-4-carboxamide, or a pharmaceutically acceptable salt thereof.

[0244] In some embodiments, a compound is not 2-((2S,4R)-4-amino-l-(6- chloroimidazo[l,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)-N-((l-amino-5,7-dimethylisoquinolin- 6-yl)methyl)thiazole-4-carboxamide, or a pharmaceutically acceptable salt thereof.

[0245] In some embodiments, a compound is selected from:N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-l-((6-methylisoquinolin-3-yl)methyl)-lH- pyrazole-4-carboxamide (1-1);N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-l-(4-cyclopropyl-3-methylbenzyl)-lH- pyrazole-4-carboxamide (1-2); diisopropyl (5,7-dimethyl-6-((l-((6-methylimidazo[l,2-a]pyridin-2-yl)methyl)-lH-pyrazole-4- carboxamido)methyl)isoquinolin-l-yl)iminodicarbonate (1-3); benzyl ((benzyloxy)carbonyl)(5,7-dimethyl-6-((l-((6-methylimidazo[l,2-a]pyridin-2-yl)methyl)- lH-pyrazole-4-carboxamido)methyl)isoquinolin-l-yl)carbamate (1-4);isobutyl (5,7-dimethyl-6-((l-((6-methylimidazo[l,2-a]pyridin-2-yl)methyl)-lH-pyrazole-4- carboxamido)methyl)isoquinolin-l-yl)carbamate (1-5); isopropyl (5,7-dimethyl-6-((l-((6-methylimidazo[l,2-a]pyridin-2-yl)methyl)-lH-pyrazole-4- carboxamido)methyl)isoquinolin-l -yl)carbamate (1-6); benzyl (5,7-dimethyl-6-((l-((6-methylimidazo[l,2-a]pyridin-2-yl)methyl)-lH-pyrazole-4- carboxamido)methyl)isoquinolin-l-yl)carbamate (1-7);N-(( 1 -acetamido-5,7-dimethylisoquinolin-6-yl)methyl)- 1 -((6-methylimidazo[ 1 ,2-a]pyridin-2- yl)methyl)-lH-pyrazole-4-carboxamide (1-8); ethyl (5,7-dimethyl-6-((l-((6-methylimidazo[l,2-a]pyridin-2-yl)methyl)-lH-pyrazole-4- carboxamido)methyl)isoquinolin-l-yl)carbamate (1-9);N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-l-((6-methylimidazo[l,2-a]pyri din-2- y 1 )methy 1 )- 1 H-py razol e-4-carb oxami de (I- 10) ;(R*)-N-(( 1 -amino-5,7-dimethylisoquinolin-6-yl)m ethyl)- 1 -( 1 -(6-methylimidazo[ 1 ,2-a]pyri din-2 - yl)ethyl)-lH-pyrazole-4-carboxamide (1-11);(R)-N-(( 1 -amino-5,7-dimethyli soquinolin-6-yl)methyl)- 1 -( 1 -(6-methylimidazo[ 1 ,2-a]pyridin-2- yl)ethyl)-lH-pyrazole-4-carboxamide (1-1 la);(S*)-N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-l-(l-(6-methylimidazo[l,2-a]pyri din-2- yl)ethyl)-lH-pyrazole-4-carboxamide (1-12);(S)-N-(( 1 -amino-5, 7-dimethylisoquinolin-6-yl)methyl)- 1 -( 1 -(6-methylimidazo[ 1 ,2-a]pyri din-2 - yl)ethyl)- lH-pyrazole-4-carboxamide (I- 12a);N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-(l-(6-methylimidazo[l,2-a]pyri din-2- yl)ethyl)- lH-pyrazole-4-carboxamide (I- 13); methyl 2-(4-(((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)carbamoyl)-lH-pyrazol-l-yl)-2-(6- methylimidazo[l,2-a]pyridin-2-yl)acetate (1-14);N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-((6-methyl-[ 1,2, 4]triazolo[l, 5-a]pyri din-2 - yl)methyl)-lH-pyrazole-4-carboxamide (1-15);N-((l -amino-5, 7-dimethy lisoquinolin-6-yl)methyl)- l-((2-methylquinazolin-7-yl)methyl)- 1H- pyrazole-4-carboxamide (1-16);N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-(4-((5-chl oro-1 -methyl-2-oxo-l, 2- dihydropyridin-3-yl)oxy)benzyl)-lH-pyrazole-4-carboxamide (1-17);N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-(4-((l-methyl-2-oxo-l,2-dihydropyridin-3- yl)oxy)benzyl)-lH-pyrazole-4-carboxamide (1-18); l-(4-(l-acetamidocyclopropyl)benzyl)-N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-lH- pyrazole-4-carboxamide (1-19);N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-l-(4-(2-(dimethylamino)-2-oxoethyl)-3,5- dimethylbenzyl)- lH-pyrazole-4-carboxamide (1-20);N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-(4-(N-methylpyrrolidine-l- carboxamido)benzyl)-lH-pyrazole-4-carboxamide (1-21);N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-l-(4-(l,3,3-trimethylureido)benzyl)-lH- pyrazole-4-carboxamide (1-22);N-(( 1 -amino-5, 7-dimethy lisoquinolin-6-yl)methyl)- 1 -(4-(2-(dimethylamino)- 1 , 1 -difluoro-2- oxoethyl)benzyl)-lH-pyrazole-4-carboxamide (1-23);N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-((3-methylquinoxalin-6-yl)methyl)-lH- pyrazole-4-carboxamide (1-24); ethyl (4-((4-(((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)carbamoyl)-lH-pyrazol-l- yl)methyl)phenyl)(methyl)carbamate (1-25);N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-(4-(2-(dimethylamino)-2-oxoethyl)-3- methylbenzyl)-lH-pyrazole-4-carboxamide (1-26);N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-((2-methylquinolin-7-yl)methyl)-lH- pyrazole-4-carboxamide (1-27);N-(( 1 -amino-5 , 7-dimethy li soquinolin-6-yl)methy 1)- 1 -((3 -cy clopropylquinolin-6-yl)methyl)- 1 H- pyrazole-4-carboxamide (1-28);N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-(4-cy cl opropylbenzyl)-lH-pyrazole-4- carboxamide (1-29);N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-(4-((l-methyl-2-oxo-l,2-dihydropyridin-3- yl)methyl)benzyl)-lH-pyrazole-4-carboxamide (1-30);N-((l -amino-5, 7-dimethy lisoquinolin-6-yl)methyl)- l-(3-cycl opropylbenzyl)-lH-pyrazole-4- carboxamide (1-31);N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-(2-cy anobenzyl)-lH-pyrazole-4- carboxamide (1-32);N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l -(2 -methoxybenzyl)- lH-pyrazole-4- carboxamide (1-33);(S)-N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-l-(l-phenylethyl)-lH-pyrazole-4- carboxamide (1-34);N-(( 1 -amino-5 , 7-dimethy li soquinolin-6-yl)methy 1)- 1 -(4-methylbenzyl)- 1 H-py razole-4- carboxamide (1-35);N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-(4-methyl-3-(trifluoromethyl)benzyl)-lH- pyrazole-4-carboxamide (1-36);N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l -(3, 5-dichlorobenzyl)-lH-pyrazole-4- carboxamide (1-37);N-((l -amino-5, 7-dimethy lisoquinolin-6-yl)methyl)-l -(2-fluorobenzyl)-lH-pyrazole-4- carboxamide (1-38);N-(( 1 -amino-5 , 7-dimethy li soquinolin-6-yl)methy 1)- 1 -(4-fluorobenzyl)- 1 H-pyrazole-4- carboxamide (1-39);N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l -(2 -methylbenzyl)- lH-pyrazole-4- carboxamide (1-40);N-((l -amino-5, 7-dimethy lisoquinolin-6-yl)methyl)-l -(3 -methylbenzyl)- lH-pyrazole-4- carboxamide (1-41);N-((l -amino-5, 7-dimethy lisoquinolin-6-yl)methyl)- l-(2-(trifluoromethyl)benzyl)- IH-pyrazole- 4-carboxamide (1-42);N-(( 1 -amino-5 , 7-dimethy li soquinolin-6-yl)methy 1)- 1 -(3 -methoxybenzyl)- 1 H-pyrazole-4- carboxamide (1-43); l-(4-((l,3,4-oxadiazol-2-yl)methyl)benzyl)-N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)- lH-pyrazole-4-carboxamide (1-44);N-(( 1 -amino-5 , 7-dimethy li soquinolin-6-yl )methy 1 )- 1 -(3 -fluorobenzyl )- 1 H-pyrazole-4- carboxamide (1-45);N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-((2-oxo-2H-[l,2'-bipyridin]-5'-yl)methyl)- lH-pyrazole-4-carboxamide (1-46);N-(( 1 -amino-5 , 7-dimethy li soquinolin-6-yl)methyl)- 1 -((3 -methylb enzofuran-2-yl)methyl)- 1 H- pyrazole-4-carboxamide (1-47);l-(4-(2-(lH-pyrazol-l-yl)ethyl)benzyl)-N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-lH- pyrazole-4-carboxamide (1-48);N-(( 1 -amino-5, 7-dimethylisoquinolin-6-yl)m ethyl)- 1 -(4-(2-(2-oxopyridin- 1 (2H)- yl)ethyl)benzyl)-lH-pyrazole-4-carboxamide (1-49);N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-((5-bromobenzofuran-2-yl)methyl)-lH- pyrazole-4-carboxamide (1-50);N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-((5-bromobenzo[b]thiophen-2-yl)methyl)- lH-pyrazole-4-carboxamide (1-51);N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-((l -methyl- lH-indazol-5-yl)methyl)-lH- pyrazole-4-carboxamide (1-52);N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-(imidazo[l,2-a]pyridin-2-ylmethyl)-lH- pyrazole-4-carboxamide (1-53);N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-((8-methylimidazo[l,2-a]pyri din-2- yl)methyl)-lH-pyrazole-4-carboxamide (1-54); ethyl 2-(4-((4-((( 1 -amino-5 ,7-dimethyli soquinolin-6-yl)methyl)carbamoy 1)- 1 H-pyrazol- 1 - yl)methyl)phenyl)acetate (1-55);N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l -(naphthal en-2-ylmethyl)- lH-pyrazole-4- carb oxami de (1-56);N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-((5-fluorobenzofuran-2-yl)methyl)-lH- pyrazole-4-carboxamide (1-57);N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-((l-methyl-lH-benzo[d] [1,2, 3]triazol-5- y l)methy 1 )- 1 H-py razol e-4-carb oxami de (I- 58) ;N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-((l -methyl- lH-indazol-6-yl)methyl)-lH- pyrazole-4-carboxamide (1-59);N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-(quinolin-6-ylmethyl)-lH-pyrazole-4- carboxamide (1-60);N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-((7-chloroquinolin-3-yl)methyl)-lH- pyrazole-4-carboxamide (1-61);N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-((4-chlorobenzo[b]thiophen-2-yl)methyl)- lH-pyrazole-4-carboxamide (1-62);N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-(4-(2-(dimethylamino)-2-oxoethyl)benzyl)- 1 H-pyrazole-4-carboxamide (1-63);N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-l-((2-methylquinolin-6-yl)methyl)-lH- pyrazole-4-carboxamide (1-64);N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-l-((5-chlorobenzo[b]thiophen-2-yl)methyl)- lH-pyrazole-4-carboxamide (1-65);N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-l-((5-(trifluoromethyl)benzo[b]thiophen-2- yl)methyl)- lH-pyrazole-4-carboxamide (1-66);N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-l-((2-methoxyquinolin-3-yl)methyl)-lH- pyrazole-4-carboxamide (1-67);N-(( 1 -amino-5, 7-dimethy lisoquinolin-6-yl)methyl)- 1 -(( 1 -(difluoromethyl)- 1H- benzo[d]imidazol-2-yl)methyl)-lH-pyrazole-4-carboxamide (1-68);N-((l -amino-5, 7-dimethy lisoquinolin-6-yl)methyl)-l-((6-bromoquinolin-2-yl)m ethyl)- 1H- pyrazole-4-carboxamide (1-69);N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-((6-bromoquinolin-3-yl)methyl)-lH- pyrazole-4-carboxamide (1-70);N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-l-((l-isopropyl-lH-benzo[d]imidazol-2- yl)methyl)-lH-pyrazole-4-carboxamide (1-71);N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-((8-methylquinolin-3-yl)methyl)-lH- pyrazole-4-carboxamide (1-72);N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-((2-chloro-8-methylquinolin-3-yl)methyl)- lH-pyrazole-4-carboxamide (1-73);N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-(isoquinolin-6-ylmethyl)-lH-pyrazole-4- carboxamide (1-74);N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-((l -methyl-lH-benzo[d]imidazol-2- yl)methyl)-lH-pyrazole-4-carboxamide (1-75);N-((l -amino-5, 7-dimethy lisoquinolin-6-yl)methyl)-l-(benzo[d]thi azol -2 -ylmethyl)-lH-pyrazole- 4-carboxamide (1-76);N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-(pyrimidin-5-ylmethyl)-lH-pyrazole-4- carboxamide (1-77);N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-l-(pyridin-2-ylmethyl)-lH-pyrazole-4- carboxamide (1-78);N-(( 1 -amino-5 , 7-dimethy li soquinolin-6-yl )methy 1)- 1 -(quinoxalin-6-y Imethyl )- 1 H-pyrazole-4- carboxamide (1-79);N-((l -amino-5, 7-dimethy lisoquinolin-6-yl)methyl)-l-((3-chlorobenzo[b]thiophen-2-yl)methyl)- lH-pyrazole-4-carboxamide (1-80);N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-((6-chlorobenzo[b]thiophen-2-yl)methyl)- lH-pyrazole-4-carboxamide (1-81);N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-(benzofuran-2-ylmethyl)-lH-pyrazole-4- carboxamide (1-82);N-((l -amino-5, 7-dimethy lisoquinolin-6-yl)methyl)- l-(pyrimidin-2-y Imethyl)- lH-pyrazole-4- carb oxami de (1-83);N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-(benzo[b]thiophen-2-ylmethyl)-lH- pyrazole-4-carboxamide (1-84);N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-(benzo[d]oxazol -2 -ylmethyl)-lH-pyrazole- 4-carboxamide (1-85);N-((l -amino-5, 7-dimethy lisoquinolin-6-yl )methyl)-l -(pyrazin-2-ylmethyl)-lH-pyrazole-4- carb oxami de (1-86);N-((l -amino-5, 7-dimethy lisoquinolin-6-yl)methyl)- l-(pyridin-4-ylmethyl)- lH-pyrazole-4- carb oxami de (1-87);N-(( 1 -amino-5 , 7-dimethy li soquinolin-6-yl)methy 1)- 1 -(pyridin-3 -ylmethyl)- 1 H-pyrazole-4- carboxamide (1-88);N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l -((3-chloroquinolin-6-yl)methyl)-lH- pyrazole-4-carboxamide (1-89); l-((6-(2-(3-azabicyclo[3.1.0]hexan-3-yl)-2-oxoethyl)pyridin-3-yl)methyl)-N-((l -amino-5, 7- dimethylisoquinolin-6-yl)methyl)-lH-pyrazole-4-carboxamide (1-90);N-((l -amino-5, 7-dimethy lisoquinolin-6-yl)methyl)-l-(4-methoxybenzyl)-lH-pyrazole-4- carboxamide (1-91);N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-(4-cy anobenzyl)-lH-pyrazole-4- carboxamide (1-92);N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-(4-(trifluoromethyl)benzyl)-lH-pyrazole- 4-carboxamide (1-93);N-(( 1 -amino-5 , 7-dimethy li soquinolin-6-yl )methy 1)- 1 -(3 -cyanobenzyl)- 1 H-pyrazole-4- carboxamide (1-94);N-((l -amino-5, 7-dimethy lisoquinolin-6-yl)methyl)-l-(3,5-bis(trifluoromethyl)benzyl)-lH- pyrazole-4-carboxamide (1-95);N-((l -amino-5, 7-dimethy lisoquinolin-6-yl)methyl)- l-(3-chl oro-4-methylbenzyl)-lH-pyrazole-4- carboxamide (1-96);N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l -(3-(trifluoromethyl)benzyl)- IH-pyrazole- 4-carboxamide (1-97);N-((l -amino-5, 7-dimethy lisoquinolin-6-yl)methyl)-l -(3 -chlorobenzyl)- lH-pyrazole-4- carboxamide (1-98);N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-((6-cyclopropylimidazo[l,2-a]pyridin-2- yl)methyl)-lH-pyrazole-4-carboxamide (1-99);N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-((7-cy cl opropylimidazo[ l,2-a]pyridin-2- yl)methyl)-lH-pyrazole-4-carboxamide (I- 100);N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-((6-chloroimidazo[l,2-a]pyridin-2- yl)methyl)-lH-pyrazole-4-carboxamide (I- 101 );N-((l -amino-5, 7-dimethy lisoquinolin-6-yl)methyl)- 1-((6, 7-dimethylimidazo[ l,2-a]pyri din-2 - yl)methyl)-lH-pyrazole-4-carboxamide (1-102);N-((l -amino-5, 7-dimethy lisoquinolin-6-yl)methyl)- l-((7-methylimidazo[l, 2-a]pyridin-2- yl)methyl)-lH-pyrazole-4-carboxamide (1-103);N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-((5-methylimidazo[l,2-a]pyridin-2- yl)methyl)-lH-pyrazole-4-carboxamide (1-105);N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-((6-chloro-5-methylimidazo[l,2-a]pyridin- 2-yl)methyl)-lH-pyrazole-4-carboxamide (1-106);N-((l -amino-5, 7-dimethy lisoquinolin-6-yl)methyl)- l-((7-chloroquinolin-2-yl)methyl)-lH- pyrazole-4-carboxamide (1-107);N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-((2-chloro-7-methoxyquinolin-3- yl)methyl)-lH-pyrazole-4-carboxamide (1-108);N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-((2-chloro-7-methoxyquinolin-3- yl)methyl)-lH-pyrazole-4-carboxamide (1-109);N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-l-((7-methoxyquinolin-3-yl)methyl)-lH- pyrazole-4-carboxamide (1-110);N-(( 1 -amino-5 , 7-dimethy li soquinolin-6-yl)methy 1)- 1 -((7 -methoxy quinolin-3 -yl)methyl)- 1 H- pyrazole-4-carboxamide (1-111); l-((5-(lH-pyrazol-l-yl)naphthalen-2-yl)methyl)-N-((l -amino-5, 7-dimethylisoquinolin-6- yl)methyl)-lH-pyrazole-4-carboxamide (1-112);N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-((5-bromonaphthalen-2-yl)methyl)-lH- pyrazole-4-carboxamide (1-113);N-((l -amino-5, 7-dimethy lisoquinolin-6-yl)methyl)-l-((5-(pyridin-2-yl)naphthalen-2-yl)methyl)- lH-pyrazole-4-carboxamide (1-114);N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-((3-methylquinolin-6-yl)methyl)-lH- pyrazole-4-carboxamide (1-115);N-(( 1 -amino-5 , 7-dimethy li soquinolin-6-yl)methyl)- 1 -(4-(3 -fluoro-2-methoxybenzyl)benzyl)- 1 H- pyrazole-4-carboxamide (1-116);N-((l -amino-5, 7-dimethy lisoquinolin-6-yl)methyl)-l-(4-((4-methyl-4H-l, 2, 4-triazol-3- yl)methyl)benzyl)-lH-pyrazole-4-carboxamide (1-117);N-((l -amino-5, 7-dimethy lisoquinolin-6-yl)methyl)-l-(2-cyclopropylbenzyl)-lH-pyrazole-4- carboxamide (1-118);N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-(4-(l -(dimethylamino)- 1 -oxopropan-2- yl)benzyl)-lH-pyrazole-4-carboxamide (1-119);N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-(l-(3-chloroquinolin-6-yl)ethyl)-lH- pyrazole-4-carboxamide (1-120);N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-l-((5-cyclopropylpyrazolo[l,5-a]pyridin-2- yl)methyl)-lH-pyrazole-4-carboxamide (1-121 );N-(( 1 -amino-5 , 7-dimethy li soquinolin-6-y l)methy 1)- 1 -(4-( 1 -(pyrrolidine- 1 - carbonyl)cyclopropyl)benzyl)-lH-pyrazole-4-carboxamide (1-122);N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-((3-vinylquinolin-6-yl)methyl)-lH- pyrazole-4-carboxamide (1-123);N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-l-((3-ethylquinolin-6-yl)methyl)-lH- pyrazole-4-carboxamide (1-124);N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-l-((5-(2-oxopyridin-l(2H)-yl)naphthalen-2- yl)methyl)-lH-pyrazole-4-carboxamide (1-125);N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-l-((6-methoxyquinazolin-2-yl)methyl)-lH- pyrazole-4-carboxamide (1-126);(R)-N-((l-amino-5,7-dimethylisoquinolin-6-yl)rnethyl)-l-(l -phenylethyl)- lH-pyrazole-4- carboxamide (1-127);N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N-methyl-l-((6-methylimidazo[l,2- a]pyridin-2-yl)methyl)-lH-pyrazole-4-carboxamide (1-128);2-(4-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)carbamoyl)-lH-pyrazol-l-yl)-2-(6- methylimidazo[l,2-a]pyridin-2-yl)acetic acid (1-129);N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-l-(2-hydroxy-l-(6-methylimidazo[l,2- a]pyridin-2-yl)ethyl)-lH-pyrazole-4-carboxamide (1-130);2-(4-((4-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)carbamoyl)-lH-pyrazol-l- yl)methyl)phenyl)acetic acid (1-131); ethyl (6-((l-((3-chloroquinolin-6-yl)methyl)-lH-pyrazole-4-carboxamido)methyl)-5,7- dimethylisoquinolin- 1 -yl)carbamate (I- 132);N-((l-acetamido-5,7-dimethylisoquinolin-6-yl)methyl)-l-((3-chloroquinolin-6-yl)methyl)-lH- pyrazole-4-carboxamide (1-133);1-((6-cyclopropylimidazo[l,2-a]pyridin-2-yl)methyl)-N-((5,7-dimethyl-l- (methylamino)isoquinolin-6-yl)methyl)-lH-pyrazole-4-carboxamide (1-134);N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-l-((6-bromo-7-methylimidazo[l,2-a]pyridin-2-yl)methyl)-lH-pyrazole-4-carboxamide (1-135);N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-l-((5,6-dimethylimidazo[l,2-a]pyri din-2- yl)methyl)-lH-pyrazole-4-carboxamide (1-136);N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-l-((5-cy cl opropylimidazo[l,2-a]pyri din-2- yl)methyl)-lH-pyrazole-4-carboxamide (1-137);N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-l-((6-bromo-5-chloroimidazo[l,2-a]pyridin- 2-yl)methyl)-lH-pyrazole-4-carboxamide (1-138);N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-l-((5-bromoimidazo[l,2-a]pyri din-2- yl)methyl)-lH-pyrazole-4-carboxamide (1-139);N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-l-((5-ethylimidazo[l,2-a]pyridin-2- yl)methyl)-lH-pyrazole-4-carboxamide (1-140);N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-l-((6-chloro-5-ethylimidazo[l,2-a]pyri din-2- yl)methyl)- lH-pyrazole-4-carboxamide (1-141 );N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-l-((6-cyclopropyl-5-fluoroimidazo[l,2- a]pyridin-2-yl)methyl)-lH-pyrazole-4-carboxamide (1-142);N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-l-((5-cyanoimidazo[l,2-a]pyridin-2- yl)methyl)-lH-pyrazole-4-carboxamide (1-143);N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-l-((5-methoxyimidazo[l,2-a]pyri din-2- yl)methyl)- lH-pyrazole-4-carboxamide (I- 144);N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-l-((6-bromo-5-methylimidazo[l,2-a]pyridin- 2-yl)methyl)-lH-pyrazole-4-carboxamide (1-145);N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-l-((6-cyclopropyl-7-methylirnidazo[l,2- a]pyridin-2-yl)methyl)-lH-pyrazole-4-carboxamide (1-146);N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-l-((7-chloro-6-cyclopropylimidazo[l,2- a]pyridin-2-yl)methyl)-lH-pyrazole-4-carboxamide (1-147);N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-l-((5-chloro-6-cyclopropylimidazo[l,2- a]pyridin-2-yl)methyl)-lH-pyrazole-4-carboxamide (1-148);N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-l-((6-bromo-7-chloroimidazo[l,2-a]pyridin- 2-yl)methyl)-lH-pyrazole-4-carboxamide (1-149); l-((l,5-naphthyridin-2-yl)methyl)-N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-lH- pyrazole-4-carboxamide (1-150);N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-l-(3-chloro-4-(2-(dimethylamino)-2- oxoethyl)benzyl)-lH-pyrazole-4-carboxamide (1-151);N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-l-(4-(2-(dimethylamino)-2-oxoethyl)-3- (trifluoromethyl)benzyl)-lH-pyrazole-4-carboxamide (1-152);N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-l-((7-methylnaphthalen-2-yl)methyl)-lH- pyrazole-4-carboxamide (1-153);N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-(2-oxo-2-(phenylamino)ethyl)-lH- pyrazole-4-carboxamide (1-154);N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-l-(2-(methyl(phenyl)amino)-2-oxoethyl)-lH- pyrazole-4-carboxamide (1-155);N-((l -amino-5, 7-dimethy lisoquinolin-6-yl)methyl)-l-((7-bromoquinolin-2-yl)methyl)-lH- pyrazole-4-carboxamide (1-156);N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-((6-chloroquinolin-2-yl)methyl)-lH- pyrazole-4-carboxamide (1-157);N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-((6-fluoroquinolin-2-yl)methyl)-lH- pyrazole-4-carboxamide (1-158);N-((l -amino-5, 7-dimethy lisoquinolin-6-yl)methyl)-l-((8-bromoquinolin-2-yl)methyl)-lH- pyrazole-4-carboxamide (1-159);N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-l-benzyl-lH-pyrazole-4-carboxamide (I- 160);N-(( 1 -amino-5 , 7-dimethy li soquinolin-6-yl)methyl)-5-(methoxymethy 1)- 1 -((2-(pyrrolidin- 1 - yl)pyrimidin-5-yl)methyl)- lH-pyrazole-4-carboxamide (1-161 );N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-3-(methoxymethyl)-l-((2-(pyrrolidin-l- yl)pyrimidin-5-yl)methyl)-lH-pyrazole-4-carboxamide (1-162);N-((l -amino-5, 7-dimethy lisoquinolin-6-yl)methyl)- l-((3-chloroquinolin-6-yl)methyl)-lH- pyrazole-4-carboxamide (1-163);N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-((3-hydroxyquinolin-6-yl)methyl)-lH- pyrazole-4-carboxamide (1-164);N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l -(4-(pyridin-2-ylmethyl)benzyl)-lH- pyrazole-4-carboxamide (1-165);N-((l -amino-5, 7-dimethy lisoquinolin-6-yl )methyl)- l-(4-(thi azol-2-ylmethyl)benzyl)- 1H- pyrazole-4-carboxamide (1-166);N-((l -amino-5, 7-dimethy lisoquinolin-6-yl)methyl)-l-(4-(imidazo[l,2-a]pyri din-8- ylmethyl)benzyl)-lH-pyrazole-4-carboxamide (1-167);N-(( 1 -amino-5 , 7-dimethy li soquinolin-6-yl)methyl)- 1 -(4-(pyrimidin-2-ylmethyl)benzy 1)- 1 H- pyrazole-4-carboxamide (1-168);N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-l-(3,5-dimethyl-4-(pyridin-2- ylmethyl)benzyl)-lH-pyrazole-4-carboxamide (1-169);N-((l-amino-5,7,8-trimethylisoquinolin-6-yl)methyl)-l-benzyl-lH-pyrazole-4-carboxamide(I-170);N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-l-benzyl-lH-pyrazole-4-carboxamide (I-171);1 -((8 -(( 1 ,3 ,4-oxadiazol-2-yl)methyl)-6-cyclopropylimidazo[ 1 ,2-a]pyridin-2-yl)methyl)-N-((l - amino-5,7-dimethylisoquinolin-6-yl)methyl)-lH-pyrazole-4-carboxamide (1-172);N-((l -amino-7-ethyl-5-methylisoquinolin-6-yl)methyl)-l -benzyl- lH-pyrazole-4-carboxamide (I- 173);N-((l -amino-7-cy cl opropyl-5-methylisoquinolin-6-yl)methyl)-l -benzyl- lH-pyrazole-4- carboxamide (1-174);N-(( 1 -amino-5-methyl-7-( 1 -methylcyclopropyl)isoquinolin-6-yl)methyl)- 1 -benzyl- IH-pyrazole- 4-carboxamide (1-175);N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-l-((6-(2,2-dimethylcyclopropyl)imidazo[l,2- a]pyridin-2-yl)methyl)-lH-pyrazole-4-carboxamide (1-176);(Z)-N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-l-((6-(prop-l-en-l-yl)imidazo[l,2- a]pyridin-2-yl)methyl)-lH-pyrazole-3-carboxamide (1-177);N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-l-((6-(2-methylcyclopropyl)imidazo[l,2- a]pyridin-2-yl)methyl)-lH-pyrazole-4-carboxamide (1-178);N-(( 1 -amino-5,7-dimethylisoquinolin-6-yl)methyl)- 1 -((6-(2-methylprop- 1 -en- 1 -yl)imidazo[ 1 ,2- a]pyridin-2-yl)methyl)-lH-pyrazole-4-carboxamide (1-179); l-(2-amino-l-phenylethyl)-N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-lH-pyrazole-4- carboxamide (1-180); tert-butyl (2-(4-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)carbamoyl)-lH-pyrazol-l-yl)-2- phenylethyl)carbamate (1-181);1-(4-(2-(3-azabicyclo[3.1.0]hexan-3-yl)-2-oxoethyl)benzyl)-N-((l-amino-5,7- dimethylisoquinolin-6-yl)methyl)-3-(trifluoromethyl)-lH-pyrazole-4-carboxamide (1-182);2-(4-(( 1 H-pyrazol- 1 -yl)methyl)benzyl)-N-(( 1 -amino-5 ,7-dimethyli soquinolin-6- yl)methyl)isonicotinamide (1-183);N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-(4-((4-methyl-lH-pyrazol-l- yl)methyl)benzyl)-3-(trifluoromethyl)-lH-pyrazole-4-carboxamide (1-184); l-(4-((lH-pyrazol-l-yl)methyl)benzyl)-N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-3- (trifluoromethyl)- lH-pyrazole-4-carboxamide (1-185);N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-(4-((2-oxopyridin-l(2H)- yl)methyl)benzyl)-lH-l,2,3-triazole-4-carboxamide (1-186); l-(4-((lH-pyrazol-l-yl)methyl)benzyl)-N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-3-(methoxymethyl)-lH-pyrazole-4-carboxamide (1-187); l-(4-((lH-pyrazol-l-yl)methyl)benzyl)-N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-5-(methoxyrnethyl)-lH-pyrazole-4-carboxamide (1-188);N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-2-(6-cyclopropylimidazo[l,2-a]pyridine-2- carb ony l)i soni coti nami de (I- 189);N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-5-((6-cyclopropylimidazo[l,2-a]pyridin-2- yl)methyl)-l,3,4-oxadiazole-2-carboxamide (1-190);N-((l-amino-5,7,8-trimethylisoquinolin-6-yl)methyl)-l-((6-cyclopropylimidazo[l,2-a]pyridin-2- yl)methyl)- lH-pyrazole-4-carboxamide (1-191 );N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-(4-((2-oxopyridin-l(2H)- yl)methyl)benzyl)- lH-pyrazole-4-carboxamide (I- 192);N-(( 1 -amino-5 ,7-dimethylisoquinolin-6-yl)methyl)- 1 -((6-(pyrrolidin- 1 -yl)pyri din-3 -yl)methyl)- 5 -(trifluoromethyl)- 1 H-pyrazol e-4-carboxami de (1-193);N-(( 1 -amino-5 ,7-dimethylisoquinolin-6-yl)methyl)- 1 -((6-(pyrrolidin- 1 -yl)pyri din-3 -yl)methyl)- 3 -(trifluoromethyl)- lH-pyrazole-4-carboxamide (I- 194);N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-((2-phenylpyrimidin-5-yl)methyl)-lH- pyrazole-4-carboxamide (1-195);N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-(4-((2-oxo-l -(2,2, 2-trifluoroethyl)- 1,2- dihydropyridin-3-yl)methyl)benzyl)-lH-pyrazole-4-carboxamide (1-196);N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-2-((3-chloroquinolin-6- yl)methyl)i sonicotinamide (I- 197);N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-2-((6-cyclopropylimidazo[l,2-a]pyridin-2- yl)methyl)thiazole-5-carboxamide (1-198);N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-l-((6-cyclopropylimidazo[l,2-a]pyridin-2- yl)methyl)-3-(difluoromethyl)-lH-pyrazole-4-carboxamide (1-199);N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-l-(l-(3-chloroquinolin-6-yl)ethyl)-lH-l,2,3- triazole-4-carboxamide (1-200);N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-l-((6-(trifluoromethyl)imidazo[l,2-a]pyridin- 2-yl)methyl)-lH-pyrazole-4-carboxamide (1-201);N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-3-(aminomethyl)-l-benzyl-lH-pyrazole-5- carboxamide (1-202);N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-5-(aminomethyl)-l-benzyl-lH-pyrazole-3- carboxamide (1-203);N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-(4-(2-((cyclopropylmethyl)(methyl)amino)-2-oxoethyl)benzyl)-lH-pyrazole-4-carboxamide (1-204);N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-(4-(2-((lR,5S,6r)-6-methyl-3- azabicyclo[3.1.0]hexan-3-yl)-2-oxoethyl)benzyl)-lH-pyrazole-4-carboxamide (1-205);N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-(4-(2-((lR,5S,6s)-6-(fluoromethyl)-3- azabicyclo[3.1.0]hexan-3-yl)-2-oxoethyl)benzyl)-lH-pyrazole-4-carboxamide (1-206);N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-(4-(2-((lR,5S,6r)-6-(fluoromethyl)-3- azabicyclo[3.1.0]hexan-3-yl)-2-oxoethyl)benzyl)-lH-pyrazole-4-carboxamide (1-207);N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-(4-(2-((lR,5S,6r)-6-(hydroxymethyl)-3- azabicyclo[3.1.0]hexan-3-yl)-2-oxoethyl)benzyl)-lH-pyrazole-4-carboxamide (1-208);N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-(4-(2-((lR,5S,6s)-6-(hydroxymethyl)-3- azabicyclo[3.1.0]hexan-3-yl)-2-oxoethyl)benzyl)-lH-pyrazole-4-carboxamide (1-209);(lR,5S,6s)-3-(2-(4-((4-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)carbamoyl)-lH-pyrazol- l-yl)methyl)phenyl)acetyl)-3-azabicyclo[3.1.0]hexane-6-carboxylic acid (1-210); ethyl (lR,5S,6s)-3-(2-(4-((4-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)carbamoyl)-lH- pyrazol- 1 -yl)methyl)phenyl)acetyl)-3 -azabicyclo[3.1.0]hexane-6-carboxylate (1-211); ethyl ( 1 R, 5 S,6r)-3 -(2-(4-((4-((( 1 -amino-5 , 7 -dimethyli soquinolin-6-yl)methy l)carbamoy 1)- 1 H- pyrazol-l-yl)methyl)phenyl)acetyl)-3-azabicyclo[3.1.0]hexane-6-carboxylate (1-212);(1R, 5 S,6r)-3-(2-(4-((4-(((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)carbamoyl)-lH-pyrazol- l-yl)methyl)phenyl)acetyl)-3-azabicyclo[3.1.0]hexane-6-carboxylic acid (1-213);N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-(4-(2-(6,6-difluoro-3- azabicyclo[3.1.0]hexan-3-yl)-2-oxoethyl)benzyl)-lH-pyrazole-4-carboxamide (1-214); l-(4-(2-(3-azabicyclo[3.1.1]heptan-3-yl)-2-oxoethyl)benzyl)-N-((l-amino-5,7- dimethylisoquinolin-6-yl)methyl)-lH-pyrazole-4-carboxamide (1-215);3-(2-(4-((4-(((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)carbamoyl)-lH-pyrazol-l- yl)methyl)phenyl)acetyl)-3-azabicyclo[3.1.0]hexane-l-carboxylic acid (1-216); methyl 3-(2-(4-((4-(((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)carbamoyl)-lH-pyrazol-l- yl)methyl)phenyl)acetyl)-3 -azabicyclo[3.1 ,0]hexane- 1 -carboxylate (1-217);N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-(4-(2-(2,5-dimethylpyrrolidin-l-yl)-2- oxoethyl)benzyl)-lH-pyrazole-4-carboxamide (1-218);N-(( 1 -amino-5 ,7-dimethylisoquinolin-6-yl)methyl)- 1 -(4-(2-(azetidin- 1 -yl)-2-oxoethyl)benzyl)- lH-pyrazole-4-carboxamide (1-219);N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-(4-(2-(benzyl(methyl)amino)-2- oxoethyl)benzyl)-lH-pyrazole-4-carboxamide (1-220);N-((l -amino-5 ,7-dimethylisoquinolin-6-yl)methyl)- 1 -(4-(2-(bicyclo[ 1.1.1 ]pentan- 1 -ylamino)-2- oxoethyl)benzyl)-lH-pyrazole-4-carboxamide (1-221); l-(4-(2-(3-azabicyclo[3.1.0]hexan-3-yl)-2-oxoethyl)benzyl)-N-((l -amino-5, 7- dimethylisoquinolin-6-yl)methyl)-lH-pyrazole-4-carboxamide (1-222);N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-(4-(2-oxo-2-(piperi din- l-yl)ethyl)benzyl)- lH-pyrazole-4-carboxamide (1-223);N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-(4-(2-(cy cl opropyl(methyl)amino)-2- oxoethyl)benzyl)-lH-pyrazole-4-carboxamide (1-224);N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-(4-(2-morpholino-2-oxoethyl)benzyl)-lH- pyrazole-4-carboxamide (1-225);N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-(4-(2-(diethylamino)-2-oxoethyl)benzyl)- lH-pyrazole-4-carboxamide (1-226);N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)- l-(4-(2-oxo-2-(phenylamino)ethyl)benzyl)- lH-pyrazole-4-carboxamide (1-227);N-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-l-(4-(2-(methyl(phenyl)amino)-2- oxoethyl)benzyl)-lH-pyrazole-4-carboxamide (1-228);N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-l-(4-(2-(benzylamino)-2-oxoethyl)benzyl)- lH-pyrazole-4-carboxamide (1-229);N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-l-(4-(2-(methylamino)-2-oxoethyl)benzyl)- lH-pyrazole-4-carboxamide (1-230); l-(4-(2-amino-2-oxoethyl)benzyl)-N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-lH- pyrazole-4-carboxamide (1-231);N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-l-(4-(2-oxo-2-(pyrrolidin-l-yl)ethyl)benzyl)- lH-pyrazole-4-carboxamide (1-232);N4-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N6-(naphthalen-2-ylmethyl)pyrimidine-4,6- diamine (1-233);N4-(4-((lH-pyrazol-l-yl)methyl)benzyl)-N6-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-5- fluoropyrimidine-4,6-diamine (1-234);N5-(4-((lH-pyrazol-l-yl)methyl)benzyl)-N3-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N5- methylpyridazine-3,5-diamine (1-235); l-(4-(((6-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyridazin-4- yl)amino)methyl)benzyl)pyridin-2(lH)-one (1-236);1-(4-(((6-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimi din-4- yl)amino)methyl)benzyl)pyridin-2(lH)-one (1-237);6-(aminomethyl)-N-(4-((3-cyclopropylquinolin-6-yl)methoxy)pyridin-2-yl)-5,7- dimethylisoquinolin-1 -amine (1-238);6-(((4-((3-cyclopropylquinolin-6-yl)methoxy)pyridin-2-yl)amino)methyl)-5,7- dimethyli soquinolin- 1 -amine (1-239);N2-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N3-((6-cyclopropylimidazo[l,2-a]pyridin-2-yl)methyl)pyrazine-2, 3 -diamine (1-240);N4-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N6-((5-(pyridin-2-yl)naphthalen-2- yl)methyl)pyrimidine-4,6-diamine (1-241);N4-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N6-((6-cyclopropylimidazo[l,2-b]pyridazin- 2-yl)methyl)pyrimidine-4,6-diamine (1-242);N4-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N6-((5-cyclopropylthieno[2,3-b]pyri din-2- yl)methyl)pyrimidine-4,6-diamine (1-243);N4-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N6-((5-cyclopropylpyrazolo[l,5-a]pyridin-2- yl)methyl)pyrimidine-4,6-diamine (1-244);1-(6-(((6-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimidin-4- yl)amino)methyl)naphthalen-l-yl)pyridin-2(lH)-one (1-245);N4-((5-(lH-pyrazol-l-yl)naphthalen-2-yl)methyl)-N6-((l-amino-5,7-dimethylisoquinolin-6- yl)methyl)pyrimidine-4,6-diamine (1-246);N-(6,8-dimethyl-7-(((6-((4-((2-oxopyridin-l(2H)-yl)methyl)benzyl)amino)pyrimi din-4- yl)amino)methyl)isoquinolin-l-yl)acetamide (1-247); benzyl (6,8-dimethyl-7-(((6-((4-((2-oxopyridin-l(2H)-yl)methyl)benzyl)amino)pyrirnidin-4- yl)amino)methyl)isoquinolin-l-yl)carbamate (1-248); ethyl (5,7-dimethyl-6-(((6-((4-((2-oxopyridin-l(2H)-yl)methyl)benzyl)amino)pyrimidin-4- yl)amino)methyl)isoquinolin-l-yl)carbamate (1-249);3-(2-(((6-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimidin-4-yl)oxy)methyl)-6- cy cl opropylimidazo[l,2-a]pyridin-8-yl)ox etan-3 -ol (1-250);6-(((6-((4-((lH-pyrazol-l-yl)methyl)benzyl)oxy)pyrimidin-4-yl)amino)methyl)-5,7- dimethylisoquinolin-1 -amine (1-251);5,7-dimethyl-6-(((5-(naphthalen-2-ylmethoxy)pyridazin-3-yl)amino)methyl)isoquinolin-l-amine(1-252);6-(((3-((6-cyclopropylimidazo[l,2-a]pyridin-2-yl)methyl)-3H-[l,2,3]triazolo[4,5-c]pyridin-4- yl)amino)methyl)-5,7-dimethylisoquinolin-l -amine (1-253);6-(((l-((6-cyclopropylimidazo[l,2-a]pyridin-2-yl)methyl)-lH-[l,2,3]triazolo[4,5-c]pyridin-4- yl)amino)methyl)-5,7-dimethylisoquinolin-l -amine (1-254);6-(aminomethyl)-N-(6-((6-cyclopropylimidazo[l,2-a]pyridin-2-yl)methoxy)pyrimidin-4-yl)-5- methyl-7-(l-methylcyclopropyl)isoquinolin-l -amine (1-255);3-(2-(((6-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimidin-4-yl)oxy)methyl)-5- cyclopropylpyrazolo[l,5-a]pyridin-7-yl)oxazolidin-2-one (1-256);6-(((6-((6-cyclopropyl-8-(3,5-dimethyl-4H-l,2,4-triazol-4-yl)imidazo[l,2-a]pyridin-2- yl)methoxy)pyrimidin-4-yl)amino)methyl)-5,7-dimethylisoquinolin-l -amine (1-257);2-(((6-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimidin-4-yl)oxy)methyl)-6- cyclopropylimidazo[l,2-a]pyridine-8-carbonitrile (1-258);l-(2-(((6-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimidin-4-yl)oxy)methyl)-6- cyclopropylimidazo[l,2-a]pyridin-8-yl)pyrrolidin-2-one (1-259);6-(((2-(4-((lH-pyrazol-l-yl)methyl)benzyl)-2H-pyrazolo[3,4-c]pyridin-7-yl)amino)methyl)-5,7- dimethylisoquinolin- 1 -amine (1-260);6-(((6-((6-cyclopropylimidazo[l,2-b]pyridazin-2-yl)methoxy)pyrimidin-4-yl)amino)methyl)-5,7- dimethylisoquinolin-1 -amine (1-261);6-(((6-((6-cyclopropylimidazo[l,2-a]pyrimidin-2-yl)methoxy)pyrimidin-4-yl)amino)methyl)-5,7- dimethylisoquinolin-1 -amine (1-262);6-(((2-((6-cyclopropyl-[l,2,4]triazolo[l,5-a]pyridin-2-yl)methyl)-2H-pyrazolo[3,4-c]pyridin-7- yl)amino)methyl)-5,7-dimethylisoquinolin-l -amine (1-263);6-(((2-((6-cyclopropylimidazo[l,2-a]pyrimidin-2-yl)methyl)-2H-pyrazolo[3,4-c]pyridin-7- yl)amino)methyl)-5,7-dimethylisoquinolin-l -amine (1-264);6-(((2-((6-cyclopropylimidazo[l,2-b]pyridazin-2-yl)methyl)-2H-pyrazolo[3,4-c]pyridin-7- yl)amino)methyl)-5,7-dimethylisoquinolin-l -amine (1-265);6-(((l-((6-cyclopropylimidazo[l,2-a]pyridin-2-yl)methyl)-lH-pyrazolo[4,3-c]pyri din-4- yl)amino)methyl)-5,7-dimethylisoquinolin-l -amine (1-266);6-(((2-((6-cyclopropylimidazo[l,2-a]pyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4- yl)amino)methyl)-5,7-dimethylisoquinolin-l -amine (1-267);6-(((l -((6-cy cl opropylimidazo[l,2-a]pyridin-2-yl)methyl)-lH-pyrazolo[4,3-c]pyri din-6- yl)amino)methyl)-5,7-dimethylisoquinolin-l -amine (1-268);6-(((2-((6-cyclopropylimidazo[l,2-a]pyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-6- yl)amino)methyl)-5,7-dimethylisoquinolin-l -amine (1-269); ethyl 3-(2-(((6-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimidin-4- yl)oxy)methyl)-5-cyclopropylpyrazolo[l,5-a]pyridin-7-yl)propanoate (1-270);6-(((2-((6-cyclopropylimidazo[l,2-a]pyridin-2-yl)methyl)-2H-pyrazolo[3,4-c]pyridin-7- yl)amino)methyl)-5,7-dimethylisoquinolin-l -amine (1-271);6-(((6-((6-cyclopropyl-8-(3-fluorooxetan-3-yl)imidazo[l,2-a]pyridin-2-yl)methoxy)pyrimidin-4- yl)amino)methyl)-5,7-dimethylisoquinolin-l -amine (1-272);3-(2-(((6-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimidin-4-yl)oxy)methyl)-5- cyclopropylpyrazolo[l,5-a]pyridin-7-yl)propanoic acid (1-273);ethyl 3-(4-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)-6-((6- cyclopropylimidazo[l,2-a]pyridin-2-yl)methoxy)pyrimidin-2-yl)propanoate (1-274);6-(((5-(l-(4-((lH-pyrazol-l-yl)methyl)phenyl)ethoxy)pyridazin-3-yl)amino)methyl)-5,7- dimethylisoquinolin- 1 -amine (1-275);(R*)-6-(((5-(l-(4-((lH-pyrazol-l-yl)methyl)phenyl)ethoxy)pyridazin-3-yl)amino)methyl)-5,7- dimethylisoquinolin- 1 -amine (1-276);(S*)-6-(((5-(l-(4-((lH-pyrazol-l-yl)methyl)phenyl)ethoxy)pyridazin-3-yl)amino)methyl)-5,7- dimethylisoquinolin- 1 -amine (1-277);(S)-6-(((5-(l-(4-((lH-pyrazol-l-yl)methyl)phenyl)ethoxy)pyridazin-3-yl)amino)methyl)-5,7- dimethylisoquinolin- 1 -amine;(R)-6-(((5-(l-(4-((lH-pyrazol-l-yl)methyl)phenyl)ethoxy)pyridazin-3-yl)amino)methyl)-5,7- dimethylisoquinolin- 1 -amine;6-(((5-((4-(2-(lH-pyrazol-l-yl)ethyl)benzyl)oxy)pyridazin-3-yl)amino)methyl)-5,7- dimethylisoquinolin- 1 -amine (1-278);6-(((2-((6-cyclopropylimidazo[l,2-a]pyridin-2-yl)methoxy)pyridin-4-yl)amino)methyl)-5,7- dimethylisoquinolin- 1 -amine (1-279);6-(((5-chloro-4-((6-cyclopropylimidazo[l,2-a]pyridin-2-yl)methoxy)pyri din-2- yl)amino)methyl)-5,7-dimethylisoquinolin-l -amine (1-280);6-(((6-((5-cyclopropylthieno[2,3-b]pyridin-2-yl)methoxy)pyrimidin-4-yl)amino)methyl)-5,7- dimethylisoquinolin- 1 -amine (1-281);6-(((6-((5-cyclopropylbenzo[d]thiazol-2-yl)methoxy)pyrimidin-4-yl)amino)methyl)-5,7- dimethylisoquinolin- 1 -amine (1-282);6-(((l-((5-cyclopropylthieno[2,3-b]pyridin-2-yl)methyl)-lH-pyrrolo[3,2-c]pyridin-6- yl)amino)methyl)-5,7-dimethylisoquinolin-l -amine (1-283);6-(((4-((6-cyclopropylimidazo[l,2-a]pyridin-2-yl)methoxy)pyridin-2-yl)amino)methyl)-5,7- dimethylisoquinolin-1 -amine (1-284);6-((( 1 -((6-cy clopropylimidazof 1 ,2-a]pyri din-2 -yl)methyl)-3 -fluoro- lH-pyrrolo[3 ,2-c]pyridin-6- yl)amino)methyl)-5,7-dimethylisoquinolin-l -amine (1-285);6-(((l-((5-cyclopropylthieno[2,3-b]pyridin-2-yl)methyl)-3-fluoro-lH-pyrrolo[3,2-c]pyridin-6- yl)amino)methyl)-5,7-dimethylisoquinolin-l -amine (1-286);6-(((3-((6-cyclopropylimidazo[l,2-a]pyridin-2-yl)methoxy)pyrazin-2-yl)amino)rnethyl)-5,7- dimethylisoquinolin- 1 -amine (1-287);N4-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N5-((6-cyclopropylimidazo[l,2-a]pyridin-2- yl)methyl)pyrimidine-4,5-diamine (1-288);6-(((3-((6-cyclopropylimidazo[l,2-a]pyridin-2-yl)methoxy)pyridin-2-yl)amino)methyl)-5,7- dimethylisoquinolin- 1 -amine (1-289);6-(((6-(((6-cyclopropylimidazo[l,2-a]pyridin-2-yl)methyl)thio)pyrimidin-4-yl)amino)methyl)-5.7 -dimethyli soquinolin- 1 -amine (1-290); ethyl 3-(4-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)-6-((6- cyclopropylimidazo[l,2-a]pyrimidin-2-yl)methoxy)pyrimidin-2-yl)propanoate (1-291); ethyl 3-(4-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)-6-((6-cyclopropyl-[1.2.4]triazolo[l,5-a]pyridin-2-yl)methoxy)pyrimidin-2-yl)propanoate (1-292);3-(4-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)-6-((6-cyclopropylimidazo[l,2- a]pyridin-2-yl)methoxy)pyrimidin-2-yl)propanoic acid (1-293);3-(4-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)-6-((6-cyclopropylimidazo[l,2- a]pyrimidin-2-yl)methoxy)pyrimidin-2-yl)propanoic acid (1-294);3-(4-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)-6-((6-cyclopropyl-[1.2.4]triazolo[l,5-a]pyridin-2-yl)methoxy)pyrimidin-2-yl)propanoic acid (1-295); l-(4-(((6-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimi din-4- yl)oxy)methyl)phenyl)pyridin-2(lH)-one (1-296);5.7-dimethyl-6-(((6-((4-((l -methyl- lH-pyrazol-3-yl)methyl)benzyl)oxy)pyrimi din-4- yl)amino)methyl)isoquinolin-l -amine, formic acid salt (1-297);5.7-dimethyl-6-(((6-((4-((l -methyl- lH-pyrazol-3-yl)methyl)benzyl)oxy)pyrimidin-4- yl)amino)methyl)isoquinolin-l -amine;5.7-dimethyl-6-(((6-((2-(pyrrolidin-l-yl)pyrimidin-5-yl)methoxy)pyrimidin-4- yl)amino)methyl)isoquinolin-l -amine (1-298);3-(4-(((6-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimi din-4- yl)oxy)methyl)benzyl)-l-methylpyridin-2(lH)-one (1-299);6-(((6-((6-((lH-pyrazol-l-yl)methyl)pyridin-3-yl)methoxy)pyrimidin-4-yl)amino)methyl)-5,7- dimethylisoquinolin- 1 -amine (1-300);l-(4-(((6-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimi din-4- yl)oxy)methyl)benzyl)pyridin-2(lH)-one (1-301);4-(4-(((6-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimidin-4- yl)oxy)methyl)benzyl)morpholin-3-one, trifluoroacetic acid salt (1-302);4-(4-(((6-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimi din-4- yl)oxy)methyl)benzyl)morpholin-3-one; l-(4-(((6-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimi din-4- yl)oxy)methyl)benzyl)-3-cyclopropylpyridin-2(lH)-one, formic acid salt (1-303); l-(4-(((6-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimi din-4- yl)oxy)methyl)benzyl)-3-cyclopropylpyridin-2(lH)-one;6-(((6-((6-chloro-5-methylimidazo[l,2-a]pyridin-2-yl)methoxy)pyrimidin-4-yl)amino)methyl)- 5,7-dimethylisoquinolin-l -amine (1-304);6-(((6-((6-cyclopropylimidazo[l,2-a]pyridin-2-yl)methoxy)pyrimidin-4-yl)amino)methyl)-5,7- dimethylisoquinolin- 1 -amine (1-305);N4-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N6-(quinolin-2-ylmethyl)pyrimidine-4,6- diamine (1-306);N4-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N6-((6-methoxyquinolin-2- yl)methyl)pyrimidine-4,6-diamine (1-307);N4-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N6-methyl-N6-(quinolin-6- ylmethyl)pyrimidine-4,6-diamine (1-308);N4-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N6-((3-chloroquinolin-6- yl)methyl)pyrimidine-4,6-diamine (1-309);N4-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N6-(l-(3-chloroquinolin-6- yl)ethyl)pyrimidine-4,6-diamine (1-310);N4-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N6-((3-methylquinolin-7- yl)methyl)pyrimidine-4,6-diamine (1-311);N4-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N6-((3-(trifluoromethyl)quinolin-6- yl)methyl)pyrimidine-4,6-diamine (1-312);N4-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N6-((6-chloroimidazo[l,2-a]pyri din-2- yl)methyl)pyrimidine-4,6-diamine, formic acid salt (1-313);N4-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N6-((6-chloroimidazo[l,2-a]pyridin-2- yl)methyl)pyrimidine-4,6-diamine;N4-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N6-((3-cyclopropylquinolin-6- yl)methyl)pyrimidine-4,6-diamine (1-314);N4-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N6-(isoquinolin-3-ylmethyl)pyrimidine-4,6- diamine (1-315);N4-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N6-methyl-N6-(quinolin-3- ylmethyl)pyrimidine-4,6-diamine (1-316);N4-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N6-(quinolin-3-ylmethyl)pyrimidine-4,6- diamine, formic acid salt (1-317);N4-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N6-(quinolin-3-ylmethyl)pyrimidine-4,6- di amine;N4-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N6-((6-methoxynaphthalen-2-yl)methyl)-N6- methylpyrimidine-4,6-diamine (1-318);N4-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N6-(benzo[d]thiazol-2-ylmethyl)pyrimidine- 4,6-diamine (1-319);N4-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N6-(isoquinolin-6-ylmethyl)pyrimidine-4,6- diamine (1-320);N4-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N6-(imidazo[l,2-a]pyridin-2- ylmethyl)pyrimidine-4,6-diamine (1-321);N4-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N6-((7-methylimidazo[l,2-a]pyridin-2- yl)methyl)pyrimidine-4,6-diamine (1-322);N4-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N6-((4-methoxyquinolin-6- yl)methyl)pyrimidine-4,6-diamine (1-323);N4-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N6-((4-methylquinolin-6- yl)methyl)pyrimidine-4,6-diamine (1-324);N4-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N6-((6,7-dimethylquinolin-3- yl)methyl)pyrimidine-4,6-diamine (1-325);N4-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N6-((4-methyl-3,4-dihydro-2H- benzo[b][l,4]oxazin-7-yl)methyl)pyrimidine-4,6-diamine, formic acid salt (1-326);N4-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-N6-((4-methyl-3,4-dihydro-2H- benzo[b][l,4]oxazin-7-yl)rnethyl)pyrimidine-4,6-diamine;6-(((6-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimidin-4-yl)amino)methyl)-4- methyl-2H-benzo[b][l,4]oxazin-3(4H)-one, formic acid salt (1-327);6-(((6-((( 1 -amino-5 , 7 -dimethyli soquinolin-6-yl)methyl)amino)pyrimidin-4-y l)amino)methyl)-4- methyl-2H-benzo[b][l,4]oxazin-3(4H)-one;N4-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-N6-((5-chloroisoquinolin-3- yl)methyl)pyrimidine-4,6-diamine, formic acid salt (1-328);N4-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-N6-((5-chloroisoquinolin-3- yl)methyl)pyrimidine-4,6-diamine;N4-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-N6-((6-(trifluoromethyl)imidazo[ 1,2- a]pyridin-2-yl)methyl)pyrimidine-4,6-diamine (1-329);N4-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-N6-((6-chloro-5-methylimidazo[ 1,2- a]pyridin-2-yl)methyl)pyrimidine-4,6-diamine (1-330);N4-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-N6-((6-cyclopropylimidazo[l,2-a]pyri din-2- yl)methyl)pyrimidine-4,6-diamine (1-331);2-(((6-((( 1 -amino-5, 7-dimethylisoquinolin-6-yl)methyl)amino)pyrimidin-4- yl)amino)methyl)imidazo[l,2-a]pyridine-6-carbonitrile (1-332) ;N4-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-N6-((6-methylimidazo[l,2-a]pyri din-2- yl)methyl)pyrimidine-4,6-diamine (1-333);N4-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-N6-((3-fluoroquinolin-6- yl)methyl)pyrimidine-4,6-diamine (1-334);N4-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-N6-((2-methylquinolin-6- yl)methyl)pyrimidine-4,6-diamine (1-335);N4-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-N6-((3-methylquinolin-6- yl)methyl)pyrimidine-4,6-diamine (1-336);N4-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-N6-(quinolin-6-ylmethyl)pyrimidine-4, 6- diamine (1-337);N4-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-N6-(4-(pyrazin-2- ylmethyl)benzyl)pyrimidine-4,6-diamine (1-338);N4-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N6-(4-cyclopropylbenzyl)pyrimidine-4,6- diamine (1-339);N4-(4-((lH-pyrazol-l-yl)methyl)benzyl)-N6-((l-amino-5,7-dimethylisoquinolin-6- yl)methyl)pyrimidine-4,6-diamine (1-340);N4-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N6-benzylpyrimidine-4,6-diamine (1-341);N4-(( 1 -amino-5,7-dimethylisoquinolin-6-yl)methyl)-N6-(4-(( 1 -methyl- 1 H- 1 ,2,4-triazol-5- yl)methyl)benzyl)pyrimidine-4,6-diamine (1-342);N4-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N6-(4-((5-methyl-l,3,4-thiadiazol-2- yl)methyl)benzyl)pyrimidine-4,6-diamine (1-343);2-(4-(((6-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimi din-4- yl)amino)methyl)phenoxy)-l-(3-azabicyclo[3.1.0]hexan-3-yl)ethan-l-one, formic acid salt (I- 344);2-(4-(((6-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimi din-4- yl)amino)methyl)phenoxy)-l-(3-azabicyclo[3. 1.0]hexan-3-yl)ethan-l-one;2-(4-(((6-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimi din-4- yl)amino)methyl)phenoxy)-l-(pyrrolidin-l-yl)ethan-l-one (1-345);2-(4-(((6-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimi din-4- yl)amino)methyl)phenoxy)- 1 -(piperidin- 1 -yl)ethan- 1 -one (1-346);2-(4-(((6-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimi din-4- yl)amino)methyl)phenoxy)-l-(azetidin-l-yl)ethan-l-one, formic acid salt (1-347);2-(4-(((6-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimi din-4- yl)amino)methyl)phenoxy )- 1 -(azetidin- 1 -yl)ethan- 1 -one;2-(4-(((6-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimidin-4-yl)amino)methyl)- 2,6-dimethylphenoxy)-N,N-dimethylacetamide (1-348);N4-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N6-(4-(pyridin-2- ylmethoxy)benzyl)pyrimidine-4,6-diamine, formic acid salt (1-349);N4-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N6-(4-(pyridin-2- ylmethoxy)benzyl)pyrimidine-4,6-di amine;N4-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N6-(4-(thiazol-4- ylmethyl)benzyl)pyrimidine-4,6-diamine (1-350);N4-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N6-(4-(oxazol-2- ylmethoxy)benzyl)pyrimidine-4,6-diamine (1-351);2-(4-(((6-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimidin-4- yl)amino)methyl)phenoxy)-2,2-difluoro-N,N-dimethylacetamide (1-352);N4-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N6-(3,5-dimethyl-4-(pyri din-2- ylmethoxy)benzyl)pyrimidine-4,6-diamine, formic acid salt (1-353);N4-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N6-(3,5-dimethyl-4-(pyridin-2- ylmethoxy)benzyl)pyrimidine-4,6-diamine;2-(4-(((6-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimi din-4- yl)amino)methyl)phenoxy)-N,N,2-trimethylpropanamide, formic acid salt (1-354);2-(4-(((6-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimi din-4- yl)amino)methyl)phenoxy)-N,N,2-trimethylpropanamide;N4-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N6-(3,5-dimethyl-4-(thiazol-2- ylmethoxy)benzyl)pyrimidine-4,6-diamine (1-355);N4-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N6-(4-(thiazol-2- ylmethoxy)benzyl)pyrimidine-4,6-diamine (1-356); l-(4-(((6-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimi din-4- yl)amino)methyl)phenoxy)-N,N-dimethylcyclopropane-l-carboxamide, formic acid salt (1-357)1-(4-(((6-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimi din-4- yl)amino)methyl)phenoxy)-N,N-dimethylcyclopropane-l -carboxamide;N4-(4-((lH-pyrazol-3-yl)methyl)benzyl)-N6-((l-amino-5,7-dimethylisoquinolin-6- yl)methyl)pyrimidine-4,6-diamine (1-358);2-(4-(((6-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimidin-4-yl)amino)methyl)-2.6-dimethylphenyl)- 1 -(3 -azabicy clo[3.1.0]hexan-3 -yl)ethan- 1 -one (1-359);2-(4-(((6-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimidin-4-yl)amino)methyl)-2.6-dimethylphenyl)-N,N-dimethylacetamide (1-360);N4-((l -amino-5,7-dimethylisoquinolin-6-yl)methyl)-N6-(4-(pyri din-2 -yloxy )benzyl)pyrimidine-4.6-diamine (1-361);N4-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N6-(4-(thiazol-2- ylmethyl)benzyl)pyrimidine-4,6-diamine (1-362);N4-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-N6-(4-(pyridin-2- ylmethyl)benzyl)pyrimidine-4,6-diamine (1-363);N4-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-N6-(4-((4-methylpyridin-2- yl)methyl)benzyl)pyrimidine-4,6-diamine (1-364);N4-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-N6-(4-((3-chloropyridin-2- yl)methyl)benzyl)pyrimidine-4,6-diamine (1-365);N4-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N6-(l-(4-(pyridin-2- ylmethyl)phenyl)ethyl)pyrimidine-4,6-diamine (1-366);N4-(4-((lH-pyrazol-l-yl)methyl)-3,5-dimethylbenzyl)-N6-((l-amino-5,7-dimethylisoquinolin-6- yl)methyl)pyrimidine-4,6-diamine (1-367);N4-(( 1 -amino-5 , 7-dimethyli soquinolin-6-yl)methyl)-N6-(3 , 5 -dimethyl-4-(pyridin-2- ylmethyl)benzyl)pyrimidine-4,6-diamine (1-368);N4-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-N6-(4-((5-chloropyridin-2- yl)methyl )benzyl )py rimidine-4, 6-diamine (1-369); l-(3-(((6-(((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)amino)pyrimi din-4- yl)oxy)methyl)phenyl)pyridin-2(lH)-one (1-370);5.7-dimethyl-6-(((6-((2-methylquinolin-6-yl)methoxy)pyrimidin-4-yl)amino)methyl)isoquinolin- 1 -amine (1-371);5.7-dimethyl-6-(((6-((6-methylquinolin-3-yl)methoxy)pyrimidin-4-yl)amino)methyl)isoquinolin- 1-amine (1-372);6-(((6-((3-chloroquinolin-6-yl)methoxy)pyrimidin-4-yl)amino)methyl)-5,7-dimethylisoquinolin-1 -amine (1-373);5.7-dimethyl-6-(((6-(quinolin-6-ylmethoxy)pyrimidin-4-yl)amino)methyl)isoquinolin-l -amine (1-374);2-(4-(((6-(((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)amino)pyrimidin-4- yl)amino)methyl)phenyl)-N,N-dimethylacetamide (1-375);N5-(4-((lH-pyrazol-l-yl)methyl)benzyl)-N3-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)- l,2,4-triazine-3,5-diamine (1-376);2-(4-(((6-(((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)amino)pyrimidin-4- yl)amino)methyl)phenoxy)-N,N-dimethylacetamide (1-377);2-(4-(((6-(((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)amino)pyrimi din-4- yl)amino)methyl)phenyl)- 1 -(3 -azabicy clo[3.1.0]hexan-3 -y l)ethan- 1 -one (1-378);N4-(4-((lH-pyrazol-l-yl)methyl)-2-fluorobenzyl)-N6-((l -amino-5, 7-dimethylisoquinolin-6- yl)methyl)pyrirnidine-4,6-diamine (1-379);N4-(4-(( IH-pyrazol- 1 -yl)methyl)-2-(trifluoromethyl)benzyl)-N6-(( 1 -amino-5, 7- dimethylisoquinolin-6-yl)methyl)pyrimidine-4,6-diamine (1-380) ;N-(4-((lH-pyrazol-l-yl)methyl)-2-(trifluoromethyl)benzyl)-N-(6-(((l -amino-5, 7- dimethylisoquinolin-6-yl)methyl)amino)pyrimidin-4-yl)nitrous amide (1-381);N4-((l -amino-5, 7-dimethylisoquinolin-6-yl)methyl)-N6-(4-(difluoro(lH-pyrazol- 1- yl)methyl)benzyl)pyrimidine-4,6-diamine (1-382);N4-(4-((lH-pyrazol- l-yl)methyl)-3-(trifluoromethyl)benzyl)-N6-((l -amino-5, 7- dimethylisoquinolin-6-yl)methyl)pyrimidine-4,6-diamine (1-383);6-(((6-((6-cyclopropyl-[l,2,4]triazolo[l,5-a]pyrimidin-2-yl)methoxy)pyrimidin-4- yl)amino)methyl)-5,7-dimethylisoquinolin-l -amine (1-384);N5-(4-((lH-pyrazol- l-yl)methyl)-2-fluorobenzyl)-N3-((l -amino-5, 7-dimethylisoquinolin-6- yl)methy l)py ridazine-3 , 5 -diamine (1-385);6-(((6-((3-cyclopropylquinolin-6-yl)methoxy)pyrimidin-4-yl)amino)methyl)-5,7- dimethylisoquinolin- 1 -amine (1-386);6-(((6-((6-cyclopropylquinolin-3-yl)methoxy)pyrimidin-4-yl)amino)methyl)-5,7- dimethylisoquinolin-1 -amine (1-387);6-(((6-((6-cyclopropyl-[l,2,4]triazolo[l,5-a]pyridin-2-yl)methoxy)pyrimidin-4- yl)amino)methyl)-5,7-dimethylisoquinolin-l -amine (1-388);6-(((6-((6-cyclopropylimidazo[l,2-b]pyridazin-2-yl)methoxy)-2-(trifluoromethyl)pyrimidin-4- yl)amino)methyl)-5,7-dimethylisoquinolin-l -amine (1-389);6-(((6-((6-cyclopropylimidazo[l,2-a]pyridin-2-yl)methoxy)pyrimidin-4-yl)amino)methyl)-5- methyl-7-(l -methylcy cl opropyl)isoquinolin-l -amine (1-390);6-(((6-((6-cyclopropyl-[l,2,4]triazolo[l,5-b]pyridazin-2-yl)methoxy)pyrimidin-4- yl)amino)methyl)-5,7-dimethylisoquinolin-l -amine (1-391);6-(((2-((6-cyclopropylimidazo[l,2-a]pyrimidin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4- yl)amino)methyl)-5,7-dimethylisoquinolin-l -amine (1-392);6-(((l-((6-cyclopropylimidazo[l,2-a]pyrimidin-2-yl)methyl)-lH-pyrazolo[4,3-c]pyridin-4- yl)amino)methyl)-5,7-dimethylisoquinolin-l -amine (1-393);6-(((6-((6-cyclopropyl-8-(pyrrolidin-l-ylmethyl)imidazo[l,2-b]pyridazin-2- yl)methoxy)pyrimidin-4-yl)amino)methyl)-5,7-dimethylisoquinolin-l -amine (1-394);6-(((6-((5-cyclopropylbenzo[b]thiophen-2-yl)methoxy)pyrimidin-4-yl)amino)methyl)-5,7- dimethylisoquinolin-1 -amine (1-395); ethyl 3-(2-(((6-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimidin-4- yl)oxy)methyl)-5-cyclopropylpyrazolo[l,5-a]pyridin-7-yl)-2,2-dimethylpropanoate (1-396);2-(((6-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimidin-4-yl)oxymethyl)-6- cyclopropylimidazo[l,2-c]pyrimidin-5(6H)-one (1-397);6-(((6-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimidin-4-yl)oxy)methyl)-3- chloroquinoline-8-carbonitrile (1-398);6-(((6-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimidin-4-yl)oxy)methyl)-8- butyl-3 -chloroquinoline 1 -oxide (1-399);6-(((6-((5-cyclopropylpyrazolo[l,5-a]pyridin-2-yl)methoxy)pyrimidin-4-yl)amino)methyl)-5,7- dimethylisoquinolin- 1 -amine (1-400);6-(((6-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimidin-4-yl)oxy)methyl)-3- chloroquinoline-8-carboxamide (1-401);6-(((6-((8-butyl-3-chloroquinolin-6-yl)methoxy)pyrimidin-4-yl)amino)methyl)-5,7- dimethylisoquinolin-1 -amine (1-402);6-(((6-((6-cyclopropylimidazo[l,2-a]pyridin-2-yl)methyl)pyrimidin-4-yl)amino)methyl)-5,7- dimethylisoquinolin- 1 -amine (1-403);6-(((6-((6-cy cl opropylimidazo[l,2-a]pyri din-2 -yl)difluoromethyl)pyrimidin-4-yl)amino)methyl)-5.7 -dimethyli soquinolin- 1 -amine (1-404);6-(((6-((6-cyclopropylimidazo[l,2-a]pyridin-2-yl)fluoromethyl)pyrimidin-4-yl)amino)methyl)-5.7-dimethylisoquinolin-l -amine (1-405);(6-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimidin-4-yl)(6- cyclopropylimidazofl ,2-a]pyridin-2-yl)methanol (1-406);6-(((5-((3-chloroquinolin-6-yl)methoxy)pyridazin-3-yl)amino)methyl)-5,7-dimethylisoquinolin- 1 -amine (1-407);5.7-dimethyl-6-(((5-((6-methylquinolin-3-yl)methoxy)pyridazin-3-yl)amino)methyl)isoquinolin- 1 -amine (1-408);5.7-dimethyl-6-(((5-(quinolin-6-ylmethoxy)pyridazin-3-yl)amino)methyl)isoquinolin-l-amine (I- 409);6-(((5-(imidazo[l,2-a]pyridin-6-ylmethoxy)pyridazin-3-yl)amino)methyl)-5,7- dimethylisoquinolin- 1 -amine (1-410);6-(((5-(imidazo[l,2-a]pyridin-2-ylmethoxy)pyridazin-3-yl)amino)methyl)-5,7- dimethylisoquinolin- 1 -amine (1-411);5.7-dimethyl-6-(((5-((2-methylquinolin-6-yl)methoxy)pyridazin-3-yl)amino)methyl)isoquinolin- 1 -amine (1-412);5.7-dimethyl-6-(((5-((l -methyl- lH-indazol-5-yl)methoxy)pyridazin-3- yl)amino)methyl)isoquinolin- 1 -amine (1-413);6-(((5-(imidazo[l,2-a]pyridin-3-ylmethoxy)pyridazin-3-yl)amino)methyl)-5,7- dimethylisoquinolin- 1 -amine (1-414);6-(((5-((6-fluoroquinolin-3-yl)methoxy)pyridazin-3-yl)amino)methyl)-5,7-dimethylisoquinolin-1 -amine (1-415);5.7-dimethyl-6-(((5-((3-methylquinolin-6-yl)methoxy)pyridazin-3-yl)amino)methyl)isoquinolin- 1 -amine (1-416);6-(((5-((5-chlorobenzo[b]thiophen-2-yl)methoxy)pyridazin-3-yl)amino)methyl)-5,7- dimethylisoquinolin- 1 -amine formic acid salt (1-417);6-(((5-((5-chlorobenzo[b]thi ophen-2 -yl)methoxy)pyridazin-3-yl)amino)methyl)-5, 7- dimethylisoquinolin-1 -amine6-(((5-((2,3-dimethylquinoxalin-6-yl)methoxy)pyridazin-3-yl)amino)methyl)-5,7- dimethylisoquinolin- 1 -amine formic acid salt (1-418);6-(((5-((2,3-dimethylquinoxalin-6-yl)methoxy)pyridazin-3-yl)amino)methyl)-5,7- dimethylisoquinolin- 1 -amine5.7-dimethyl-6-(((5-(l-(3-methylquinolin-6-yl)ethoxy)pyridazin-3-yl)amino)methyl)isoquinolin- 1 -amine (1-419);6-(((5-(l-(3-chloroquinolin-6-yl)ethoxy)pyridazin-3-yl)amino)methyl)-5,7-dimethylisoquinolin- 1 -amine formic acid salt (1-420);6-(((5-(l-(3-chloroquinolin-6-yl)ethoxy)pyridazin-3-yl)amino)methyl)-5,7-dimethylisoquinolin- 1 -amine;5,7-dimethyl-6-(((5-((4-methylquinolin-6-yl)methoxy)pyridazin-3-yl)amino)methyl)isoquinolin- 1 -amine formic acid salt (1-421);5.7-dimethyl-6-(((5-((4-methylquinolin-6-yl)methoxy)pyridazin-3-yl)amino)methyl)isoquinolin- 1 -amine;6-(((5-((3-cyclopropylquinolin-6-yl)methoxy)pyridazin-3-yl)amino)methyl)-5,7- dimethylisoquinolin- 1 -amine (1-422);5.7-dimethyl-6-(((5-((3-(trifluoromethyl)quinolin-6-yl)methoxy)pyridazin-3- yl)amino)methyl)isoquinolin-l -amine (1-423);5.7-dimethyl-6-(((5-((6-(trifluoromethyl)imidazo[l,2-a]pyridin-2-yl)methoxy)pyridazin-3- yl)amino)methyl)isoquinolin-l -amine (1-424);5.7-dimethyl-6-(((5-((6-methylimidazo[l,2-a]pyridin-2-yl)methoxy)pyridazin-3- yl)amino)methyl)isoquinolin-l -amine (1-425);6-(((5-((6-cyclopropylimidazo[l,2-a]pyridin-2-yl)methoxy)pyridazin-3-yl)amino)methyl)-5,7- dimethylisoquinolin- 1 -amine formic acid salt (1-426);6-(((5-((6-cyclopropylimidazo[l,2-a]pyridin-2-yl)methoxy)pyridazin-3-yl)amino)methyl)-5,7- dimethylisoquinolin- 1 -amine;3-(4-(((6-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyridazin-4- yl)oxy)methyl)phenoxy)-l-methylpyridin-2(lH)-one (1-427);N3-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N5-methyl-N5-(quinolin-6- ylmethyl)pyridazine-3,5-diamine (1-428);6-(((5-(l-(4-((lH-pyrazol-l-yl)methyl)phenyl)ethoxy)pyridazin-3-yl)amino)methyl)-5,7- dimethylisoquinolin- 1 -amine (1-429);5.7-dimethyl-6-(((5-((2-phenylthiazol-4-yl)methoxy)pyridazin-3-yl)amino)methyl)isoquinolin-l- amine (1-430);6-(((5-((4-((3-cyclopropyl-lH-pyrazol-l-yl)methyl)benzyl)oxy)pyridazin-3-yl)amino)methyl)-5.7-dimethylisoquinolin-l -amine (1-431);6-(((5 -((4-(( 1 H-pyrazol- 1 -yl)methyl)benzyl)oxy)py ridazin-3 -yl)amino)methyl)-5 , 7 - dimethylisoquinolin- 1 -amine (1-432);l-(4-(((6-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyridazin-4- yl)oxy)methyl)benzyl)piperidin-2-one (1-433);4-(4-(((6-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyridazin-4- yl)oxy)methyl)benzyl)morpholin-3-one (1-434); l-(3-(((6-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyridazin-4- yl)oxy)methyl)phenyl)pyridin-2(lH)-one (1-435); l-(4-(((6-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyridazin-4- yl)oxy)methyl)benzyl)pyridin-2(lH)-one (1-436); l-(4-(((6-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyridazin-4- yl)oxy)methyl)benzyl)-3-cyclopropylpyridin-2(lH)-one (1-437); l-(4-(((6-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyridazin-4- yl)oxy)methyl)phenyl)pyridin-2(lH)-one (1-438);5.7-dimethyl-6-(((5-((4-((l -methyl- lH-pyrazol-3-yl)methyl)benzyl)oxy)pyridazin-3- yl)amino)methyl)isoquinolin-l -amine (1-439);3-(4-(((6-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyridazin-4- yl)oxy)methyl)benzyl)-l-methylpyridin-2(lH)-one (1-440);6-(((5-((4-(lH-imidazol-l-yl)benzyl)oxy)pyridazin-3-yl)amino)methyl)-5,7-dimethylisoquinolin- 1 -amine formate (1-441);6-(((5-((4-(lH-imidazol-l-yl)benzyl)oxy)pyridazin-3-yl)amino)methyl)-5,7-dimethylisoquinolin- 1 -amine;5.7 -dimethyl-6-(((5 -(( 1 -phenyl- 1 H-pyrazol-4-yl)methoxy)pyridazin-3 - yl)amino)methyl)isoquinolin- 1 -amine (1-442);6-(((5-(benzyloxy)pyridazin-3-yl)amino)methyl)-5,7-dimethylisoquinolin-l -amine (1-443);6-(((5-((4-(imidazo[l,2-a]pyridin-8-ylmethyl)benzyl)oxy)pyridazin-3-yl)amino)methyl)-5,7- dimethylisoquinolin- 1 -amine (1-444);6-(((5-((6-((lH-pyrazol-l-yl)methyl)pyridin-3-yl)methoxy)pyridazin-3-yl)amino)methyl)-5,7- dimethylisoquinolin-1 -amine (1-445);6-(((5-((5-((lH-pyrazol-l-yl)methyl)pyridin-2-yl)methoxy)pyridazin-3-yl)amino)methyl)-5,7- dimethylisoquinolin-1 -amine (1-446);N5-(4-((lH-pyrazol-l-yl)methyl)benzyl)-N3-((l-amino-5,7-dimethylisoquinolin-6- yl)methyl)pyridazine-3,5-diamine (1-447);N3-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N5-benzylpyridazine-3,5-diamine (1-448); 6-(((6-(benzyloxy)pyrimidin-4-yl)amino)methyl)-5,7-dimethylisoquinolin-l -amine (1-449); 6-(((5-((4-((lH-pyrazol-l-yl)methyl)benzyl)oxy)-6-(trifluoromethyl)pyridazin-3- yl)amino)methyl)-5,7-dimethylisoquinolin-l -amine (1-450);N5-(4-((lH-pyrazol-l-yl)methyl)benzyl)-N3-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-6- (trifluoromethyl)pyridazine-3,5-diamine (1-451);6-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)-4-((quinolin-6- ylmethyl)amino)pyridazine-3 -carboxamide (1-452);2-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyridin-4-yl)(6- cy cl opropylimidazo[l,2-a]pyri din-2 -yl)m ethanol (1-453);6-(((4-((4-((lH-pyrazol-l-yl)methyl)benzyl)oxy)pyridin-2-yl)amino)methyl)-5,7- dimethylisoquinolin-1 -amine (1-454);6-(((2-((4-((lH-pyrazol-l-yl)methyl)benzyl)oxy)pyridin-4-yl)amino)methyl)-5,7- dimethylisoquinolin- 1 -amine (1-455);1-(4-(((2-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)-5-chloropyridin-4- yl)oxy)methyl)benzyl)pyridin-2(lH)-one (1-456);6-(((5-(4-((lH-pyrazol-l-yl)methyl)benzyl)-5H-pyrrolo[3,2-c]pyridazin-3-yl)amino)methyl)-5,7- dimethylisoquinolin-1 -amine (1-457);6-(((l-(4-((lH-pyrazol-l-yl)methyl)benzyl)-lH-pyrazolo[4,3-c]pyridin-6-yl)amino)methyl)-5,7- dimethylisoquinolin-1 -amine (1-458);6-(((2-(4-((lH-pyrazol-l-yl)methyl)benzyl)-2H-pyrazolo[4,3-c]pyridin-6-yl)amino)methyl)-5,7- dimethylisoquinolin-1 -amine (1-459);6-((6-(4-((lH-pyrazol-l-yl)methyl)phenethyl)pyrimidin-4-ylamino)methyl)-5,7- dimethylisoquinolin-1 -amine (1-460);(4-(((6-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimidin-4- yl)amino)methyl)phenyl)methanol (1-461);2-(4-(((5-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyridazin-3- yl)oxy)methyl)phenyl)-N,N-dimethylacetamide (1-462); l-(4-(((6-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimi din-4- yl)amino)methyl)benzyl)-3,5-dichloropyridin-2(lH)-one (1-463);N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-l-((2,3-dimethylquinoxalin-6-yl)methyl)-lH- pyrazole-4-carboxamide (1-464);2-(4-(((6-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyridazin-4- yl)oxy)methyl)phenyl)-N,N-dimethylacetamide (1-465);2-(4-(((6-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimi din-4- yl)oxy)methyl)phenyl)-N,N-dimethylacetamide (1-466);2-(4-(((6-((6-(aminomethyl)-5,7-dimethylisoquinolin-l-yl)amino)pyrimidin-4- yl)oxy)methyl)phenyl)-N,N-dimethylacetamide (1-467);4-((4-((lH-pyrazol-l-yl)methyl)benzyl)oxy)-6-(((l-amino-5,7-dimethylisoquinolin-6- yl)methyl)amino)-2-methylisoindolin-l-one (1-468);N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-l-((4-bromophenyl)diflu orom ethyl)- 1H- pyrazole-4-carboxamide (1-469);N-(6-(((5 -((4-(( 1 H-pyrazol- 1 -yl)methyl)benzyl)oxy)py ridazin-3 -yl)amino)methyl)-5 , 7- dimethylisoquinolin- l-yl)acetamide (1-470); l-(4-((4-(l-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)arnino)-2,2,2-trifluoroethyl)-lH- pyrazol-l-yl)methyl)benzyl)pyridin-2(lH)-one (1-471);N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-l-(difluoro(phenyl)methyl)-lH-pyrazole-4- carboxamide (1-472);6-((6-(4-((lH-pyrazol-l-yl)methyl)phenethyl)pyrimidin-4-ylamino)methyl)-5,7- dimethylisoquinolin- 1 -amine (1-473); l-(4-(2-(3-azabicyclo[3.1.0]hexan-3-yl)-2-oxoethyl)-3-chlorobenzyl)-N-((l-amino-5,7- dimethylisoquinolin-6-yl)methyl)-lH-pyrazole-4-carboxamide (1-474);N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-l-(4-(l-methyl-2-oxopyrrolidin-3-yl)benzyl)- lH-pyrazole-4-carboxamide (1-475);N2-(4-((lH-pyrazol-l-yl)methyl)benzyl)-N6-((l-amino-5,7-dimethylisoquinolin-6- yl)methyl)pyrazine-2,6-diamine (1-476); l-(4-(2-(3-azabicyclo[3.1.0]hexan-3-yl)-2-oxoethyl)benzyl)-N-((l-amino-5,7- dimethylisoquinolin-6-yl)methyl)-3-fluoro-lH-pyrazole-4-carboxamide (1-477); l-(4-(((2-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimi din-4- yl)oxy)methyl)benzyl)pyridin-2(lH)-one (1-478);l-(4-(2-(3-azabicyclo[3.1 ,0]hexan-3-yl)-2-oxoethyl)benzyl)-N-((l -amino -5,7- dimethylisoquinolin-6-yl)rnethyl)-4-fluoro-lH-pyrrole-3-carboxamide (1-479); ethyl (6-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimidin-4-yl)(4-((2- oxopyridin- 1 (2H)-yl)methyl)benzyl)carbamate (1-480); ethyl (6-(((l-((ethoxycarbonyl)amino)-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimidin-4- yl)(4-((2-oxopyridin-l(2H)-yl)methyl)benzyl)carbamate (1-481) ;N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-l-((6-cyclopropyl-[l,2,4]triazolo[l,5- a]pyridin-2-yl)methyl)-lH-pyrazole-4-carboxamide (1-482);(Z)-N4-(4-(l-(lH-pyrazol-l-yl)prop-l-en-l-yl)benzyl)-N6-((l-amino-5,7-dimethylisoquinolin-6- yl)methyl)pyrimidine-4,6-diamine (1-483);N4-(4-(l-(lH-pyrazol-l-yl)propyl)benzyl)-N6-((l-amino-5,7-dimethylisoquinolin-6- yl)methyl)pyrimidine-4,6-diamine (1-484);N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-l-((6-cyclopropylimidazo[l,2-a]pyridin-2- yl)methyl)-lH-pyrrolo[3,2-b]pyridine-3-carboxamide (1-485);4-(((l -amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)-6-((6-cyclopropyl-[l, 2, 4]tri azolof 1,5- a]pyridin-2-yl)methoxy)pyrimidine-2-carboxylic acid (1-486);4-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)-6-((6-cyclopropylimidazo[l,2- a]pyridin-2-yl)methoxy)pyrimidine-2-carboxylic acid (1-487);4-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)-6-((6-cyclopropylimidazo[l,2- a]pyrimidin-2-yl)methoxy)pyrimidine-2-carboxylic acid (1-488); ethyl 4-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)-6-((6-cyclopropylimidazo[l,2- a]pyrimidin-2-yl)methoxy)pyrimidine-2-carboxylate (1-489);N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-l-((6-cyclopropylimidazo[l,2-a]pyridin-2- yl)methyl)-lH-pyrazole-4-sulfonamide (1-490);N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-l-((6-cyclopropylimidazo[l,2-a]pyridin-2- yl)methyl)-lH-l,2,3-triazole-4-sulfonamide (1-491);6-(((4-((6-cyclopropylimidazo[l,2-a]pyridin-2-yl)methoxy)pyrimidin-2-yl)amino)methyl)-5,7- dimethylisoquinolin-1 -amine (1-492);6-(((6-(l-(6-cyclopropylimidazo[l,2-b]pyridazin-2-yl)ethoxy)pyrimidin-4-yl)amino)methyl)-5,7- dimethylisoquinolin- 1 -amine (1-493 );7-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-4-((6-cyclopropylimidazo[l,2-a]pyridin-2- yl)methoxy)-2,7-diazabicyclo[4.2.0]octa-l,3,5-trien-8-one (1-494);3-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)-5-((6-cyclopropylimidazo[l,2- a]pyridin-2-yl)methoxy)picolinic acid (1-495);7-((l -amino-5,7-dimethylisoquinolin-6-yl)methyl)-4-(((6-cy cl opropylimidazo[l,2-a]pyri din-2- yl)methyl)amino)-2,7-diazabicyclo[4.2.0]octa-l,3,5-trien-8-one (1-496);3-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)-5-(((6-cyclopropylimidazo[l,2- a]pyridin-2-yl)methyl)amino)picolinic acid (1-497);6-(((2-((6-cyclopropylimidazo[l,2-a]pyridin-2-yl)methyl)-[l,2,4]triazolo[l,5-a]pyrazin-8- yl)amino)methyl)-5,7-dimethylisoquinolin-l -amine (1-498);6-(((l-((6-cyclopropylimidazo[l,2-a]pyridin-2-yl)methyl)-lH-imidazo[4,5-c]pyridin-6- yl)amino)methyl)-5,7-dimethylisoquinolin-l -amine (1-499);6-(((2-((6-cyclopropylimidazo[l,2-a]pyridin-2-yl)methyl)-3H-imidazo[4,5-c]pyri din-4- yl)amino)methyl)-5,7-dimethylisoquinolin-l -amine (1-500);6-(((l-((6-cyclopropylimidazo[l,2-a]pyridin-2-yl)methyl)-lH-[l,2,3]triazolo[4,5-c]pyridin-6- yl)amino)methyl)-5,7-dimethylisoquinolin-l -amine (1-501);6-((12-azanyl)methyl)-N-(l-((6-cyclopropylimidazo[l,2-a]pyridin-2-yl)methyl)-lH-[ 1,2, 3]triazolo[4,5-c]pyridin-6-yl)-5,7-dimethylisoquinolin-l -amine (1-502);6-(((l -((6-cyclopropyl-[l, 2, 4]tri azolof l,5-a]pyridin-2-yl)methyl)-lH-imidazo[4,5-c]pyri din-6- yl)amino)methyl)-5,7-dimethylisoquinolin-l -amine (1-503);6-(((l-((5-cyclopropylthieno[2,3-b]pyridin-2-yl)methyl)-lH-imidazo[4,5-c]pyri din-6- yl)amino)methyl)-5,7-dimethylisoquinolin-l -amine (1-504);2-((4-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)-6-oxopyrimidin-l(6H)- yl)methyl)-6-cyclopropylimidazo[l,2-c]pyrimidin-5(6H)-one (1-505);N2-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N3-((6-cyclopropylimidazo[l,2-a]pyridin-2- yl)methyl)pyridine-2,3-diamine (1-506); l-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-3-(5-((6-cyclopropylimidazo[l,2-a]pyri din-2- yl)methoxy)pyrimidin-4-yl)urea (1-507);4-(2-(((6-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimidin-4-yl)oxy)methyl)-5- cyclopropylpyrazolo[l,5-a]pyridin-7-yl)-2-methylbutan-2-ol (1-508);3-(2-(((6-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimidin-4-yl)oxy)methyl)-5- cyclopropylpyrazolo[l,5-a]pyridin-7-yl)-2,2-dimethylpropanamide (1-509);3-(2-(((6-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimidin-4-yl)oxy)methyl)-5- cyclopropylpyrazolo[l,5-a]pyridin-7-yl)-2,2-dimethylpropanenitrile (1-510);N3-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N5-((6-cyclopropylimidazo[l,2-a]pyri din-2- yl)methyl)-l,2,4-thiadiazole-3,5-diamine (1-511);6-(((6-((2R,4S)-4-((tert-butyldimethylsilyl)oxy)-2-(6-cyclopropylimidazo[l,2-a]pyridin-2- yl)py rrolidin- 1 -yl)pyrimidin-4-yl)amino)methy l)-5 , 7-dimethy li soquinolin- 1 -amine (1-512); (3S,5R)-l-(6-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimidin-4-yl)-5-(6- cyclopropylimidazo[l,2-a]pyridin-2-yl)pyrrolidin-3-ol (1-513);N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-2-((6-cyclopropylimidazo[l,2-a]pyridin-2- yl)methyl)isonicotinamide (1-514);5.7-dimethyl-6-(((5-((2-methylquinolin-6-yl)methyl)-5H-pyrrolo[3,2-c]pyridazin-3- yl)amino)methyl)isoquinolin-l -amine (1-515);N4-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N6-((6-cyclopropylimidazo[l,2-b]pyridazin- 2-yl)methyl)-N6-(2,2,2-trifluoroethyl)pyrimidine-4,6-diamine (1-516);5.7-dimethyl-6-(((l-(quinolin-6-ylmethyl)-lH-pyrrolo[3,2-c]pyridin-6- yl)amino)methyl)isoquinolin-l -amine (1-517);6-(((l-((3-chloroquinolin-6-yl)methyl)-lH-pyrrolo[3,2-c]pyridin-6-yl)amino)methyl)-5,7- dimethylisoquinolin-1 -amine (1-518);6-(((3-((3-chloroquinolin-6-yl)methyl)-[l,2,4]triazolo[4,3-a]pyridin-6-yl)amino)methyl)-5,7- dimethylisoquinolin-l-amine (1-519);6-(((3-((3-chloroquinolin-6-yl)methyl)imidazo[l,5-a]pyridin-6-yl)amino)methyl)-5,7- dimethylisoquinolin-1 -amine (1-520);(6-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)imidazo[l,2-a]pyri din-3- yl)(naphthalen-2-yl)methanol (1-521);5.7-dimethyl-6-(((3-(naphthalen-2-ylmethyl)imidazo[l,2-a]pyridin-6-yl)amino)methyl)- isoquinolin-1 -amine (1-522);5.7-dimethyl-6-(((3-(naphthalen-2-ylmethyl)imidazo[l,5-a]pyrazin-6- yl)amino)methyl)isoquinolin- 1 -amine (1-523);5.7-dimethyl-6-(((l-methyl-3-(naphthalen-2-ylmethyl)-lH-pyrrolo[2,3-c]pyridin-5- yl)amino)methyl)isoquinolin-l -amine (1-524);5.7-dimethyl-6-(((2-(naphthalen-2-ylmethyl)imidazo[l,2-a]pyrazin-8- yl)amino)methyl)isoquinolin-l -amine (1-525);5.7-dimethyl-6-(((3-(naphthalen-2-ylmethyl)-lH-pyrrolo[2,3-c]pyridin-5- yl)amino)methyl)isoquinolin-l -amine (1-526);5.7-dimethyl-6-(((3-(naphthalen-2-ylmethyl)-lH-pyrrolo[2,3-b]pyridin-5- yl)amino)methyl)isoquinolin-l -amine (1-527);5.7-dimethyl-6-(((l-(quinolin-6-ylmethyl)-lH-pyrrolo[3,2-c]pyridin-6- yl)amino)methyl)isoquinolin-l -amine (1-528);6-(((6-((6-cyclopropylimidazo[l,2-a]pyridin-2-yl)fluoromethyl)pyrimidin-4-yl)amino)methyl)-5.7-dimethylisoquinolin-l -amine (1-529);6-(((6-((4-((lH-pyrazol-l-yl)methyl)benzyl)oxy)pyridazin-4-yl)amino)methyl)-5,7- dimethylisoquinolin-1 -amine (1-530);6-(((l-((3-chloroquinolin-6-yl)methyl)-lH- pyrrolo[3,2-c]pyridin-6-yl)amino)methyl)-5,7- dimethylisoquinolin-1 -amine (1-531);6-(((2-((6-cyclopropylimidazo[l,2-a]pyridin-2-yl)methoxy)pyridin-4-yl)amino)methyl)-5,7- dimethylisoquinolin-1 -amine (1-532);6-(((6-((4-((lH-pyrazol-l-yl)methyl)benzyl)oxy)pyrimidin-4-yl)amino)methyl)-5- methylisoquinolin-1 -amine (1-533);6-(((6-((4-((lH-pyrazol-l-yl)methyl)benzyl)oxy)pyrimidin-4-yl)amino)methyl)-7- methylisoquinolin- 1 -amine. (1-534);6-(((6-((4-((lH-pyrazol-l-yl)methyl)benzyl)oxy)pyrimidin-4-yl)amino)methyl)-7- (trifluoromethyl)isoquinolin- 1 -amine (1-535); l-(4-(((6-(((l-amino-5-methylisoquinolin-6-yl)methyl)amino)pyridazin-4-yl)amino) methyl)benzyl)pyridin-2(lH)-one (1-536); l-(4-(((5-(((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyridazin-3-yl)amino) methyl)benzyl)pyridin-2(lH)-one (1-537);N-((l-amino-5,7-dimethylisoquinolin-6-yl)methyl)-2-((3-chloroquinolin-6- yl)methyl)oxazolo[5,4-d]pyrimidin-7-amine (1-538);6-(((8-((3-chloroquinolin-6-yl)methyl)-9-methyl-9H-purin-6-yl)amino)methyl)-5,7- dimethylisoquinolin- 1 -amine (1-539);5,7-dimethyl-6-(((6-(naphthalen-2-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)methyl)isoquinolin-l -amine (1-540);6-(((6-((4-((lH-pyrazol-l-yl)methyl)benzyl)oxy)pyrimidin-4-yl)amino)methyl)-4- fluoroisoquinolin- 1 -amine; or6-(((6-((4-((lH-pyrazol-l-yl)methyl)benzyl)oxy)pyrimidin-4-yl)amino)methyl)isoquinolin-l- amine; or a pharmaceutically acceptable salt thereof.

[0246] In some embodiments, a compound is selected from:1-541 1-542 or a pharmaceutically acceptable salt thereof.C. Pharmaceutical Compositions

[0247] In another aspect, the present invention provides pharmaceutical compositions comprising a compound of Formulae (I)-(XVI-c) or a compound of Formulae (I)-(XVI-c) in combination with a pharmaceutically acceptable excipient (e.g., carrier).

[0248] The pharmaceutical compositions include optical isomers, diastereomers, or pharmaceutically acceptable salts of the inhibitors disclosed herein. A compound of Formulae (I)-(XVI-c) included in the pharmaceutical composition may be covalently attached to a carrier moiety, as described above. Alternatively, a compound of Formulae (I)-(XVI-c) included in the pharmaceutical composition is not covalently linked to a carrier moiety.

[0249] A “pharmaceutically acceptable carrier,” as used herein refers to pharmaceutical excipients, for example, pharmaceutically, physiologically, acceptable organic or inorganic carrier substances suitable for enteral or parenteral application that do not deleteriously react with the active agent. Suitable pharmaceutically acceptable carriers include water, salt solutions (such as Ringer's solution), alcohols, oils, gelatins, and carbohydrates such as lactose, amylose orstarch, fatty acid esters, hydroxymethycellulose, and polyvinyl pyrrolidine. Such preparations can be sterilized and, if desired, mixed with auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and / or aromatic substances and the like that do not deleteriously react with the compounds of the invention.

[0250] The compounds of the invention can be administered alone or can be coadministered to the subject. Coadministration is meant to include simultaneous or sequential administration of the compounds individually or in combination (more than one compound). The preparations can also be combined, when desired, with other active substances (e.g. to reduce metabolic degradation).

[0251] In some embodiments, a test agent as described herein can be incorporated into a pharmaceutical composition for administration by methods known to those skilled in the art and described herein for provided compounds.D. Formulations

[0252] Compounds of the present invention can be prepared and administered in a wide variety of oral, parenteral, and topical dosage forms. Thus, the compounds of the present invention can be administered by injection (e.g. intravenously, intramuscularly, intracutaneously, subcutaneously, intraduodenally, or intraperitoneally). Also, the compounds described herein can be administered by inhalation, for example, intranasally. Additionally, the compounds of the present invention can be administered transdermally. It is also envisioned that multiple routes of administration (e.g., intramuscular, oral, transdermal) can be used to administer the compounds of the invention. Accordingly, the present invention also provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier or excipient and one or more compounds of the invention.

[0253] For preparing pharmaceutical compositions from the compounds of the present invention, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid carrier can be one or more substance that may also act as diluents, flavoring agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.

[0254] In powders, the carrier is a finely divided solid in a mixture with the finely divided active component. In tablets, the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.

[0255] The powders and tablets preferably contain from 5% to 70% of the active compound. Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methyl cellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like. The term “preparation” is intended to include the formulation of the active compound with encapsulating material as a carrier providing a capsule in which the active component with or without other carriers, is surrounded by a carrier, which is thus in association with it. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.

[0256] For preparing suppositories, a low melting wax, such as a mixture of fatty acid glycerides or cocoa butter, is first melted and the active component is dispersed homogeneously therein, as by stirring. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool, and thereby to solidify.

[0257] Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water / propylene glycol solutions. For parenteral injection, liquid preparations can be formulated in solution in aqueous polyethylene glycol solution.

[0258] When parenteral application is needed or desired, particularly suitable admixtures for the compounds of the invention are injectable, sterile solutions, preferably oily or aqueous solutions, as well as suspensions, emulsions, or implants, including suppositories. Ampoules are convenient unit dosages. The compounds of the invention can also be incorporated into liposomes or administered via transdermal pumps or patches. Pharmaceutical admixtures suitable for use in the present invention include those described, for example, in Pharmaceutical Sciences (17th Ed., Mack Pub. Co., Easton, PA) and WO 96 / 05309, the teachings of both of which are hereby incorporated by reference.

[0259] Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizers, and thickening agents as desired. Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, such as well-known suspending agents.Ill

[0260] Also included are solid form preparations that are intended to be converted, shortly before use, to liquid form preparations for oral administration. Such liquid forms include solutions, suspensions, and emulsions. These preparations may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.

[0261] The pharmaceutical preparation is preferably in unit dosage form. In such form the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.

[0262] The quantity of active component in a unit dose preparation may be varied or adjusted according to the particular application and the potency of the active component. The composition can, if desired, also contain other compatible therapeutic agents.E. Effective Dosages

[0263] Pharmaceutical compositions provided by the present invention include compositions wherein the active ingredient is contained in a therapeutically effective amount, i.e., in an amount effective to achieve its intended purpose. The actual amount effective for a particular application will depend, inter alia, on the condition being treated. For example, when administered in methods to treat HAE, such compositions will contain an amount of active ingredient effective to achieve the desired result (e.g. inhibiting PKa and / or decreasing the amount of bradykinin in a subject).

[0264] The dosage and frequency (single or multiple doses) of compound administered can vary depending upon a variety of factors, including route of administration; size, age, sex, health, body weight, body mass index, and diet of the recipient; nature and extent of symptoms of the disease being treated (e.g., the disease responsive to PKa inhibition); presence of other diseases or other health-related problems; kind of concurrent treatment; and complications from any disease or treatment regimen. Other therapeutic regimens or agents can be used in conjunction with the methods and compounds of the invention.

[0265] For any provided compound or test agent, the therapeutically effective amount can be initially determined from cell culture assays. Target concentrations will be those concentrations of active compound(s) that are capable of decreasing PKa enzymatic activity as measured, for example, using the methods described.

[0266] Therapeutically effective amounts for use in humans may be determined from animal models. For example, a dose for humans can be formulated to achieve a concentration that has been found to be effective in animals. The dosage in humans can be adjusted by monitoring PKa inhibition and adjusting the dosage upwards or downwards, as described above.

[0267] Dosages may be varied depending upon the requirements of the patient and the compound being employed. The dose administered to a patient, in the context of the present invention, should be sufficient to effect a beneficial therapeutic response in the patient over time. The size of the dose also will be determined by the existence, nature, and extent of any adverse side effects.

[0268] In one aspect, compounds provided herein display one or more improved pharmacokinetic (PK) properties (e.g., Cmax, tmax, Cmin, ti / 2, AUC, CL, bioavailability, etc.) when compared to a reference compound. In some embodiments, a reference compound is a PKa inhibitor known in the art. In some embodiments, a reference compound is a PKa inhibitor selected from those disclosed in PCT Publication Number WO 2019 / 178129.F. Methods of Treatment

[0269] The present disclosure provides compounds for use in medicine. The present disclosure further provides the use of any compounds described herein for inhibiting the activity of PKa, which would be beneficial to treatment of PKa-mediated diseases and conditions.Exemplary PKa-mediated disorders include edema, which refers to swelling in the whole body of a subject or a part thereof due to inflammation or injury when small blood vessels become leaky and releases fluid into nearby tissues. In some examples, the edema is HAE. In other examples, the edema occurs in eyes, e.g., diabetic macular edema (DME). The present disclosure provides methods of inhibiting the activity of PKa. In certain embodiments, the application provides a method of inhibiting the activity of PKa in vitro via contacting any of the compounds described herein with PKa molecules in a sample, such as a biological sample. In certain embodiments, the application provides a method of inhibiting the activity of PKa in vivo via delivering an effectiveamount of any of the compounds described herein to a subject in need of the treatment through a suitable route.

[0270] In certain embodiments, the methods comprise administering to a subject in need thereof (e.g., a subject such as a human patient with edema) any of the compounds described herein or a pharmaceutically acceptable salt thereof. In certain embodiments, the methods comprise administering a compound of Formulae (I)-(XVI-c), or a pharmaceutically acceptable salt or composition thereof, to a subject in need thereof. In some embodiments, the method comprises administering a pharmaceutical composition comprising a compound of Formulae (I)- (XVI-c), or a pharmaceutically acceptable salt to a subject in need thereof.

[0271] In certain embodiments, the subject to be treated by any of the methods described herein is a human patient having, suspected of having, or at risk for edema, for example, HAE or diabetic macular edema (DME). A subject having an edema can be identified by routine medical examination, e.g., laboratory tests. A subject suspected of having an edema might show one or more symptoms of the disease / disorder. A subject at risk for edema can be a subject having one or more of the risk factors associated with the disease, for example, deficiency in Cl -INH as for HAE.

[0272] In certain embodiments, provided herein are methods of alleviating one or more symptoms of HAE in a human patient who is suffering from an HAE attack. Such a patient can be identified by routine medical procedures. An effective amount of one or more of the provided compounds can be given to the human patient via a suitable route, for example, those described herein. The compounds described herein may be used alone, or may be used in combination with other anti-HAE agents, for example, a Cl esterase inhibitor (e.g., Cinryze® or Berinert®), a PKa inhibitor (e.g., ecallantide or lanadelumab) or a bradykinin B2 receptor antagonist (e.g., Firazyr®).

[0273] In some embodiments, provided herein are methods or reducing the risk of HAE attack in a human HAE patient who is in quiescent stage. Such a patient can be identified based on various factors, including history of HAE attack. An effective amount of one or more of the compounds can be given to the human patient via a suitable route, for example, those described herein. The compounds described herein may be used alone, or may be used in combination with other anti-HAE agents, for example, a Cl esterase inhibitor (e.g., Cinryze® or Berinert®), a PKainhibitor (e.g, ecallantide or lanadelumab) or a bradykinin B2 receptor antagonist (e.g., Firazyr®).

[0274] In some embodiments, provided herein is prophylactic treatment of HAE in human patients having risk to HAE attacks with one or more of the compounds described herein. In some embodiments, patients suitable for prophylactic treatment of HAE are human subjects suffering from HAE (e.g., having history of HAE attacks). In some embodiments, patients suitable for such prophylactic treatment are human subjects where a physician determines a history of HAE attacks warrants a prophylactic approach (e.g., human subjects experiencing more than a particular average number of attacks over a time period, including by way of nonlimiting example, one, two, or more attacks per month). Alternatively, patients suitable for the prophylactic treatment may be human subjects having no HAE attack history but bearing one or more risk factors for HAE (e.g, family history, genetic defects in Cl -INH gene, etc.) Such prophylactic treatment may involve the compounds described herein as the sole active agent, or involve additional anti-HAE agents, such as those described herein.

[0275] In certain embodiments, provided herein are methods for preventing or reducing edema in an eye of a subject (e.g., a human patient). In some examples, the human patient is a diabetic having, suspected of having, or at risk for diabetic macular edema (DME). DME is the proliferative form of diabetic retinopathy characterized by swelling of the retinal layers, neovascularization, vascular leak, and retinal thickening in diabetes mellitus due to leaking of fluid from blood vessels within the macula. To practice this method, an effective amount of one or more of the compounds described herein, or pharmaceutically acceptable salts thereof, may be delivered into the eye of the subject where treatment is needed. For example, the compound may be delivered topically, by intraocular injection, or intravitreal injection. A subject may be treated with the compound as described herein, either as the sole active agent, or in combination with another treatment for DME. Non-limiting examples of treatment for DME include laser photocoagulation, steroids, VEGF pathway targeting agents (e.g., Lucentis® (ranibizumab) or Eylea® (aflibercept)), and / or anti-PDGF agents.

[0276] In certain embodiments, the methods disclosed herein comprise administering to the subject an effective amount of a compound of Formulae (I)-(VLb), or a pharmaceutically acceptable salt or composition thereof. In some embodiments, the effective amount is atherapeutically effective amount. In some embodiments, the effective amount is a prophylactically effective amount.

[0277] In certain embodiments, the subject being treated is an animal. The animal may be of either sex and may be at any stage of development. In certain embodiments, the subject is a mammal. In certain embodiments, the subject being treated is a human. In certain embodiments, the subject is a domesticated animal, such as a dog, cat, cow, pig, horse, sheep, or goat. In certain embodiments, the subject is a companion animal, such as a dog or cat. In certain embodiments, the subject is a livestock animal, such as a cow, pig, horse, sheep, or goat. In certain embodiments, the subject is a zoo animal. In another embodiment, the subject is a research animal such as a rodent (e.g., mouse, rat), dog, pig, or non-human primate. In certain embodiments, the animal is a genetically engineered animal. In certain embodiments, the animal is a transgenic animal.

[0278] Certain methods described herein may comprise administering one or more additional pharmaceutical agent(s) in combination with the compounds described herein. The additional pharmaceutical agent(s) may be administered at the same time as the compound of Formulae (I)- (XVI-c), or at different times than the compound of Formulae (I)-(XVI-c). For example, the compound of Formulae (I)-(XVl-c) and any additional pharmaceutical agent(s) may be on the same dosing schedule or different dosing schedules. All or some doses of the compound of Formulae (I)-(XVI-c) may be administered before all or some doses of an additional pharmaceutical agent, after all or some does an additional pharmaceutical agent, within a dosing schedule of an additional pharmaceutical agent, or a combination thereof. The timing of administration of the compound of Formulae (I)-(XVI-c) and additional pharmaceutical agents may be different for different additional pharmaceutical agents.

[0279] In certain embodiments, the additional pharmaceutical agent comprises an agent useful in the treatment of an edema, such as HAE or DME. Examples of such agents are provided herein.Exemplary Enumerated Embodiments1. A compound of F ormul a (I) :CyB— L'— CyA— L— Cyc(I) or a pharmaceutically acceptable salt thereof, wherein:CyAis phenylene, a 5- to 6-membered monocyclic heteroarylene having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, a 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclene having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, an 8- to 12-membered bicyclic heteroarylene having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, or an 8- to 10-membered bicyclic arylene, wherein CyAis substituted with 0-4 -RAgroups; each RAis independently selected from oxo, halogen, -CN, -C(O)R, -C(O)2R, -C(O)N(R)2, - NO2, -N(R)2, -N(R)C(O)R, -N(R)C(O)2R, -N(R)S(O)2R, -OR, -OC(O)R, -OC(O)N(R)2, - SR, -S(O)R, -S(O)2R, -S(O)N(R)2, -S(O)2N(R)2, or an optionally substituted group selected from C1-6 aliphatic, phenyl, a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur, or a 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from oxygen, nitrogen or sulfur; each R is independently hydrogen or an optionally substituted C1-6 aliphatic group;L’ is a covalent bond or an optionally substituted C1-4 hydrocarbon chain, wherein 1 to 3 methylene units are optionally and independently replaced with -O-, -C(O)-, -NRZ-, -S-, -SO- , -SO2-, -S(NH)(O)-, or cyclopropylene; each Rzis independently selected from hydrogen, -(CH2)o-30R, -(CH2)o-3C(0)OR, or an optionally substituted C1-6 aliphatic group;wherein: each of RB1and RB2is independently hydrogen or an optionally substituted group selected from C1-6 aliphatic or a 3- to 7-membered saturated or partially unsaturated monocyclic carbocycyl;RB3is hydrogen or C1-6 aliphatic;RB4is -N(RX)2; each Rxis independently selected from hydrogen, -C(O)R, -C(O)2R, or optionally substituted C1-6 aliphatic. wherein no more than one of RB1or RB2is hydrogen; orwherein:RB5is hydrogen or Ci-6 aliphatic or an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic carbocycyl; each of RB6and RB7is independently hydrogen or an optionally substituted Ci-6 aliphatic;L is an optionally substituted C1-3 hydrocarbon chain, wherein 1 to 3 methylene units are optionally and independently replaced with -C(O)-, -O-, -NRZ-, -N(NO)- -S-, -SO-, -SO2-, an optionally substituted cyclopropylene, or an optionally substituted 5- to 6-membered saturated or partially unsaturated heterocyclene, having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur; andCycis selected from a 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, phenyl, 8- to 10-membered bicyclic aryl, a 7- to 10-membered heteroaryl having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, or a 6- to 12- membered saturated or partially unsaturated fused bicyclic heterocyclyl having 1-4 heteroatoms independently selected from oxygen, nitrogen, or sulfur, wherein Cycis substituted with 0-6 -Lc-Rcgroups; each Lcis independently selected from a covalent bond or an optionally substituted C1-6 hydrocarbon chain, wherein 1 to 3 methylene units are optionally and independently replaced with -C(O)-, -O-, or -NR-; and each Rcis independently selected from oxo, halogen, -CN, -C(O)R,-C(O)2R, -C(O)N(R)2, -NO2, -N(R)2, -N(R)C(O)R, -N(R)C(O)2R, -N(R)S(O)2R,-OR, -OC(O)R, -OC(O)N(R)2, -SR, -S(O)R, -S(O)2R, -S(O)N(R)2, -S(O)2N(R)2, or an optionally substituted group selected from C1-6 aliphatic, phenyl, a 3- to 7-memberedsaturated or partially unsaturated monocyclic carbocyclyl, a 5- or 6-membered heteroaryl having 1-3 heteroatoms selected from oxygen, nitrogen, or sulfur; a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur; a 6- to 12-membered saturated or unsaturated bicyclic heterocyclyl having 1-3 heteroatoms selected from oxygen, nitrogen, or sulfur; a 5- to 12- membered saturated or unsaturated bicyclic carbocyclyl; or a 7- to 10- membered heteroaryl having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur.2. The compound of embodiment 1, wherein the compound is of Formula (Il-a):or a pharmaceutically acceptable salt thereof.3. The compound of any one of embodiments 1-2, wherein the compound is of Formula (Ill-a), (IILb), (III-c), or (IILd):(III-c) (in-d) or a pharmaceutically acceptable salt thereof.4. The compound of any one of embodiments 1-2, wherein the compound is of Formula (III-a-1), (III-a-2), or (III-a-3):or a pharmaceutically acceptable salt thereof.5. The compound of any one of embodiments 1-3, wherein the compound is of Formula (III-b-1), (III-b-2), or (III-b-3):(III-b-3) or a pharmaceutically acceptable salt thereof.6. The compound of any one of embodiments 1-3, wherein the compound is of Formulaor a pharmaceutically acceptable salt thereof7. The compound of any one of embodiments 1-6, wherein the compound is of Formula (V- a), (V-b), or (V-c):(V-c) or a pharmaceutically acceptable salt thereof8. The compound of any one of embodiments 1-6, wherein the compound is of Formula (VLa), (VLb), or (VI-c):or a pharmaceutically acceptable salt thereof.9. The compound of any one of embodiments 1-6, wherein the compound is of Formula (VILa), (VILb), or (VII-c):(VII-c) or a pharmaceutically acceptable salt thereof.10. The compound of any one of embodiments 1-6, wherein the compound is of Formula(VIILa), (Vlll-b), or (VIILc):(Vlll-a) (Vlll-b)(VIII-c) or a pharmaceutically acceptable salt thereof.11. The compound of any one of embodiments 1-6, wherein the compound is of Formula(IX-c) or a pharmaceutically acceptable salt thereof.12. The compound of any one of embodiments 1-6, wherein the compound is of Formula (X-or a pharmaceutically acceptable salt thereof.13. The compound of any one of embodiments 1-6, wherein the compound is of Formula(XI-c) or a pharmaceutically acceptable salt thereof.14. The compound of any one of embodiments 1-6, wherein the compound is of Formula(XII-c) or a pharmaceutically acceptable salt thereof.15. The compound of any one of embodiments 1-6, wherein the compound is of Formula (Xlll-a), (XIILb), or (XIILc):(XIILa) (Xlll-b)or a pharmaceutically acceptable salt thereof.16. The compound of any one of embodiments 1-6, wherein the compound is of Formula(XIV-c) or a pharmaceutically acceptable salt thereof.17. The compound of any one of embodiments 1-6, wherein the compound is of Formula(XV-a), (XV-b), or (XV-c):(XV-a)(XV-c) or a pharmaceutically acceptable salt thereof.18. The compound of any one of embodiments 1-6, wherein the compound is of Formula(XVI-a), (XVI-b), or (XVI-c):(XVI-c) or a pharmaceutically acceptable salt thereof.19. The compound of any one of embodiments 1-3, 5, or 7-18, wherein RB1is hydrogen or Ci-6 aliphatic.20. The compound of any one of embodiments 1-3, 5, or 7-19, wherein RB1is hydrogen.21. The compound of any one of embodiments 1-3, 5, or 7-19, wherein RB1is Ci-6 aliphatic.22. The compound of any one of embodiments 1-3, 5, 7-19, or 21, wherein RB1is methyl23. The compound of any one of embodiments 1-4 or 7-22, wherein RB2is hydrogen or Ci-6 aliphatic.24. The compound of any one of embodiments 1-4 or 7-23, wherein RB2is hydrogen.25. The compound of any one of embodiments 1-4 or 7-23, wherein RB2is methyl, ethyl, - CF. or26. The compound of any one of embodiments 1-4, 7-23, or 25, wherein RB2is methyl.27. The compound of any one of embodiments 1-3, 6, or 19-26, wherein RB3is hydrogen.28. The compound of any one of embodiments 1-3, 6, or 19-26, wherein RB3is methyl.29. The compound of any one of embodiments 1-6 or 19-26, wherein each Rxis hydrogen.30. The compound of any one of embodiments 1-6 or 19-26, wherein each Rxis independently selected from -C(O)R, -C(O)2R, or optionally substituted Ci-6 aliphatic.31. The compound of any one of embodiments 1-6 or 19-26, wherein one Rxis hydrogen, and the other is selected from -C(O)R, -C(O)2R, or optionally substituted Ci-6 aliphatic.32. The compound of embodiment 1 or 2, wherein CyBis selected from the group consisting of:33. The compound of embodiment 1, wherein the compound is of Formula (II-b):or a pharmaceutically acceptable salt thereof.34. The compound of embodiment 1 or 33, wherein RB5is Ci-6 aliphatic or an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic carbocycyl.35. The compound of any one of embodiments 1 or 33-34, wherein RB6is an optionally substituted Ci-6 aliphatic.36. The compound of any one of embodiments 1 or 33-35, wherein RB7is Ci-6 aliphatic.37. The compound of any one of embodiments 1-6 or 10-36, wherein CyAis phenylene, wherein CyAis substituted with 0-4 -RAgroups.38. The compound of any one of embodiments 1-6 or 10-36, wherein CyAis a 5- to 6- membered monocyclic heteroarylene having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein CyAis substituted with 0-4 -RAgroups.39. The compound of any one of embodiments 1-6, 10-36, or 38, wherein CyAis selected from the group consisting of phenylene, thiazolediyl, pyridinediyl, pyrazinediyl, pyrimidinediyl, pyridazinediyl, triazinediyl, thiadiazolediyl, oxadiazolediyl, triazolediyl, pyrrolediyl, pyrazolediyl, imidazolediyl, wherein CyAis substituted with 0-4 -RAgroups.40. The compound of any one of embodiments 1-6 or 10-36, wherein CyAis an 8- to 12- membered bicyclic heteroarylene having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein CyAis substituted with 0-4 -RAgroups.41. The compound of any one of embodiments 1-6, 10-36, or 40, wherein CyAis an 8- membered bicyclic heteroarylene having 1-2 nitrogen heteroatoms, wherein CyAis substituted with 0-4 -RAgroups.42. The compound of any one of embodiments 1-6, 10-36, or 40, wherein CyAis a 9- membered bicyclic heteroarylene having 1-4 nitrogen heteroatoms, wherein CyAis substituted with 0-4 -RAgroups.43. The compound of any one of embodiments 1-6, 10-36, or 40, wherein CyAis a 10- membered bicyclic heteroarylene having 1-2 nitrogen heteroatoms, wherein CyAis substituted with 0-4 -RAgroups.44. The compound of any one of embodiments 1-6 or 10-36, wherein CyAis a 7- to 12- membered bicyclic heteroarylene having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein CyAis substituted with 0-4 -RAgroups.45. The compound of any one of embodiments 1-6, 10-36, or 44, wherein CyAis a 9- membered bicyclic heteroarylene having 3-4 heteroatoms independently selected from oxygen and nitrogen, wherein CyAis substituted with 0-1 -RAgroups.46. The compound of any one of embodiments 1-6, 10-36, or 44, wherein CyAis a 10- membered bicyclic heteroarylene having 3-4 heteroatoms independently selected from oxygen and nitrogen, wherein CyAis substituted with 0-1 -RAgroups.47. The compound of any one of embodiments 1-6 or 10-36, wherein CyAis selected from the group consisting ofwherein * represents the point of attachment to L’.48. The compound of any one of embodiments 1-47, wherein each RAis independently selected from oxo, halogen, -C(O)2R, -OR, -C(O)N(R)2, or an optionally substituted C1-6 aliphatic.49. The compound of any one of embodiments 1-9 or 12-48, wherein L’ is an optionally substituted Ci-4 hydrocarbon chain, wherein 1 to 3 methylene units are optionally and independently replaced with -O-, -C(O)-, -NRZ-, -S-, -SO-, -SO2-, -S(NH)(O)-, or cyclopropylene.50. The compound of any one of embodiments 1-9 or 12-49, wherein L’ is selected from the group consisting ofand O , wherein # represents the point of attachment to CyB.51. The compound of any one of embodiments 1-9 or 12-50, wherein L’ is selected from the group consisting of:, wherein # represents the point of attachment to CyB.52. The compound of any one of embodiments 1-11 or 14-51, wherein L is an optionally substituted C1-3 hydrocarbon chain, wherein 1 to 3 methylene units are optionally and independently replaced with -C(O)-, -O-, -NRZ-, -N(N0)- -S-, -SO-, -SO2-, an optionally substituted cyclopropylene, or a 5-membered saturated or partially unsaturated heterocyclene having 1 nitrogen heteroatom, optionally substituted with -(CH2)o-40R° or -OSiR°3, wherein each R° is independently hydrogen of Ci-6 aliphatic.53. The compound of any one of embodiments 1-11 or 14-52, wherein L is an optionally substituted C1-3 hydrocarbon chain, wherein 1-3 methylene units are optionally and independently replaced with -C(O)-, -O-, -NRZ-, or -S-.54. The compound of any one of embodiments 1-11 or 14-52, wherein L is selected from the group consisting of:wherein % represents the point of attachment to Cyc.55. The compound of any one of embodiments 1-11, 14-52, or 54, wherein L is selected from the group consisting of:wherein % represents the point of attachment to Cyc.56. The compound of any one of embodiments 1-13 or 19-55, wherein Cycis phenyl, wherein Cycis substituted with 0-5 -Lc-Rcgroups.57. The compound of any one of embodiments 1-13 or 19-55, wherein Cycis 5- to 6- membered heteroaryl having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein Cycis substituted with 0-6 -Lc-Rcgroups.58. The compound of any one of embodiments 1-13 or 19-55, wherein Cycis pyrazolyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl, wherein Cycis substituted with 0-4 - Lc-Rcgroups.58. The compound of any one of embodiments 1-13, 19-55, or 58, wherein Cycis selected from the group consisting of:59. The compound of any one of embodiments 1-13 or 19-55, wherein Cycis an 8- to 10- membered bicyclic aryl, wherein Cycis substituted with 0-6 -Lc-Rcgroups.60. The compound of any one of embodiments 1-13, 19-55, or 59, wherein Cycis indazolyl, benzotri azolyl, naphthalenyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, tetrahydro- 2J / -benzo[Z>][l,4]oxazinyl, or dihydro-2 / f-benzo[6][l,4]oxazinonyl, substituted with 0-6 -Lc-Rcgroups.61. The compound of any one of embodiments 1-13 or 19-55, wherein Cycis a 7- to 10- membered heteroaryl having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein Cycis substituted with 0-6 -Lc-Rcgroups.62. The compound of any one of embodiments 1-13, 19-55, or 61, wherein Cycis imidazopyridinyl, pyrazolopyridinyl, indazolyl, pyrrolopyridinyl, benzoimidazolyl, triazolopyridinyl, imidazopyridazinyl, imidazopyrimidinyl, imidazopyrimidinonyl, benzotri azolyl, triazolopyrimidinyl, triazolopyridazinyl, benzothiophenyl, benzothiozolyl, thienopyridinyl, benzofuranyl, benzooxazolyl, pyrazolopyrimidinyl, imidazopyrazinyl, quinolinyl, isoquinolinyl, quinazolinyl, naphthyridinyl, wherein Cycis substituted with 0-6 -Lc- Rcgroups.63. The compound of any one of embodiments 1-13 or 19-55, wherein Cycis selected from the group consisting of64. The compound of any one of embodiments 1-13 or 19-55, wherein Cycis65. The compound of any one of embodiments 1-64, wherein Lcis selected from the group consisting of: *-NH-, *-NCH3-, *-O-, *-CH2-, *-CH2C(CH3)2-, *-CH2CH2-, *-CH2C(O)N(CH3)-, *-CH2C(O)N(CH3)CH2-, *-CF2-, *-CH(CH3)-, *-OCH2-, *-OCF2-, *-OC(CH3)2-, *-CH2C(O)-, *-OCH2C(O)-, *-CH2C(O)NH-,*-CH2C(O)NHCH2-,*-N(CH3)C(O)-, *-C(CH2CH3)-, *- C(CHCH3)-, *-C(FCH3)-, wherein * represents the point of attachment to Cyc.66. The compound of any one of embodiments 1-65, wherein each Rcis independently selected from oxo, halogen, -CN, -C(O)2R, -C(0)N(R)2, or an optionally substituted group selected from Ci-6 aliphatic, phenyl, a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, a 5- or 6-membered heteroaryl having 1-3 heteroatoms selected fromoxygen, nitrogen, or sulfur; a 3 - to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur; a 6- to 12- membered saturated or unsaturated bicyclic heterocyclyl having 1-3 heteroatoms selected from oxygen, nitrogen, or sulfur; a 5- to 12- membered saturated or unsaturated bicyclic carbocyclyl; or a 7- to 10-membered heteroaryl having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur.67. The compound of any one of the preceding embodiments, wherein the compound is selected from compounds 1-1 through 1-540, or a pharmaceutically acceptable salt thereof.68. A pharmaceutical composition comprising a compound of any one of the preceding embodiments.69. The pharmaceutical composition comprising a compound of any one of the preceding embodiments, further comprising a pharmaceutically acceptable excipient.70. The composition of embodiment 68 or 69, wherein the composition is suitable for oral administration.71. A method of treating a plasma kallikrein-mediated disease or disorder using a compound or composition of any one of the preceding embodiments.72. The method of embodiment 71, wherein the disease or disorder is hereditary angioedema.73. The method of embodiment 71, wherein the disease or disorder is diabetic macular edema.74. A method of treating hereditary angioedema comprising administering to a patient in need thereof a compound or composition of any one of the preceding embodiments.75. A method of treating diabetic macular edema comprising administering to a patient in need thereof a compound or composition of any one of the preceding embodiments.76. The method of any one of embodiments 72 or 74, wherein administration of the compound partially or completely inhibits, delays onset of, reduces severity of, and / or reduces incidence of one or more symptoms, features, and / or causes of a hereditary angioedema.77. The method of embodiment 76, wherein the compound is administered orally.IV. Examples

[0280] In certain embodiments, the Examples describe compounds comprising one or more stereocenters, where a particular stereocenter is designated “S*” or “R* ” In both cases, the depiction of the generally indicates that the exact configuration is unknown (e.g., for a compound with a single stereocenter, the depiction R*- or S*- indicates that either the R- or S- isomer was isolated, but the configuration at the stereocenter of the particular isomer isolated was not determined).

[0281] It will be appreciated that compounds described within the Examples may comprise more than one stereocenter. As described above, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention. Within a particular compound name, where more than one “S*” or “R*” appear within a single pair of parentheses (e.g., “(1S*,2S*)”), it is understood that the S* and / or R* configurations are relative to each other. For example, a compound denoted “(1S*,2S*)-” or “(1R*,2R*)-” would be understood to refer specifically to either the “(1S,2S)-” or “(1R,2R)-” isomer, but not the “(1 S,2R)-” or “(1R,2S)-” isomers. Furthermore, a compound denoted “rac-(lS*,2S*)-” or “rac-(lR*,2R*)-” would be understood to include a racemic mixture of the “(1S,2S)-” and “(1R,2R)-” isomers. Similarly, a compound denoted “(1S*,2R*)-” or “(1R*,2S*)-” would be understood to refer specifically to either the “(1R,2S)-” or “(1S,2R)-” isomer, but not the “(1S,2S)-” or “(1R,2R)-” isomers. In addition, a compound denoted “rac-(lR*,2S*)-” or “rac-(lS*,2R*)-” would be understood to include a racemic mixture of the “(1R,2S)-” and “(1S,2R)-” isomers.

[0282] In certain embodiments, the Examples include schemes that depict compounds with one or more stereocenters. In some embodiments, the symbolfollowed by a number appears adjacent to a stereocenter. In such cases, it is understood to include a mixture of both configurations (e.g., R- and S-) at that position.

[0283] In some embodiments, the term “or” followed by a number appears adjacent to a stereocenter. In such cases, it is understood to denote either an “R-” or “S-” isomer, but the particular isomer was not determined.

[0284] In some embodiments, the numbering following the symbolor term “or” refers to one stereocenter’s relation to another stereocenter in that compound. For example, where two stereocenters in a compound are each denoted with the same number (e.g., two instances of “&1”), it is understood that the configurations are relative to each other (e.g., if the structure is drawn as (S,S) and both stereocenters are denoted “&1”, it is understood to include a mixture of the (S,S) and (R,R) isomers, but not the (S,R) or (R,S) isomers). However, where each stereocenter is denoted with a different number (e.g., one instance of “&1” and one instance of “&2”), it is understood that that the configurations may be independent to each other (e.g., if the structure is drawn (S,S) and one stereocenter is denoted “&1” and one is denoted “&2,” it is understood to include a mixture of the (S,S), (S,R), (R,S), and (R,R) isomers).Synthesis of Intermediates

[0285] Synthesis of methyl 4-cyclopropyl-3-methylbenzoate. To a solution of methyl 4- bromo-3 -methylbenzoate (700 mg, 3.1 mmol) in toluene / H2O = 1 : 1(10 mL) was added K3PO4 (1.95 g, 9.2 mmol), Pdi(dba)3 (283 mg, 0.31 mmol) and Xantphos (359 mg, 0.62 mmol). The mixture was stirred at 90 °C for 16 h under N2. After the reaction was cooled to room temperature, the reaction was quenched with NH4Q (sat. aq., 80 mL) and then extracted with DCM (100 mL x3). The combined organic layers were washed with brine (200 mL), dried over Na2SO4, and concentrated in vacuo to give the residue, which was purified by columnchromatography on silica gel, eluting with 0-70% EtOAc in PE to give methyl 4-cyclopropyl-3- methylbenzoate(390 mg, yield: 66%) as yellow oil . ESI-MS [M +H]+: 191.1.

[0286] Synthesis of (4-cyclopropyl-3-methylphenyl)methanol. To a solution of methyl 4- cy cl opropyl-3 -methylbenzoate (390 mg, 2.1 mmol) in THF (6 m ) was added LiAlIE (IM in THF, 6.3 mL, 6.3 mmol) dropwise slowly at 0 °C. The mixture stirred at 0 °C for 2 h. The reaction mixture was quenched NH4CI (sat. aq., 40 mL) at 0 °C and then extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, and concentrated in vacuo to give the residue, which was purified by column chromatography on silica gel, eluting with 0-80% EtOAc in PE to give (4-cyclopropyl-3- methylphenyl)methanol(214 mg, yield: 63%) as colorless oil. ESLMS [M +H]+: 163.1.

[0287] Synthesis of ethyl 6-methyliniidazo[l,2-a]pyridine-2-carboxylate. A mixture of 5- methylpyridin-2-amine (500 mg, 4.6 mmol) and ethyl 3-bromo-2-oxopropanoate (1.8 g, 9.2 mmol) in EtOH (20 mL) was stirred at 95 °C for 12 h. After the reaction was cooled to room temperature, NaHCOi (sat. aq., 80 mL) was added, and the reaction was extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine, dried with Na2SO4, and concentrated in vacuo to give the crude, which was purified by column chromatography on silica gel (PE / EtOAc= 5 / 1) to give ethyl 6-methylimidazo[l,2-a]pyridine-2-carboxylate (300 mg, yield: 32%). ESLMS [M +H]+: 205.2.

[0288] Synthesis of (6-methylimidazo[l,2-a]pyridin-2-yl)methanol. To a solution of ethyl 6-methylimidazo[l,2-a]pyridine-2-carboxylate (300 mg, 1.5 mmol) in THF (20 mL) was added LiAULi (1 M in THF, 3.0 mL, 3mmol) slowly at 0 °C under Nr. The reaction mixture was warmed to room temperature and stirred for 1 h. The reaction was then quenched with water (5 mL), solid precipitate was filtered through the Celite1® and washed with MeOH (20 mL.) The filtrate was concentrated to give the crude product, which was purified by Prep-TLC (eluent: MeOH / DCM = 1 / 10) to give (6-methylimidazo[l,2-a]pyridin-2-yl)methanol (200 mg, yield: 82%) as a brown solid. ESLMS [M +H]+: 163.2

[0289] Synthesis of 2-imino-5-methylpyridin-l(2H)-amine. To a solution of 5- methylpyridin-2-amine (3.24 g, 30 mmol) in DCM (50 mL) was added O-(mesitylsulfonyl)hydroxylamine (12.9 g, 60 mmol) at 0 °C. The mixture was stirred at room temperature for 12 h. The reaction was concentrated to give 2-imino-5-methylpyridin-l(2H)- amine (16.2 g, crude) as a yellow solid, which was used in the next step directly. ESI-MS [M +H]+: 124.1

[0290] Synthesis of ethyl 6-methyl-[l,2,4]triazolo[l,5-a]pyridine-2-carboxylate. A mixture of 2-imino-5-methylpyridin-l(2H)-amine (16.2 g, crude) and ethyl 2-chloro-2-oxoacetate (8.16 g, 60 mmol) in pyridine (50 mL) was stirred at 100 °C for 14 h. After the reaction was cooled to room temperature, the mixture was concentrated. The residue was diluted with NaHCCh (sat. aq., 100 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, and concentrated in vacuo to give the crude, which was purified by column chromatography (eluent: EtOAc / PE from 0 to 50%) to give ethyl 6-methyl- [l,2,4]triazolo[l,5-a]pyridine-2-carboxylate (2.0 g, yield: 32 % over two steps) as a yellow solid. ESI-MS [M +H]+: 206.2

[0291] Synthesis of ethyl 6-methyl-[l,2,4]triazolo[l,5-a]pyridine-2-carboxylate. To a solution of ethyl 6-methyl-[l,2,4]triazolo[l,5-a]pyridine-2-carboxylate (710 mg, 3.46 mmol)) in THF / EtOH (30mL / 5 mL) was added LiBH4 (440 mg, 20.0 mmol) at 0 °C. The mixture was stirred at room temperature for 3 h and then quenched with NH4Q (sat. aq., 50 mL). The mixture was extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, and concentrated in vacuo to give the crude, which was purified by column chromatography (eluent: EtOAc / PE from 0 to 100%) to give ethyl 6-methyl- [l,2,4]triazolo[l,5-a]pyridine-2-carboxylate (450 mg, 80%) as a white solid. ESI-MS [M +H]+: 164.2.

[0292] Synthesis of 2-bromo-4-(hydroxymethyl)benzaldehyde. To a solution of methyl 3- bromo-4-cyanobenzoate (1.0 g, 4.17 mmol) in THF (10 mL) was added dropwise of DIBAL-H(IM in hexane, 12.5 mL, 12.5 mmol) at -65 °C. The mixture was stirred at -65 °C for 0.5 h. The resulting mixture was warmed to room temperature and stirred for another 0.5 h. The reaction mixture was quenched with NaOH (1 M aq., 20 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, and concentrated to give the residue, which was purified by column chromatography on silica gel, eluting with 0-20% EtOAc in PE to give 2-bromo-4-(hydroxymethyl)benzaldehyde (500 mg, yield: 56%) as a white solid. ESLMS [M +H]+: 215.0.

[0293] Synthesis of 2-bromo-4-(((tert-butyldimethylsilyl)oxy)methyl)benzaldehyde. To a solution of 2-bromo-4-(hydroxymethyl)benzaldehyde(500 mg, 2.33 mmol) in DCM (10 mL) was added Imidazole (476 mg, 6.99 mmol) and TBSC1 (351 mg, 2.33 mmol). The mixture was stirred at room temperature for 2 h. Water (20 mL) was added and extracted with ethyl acetate (20 mL*3). The organic layers were dried over sodium sulfate, filtered, and concentrated to give the crude, which was purified by silica gel chromatography, eluting with 0-50% EtOAc in PE to give 2-bromo-4-(((tert-butyldimethylsilyl)oxy)methyl)benzaldehyde (500 mg, yield: 65 %) as a white solid. ESLMS [M +H]+: 329.1

[0294] Synthesis of 7-(((tert-butyldimethylsilyl)oxy)methyl)-2-methylquinazoline. To a mixture of 2-bromo-4-(((tert-butyldimethylsilyl)oxy)methyl)benzaldehyde (500 mg, 1.52 mmol) and acetamidine (265 mg, 4.56 mmol) in DMSO (5 mL) was added Cui (57 mg, 0.3 mmol), L- proline (70 mg, 0.61 mmol), and CS2CO3 (1.49 g, 4.56 mmol) at room temperature under N2 atmosphere. After the mixture was stirred at 70 °C for 1 h, the mixture was cooled to room temperature and filtered. The filter cake was washed with DCM / MeOH (v / v = 3 / 1, 30 mL). The filtrates were concentrated in vacuo and the residue was diluted with water (20 mL) and extracted with EtOAc (30 mL x 2). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, and concentrated to give the residue, which was purified by column chromatography on silica gel, eluting with 0-5% MeOH in DCM to give 7-(((tert- butyldimethylsilyl)oxy)methyl)-2-methylquinazoline (100 mg, 23%) as a pale-yellow solid. ESIMS [M +H]+: 289.2

[0295] Synthesis of (2-methylquinazolin-7-yI)methanoi. To a solution of 7-(((tert- butyldimethylsilyl)oxy)methyl)-2-methylquinazoline (80 mg, 0.28 mmol) in MeOH (3 mL) was added HC1 (1 mL, 4M in MeOH) at room temperature, and the mixture was stirred at room temperate for 1 h. The reaction was concentrated to give to give (2-methylquinazolin-7-yl)methanol (50 mg, quant) as a white solid, which was used in the net step without purification.ESLMS [M +H]+: 175.1

[0296] Synthesis of methyl 4-(l-aminocyclopropyl)benzoate. To a solution of methyl 4- cyanobenzoate (1.0 g, 6.21 mmol) in PhMe (20 mL) was added Ti(OPr-i)4 (1.9 g, 6.82 mmol) at -40 °C, followed by dropwise addition of EtMgBr (4.5 mL, 13.6 mmol, 3 M in ether). The mixture was stirred at -40 °C for 1 h, and boron trifluoride etherate (1.57ml, 12.7 mmol) was added at once. After the reaction mixture was stirred at the same temperature for 2 h, HC1 (2 M aq., 20 mL) was added to quench the reaction. The reaction mixture was filtered. The aqueous phase was separated, and the organic layer was washed with water (30 mL x 3). The combined aqueous layers were basified with NaOH (2 M aq.) to adjust the pH to 8. The mixture was then extracted with EtOAc (100 mL x 3). The combined organic layers were washed dried over Na2SO4 and concentrated in vacuo to give the crude, which was purified by column chromatography on silica gel, eluting with 0-50% EtOAc in PE to give methyl 4-(l- aminocyclopropyl)benzoate (290 mg, yield: 24.4%) as a white solid. ESLMS [M +H]+: 192.1.

[0297] Synthesis of methyl 4-(l-acetamidocyclopropyl)benzoate. To a solution of methyl 4- (l-aminocyclopropyl)benzoate (140 mg, 0.73 mmol) in DCM (10 mL) was added F.tiN (148 mg, 1.46 mmol) and AcCl (57 mg, 0.73 mmol). After the mixture was stirred at 0 °C for 1 h, water (10 mL) was added and extracted with DCM (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, and concentrated in vacuo to give the residue, which was purified by column chromatography on silica gel, eluting with 0-40% EtOAc in PE to give methyl 4-(l-acetamidocyclopropyl)benzoate (140 mg, yield 82.3%) as a white solid. ESIMS [M +H]+: 234.1

[0298] Synthesis ofN-(l-(4-(hydroxymethyl)phenyl)cyclopropyl)acetamide. To a solution of methyl 4-(l-acetamidocyclopropyl)benzoate (140 mg, 0.60 mmol) in THF (10 mL) was added DIBAL-H (1.8 mL, IM in hexane, 1.80 mmol) at -60 °C. After the mixture was stirred at -60 °C for 1 h, the reaction mixture was quenched with H2O (20 mL) at -60 °C and extracted with EtOAc (20 mL x 2). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, and concentrated in vacuo to give the residue, which was purified by column chromatography on silica gel, eluting with 0-50% EtOAc in PE to give N-(l-(4- (hydroxymethyl)phenyl)cyclopropyl)acetamide (25 mg, yield 20.3%) as white solid. ESI-MS [M + H]+: 206.1.

[0299] Synthesis of (4-bromo-3,5-dimethylphenyl)methanol. To a solution of 4-bromo-3,5- dimethylbenzaldehyde (106 mg, 0.5 mmol) in EtOH (2 mL) was added NaBHi(38 mg, 1 mmol). The mixture was stirred at room temperature for 2 h. The reaction was quenched by H2O (0.5 mL) and concentrated in vacuo to give the crude, which was purified by Prep-TLC(DCM / MeOH=20 / l) to give (4-bromo-3, 5 -dimethylphenyl)m ethanol (80 mg, yield: 75%) as a yellow solid. ESI-MS (M+H)+:214.1.

[0300] Synthesis of 5-((benzyloxy)methyl)-2-bromo-l,3-dimethylbenzene. To a solution of (4-bromo-3,5-dimethylphenyl)methanol (85 mg, 0.4 mmol) in THF(5 mL) was added NaH (60% in mineral oil, 40 mg, 1.0 mmol) at 0 °C. The mixture was stirred at 0 °C for 30 min. Then benzyl chloride (126 mg, 1.0 mmol) was added. The mixture was stirred at room temperature for15 h. The reaction was then quenched by NH4CI (sat.aq., 20 mL) and extracted by EtOAc (20 mL *3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, and concentrated in vacuo to give the crude, which was purified by Prep-TLC (PE / EtOAc=l / l) to give 5-((benzyloxy)methyl)-2-bromo-l,3-dimethylbenzene (84 mg, yield: 69%) as a yellow oil. ESI-MS (M+H)+: 305.1.

[0301] Synthesis of tert-butyl 2-(4-((benzyloxy)methyl)-2,6-diniethylphenyl)acetate. To a solution of (2-(tert-butoxy)-2-oxoethyl)zinc(II) bromide (1 mL, 0.4 mmol, 0.4 M in THF) in THF (3 mL) was added 5-((benzyloxy)methyl)-2-bromo-l,3-dimethylbenzene (84 mg, 0.28 mmol), Pd2(dba)3 (27 mg, 0.03 mmol), and X-Phos (28 mg, 0.06 mmol) under N2. The mixture was stirred at 70 °C for 4 h. After the mixture was cooled to room temperature, the reaction was filtered by Celite®. The filter cake was washed with THF (20 mL), and the filtrate was concentrated in vacuo to give the residue, which was purified by Prep-TLC (PE / EtOAc=3 / l) to afford tert-butyl 2-(4-((benzyloxy)methyl)-2,6-dimethylphenyl)acetate (56 mg, yield: 59%) as a yellow oil. ESI-MS (M+H)+:341.2.

[0302] Synthesis of 2-(4-((benzyloxy)methyl)-2,6-dimethylphenyl)acetic acid. To a solution of tert-butyl 2-(4-((benzyloxy)methyl)-2,6-dimethylphenyl)acetate (56 mg, 0.16 mmol) in DCM (3 mL) was added TFA (0.5 mL). After the mixture was stirred at room temperature for 2 h, water (15 mL) was added to dilute the reaction, and the pH of the mixture was adjusted to 5-6 by adding NaHCCh (sat. aq.). The reaction mixture was extracted with DCM (20 mL x 3). The combined organics were concentrated in vacuo to give 2-(4-((benzyloxy)methyl)-2,6- dimethylphenyl)acetic acid (60 mg, crude) as a yellow solid, which was used in the next step without purification. ESI-MS (M+H)+:285.2.

[0303] Synthesis of 2-(4-((benzyloxy)methyl)-2,6-dimethylphenyl)-N,N-dimethylacetamide.To a solution of 2-(4-((benzyloxy)methyl)-2,6-dimethylphenyl)acetic acid (60 mg, crude) in DMF (2 mL) was added HOBT (35 mg, 0.26 mmol) and EDCI (50 mg, 0.26 mmol). The mixture was stirred at room temperature for 30 min. Then dimethylamine (8 mg, 0.17 mmol) and DIPEA (66 mg, 0.51 mmol) was added. The reaction was stirred at room temperature for another 16 h. The reaction was quenched by water (10 mL) and extracted by EtOAc(10 mLx3). The combined organic layers were concentrated in vacuo, and the residue was purified by Prep-TLC (PE / EtOAc=l / l)to give 2-(4-((benzyloxy)methyl)-2,6-dimethylphenyl)-N,N-dimethylacetamide (40 mg, yield: 80% over 2 steps) as a yellow oil. ESI-MS (M+H)+:312.2.

[0304] Synthesis of 2-(4-(hydroxymethyl)-2,6-dimethylphenyl)-N,N-dimethylacetamide.To a solution of 2-(4-((benzyloxy)methyl)-2,6-dimethylphenyl)-N,N-dimethylacetamide (40 mg, 0.13 mmol) in MeOH (4 mL) was added Pd / C(10 mg). After the reaction was stirred at room temperature for 1 h under H2, the mixture was filtered through Celite®. The filter cake was washed with MeOH (15 mL), and the filtrate was concentrated to give the crude, which was purified by Prep-TLC (PE / EtOAc=l / 2) to give 2-(4-(hydroxymethyl)-2,6-dimethylphenyl)-N,N- dimethylacetamide (24 mg, yield: 84%) as a pale solid. ESLMS (M+H)+:222.3.Synthesis ofN-(4-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)-N-methylpyrrolidine-l- carboxamide

[0305] Synthesis of tert-butyldimethyl((4-nitrobenzyl)oxy)silane. To a solution of (4- nitrophenyl)m ethanol (5.0 g, 32.65 mmol) in DMF (10 mL) was added imidazole (6.7 g, 98.41 mmol) and TBSC1 (4.9 g, 32.51 mmol) at 0 °C. After the mixture was stirred 0 °C for 1 h, the reaction was quenched with H2O (100 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na2SOr, and concentrated in vacuo to give the residue, which was purified by column chromatography on silica gel, eluting with 0-50% EtOAc in PE to give tert-butyldimethyl((4-nitrobenzyl)oxy)silane (8.0 g, yield: 92%) as a white solid. ESLMS [M +H]+: 268.1

[0306] Synthesis of 4-(((tert-butyldimethylsilyl)oxy)methyl)aniline. To a solution of tert- butyldimethyl((4-nitrobenzyl)oxy)silane (2.0 g, 7.5 mmol) in MeOH (20 mL) was added Pd / C (0.2 g) at room temperature, the mixture was stirred at this temperature under H2 atmosphere for 14 h. Then the mixture was filtered through celite, the filter cake was washed with MeOH (20 mL), and the filtrates was concentrated to give the crude, which was purified by column chromatography on silica gel, eluting with 0-50% EtOAc in PE to give 4-(((tert- butyldimethylsilyl)oxy)methyl)aniline (1.25 g, yield: 70%) as a white solid. ESLMS [M +H]+: 238.1

[0307] Synthesis of 2-bromo-4-(((tert-butyldimethylsilyl)oxy)methyl)benzaldehyde. To a solution of 4-(((tert-butyldimethylsilyl)oxy)methyl)aniline (3.8 g, 16 mmol) in MeOH (20 mL) was added formaldehyde (482 mg, 16 mmol) and NaOCHa (1.7 g, 32 mmol). The mixture was stirred at 80 °C for 3 h. After cooling to room temperature, NaBEh (1.2 g, 32 mmol) was added to the solution and the mixture was stirred at rt for another 1 h. Water (50 mL) was added, and the reaction was extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous NaaSCU, and concentrated in vacuo to give the crude, which was purified by column chromatography on silica gel, eluting with 0-50% EtOAc in PE to give 4-(((tert-butyldimethylsilyl)oxy)methyl)-N-methylaniline (1.0 g, yield 24.9%) as white solid. ESI-MS [M +H]+: 252.2

[0308] Synthesis of N-(4-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)-N- methylpyrrolidine-1 -carboxamide. To a solution of pyrrolidine- 1 -carbonyl chloride (107 mg, 0.80 mmol) in DCM (10 mL) was added 4-(((tert-butyldimethylsilyl)oxy)methyl)-N- methylaniline (200 mg, 0.80 mmol) and pyridine (190 mg, 2.4 mmol). The mixture was stirred at 0 °C for 5 h. Water (50 mL) was added and the reaction was extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, and concentrated in vacuo to give the crude, which was purified by column chromatography on silica gel, eluting with 0-40% EtOAc in PE to give N-(4-(((tert- butyldimethylsilyl)oxy)methyl)phenyl)-N-methylpyrrolidine-l-carboxamide (120 mg, yield: 43%) as a white solid. ESI-MS [M +H]+: 349.2Synthesis of l-(4-(hydroxymethyl)phenyl)-l,3,3-trimethylurea

[0309] Synthesis of tert-butyldimethyl((4-nitrobenzyl)oxy)silane. To a solution of dimethylcarbamoyl chloride (137 mg, 1.27 mmol) in DCM (10 mL) was added 4-(((tert- butyldimethylsilyl)oxy)methyl)-N-methylaniline (320 mg, 1.27 mmol) and pyridine (300 mg, 3.81 mmol). The mixture was stirred at 40 °C for 5 h. Water (20 mL) was added and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, and concentrated in vacuo to give the crude, which was purified bycolumn chromatography on silica gel, eluting with 0-40% EtOAc in PE to give N-(4-(((tert- butyldimethylsilyl)oxy)methyl)phenyl)-N-methylpyrrolidine-l-carboxamide (126 mg, yield: 31%) as a white solid. ESLMS [M +H]+: 323.2

[0310] Synthesis of 4-(((tert-butyldimethylsilyl)oxy)methyl)aniline. To a solution of l-(4-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)-l,3,3-trimethylurea (50 mg, 0.15 mmol) in EtOAc (5.0 mL) was added HC1 (1 mL, 4 M in EtOAc). The resulting mixture was stirred at room temperature for 5 h, then concentrated. The residue was neutralized with NH3 (2 mL, 7 M in MeOH) and stirred for 10 min then concentrated, the residue was purified by Prep-TLC to give l-(4-(hydroxymethyl)phenyl)-l,3,3-trimethylurea (16 mg, yield: 49.6%) as a white solid. ESL MS [M +H]+: 209.1Synthesis of (2,3-dimethylquinoxalin-6-yl)methanol

[0311] Synthesis of methyl 3-methylquinoxaline-6-carboxylate. To a solution of methyl3, 4-di aminobenzoate (180 mg, 1.08 mmol) in MeOH (5 mb) was added oxopropanal (117 mg, 1.62 mmol). After the resulting mixture was stirred at 25 °C for 24 h, the reaction was concentrated in vacuo. The residue was diluted with H2O (25 mL) and extracted with DCM (20 mL x 3). The combined organics were washed with brine (20 mL), dried over Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with 0-40% EtOAc in PE to give methyl 3-methylquinoxaline-6-carboxylate (100 mg, yield 45.8%) as a white solid. ESLMS [M +H]+: 203.1

[0312] Synthesis of (2,3-dimethylquinoxalin-6-yl)methanol. To a solution of methyl 3- methylquinoxaline-6-carboxylate (100 mg, 0.46 mmol) in THF (5 mL) was added dropwise of DIBAL-H (IM in THF, 1.38 mL, 1.38 mmol) at -65 °C. The mixture was stirred at -65 °C for 0.5 h. The resulting mixture was warmed to room temperature and stirred for another 0.5 h. The reaction mixture was quenched with NaOH (1 M aq., 5 mL) and water (15 mL), extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with 0-20% EtOAc in PE to give (2,3 -dimethylquinoxalin-6-yl)m ethanol (40 mg, yield: 46.2%) as a white solid. ESLMS [M +H]+: 189.1

[0313] To a solution of ethyl chloroformate (173 mg, 1 .59 mmol) in DCM (10 mL) was added 4-(((tert-butyldimethylsilyl)oxy)methyl)-N-methylaniline (400 mg, 1.59 mmol) and pyridine (377 mg, 4.77 mmol) at 0 °C. The mixture was stirred at 0 °C for 5 h. Water (20 mL) was added and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous NazSCh, and concentrated in vacuo to give the crude, which was purified by column chromatography on silica gel, eluting with 0-40% EtOAc in PE to give ethyl (4-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)(methyl)carbamate (459 mg, yield: 89%) as white solid. ESLMS [M +H]+: 324.2

[0314] Synthesis of (4-bromo-3-methylphenyl)methanol. To a solution of 4-bromo-3- methylbenzaldehyde (100 mg, 0.5 mmol) in EtOH (4 mL) was added NaBHi (38 mg, 1 mmol).The mixture was stirred at room temperature for 2 h. The reaction was quenched by H2O (1 mL) and concentrated in vacuo to give the crude, which was purified by Prep- TLC(DCM / MeOH=20 / l) to give (4-bromo-3-methylphenyl)methanol (80 mg, yield: 80%) as a yellow solid. ESLMS (M+H)+:201.1.

[0315] Synthesis of 4-((benzyloxy)methyl)-l-bromo-2-methylbenzene. To a solution of (4- bromo-3-methylphenyl)methanol (80 mg, 0.4 mmol) in THF(4 mL) was added NaH (60% in mineral oil, 40 mg, 1.0 mmol) at 0 °C. The mixture was stirred at 0 °C for 30 min. Then (chloromethyl)benzene (126 mg, 1.0 mmol) was added. The resulting mixture was stirred at room temperature for 15 h. The reaction was quenched by NHtCl (sat.aq., 20 mL) and extracted by EtOAc (20 mL *3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, concentrated in vacuo to give the crude, which was purified by Prep-TLC (PE / EtOAc=l / l) to give 4-((benzyloxy)methyl)-l-bromo-2-methylbenzene (84 mg, yield:72%) as a yellow oil. ESLMS (M+H)+:291.1.

[0316] Synthesis of tert-butyl 2-(4-((benzyloxy)methyl)-2-methylphenyl) acetate. To a solution of (2-(tert-butoxy)-2-oxoethyl)zinc(II) bromide (1.1 mL, 0.4 M in THF, 0.44 mmol) in THF (4 mL) was added 4-((benzyloxy)methyl)-l-bromo-2-methylbenzene (84 mg, 0.29 mmol), Pd2(dba)3 (27 mg, 0.03 mmol), and X-Phos (28 mg, 0.06 mmol). After the mixture was stirred at 70 °C for 4 h under N2, the mixture was cooled to room temperature and then filtered by Celite®. The filter cake was washed with THF (20 mL), and the filtrate was concentrated in vacuo to give the residue, which was purified by Prep-TLC (PE / EtOAc=3 / l) to afford tert-butyl 2-(5-(((tert- butyldimethylsilyl)oxy)methyl)pyridin-2-yl)acetate (56mg, yield: 59%) as a yellow oil. ESLMS (M+H)+: 327.1.

[0317] Synthesis of 2-(4-((benzyloxy)methyl)-2-methylphenyl)acetic acid. To a solution of tert-butyl 2-(4-((benzyloxy)methyl)-2-methylphenyl)acetate (56 mg, 0.17 mmol) in DCM (3 mL) was added TFA (0.5 mL). The mixture was stirred at room temperature for 2 h. Water (15 mL) was added, and the pH of the reaction was adjusted to 5-6 by adding NaHCCh (sat. aq.). The reaction was extracted with DCM (20 mL*3). The combined organics were concentrated in vacuo to give 2-(4-((benzyloxy)methyl)-2-methylphenyl)acetic acid (60 mg, crude) as a yellow solid. ESI-MS (M+H)+:271.2.

[0318] Synthesis of 2-(4-((benzyloxy)niethyl)-2-methylphenyl)-N,N-dimethylacetamide.To a solution of 2-(4-((benzyloxy)methyl)-2-methylphenyl)acetic acid (60 mg, crude) in DMF (3 mL) was added HOBT(35 mg, 0.26 mmol) and EDCI(50 mg, 0.26 mmol). The mixture was stirred at room temperature for 30 min. Then dimethylamine (12 mg, 0.25 mmol) and DIPEA (66 mg, 0.51 mmol) were added. The resulting reaction mixture was stirred at room temperature for another 16 h. The reaction was quenched by H2O (20 mL) and extracted by EtOAc (20 mL><3).The combined organics were concentrated in vacuo and the residue was purified by Prep-TLC (PE / EtOAc=l / l)to give 2-(4-((benzyloxy)methyl)-2-methylphenyl)-N,N-dimethylacetamide(40 mg, yield: 80%) as a yellow oil. ESI-MS (M+H)+:298.2.

[0319] Synthesis of 2-(4-(hydroxymethyl)-2-methylphenyl)-N,N-dimethylacetamide. To a solution of 2-(4-((benzyloxy)methyl)-2-methylphenyl)-N,N-dimethylacetamide(40 mg, 0.13 mmol) in MeOH (4 mL) was added Pd / C(10 mg). The reaction was stirred at room temperature for 1 h under H2. The mixture was filtered through Celite®. The filter cake was washed with MeOH (10 mL), and the filtrate was concentrated and purified by Prep-TLC (PE / EtOAc=l / 2) to give 2-(4-(hydroxymethyl)-2-methylphenyl)-N,N-dimethylacetamide(24 mg, yield: 88%) as a pale solid. ESI-MS (M+H)+:208.3.

[0320] Synthesis of 7-bromo-2-methylquinoline. A mixture of 3 -bromoaniline (500 mg, 2.91 mmol) and 2,4,6-trimethyl-l,3,5-trioxane (3.46 g, 26.19 mmol) in HC1 (cone. 5 mL) was stirred at room temperature for 1 hour, and then heated to reflux for 3 hours. After cooling to 0 °C, a solution of NaOH (sat. aq., 10 mL) was added slowly and the mixture was extracted with DCM (20 mL*3). The combined organic layers were washed with brine (15 mL), dried over Na2SO4 and concentrated to give the crude, which was purified by flash column chromatography on silica gel, eluting with 0-10% EtOAc / PE to afford 7-bromo-2-methylquinoline (100 mg, yield: 15%) as pale-yellow solid. ESI-MS [M +H]+: 222.2.

[0321] Synthesis of 2-methylquinoline-7-carboxylic acid. To a solution of 7-bromo-2- methylquinoline(146 mg, 0.66 mmol) in THF (5 mL) was added n-BuLi (0.66 mL, 2M in hexane, 1.32 mmol) slowly at -78 °C under CO2. After the mixture was stirred at - 78 °C for 3 h, the reaction was quenched by NH4CI (sat.aq., 10 mL) and extracted by EtOAc (20 mL*3). Thecombined organic layers were dried over Na2SO4 and concentrated to give the crude, which was purified by Prep-TLC (PE / EtOAc=l / l) to give 2-methylquinoline-7-carboxylic acid (100 mg, yield: 81%) as a yellow oil. ESI-MS (M+H)+: 188.1.

[0322] Synthesis of (2-methylquinolin-7-yl)methanol . To a solution of 2-methylquinoline-7-carboxylic acid (100 mg, 0.53 mmol) in THF (5 mL) was added BHs-THF (2 mL, 1 M in THF, 2 mmol) at 0 °C. The mixture was stirred at room temperature for 16 h. The reaction was quenched by NEECl (sat. aq., 10 mL) and extracted by EtOAc (20 mL*3). The combined organic layers were dried over NazSCE and concentrated to give the crude, which was purified by Prep- TLC (MeOH / DCM=l :20) to give (2-methylquinolin-7-yl)methanol (30 mg, yield: 33%) as a pale solid. ESLMS (M+H)+: 174.1.Synthesis of 3-(4-(hydroxymethyl)benzyl)-l-methylpyridin-2(lH)-one

[0323] Synthesis of methyl 4-((2-methoxypyridin-3-yl)methyl)benzoate. To a solution of methyl 4-(bromomethyl)benzoate (1 g, 4.37 mmol) in MeOH(15 mL) was added (2- methoxypyridin-3-yl)boronic acid (802 mg, 5.24 mmol), Pd(PPhs)4(509 mg, 0.44 mmol), and Na2CO3(1.6 g, 13.11 mmol). The mixture was stirred at 115 °C for 2 h under N2. After cooled to the room temperature, the reaction was diluted with H2O (50 mL) and extracted with EtOAc (50 mL*3). The combined organic layers were dried over Na2SO4 and concentrated to give the crude, which was purified by column chromatography on silica gel, eluting with 0-100% EtOAc in PE to give methyl 4-((2-methoxypyridin-3-yl)methyl)benzoate(500 mg, yield: 44%) as a yellow solid. ESI-MS (M+H)+: 258.1.

[0324] Synthesis of 4-((2-oxo-l,2-dihydropyridin-3-yl)methyl)benzoic acid. A mixture of methyl 4-((2-methoxypyridin-3-yl)methyl)benzoate (300 mg, 1.17 mmol) in HBr (40% in AcOH, 5 mL) was stirred at 70 °C for 16 h under N2. After cooled to the room temperature, thereaction was concentrated, and the residue was diluted with water (20 mL) and neutralized with NaHCO3(sat. aq.) to adjust to pH to 6, then extracted by EtOAc (40 mL*3). The combined organics were concentrated in vacuo and the residue was purified by column chromatography on silica gel, eluting with 0-100% EtOAc in PE to give 4-((2-oxo-l,2-dihydropyridin-3- yl)methyl)benzoic acid (250 mg, yield: 93%) as a yellow solid. ESI-MS (M+H)+:230.1.

[0325] Synthesis of methyl 4-((l-methyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)benzoate.To a solution of 4-((2-oxo-l,2-dihydropyridin-3-yl)methyl)benzoic acid (98 mg, 0.43 mmol) in DMF(3 mL) was added Mel (303 mg, 2.15 mmol) and NaH (60% in mineral oil, 86 mg, 2.15 mmol). The mixture was stirred at room temperature for 6 h. Water (10 mL) was added and the reaction was extracted by EtOAc (10 mL x 3). The combined organic layers were concentrated in vacuo and the residue was purified by column chromatography on silica gel, eluting with 0- 60% EtOAc in PE to give methyl 4-((l-methyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)benzoate (80 mg, yield: 72%) as a yellow oil. ESLMS (M+H)+: 258.1.

[0326] Synthesis of 3-(4-(hydroxymethyl)benzyl)-l-methylpyridin-2(lH)-one. To a solution of methyl 4-((l-methyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)benzoate (80 mg, 0.31 mmol) in THF (4 mL) was added Li Al FL (24 mg, 0.62 mmol) at 0 °C. After the reaction was stirred at 0 °C for 1 h, the reaction was quenched by NaSO-i-10H2O (500 mg) and stirred at room temperature for lOmin. The mixture was filtered through Celite®. The filter cake was washed with THF (20 mL), and the filtrate was concentrated and purified by Prep-TLC (DCM / MeOH=20 / l) to give 3-(4-(hydroxymethyl)benzyl)-l-methylpyridin-2(lH)-one(50 mg, yield: 70%) as a yellow solid. ESI-MS (M+H)+:230.1.

[0327] Synthesis of 3-cyclopropylbenzoic acid. To a solution of l-bromo-3- cyclopropylbenzene (400 mg, 2.05 mmol) in THF (5 mL) was added n-BuLi (2M in THF, 2 mL, 4 mmol) slowly at -78 °C under CO2. After the mixture was stirred at -78 °C for 3 h, the reaction was quenched by NH4Q (sat.aq., 20 mL) and extracted by EtOAc(20 mLx3). The combinedorganic layers were dried over Na2SO4 and concentrated to give the crude, which was purified by Prep-TLC (PE / EtOAc=l / l) to give 2-methylquinoline-7-carboxylic acid (200 mg, yield: 60%) as a yellow oil. ESI-MS (M+H)+: 163.2.

[0328] Synthesis of (3-cyclopropylphenyl)methanol. To a solution of 3 -cyclopropylbenzoic acid (200 mg, 1.23 mmol) in THF (5 mL) was added to BH3-THF (3 mL, 1 M in THF, 3 mmol) at 0 °C. The mixture was stirred at room temperature for 16 h. The reaction was quenched by NH4Q (sat.aq., 20 mL), and extracted by EtOAc(20 mL*3). The combined organic layers were dried over Na2SC>4 and concentrated to give the crude, which was purified by Prep-TLC (MeOH / DCM=l :20) to give (3-cyclopropylphenyl)methanol (150 mg, yield: 82%) as a pale solid. ESI-MS (M+H)+: 149.2.Synthesis of (S)-l-phenylethan-l-ol

[0329] To a solution of acetophenone (1 g, 8.32 mmol) in MeOH (10 mL) was added NaBHi (629 mg, 16.64 mmol) at 0 °C. The mixture was stirred at room temperature for 1 h. The reaction was quenched by NH4Q (sat. aq., 20 mL) and extracted by EtOAc (30 mL*3). The combined organic layers were concentrated in vacuo, and the residue was purified by column chromatography on silica gel, eluting with 0-20% MeOH in DCM to give 1-phenylethan-l-ol (800 mg, yield: 79%) as a pale solid. ESI-MS (M+H)+: 123.2.Synthesis of 4-(chloromethyl)-l -methyl-2-(trifluoromethyl)benzene

[0330] To a solution of 4-methyl-3-(trifluoromethyl)benzoic acid (500 mg, 2.45 mmol) in THF (10 mL) was added to BH3-THF(10 mL, 1 M in THF, 10 mmol) at 0°C. The mixture was stirred at room temperature for 16 h. The reaction was quenched by HC1 (IM aq., 10 mL), and extracted by EtOAc (20 mL*3). The combined organic layers were dried over Na2SO4 and concentrated to give the crude, which was purified by Prep-TLC (MeOH / DCM=l :20) to give 4-(chloromethyl)- l-methyl-2-(trifluoromethyl)benzene (400 mg, yield: 86%) as a pale solid. ESIMS (M+H)+: 191.1.Synthesis of (4-((l,3,4-oxadiazol-2-yl)methyl)phenyl)methanol

[0331] Synthesis of 2-(4-(hydroxymethyl)phenyl)acetohydrazide. A mixture of ethyl 2-(4- (hydroxymethyl)phenyl)acetate (200 mg, 1.03 mmol) and hydrazine solution (0.1 mL, 80% aq.) in MeOH (4 mL) was stirred at 50 °C for 3 h. After the reaction mixture was cooled to room temperature, the mixture was concentrated in vacuo to afford 2-(4- (hydroxymethyl)phenyl)acetohydrazide (180 mg, yield: 97%) as a yellow solid, which was used in the next step without purification. ESI-MS [M +H]+: 181.1

[0332] Synthesis of (4-((l,3,4-oxadiazol-2-yl)niethyl)phenyl)methanol. To a solution of 2- (4-(hydroxymethyl)phenyl)acetohydrazide (100 mg, 0.56 mmol) in xylene (5 mL) was added triethoxymethane (415 mg, 2.80 mmol) and AcOH (1 mL), and the mixture was stirred at 140 °C for 20 h. After the reaction mixture was cooled to room temperature, the reaction was quenched with NaHCOs (sat. aq.,15 mL) and extracted with EtOAc (20 mL x 2). The combined organic layers were concentrated and purified by Prep-TLC(EtOAc / PE=2 / 1) to give (4-((l ,3,4- oxadiazol-2-yl)methyl)phenyl)methanol (80 mg, yield: 75%) as a white solid. ESLMS [M +H]+: 191.2

[0333] Synthesis of ethyl 2-oxo-2H-[l,2'-bipyridine]-5'-carboxylate. To a solution of ethyl6-chloronicotinate (650 mg, 3.51 mmol) and pyridin-2(lH)-one (500 mg, 5.27 mmol) in DMF(15 mL) was added K2CO3 (1.21 g, 8.78 mmol), and the mixture was stirred at 80 °C for 10 h. After the reaction mixture was cooled to room temperature, the reaction was quenched with water (150 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were concentrated and purified by flash column chromatography on silica gel, eluting with a gradient of 0-50% EtOAc / PE to give ethyl 2-oxo-2H-[l,2'-bipyridine]-5'-carboxylate (550 mg, yield: 64%) as a yellow solid. ESLMS [M +H]+: 245.2

[0334] Synthesis of 5'-(hydroxymethyl)-2H-[l,2'-bipyridin]-2-one. To a solution of 2-oxo- 2H-[l,2'-bipyridine]-5'-carboxylate (280 mg, 1.15 mmol) in EtOH (5 mL) was added NaBEh (131 mg, 3.45 mmol), and the mixture was stirred at room temperature for 2 h. The reaction was quenched with water (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were concentrated and purified by flash column chromatography on silica gel, eluting with a gradient of 0-80% EtOAc / PE to give 5'-(hydroxymethyl)-2H-[l,2'-bipyridin]-2-one (210 mg, yield: 91%) as a white solid. ESLMS [M +H]+: 203.2Synthesis of (4-(2-(lH-pyrazol-l-yl)ethyl)phenyl)methanol

[0335] Synthesis of ethyl 4-(2-chloroethyl)benzoate. To a solution of 4-(2- chloroethyl)benzoic acid (5.0 g, 27.17 mmol) in EtOH (80 mL) was added con. H2SO4 (2 mL), and the mixture was reflux for 12 h. After the reaction was cooled to room temperature, the reaction mixture was concentrated, the residue was diluted with water (50 mL) and neutralized with Na2COs (sat. aq., 50 mL), and extracted with EtOAc (100 mL x 3). The combined organic layers were concentrated and purified by flash column chromatography on silica gel, eluting with a gradient of 0-40% EtOAc / PE to give ethyl 4-(2-chloroethyl)benzoate (5.3 g, yield: 92%) as a yellow solid. ESLMS [M +H]+: 213.2

[0336] Synthesis of ethyl 4-(2-(lH-pyrazol-l-yl)ethyl)benzoate. To a solution of ethyl 4-(2- chloroethyl)benzoate (1.0 g, 4.72 mmol) in DMF (10 mL) was added CS2CO3 ( 4.6 g, 14.16mmol), Nal (2.1 g, 14.16 mmol), and IH-pyrazole (481 mg, 7.08 mmol), and the mixture was stirred at 90 °C for 12 h. After the reaction mixture was cooled to room temperature, water (50 mL) was added, and the reaction was extracted with EtOAc (80 mL x 3). The combined organic layers were concentrated and purified by flash column chromatography on silica gel, eluting with a gradient of 0-50% EtOAc / PE to give ethyl 4-(2-(lH-pyrazol-l-yl)ethyl)benzoate (550 mg, yield: 48%) as a yellow solid. ESI-MS [M +H]+: 245.2

[0337] Synthesis of (4-(2-(lH-pyrazol-l-yl)ethyl)phenyl)methanol. To a solution of ethyl 4- (2-(lH-pyrazol-l-yl)ethyl)benzoate (50 mg, 0.20 mmol) in MeOH (1 mL) and THF (1 mL) was added LiBHi (13 mg, 0.60 mmol), and the mixture was stirred at room temperature for 2 h. The reaction was concentrated and purified by Prep-TLC (PE / EtOAc=l / l) to give (4-(2-(lH-pyrazol- l-yl)ethyl)phenyl)methanol (30 mg, yield: 73%) as a white solid. ESLMS [M +H]+: 203.2Synthesis of l-(4-(hydroxymethyl)phenethyl)pyridin-2(lH)-one

[0338] Synthesis of ethyl 4-(2-(2-oxopyridin-l(2H)-yl)ethyl)benzoate. To a solution of ethyl 4-(2-chloroethyl)benzoate (106 mg, 0.50 mmol) in DMF (5 mL) was added CS2CO3 ( 489 mg, 1.50 mmol), Nal (225 mg, 1.50 mmol), and pyridin-2-ol (71 mg, 0.75 mmol), and the mixture was stirred at 90 °C for 16 h. After the reaction mixture was cooled to room temperature, the reaction mixture was quenched with H2O (25 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were concentrated and purified by Prep-TLC (PE / EtOAc=l / l) to give ethyl 4-(2-(2-oxopyridin-l(2H)-yl)ethyl)benzoate (71 mg, yield: 52%) as a yellow solid. ESLMS [M +H]+: 272.2

[0339] Synthesis of l-(4-(hydroxymethyl)phenethyl)pyridin-2(lH)-one. To a solution of ethyl 4-(2-(2-oxopyridin-l(2H)-yl)ethyl)benzoate (71 mg, 0.26 mmol) in MeOH (1 mL) and THF (1 mL) was added LiBFL (18 mg, 0.78 mmol), and the mixture was stirred at room temperature for 3 h. The reaction was concentrated and purified by Prep-TLC (PE / EtOAc=l / 2)to give l-(4-(hydroxymethyl)phenethyl)pyridin-2(lH)-one (31 mg, yield: 52%) as a white solid.ESI-MS [M +H]+: 230.2Synthesis of (7-chloroquinolin-3-yl)methanol

[0340] To a solution of 7-chloroquinoline-3-carboxylic acid (500 mg, 2.41 mmol) in THF (10 mL) was added isobutyl chloroformate (658 mg, 4.82 mmol) and EtsN (487 mg, 4.82 mmol) at -20 °C, and the mixture was stirred at -20 °C for 20 min. After the mixture was warmed to 0 °C, NaBH4 (275 mg, 7.23 mmol) was added and the reaction was stirred at room temperature for 18 h. Water (30 mL) was added and the reaction was extracted with EtOAc (40 mL x 3). The combined organic layers were concentrated and purified by flash column chromatography on silica gel, eluting with a gradient of 0-80% EtOAc / PE to give (7-chloroquinolin-3-yl)methanol (121 mg, yield: 26%) as a yellow solid. ESI-MS [M +H]+: 194.1

[0341] To a solution of 2-(4-(hydroxymethyl)phenyl)acetic acid (500 mg, 3.01 mmol) in DMF (10 mL) was added dimethyl amine (180 mg, 4 mmol), EDCI (1.1 g, 6.02 mmol), and HOBT (813 mg, 6.02 mmol) and DIPEA (1.9 g, 15.05 mmol). The mixture was stirred at room temperature for 3 h. Water (100 mL) was added, and the reaction was extracted with EtOAc (60 mL x 3). The combined organic layers were concentrated and purified by flash column chromatography on silica gel, eluting with a gradient of 0-60% EtOAc / PE to give 2-(4- (hydroxymethyl)phenyl)-N,N-dimethylacetamide ( 470 mg, yield: 81%) as a yellow solid. ESIMS [M +H]+: 194.2

[0342] To a solution of (lH-benzo[d]imidazol-2-yl)methanol (148 mg, 1 mmol) in MeCN (10 mL) was added KF (116 mg, 2 mmol) and diethyl (bromodifluoromethyl)phosphonate (266 mg, 1 mmol), the mixture was stirred at room temperature for 12 h under N2. The reaction was quenched with water (50 mL) and extracted with EtOAc (60 mL x 3). The combined organic layers were concentrated and purified by flash column chromatography on silica gel, eluting with a gradient of 0-50% EtOAc / PE to give 2-(4-(hydroxymethyl)phenyl)-N,N-dimethylacetamide (150 mg, yield: 75%) as a yellow solid. ESI-MS [M +H]+: 199.2Synthesis of (6-bromoquinolin-2-yl) methanol

[0343] Synthesis of 6-bromoquinoline-2-carbaldehyde. SeCh (103 mg, 1.2 mmol, 1.3 eq) in suspension in dioxane (5 mL) was heated at 60°C. 6-bromoquinaldine (200 mg, 0.9 mmol) was added, and the mixture was stirred at 80 °C for 3 hours. After cooling to room temperature, the mixture was filtered through celite, washed with dioxane, and concentrated under reduced pressure to give 6-bromoquinoline-2-carbaldehyde (330 mg, crude) as a white solid, which was used in the next step without purification. ESI-MS [M +H]+: 236.2

[0344] Synthesis of (6-bromoquinolin-2-y I) methanol. To a solution of 6-bromoquinoline-2- carbaldehyde (330 mg, crude) in EtOH (10 mL) was added sodium borohydride (58 mg, 1.5 mmol) at 0°C. The mixture was stirred at room temperature for 1 hour. The reaction was quenched with water (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were concentrated and purified by Prep-TLC (EtOAc / PE=l / l) to give (6-bromoquinolin- 2-yl)methanol (120 mg, yield: 56% over 2 steps) as a white solid. ESI-MS [M +H]+: 238.2Synthesis of (8-methylquinolin-3-yl)methanol NaBH4, Pd(dppf)CI2. TMEDATHF, r.t., 12 h HO^XXCX

[0345] Synthesis of (2-chloro-8-niethylquinolin-3-yl)methanol. To a solution of 2-chloro- 8-methylquinoline-3-carbaldehyde (205 mg, 1.00 mmol) in MeOH (5 mL) was added NaBHi (114 mg, 3.00 mmol), and the mixture was stirred at room temperature for 3 h. The reaction was quenched with water (30 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were concentrated and purified by flash column chromatography on silica gel, eluting with a gradient of 0-60% EtOAc / PE to (2-chloro-8-methylquinolin-3-yl)methanol (200 mg, yield: 97%) as a white solid. ESLMS [M +H]+: 208.2

[0346] Synthesis of (8-methylquinolin-3-yl)nethanol. To a solution of (2-chloro-8- methylquinolin-3-yl)m ethanol (200 mg, 0.97 mmol) in THF (5 mL) was added Pd(dppf)Ch (139 mg, 0.19 mmol), TMEDA (337 mg, 2.91 mmol) and NaBHi (110 mg, 2.91 mmol), and the mixture was stirred at room temperature for 12 h under N2. Water (30 mL) was added, and the reaction was extracted with EtOAc (30 mL x 3). The combined organic layers were concentrated and purified by flash column chromatography on silica gel, eluting with a gradient of 0-60% EtOAc / PE to (8-methylquinolin-3-yl)methanol (105 mg, yield: 62.5%) as a yellow solid. ESIMS [M +H]+: 174.2Synthesis of quinoxalin-6-ylmethanol

[0347] To a solution of quinoxaline-6-carboxylic acid (200 mg, 1.15 mmol) in THF (5 mL) was added LiAlHi (52 mg, 1.38 mmol) at 0 °C, and the reaction mixture was stirred at room temperature for 1 h. The reaction was quenched with water (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were concentrated and purified by flash column chromatography on silica gel, eluting with a gradient of 0-70% EtOAc / PE to give quinoxalin-6- ylmethanol (134 mg, yield: 73%) as a white solid. ESLMS [M +H]+: 161.1Synthesis of (3-chloroquinolin-6-yl)methanol

[0348] Synthesis of methyl 3-chloroquinoline-6-carboxylate. A mixture of methyl quinoline-6-carboxylate (6 g, 32 mmol) and NCS (4.7 g, 35 mmol) in DMF (50 mL) was stirred at 80 °C for 2 h. After cooled to room temperature, the reaction was quenched with NaHCCh (sat. aq., 150 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (100 mL), dried over NarSCL, and concentrated in vacuo to give the crude, which was purified with silica gel column chromatography, eluting with a gradient of 0-20% EtOAc in PE to give methyl 3-chloroquinoline-6-carboxylate (5 g, 71%) as a yellow solid. ESI-MS [M +H]+: 222.2

[0349] Synthesis of (3-chloroquinolin-6-yl) methanol. To a solution of methyl 3- chloroquinoline-6-carboxylate (500 mg, 2.3 mmol) in THF / MeOH (20 mL / 4 mL) was added LiBFL (202 mg, 9.2 mmol). The mixture was stirred at 50 °C for 12 h. After cooled to room temperature, the reaction was quenched with NHrCl (sat. aq., 50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (80 mL), dried over Na2SOr, and concentrated in vacuo to give the crude, which was purified with silica gel column chromatography, eluting with a gradient of 0-60% EtOAc in PE to give (3-chloroquinolin-6- yl)methanol (350 mg, 79%) as a yellow solid. ESI-MS [M +H]+: 194.2Synthesis of (7-chloroquinolin-3-yl)methanol

[0350] To a solution of 7-chloroquinoline-3-carboxylic acid (500 mg, 2.41 mmol) in THF (10 mL) was added isobutyl chloroformate (658 mg, 4.82 mmol) and EtsN (487 mg, 4.82 mmol) at -20 °C, and the mixture was stirred at -20 °C for 20 min. After the mixture was warmed to 0 °C, NaBJL (275 mg, 7.23 mmol) was added and the reaction was stirred at room temperature for 18 h. Water (30 mL) was added, and the reaction was extracted with EtOAc (40 mL x 3). The combined organic layers were concentrated and purified by flash column chromatography onsilica gel, eluting with a gradient of 0-80% EtOAc / PE to give (7-chloroquinolin-3-yl)methanol (121 mg, yield: 26%) as a yellow solid. ESLMS [M +H]+: 194.1

[0351] To a solution of 2-(4-(hydroxymethyl)phenyl)acetic acid (500 mg, 3.01 mmol) in DMF (10 mL) was added dimethyl amine (180 mg, 4 mmol), EDCI (1.1 g, 6.02 mmol), HOBT (813 mg, 6.02 mmol), and DIPEA (1.9 g, 15.05 mmol). The mixture was stirred at room temperature for 3 h. Water (100 mL) was added, and the reaction was extracted with EtOAc (60 mL x 3). The combined organic layers were concentrated and purified by flash column chromatography on silica gel, eluting with a gradient of 0-60% EtOAc / PE to give 2-(4- (hydroxymethyl)phenyl)-N,N-dimethylacetamide ( 470 mg, yield: 81%) as a yellow solid. ESIMS [M +H]+: 194.2

[0352] To a solution of (lH-benzo[d]imidazol-2-yl)methanol (148 mg, 1 mmol) in MeCN (10 mL) was added KF (116 mg, 2 mmol) and diethyl (bromodifluoromethyl)phosphonate (266 mg, 1 mmol), the mixture was stirred at room temperature for 12 h under N2. The reaction was quenched with water (50 mL), extracted with EtOAc (60 mL x 3). The combined organic layers were concentrated and purified by flash column chromatography on silica gel, eluting with a gradient of 0-50% EtOAc / PE to give 2-(4-(hydroxymethyl)phenyl)-N,N-dimethylacetamide (150 mg, yield: 75%) as a yellow solid. ESLMS [M +H]+: 199.2.Synthesis of (6-bromoquinolin-2-y I) methanol

[0353] Synthesis of 6-bromoquinoline-2-carbaldehyde. SeCh (103 mg, 1.2 mmol, 1.3 eq) in suspension in dioxane (5 mL) was heated at 60 °C. 6-bromoquinaldine (200 mg, 0.9 mmol) was added and the mixture was stirred at 80 °C for 3 hours. After cooling to room temperature, the mixture was filtered through celite, washed with dioxane and concentrated under reduced pressure to give 6-bromoquinoline-2-carbaldehyde (330 mg, crude) as a white solid, which was used in the next step without purification. ESI-MS [M +H]+: 236.2.

[0354] Synthesis of (6-bromoquinolin-2-yl)methanol. To a solution of 6-bromoquinoline-2- carbaldehyde (330 mg, crude) in EtOH (10 mL) was added Sodium borohydride (58 mg, 1.5 mmol) at 0 °C. The mixture was stirred at room temperature for 1 hour. The reaction was quenched with water (20 mL), extracted with EtOAc (20 mL x 3). The combined organic layers were concentrated and purified by Prep-TLC (EtOAc / PE=l / l) to give (6-bromoquinolin-2- yl)methanol (120 mg, yield: 56% over 2 steps) as a white solid. ESI-MS [M +H]+: 238.2.Synthesis of (8-methylquinolin-3-yl)methanol

[0355] Synthesis of (2-chloro-8-methylquinolin-3-yl)methanol. To a solution of 2-chloro- 8-methylquinoline-3-carbaldehyde (205 mg, 1.00 mmol) in MeOH (5 mL) was added NaBHt (114 mg, 3.00 mmol), the mixture was stirred at room temperature for 3 h. The reaction was quenched with water (30 mL), extracted with EtOAc (20 mL x 3). The combined organic layers were concentrated and purified by flash column chromatography on silica gel, eluting with a gradient of 0-60% EtOAc / PE to (2-chloro-8-methylquinolin-3-yl)methanol (200 mg, yield: 97%) as a white solid. ESI-MS [M +H]+: 208.2.

[0356] Synthesis of (8-methylquinolin-3-y I) methanol. To a solution of (2-chloro-8- methylquinolin-3-yl)m ethanol (200 mg, 0.97 mmol) in THF (5 mL) was added Pd(dppf)C12 (139 mg, 0.19 mmol), TMEDA (337 mg, 2.91 mmol) and NaBH4 (110 mg, 2.91 mmol), the mixture was stirred at room temperature for 12 h under N2. Water (30 mL) was added and the reactionwas extracted with EtOAc (30 mL x 3). The combined organic layers were concentrated and purified by flash column chromatography on silica gel, eluting with a gradient of 0-60% EtOAc / PE to (8-methylquinolin-3-yl)methanol (105 mg, yield: 62.5%) as a yellow solid. ESIMS [M +H]+: 174.2.Synthesis of quinoxalin-6-ylmethanol

[0357] To a solution of quinoxaline-6-carboxylic acid (200 mg, 1.15 mmol) in THF (5 mL) was added LiAlHi (52 mg, 1.38 mmol) at 0 °C, the reaction mixture was stirred at room temperature for 1 h. The reaction was quenched with water (20 mL), extracted with EtOAc (20 mL x 3). The combined organic layers were concentrated and purified by flash column chromatography on silica gel, eluting with a gradient of 0-70% EtOAc / PE to give quinoxalin-6- ylmethanol (134 mg, yield: 73%) as a white solid. ESI-MS [M +H]+: 161.1.Synthesis of (3-chloroquinolin-6-yl)methanol

[0358] Synthesis of methyl 3-chloroquinoline-6-carboxylate. A mixture of methyl quinoline-6-carboxylate (6 g, 32 mmol) and NCS (4.7 g, 35 mmol) in DMF (50 mL) was stirred at 80 °C for 2 h. After cooled to room temperature, the reaction was quenched with NaHCCh (sat. aq., 150 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, concentrated in vacuo to give the crude, which was purified with silica gel column chromatography, eluting with a gradient of 0-20% EtOAc in PE to give methyl 3-chloroquinoline-6-carboxylate (5 g, 71%) as a yellow solid. ESLMS [M +H]+: 222.2.

[0359] Synthesis of (3-chloroquinolin-6-yl)methanol. To a solution of methyl 3- chloroquinoline-6-carboxylate (500 mg, 2.3 mmol) in THF / MeOH (20 mL / 4 mL) was added LiBHi (202 mg, 9.2 mmol). The mixture was stirred at 50 °C for 12 h. After cooled to roomtemperature, the reaction was quenched with NH-iCI (sat. aq., 50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (80 mL), dried over Na2SO4, concentrated in vacuo to give the crude, which was purified with silica gel column chromatography, eluting with a gradient of 0-60% EtOAc in PE to give (3-chloroquinolin-6- yl)methanol (350 mg, 79%) as a yellow solid. ESI-MS [M +H]+: 194.2.Synthesis of methyl 3-chloroquinoline-6-carboxylate

[0360] A mixture of methyl quinoline-6-carboxylate (6 g, 32 mmol) and NCS (4.7 g, 35 mmol) in DMF (50 mL) was stirred at 80 °C for 2 h. After cooled to room temperature, the reaction was quenched with NaHCOs (sat. aq., 150 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, concentrated in vacuo to give the crude, which was purified with silica gel column chromatography, eluting with a gradient of 0-20% EtOAc in PE to give methyl 3- chloroquinoline-6-carboxylate (5 g, 71%) as a yellow solid. ESLMS [M +H]+: 222.2.Synthesis of (3-chloroquinolin-6-yl)methanol

[0361] To a solution of methyl 3-chloroquinoline-6-carboxylate (500 mg, 2.3 mmol) in THF / MeOH (20 mL / 4 mL) was added LiBHi (202 mg, 9.2 mmol). The mixture was stirred at 50 °C for 12 h. After cooled to room temperature, the reaction was quenched with NH-iCl (sat. aq., 50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (80 mL), dried over Na2SO4, concentrated in vacuo to give the crude, which was purified with silica gel column chromatography, eluting with a gradient of 0-60% EtOAc in PE to give (3-chloroquinolin-6-yl)methanol (350 mg, 79%) as a yellow solid. ESLMS [M +H]+: 194.2.Synthesis of (6-chloroimidazo l, 2-a]pyridin-2-yl) methanol

[0362] To a solution of ethyl 6-chloroimidazo[l,2-a]pyridine-2-carboxylate (200 mg, 0.9 mmol) in THF (10 mL) was added DIBAL-H (1 M in THF, 2.7 mL, 2.7 mmol) slowly at -20 °C under N2. After the reaction mixture was at stirred at -20 °C for 1 h, Na2SO4*10H2O (2 g) was added and the mixture was stirred at room temperature for 10 min. Then the reaction was filtered through celite, filter cake was washed with THF (20 mL), the filtrate was concentrated to give the crude product, which was purified by column chromatography (eluent: MeOH / DCM = 1 / 10) to give (6-chloroimidazo[l,2-a]pyridin-2-yl)methanol (50 mg, yield: 30%) as a yellow solid. ESLMS [M +H]+: 183.2.Synthesis of (6, 7-dimethylimidazo[l ,2-a]pyridin-2-yl) methanol

[0363] Synthesis of ethyl 6, 7-dimethylimidazofL,2-a]pyridine-2-carboxylate. To a solution of 4,5-dimethylpyridin-2-amine (500 mg, 4.1 mmol) in EtOH (10 mL) was added ethyl 3-bromo- 2-oxopropanoate (1.58 g, 8.2 mmol), the mixture was stirred at 95 °C for 12 h. After the reaction was cooled to room temperature, NaHCOs (30 mL, 10%) was added, the reaction was extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine, dried with Na2SO4, concentrated in vacuo to give the crude, which was purified with combi flash chromatography with (PE / EtOAc= 5 / 1) to give ethyl 6,7-dimethylimidazo[l,2-a]pyridine-2- carboxylate (300 mg, 33%) as a yellow solid. ESLMS [M +H]+: 219.2.

[0364] Synthesis of (6, 7-dimethylimidazo[l,2-a]pyridin-2-yl)methanol. To a solution of ethyl 6,7-dimethylimidazo[l,2-a]pyridine-2-carboxylate (300 mg, 1.38 mmol) in THF (10 mL) was added LiAlHi (1 M in THF, 2.8 mL, 2.8 mmol) slowly at 0 °C under N2. The reaction mixture was raised to room temperature and stirred for 1 h. The reaction was quenched with Na2SO4*10H2O (3 g) and stirred at room temperature for 10 min. Then filtered, the filter cake was washed with THF (20 mL) and the filtrate was concentrated to give the crude, which waspurified by column chromatography (eluent: MeOH / DCM = 1 / 10) to give (6,7- dimethylimidazo[l,2-a]pyridin-2-yl)methanol (200 mg, yield:82%) as a brown solid. ESI-MS [M +H]+: 177.2.Synthesis of (7-methylimidazo[l,2-a]pyridin-2-yl)methanol

[0365] Synthesis of ethyl 7-methylimidazo[l,2-a]pyridine-2-carboxylate. To a solution of 4-methylpyridin-2-amine (500 mg, 4.6 mmol) in EtOH (10 mL) was added ethyl 3-bromo-2- oxopropanoate (1.77 g, 9.2 mmol). The mixture was stirred at 95 °C for 12 h. After the reaction was cooled to room temperature, NaHCOi (80 mL, 10% aq.) was added and the reaction was extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine, dried with Na2SO4, concentrated in vacuo to give the crude, which was purified with combi flash chromatography with (PE / EtOAc= 5 / 1) to give ethyl ethyl 7-methylimidazo[l,2-a]pyridine-2- carboxylate (300 mg, yield: 32%). ESI-MS [M +H]+: 205.2.

[0366] Synthesis of (7-niethylimidazo[l,2-a]pyridin-2-yl)methanoL To a solution of ethyl 7-methylimidazo[l,2-a]pyridine-2-carboxylate (300 mg, 1.5 mmol) in THF (10 mL) was added LiAlH4 (1 M in THF, 3.0 mL, 3 mmol) slowly at 0 °C under N2. The reaction mixture was then slowly raised to room temperature and stirred for 1 h. The reaction was quenched with Na2SO4*10H2O (3 g) and stirred at room temperature for 10 min. Then filtered, the filter cake was washed with THF (20 mL) and the filtrate was concentrated to give the crude product, which was purified by column chromatography (eluent: MeOH / DCM = 1 / 10) to give (7- methylimidazo[l,2-a]pyridin-2-yl)methanol (220 mg, yield: 82%) as a brown solid. ESI-MS [M +H]+: 163.2.

[0367] Synthesis of methyl 4-cyclopropylbenzoate. A mixture of methyl 4-bromobenzoate (500 mg, 2.3 mmol), cyclopropylboronic acid (300 mg, 3.5 mmol), Pd(OAc)2 (52 mg, 0.23 mmol), PPhs (61 mg, 0.23 mmol) and K3PO4 (1.5 g, 6.9 mmol) in dioxane / BLO (25 mL / 2.5 mL) was stirred at 100 °C for 12 h under N2. The reaction mixture was cooled to room temperature and concentrated. Water (40 mL) was added and extracted by EtOAc (50 mL x 3). The combined organic layers were concentrated to give the crude, which was purified with silica gel chromatography (PE / EtOAc = 10 / 1) to give methyl 4-cyclopropylbenzoate (400 mg, yield: 98%) as a yellow solid, ESI-MS [M +H]+: 177.2.

[0368] Synthesis of (4-cyclopropylphenyl) methanol To a solution of methyl 4- cyclopropylbenzoate (400 mg, 2.3 mmol) in THF (10 mL) was added LiAlHi (1 M in THF, 4.6 mL, 4.6 mol) slowly at 0 °C under N2. The reaction mixture was then slowly raised to room temperature and stirred for 1 h. The reaction was quenched with Na2SO4* I OH2O (5 g) and filtered. The filter cake was washed with THF (20 mL) and the filtrate was concentrated to give the crude product, which was purified by column chromatography (eluent: MeOH / DCM = 1 / 10) to give (4-cyclopropylphenyl)methanol (200 mg, yield: 59%) as a yellow solid. ESI-MS [M +H]+: 149.2.

[0369] Synthesis of ethyl 6-cyclopropyl-5-methylimidazo[l,2-a]pyridine-2-carboxylate. A mixture of 5-cyclopropyl-6-methylpyridin-2-amine (300 mg, 2.0 mmol) and ethyl 3-bromo-2- oxopropanoate (776 mg, 4.0 mmol) in EtOH (10 mL) was stirred at 90 °C for 16 h. After the reaction was cooled to room temperature, NaHCO3 (50 mL, 10% aq.) was added and the reaction was extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine, dried with Na2SO4, concentrated in vacuo to give the crude, which was purified by column chromatography (eluent: PE / EtOAc = 5 / 1) to give ethyl 6-cyclopropyl-5-methylimidazo[l,2- a]pyridine-2-carboxylate (150 mg, yield: 31%) as a yellow solid. ESI-MS [M +H]+: 245.2.

[0370] Synthesis of (6-cyclopropyl-5-methylinndazo[l,2-a]pyridin-2-yl)methanol. To a solution of ethyl 6-cyclopropyl-5-methylimidazo[l,2-a]pyridine-2-carboxylate (100 mg, 0.41 mmol) in THF (5 mL) was added LiAlH4 (IM solution in THF, 1.2 mL, 1.2 mmol) at 0 °C under N2. The reaction mixture was stirred at 0 °C for 2 h. The reaction was quenched with NH4CI (sat. aq., 20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, and concentrated to give the crude, which was purified by Prep-TLC (eluent: DCM / MeOH = 30 / 1) to give (6-cyclopropyl-5- methylimidazo[l,2-a]pyridin-2-yl)methanol (50 mg, yield: 60%) as a colorless oil. ESI-MS [M +H]+: 203.2.

[0371] Synthesis of ethyl 6-chloro-5-methylimidazo[l,2-a]pyridine-2-carboxylate. A mixture of 5-chloro-6-methylpyridin-2-amine (600 mg, 4.2 mmol) and ethyl 3-bromo-2- oxopropanoate (1.6 g, 8.4 mmol) in EtOH (20 mL) was stirred at 90 °C for 16 h. After the reaction was cooled to room temperature, NaHCCh (50 mL, 10% aq.) was added and the reaction was extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine, dried with Na SCL, concentrated in vacuo to give the crude, which was purified by column chromatography (eluent: PE / EtOAc = 5 / 1) to give ethyl 6-chloro-5-methylimidazo[l,2- a]pyridine-2-carboxylate (500 mg, yield: 50%) as a yellow solid. ESLMS [M +H]+: 239.2.

[0372] Synthesis of (5-methylimidazo[l,2-a]pyridin-2-yl)methanol. To a solution of ethyl 6-chloro-5-methylimidazo[l,2-a]pyridine-2-carboxylate (500 mg, 2.1 mmol) in THF (10 mL) was added LiAULi (IM solution in THF, 6.3 mL, 6.3 mmol) at 0 °C under N2. The reaction mixture was stirred at 0 °C for 3 h. The reaction was quenched with Na2SO4*10H2O (5 g) and filtered. The filter cake was washed with THF (20 mL) and the filtrate was concentrated to give the crude, which was purified by Prep-TLC (eluent: DCM / MeOH = 30 / 1) to give (5-methylimidazo[l,2-a]pyridin-2-yl)methanol (150 mg, yield: 44%) as a colorless oil. ESI-MS [M +H]+: 163.2.Synthesis of (6-chloro-5-methylimidazo[l,2-a]pyridin-2-yl)methanol

[0373] To a solution of ethyl 6-chloro-5-methylimidazo[l,2-a]pyridine-2-carboxylate (150 mg, 0.63 mmol) in THF (5 mL) was added DIBAL-H (IM solution in THF, 1.9 mL, 1.9 mmol) at 0 °C under N2. The reaction mixture was stirred at 0 °C for 1 h. The reaction was quenched with Na2SO4*10H2O (2 g) and filtered. The filter cake was washed with THF (20 mL) and the filtrate was concentrated to give the crude product, which was purified by Prep-TLC (eluent: DCM / MeOH = 30 / 1) to give (6-chloro-5-methylimidazo[l,2-a]pyridin-2-yl)methanol (50 mg, yield: 40%) as a colorless oil. ESI-MS [M +H]+: 197.2.Synthesis of (2-chloro-7-methoxyquinolin-3-yl)methanol and (7-niethoxyquinolin-3- yl) methanol

[0374] Synthesis of N-(3-methoxyphenyl)acetamide. To a solution of 3 -methoxy aniline (2 g, 16.3 mmol) and TEA (4.9 g, 48.6 mmol) in DCM (50 mL) was added AC2O (3.3 g, 32.6 mmol) at 0 °C. The reaction was warmed to room temperature and stirred for 8 h. Water (70 mL) was added and the reaction was extracted with DCM (50 mL x 3). The combined organic layers were washed with brine (80 mL), dried over NaiSCh, concentrated in vacuo to give the crude, which was purified with silica gel column chromatography, eluting with a gradient of 0-20% EtOAc in PE to give N-(3-methoxyphenyl)acetamide (2.1 g, 78%) as a yellow solid. ESI-MS [M +H]+: 166.1.

[0375] Synthesis of 2-chloro-7-niethoxyquinoline-3-carbaldehyde. To a solution ofN-(3- methoxyphenyl)acetamide (2.1 g, 12.7 mmol) in DMF (20 mL) was added POCh (7.7 g, 50.8mmol) at 0 °C. The resulting reaction was stirred at 100 °C for 14 h. After cooled to room temperature, the reaction was quenched with H2O (70 mL), extracted with EtOAc (70 mL x 3). The combined organic layers were washed with brine (80 mL), dried over Na2SO4, concentrated in vacuo to give the crude, which was purified with silica gel column chromatography, eluting with a gradient of 0-4% EtOAc in PE to give 2-chloro-7-methoxyquinoline-3-carbaldehyde (1.6 g, 57%) as a yellow solid. ESI-MS [M +H]+: 222.1.

[0376] Synthesis of (2-chloro-7-methoxyquinolin-3-yl)methanol and (7-methoxyquinolin- 3-yl) methanol. To a solution of 2-chloro-7-methoxyquinoline-3-carbaldehyde (222 mg, 1 mmol) in THF (10 mL) was added LiAlLh (5 mL, 5 mmol, 1 M solution in THF) at -40 °C. The reaction was stirred at room temperature for 12 h. After completed, the reaction was quenched with NH4CI (sat. aq., 30 mL), extracted with EtOAc (40 mL x 3). The combined organic layers were washed with brine (40 mL), dried over Na2SO4, concentrated in vacuo to give the crude, which was purified with Prep-TLC (eluent: DCM / MeOH = 10 / 1) to give (2-chloro-7-methoxyquinolin- 3-yl)methanol (45 mg, 20%), and (7-methoxyquinolin-3-yl)m ethanol (35 mg, 19%) as yellow oil. (2-chloro-7-methoxyquinolin-3-yl)methanol, ESLMS [M +H]+: 224.1 and (7- m ethoxy quinolin-3-yl)m ethanol, ESI-MS [M +H]+: 190.1.Synthesis of (5-(lH-pyrazol-l-yl)naphthalen-2-yl)methanol

[0377] Synthesis of 5-(lH-pyrazol-l-yl)-2-naphthoic acid. A mixture of methyl 5-bromo-2- naphthoate (1 g, 3.8 mmol), IH-pyrazole (775 mg, 11.4 mmol), t-BuONa (730 mg, 7.6 mmol) and CU2O (107 mg, 0.76 mmol) in NMP (10 mL) was degassed with N2 for 10 min, then heated to 120 °C under microwave for 12 h. After cooled to room temperature, the reaction was diluted with H2O (70 mL), extracted with EtOAc (70 mL x 4). The combined organic layers werewashed with brine (80 mL), dried over NaiSCh, concentrated in vacuo to give the crude, which was purified with silica gel column chromatography, eluting with a gradient of 0-10% MeOH in DCM 5 to give (lH-pyrazol-l-yl)-2-naphthoic acid (530 mg, 58%) as a yellow solid. ESI-MS [M +H]+: 239.2.

[0378] Synthesis of methyl 5-(lH-pyrazol-l-yl)-2-naphthoate. A mixture of 5-(lH-pyrazol- l-yl)-2-naphthoic acid (530 mg, 2.2 mmol) and SOCh (772 mg, 6.6 mmol) in MeOH (25 mL) was stirred at 50 °C for 6 h. After cooled to room temperature, the reaction was concentrated in vacuo. NaHCOs (sat. aq., 40 mL) was added to the residue and extracted with extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (40 mL), dried over Na2SO4, concentrated in vacuo to give the crude, which was purified with silica gel column chromatography, eluting with a gradient of 0-50% EtOAc in PE to give methyl 5-(lH-pyrazol-l- yl)-2-naphthoate (410 mg, 74%) as a yellow solid. ESI-MS [M +H]+: 253.3.

[0379] Synthesis of (5-(lH-pyrazol-l-yl)naphthalen-2-yl)methanol. A mixture of methyl 5- (lH-pyrazol-l-yl)-2-naphthoate (410 mg, 1.62 mmol) and LiBHi (107 mg, 4.86 mmol) in MeOH / THF (2 mL / 10 mL) was stirred at 70 °C for 14 h. After cooled to room temperature, the reaction was quenched with NH4CI (50 mL), extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (60 mL), dried over Na2SO4, concentrated in vacuo to give the crude, which was purified with silica gel column chromatography, eluting with a gradient of 0-70% EtOAc in PE to give (5-(lH-pyrazol-l-yl)naphthalen-2-yl)methanol (305 mg, 84%) as a yellow solid. ESI-MS [M +H]+: 225.3.Synthesis of (5-bromonaphthalen-2-yl)methanol

[0380] To a mixture of methyl 5-bromo-2-naphthoate (100 mg, 0.38 mmol) in THF (2 mL) and MeOH (0.5 mL) was added LiBHi (25 mg, 1.13 mmol), the reaction mixture was stirred at room temperature for 16 h. NH4CI (sat. aq., 10 mL) was added and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, and concentrated to give (5-bromonaphthalen-2-yl)methanol (80 mg, yield: 89%) as a yellow solid. ESI-MS [M +H]+: 237.1.Synthesis of (5-(pyridin-2-yl)naphthalen-2-yl)methanol

[0381] Synthesis of methyl 5-bromo-2-naphthoate. To a mixture of 5-bromo-2-na...

Claims

CLAIMS1. A compound of F ormul a (I) :CyB_ L'— cyA— [_— Cyc(I) or a pharmaceutically acceptable salt thereof, wherein:CyAis phenylene, a 5- to 6-membered monocyclic heteroarylene having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, a 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclene having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, an 8- to 12-membered bicyclic heteroarylene having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, or an 8- to 10-membered bicyclic arylene, wherein CyAis substituted with 0-4 -RAgroups; each RAis independently selected from oxo, halogen, -CN, -C(O)R, -C(O)2R, -C(O)N(R)2, - NO2, -N(R)2, -N(R)C(O)R, -N(R)C(O)2R, -N(R)S(O)2R, -OR, -OC(O)R, -OC(O)N(R)2, - SR, -S(O)R, -S(O)2R, -S(O)N(R)2, -S(O)2N(R)2, or an optionally substituted group selected from C1-6 aliphatic, phenyl, a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur, or a 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from oxygen, nitrogen or sulfur; each R is independently hydrogen or an optionally substituted C1-6 aliphatic group;L’ is a covalent bond or an optionally substituted Ci-4 hydrocarbon chain, wherein 1 to 3 methylene units are optionally and independently replaced with -O-, -C(O)-, -NRZ-, -S-, -SO- , -SO2-, -S(NH)(O)-, or cyclopropylene; each Rzis independently selected from hydrogen, -(CH2)o-30R, -(CH2)o-3C(0)OR, or an optionally substituted C1-6 aliphatic group;wherein:each of RB1and RB2is independently hydrogen or an optionally substituted group selected from Ci-6 aliphatic or a 3- to 7-membered saturated or partially unsaturated monocyclic carbocycyl;RB3is hydrogen or Ci-6 aliphatic;RB4is -N(RX)2; each Rxis independently selected from hydrogen, -C(O)R, -C(O)2R, or optionally substituted Ci-6 aliphatic. wherein no more than one of RB1or RB2is hydrogen; orwherein:RB5is hydrogen or Ci-6 aliphatic or an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic carbocycyl; each of RB6and RB7is independently hydrogen or an optionally substituted Ci-6 aliphatic;L is an optionally substituted C1-3 hydrocarbon chain, wherein 1 to 3 methylene units are optionally and independently replaced with -C(O)-, -O-, -NRZ-, -N(NO)- -S-, -SO-, -SO2-, an optionally substituted cyclopropylene, or an optionally substituted 5- to 6-membered saturated or partially unsaturated heterocyclene, having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur; andCycis selected from a 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, phenyl, 8- to 10-membered bicyclic aryl, a 7- to 10-membered heteroaryl having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, or a 6- to 12- membered saturated or partially unsaturated fused bicyclic heterocyclyl having 1-4 heteroatoms independently selected from oxygen, nitrogen, or sulfur, wherein Cycis substituted with 0-6 -Lc-Rcgroups; each Lcis independently selected from a covalent bond or an optionally substituted C1-6 hydrocarbon chain, wherein 1 to 3 methylene units are optionally and independently replaced with -C(O)-, -O-, or -NR-; andeach Rcis independently selected from oxo, halogen, -CN, -C(O)R, -C(O)2R, -C(0)N(R)2, -NO2, -N(R)2, -N(R)C(O)R, -N(R)C(O)2R, -N(R)S(O)2R, -OR, -OC(O)R, -OC(O)N(R)2, -SR, -S(O)R, -S(O)2R, -S(O)N(R)2, -S(O)2N(R)2, or an optionally substituted group selected from C1-6 aliphatic, phenyl, a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, a 5- or 6-membered heteroaryl having 1-3 heteroatoms selected from oxygen, nitrogen, or sulfur; a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur; a 6- to 12-membered saturated or unsaturated bicyclic heterocyclyl having 1-3 heteroatoms selected from oxygen, nitrogen, or sulfur; a 5- to 12- membered saturated or unsaturated bicyclic carbocyclyl; or a 7- to 10- membered heteroaryl having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur.

2. The compound of claim 1, wherein the compound is of Formula (Il-a):or a pharmaceutically acceptable salt thereof.

3. The compound of any one of claims claim 1-2, wherein the compound is of Formula (III- a), (Ill-b), (III-c), or (Ill-d):or a pharmaceutically acceptable salt thereof.

4. The compound of any one of claims 1-2, wherein the compound is of Formula (III-a-1),(III-a-3) or a pharmaceutically acceptable salt thereof.

5. The compound of any one of claims 1-3, wherein the compound is of Formula (III-b-1), (III-b-2), or (III-b-3):(III-b-3) or a pharmaceutically acceptable salt thereof.

6. The compound of any one of claims 1-3, wherein the compound is of Formula (IV), (IV- a), (IV-b), or (IV-c):(IV-b) (IV-c) or a pharmaceutically acceptable salt thereof7. The compound of any one of claims 1-6, wherein the compound is of Formula (V-a), (V- b), or (V-c):(V-c) or a pharmaceutically acceptable salt thereof8. The compound of any one of claims 1-6, wherein the compound is of Formula (Vl-a), (Vl-b), or (VI-c):(Vl-a) (Vl-b)or a pharmaceutically acceptable salt thereof.

9. The compound of any one of claims 1-6, wherein the compound is of Formula (Vll-a), (Vn-b), or (VII-c):or a pharmaceutically acceptable salt thereof.

10. The compound of any one of claims 1-6, wherein the compound is of Formula (Vlll-a),(Vlll-b(VIILa) (Vlll-b)(VIII-c) or a pharmaceutically acceptable salt thereof.

11. The compound of any one of claims 1-6, wherein the compound is of Formula (IX-a),(IX-c) or a pharmaceutically acceptable salt thereof.

12. The compound of any one of claims 1-6, wherein the compound is of Formula (X-a), (X- b), or (X-c):or a pharmaceutically acceptable salt thereof.

13. The compound of any one of claims 1-6, wherein the compound is of Formula (Xl-a), (XLb), or (XI-c):(XI-c) or a pharmaceutically acceptable salt thereof.

14. The compound of any one of claims 1-6, wherein the compound is of Formula (Xll-a),or a pharmaceutically acceptable salt thereof.

15. The compound of any one of claims 1-6, wherein the compound is of Formula (XIILa), (XIILb), or (XIII-c):(XIILa) (Xlll-b)or a pharmaceutically acceptable salt thereof.

16. The compound of any one of claims 1-6, wherein the compound is of Formula (XlV-a),(XlV-b), or (XIV-c):(XIV-c) or a pharmaceutically acceptable salt thereof.

17. The compound of any one of claims 1-6, wherein the compound is of Formula (XV-a), (XV-b), or (XV-c):(XV-a)(XV-c) or a pharmaceutically acceptable salt thereof.

18. The compound of any one of claims 1-6, wherein the compound is of Formula (XVI-a),(XVI-b), or (XVI-c):(XVI-c) or a pharmaceutically acceptable salt thereof.

19. The compound of any one of claims 1-3, 5, or 7-18, wherein RB1is hydrogen or Ci-6 aliphatic.

20. The compound of any one of claims 1-4 or 7-19, wherein RB2is hydrogen, methyl, ethyl, ■CF. or .

21. The compound of any one of claims 1-3, 6, or 19-20, wherein RB3is hydrogen or methyl.

22. The compound of any one of claims 1-6 or 19-20, wherein each Rxis hydrogen.

23. The compound of any one of claims 1-6 or 19-20, wherein one Rxis hydrogen, and the other is selected from -C(O)R, -C(O)2R, or optionally substituted Ci-6 aliphatic.

24. The compound of claim 1 or 2, wherein CyBis selected from the group consisting of:

25. The compound of claim 1, wherein the compound is of Formula (Il-b):(Il-b) or a pharmaceutically acceptable salt thereof.

26. The compound of claim 1 or 25, wherein RB5is Ci-6 aliphatic or an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic carbocycyl.

27. The compound of any one of claims 1 or 25-26, wherein RB6is an optionally substituted Ci-6 aliphatic.

28. The compound of any one of claims 1 or 25-27, wherein RB7is Ci-6 aliphatic.

29. The compound of any one of claims 1-6 or 10-28, wherein CyAis selected from the group consisting ofwherein * represents the point of attachment to L’.

30. The compound of any one of claims 1-29, wherein each RAis independently selected from oxo, halogen, -C(O)2R, -OR, -C(O)N(R)2, or an optionally substituted C1-6 aliphatic.

31. The compound of any one of claims 1-9 or 12-30, wherein L’ is an optionally substituted Ci-4 hydrocarbon chain, wherein 1 to 3 methylene units are optionally and independently replaced with -O-, -C(O)-, -NRZ-, -S-, -SO-, -SO2-, -S(NH)(O)-, or cyclopropylene.

32. The compound of any one of claims 1-9 or 12-31, wherein L’ is selected from the group consisting of:and O , wherein # represents the point of attachment to CyB.

33. The compound of any one of claims 1-11 or 14-32, wherein L is an optionally substituted C1-3 hydrocarbon chain, wherein 1-3 methylene units are optionally and independently replaced with -C(O)-, -O-, -NRZ-, or -S-.

34. The compound of any one of claims 1-11 or 14-32, wherein L is selected from the group consisting of:

35. The compound of any one of claims 1-13, or 19-34, wherein Cycis selected from the group consisting of:

36. The compound of any one of claims 1-13 or 19-34, wherein Cycis selected from the group consisting of:

37. The compound of any one of claims 1-13 or 19-34, wherein Cycis38. The compound of any one of claims 1-37, wherein Lcis selected from the group consisting of: *-NH-, *-NCH3-, *-O-, *-CH2-, *-CH2C(CH3)2-, *-CH2CH2-, <CH2C(O)N(CH3)-, *-CH2C(O)N(CH3)CH2-, *-CF2-, *-CH(CH3)-, *-OCH2-, *-OCF2-, *-OC(CH3)2-, *-CH2C(O)-, *-OCH2C(O)-, *-CH2C(O)NH-,*-CH2C(O)NHCH2-,*-N(CH3)C(O)-, *-C(CH2CH3)-, *- C(CHCH3)-, *-C(FCH3)-, wherein * represents the point of attachment to Cyc.

39. The compound of any one of claims 1-38, wherein each Rcis independently selected from oxo, halogen, -CN, -C(0)2R, -C(0)N(R)2, or an optionally substituted group selected from Ci-6 aliphatic, phenyl, a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, a 5- or 6-membered heteroaryl having 1-3 heteroatoms selected from oxygen, nitrogen, or sulfur; a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur; a 6- to 12- membered saturated or unsaturated bicyclic heterocyclyl having 1-3 heteroatoms selected from oxygen, nitrogen, or sulfur; a 5- to 12- membered saturated or unsaturated bicyclic carbocyclyl; or a 7- to 10-membered heteroaryl having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur.

40. The compound of any one of the preceding claims, wherein the compound is selected from compounds 1-1 through 1-540, or a pharmaceutically acceptable salt thereof.

41. A pharmaceutical composition comprising a compound of any one of the preceding claims.

42. The pharmaceutical composition comprising a compound of any one of the preceding claims, further comprising a pharmaceutically acceptable excipient.

43. A method of treating a plasma kallikrein-mediated disease or disorder using a compound or composition of any one of the preceding claims.

44. A method of treating hereditary angioedema comprising administering to a patient in need thereof a compound or composition of any one of the preceding claims.

45. A method of treating diabetic macular edema comprising administering to a patient in need thereof a compound or composition of any one of the preceding claims.

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