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

Abstract

The present invention provides compounds and compositions thereof that are useful as inhibitors of plasma kallikrein and exhibit desirable characteristics therefor. The present invention provides isoquinoline derivatives of formula (I) (wherein Cy is a hydroxybenzoate or hydroxybenzoate) as plasma kallikrein (PKa) inhibitors for use in methods of treating hereditary angioedema (HAE) or diabetic macular edema (DME). B is of formula (II) or formula (III). Preferred compounds are, for example, N-((isoquinolin-6-yl)methyl)-1H-pyrazole-4-carboxamide derivatives and similar compounds. TIFF2025531207000704.tif84165

Description

[Background technology]

[0001] I. Background of the Invention Plasma kallikrein (PKa) is a serine protease zymogen in blood that is converted to its catalytically active form by coagulation factor XIIa and contributes to the innate inflammatory response and the intrinsic blood coagulation cascade. In vivo mechanisms leading to activation of this pathway include interaction with polyphosphates released from activated platelets and the absence of C1 inhibitor (C1-INH), the primary physiological inhibitor of PKa. PKa-mediated cleavage of high-molecular-weight kininogen generates the potent vasodilator and proinflammatory nonapeptide bradykinin (BK), which activates the bradykinin 2 receptor. Subsequent cleavage of BK by carboxypeptidases generates des-Arg9-BK, which activates the B1 receptor. Both B1 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 the inner and outer nuclear layers. Activation of B1 and B2 receptors causes vasodilation and increases vascular permeability.

[0002] PKa is also associated with numerous disorders, such as hereditary angioedema (HAE), an autosomal dominant disease characterized by painful, unpredictable, recurrent inflammatory attacks affecting the hands, feet, face, abdomen, genitourinary tract, and larynx. The prevalence of HAE is uncertain but estimated to be approximately 1 case per 50,000 people, with no known differences between racial groups. HAE is caused by a deficiency (type I) or dysfunction (type II) of C1-INH, which inhibits PKa, bradykinin, and other serine proteases in the blood. Individuals with hereditary angioedema (HAE) lack C1-INH, resulting in excessive bradykinin production, which in turn leads to 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. Summary of the Invention [Means for solving the problem]

[0003] II. Summary of the Invention The present disclosure is based, at least in part, on the development of a number of compounds that bind to and effectively inhibit the activity of plasma kallikrein. 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): [ka] or a pharmaceutically acceptable salt thereof (wherein Cy A , Cy B , Cy C wherein each of L, L, and L', both alone and in combination, is as defined and described in classes and subclasses herein. In certain embodiments, the present invention provides compounds of formula (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): [ka]

[0006] or a pharmaceutically acceptable salt thereof (wherein Cy A , Cy B , Cy C Each of L, L, and L', both alone and in combination, is provided as defined and described in classes and subclasses herein.

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

[0008] III. Detailed Description of Certain Embodiments A.Definition Compounds of the present invention include those generally described above and are further described by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise indicated. For purposes of this invention, chemical elements are defined as defined in the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75 th The general principles of organic chemistry are specified in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry", 5 th Ed., Ed.: Smith, M. B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are incorporated herein by reference.

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

[0010] The terms "aliphatic" or "aliphatic group," as used herein, mean a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is fully saturated or contains one or more units of unsaturation, or a monocyclic or bicyclic hydrocarbon that is fully saturated or contains one or more units of unsaturation, but is not aromatic (also referred to herein as "carbocyclyl," "alicyclic," or "cycloalkyl"), and has a single point of attachment to the remainder of the molecule. Unless otherwise specified, an aliphatic group contains 1-6 aliphatic carbon atoms. In some embodiments, an aliphatic group contains 1-5 aliphatic carbon atoms. In some embodiments, an aliphatic group contains 1-4 aliphatic carbon atoms. In some embodiments, an aliphatic group contains 1-3 aliphatic carbon atoms, and in still other embodiments, an aliphatic group contains 1-2 aliphatic carbon atoms. In some embodiments, "alicyclic" (or "carbocyclyl" or "cycloalkyl") refers to a monocyclic C3-C7 hydrocarbon that is fully saturated or contains one or more units of unsaturation, but is not aromatic, and 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" refers to oxygen, sulfur, nitrogen, phosphorus, or silicon (any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized form of any basic nitrogen; or a substitutable nitrogen of a heterocyclic ring, such as N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR + (including 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 divalent alkyl group. An "alkylene chain" is a polymethylene group, i.e., -(CH) n - (where n is a positive integer, preferably 1 to 6, 1 to 4, 1 to 3, 1 to 2, or 2 to 3). A substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms have been replaced with a substituent. Suitable substituents include those described below for substituted aliphatic groups.

[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 5 to 10 ring members, wherein at least one ring in the system is aromatic and each ring in the system contains 3 to 7 ring members. The term "aryl" may be used interchangeably with the term "aryl ring." In some embodiments, an 8- to 10-membered bicyclic aryl group is an optionally substituted naphthyl ring. In certain embodiments of the present invention, "aryl" refers to aromatic ring systems, including, 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 used herein, are groups in which an aromatic ring is fused to one or more non-aromatic rings, such as indanyl, phthalimidyl, naphthymidyl, phenanthridinyl, or tetrahydronaphthyl.

[0016] The terms "heteroaryl" and "heteroari-" refer to groups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms; having 6, 10, or 14 pi electrons shared in a cyclic array; and having 1 to 5 heteroatoms in addition to carbon atoms. Heteroaryl groups include, but are not limited to, 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 "heteroari-," as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, alicyclic, or heterocyclyl rings, where the radical or point of attachment is on the heteroaromatic ring (or in the case of a divalent fused heteroarylene ring system, at least one radical or point of attachment is on the heteroaromatic ring). Non-limiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-1,4-oxazin-3(4H)-one. Heteroaryl groups can be monocyclic or bicyclic. The term "heteroaryl" can be used interchangeably with the terms "heteroaryl ring," "heteroaryl group," or "heteroaromatic," any of which terms include optionally substituted rings.

[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- to 10-membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated and that, in addition to carbon atoms, has one or more, preferably 1 to 4, heteroatoms as defined above. When used in this context with respect to a ring atom, the term "nitrogen" includes substituted nitrogen. By way of example, in a saturated or partially unsaturated ring having 0 to 3 heteroatoms selected from oxygen, sulfur, or nitrogen, the nitrogen can be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or + It can be NR (as in N-substituted 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, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenylpyrrolidinyl, 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 alicyclic rings, such as indolinyl, 3H-indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl (the radical or point of attachment is on the heterocyclyl ring). Heterocyclyl groups can be monocyclic or bicyclic. The term "heterocyclylalkyl" refers to an alkyl group substituted by a heterocyclyl, where the alkyl and heterocyclyl portions are independently 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 with multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties as defined herein.

[0020] As used herein, and unless otherwise specified, the suffix "-ene" is used to represent a divalent group. Thus, any of the above terms can be modified with the suffix "-ene" to represent a divalent version of that moiety. For example, a divalent carbocycle is a "carboxiylene," a divalent aryl ring is an "arylene," a divalent benzene ring is a "phenylene," a divalent heterocycle is a "heterocyclylene," a divalent heteroaryl ring is a "heteroarylene," a divalent alkyl chain is an "alkylene," a divalent alkenyl chain is an "alkenylene," a divalent alkynyl chain is an "alkynylene," etc.

[0021] As described herein, the compounds of the invention may contain "optionally substituted" moieties, where specified. Generally, the term "substituted," whether preceded by the term "optionally" or not, means that one or more hydrogens at the specified moiety have been replaced with a suitable substituent. "Substituted" applies to one or more hydrogens that are explicit or implied from the structure (e.g., [ka] At least [ka] refers to; [ka] At least [ka] In polycyclic ring systems, substituents may also replace a hydrogen on any individual ring unless otherwise indicated (e.g., [ka] At least [ka] (refers to "optionally substituted"). Unless otherwise indicated, an "optionally substituted" group may have a suitable substituent at each substitutable position of the group, and if multiple positions in any given structure may be substituted with multiple substituents selected from the specified groups, the substituents may be the same or different at every position. Combinations of substituents envisioned by the present 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 that permit 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; -(CH) 0-4 R°;-(CH2) 0-4 OR°;-O(CH2) 0-4 R°, -O(CH2) 0-4 C(O)OR°;-O(CH2) 0-4 OR°;-(CH2) 0-4 CH(OR°)2;-(CH2) 0-4 SR°; may be substituted with R° -(CH2) 0-4 Ph; R° may be substituted with -(CH2) 0-4 O(CH2) 0-1 Ph; -CH=CHPh, which may be substituted with R°; -(CH2), which may be substituted with R° 0-4 O(CH2) 0-1 -pyridyl; -NO2; -CN; -N3; ​​-(CH2) 0-4 N(R°)2;-(CH2) 0-4 N(R°)C(O)R°;-N(R°)C(S)R°;-(CH2)0-4 N(R°)C(O)NR°2;-N(R°)C(S)NR°2;-(CH2) 0-4 N(R°)C(O)OR°;-N(R°)N(R°)C(O)R°;-N(R°)N(R°)C(O)NR°2;-N(R°)N(R°)C(O)OR°;-(CH2) 0-4 C(O)R°;-C(S)R°;-(CH2) 0-4 C(O)OR°;-(CH2) 0-4 C(O)SR°;-(CH2) 0-4 C(O)OSiR°3;-(CH2) 0-4 OC(O)R°;-OC(O)(CH2) 0-4 SR°, -SC(S)SR°;-(CH2) 0-4 SC(O)R°;-(CH2) 0-4 C(O)NR°2;-C(S)NR°2;-C(S)SR°;-SC(S)SR°, -(CH2) 0-4 OC(O)NR°2;-C(O)N(OR°)R°;-C(O)C(O)R°;-C(O)CH2C(O)R°;-C(NOR°)R°;-(CH2) 0-4 SSR°;-(CH2) 0-4 S(O)2R°;-(CH2) 0-4 S(O)2OR°;-(CH2) 0-4 OS(O)2R°;-S(O)2NR°2;-(CH2) 0-4 S(O)R°;-N(R°)S(O)2NR°2;-N(R°)S(O)2R°;-N(OR°)R°;-C(NH)NR°2;-P(O)2R°;-P(O)R°2;-OP(O)R°2;-OP(O)(OR°)2;SiR°3;-OSiR°3, -(C 1-4 Linear or branched alkylene)ON(R°)2; or -(C 1-4 linear or branched alkylene)C(O)ON(R°)2, where each R° is substituted as defined below and independently represents hydrogen, C 1-6 Aliphatic, -CH2Ph, -O(CH2) 0-1Ph, -CH2- (a 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 above definitions, two independent occurrences of R° together with their intervening atom(s) form a 3-12 membered saturated, partially unsaturated, or aryl monocyclic 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 a ring formed by taking two independent occurrences of R° together with their intervening atoms) are independently halogen, —(CH2), 0-2 R ● ,-(Halo R ● ), -(CH2) 0-2 OH, -(CH2) 0-2 OR ● , -(CH2) 0-2 CH(OR ● )2;-O(HaloR ● ), -CN, -N3, -(CH2) 0-2 C(O)R ● , -(CH2) 0-2 C(O)OH, -(CH2) 0-2 C(O)OR ● , -(CH2) 0-2 SR ● , -(CH2) 0-2 SH, -(CH2) 0-2 NH2, -(CH2) 0-2 NHR ● , -(CH2) 0-2 NR ● 2, -NO2, -SiR ● 3. -OSiR ● 3. -C(O)SR ● , -(C 1-4 Linear or branched alkylene)C(O)OR ● , or -SSR ● (In the formula, each R ● is unsubstituted or, if preceded by "halo", substituted only with one or more halogens, and C 1-4Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph, 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 ═O and ═S.

[0024] Suitable divalent substituents on a saturated carbon atom of an "optionally substituted" group include: ═O, ═S, ═NNR # 2, =NNHC(O)R # , =NNHC(O)OR # , =NNHS(O)2R # , =NR # , =NOR # , -O(C(R # 2)) 2-3 O-, or -S(C(R # 2)) 2-3 S-(wherein, R # Each independent occurrence of is hydrogen, which may be substituted as defined below, C 1-6 aliphatic or unsubstituted 5-6 membered saturated, partially unsaturated, or aryl rings having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Preferred divalent substituents attached to adjacent substitutable carbon atoms of an "optionally substituted" group include -O(CR # 2) 2-3 O-(wherein, R # Each independent occurrence of is hydrogen, which may be substituted as defined below, C 1-6 aliphatic, or unsubstituted 5-6 membered saturated, partially unsaturated, or aryl rings having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0025] R # Suitable substituents on the aliphatic group include halogen, -R ● ,-(Halo R ● ), -OH, -OR ● , -O(HaloR ● ), -CN, -C(O)OH, -C(O)OR ● , -NH2, -NHR● , -NR ● 2, or -NO2 (wherein each R ● is unsubstituted or, if preceded by "halo", is substituted with only one or more halogens, and independently represents C 1-4 Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph, 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 -R † , -NR † 2. -C(O)R † , -C(O)OR † , -C(O)C(O)R † , -C(O)CHC(O)R † , -S(O)2R † , -S(O)NR † 2. -C(S)NR † 2. -C(NH)NR † 2, or -N(R † )S(O)2R † (In the formula, each R † are independently hydrogen, C which may be substituted as defined below 1-6 an aliphatic, unsubstituted -OPh, or unsubstituted 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, regardless of the above definitions, R † two independent occurrences of, taken together with their intervening atom(s), form an unsubstituted 3-12 membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0027] R † Suitable substituents on the aliphatic group are independently halogen, —R ● ,-(Halo R ● ), -OH, -OR ● , -O(HaloR ●), -CN, -C(O)OH, -C(O)OR ● , -NH2, -NHR ● , -NR ● 2, or -NO2 (wherein each R ● is unsubstituted or, if preceded by "halo", is substituted with only one or more halogens, and independently represents C 1-4 Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph, 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 salts" refers to those salts that, within the scope of reasonable medical judgment, are suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, etc., 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 form of the compound is 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 salts 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 stereoisomers. 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, the replacement of hydrogen by deuterium or tritium, or 13 C or 14 Compounds having this structure containing a carbon replacement with a C-enriched carbon are within the scope of this invention. Such compounds are useful, for example, as analytical tools, probes in biological assays, or as therapeutic agents according to 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] symbol [ka] indicates the point of attachment of a chemical moiety to the rest of the molecule or chemical formula, except when used as a bond to indicate unknown or mixed stereochemistry.

[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 multiple) administered individually to a subject, typically separated by time. In some embodiments, a given therapeutic agent has a recommended dosing regimen that may involve one or more doses. In some embodiments, a dosing regimen includes multiple doses, each of which is separated from each other by the same length of time; in some embodiments, a dosing regimen includes multiple doses and at least two different time periods separating the individual doses.

[0035] As understood from the context, a "reference" compound is one that is sufficiently similar to the particular compound of interest to allow a relevant comparison. In some embodiments, information about the reference compound is obtained simultaneously with information about the particular compound. In some embodiments, information about the reference compound is historical. In some embodiments, information about the reference compound is stored, for example, on a computer-readable medium. In some embodiments, comparison of the particular compound of interest with the reference compound establishes identity, similarity, or difference between the particular compound of interest and the compound.

[0036] As used herein, the phrase "therapeutic agent" refers to any agent that has a therapeutic effect and / or induces 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 a treated subject at a reasonable benefit / risk ratio applicable to any medical treatment. The therapeutic effect can be objective (i.e., measurable by some test or marker) or subjective (i.e., the subject provides an indication of or feels an effect). In particular, a "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 prophylactic effect, for example, by improving symptoms associated with the disease, preventing or delaying the onset of the disease, and / or further reducing the severity or frequency of symptoms of the disease. A therapeutically effective amount is generally administered in a dosing regimen that may include multiple unit doses. For any particular therapeutic agent, the therapeutically effective amount (and / or an appropriate unit dose within an effective dosing regimen) may vary depending, for example, on the route of administration, combination with other pharmaceutical agents, etc. In addition, the particular therapeutically effective amount (and / or unit dose) for any particular subject will depend on a variety of factors, including the disorder being treated and the severity of the disorder; the activity of the particular therapeutic agent used; the particular composition used; the age, weight, general health, sex, and diet of the subject; the time of administration, route of administration, and / or excretion or metabolic rate of the particular therapeutic agent used; the duration of treatment; and similar factors as are well known in the medical field.

[0038] As used herein, the term "treatment" (also "treat" or "treating") refers to any administration of a substance (e.g., a provided composition) that partially or completely relieves, ameliorates, alleviates, inhibits, delays the onset of, reduces the severity of, and / or reduces the frequency of occurrence of one or more symptoms, characteristics, and / or causes of a particular disease, disorder, and / or condition. Such treatment may be of subjects who do not exhibit signs of the associated disease, disorder, and / or condition and / or subjects who exhibit only early signs of the disease, disorder, and / or condition. Alternatively or additionally, such treatment may be of subjects who exhibit one or more established signs of the associated disease, disorder, and / or condition. In some embodiments, treatment may be of subjects who have been diagnosed as suffering from the associated disease, disorder, and / or condition. In some embodiments, treatment may be of subjects known to have one or more susceptibility factors that statistically correlate with an increased risk of developing the associated disease, disorder, and / or condition.

[0039] B. Compound In some embodiments, provided compounds have formula (I): [ka] or a pharmaceutically acceptable salt thereof (In the formula, Cy A is a 5- to 6-membered monocyclic heteroarylene having 1 to 3 heteroatoms independently selected from phenylene, oxygen, nitrogen, and sulfur, a 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclene having 1 to 4 heteroatoms independently selected from oxygen, nitrogen, or sulfur, an 8- to 12-membered bicyclic heteroarylene having 1 to 4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, or an 8- to 10-membered bicyclic arylene; and Cy is A 0 to 4 -R A substituted with a group; Each R Ais 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 C 1-6 independently selected from optionally substituted groups selected from aliphatic, phenyl, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur, or 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 C 1-6 is an aliphatic group; L' is a covalent bond or an optionally substituted C 1-4 The hydrocarbon chain (1 to 3 methylene units are optionally and independently -O-, -C(O)-, -NR z -, -S-, -SO-, -SO2-, -S(NH)(O)-, or cyclopropylene); Each R z is hydrogen, -(CH2) 0-3 OR, -(CH2) 0-3 C(O)OR or optionally substituted C 1-6 independently selected from aliphatic groups; Cy B teeth, [ka] (In the formula, R B1 and R B2 each independently represents hydrogen or C 1-6 an optionally substituted group selected from aliphatic or 3- to 7-membered saturated or partially unsaturated monocyclic carboxyl; R B3 is hydrogen or C 1-6 It is aliphatic; R B4 is -N(Rx )2; Each R x is hydrogen, -C(O)R, -C(O)R, or an optionally substituted C 1-6 independently selected from aliphatic, R B1 or R B2 At most one of the is hydrogen) and Cy B teeth, [ka] (In the formula, R B5 is hydrogen or C 1-6 an aliphatic or optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic carboxyl; R B6 and R B7 each independently represents hydrogen or an optionally substituted C 1-6 aliphatic) and; L is an optionally substituted C 1-3 The hydrocarbon chain (1 to 3 methylene units may optionally and independently be -C(O)-, -O-, -NR z -, -N(NO)-, -S-, -SO-, -SO2-, optionally substituted cyclopropylene, or optionally substituted 5- to 6-membered saturated or partially unsaturated heterocyclene having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur; Cy C is selected from a 5- to 6-membered heteroaryl having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, phenyl, an 8- to 10-membered bicyclic aryl, a 7- to 10-membered heteroaryl having 1 to 4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, or a 6- to 12-membered saturated or partially unsaturated fused bicyclic heterocyclyl having 1 to 4 heteroatoms independently selected from oxygen, nitrogen, or sulfur; and Cy C 0 to 6 -L C -R C substituted with a group; Each LC is a covalent bond or an optionally substituted C 1-6 independently selected from hydrocarbon chains (wherein 1 to 3 methylene units are optionally and independently replaced with -C(O)-, -O-, or -NR-); Each R C is 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 C 1-6 (independently selected from optionally substituted groups selected from aliphatic, phenyl, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, 5- or 6-membered heteroaryl having 1-3 heteroatoms selected from oxygen, nitrogen, or sulfur, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur, 6- to 12-membered saturated or unsaturated bicyclic heterocyclyl having 1-3 heteroatoms selected from oxygen, nitrogen, or sulfur, 5- to 12-membered saturated or unsaturated bicyclic carbocyclyl, or 7- to 10-membered heteroaryl having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur) is.

[0040] In some embodiments, provided compounds have formula (I'): [ka] or a pharmaceutically acceptable salt thereof (wherein Cy A , Cy C , L, and L′, both alone and in combination, are as defined and described in classes and subclasses herein; Cy B is an optionally substituted 9-10 membered heteroaryl having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur.

[0041] Unless otherwise specified or prohibited by the preceding definition of formula (I'), the variables Cy, as defined above and described in classes and subclasses herein, A , Cy C It will be understood that the embodiments of, L, and L', both alone and in combination, also apply to compounds of formula (I').

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

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

[0044] In some embodiments, Cy A is phenylene, and Cy A 0 to 4 -R A In some embodiments, Cy is substituted with a group. A is phenylene, and Cy A 0 to 2 -R A is substituted with a group.

[0045] In some embodiments, Cy A is a 5- to 6-membered monocyclic heteroarylene having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur; Cy A 0 to 4 -R A is substituted with a group.

[0046] In some embodiments, Cy A is a 6-membered monocyclic heteroarylene having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur; Cy A 0 to 4 -R A In some embodiments, Cy is substituted with a group. A is a 6-membered monocyclic heteroarylene having 1 to 3 nitrogen heteroatoms, and Cy A is 0 to 4 R A In some embodiments, Cy is substituted with a group. A is 0 to 3 R A In some embodiments, Cy is a pyridinediyl substituted with a cysteine ​​group. A is 0 to 2 R A In some embodiments, Cy is a pyrimidinediyl substituted with a cysteine ​​group. A is 0 to 2 R AIn some embodiments, Cy is a pyridazinediyl substituted with a group. A is 0 to 2 R A In some embodiments, Cy is a pyrazinediyl substituted with a cysteine ​​group. A is 0 to 1 R A It is a triazinediyl substituted with a group.

[0047] In some embodiments, Cy A is a 5-membered monocyclic heteroarylene having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur; Cy A 0 to 2 -R A In some embodiments, Cy is substituted with a group. A is thiazoldiyl, Cy A is 0 to 1 -R A In some embodiments, Cy is substituted with a group. A is unsubstituted thiadiazoldiyl. In some embodiments, Cy A is unsubstituted oxadiazoldiyl. In some embodiments, Cy A is unsubstituted triazolediyl. In some embodiments, Cy A is pyrrolediyl, and Cy A 0 to 2 -R A In some embodiments, Cy is substituted with a group. A is pyrazolediyl, and Cy A 0 to 2 -R A In some embodiments, Cy is substituted with a group. A is imidazolediyl, and Cy A 0 to 2 -R A In some embodiments, Cy is substituted with a group. A is unsubstituted pyrazoldiyl. In some embodiments, Cy A is unsubstituted imidazolediyl.

[0048] In some embodiments, Cy Ais a 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclene having 1 to 4 heteroatoms selected from oxygen, nitrogen, or sulfur; Cy A 0 to 4 -R A is substituted with a group.

[0049] In some embodiments, Cy A is an 8- to 12-membered bicyclic heteroarylene having 1 to 4 heteroatoms independently selected from oxygen, nitrogen, and sulfur; Cy A 0 to 4 -R A In some embodiments, Cy is substituted with a group. A is an 8- to 10-membered bicyclic heteroarylene having 1 to 4 heteroatoms independently selected from oxygen, nitrogen, and sulfur; Cy A 0 to 4 -R A In some embodiments, Cy is substituted with a group. A is a 9- to 10-membered bicyclic heteroarylene having 1 to 4 heteroatoms independently selected from oxygen, nitrogen, and sulfur; Cy A 0 to 4 -R A is substituted with a group.

[0050] In some embodiments, Cy A is an 8-membered bicyclic heteroarylene having 1 to 4 heteroatoms independently selected from oxygen, nitrogen, and sulfur; Cy A 0 to 4 -R A In some embodiments, Cy is substituted with a group. A is an 8-membered bicyclic heteroarylene having 1-2 nitrogen heteroatoms, and Cy A 0 to 4 -R A In some embodiments, Cy is substituted with a group. A is an 8-membered bicyclic heteroarylene having two nitrogen heteroatoms, and Cy A 0 to 4 -R A is substituted with a group.

[0051] In some embodiments, Cy Ais a 9-membered bicyclic heteroarylene having 1 to 4 heteroatoms independently selected from oxygen, nitrogen, and sulfur; Cy A 0 to 4 -R A In some embodiments, Cy is substituted with a group. A is a 9-membered bicyclic heteroarylene having 1 to 4 nitrogen heteroatoms, and Cy A 0 to 4 -R A In some embodiments, Cy is substituted with a group. A is a 9-membered bicyclic heteroarylene having two nitrogen heteroatoms, and Cy A 0 to 4 -R A In some embodiments, Cy is substituted with a group. A is a 9-membered bicyclic heteroarylene having three nitrogen heteroatoms, and Cy A 0 to 4 -R A In some embodiments, Cy is substituted with a group. A is a 9-membered bicyclic heteroarylene having four nitrogen heteroatoms, and Cy A 0 to 4 -R A is substituted with a group.

[0052] In some embodiments, Cy A is a 10-membered bicyclic heteroarylene having 1 to 4 heteroatoms independently selected from oxygen, nitrogen, and sulfur; Cy A 0 to 4 -R A In some embodiments, Cy is substituted with a group. A is a 10-membered bicyclic heteroarylene having 1-2 nitrogen heteroatoms, and Cy A 0 to 4 -R A In some embodiments, Cy is substituted with a group. A is a 10-membered bicyclic heteroarylene having one nitrogen heteroatom, and Cy A 0 to 4 -R A is substituted with a group.

[0053] In some embodiments, Cy Ais a 7- to 12-membered bicyclic heteroarylene having 1 to 4 heteroatoms independently selected from oxygen, nitrogen, and sulfur; Cy A 0 to 4 -R A In some embodiments, Cy is substituted with a group. A is a 9-membered bicyclic heteroarylene having 3 to 4 heteroatoms independently selected from oxygen and nitrogen, and Cy A is 0 to 1 -R A In some embodiments, Cy is substituted with a group. A is a 10-membered bicyclic heteroarylene having 3 to 4 heteroatoms independently selected from oxygen and nitrogen, and Cy A is 0 to 1 -R A is substituted with a group.

[0054] In some embodiments, Cy A teeth, [ka] [ka] wherein * represents the point of attachment to L'.

[0055] In some embodiments, Cy A teeth, [ka] wherein * represents the point of attachment to L'.

[0056] In some embodiments, Cy A teeth, [ka] wherein * represents the point of attachment to L'.

[0057] In some embodiments, Cy A teeth, [ka] wherein * represents the point of attachment to L'.

[0058] In some embodiments, Cy A teeth, [ka] wherein * represents the point of attachment to L'.

[0059] In some embodiments, Cy A teeth, [ka] where * represents the point of attachment to L'.

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

[0061] In some embodiments, Cy A is selected from the group consisting of phenylene, thiazoldiyl, pyrimidinediyl, pyridazinediyl, triazinediyl, thiadiazolediyl, oxadiazolediyl, triazolediyl, pyrrolidinediyl, pyrazolediyl, and imidazolediyl; Cy A 0 to 4 -R A is substituted with a group.

[0062] In some embodiments, Cy A teeth, [ka] [ka] wherein * represents the point of attachment to L'.

[0063] In some embodiments, Cy A is not a 6-membered monocyclic heteroarylene having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur. A is not a 6-membered monocyclic heteroarylene having 1-2 nitrogen heteroatoms. A is 0 to 3 R A In some embodiments, Cy is not a pyridinediyl or pyrazinediyl substituted with a group. A is 0 to 3 R A In some embodiments, Cy is not a pyridinediyl substituted with a group. A is 0 to 2 R A In some embodiments, Cy is not a pyrazinediyl substituted with a group. A teeth, [ka] In some embodiments, Cy A teeth, [ka] In some embodiments, Cy A teeth, [ka] isn't it.

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

[0065] In some embodiments, Cy A teeth, [ka] [ka] is selected from the group consisting of:

[0066] In some embodiments, Cy A is not a 5-membered monocyclic heteroarylene having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur. A is not a 5-membered monocyclic heteroarylene having one nitrogen and one sulfur heteroatom. A is 0 to 3 R A In some embodiments, Cy is not a thiazoldiyl or pyrazindiyl substituted with a group. A teeth, [ka] isn't it.

[0067] In some embodiments, Cy A 0 -R A substituted with a group (i.e., Cy A is non-permutation).

[0068] In some embodiments, Cy Ais a 5- to 6-membered monocyclic heteroarylene having 1 to 3 heteroatoms independently selected from phenylene, oxygen, nitrogen, and sulfur, an 8- to 12-membered bicyclic heteroarylene having 1 to 4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, or an 8- to 10-membered bicyclic arylene; Cy is A 0 to 4 -R A is substituted with a group.

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

[0070] In some embodiments, each R A is 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 C 1-6 Independently selected from optionally substituted groups selected from aliphatic, phenyl, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 2 heteroatoms selected from oxygen, nitrogen, or sulfur, or 5- to 6-membered monocyclic heteroaryl having 1 to 4 heteroatoms independently selected from oxygen, nitrogen, or sulfur.

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

[0072] In some embodiments, each R A is oxo, halogen, -C(O)R, -OR, -C(O)N(R), or optionally substituted C 1-6 independently selected from aliphatic.

[0073] In some embodiments, each R A is halogen, -OR, or optionally substituted C 1-6 In some embodiments, each R A is a halogen or an optionally substituted C 1-6 In some embodiments, each R A are independently selected from fluorine or methyl.

[0074] In some embodiments, optionally substituted R A The substituents on the group are independently halogen, -(CH2) 0-4 OR°, or -(CH2) 0-4 N(R°)2, where each R° is independently as defined above and as described in the 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 understood that references herein to embodiments defining a "single occurrence" of a substituent are not limited to monosubstituted embodiments. For example, "In some embodiments, R A A single occurrence of is oxo' A is oxo and one or more additional R AIncluded are embodiments that may include groups.

[0076] In some embodiments, R A A single occurrence of is oxo. In some embodiments, R A A single occurrence of is a halogen. In some embodiments, R A A single occurrence of is fluorine. In some embodiments, R A A single occurrence of R is chlorine. A A single occurrence of is -CN.

[0077] In some embodiments, R A A single occurrence of is -C(O)R. In some embodiments, R A A single occurrence of is —C(O)R, where R is hydrogen, methyl, or ethyl. In some embodiments, R A A single occurrence of is —C(O)H. In some embodiments, R A A single occurrence of is C(O)2CH3. In some embodiments, R A A single occurrence of is —C(O)CHCH. In some embodiments, R A A single occurrence of is —C(O)N(R). In some embodiments, R A A single occurrence of is -C(O)NH2.

[0078] In some embodiments, R A A single occurrence of is -N(R). In some embodiments, R A The single occurrence of is -OR.

[0079] In some embodiments, R A A single occurrence of halogen-substituted C 1-6 In some embodiments, R A is -CHF. In some embodiments, R A is -CF3.

[0080] In some embodiments, RA The single occurrence of -(CH2) 0-4 C substituted with OR° 1-6 Aliphatic, R° is hydrogen or C 1-6 In some embodiments, R A A single occurrence of is —CHOH. In some embodiments, R A A single occurrence of is -CH2OCH3. In some embodiments, R A The single occurrence of -(CH2) 0-4 C substituted with N(R°)2 1-6 Aliphatic, each R° is hydrogen or C 1-6 In some embodiments, R A A single occurrence of is -CHNH. In some embodiments, R A The single occurrence of -(CH2) 0-4 C substituted with C(O)OR° 1-6 Aliphatic, R° is hydrogen or C 1-6 In some embodiments, R A The single existence of [ka] In some embodiments, R A The single existence of [ka] is.

[0081] In some embodiments, R A A single occurrence of is methyl, ethyl, or propyl. In some embodiments, R A A single occurrence of is methyl.

[0082] In some embodiments, R A A single occurrence of is an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, R A A single occurrence of is optionally substituted cyclopropyl.

[0083] In some embodiments, R A A single occurrence of is an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur. In some embodiments, R A A single occurrence of is an optionally substituted 3-7 membered saturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen and nitrogen. A A single occurrence of is optionally substituted oxetanyl. In some embodiments, R A A single occurrence of is a halogen or -(CH2) 0-4 In some embodiments, R is oxetanyl optionally substituted with OR°. A A single occurrence of is pyrrolidinyl.

[0084] In some embodiments, each R A is 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 C 1-6 Independently selected from optionally substituted groups selected from aliphatic, phenyl, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 2 heteroatoms selected from oxygen, nitrogen, or sulfur, or 5- to 6-membered monocyclic heteroaryl having 1 to 4 heteroatoms independently selected from oxygen, nitrogen, or sulfur.

[0085] In some embodiments, R A is not oxo.

[0086] In some embodiments, L' is a covalent bond or an optionally substituted C 1-4The hydrocarbon chain (1 to 3 methylene units are optionally and independently -O-, -C(O)-, -NR z -, -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 C 1-4 The hydrocarbon chain (1 to 3 methylene units are optionally and independently -O-, -C(O)-, -NR z -, -S-, -SO-, -SO2-, -S(NH)(O)-, or cyclopropylene).

[0088] In some embodiments, L' is optionally substituted C 1-4 The hydrocarbon chain (1 to 3 methylene units are optionally and independently -O-, -C(O)-, -NR z In some embodiments, L' is an optionally substituted C 1-4 The hydrocarbon chain (1 to 3 methylene units are optionally and independently -C(O)- or -NR z In some embodiments, L' is optionally substituted C 2-4 A hydrocarbon chain (one methylene unit is replaced by -C(O)- and one or two additional methylene units are replaced by -NR z In some embodiments, L' is an optionally substituted C 3-4 A hydrocarbon chain (one methylene unit is replaced by -C(O)- and one or two additional methylene units are replaced by -NR z In some embodiments, L' is an optionally substituted C 1-4 Hydrocarbon chain (one methylene unit is -NR z In some embodiments, L' is optionally substituted C 1-3 Hydrocarbon chain (one methylene unit is -NR z(which has been replaced by ).

[0089] In some embodiments, L' is optionally substituted C 2-4 A hydrocarbon chain (one methylene unit is replaced by -SO2- and one or two additional methylene units are replaced by -NR z In some embodiments, L' is an optionally substituted C 3-4 A hydrocarbon chain (one methylene unit is replaced by -SO2- and one or two additional methylene units are replaced by -NR z In some embodiments, L' is an optionally substituted C 1-4 The hydrocarbon chain (wherein one methylene unit is optionally and independently -NR z (which has been replaced by ).

[0090] In some embodiments, L' is optionally substituted with halogen. In some embodiments, L' is -(CH) 0-4 R° (wherein R° is hydrogen or C 1-6 In some embodiments, L' is optionally substituted with -CF3.

[0091] In some embodiments, L' is [ka] (Wherein, # represents Cy B represents the point of attachment to

[0092] In some embodiments, L' is [ka] (Wherein, # represents Cy B represents the point of attachment to

[0093] In some embodiments, L' is [ka] (Wherein, # represents Cy B In some embodiments, L' is [ka] (Wherein, # represents Cy B represents the attachment point to

[0094] In some embodiments, L' is a covalent bond or an optionally substituted C 1-4 The hydrocarbon chain (1 to 3 methylene units are optionally and independently -O-, -NR z -, -S-, -SO-, -SO2-, -S(NH)(O)-, or cyclopropylene).

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

[0096] In some embodiments, L' is [ka] (Wherein, # represents Cy B represents the point of attachment to

[0097] In some embodiments, L' is [ka] (Wherein, # represents Cy B (represents a point of attachment to the

[0098] In some embodiments, L' is a covalent bond or an optionally substituted C 2-4The hydrocarbon chain (1 to 3 methylene units are optionally and independently -O-, -C(O)-, -NR z -, -S-, -SO-, -SO2-, -S(NH)(O)-, or cyclopropylene).

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

[0100] In some embodiments, Cy B is an optionally substituted 9-10 membered heteroaryl having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, Cy B is an optionally substituted 10-membered heteroaryl having one nitrogen heteroatom. In some embodiments, Cy B is optionally substituted isoquinolinyl. In some embodiments, Cy B is an arbitrarily substituted [ka] In some embodiments, Cy B is a halogen; -(CH2) 0-4 R°;-(CH2) 0-4 OR°; OR-(CH2) 0-4 In some such embodiments, R is optionally substituted with N(R°). 1-6 It is aliphatic.

[0101] In some embodiments, Cy B teeth, [ka] In some embodiments, Cy B teeth, [ka] In some embodiments, Cy B teeth, [ka] (In the formula, R B1 or R B2 In some embodiments, Cy B teeth, [ka] (In the formula, R B1 is not hydrogen). In some embodiments, Cy B teeth, [ka] (In the formula, R B2 is not hydrogen). In some embodiments, Cy B teeth, [ka] (In the formula, R B1 and R B2 is not hydrogen).

[0102] In some embodiments, R B1 is hydrogen or C 1-6 In some embodiments, R is an optionally substituted group selected from aliphatic or 3- to 7-membered saturated or partially unsaturated monocyclic carboxyl. B1 is hydrogen or C 1-6 In some embodiments, R B1 is hydrogen. In some embodiments, R B1 is C 1-6 In some embodiments, R B1 is methyl. In some embodiments, R B1 is ethyl. In some embodiments, R B1 is methyl optionally substituted with halogen. In some embodiments, R B1 is -CF3. In some embodiments, R B1 is an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic carboxyl. In some embodiments, R B1is optionally substituted cyclopropyl. In some embodiments, R B1 is cyclopropyl. In some embodiments, R B1 is -(CH2) 0-4 cyclopropyl optionally substituted with R°, where R° is hydrogen or C 1-6 In some embodiments, R B1 teeth, [ka] In some embodiments, R B1 is methyl, ethyl, -CF3, or [ka] is.

[0103] In some embodiments, R B2 is hydrogen or C 1-6 In some embodiments, R is an optionally substituted group selected from aliphatic or 3- to 7-membered saturated or partially unsaturated monocyclic carboxyl. B2 is hydrogen or C 1-6 In some embodiments, R B2 is hydrogen. In some embodiments, R B2 is C 1-6 In some embodiments, R B2 is methyl. In some embodiments, R B2 is ethyl. In some embodiments, R B2 is methyl optionally substituted with halogen. In some embodiments, R B2 is -CF3. In some embodiments, R B2 is an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic carboxyl. In some embodiments, R B2 is optionally substituted cyclopropyl. In some embodiments, R B2 is cyclopropyl. In some embodiments, R B2 is -(CH2) 0-4cyclopropyl optionally substituted with R°, where R° is hydrogen or C 1-6 In some embodiments, R B2 teeth, [ka] is.

[0104] In some embodiments, R B1 and R B2 are the same. In some embodiments, R B1 and R B2 are different. In some embodiments, R B1 is hydrogen and R B2 is C 1-6 In some embodiments, R B1 is C 1-6 It is aliphatic and R B2 is hydrogen. In some embodiments, R B1 and R B2 is C 1-6 In some embodiments, R B1 is hydrogen and R B2 is methyl. In some embodiments, R B1 is methyl and R B2 is hydrogen. In some embodiments, R B1 and R B2 is methyl. In some embodiments, R B1 is methyl, ethyl, -CF3, or [ka] and R B2 is hydrogen, methyl, ethyl, -CF3, or [ka] In some embodiments, R B1 is hydrogen, methyl, ethyl, -CF3, or [ka] and R B2 is methyl, ethyl, -CF3, or [ka] In some embodiments, R B1 is methyl, ethyl, -CF3, or [ka] and R B2 is methyl, ethyl, -CF3, or [ka] is.

[0105] Without being bound by any particular theory, R B1 and / or R B2 The size of the group is believed to affect potency without a loss of binding efficiency. B1 and / or R B2 It is advantageous to have larger substituents (e.g., non-hydrogen substituents) at positions R B1 It is advantageous to have larger substituents (e.g., non-hydrogen substituents) at positions R B2 It is advantageous to have larger substituents (e.g., non-hydrogen substituents) at positions R B1 and R B2 It is advantageous to have larger substituents (eg, non-hydrogen substituents) at positions.

[0106] Groups (e.g., in this example, R B1 and R B2The relative size of a group 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 in which there is a path between any two atoms along a covalent bond), the van der Waals surface is a closed surface and, as such, it contains a volume. This volume is called the molecular volume, or van der Waals volume, and is usually expressed in Å. 3 A convenient way to calculate the A-value on a computer is by numerical integration, i.e., by surrounding the van der Waals envelope of the molecule with a grid of small blocks and summing over the blocks whose centers lie within the van der Waals envelope of the molecule (i.e., within a van der Waals radius of the nucleus) (see, e.g., 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" is the conformational energy (-G) calculated for the relative axial-equatorial conformation of a substituted cyclohexane and the substituents. 0(See Table 1 provided below, and Eliel and Wilen, Chapter 11 entitled "Configuration and Confirmation of Cyclic Molecules" of Stereochemistry of Organic Compounds, John Wiley & Sons, Inc., New York: 1994, pages 695-697, incorporated herein by reference.) A more detailed summary is 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 Resonance Substituent-induced Shieldings and Conformational Equilibria in Cyclohexanes," J. Org. Chem. (1978) 43:3866. [Table 1]

[0108] In some embodiments, R B1 is selected from moieties having an A-value of greater than about 1.0 kcal / mol (e.g., as shown in Table 1). In some embodiments, R B1 is selected from moieties having an A-value of greater than about 1.5 kcal / mol (e.g., as shown in Table 1). In some embodiments, R B1 is selected from moieties having an A-value of greater than about 1.70 kcal / mol (e.g., as shown in Table 1). In some embodiments, R B1is selected from moieties having an A-value of greater than about 2.0 kcal / mol (e.g., as shown in Table 1). In some embodiments, R B1 is selected from moieties having an A-value of greater than about 2.25 kcal / mol (e.g., as shown in Table 1). In some embodiments, R B1 is selected from moieties having an A-value of greater than about 2.5 kcal / mol (e.g., as shown in Table 1). In some embodiments, R B1 is selected from moieties having an A-value of greater than about 2.75 kcal / mol (e.g., as shown in Table 1). B1 is selected from moieties having an A-value of greater than about 3.0 kcal / mol (e.g., as shown in Table 1). In some embodiments, R B1 is selected from sites having an A-value greater than about 4.0 kcal / mol (eg, as shown in Table 1).

[0109] In some embodiments, R B1 is selected from moieties having an A-value of about 0.25 to about 5.0 (e.g., as shown in Table 1). B1 is selected from moieties having an A-value of about 0.5 to about 5.0 (e.g., as shown in Table 1). B1 is selected from moieties having an A-value of about 1.0 to about 5.0 (e.g., as shown in Table 1). B1 is selected from moieties having an A-value of about 1.5 to about 5.0 (e.g., as shown in Table 1). B1 is selected from moieties having an A-value of about 1.70 to about 5.0 (e.g., as shown in Table 1). B1 is selected from moieties having an A-value of about 2.0 to about 5.0 (e.g., as shown in Table 1). B1 is selected from moieties having an A-value of about 2.25 to about 5.0 (e.g., as shown in Table 1). B1is selected from moieties having an A-value of about 2.5 to about 5.0 (e.g., as shown in Table 1). B1 is selected from moieties having an A-value of about 3.0 to about 5.0 (e.g., as shown in Table 1). B1 is selected from moieties having an A-value of about 4.0 to about 5.0 (eg, as shown in Table 1).

[0110] In some embodiments, R B1 is selected from moieties having an A-value of about 0.25 to about 4.0 (e.g., as shown in Table 1). B1 is selected from moieties having an A-value of about 0.25 to about 3.0 (e.g., as shown in Table 1). B1 is selected from moieties having an A-value of about 0.25 to about 2.5 (e.g., as shown in Table 1). B1 is selected from moieties having an A-value of about 0.25 to about 2.0 (e.g., as shown in Table 1). B1 is selected from moieties having an A-value of about 0.5 to about 2.5 (e.g., as shown in Table 1). In some embodiments, R B1 is selected from moieties having an A-value of about 1.0 to about 2.5 (e.g., as shown in Table 1). B1 is selected from moieties having an A-value of about 1.0 to about 2.0 (e.g., as shown in Table 1). B1 is selected from moieties having an A-value of about 1.5 to about 2.0 (e.g., as shown in Table 1). B1 is selected from moieties having an A-value of about 1.5 to about 2.5 (eg, as shown in Table 1).

[0111] In some embodiments, R B2 is selected from moieties having an A-value of greater than about 1.0 kcal / mol (e.g., as shown in Table 1). In some embodiments, RB2 is selected from moieties having an A-value of greater than about 1.5 kcal / mol (e.g., as shown in Table 1). In some embodiments, R B2 is selected from moieties having an A-value of greater than about 1.70 kcal / mol (e.g., as shown in Table 1). In some embodiments, R B2 is selected from moieties having an A-value of greater than about 2.0 kcal / mol (e.g., as shown in Table 1). In some embodiments, R B2 is selected from moieties having an A-value of greater than about 2.25 kcal / mol (e.g., as shown in Table 1). In some embodiments, R B2 is selected from moieties having an A-value of greater than about 2.5 kcal / mol (e.g., as shown in Table 1). In some embodiments, R B2 is selected from moieties having an A-value of greater than about 2.75 kcal / mol (e.g., as shown in Table 1). B2 is selected from moieties having an A-value of greater than about 3.0 kcal / mol (e.g., as shown in Table 1). In some embodiments, R B2 is selected from sites having an A-value greater than about 4.0 kcal / mol (eg, as shown in Table 1).

[0112] In some embodiments, R B2 is selected from moieties having an A-value of about 0.25 to about 5.0 (e.g., as shown in Table 1). B2 is selected from moieties having an A-value of about 0.5 to about 5.0 (e.g., as shown in Table 1). B2 is selected from moieties having an A-value of about 1.0 to about 5.0 (e.g., as shown in Table 1). B2 is selected from moieties having an A-value of about 1.5 to about 5.0 (e.g., as shown in Table 1). B2is selected from moieties having an A-value of about 1.70 to about 5.0 (e.g., as shown in Table 1). B2 is selected from moieties having an A-value of about 2.0 to about 5.0 (e.g., as shown in Table 1). B2 is selected from moieties having an A-value of about 2.25 to about 5.0 (e.g., as shown in Table 1). B2 is selected from moieties having an A-value of about 2.5 to about 5.0 (e.g., as shown in Table 1). B2 is selected from moieties having an A-value of about 3.0 to about 5.0 (e.g., as shown in Table 1). B2 is selected from moieties having an A-value of about 4.0 to about 5.0 (eg, as shown in Table 1).

[0113] In some embodiments, R B2 is selected from moieties having an A-value of about 0.25 to about 4.0 (e.g., as shown in Table 1). B2 is selected from moieties having an A-value of about 0.25 to about 3.0 (e.g., as shown in Table 1). B2 is selected from moieties having an A-value of about 0.25 to about 2.5 (e.g., as shown in Table 1). B2 is selected from moieties having an A-value of about 0.25 to about 2.0 (e.g., as shown in Table 1). B2 is selected from moieties having an A-value of about 0.5 to about 2.5 (e.g., as shown in Table 1). In some embodiments, R B2 is selected from moieties having an A-value of about 1.0 to about 2.5 (e.g., as shown in Table 1). B2 is selected from moieties having an A-value of about 1.0 to about 2.0 (e.g., as shown in Table 1). B2is selected from moieties having an A-value of about 1.5 to about 2.0 (e.g., as shown in Table 1). B2 is selected from moieties having an A-value of about 1.5 to about 2.5 (eg, as shown in Table 1).

[0114] In some embodiments, R B3 is hydrogen or C 1-6 In some embodiments, R B3 is hydrogen. In some embodiments, R B3 is C 1-6 In some embodiments, R B3 is methyl, ethyl, or propyl. In some embodiments, R B3 is methyl.

[0115] In some embodiments, R B4 is -N(R x )2. In some embodiments, R B4 is -NH. In some embodiments, R B4 -NHR x is.

[0116] In some embodiments, each R x is hydrogen, -C(O)R, -C(O)R, or an optionally substituted C 1-6 In some embodiments, each R x is hydrogen. In some embodiments, each R x is -C(O)R, -C(O)R, or an optionally substituted C 1-6 In some embodiments, one R x is hydrogen and the other is —C(O)R, —C(O)R, or an optionally substituted C 1-6 is selected from aliphatic.

[0117] In some embodiments, R x is —C(O)R. In some embodiments, R xis -C(O)R, where R is C 1-6 In some embodiments, R x is —C(O)CH. In some embodiments, R x is —C(O)R. In some embodiments, R x is —C(O)R, where R is an optionally substituted C 1-6 In some embodiments, R x is -C(O)R, where R is -(CH) 0-4 C optionally substituted with Ph 1-6 In some embodiments, R x is —C(O)2CH2Ph. In some embodiments, R x is -C(O)R, where R is C 1-6 In some embodiments, R x is —C(O)R, where R is methyl, ethyl, isopropyl, or isobutyl. In some embodiments, R x is —C(O)2CH2CH3. In some embodiments, R x is —C(O)C(CH). In some embodiments, R x is —C(O)CHC(CH). In some embodiments, R x is an arbitrarily substituted C 1-6 In some embodiments, R x is C 1-6 In some embodiments, R x is methyl, ethyl, or propyl. In some embodiments, R x is methyl.

[0118] In some embodiments, Cy B teeth, [ka] is selected from the group consisting of:

[0119] In some embodiments, Cy B teeth, [ka] is selected from the group consisting of:

[0120] In some embodiments, Cy B teeth, [ka] is.

[0121] In some embodiments, Cy B teeth, [ka] is selected from the group consisting of:

[0122] In some embodiments, Cy B teeth, [ka] isn't it.

[0123] In some embodiments, Cy B teeth, [ka] is.

[0124] In some embodiments, R B5 is hydrogen or C 1-6 In some embodiments, R is an aliphatic or optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic carboxyl. B5 is hydrogen. In some embodiments, R B5 is C 1-6 In some embodiments, R is an aliphatic or optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic carboxyl. B5 is C 1-6 In some embodiments, R B5is methyl, ethyl, or propyl. In some embodiments, R B5 is methyl. In some embodiments, R B5 is an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic carboxyl. In some embodiments, R B5 is optionally substituted cyclopropyl. In some embodiments, R B5 is -(CH2) 0-4 cyclopropyl optionally substituted with R°, where R° is hydrogen or C 1-6 In some embodiments, R B5 teeth, [ka] is.

[0125] In some embodiments, R B6 is hydrogen or an optionally substituted C 1-6 In some embodiments, R B6 is hydrogen. In some embodiments, R B6 is an arbitrarily substituted C 1-6 In some embodiments, R B6 is C 1-6 Aliphatic or optionally substituted -(CH2) 0-4 N(R°)2, where each R° is independently hydrogen or C 1-6 It is aliphatic.

[0126] In some embodiments, R B7 is hydrogen or an optionally substituted C 1-6 In some embodiments, R B7 is hydrogen. In some embodiments, R B7 is an arbitrarily substituted C 1-6 In some embodiments, R B7 is C 1-6 In some embodiments, R B7 is C 1-3 In some embodiments, R B7is methyl, ethyl, or propyl. In some embodiments, R B7 is methyl.

[0127] In some embodiments, Cy B teeth, [ka] is selected from the group consisting of:

[0128] In some embodiments, L is optionally substituted C 1-3 The hydrocarbon chain (1 to 3 methylene units may optionally and independently be -C(O)-, -O-, -NR z -, -N(NO)-, -S-, -SO-, -SO2-, optionally substituted cyclopropylene, or optionally substituted 5- to 6-membered saturated or partially unsaturated heterocyclene having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur.

[0129] In some embodiments, L is optionally substituted C 1-3 The hydrocarbon chain (1 to 3 methylene units may optionally and independently be -C(O)-, -O-, -NR z -, -N(NO)-, -S-, -SO-, -SO2-, optionally substituted cyclopropylene, or optionally substituted 5-membered saturated or partially unsaturated heterocyclene having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur.

[0130] In some embodiments, L is optionally substituted C 1-3 The hydrocarbon chain (1 to 3 methylene units may optionally and independently be -C(O)-, -O-, -NR z -, -N(NO)-, -S-, -SO-, -SO2-, optionally substituted cyclopropylene, or -(CH2) 0-4In some embodiments, L is substituted with an optionally substituted C. 1-3 The hydrocarbon chain (1 to 3 methylene units may optionally and independently be -C(O)-, -O-, -NR z -, -N(NO)-, -S-, -SO-, -SO2-, optionally substituted cyclopropylene, or -(CH2) 0-4 In some such embodiments, each R is independently selected from the group consisting of -OR°, -OSiR°, -C ... 1-6 It is an aliphatic hydrogen.

[0131] In some embodiments, L is optionally substituted C 1-3 The hydrocarbon chain (1 to 3 methylene units may optionally and independently be -C(O)-, -O-, -NR z In some embodiments, L is optionally substituted C 1-3 The hydrocarbon chain (1 to 3 methylene units may optionally and independently be -C(O)-, -O-, -NR z -, or -S-).

[0132] In some embodiments, L is optionally substituted C 1-2 Hydrocarbon chain (one methylene unit can be -C(O)-, -O-, -NR z In some embodiments, L is optionally substituted with -, -N(NO)-, or -S-. 1-2 Hydrocarbon chain (one methylene unit can be -C(O)-, -O-, -NR zIn some embodiments, L is optionally substituted with -, -N(NO)-, -S-, or optionally substituted cyclopropylene. 1-2 Hydrocarbon chain (one methylene unit can be -C(O)-, -O-, -NR z In some embodiments, L is optionally substituted with C 1-2 Hydrocarbon chain (one methylene unit can be -C(O)-, -O-, -NR z -, -N(NO)-, or -S-).

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

[0134] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is a C hydrocarbon chain substituted with a halogen. In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is -(CH) 0-4 A C1 hydrocarbon chain substituted with R°, where R° is hydrogen or C 1-6 In some embodiments, L is [ka] In some embodiments, L is [ka] (wherein % is Cy C In some embodiments, L is [ka] (wherein % is Cy C In some embodiments, L is -(CH) 0-4 C1 hydrocarbon chain substituted with OR°, where R° is hydrogen or C 1-6 In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is -(CH) 0-4 C(O)OR°-substituted C1 hydrocarbon chain, where R° is hydrogen or C 1-6 In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is -(CH) 0-4 A C hydrocarbon chain substituted with N(R°)2, where each R° is independently hydrogen or C 1-6 In some embodiments, L is [ka] In some embodiments, L is -(CH) 0-4 A C1 hydrocarbon chain substituted with N(R°)C(O)OR°, where R° is hydrogen or C 1-6 In some embodiments, L is [ka] is.

[0135] In some embodiments, L is an optionally substituted C hydrocarbon chain (where one methylene unit is -NR z In some embodiments, L is -(CH) 0-4 C hydrocarbon chain optionally substituted with R° (R° is hydrogen or C 1-6 aliphatic, and each methylene unit is independently -NR z -, -O-, -N(NO)-, -S-).

[0136] In some embodiments, L is —(CH) 0-4 A C hydrocarbon chain optionally substituted with R°, where R° is hydrogen or C 1-6 In some embodiments, L is [ka] is.

[0137] In some embodiments, L is —(CH) 0-4 C hydrocarbon chain optionally substituted with R° (R° is hydrogen or C 1-6aliphatic, wherein one methylene unit is replaced with -O-. In some embodiments, L is [ka] (wherein % is Cy C In some embodiments, L is [ka] (wherein % is Cy C In some embodiments, L is [ka] (wherein % is Cy C In some embodiments, L is [ka] (wherein % is Cy C In some embodiments, L is [ka] (wherein % is Cy C represents the attachment point to

[0138] In some embodiments, L is —(CH) 0-4 C hydrocarbon chain optionally substituted with R° (R° is hydrogen or C 1-6 In some embodiments, L is: [ka] (wherein % is Cy C represents the attachment point to

[0139] In some embodiments, L is —(CH) 0-4 C hydrocarbon chain optionally substituted with R° (R° is hydrogen or C1-6 In some embodiments, L is: [ka] (wherein % is Cy C represents the attachment point to

[0140] In some embodiments, L is —(CH) 0-4 C hydrocarbon chain optionally substituted with R° (R° is hydrogen or C 1-6 It is aliphatic and one methylene unit is -NR z In some embodiments, L is -(CH) 0-4 C hydrocarbon chain optionally substituted with R° (R° is hydrogen or C 1-6 It is aliphatic and one methylene unit is -NR z - is replaced by R z is hydrogen, -(CH2) 0-3 C(O)OR or optionally substituted C 1-6 In some embodiments, L is [ka] (wherein % is Cy C In some embodiments, L is [ka] (wherein % is Cy C In some embodiments, L is [ka] (wherein % is Cy C In some embodiments, L is [ka] (wherein % is Cy CIn some embodiments, L is [ka] (wherein % is Cy C In some embodiments, L is [ka] (wherein % is Cy C In some embodiments, L is [ka] (wherein % is Cy C In some embodiments, L is [ka] (wherein % is Cy C represents the attachment point to

[0141] In some embodiments, L is an optionally substituted C hydrocarbon chain (one or two methylene units are optionally and independently -C(O)-, -NR z In some embodiments, L is an optionally substituted C hydrocarbon chain (one or two methylene units are optionally and independently replaced by -C(O)- or -NR z In some embodiments, L is -(CH) 0-4 C3 hydrocarbon chain optionally substituted with R° (R° is hydrogen or C 1-6 aliphatic, which may be further substituted with halogen, and one or two methylene units are optionally and independently -C(O)- or -NR z In some embodiments, L is [ka] (wherein % is Cy CIn some embodiments, L is [ka] (wherein % is Cy C In some embodiments, L is [ka] (wherein % is Cy C represents the attachment point to

[0142] In some embodiments, L is optionally substituted [ka] (wherein % is Cy C In some embodiments, L is an optionally substituted [ka] (wherein % is Cy C In some embodiments, L is -(CH) 0-4 Optionally substituted with OR° or -OSiR°3 [ka] (wherein % is Cy C In some embodiments, L is an optionally substituted [ka] (wherein % is Cy C In some embodiments, L is -(CH) 0-4 Optionally substituted with OR° or -OSiR°3 [ka] (wherein % is Cy C In some embodiments, L is [ka] (wherein % is Cy C In some embodiments, L is [ka] (wherein % is Cy C In some embodiments, L is [ka] (wherein % is Cy C In some embodiments, L is not [ka] (wherein % is Cy C (represents a point of attachment to the

[0143] In some embodiments, L is [ka] (wherein % is Cy C represents the point of attachment to

[0144] In some embodiments, L is [ka] (wherein % is Cy C represents the point of attachment to

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

[0146] In some embodiments, L is optionally substituted C 1-3The hydrocarbon chain (1 to 3 methylene units may optionally and independently be -C(O)-, -O-, -NR z -, -N(NO)-, -S-, -SO-, optionally substituted cyclopropylene, or optionally substituted 5- to 6-membered saturated or partially unsaturated heterocyclene having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur.

[0147] In some embodiments, L is -NHS(O)2- % (wherein % is Cy C (represents a point of attachment to the

[0148] In some embodiments, each R z is hydrogen, -(CH2) 0-3 OR, -(CH2) 0-3 C(O)OR or optionally substituted C 1-6 In some embodiments, R z is hydrogen. In some embodiments, R z is -(CH2) 0-3 OR, -(CH2) 0-3 C(O)OR or optionally substituted C 1-6 In some embodiments, R z is -(CH2) 0-3 In some embodiments, R z is -(CH2) 0-3 C(O)OR. In some embodiments, R z is —C(O)OH. In some embodiments, R z is —C(O)OCH. In some embodiments, R z is —C(O)OCH2CH3. In some embodiments, R z is an arbitrarily substituted C 1-6 In some embodiments, R z is C optionally substituted with halogen 1-6 In some embodiments, R zis —CH 2 CF 3 . In some embodiments, R z is C 1-6 In some embodiments, R z is methyl, ethyl, or propyl. In some embodiments, R z is methyl.

[0149] In some embodiments, Cy C is selected from a 5- to 6-membered heteroaryl having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, phenyl, an 8- to 10-membered bicyclic aryl, a 7- to 10-membered heteroaryl having 1 to 4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, or a 6- to 12-membered saturated or partially unsaturated fused bicyclic heterocyclyl having 1 to 4 heteroatoms independently selected from oxygen, nitrogen, or sulfur; and Cy C 0 to 6 -L C -R C is substituted with a group.

[0150] In some embodiments, Cy C is phenyl and Cy C 0 to 5 -L C -R C is substituted with a group.

[0151] In some embodiments, Cy C is a 5- to 6-membered heteroaryl having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur; Cy C 0 to 6 -L C -R C In some embodiments, Cy is substituted with a group. C is a 5-membered heteroaryl having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur; Cy C 0 to 6 -L C -R C In some embodiments, Cy is substituted with a group. C is a 5-membered heteroaryl having 1 to 2 heteroatoms independently selected from oxygen, nitrogen, and sulfur; CyC 0 to 6 -L C -R C In some embodiments, Cy is substituted with a group. C is a 5-membered heteroaryl having one nitrogen heteroatom and one sulfur heteroatom, and Cy C 0 to 4 -L C -R C In some embodiments, Cy is substituted with a group. C is a 5-membered heteroaryl having two nitrogen heteroatoms, and Cy C 0 to 4 -L C -R C In some embodiments, Cy is substituted with a group. C is pyrazolyl or thiazolyl, and Cy C 0 to 4 -L C -R C In some embodiments, Cy is substituted with a group. C is pyrazolyl, and Cy C 0 to 4 -L C -R C In some embodiments, Cy is substituted with a group. C is thiazolyl, and Cy C 0 to 4 -L C -R C is substituted with a group.

[0152] In some embodiments, Cy C is a 6-membered heteroaryl having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur; Cy C 0 to 6 -L C -R C In some embodiments, Cy is substituted with a group. C is a 6-membered heteroaryl having 1 to 3 nitrogen heteroatoms, and Cy C 0 to 6 -L C -R C In some embodiments, Cy is substituted with a group. C is a 6-membered heteroaryl having 1-2 nitrogen heteroatoms, and Cy C 0 to 6 -LC -R C is substituted with a group.

[0153] In some embodiments, Cy C is pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl, and Cy C 0 to 4 -L C -R C In some embodiments, Cy is substituted with a group. C is pyridinyl and Cy C 0 to 4 -L C -R C In some embodiments, Cy is substituted with a group. C is pyrimidinyl, and Cy C 0 to 3 -L C -R C In some embodiments, Cy is substituted with a group. C is pyrazinyl and Cy C 0 to 3 -L C -R C In some embodiments, Cy is substituted with a group. C is pyridazinyl, and Cy C 0 to 3 -L C -R C is substituted with a group.

[0154] In some embodiments, Cy C teeth, [ka] is selected from the group consisting of:

[0155] In some embodiments, Cy C teeth, [ka] isn't it.

[0156] In some embodiments, Cy C is an 8- to 10-membered bicyclic aryl, and Cy C 0 to 6 -LC -R C In some embodiments, Cy is substituted with a group. C is an 8-membered bicyclic aryl, and Cy C 0 to 6 -L C -R C In some embodiments, Cy is substituted with a group. C is a 9-membered bicyclic aryl, and Cy C 0 to 6 -L C -R C In some embodiments, Cy is substituted with a group. C is a 10-membered bicyclic aryl, and Cy C 0 to 6 -L C -R C is substituted with a group.

[0157] In some embodiments, Cy C 0 to 6 -L C -R C and indazolyl, benzotriazolyl, naphthalenyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, tetrahydro-2H-benzo[b][1,4]oxazinyl, or dihydro-2H-benzo[b][1,4]oxazinonyl substituted with a group.

[0158] In some embodiments, Cy C 0 to 5 -L C -R C In some embodiments, Cy is an indazolyl substituted with a group. C 0 to 4 -L C -R C and benzotriazolyl substituted with a group.

[0159] In some embodiments, Cy C 0 to 6 -L C -R C In some embodiments, Cy is a naphthalenyl substituted with a hydroxyl group. C 0 to 6 -L C -R C In some embodiments, Cy is a quinolinyl substituted with a quinolinyl group.C 0 to 6 -L C -R C In some embodiments, Cy is an isoquinolinyl substituted with a hydroxyl group. C 0 to 5 -L C -R C In some embodiments, Cy is quinoxalinyl substituted with a group. C 0 to 5 -L C -R C In some embodiments, Cy is quinazolinyl substituted with a group. C 0 to 6 -L C -R C In some embodiments, Cy is a tetrahydro-2H-benzo[b][1,4]oxazinyl substituted with a hydroxyl group. C 0 to 6 -L C -R C and dihydro-2H-benzo[b][1,4]oxazinonyl substituted with a group.

[0160] In some embodiments, Cy C is a 7- to 10-membered heteroaryl having 1 to 4 heteroatoms independently selected from oxygen, nitrogen, and sulfur; Cy C 0 to 6 -L C -R C In some embodiments, Cy is substituted with a group. C is a 9- to 10-membered heteroaryl having 1 to 4 heteroatoms independently selected from oxygen, nitrogen, and sulfur; Cy C 0 to 6 -L C -R C is substituted with a group.

[0161] In some embodiments, Cy C is a 9-membered heteroaryl having 1 to 4 nitrogen heteroatoms, and Cy C 0 to 6 -L C -R C In some embodiments, Cy is substituted with a group. C is a 9-membered heteroaryl having 1 to 4 nitrogen heteroatoms, and Cy C 0 to 6 -LC -R C In some embodiments, Cy is substituted with a group. C is a 9-membered heteroaryl having 2-3 nitrogen heteroatoms, and Cy C 0 to 6 -L C -R C In some embodiments, Cy is substituted with a group. C is a 9-membered heteroaryl having one nitrogen heteroatom, and Cy C 0 to 6 -L C -R C In some embodiments, Cy is substituted with a group. C is a 9-membered heteroaryl having two nitrogen heteroatoms, and Cy C 0 to 6 -L C -R C In some embodiments, Cy is substituted with a group. C is a 9-membered heteroaryl having three nitrogen heteroatoms, and Cy C 0 to 6 -L C -R C In some embodiments, Cy is substituted with a group. C is a 9-membered heteroaryl having four nitrogen heteroatoms, and Cy C 0 to 6 -L C -R C In some embodiments, Cy is substituted with a group. C is a 9-membered heteroaryl having one oxygen heteroatom, and Cy C 0 to 6 -L C -R C In some embodiments, Cy is substituted with a group. C is a 9-membered heteroaryl having one sulfur heteroatom, and Cy C 0 to 6 -L C -R C In some embodiments, Cy is substituted with a group. C is a 9-membered heteroaryl having one nitrogen and one sulfur heteroatom, and Cy C 0 to 6 -L C -R CIn some embodiments, Cy is substituted with a group. C is a 9-membered heteroaryl having one nitrogen and one oxygen heteroatom, and Cy C 0 to 6 -L C -R C is substituted with a group.

[0162] In some embodiments, Cy C is a 10-membered heteroaryl having 1 to 4 heteroatoms independently selected from oxygen, nitrogen, and sulfur; Cy C 0 to 6 -L C -R C In some embodiments, Cy is substituted with a group. C is a 10-membered heteroaryl having 1-2 nitrogen heteroatoms, and Cy C 0 to 6 -L C -R C In some embodiments, Cy is substituted with a group. C is a 10-membered heteroaryl having one nitrogen heteroatom, and Cy C 0 to 6 -L C -R C In some embodiments, Cy is substituted with a group. C is a 10-membered heteroaryl having two nitrogen heteroatoms, and Cy C 0 to 6 -L C -R C is substituted with a group.

[0163] In some embodiments, Cy C is imidazopyridinyl, pyrazolopyridinyl, indazolyl, pyrrolopyridinyl, benzimidazolyl, triazolopyridinyl, imidazopyridazinyl, imidazopyrimidinyl, imidazopyrimidinonyl, benzotriazolyl, triazolopyrimidinyl, triazolopyridazinyl, benzothiophenyl, benzothiozolyl, thienopyridinyl, benzofuranyl, benzoxazolyl, pyrazolopyrimidinyl, imidazopyrazinyl, quinolinyl, isoquinolinyl, quinazolinyl, naphthyridinyl, and Cy C 0 to 6 -L C-R C is substituted with a group.

[0164] In some embodiments, Cy C is imidazopyridinyl, and Cy C 0 to 5 -L C -R C In some embodiments, Cy is substituted with a group. C is pyrazolopyridinyl, and Cy C 0 to 5 -L C -R C In some embodiments, Cy is substituted with a group. C is indazolyl, and Cy C 0 to 5 -L C -R C In some embodiments, Cy is substituted with a group. C is pyrrolopyridinyl, and Cy C 0 to 5 -L C -R C In some embodiments, Cy is substituted with a group. C is benzimidazolyl, and Cy C 0 to 5 -L C -R C In some embodiments, Cy is substituted with a group. C is triazolopyridinyl, and Cy C 0 to 4 -L C -R C In some embodiments, Cy is substituted with a group. C is imidazopyridazinyl, and Cy C 0 to 4 -L C -R C In some embodiments, Cy is substituted with a group. C is imidazopyrimidinyl, Cy C 0 to 4 -L C -R C In some embodiments, Cy is substituted with a group. C is imidazopyrimidinonyl, Cy C 0 to 4 -L C -R CIn some embodiments, Cy is substituted with a group. C is benzotriazolyl, and Cy C 0 to 4 -L C -R C In some embodiments, Cy is substituted with a group. C is triazolopyrimidinyl, and Cy C 0 to 3 -L C -R C In some embodiments, Cy is substituted with a group. C is triazolopyridazinyl, and Cy C 0 to 3 -L C -R C In some embodiments, Cy is substituted with a group. C is benzothiophenyl, and Cy C 0 to 5 -L C -R C In some embodiments, Cy is substituted with a group. C is benzothiozolyl, and Cy C 0 to 4 -L C -R C In some embodiments, Cy is substituted with a group. C is thienopyridinyl, Cy C 0 to 4 -L C -R C In some embodiments, Cy is substituted with a group. C is benzofuranyl, and Cy C 0 to 5 -L C -R C In some embodiments, Cy is substituted with a group. C is benzoxazolyl, and Cy C 0 to 4 -L C -R C In some embodiments, Cy is substituted with a group. C is pyrazolopyrimidinyl, and Cy C 0 to 4 -L C -R C In some embodiments, Cy is substituted with a group. C is imidazopyrazinyl, and CyC 0 to 4 -L C -R C is substituted with a group.

[0165] In some embodiments, Cy C is quinolinyl, and Cy C 0 to 6 -L C -R C In some embodiments, Cy is substituted with a group. C is isoquinolinyl, and Cy C 0 to 6 -L C -R C In some embodiments, Cy is substituted with a group. C is quinazolinyl, and Cy C 0 to 5 -L C -R C In some embodiments, Cy is substituted with a group. C is naphthyridinyl, and Cy C 0 to 5 -L C -R C is substituted with a group.

[0166] In some embodiments, Cy C teeth, [ka] is selected from the group consisting of:

[0167] In some embodiments, Cy C teeth, [ka] is selected from the group consisting of:

[0168] In some embodiments, Cy C teeth, [ka] is selected from the group consisting of:

[0169] In some embodiments, Cy C teeth, [ka] is.

[0170] In some embodiments, Cy C is selected from a 5- to 6-membered heteroaryl having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, phenyl, an 8- to 10-membered bicyclic aryl, or a 6- to 12-membered saturated or partially unsaturated fused bicyclic heterocyclyl having 1 to 4 heteroatoms independently selected from oxygen, nitrogen, or sulfur; Cy C 0 to 6 -L C -R C is substituted with a group.

[0171] In some embodiments, Cy C teeth, [ka] isn't it.

[0172] In some embodiments, Cy C is pyrazolopyridinyl, indazolyl, pyrrolopyridinyl, benzimidazolyl, triazolopyridinyl, imidazopyridazinyl, imidazopyrimidinyl, imidazopyrimidinonyl, benzotriazolyl, triazolopyrimidinyl, triazolopyridazinyl, benzothiophenyl, benzothiozolyl, thienopyridinyl, benzofuranyl, benzoxazolyl, pyrazolopyrimidinyl, imidazopyrazinyl, and Cy C 0 to 6 -L C -R C is substituted with a group.

[0173] In some embodiments, Cy C 0 to 6 -L C -R C It is not an imidazopyridinyl substituted with a group.

[0174] In some embodiments, Cy C teeth, [ka] is selected from the group consisting of:

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

[0176] In some embodiments, L C A single occurrence of L is a covalent bond. C A single occurrence of is an optionally substituted C 1-6 A hydrocarbon chain in which 1 to 3 methylene units are optionally and independently replaced with -C(O)-, -O-, or -NR-. In some embodiments, L C A single occurrence of is an optionally substituted C 1-6 A hydrocarbon chain in which 1 to 3 methylene units are optionally and independently replaced with -O- or -NR-.

[0177] In some embodiments, L C is -(CH2) 0-4 Optionally substituted with R°, where R° is independently as defined above and as described in classes and subclasses herein. In some such embodiments, R° is hydrogen or C 1-6 It is aliphatic.

[0178] In some embodiments, L CA single occurrence of is *-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)- (where * is a Cy C represents the point of attachment to

[0179] In some embodiments, L C A single occurrence of *-NH- (where * is a Cy C In some embodiments, L C A single occurrence of *-NCH3- (where * is a Cy C In some embodiments, L C A single occurrence of is *-O- (where * is a Cy C In some embodiments, L C A single occurrence of *-CH2- (where * is a Cy C In some embodiments, L C A single occurrence of *-CH2C(CH3)2- (where * is a Cy C In some embodiments, L C A single occurrence of *-CHCH- (where * is a Cy C In some embodiments, L C A single occurrence of is *-CH2C(O)N(CH3)- (where * is a Cy C In some embodiments, L C A single occurrence of *-CH2C(O)N(CH3)CH2- (where * is a Cy C In some embodiments, L CA single occurrence of *-CF2- (where * is a Cy C In some embodiments, L C A single occurrence of *-CH(CH3)- (where * is a Cy C In some embodiments, L C A single occurrence of *-OCH2- (where * is a Cy C In some embodiments, L C A single occurrence of *-OCF2- (where * is Cy C In some embodiments, L C A single occurrence of *-OC(CH3)2- (where * is a Cy C In some embodiments, L C A single occurrence of *-CHC(O)- (where * is a Cy C In some embodiments, L C A single occurrence of *-OCH2C(O)- (where * is a Cy C In some embodiments, L C A single occurrence of *-CHC(O)NH- (where * is a Cy C In some embodiments, L C A single occurrence of *-CH2C(O)NHCH2- (where * is a Cy C In some embodiments, L C A single occurrence of is *-N(CH3)C(O)- (where * is a Cy C In some embodiments, L C A single occurrence of *-C(CH2CH3)- (where * is a Cy C In some embodiments, L C A single occurrence of *-C(CHCH3)- (where * is a Cy C In some embodiments, L C A single occurrence of *-C(FCH3)- (where * is a Cy Crepresents the attachment point to

[0180] In some embodiments, each R C is 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 C 1-6 Independently selected from optionally substituted groups selected from aliphatic, phenyl, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, 5- or 6-membered heteroaryl having 1-3 heteroatoms selected from oxygen, nitrogen, or sulfur; 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur; 6- to 12-membered saturated or unsaturated bicyclic heterocyclyl having 1-3 heteroatoms selected from oxygen, nitrogen, or sulfur; 5- to 12-membered saturated or unsaturated bicyclic carbocyclyl; or 7- to 10-membered heteroaryl having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur.

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

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

[0183] In some embodiments, R C A single occurrence of is oxo. In some embodiments, R C A single occurrence of is a halogen. In some embodiments, R C A single occurrence of is fluorine. In some embodiments, R C A single occurrence of R is chlorine. C A single occurrence of is bromine. In some embodiments, R C A single occurrence of is -CN. In some embodiments, R C A single occurrence of is -C(O)R. In some embodiments, R C A single occurrence of is -COOH. In some embodiments, R C A single occurrence of is —C(O)OCH. In some embodiments, R C A single occurrence of is —C(O)OCH CH. In some embodiments, R C A single occurrence of is -OR. In some embodiments, R C A single occurrence of is —OH. In some embodiments, R C A single occurrence of is -OMe. In some embodiments, R C A single occurrence of is —C(O)N(R). In some embodiments, R CA single occurrence of is —C(O)NH. In some embodiments, R C A single occurrence of is —C(O)NHCH. In some embodiments, R C A single occurrence of is —C(O)N(CH). In some embodiments, R C A single occurrence of is -C(O)N(CH2CH3)2.

[0184] In some embodiments, R C A single occurrence of is an optionally substituted C 1-6 In some embodiments, R C A single occurrence of C optionally substituted with halogen 1-6 In some embodiments, R C A single occurrence of C optionally substituted with fluorine 1-6 In some embodiments, R C A single occurrence of is -CF. In some embodiments, R C A single occurrence of is -CHF. In some embodiments, R C A single occurrence of is methyl. In some embodiments, R C A single occurrence of is ethyl. In some embodiments, R C A single occurrence of is isopropyl. In some embodiments, R C A single occurrence of is -CHCHCH3. In some embodiments, R C A single occurrence of is —CHC(CH). In some embodiments, R C A single occurrence of R is butyl. C A single occurrence of is n-butyl.

[0185] In some embodiments, R C A single occurrence of is optionally substituted phenyl. In some embodiments, R C A single occurrence of is phenyl.

[0186] In some embodiments, R CA single occurrence of is an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, R C A single occurrence of is optionally substituted cyclopropyl. In some embodiments, R C The single occurrence of -(CH2) 0-4 R°, -(CH2) 0-4 N(R°)C(O)R°, or -(CH2) 0-4 is cyclopropyl optionally substituted with N(R°)C(O)OR°; R° is hydrogen or C 1-6 In some embodiments, R C A single occurrence of is cyclopropyl. In some embodiments, R C The single existence of [ka] In some embodiments, R C The single existence of [ka] In some embodiments, R C The single existence of [ka] In some embodiments, R C The single existence of [ka] In some embodiments, R C The single existence of [ka] In some embodiments, R C The single existence of [ka] In some embodiments, Cy C 1 to 6 -LC -R C is substituted with an R C A single occurrence of is cyclopropyl.

[0187] In some embodiments, R C A single occurrence of is an optionally substituted 5- or 6-membered heteroaryl having 1-3 heteroatoms selected from oxygen, nitrogen, or sulfur. In some embodiments, R C The single occurrence of is an optionally substituted 5- or 6-membered heteroaryl having 1 to 2 heteroatoms selected from oxygen, nitrogen, or sulfur.

[0188] In some embodiments, R C A single occurrence of is an optionally substituted 5-membered heteroaryl having 1-3 heteroatoms selected from oxygen, nitrogen, or sulfur. In some embodiments, R C A single occurrence of is an optionally substituted 5-membered heteroaryl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur. In some embodiments, R C A single occurrence of is an optionally substituted 5-membered heteroaryl having two nitrogen heteroatoms. In some embodiments, R C A single occurrence of is optionally substituted pyrazolyl. In some embodiments, R C The single occurrence of -(CH2) 0-4 R° is optionally substituted pyrazolyl; R° is C 1-6 In some embodiments, R is aliphatic (e.g., methyl or cyclopropyl). C A single occurrence of is optionally substituted imidazolyl. In some embodiments, R C The single occurrence of -(CH2) 0-4 imidazolyl optionally substituted with R°; 1-6 It is aliphatic (eg, methyl or cyclopropyl).

[0189] In some embodiments, R CA single occurrence of is an optionally substituted 5-membered heteroaryl having one nitrogen heteroatom and one sulfur heteroatom. In some embodiments, R C A single occurrence of is optionally substituted thiazolyl. In some embodiments, R C A single occurrence of is thiazolyl. In some embodiments, R C A single occurrence of is an optionally substituted 5-membered heteroaryl having one nitrogen heteroatom and one oxygen heteroatom. In some embodiments, R C A single occurrence of is optionally substituted oxazolyl. In some embodiments, R C A single occurrence of is oxazolyl.

[0190] In some embodiments, R C A single occurrence of is an optionally substituted 5-membered heteroaryl having three heteroatoms selected from oxygen, nitrogen, or sulfur. In some embodiments, R C A single occurrence of is an optionally substituted 5-membered heteroaryl having two nitrogen heteroatoms and one oxygen heteroatom. In some embodiments, R C A single occurrence of is optionally substituted oxadiazolyl. In some embodiments, R C The single occurrence of -(CH2) 0-4 R° is an optionally substituted oxadiazolyl; R° is C 1-6 In some embodiments, R is aliphatic (e.g., methyl or cyclopropyl). C A single occurrence of is oxadiazolyl.

[0191] In some embodiments, R C A single occurrence of is an optionally substituted 5-membered heteroaryl having two nitrogen heteroatoms and one sulfur heteroatom. In some embodiments, R C A single occurrence of is optionally substituted thiadiazolyl. In some embodiments, R C The single occurrence of -(CH2) 0-4thiadiazolyl optionally substituted with R°; 1-6 In some embodiments, R is aliphatic (e.g., methyl or cyclopropyl). C A single occurrence of is thiadiazolyl.

[0192] In some embodiments, R C A single occurrence of is an optionally substituted 5-membered heteroaryl having 3 nitrogen heteroatoms. In some embodiments, R C A single occurrence of is optionally substituted triazolyl. In some embodiments, R C The single occurrence of -(CH2) 0-4 R° is optionally substituted triazolyl; R° is C 1-6 In some embodiments, R is aliphatic (e.g., methyl or cyclopropyl). C A single occurrence of is triazolyl.

[0193] In some embodiments, R C A single occurrence of is an optionally substituted 6-membered heteroaryl having 1-3 heteroatoms selected from oxygen, nitrogen, or sulfur. In some embodiments, R C A single occurrence of is an optionally substituted 6-membered heteroaryl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur. In some embodiments, R C A single occurrence of is an optionally substituted 6-membered heteroaryl having one nitrogen heteroatom. In some embodiments, R C A single occurrence of is optionally substituted pyridinyl. In some embodiments, R C A single occurrence of is a halogen or -(CH2) 0-4 pyridinyl optionally substituted with R°; R° is C 1-6 In some embodiments, R is aliphatic (e.g., methyl or cyclopropyl). C A single occurrence of is optionally substituted pyridinonyl. In some embodiments, R C A single occurrence of is a halogen or -(CH2) 0-4pyridinonyl optionally substituted with R°; R° is C 1-6 R is aliphatic (e.g., methyl, ethyl, or cyclopropyl), and R can be further substituted with a halogen (e.g., fluorine). C A single occurrence of is pyridinonyl.

[0194] In some embodiments, R C A single occurrence of is optionally substituted pyrimidinyl. In some embodiments, R C A single occurrence of is pyrimidinyl. In some embodiments, R C A single occurrence of is optionally substituted pyrazinyl. In some embodiments, R C A single occurrence of is pyrazinyl.

[0195] In some embodiments, R C A single occurrence of is an optionally substituted 6-membered heteroaryl having two nitrogen heteroatoms.

[0196] In some embodiments, R C The single existence of [ka] is selected from the group consisting of:

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

[0198] In some embodiments, R C A single occurrence of is an optionally substituted 4-6 membered saturated or partially unsaturated monocyclic heterocyclyl having one nitrogen heteroatom. In some embodiments, R C A single occurrence of is an optionally substituted 4-membered saturated or partially unsaturated monocyclic heterocyclyl having one nitrogen heteroatom. In some embodiments, RC A single occurrence of is optionally substituted azetidinyl. In some embodiments, R C The single existence of [ka] In some embodiments, R C A single occurrence of is an optionally substituted 5-membered saturated or partially unsaturated monocyclic heterocyclyl having one nitrogen heteroatom. In some embodiments, R C A single occurrence of is optionally substituted pyrrolidinyl. In some embodiments, R C The single occurrence of -(CH2) 0-4 pyrrolidinyl optionally substituted with R°; R° is C 1-6 In some embodiments, R C The single existence of [ka] In some embodiments, R C A single occurrence of is optionally substituted pyrrolidinonyl. In some embodiments, R C The single existence of [ka] In some embodiments, R C The single existence of [ka] In some embodiments, R C A single occurrence of is an optionally substituted 5-6 membered saturated or partially unsaturated monocyclic heterocyclyl having one nitrogen heteroatom. In some embodiments, R C A single occurrence of is optionally substituted piperidinyl. In some embodiments, R C The single existence of [ka] In some embodiments, R C A single occurrence of is optionally substituted piperidinonyl. In some embodiments, R C The single existence of [ka] is.

[0199] In some embodiments, R C A single occurrence of is an optionally substituted 4-membered saturated or partially unsaturated monocyclic heterocyclyl having one heteroatom selected from oxygen, nitrogen, or sulfur. In some embodiments, R C A single occurrence of is an optionally substituted 4-membered saturated or partially unsaturated monocyclic heterocyclyl having one oxygen heteroatom. In some embodiments, R C A single occurrence of is optionally substituted oxetanyl. In some embodiments, R C A single occurrence of is a halogen or -(CH2) 0-4 Oxetanyl optionally substituted with OR°, where R° is hydrogen or C 1-6 In some embodiments, R C The single existence of [ka] In some embodiments, R C The single existence of [ka] is.

[0200] In some embodiments, R C A single occurrence of is an optionally substituted 5-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur. In some embodiments, R CA single occurrence of is an optionally substituted 5-membered saturated or partially unsaturated monocyclic heterocyclyl having one nitrogen heteroatom and one oxygen heteroatom. In some embodiments, R C A single occurrence of is optionally substituted oxazolidinonyl. In some embodiments, R C The single existence of [ka] is.

[0201] In some embodiments, R C A single occurrence of is an optionally substituted 6-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur. In some embodiments, R C A single occurrence of is an optionally substituted 6-membered saturated or partially unsaturated monocyclic heterocyclyl having one nitrogen heteroatom and one oxygen heteroatom. In some embodiments, R C A single occurrence of is optionally substituted morpholinyl. In some embodiments, R C The single existence of [ka] In some embodiments, R C A single occurrence of is optionally substituted morpholinonyl. In some embodiments, R C The single existence of [ka] is.

[0202] In some embodiments, R C A single occurrence of is an optionally substituted 6-12 membered saturated or unsaturated bicyclic heterocyclyl having 1-3 heteroatoms selected from oxygen, nitrogen, or sulfur. In some embodiments, R CA single occurrence of is an optionally substituted 6-membered saturated or unsaturated bicyclic heterocyclyl having 1 to 3 heteroatoms selected from oxygen, nitrogen, or sulfur. In some embodiments, R C A single occurrence of is an optionally substituted 6-membered saturated or unsaturated bicyclic heterocyclyl having one nitrogen heteroatom.

[0203] In some embodiments, R C A single occurrence of is optionally substituted azabicyclo[3.1.0]hexanyl. In some embodiments, R C A single occurrence of the halogen, -(CH2) 0-4 R°, -(CH2) 0-4 OR°, -(CH2) 0-4 azabicyclo[3.1.0]hexanyl optionally substituted with C(O)OR°; R° is hydrogen or C 1-6 It is aliphatic (eg, methyl), and R° may be further substituted with halogen (eg, fluorine).

[0204] In some embodiments, R C The single existence of [ka] In some embodiments, R C The single existence of [ka] In some embodiments, R C The single existence of [ka] In some embodiments, R C The single existence of [ka] In some embodiments, R C The single existence of [ka] In some embodiments, R C The single existence of [ka] In some embodiments, R C The single existence of [ka] In some embodiments, R C The single existence of [ka] In some embodiments, R C The single existence of [ka] In some embodiments, R C The single existence of [ka] In some embodiments, R C The single existence of [ka] In some embodiments, R C The single existence of [ka] In some embodiments, R C The single existence of [ka] In some embodiments, R C The single existence of [ka] is.

[0205] In some embodiments, R C A single occurrence of is an optionally substituted 7-membered saturated or unsaturated bicyclic heterocyclyl having 1 to 3 heteroatoms selected from oxygen, nitrogen, or sulfur. In some embodiments, R C The single occurrence of is an optionally substituted 7-membered saturated or unsaturated bicyclic heterocyclyl having one nitrogen heteroatom.

[0206] In some embodiments, R C A single occurrence of is optionally substituted 3-azabicyclo[3.1.1]heptanyl. In some embodiments, R C The single existence of [ka] is.

[0207] In some embodiments, R C A single occurrence of is an optionally substituted 5- to 12-membered saturated or unsaturated bicyclic carbocyclyl. In some embodiments, R C A single occurrence of is an optionally substituted 5-membered saturated or unsaturated bicyclic carbocyclyl. In some embodiments, R C A single occurrence of is an optionally substituted 5-membered saturated bicyclic carbocyclyl. In some embodiments, R C A single occurrence of is bicycle[1.1.1]pentanyl. In some embodiments, R C The single existence of [ka] is.

[0208] In some embodiments, R C A single occurrence of is an optionally substituted 7-10 membered heteroaryl having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, R CA single occurrence of is an optionally substituted 9-membered heteroaryl having 1 to 4 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, R C A single occurrence of is an optionally substituted 9-membered heteroaryl having two nitrogen heteroatoms. In some embodiments, R C A single occurrence of is optionally substituted imidazopyridinyl. In some embodiments, R C The single existence of [ka] is.

[0209] In some embodiments, provided compounds have formula (II-a) or (II-b): [ka] or a pharmaceutically acceptable salt thereof (In the formula, Cy A , Cy C , L, L', R B1 , R B2 , R B3 , R B4 , R B5 , R B6 , and R B7 each of which, both alone and in combination, is defined and described in classes and subclasses herein.

[0210] Unless otherwise specified or prohibited by the preceding definitions of formulas (II-a) and (II-b), the variables Cy, as defined above and described in classes and subclasses herein, A , Cy C , L, L', R B1 , R B2 , R B3 , R B4 , R B5 , R B6 , and R B7 It will be understood that this embodiment also applies to compounds of formula (II-a) and (II-b), both alone and in combination.

[0211] In some embodiments, provided compounds have formula (III-a), (III-b), (III-c), or (III-d): [ka] or a pharmaceutically acceptable salt thereof (In the formula, Cy A , Cy C , L, L', R B1 , R B2 , R B3 , and R B4 each of which, both alone and in combination, is defined and described in classes and subclasses herein.

[0212] Unless otherwise specified or prohibited by the preceding definitions of formulas (III-a), (III-b), (III-c), and (III-d), the variables Cy, as defined above and described in classes and subclasses herein, A , Cy C , L, L', R B1 , R B2 , R B3 , and R B4 It will be understood that this embodiment also applies to compounds of formulae (III-a), (III-b), (III-c), and (III-d), both alone and in combination.

[0213] In some embodiments, provided compounds have formula (III-a-1), (III-a-2), or (III-a-3): [ka] or a pharmaceutically acceptable salt thereof (In the formula, Cy A , Cy C , L, L', R B2 , R B4 , and R xeach of which, both alone and in combination, is defined and described in classes and subclasses herein.

[0214] Unless otherwise specified or prohibited by the preceding definitions of formulas (III-a-1), (III-a-2), and (III-a-3), the variables Cy as defined above and described in classes and subclasses herein are A , Cy C , L, L', R B2 , R B4 , and R x It will be understood that this embodiment also applies to compounds of formulae (III-a-1), (III-a-2), and (III-a-3), both alone and in combination.

[0215] In some embodiments, provided compounds have formula (III-b-1), (III-b-2), or (III-b-3): [ka] or a pharmaceutically acceptable salt thereof (In the formula, Cy A , Cy C , L, L', R B1 , R B4 , and R x each of which, both alone and in combination, is defined and described in classes and subclasses herein.

[0216] Unless otherwise specified or prohibited by the preceding definitions of formulae (III-b-1), (III-b-2), and (III-b-3), the variables Cy, as defined above and described in classes and subclasses herein, A , Cy C , L, L', R B1 , R B4 , and R x It will be understood that this embodiment also applies to compounds of formulae (III-b-1), (III-b-2), and (III-b-3), both alone and in combination.

[0217] In some embodiments, provided compounds have formula (IV), (IV-a), (IV-b), or (IV-c): [ka] or a pharmaceutically acceptable salt thereof (In the formula, Cy A , Cy C , L, L', R B3 , R B4 , and R x each of which, both alone and in combination, is defined and described in classes and subclasses herein.

[0218] Unless otherwise specified or prohibited by the preceding definitions of formulas (IV), (IV-a), (IV-b), and (IV-c), the variables Cy as defined above and described in classes and subclasses herein A , Cy C , L, L', R B3 , R B4 , and R x It will be understood that this embodiment also applies to compounds of formulae (IV), (IV-a), (IV-b), and (IV-c), both alone and in combination.

[0219] In some embodiments, provided compounds have formula (Va), (Vb), or (Vc): [ka] or a pharmaceutically acceptable salt thereof (In the formula, Cy C , L, L', R B1 , R B2 , and R A each of which, both alone and in combination, is defined and described in classes and subclasses herein.

[0220] Unless otherwise specified or prohibited by the preceding definitions of Formulas (Va), (Vb), and (Vc), the variables Cy, as defined above and described in classes and subclasses herein, C , L, L', R B1 , R B2 , and R A It will be understood that this embodiment also applies to compounds of formulae (Va), (Vb), and (Vc), both alone and in combination.

[0221] In some embodiments, provided compounds have formula (VI-a), (VI-b), or (VI-c): [ka] or a pharmaceutically acceptable salt thereof (In the formula, Cy C , L, L', R B1 , R B2 , and R A each of which, both alone and in combination, is defined and described in classes and subclasses herein.

[0222] Unless otherwise specified or prohibited by the preceding definitions of formulas (VI-a), (VI-b), and (VI-c), the variables Cy, as defined above and described in classes and subclasses herein, C , L, L', R B1 , R B2 , and R A It will be understood that this embodiment also applies to compounds of formulae (Va), (Vb), and (Vc), both alone and in combination.

[0223] In some embodiments, provided compounds have formula (VII-a), (VII-b), or (VII-c): [ka] or a pharmaceutically acceptable salt thereof (In the formula, Cy C, L, L', R B1 , R B2 , and R A each of which, both alone and in combination, is defined and described in classes and subclasses herein.

[0224] Unless otherwise specified or prohibited by the preceding definitions of formulas (VII-a), (VII-b), and (VII-c), the variables Cy, as defined above and described in classes and subclasses herein, C , L, L', R B1 , R B2 , and R A It will be understood that this embodiment also applies to compounds of formulae (VII-a), (VII-b), and (VII-c), both alone and in combination.

[0225] In some embodiments, provided compounds have formula (VIII-a), (VIII-b), or (VIII-c): [ka] or a pharmaceutically acceptable salt thereof (In the formula, Cy A , Cy C , L, R B1 , and R B2 each of which, both alone and in combination, is defined and described in classes and subclasses herein.

[0226] Unless otherwise specified or prohibited by the preceding definitions of formulas (VIII-a), (VIII-b), and (VIII-c), the variables Cy, as defined above and described in classes and subclasses herein, A , Cy C , L, R B1 , and R B2 It will be understood that this embodiment also applies to compounds of formulae (VIII-a), (VIII-b), and (VIII-c), both alone and in combination.

[0227] In some embodiments, provided compounds have formula (IX-a), (IX-b), or (IX-c): [ka] or a pharmaceutically acceptable salt thereof (In the formula, Cy A , Cy C , L, R B1 , and R B2 each of which, both alone and in combination, is defined and described in classes and subclasses herein.

[0228] Unless otherwise specified or prohibited by the preceding definitions of formulas (IX-a), (IX-b), and (IX-c), the variables Cy, as defined above and described in classes and subclasses herein, A , Cy C , L, R B1 , and R B2 It will be understood that this embodiment also applies to compounds of formulae (IX-a), (IX-b), and (IX-c), both alone and in combination.

[0229] In some embodiments, provided compounds have formula (Xa), (Xb), or (Xc): [ka] or a pharmaceutically acceptable salt thereof (In the formula, Cy A , Cy C , L', R B1 , and R B2 Each of these, both alone and in combination, is defined and described in classes and subclasses herein. A and Cy C It will be understood that the connection between is methylene.

[0230] Unless otherwise specified or prohibited by the preceding definitions of formulae (Xa), (Xb), and (Xc), the variables Cy, as defined above and described in classes and subclasses herein, A , Cy C , L', R B1 , and R B2 It will be understood that this embodiment also applies to compounds of formulae (Xa), (Xb), and (Xc), both alone and in combination.

[0231] In some embodiments, provided compounds have formula (XI-a), (XI-b), or (XI-c): [ka] or a pharmaceutically acceptable salt thereof (In the formula, Cy A , Cy C , L', R B1 , and R B2 each of which, both alone and in combination, is defined and described in classes and subclasses herein.

[0232] Unless otherwise specified or prohibited by the preceding definitions of formulas (XI-a), (XI-b), and (XI-c), the variables Cy, as defined above and described in classes and subclasses herein, A , Cy C , L', R B1 , and R B2 It will be understood that this embodiment also applies to compounds of formulae (XI-a), (XI-b), and (XI-c), both alone and in combination.

[0233] In some embodiments, provided compounds have formula (XII-a), (XII-b), or (XII-c): [ka] or a pharmaceutically acceptable salt thereof (In the formula, Cy A, L, L', R B1 , R B2 , L C , and R C each of which, both alone and in combination, is defined and described in classes and subclasses herein.

[0234] Unless otherwise specified or prohibited by the preceding definitions of formulas (XII-a), (XII-b), and (XII-c), the variables Cy, as defined above and described in classes and subclasses herein, A , L, L', R B1 , R B2 , L C , and R C It will be understood that this embodiment also applies to compounds of formulae (XII-a), (XII-b), and (XII-c), both alone and in combination.

[0235] In some embodiments, provided compounds have formula (XIII-a), (XIII-b), or (XIII-c): [ka] or a pharmaceutically acceptable salt thereof (In the formula, Cy A , L, L', R B1 , R B2 , L C , and R C each of which, both alone and in combination, is defined and described in classes and subclasses herein.

[0236] Unless otherwise specified or prohibited by the preceding definitions of formulas (XIII-a), (XIII-b), and (XIII-c), the variables Cy, as defined above and described in classes and subclasses herein, A , L, L', R B1 , R B2 , L C , and R CIt will be understood that this embodiment also applies to compounds of formulae (XIII-a), (XIII-b), and (XIII-c), both alone and in combination.

[0237] In some embodiments, provided compounds have formula (XIV-a), (XIV-b), or (XIV-c): [ka] or a pharmaceutically acceptable salt thereof (In the formula, Cy A , L, L', R B1 , R B2 , L C , and R C each of which, both alone and in combination, is defined and described in classes and subclasses herein.

[0238] Unless otherwise specified or prohibited by the preceding definitions of formulas (XIV-a), (XIV-b), and (XIV-c), the variables Cy, as defined above and described in classes and subclasses herein, A , L, L', R B1 , R B2 , L C , and R C It will be understood that this embodiment also applies to compounds of formulae (XIV-a), (XIV-b), and (XIV-c), both alone and in combination.

[0239] In some embodiments, provided compounds have formula (XV-a), (XV-b), or (XV-c): [ka] or a pharmaceutically acceptable salt thereof (In the formula, Cy A , L, L', R B1 , R B2 , L C , and R Ceach of which, both alone and in combination, is defined and described in classes and subclasses herein.

[0240] Unless otherwise specified or prohibited by the preceding definitions of formulas (XV-a), (XV-b), and (XV-c), the variables Cy, as defined above and described in classes and subclasses herein, A , L, L', R B1 , R B2 , L C , and R C It will be understood that this embodiment also applies to compounds of formulae (XV-a), (XV-b), and (XV-c), both alone and in combination.

[0241] In some embodiments, provided compounds have formula (XVI-a), (XVI-b), or (XVI-c): [ka] or a pharmaceutically acceptable salt thereof (In the formula, Cy A , L, L', R B1 , R B2 , L C , and R C each of which, both alone and in combination, is defined and described in classes and subclasses herein.

[0242] Unless otherwise specified or prohibited by the preceding definitions of formulas (XVI-a), (XVI-b), and (XVI-c), the variables Cy, as defined above and described in classes and subclasses herein, A , L, L', R B1 , R B2 , L C , and R C It will be understood that this embodiment also applies to compounds of formulae (XVI-a), (XVI-b), and (XVI-c), both alone and in combination.

[0243] In some embodiments, the compound is 2-((2S,4R)-4-amino-1-(6-chloroimidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)-N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)thiazole-4-carboxamide, or a pharmaceutically acceptable salt thereof.

[0244] In some embodiments, the compound is not 2-((2S,4R)-4-amino-1-(6-chloroimidazo[1,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)-N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)thiazole-4-carboxamide, or a pharmaceutically acceptable salt thereof.

[0245] In some embodiments, the compound is N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-((6-methylisoquinolin-3-yl)methyl)-1H-pyrazole-4-carboxamide (I-1); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-(4-cyclopropyl-3-methylbenzyl)-1H-pyrazole-4-carboxamide (I-2); Diisopropyl(5,7-dimethyl-6-((1-((6-methylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamido)methyl)isoquinolin-1-yl)iminodicarbonate (I-3); Benzyl ((benzyloxy)carbonyl) (5,7-dimethyl-6-((1-((6-methylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamido)methyl)isoquinolin-1-yl)carbamate (I-4); Isobutyl (5,7-dimethyl-6-((1-((6-methylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamido)methyl)isoquinolin-1-yl)carbamate (I-5); Isopropyl(5,7-dimethyl-6-((1-((6-methylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamido)methyl)isoquinolin-1-yl)carbamate (I-6); Benzyl (5,7-dimethyl-6-((1-((6-methylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamido)methyl)isoquinolin-1-yl)carbamate (I-7); N-((1-acetamido-5,7-dimethylisoquinolin-6-yl)methyl)-1-((6-methylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (I-8); Ethyl (5,7-dimethyl-6-((1-((6-methylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamido)methyl)isoquinolin-1-yl)carbamate (I-9); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-((6-methylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (I-10); (R*)-N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-(1-(6-methylimidazo[1,2-a]pyridin-2-yl)ethyl)-1H-pyrazole-4-carboxamide (I-11); (R)-N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-(1-(6-methylimidazo[1,2-a]pyridin-2-yl)ethyl)-1H-pyrazole-4-carboxamide (I-11a); (S*)-N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-(1-(6-methylimidazo[1,2-a]pyridin-2-yl)ethyl)-1H-pyrazole-4-carboxamide (I-12); (S)—N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-(1-(6-methylimidazo[1,2-a]pyridin-2-yl)ethyl)-1H-pyrazole-4-carboxamide (I-12a); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-(1-(6-methylimidazo[1,2-a]pyridin-2-yl)ethyl)-1H-pyrazole-4-carboxamide (I-13); Methyl 2-(4-(((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)carbamoyl)-1H-pyrazol-1-yl)-2-(6-methylimidazo[1,2-a]pyridin-2-yl)acetate (I-14); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-((6-methyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (I-15); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-((2-methylquinazolin-7-yl)methyl)-1H-pyrazole-4-carboxamide (I-16); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-(4-((5-chloro-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)oxy)benzyl)-1H-pyrazole-4-carboxamide (I-17); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-(4-((1-methyl-2-oxo-1,2-dihydropyridin-3-yl)oxy)benzyl)-1H-pyrazole-4-carboxamide (I-18); 1-(4-(1-acetamidocyclopropyl)benzyl)-N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1H-pyrazole-4-carboxamide (I-19); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-(4-(2-(dimethylamino)-2-oxoethyl)-3,5-dimethylbenzyl)-1H-pyrazole-4-carboxamide (I-20); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-(4-(N-methylpyrrolidine-1-carboxamido)benzyl)-1H-pyrazole-4-carboxamide (I-21); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-(4-(1,3,3-trimethylureido)benzyl)-1H-pyrazole-4-carboxamide (I-22); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-(4-(2-(dimethylamino)-1,1-difluoro-2-oxoethyl)benzyl)-1H-pyrazole-4-carboxamide (I-23); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-((3-methylquinoxalin-6-yl)methyl)-1H-pyrazole-4-carboxamide (I-24); Ethyl (4-((4-(((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)carbamoyl)-1H-pyrazol-1-yl)methyl)phenyl)(methyl)carbamate (I-25); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-(4-(2-(dimethylamino)-2-oxoethyl)-3-methylbenzyl)-1H-pyrazole-4-carboxamide (I-26); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-((2-methylquinolin-7-yl)methyl)-1H-pyrazole-4-carboxamide (I-27); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-((3-cyclopropylquinolin-6-yl)methyl)-1H-pyrazole-4-carboxamide (I-28); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-(4-cyclopropylbenzyl)-1H-pyrazole-4-carboxamide (I-29); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-(4-((1-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzyl)-1H-pyrazole-4-carboxamide (I-30); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-(3-cyclopropylbenzyl)-1H-pyrazole-4-carboxamide (I-31); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-(2-cyanobenzyl)-1H-pyrazole-4-carboxamide (I-32); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-(2-methoxybenzyl)-1H-pyrazole-4-carboxamide (I-33); (S)-N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-(1-phenylethyl)-1H-pyrazole-4-carboxamide (I-34); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-(4-methylbenzyl)-1H-pyrazole-4-carboxamide (I-35); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-(4-methyl-3-(trifluoromethyl)benzyl)-1H-pyrazole-4-carboxamide (I-36); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-(3,5-dichlorobenzyl)-1H-pyrazole-4-carboxamide (I-37); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-(2-fluorobenzyl)-1H-pyrazole-4-carboxamide (I-38); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-(4-fluorobenzyl)-1H-pyrazole-4-carboxamide (I-39); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-(2-methylbenzyl)-1H-pyrazole-4-carboxamide (I-40); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-(3-methylbenzyl)-1H-pyrazole-4-carboxamide (I-41); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-(2-(trifluoromethyl)benzyl)-1H-pyrazole-4-carboxamide (I-42); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-(3-methoxybenzyl)-1H-pyrazole-4-carboxamide (I-43); 1-(4-((1,3,4-oxadiazol-2-yl)methyl)benzyl)-N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1H-pyrazole-4-carboxamide (I-44); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-(3-fluorobenzyl)-1H-pyrazole-4-carboxamide (I-45); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-((2-oxo-2H-[1,2'-bipyridin]-5'-yl)methyl)-1H-pyrazole-4-carboxamide (I-46); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-((3-methylbenzofuran-2-yl)methyl)-1H-pyrazole-4-carboxamide (I-47); 1-(4-(2-(1H-pyrazol-1-yl)ethyl)benzyl)-N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1H-pyrazole-4-carboxamide (I-48); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-(4-(2-(2-oxopyridin-1(2H)-yl)ethyl)benzyl)-1H-pyrazole-4-carboxamide (I-49); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-((5-bromobenzofuran-2-yl)methyl)-1H-pyrazole-4-carboxamide (I-50); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-((5-bromobenzo[b]thiophen-2-yl)methyl)-1H-pyrazole-4-carboxamide (I-51); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-((1-methyl-1H-indazol-5-yl)methyl)-1H-pyrazole-4-carboxamide (I-52); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-(imidazo[1,2-a]pyridin-2-ylmethyl)-1H-pyrazole-4-carboxamide (I-53); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-((8-methylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (I-54); Ethyl 2-(4-((4-(((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)carbamoyl)-1H-pyrazol-1-yl)methyl)phenyl)acetate (I-55); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-(naphthalen-2-ylmethyl)-1H-pyrazole-4-carboxamide (I-56); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-((5-fluorobenzofuran-2-yl)methyl)-1H-pyrazole-4-carboxamide (I-57); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-((1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)methyl)-1H-pyrazole-4-carboxamide (I-58); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-((1-methyl-1H-indazol-6-yl)methyl)-1H-pyrazole-4-carboxamide (I-59); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-(quinolin-6-ylmethyl)-1H-pyrazole-4-carboxamide (I-60); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-((7-chloroquinolin-3-yl)methyl)-1H-pyrazole-4-carboxamide (I-61); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-((4-chlorobenzo[b]thiophen-2-yl)methyl)-1H-pyrazole-4-carboxamide (I-62); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-(4-(2-(dimethylamino)-2-oxoethyl)benzyl)-1H-pyrazole-4-carboxamide (I-63); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-((2-methylquinolin-6-yl)methyl)-1H-pyrazole-4-carboxamide (I-64); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-((5-chlorobenzo[b]thiophen-2-yl)methyl)-1H-pyrazole-4-carboxamide (I-65); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-((5-(trifluoromethyl)benzo[b]thiophen-2-yl)methyl)-1H-pyrazole-4-carboxamide (I-66); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-((2-methoxyquinolin-3-yl)methyl)-1H-pyrazole-4-carboxamide (I-67); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-((1-(difluoromethyl)-1H-benzo[d]imidazol-2-yl)methyl)-1H-pyrazole-4-carboxamide (I-68); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-((6-bromoquinolin-2-yl)methyl)-1H-pyrazole-4-carboxamide (I-69); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-((6-bromoquinolin-3-yl)methyl)-1H-pyrazole-4-carboxamide (I-70); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-((1-isopropyl-1H-benzo[d]imidazol-2-yl)methyl)-1H-pyrazole-4-carboxamide (I-71); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-((8-methylquinolin-3-yl)methyl)-1H-pyrazole-4-carboxamide (I-72); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-((2-chloro-8-methylquinolin-3-yl)methyl)-1H-pyrazole-4-carboxamide (I-73); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-(isoquinolin-6-ylmethyl)-1H-pyrazole-4-carboxamide (I-74); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-((1-methyl-1H-benzo[d]imidazol-2-yl)methyl)-1H-pyrazole-4-carboxamide (I-75); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-(benzo[d]thiazol-2-ylmethyl)-1H-pyrazole-4-carboxamide (I-76); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-(pyrimidin-5-ylmethyl)-1H-pyrazole-4-carboxamide (I-77); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-(pyridin-2-ylmethyl)-1H-pyrazole-4-carboxamide (I-78); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-(quinoxalin-6-ylmethyl)-1H-pyrazole-4-carboxamide (I-79); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-((3-chlorobenzo[b]thiophen-2-yl)methyl)-1H-pyrazole-4-carboxamide (I-80); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-((6-chlorobenzo[b]thiophen-2-yl)methyl)-1H-pyrazole-4-carboxamide (I-81); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-(benzofuran-2-ylmethyl)-1H-pyrazole-4-carboxamide (I-82); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-(pyrimidin-2-ylmethyl)-1H-pyrazole-4-carboxamide (I-83); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-(benzo[b]thiophen-2-ylmethyl)-1H-pyrazole-4-carboxamide (I-84); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-(benzo[d]oxazol-2-ylmethyl)-1H-pyrazole-4-carboxamide (I-85); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-(pyrazin-2-ylmethyl)-1H-pyrazole-4-carboxamide (I-86); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-(pyridin-4-ylmethyl)-1H-pyrazole-4-carboxamide (I-87); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-(pyridin-3-ylmethyl)-1H-pyrazole-4-carboxamide (I-88); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-((3-chloroquinolin-6-yl)methyl)-1H-pyrazole-4-carboxamide (I-89); 1-((6-(2-(3-azabicyclo[3.1.0]hexan-3-yl)-2-oxoethyl)pyridin-3-yl)methyl)-N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1H-pyrazole-4-carboxamide (I-90); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-(4-methoxybenzyl)-1H-pyrazole-4-carboxamide (I-91); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-(4-cyanobenzyl)-1H-pyrazole-4-carboxamide (I-92); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-(4-(trifluoromethyl)benzyl)-1H-pyrazole-4-carboxamide (I-93); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-(3-cyanobenzyl)-1H-pyrazole-4-carboxamide (I-94); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-(3,5-bis(trifluoromethyl)benzyl)-1H-pyrazole-4-carboxamide (I-95); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-(3-chloro-4-methylbenzyl)-1H-pyrazole-4-carboxamide (I-96); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-(3-(trifluoromethyl)benzyl)-1H-pyrazole-4-carboxamide (I-97); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-(3-chlorobenzyl)-1H-pyrazole-4-carboxamide (I-98); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (I-99); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-((7-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (I-100); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-((6-chloroimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (I-101); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-((6,7-dimethylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (I-102); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-((7-methylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (I-103); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-((5-methylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (I-105); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-((6-chloro-5-methylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (I-106); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-((7-chloroquinolin-2-yl)methyl)-1H-pyrazole-4-carboxamide (I-107); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-((2-chloro-7-methoxyquinolin-3-yl)methyl)-1H-pyrazole-4-carboxamide (I-108); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-((2-chloro-7-methoxyquinolin-3-yl)methyl)-1H-pyrazole-4-carboxamide (I-109); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-((7-methoxyquinolin-3-yl)methyl)-1H-pyrazole-4-carboxamide (I-110); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-((7-methoxyquinolin-3-yl)methyl)-1H-pyrazole-4-carboxamide (I-111); 1-((5-(1H-pyrazol-1-yl)naphthalen-2-yl)methyl)-N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1H-pyrazole-4-carboxamide (I-112); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-((5-bromonaphthalen-2-yl)methyl)-1H-pyrazole-4-carboxamide (I-113); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-((5-(pyridin-2-yl)naphthalen-2-yl)methyl)-1H-pyrazole-4-carboxamide (I-114); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-((3-methylquinolin-6-yl)methyl)-1H-pyrazole-4-carboxamide (I-115); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-(4-(3-fluoro-2-methoxybenzyl)benzyl)-1H-pyrazole-4-carboxamide (I-116); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-(4-((4-methyl-4H-1,2,4-triazol-3-yl)methyl)benzyl)-1H-pyrazole-4-carboxamide (I-117); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-(2-cyclopropylbenzyl)-1H-pyrazole-4-carboxamide (I-118); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-(4-(1-(dimethylamino)-1-oxopropan-2-yl)benzyl)-1H-pyrazole-4-carboxamide (I-119); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-(1-(3-chloroquinolin-6-yl)ethyl)-1H-pyrazole-4-carboxamide (I-120); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-((5-cyclopropylpyrazolo[1,5-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (I-121); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-(4-(1-(pyrrolidine-1-carbonyl)cyclopropyl)benzyl)-1H-pyrazole-4-carboxamide (I-122); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-((3-vinylquinolin-6-yl)methyl)-1H-pyrazole-4-carboxamide (I-123); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-((3-ethylquinolin-6-yl)methyl)-1H-pyrazole-4-carboxamide (I-124); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-((5-(2-oxopyridin-1(2H)-yl)naphthalen-2-yl)methyl)-1H-pyrazole-4-carboxamide (I-125); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-((6-methoxyquinazolin-2-yl)methyl)-1H-pyrazole-4-carboxamide (I-126); (R)-N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-(1-phenylethyl)-1H-pyrazole-4-carboxamide (I-127); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N-methyl-1-((6-methylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (I-128); 2-(4-(((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)carbamoyl)-1H-pyrazol-1-yl)-2-(6-methylimidazo[1,2-a]pyridin-2-yl)acetic acid (I-129); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-(2-hydroxy-1-(6-methylimidazo[1,2-a]pyridin-2-yl)ethyl)-1H-pyrazole-4-carboxamide (I-130); 2-(4-((4-(((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)carbamoyl)-1H-pyrazol-1-yl)methyl)phenyl)acetic acid (I-131); Ethyl (6-((1-((3-chloroquinolin-6-yl)methyl)-1H-pyrazole-4-carboxamido)methyl)-5,7-dimethylisoquinolin-1-yl)carbamate (I-132); N-((1-acetamido-5,7-dimethylisoquinolin-6-yl)methyl)-1-((3-chloroquinolin-6-yl)methyl)-1H-pyrazole-4-carboxamide (I-133); 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-((5,7-dimethyl-1-(methylamino)isoquinolin-6-yl)methyl)-1H-pyrazole-4-carboxamide (I-134); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-((6-bromo-7-methylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (I-135); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-((5,6-dimethylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (I-136); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-((5-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (I-137); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-((6-bromo-5-chloroimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (I-138); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-((5-bromoimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (I-139); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-((5-ethylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (I-140); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-((6-chloro-5-ethylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (I-141); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-((6-cyclopropyl-5-fluoroimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (I-142); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-((5-cyanoimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (I-143); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-((5-methoxyimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (I-144); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-((6-bromo-5-methylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (I-145); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-((6-cyclopropyl-7-methylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (I-146); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-((7-chloro-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (I-147); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-((5-chloro-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (I-148); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-((6-bromo-7-chloroimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (I-149); 1-((1,5-naphthyridin-2-yl)methyl)-N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1H-pyrazole-4-carboxamide (I-150); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-(3-chloro-4-(2-(dimethylamino)-2-oxoethyl)benzyl)-1H-pyrazole-4-carboxamide (I-151); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-(4-(2-(dimethylamino)-2-oxoethyl)-3-(trifluoromethyl)benzyl)-1H-pyrazole-4-carboxamide (I-152); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-((7-methylnaphthalen-2-yl)methyl)-1H-pyrazole-4-carboxamide (I-153); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-(2-oxo-2-(phenylamino)ethyl)-1H-pyrazole-4-carboxamide (I-154); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-(2-(methyl(phenyl)amino)-2-oxoethyl)-1H-pyrazole-4-carboxamide (I-155); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-((7-bromoquinolin-2-yl)methyl)-1H-pyrazole-4-carboxamide (I-156); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-((6-chloroquinolin-2-yl)methyl)-1H-pyrazole-4-carboxamide (I-157); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-((6-fluoroquinolin-2-yl)methyl)-1H-pyrazole-4-carboxamide (I-158); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-((8-bromoquinolin-2-yl)methyl)-1H-pyrazole-4-carboxamide (I-159); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-benzyl-1H-pyrazole-4-carboxamide (I-160); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-5-(methoxymethyl)-1-((2-(pyrrolidin-1-yl)pyrimidin-5-yl)methyl)-1H-pyrazole-4-carboxamide (I-161); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-3-(methoxymethyl)-1-((2-(pyrrolidin-1-yl)pyrimidin-5-yl)methyl)-1H-pyrazole-4-carboxamide (I-162); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-((3-chloroquinolin-6-yl)methyl)-1H-pyrazole-4-carboxamide (I-163); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-((3-hydroxyquinolin-6-yl)methyl)-1H-pyrazole-4-carboxamide (I-164); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-(4-(pyridin-2-ylmethyl)benzyl)-1H-pyrazole-4-carboxamide (I-165); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-(4-(thiazol-2-ylmethyl)benzyl)-1H-pyrazole-4-carboxamide (I-166); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-(4-(imidazo[1,2-a]pyridin-8-ylmethyl)benzyl)-1H-pyrazole-4-carboxamide (I-167); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-(4-(pyrimidin-2-ylmethyl)benzyl)-1H-pyrazole-4-carboxamide (I-168); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-(3,5-dimethyl-4-(pyridin-2-ylmethyl)benzyl)-1H-pyrazole-4-carboxamide (I-169); N-((1-amino-5,7,8-trimethylisoquinolin-6-yl)methyl)-1-benzyl-1H-pyrazole-4-carboxamide (I-170); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-benzyl-1H-pyrazole-4-carboxamide (I-171); 1-((8-((1,3,4-oxadiazol-2-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1H-pyrazole-4-carboxamide (I-172); N-((1-amino-7-ethyl-5-methylisoquinolin-6-yl)methyl)-1-benzyl-1H-pyrazole-4-carboxamide (I-173); N-((1-amino-7-cyclopropyl-5-methylisoquinolin-6-yl)methyl)-1-benzyl-1H-pyrazole-4-carboxamide (I-174); N-((1-amino-5-methyl-7-(1-methylcyclopropyl)isoquinolin-6-yl)methyl)-1-benzyl-1H-pyrazole-4-carboxamide (I-175); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-((6-(2,2-dimethylcyclopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (I-176); (Z)-N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-((6-(prop-1-en-1-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-3-carboxamide (I-177); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-((6-(2-methylcyclopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (I-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)-1H-pyrazole-4-carboxamide (I-179); 1-(2-amino-1-phenylethyl)-N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1H-pyrazole-4-carboxamide (I-180); tert-Butyl (2-(4-(((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)carbamoyl)-1H-pyrazol-1-yl)-2-phenylethyl)carbamate (I-181); 1-(4-(2-(3-azabicyclo[3.1.0]hexan-3-yl)-2-oxoethyl)benzyl)-N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-3-(trifluoromethyl)-1H-pyrazole-4-carboxamide (I-182); 2-(4-((1H-pyrazol-1-yl)methyl)benzyl)-N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)isonicotinamide (I-183); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-(4-((4-methyl-1H-pyrazol-1-yl)methyl)benzyl)-3-(trifluoromethyl)-1H-pyrazole-4-carboxamide (I-184); 1-(4-((1H-pyrazol-1-yl)methyl)benzyl)-N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-3-(trifluoromethyl)-1H-pyrazole-4-carboxamide (I-185); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-(4-((2-oxopyridin-1(2H)-yl)methyl)benzyl)-1H-1,2,3-triazole-4-carboxamide (I-186); 1-(4-((1H-pyrazol-1-yl)methyl)benzyl)-N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-3-(methoxymethyl)-1H-pyrazole-4-carboxamide (I-187); 1-(4-((1H-pyrazol-1-yl)methyl)benzyl)-N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-5-(methoxymethyl)-1H-pyrazole-4-carboxamide (I-188); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-2-(6-cyclopropylimidazo[1,2-a]pyridine-2-carbonyl)isonicotinamide (I-189); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-5-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1,3,4-oxadiazole-2-carboxamide (I-190); N-((1-amino-5,7,8-trimethylisoquinolin-6-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (I-191); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-(4-((2-oxopyridin-1(2H)-yl)methyl)benzyl)-1H-pyrazole-4-carboxamide (I-192); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-((6-(pyrrolidin-1-yl)pyridin-3-yl)methyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide (I-193); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-((6-(pyrrolidin-1-yl)pyridin-3-yl)methyl)-3-(trifluoromethyl)-1H-pyrazole-4-carboxamide (I-194); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-((2-phenylpyrimidin-5-yl)methyl)-1H-pyrazole-4-carboxamide (I-195); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-(4-((2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridin-3-yl)methyl)benzyl)-1H-pyrazole-4-carboxamide (I-196); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-2-((3-chloroquinolin-6-yl)methyl)isonicotinamide (I-197); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-2-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)thiazole-5-carboxamide (I-198); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-3-(difluoromethyl)-1H-pyrazole-4-carboxamide (I-199); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-(1-(3-chloroquinolin-6-yl)ethyl)-1H-1,2,3-triazole-4-carboxamide (I-200); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-((6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (I-201); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-3-(aminomethyl)-1-benzyl-1H-pyrazole-5-carboxamide (I-202); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-5-(aminomethyl)-1-benzyl-1H-pyrazole-3-carboxamide (I-203); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-(4-(2-((cyclopropylmethyl)(methyl)amino)-2-oxoethyl)benzyl)-1H-pyrazole-4-carboxamide (I-204); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-(4-(2-((1R,5S,6r)-6-methyl-3-azabicyclo[3.1.0]hexan-3-yl)-2-oxoethyl)benzyl)-1H-pyrazole-4-carboxamide (I-205); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-(4-(2-((1R,5S,6s)-6-(fluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)-2-oxoethyl)benzyl)-1H-pyrazole-4-carboxamide (I-206); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-(4-(2-((1R,5S,6r)-6-(fluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)-2-oxoethyl)benzyl)-1H-pyrazole-4-carboxamide (I-207); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-(4-(2-((1R,5S,6r)-6-(hydroxymethyl)-3-azabicyclo[3.1.0]hexan-3-yl)-2-oxoethyl)benzyl)-1H-pyrazole-4-carboxamide (I-208); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-(4-(2-((1R,5S,6s)-6-(hydroxymethyl)-3-azabicyclo[3.1.0]hexan-3-yl)-2-oxoethyl)benzyl)-1H-pyrazole-4-carboxamide (I-209); (1R,5S,6s)-3-(2-(4-((4-(((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)carbamoyl)-1H-pyrazol-1-yl)methyl)phenyl)acetyl)-3-azabicyclo[3.1.0]hexane-6-carboxylic acid (I-210); Ethyl (1R,5S,6s)-3-(2-(4-((4-(((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)carbamoyl)-1H-pyrazol-1-yl)methyl)phenyl)acetyl)-3-azabicyclo[3.1.0]hexane-6-carboxylate (I-211); Ethyl (1R,5S,6r)-3-(2-(4-((4-(((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)carbamoyl)-1H-pyrazol-1-yl)methyl)phenyl)acetyl)-3-azabicyclo[3.1.0]hexane-6-carboxylate (I-212); (1R,5S,6r)-3-(2-(4-((4-(((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)carbamoyl)-1H-pyrazol-1-yl)methyl)phenyl)acetyl)-3-azabicyclo[3.1.0]hexane-6-carboxylic acid (I-213); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-(4-(2-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)-2-oxoethyl)benzyl)-1H-pyrazole-4-carboxamide (I-214); 1-(4-(2-(3-azabicyclo[3.1.1]heptan-3-yl)-2-oxoethyl)benzyl)-N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1H-pyrazole-4-carboxamide (I-215); 3-(2-(4-((4-(((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)carbamoyl)-1H-pyrazol-1-yl)methyl)phenyl)acetyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid (I-216); Methyl 3-(2-(4-((4-(((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)carbamoyl)-1H-pyrazol-1-yl)methyl)phenyl)acetyl)-3-azabicyclo[3.1.0]hexane-1-carboxylate (I-217); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-(4-(2-(2,5-dimethylpyrrolidin-1-yl)-2-oxoethyl)benzyl)-1H-pyrazole-4-carboxamide (I-218); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-(4-(2-(azetidin-1-yl)-2-oxoethyl)benzyl)-1H-pyrazole-4-carboxamide (I-219); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-(4-(2-(benzyl(methyl)amino)-2-oxoethyl)benzyl)-1H-pyrazole-4-carboxamide (I-220); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-(4-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethyl)benzyl)-1H-pyrazole-4-carboxamide (I-221); 1-(4-(2-(3-azabicyclo[3.1.0]hexan-3-yl)-2-oxoethyl)benzyl)-N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1H-pyrazole-4-carboxamide (I-222); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-(4-(2-oxo-2-(piperidin-1-yl)ethyl)benzyl)-1H-pyrazole-4-carboxamide (I-223); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-(4-(2-(cyclopropyl(methyl)amino)-2-oxoethyl)benzyl)-1H-pyrazole-4-carboxamide (I-224); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-(4-(2-morpholino-2-oxoethyl)benzyl)-1H-pyrazole-4-carboxamide (I-225); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-(4-(2-(diethylamino)-2-oxoethyl)benzyl)-1H-pyrazole-4-carboxamide (I-226); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-(4-(2-oxo-2-(phenylamino)ethyl)benzyl)-1H-pyrazole-4-carboxamide (I-227); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-(4-(2-(methyl(phenyl)amino)-2-oxoethyl)benzyl)-1H-pyrazole-4-carboxamide (I-228); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-(4-(2-(benzylamino)-2-oxoethyl)benzyl)-1H-pyrazole-4-carboxamide (I-229); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-(4-(2-(methylamino)-2-oxoethyl)benzyl)-1H-pyrazole-4-carboxamide (I-230); 1-(4-(2-amino-2-oxoethyl)benzyl)-N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1H-pyrazole-4-carboxamide (I-231); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-(4-(2-oxo-2-(pyrrolidin-1-yl)ethyl)benzyl)-1H-pyrazole-4-carboxamide (I-232); N 4-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N 6 -(Naphthalen-2-ylmethyl)pyrimidine-4,6-diamine (I-233); N 4 -(4-((1H-pyrazol-1-yl)methyl)benzyl)-N 6 -((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-5-fluoropyrimidine-4,6-diamine (I-234); N 5 -(4-((1H-pyrazol-1-yl)methyl)benzyl)-N 3 -((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N 5 -methylpyridazine-3,5-diamine (I-235); 1-(4-(((6-(((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyridazin-4-yl)amino)methyl)benzyl)pyridin-2(1H)-one (I-236); 1-(4-(((6-(((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimidin-4-yl)amino)methyl)benzyl)pyridin-2(1H)-one (I-237); 6-(aminomethyl)-N-(4-((3-cyclopropylquinolin-6-yl)methoxy)pyridin-2-yl)-5,7-dimethylisoquinolin-1-amine (I-238); 6-(((4-((3-cyclopropylquinolin-6-yl)methoxy)pyridin-2-yl)amino)methyl)-5,7-dimethylisoquinolin-1-amine (I-239); N2-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N3-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)pyrazine-2,3-diamine (I-240); N 4 -((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N 6 -((5-(pyridin-2-yl)naphthalen-2-yl)methyl)pyrimidine-4,6-diamine (I-241); N 4 -((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N 6 -((6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)methyl)pyrimidine-4,6-diamine (I-242); N 4 -((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N 6 -((5-cyclopropylthieno[2,3-b]pyridin-2-yl)methyl)pyrimidine-4,6-diamine (I-243); N 4 -((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N 6 -((5-cyclopropylpyrazolo[1,5-a]pyridin-2-yl)methyl)pyrimidine-4,6-diamine (I-244); 1-(6-(((6-(((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimidin-4-yl)amino)methyl)naphthalen-1-yl)pyridin-2(1H)-one (I-245); N 4 -((5-(1H-pyrazol-1-yl)naphthalen-2-yl)methyl)-N 6 -((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)pyrimidine-4,6-diamine (I-246); N-(6,8-dimethyl-7-(((6-((4-((2-oxopyridin-1(2H)-yl)methyl)benzyl)amino)pyrimidin-4-yl)amino)methyl)isoquinolin-1-yl)acetamide (I-247); Benzyl (6,8-dimethyl-7-(((6-((4-((2-oxopyridin-1(2H)-yl)methyl)benzyl)amino)pyrimidin-4-yl)amino)methyl)isoquinolin-1-yl)carbamate (I-248); Ethyl (5,7-dimethyl-6-(((6-((4-((2-oxopyridin-1(2H)-yl)methyl)benzyl)amino)pyrimidin-4-yl)amino)methyl)isoquinolin-1-yl)carbamate (I-249); 3-(2-(((6-(((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimidin-4-yl)oxy)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)oxetan-3-ol (I-250); 6-(((6-((4-((1H-pyrazol-1-yl)methyl)benzyl)oxy)pyrimidin-4-yl)amino)methyl)-5,7-dimethylisoquinolin-1-amine (I-251); 5,7-dimethyl-6-(((5-(naphthalen-2-ylmethoxy)pyridazin-3-yl)amino)methyl)isoquinolin-1-amine (I-252); 6-(((3-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-3H-[1,2,3]triazolo[4,5-c]pyridin-4-yl)amino)methyl)-5,7-dimethylisoquinolin-1-amine (I-253); 6-(((1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-[1,2,3]triazolo[4,5-c]pyridin-4-yl)amino)methyl)-5,7-dimethylisoquinolin-1-amine (I-254); 6-(aminomethyl)-N-(6-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methoxy)pyrimidin-4-yl)-5-methyl-7-(1-methylcyclopropyl)isoquinolin-1-amine (I-255); 3-(2-(((6-(((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimidin-4-yl)oxy)methyl)-5-cyclopropylpyrazolo[1,5-a]pyridin-7-yl)oxazolidin-2-one (I-256); 6-(((6-((6-cyclopropyl-8-(3,5-dimethyl-4H-1,2,4-triazol-4-yl)imidazo[1,2-a]pyridin-2-yl)methoxy)pyrimidin-4-yl)amino)methyl)-5,7-dimethylisoquinolin-1-amine (I-257); 2-(((6-(((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimidin-4-yl)oxy)methyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-carbonitrile (I-258); 1-(2-(((6-(((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimidin-4-yl)oxy)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)pyrrolidin-2-one (I-259); 6-(((2-(4-((1H-pyrazol-1-yl)methyl)benzyl)-2H-pyrazolo[3,4-c]pyridin-7-yl)amino)methyl)-5,7-dimethylisoquinolin-1-amine (I-260); 6-(((6-((6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)methoxy)pyrimidin-4-yl)amino)methyl)-5,7-dimethylisoquinolin-1-amine (I-261); 6-(((6-((6-cyclopropylimidazo[1,2-a]pyrimidin-2-yl)methoxy)pyrimidin-4-yl)amino)methyl)-5,7-dimethylisoquinolin-1-amine (I-262); 6-(((2-((6-cyclopropyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)methyl)-2H-pyrazolo[3,4-c]pyridin-7-yl)amino)methyl)-5,7-dimethylisoquinolin-1-amine (I-263); 6-(((2-((6-cyclopropylimidazo[1,2-a]pyrimidin-2-yl)methyl)-2H-pyrazolo[3,4-c]pyridin-7-yl)amino)methyl)-5,7-dimethylisoquinolin-1-amine (I-264); 6-(((2-((6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)methyl)-2H-pyrazolo[3,4-c]pyridin-7-yl)amino)methyl)-5,7-dimethylisoquinolin-1-amine (I-265); 6-(((1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazolo[4,3-c]pyridin-4-yl)amino)methyl)-5,7-dimethylisoquinolin-1-amine (I-266); 6-(((2-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)amino)methyl)-5,7-dimethylisoquinolin-1-amine (I-267); 6-(((1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazolo[4,3-c]pyridin-6-yl)amino)methyl)-5,7-dimethylisoquinolin-1-amine (I-268); 6-(((2-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-6-yl)amino)methyl)-5,7-dimethylisoquinolin-1-amine (I-269); Ethyl 3-(2-(((6-(((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimidin-4-yl)oxy)methyl)-5-cyclopropylpyrazolo[1,5-a]pyridin-7-yl)propanoate (I-270); 6-(((2-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-2H-pyrazolo[3,4-c]pyridin-7-yl)amino)methyl)-5,7-dimethylisoquinolin-1-amine (I-271); 6-(((6-((6-cyclopropyl-8-(3-fluorooxetan-3-yl)imidazo[1,2-a]pyridin-2-yl)methoxy)pyrimidin-4-yl)amino)methyl)-5,7-dimethylisoquinolin-1-amine (I-272); 3-(2-(((6-(((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimidin-4-yl)oxy)methyl)-5-cyclopropylpyrazolo[1,5-a]pyridin-7-yl)propanoic acid (I-273); Ethyl 3-(4-(((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)-6-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methoxy)pyrimidin-2-yl)propanoate (I-274); 6-(((5-(1-(4-((1H-pyrazol-1-yl)methyl)phenyl)ethoxy)pyridazin-3-yl)amino)methyl)-5,7-dimethylisoquinolin-1-amine (I-275); (R*)-6-(((5-(1-(4-((1H-pyrazol-1-yl)methyl)phenyl)ethoxy)pyridazin-3-yl)amino)methyl)-5,7-dimethylisoquinolin-1-amine (I-276); (S*)-6-(((5-(1-(4-((1H-pyrazol-1-yl)methyl)phenyl)ethoxy)pyridazin-3-yl)amino)methyl)-5,7-dimethylisoquinolin-1-amine (I-277); (S)-6-(((5-(1-(4-((1H-pyrazol-1-yl)methyl)phenyl)ethoxy)pyridazin-3-yl)amino)methyl)-5,7-dimethylisoquinolin-1-amine; (R)-6-(((5-(1-(4-((1H-pyrazol-1-yl)methyl)phenyl)ethoxy)pyridazin-3-yl)amino)methyl)-5,7-dimethylisoquinolin-1-amine; 6-(((5-((4-(2-(1H-pyrazol-1-yl)ethyl)benzyl)oxy)pyridazin-3-yl)amino)methyl)-5,7-dimethylisoquinolin-1-amine (I-278); 6-(((2-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methoxy)pyridin-4-yl)amino)methyl)-5,7-dimethylisoquinolin-1-amine (I-279); 6-(((5-chloro-4-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methoxy)pyridin-2-yl)amino)methyl)-5,7-dimethylisoquinolin-1-amine (I-280); 6-(((6-((5-cyclopropylthieno[2,3-b]pyridin-2-yl)methoxy)pyrimidin-4-yl)amino)methyl)-5,7-dimethylisoquinolin-1-amine (I-281); 6-(((6-((5-cyclopropylbenzo[d]thiazol-2-yl)methoxy)pyrimidin-4-yl)amino)methyl)-5,7-dimethylisoquinolin-1-amine (I-282); 6-(((1-((5-cyclopropylthieno[2,3-b]pyridin-2-yl)methyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)amino)methyl)-5,7-dimethylisoquinolin-1-amine (I-283); 6-(((4-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methoxy)pyridin-2-yl)amino)methyl)-5,7-dimethylisoquinolin-1-amine (I-284); 6-(((1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-3-fluoro-1H-pyrrolo[3,2-c]pyridin-6-yl)amino)methyl)-5,7-dimethylisoquinolin-1-amine (I-285); 6-(((1-((5-cyclopropylthieno[2,3-b]pyridin-2-yl)methyl)-3-fluoro-1H-pyrrolo[3,2-c]pyridin-6-yl)amino)methyl)-5,7-dimethylisoquinolin-1-amine (I-286); 6-(((3-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methoxy)pyrazin-2-yl)amino)methyl)-5,7-dimethylisoquinolin-1-amine (I-287); N 4 -((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N 5 -((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)pyrimidine-4,5-diamine (I-288); 6-(((3-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methoxy)pyridin-2-yl)amino)methyl)-5,7-dimethylisoquinolin-1-amine (I-289); 6-(((6-(((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)thio)pyrimidin-4-yl)amino)methyl)-5,7-dimethylisoquinolin-1-amine (I-290); Ethyl 3-(4-(((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)-6-((6-cyclopropylimidazo[1,2-a]pyrimidin-2-yl)methoxy)pyrimidin-2-yl)propanoate (I-291); Ethyl 3-(4-(((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)-6-((6-cyclopropyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)methoxy)pyrimidin-2-yl)propanoate (I-292); 3-(4-(((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)-6-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methoxy)pyrimidin-2-yl)propanoic acid (I-293); 3-(4-(((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)-6-((6-cyclopropylimidazo[1,2-a]pyrimidin-2-yl)methoxy)pyrimidin-2-yl)propanoic acid (I-294); 3-(4-(((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)-6-((6-cyclopropyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)methoxy)pyrimidin-2-yl)propanoic acid (I-295); 1-(4-(((6-(((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimidin-4-yl)oxy)methyl)phenyl)pyridin-2(1H)-one (I-296); 5,7-dimethyl-6-(((6-((4-((1-methyl-1H-pyrazol-3-yl)methyl)benzyl)oxy)pyrimidin-4-yl)amino)methyl)isoquinolin-1-amine, formate (I-297); 5,7-dimethyl-6-(((6-((4-((1-methyl-1H-pyrazol-3-yl)methyl)benzyl)oxy)pyrimidin-4-yl)amino)methyl)isoquinolin-1-amine; 5,7-dimethyl-6-(((6-((2-(pyrrolidin-1-yl)pyrimidin-5-yl)methoxy)pyrimidin-4-yl)amino)methyl)isoquinolin-1-amine (I-298); 3-(4-(((6-(((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimidin-4-yl)oxy)methyl)benzyl)-1-methylpyridin-2(1H)-one (I-299); 6-(((6-((6-((1H-pyrazol-1-yl)methyl)pyridin-3-yl)methoxy)pyrimidin-4-yl)amino)methyl)-5,7-dimethylisoquinolin-1-amine (I-300); 1-(4-(((6-(((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimidin-4-yl)oxy)methyl)benzyl)pyridin-2(1H)-one (I-301); 4-(4-(((6-(((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimidin-4-yl)oxy)methyl)benzyl)morpholin-3-one, trifluoroacetate salt (I-302); 4-(4-(((6-(((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimidin-4-yl)oxy)methyl)benzyl)morpholin-3-one; 1-(4-(((6-(((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimidin-4-yl)oxy)methyl)benzyl)-3-cyclopropylpyridin-2(1H)-one, formate salt (I-303); 1-(4-(((6-(((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimidin-4-yl)oxy)methyl)benzyl)-3-cyclopropylpyridin-2(1H)-one; 6-(((6-((6-chloro-5-methylimidazo[1,2-a]pyridin-2-yl)methoxy)pyrimidin-4-yl)amino)methyl)-5,7-dimethylisoquinolin-1-amine (I-304); 6-(((6-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methoxy)pyrimidin-4-yl)amino)methyl)-5,7-dimethylisoquinolin-1-amine (I-305); N 4 -((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N 6 -(Quinolin-2-ylmethyl)pyrimidine-4,6-diamine (I-306); N 4 -((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N 6 -((6-methoxyquinolin-2-yl)methyl)pyrimidine-4,6-diamine (I-307); N 4 -((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N 6 -methyl-N 6 -(Quinolin-6-ylmethyl)pyrimidine-4,6-diamine (I-308); N 4 -((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N 6 -((3-chloroquinolin-6-yl)methyl)pyrimidine-4,6-diamine (I-309); N 4 -((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N 6 -(1-(3-chloroquinolin-6-yl)ethyl)pyrimidine-4,6-diamine (I-310); N 4 -((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N 6 -((3-methylquinolin-7-yl)methyl)pyrimidine-4,6-diamine (I-311); N 4 -((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N 6-((3-(trifluoromethyl)quinolin-6-yl)methyl)pyrimidine-4,6-diamine (I-312); N 4 -((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N 6 -((6-chloroimidazo[1,2-a]pyridin-2-yl)methyl)pyrimidine-4,6-diamine, formate (I-313); N 4 -((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N 6 -((6-chloroimidazo[1,2-a]pyridin-2-yl)methyl)pyrimidine-4,6-diamine; N 4 -((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N 6 -((3-cyclopropylquinolin-6-yl)methyl)pyrimidine-4,6-diamine (I-314); N 4 -((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N 6 -(isoquinolin-3-ylmethyl)pyrimidine-4,6-diamine (I-315); N 4 -((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N 6 -methyl-N 6 -(Quinolin-3-ylmethyl)pyrimidine-4,6-diamine (I-316); N 4 -((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N 6 -(Quinolin-3-ylmethyl)pyrimidine-4,6-diamine, formate (I-317); N 4 -((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N 6 -(quinolin-3-ylmethyl)pyrimidine-4,6-diamine; N 4 -((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N 6 -((6-methoxynaphthalen-2-yl)methyl)-N6 -methylpyrimidine-4,6-diamine (I-318); N 4 -((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N 6 -(benzo[d]thiazol-2-ylmethyl)pyrimidine-4,6-diamine (I-319); N 4 -((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N 6 -(isoquinolin-6-ylmethyl)pyrimidine-4,6-diamine (I-320); N 4 -((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N 6 -(imidazo[1,2-a]pyridin-2-ylmethyl)pyrimidine-4,6-diamine (I-321); N 4 -((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N 6 -((7-methylimidazo[1,2-a]pyridin-2-yl)methyl)pyrimidine-4,6-diamine (I-322); N 4 -((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N 6 -((4-methoxyquinolin-6-yl)methyl)pyrimidine-4,6-diamine (I-323); N 4 -((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N 6 -((4-methylquinolin-6-yl)methyl)pyrimidine-4,6-diamine (I-324); N 4 -((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N 6 -((6,7-dimethylquinolin-3-yl)methyl)pyrimidine-4,6-diamine (I-325); N 4 -((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N 6-((4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)methyl)pyrimidine-4,6-diamine, formate (I-326); N 4 -((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N 6 -((4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)methyl)pyrimidine-4,6-diamine; 6-(((6-(((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimidin-4-yl)amino)methyl)-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one, formate (I-327); 6-(((6-(((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimidin-4-yl)amino)methyl)-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one; N 4 -((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N 6 -((5-chloroisoquinolin-3-yl)methyl)pyrimidine-4,6-diamine, formate (I-328); N 4 -((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N 6 -((5-chloroisoquinolin-3-yl)methyl)pyrimidine-4,6-diamine; N 4 -((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N 6 -((6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)methyl)pyrimidine-4,6-diamine (I-329); N 4 -((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N 6 -((6-chloro-5-methylimidazo[1,2-a]pyridin-2-yl)methyl)pyrimidine-4,6-diamine (I-330); N 4-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N 6 -((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)pyrimidine-4,6-diamine (I-331); 2-(((6-(((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimidin-4-yl)amino)methyl)imidazo[1,2-a]pyridine-6-carbonitrile (I-332); N 4 -((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N 6 -((6-methylimidazo[1,2-a]pyridin-2-yl)methyl)pyrimidine-4,6-diamine (I-333); N 4 -((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N 6 -((3-fluoroquinolin-6-yl)methyl)pyrimidine-4,6-diamine (I-334); N 4 -((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N 6 -((2-methylquinolin-6-yl)methyl)pyrimidine-4,6-diamine (I-335); N 4 -((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N 6 -((3-methylquinolin-6-yl)methyl)pyrimidine-4,6-diamine (I-336); N 4 -((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N 6 -(quinolin-6-ylmethyl)pyrimidine-4,6-diamine (I-337); N 4 -((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N 6 -(4-(pyrazin-2-ylmethyl)benzyl)pyrimidine-4,6-diamine (I-338); N 4 -((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N6 -(4-cyclopropylbenzyl)pyrimidine-4,6-diamine (I-339); N 4 -(4-((1H-pyrazol-1-yl)methyl)benzyl)-N 6 -((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)pyrimidine-4,6-diamine (I-340); N 4 -((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N 6 -benzylpyrimidine-4,6-diamine (I-341); N 4 -((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N 6 -(4-((1-methyl-1H-1,2,4-triazol-5-yl)methyl)benzyl)pyrimidine-4,6-diamine (I-342); N 4 -((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N 6 -(4-((5-methyl-1,3,4-thiadiazol-2-yl)methyl)benzyl)pyrimidine-4,6-diamine (I-343); 2-(4-(((6-(((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimidin-4-yl)amino)methyl)phenoxy)-1-(3-azabicyclo[3.1.0]hexan-3-yl)ethan-1-one, formate (I-344); 2-(4-(((6-(((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimidin-4-yl)amino)methyl)phenoxy)-1-(3-azabicyclo[3.1.0]hexan-3-yl)ethan-1-one; 2-(4-(((6-(((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimidin-4-yl)amino)methyl)phenoxy)-1-(pyrrolidin-1-yl)ethan-1-one (I-345); 2-(4-(((6-(((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimidin-4-yl)amino)methyl)phenoxy)-1-(piperidin-1-yl)ethan-1-one (I-346); 2-(4-(((6-(((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimidin-4-yl)amino)methyl)phenoxy)-1-(azetidin-1-yl)ethan-1-one, formate (I-347); 2-(4-(((6-(((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimidin-4-yl)amino)methyl)phenoxy)-1-(azetidin-1-yl)ethan-1-one; 2-(4-(((6-(((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimidin-4-yl)amino)methyl)-2,6-dimethylphenoxy)-N,N-dimethylacetamide (I-348); N 4 -((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N 6 -(4-(pyridin-2-ylmethoxy)benzyl)pyrimidine-4,6-diamine, formate (I-349); N 4 -((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N 6 -(4-(pyridin-2-ylmethoxy)benzyl)pyrimidine-4,6-diamine; N 4 -((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N 6 -(4-(thiazol-4-ylmethyl)benzyl)pyrimidine-4,6-diamine (I-350); N 4 -((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N 6 -(4-(oxazol-2-ylmethoxy)benzyl)pyrimidine-4,6-diamine (I-351); 2-(4-(((6-(((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimidin-4-yl)amino)methyl)phenoxy)-2,2-difluoro-N,N-dimethylacetamide (I-352); N 4 -((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N 6 -(3,5-dimethyl-4-(pyridin-2-ylmethoxy)benzyl)pyrimidine-4,6-diamine, formate (I-353); N 4 -((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N 6 -(3,5-dimethyl-4-(pyridin-2-ylmethoxy)benzyl)pyrimidine-4,6-diamine; 2-(4-(((6-(((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimidin-4-yl)amino)methyl)phenoxy)-N,N,2-trimethylpropanamide, formate (I-354); 2-(4-(((6-(((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimidin-4-yl)amino)methyl)phenoxy)-N,N,2-trimethylpropanamide; N 4 -((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N 6 -(3,5-dimethyl-4-(thiazol-2-ylmethoxy)benzyl)pyrimidine-4,6-diamine (I-355); N 4 -((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N 6 -(4-(thiazol-2-ylmethoxy)benzyl)pyrimidine-4,6-diamine (I-356); 1-(4-(((6-(((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimidin-4-yl)amino)methyl)phenoxy)-N,N-dimethylcyclopropane-1-carboxamide, formate (I-357) 1-(4-(((6-(((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimidin-4-yl)amino)methyl)phenoxy)-N,N-dimethylcyclopropane-1-carboxamide; N 4 -(4-((1H-pyrazol-3-yl)methyl)benzyl)-N 6 -((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)pyrimidine-4,6-diamine (I-358); 2-(4-(((6-(((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimidin-4-yl)amino)methyl)-2,6-dimethylphenyl)-1-(3-azabicyclo[3.1.0]hexan-3-yl)ethan-1-one (I-359); 2-(4-(((6-(((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimidin-4-yl)amino)methyl)-2,6-dimethylphenyl)-N,N-dimethylacetamide (I-360); N 4 -((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N 6 -(4-(pyridin-2-yloxy)benzyl)pyrimidine-4,6-diamine (I-361); N 4 -((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N 6 -(4-(thiazol-2-ylmethyl)benzyl)pyrimidine-4,6-diamine (I-362); N 4 -((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N 6 -(4-(pyridin-2-ylmethyl)benzyl)pyrimidine-4,6-diamine (I-363); N 4 -((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N 6 -(4-((4-methylpyridin-2-yl)methyl)benzyl)pyrimidine-4,6-diamine (I-364); N 4-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N 6 -(4-((3-chloropyridin-2-yl)methyl)benzyl)pyrimidine-4,6-diamine (I-365); N 4 -((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N 6 -(1-(4-(pyridin-2-ylmethyl)phenyl)ethyl)pyrimidine-4,6-diamine (I-366); N 4 -(4-((1H-pyrazol-1-yl)methyl)-3,5-dimethylbenzyl)-N 6 -((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)pyrimidine-4,6-diamine (I-367); N 4 -((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N 6 -(3,5-dimethyl-4-(pyridin-2-ylmethyl)benzyl)pyrimidine-4,6-diamine (I-368); N 4 -((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N 6 -(4-((5-chloropyridin-2-yl)methyl)benzyl)pyrimidine-4,6-diamine (I-369); 1-(3-(((6-(((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimidin-4-yl)oxy)methyl)phenyl)pyridin-2(1H)-one (I-370); 5,7-dimethyl-6-(((6-((2-methylquinolin-6-yl)methoxy)pyrimidin-4-yl)amino)methyl)isoquinolin-1-amine (I-371); 5,7-dimethyl-6-(((6-((6-methylquinolin-3-yl)methoxy)pyrimidin-4-yl)amino)methyl)isoquinolin-1-amine (I-372); 6-(((6-((3-chloroquinolin-6-yl)methoxy)pyrimidin-4-yl)amino)methyl)-5,7-dimethylisoquinolin-1-amine (I-373); 5,7-dimethyl-6-(((6-(quinolin-6-ylmethoxy)pyrimidin-4-yl)amino)methyl)isoquinolin-1-amine (I-374); 2-(4-(((6-(((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimidin-4-yl)amino)methyl)phenyl)-N,N-dimethylacetamide (I-375); N 5 -(4-((1H-pyrazol-1-yl)methyl)benzyl)-N 3 -((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1,2,4-triazine-3,5-diamine (I-376); 2-(4-(((6-(((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimidin-4-yl)amino)methyl)phenoxy)-N,N-dimethylacetamide (I-377); 2-(4-(((6-(((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimidin-4-yl)amino)methyl)phenyl)-1-(3-azabicyclo[3.1.0]hexan-3-yl)ethan-1-one (I-378); N 4 -(4-((1H-pyrazol-1-yl)methyl)-2-fluorobenzyl)-N 6 -((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)pyrimidine-4,6-diamine (I-379); N 4 -(4-((1H-pyrazol-1-yl)methyl)-2-(trifluoromethyl)benzyl)-N 6 -((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)pyrimidine-4,6-diamine (I-380); N-(4-((1H-pyrazol-1-yl)methyl)-2-(trifluoromethyl)benzyl)-N-(6-(((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimidin-4-yl)nitrousamide (I-381); N 4-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N 6 -(4-(difluoro(1H-pyrazol-1-yl)methyl)benzyl)pyrimidine-4,6-diamine (I-382); N 4 -(4-((1H-pyrazol-1-yl)methyl)-3-(trifluoromethyl)benzyl)-N 6 -((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)pyrimidine-4,6-diamine (I-383); 6-(((6-((6-cyclopropyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methoxy)pyrimidin-4-yl)amino)methyl)-5,7-dimethylisoquinolin-1-amine (I-384); N 5 -(4-((1H-pyrazol-1-yl)methyl)-2-fluorobenzyl)-N 3 -((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)pyridazine-3,5-diamine (I-385); 6-(((6-((3-cyclopropylquinolin-6-yl)methoxy)pyrimidin-4-yl)amino)methyl)-5,7-dimethylisoquinolin-1-amine (I-386); 6-(((6-((6-cyclopropylquinolin-3-yl)methoxy)pyrimidin-4-yl)amino)methyl)-5,7-dimethylisoquinolin-1-amine (I-387); 6-(((6-((6-cyclopropyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)methoxy)pyrimidin-4-yl)amino)methyl)-5,7-dimethylisoquinolin-1-amine (I-388); 6-(((6-((6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)methoxy)-2-(trifluoromethyl)pyrimidin-4-yl)amino)methyl)-5,7-dimethylisoquinolin-1-amine (I-389); 6-(((6-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methoxy)pyrimidin-4-yl)amino)methyl)-5-methyl-7-(1-methylcyclopropyl)isoquinolin-1-amine (I-390); 6-(((6-((6-cyclopropyl-[1,2,4]triazolo[1,5-b]pyridazin-2-yl)methoxy)pyrimidin-4-yl)amino)methyl)-5,7-dimethylisoquinolin-1-amine (I-391); 6-(((2-((6-cyclopropylimidazo[1,2-a]pyrimidin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)amino)methyl)-5,7-dimethylisoquinolin-1-amine (I-392); 6-(((1-((6-cyclopropylimidazo[1,2-a]pyrimidin-2-yl)methyl)-1H-pyrazolo[4,3-c]pyridin-4-yl)amino)methyl)-5,7-dimethylisoquinolin-1-amine (I-393); 6-(((6-((6-cyclopropyl-8-(pyrrolidin-1-ylmethyl)imidazo[1,2-b]pyridazin-2-yl)methoxy)pyrimidin-4-yl)amino)methyl)-5,7-dimethylisoquinolin-1-amine (I-394); 6-(((6-((5-cyclopropylbenzo[b]thiophen-2-yl)methoxy)pyrimidin-4-yl)amino)methyl)-5,7-dimethylisoquinolin-1-amine (I-395); Ethyl 3-(2-(((6-(((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimidin-4-yl)oxy)methyl)-5-cyclopropylpyrazolo[1,5-a]pyridin-7-yl)-2,2-dimethylpropanoate (I-396); 2-(((6-(((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimidin-4-yl)oxymethyl)-6-cyclopropylimidazo[1,2-c]pyrimidin-5(6H)-one (I-397); 6-(((6-(((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimidin-4-yl)oxy)methyl)-3-chloroquinoline-8-carbonitrile (I-398); 6-(((6-(((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimidin-4-yl)oxy)methyl)-8-butyl-3-chloroquinoline 1-oxide (I-399); 6-(((6-((5-cyclopropylpyrazolo[1,5-a]pyridin-2-yl)methoxy)pyrimidin-4-yl)amino)methyl)-5,7-dimethylisoquinolin-1-amine (I-400); 6-(((6-(((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimidin-4-yl)oxy)methyl)-3-chloroquinoline-8-carboxamide (I-401); 6-(((6-((8-butyl-3-chloroquinolin-6-yl)methoxy)pyrimidin-4-yl)amino)methyl)-5,7-dimethylisoquinolin-1-amine (I-402); 6-(((6-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)pyrimidin-4-yl)amino)methyl)-5,7-dimethylisoquinolin-1-amine (I-403); 6-(((6-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)difluoromethyl)pyrimidin-4-yl)amino)methyl)-5,7-dimethylisoquinolin-1-amine (I-404); 6-(((6-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)fluoromethyl)pyrimidin-4-yl)amino)methyl)-5,7-dimethylisoquinolin-1-amine (I-405); (6-(((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimidin-4-yl)(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methanol (I-406); 6-(((5-((3-chloroquinolin-6-yl)methoxy)pyridazin-3-yl)amino)methyl)-5,7-dimethylisoquinolin-1-amine (I-407); 5,7-dimethyl-6-(((5-((6-methylquinolin-3-yl)methoxy)pyridazin-3-yl)amino)methyl)isoquinolin-1-amine (I-408); 5,7-dimethyl-6-(((5-(quinolin-6-ylmethoxy)pyridazin-3-yl)amino)methyl)isoquinolin-1-amine (I-409); 6-(((5-(imidazo[1,2-a]pyridin-6-ylmethoxy)pyridazin-3-yl)amino)methyl)-5,7-dimethylisoquinolin-1-amine (I-410); 6-(((5-(imidazo[1,2-a]pyridin-2-ylmethoxy)pyridazin-3-yl)amino)methyl)-5,7-dimethylisoquinolin-1-amine (I-411); 5,7-dimethyl-6-(((5-((2-methylquinolin-6-yl)methoxy)pyridazin-3-yl)amino)methyl)isoquinolin-1-amine (I-412); 5,7-dimethyl-6-(((5-((1-methyl-1H-indazol-5-yl)methoxy)pyridazin-3-yl)amino)methyl)isoquinolin-1-amine (I-413); 6-(((5-(imidazo[1,2-a]pyridin-3-ylmethoxy)pyridazin-3-yl)amino)methyl)-5,7-dimethylisoquinolin-1-amine (I-414); 6-(((5-((6-fluoroquinolin-3-yl)methoxy)pyridazin-3-yl)amino)methyl)-5,7-dimethylisoquinolin-1-amine (I-415); 5,7-dimethyl-6-(((5-((3-methylquinolin-6-yl)methoxy)pyridazin-3-yl)amino)methyl)isoquinolin-1-amine (I-416); 6-(((5-((5-chlorobenzo[b]thiophen-2-yl)methoxy)pyridazin-3-yl)amino)methyl)-5,7-dimethylisoquinolin-1-amine formate (I-417); 6-(((5-((5-chlorobenzo[b]thiophen-2-yl)methoxy)pyridazin-3-yl)amino)methyl)-5,7-dimethylisoquinolin-1-amine 6-(((5-((2,3-dimethylquinoxalin-6-yl)methoxy)pyridazin-3-yl)amino)methyl)-5,7-dimethylisoquinolin-1-amine formate (I-418); 6-(((5-((2,3-dimethylquinoxalin-6-yl)methoxy)pyridazin-3-yl)amino)methyl)-5,7-dimethylisoquinolin-1-amine 5,7-dimethyl-6-(((5-(1-(3-methylquinolin-6-yl)ethoxy)pyridazin-3-yl)amino)methyl)isoquinolin-1-amine (I-419); 6-(((5-(1-(3-chloroquinolin-6-yl)ethoxy)pyridazin-3-yl)amino)methyl)-5,7-dimethylisoquinolin-1-amine formate (I-420); 6-(((5-(1-(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 formate (I-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 (I-422); 5,7-dimethyl-6-(((5-((3-(trifluoromethyl)quinolin-6-yl)methoxy)pyridazin-3-yl)amino)methyl)isoquinolin-1-amine (I-423); 5,7-dimethyl-6-(((5-((6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)methoxy)pyridazin-3-yl)amino)methyl)isoquinolin-1-amine (I-424); 5,7-dimethyl-6-(((5-((6-methylimidazo[1,2-a]pyridin-2-yl)methoxy)pyridazin-3-yl)amino)methyl)isoquinolin-1-amine (I-425); 6-(((5-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methoxy)pyridazin-3-yl)amino)methyl)-5,7-dimethylisoquinolin-1-amine formate (I-426); 6-(((5-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methoxy)pyridazin-3-yl)amino)methyl)-5,7-dimethylisoquinolin-1-amine; 3-(4-(((6-(((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyridazin-4-yl)oxy)methyl)phenoxy)-1-methylpyridin-2(1H)-one (I-427); N 3 -((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N 5 -methyl-N 5 -(Quinolin-6-ylmethyl)pyridazine-3,5-diamine (I-428); 6-(((5-(1-(4-((1H-pyrazol-1-yl)methyl)phenyl)ethoxy)pyridazin-3-yl)amino)methyl)-5,7-dimethylisoquinolin-1-amine (I-429); 5,7-dimethyl-6-(((5-((2-phenylthiazol-4-yl)methoxy)pyridazin-3-yl)amino)methyl)isoquinolin-1-amine (I-430); 6-(((5-((4-((3-cyclopropyl-1H-pyrazol-1-yl)methyl)benzyl)oxy)pyridazin-3-yl)amino)methyl)-5,7-dimethylisoquinolin-1-amine (I-431); 6-(((5-((4-((1H-pyrazol-1-yl)methyl)benzyl)oxy)pyridazin-3-yl)amino)methyl)-5,7-dimethylisoquinolin-1-amine (I-432); 1-(4-(((6-(((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyridazin-4-yl)oxy)methyl)benzyl)piperidin-2-one (I-433); 4-(4-(((6-(((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyridazin-4-yl)oxy)methyl)benzyl)morpholin-3-one (I-434); 1-(3-(((6-(((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyridazin-4-yl)oxy)methyl)phenyl)pyridin-2(1H)-one (I-435); 1-(4-(((6-(((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyridazin-4-yl)oxy)methyl)benzyl)pyridin-2(1H)-one (I-436); 1-(4-(((6-(((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyridazin-4-yl)oxy)methyl)benzyl)-3-cyclopropylpyridin-2(1H)-one (I-437); 1-(4-(((6-(((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyridazin-4-yl)oxy)methyl)phenyl)pyridin-2(1H)-one (I-438); 5,7-dimethyl-6-(((5-((4-((1-methyl-1H-pyrazol-3-yl)methyl)benzyl)oxy)pyridazin-3-yl)amino)methyl)isoquinolin-1-amine (I-439); 3-(4-(((6-(((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyridazin-4-yl)oxy)methyl)benzyl)-1-methylpyridin-2(1H)-one (I-440); 6-(((5-((4-(1H-imidazol-1-yl)benzyl)oxy)pyridazin-3-yl)amino)methyl)-5,7-dimethylisoquinolin-1-amine formate (I-441); 6-(((5-((4-(1H-imidazol-1-yl)benzyl)oxy)pyridazin-3-yl)amino)methyl)-5,7-dimethylisoquinolin-1-amine; 5,7-dimethyl-6-(((5-((1-phenyl-1H-pyrazol-4-yl)methoxy)pyridazin-3-yl)amino)methyl)isoquinolin-1-amine (I-442); 6-(((5-(benzyloxy)pyridazin-3-yl)amino)methyl)-5,7-dimethylisoquinolin-1-amine (I-443); 6-(((5-((4-(imidazo[1,2-a]pyridin-8-ylmethyl)benzyl)oxy)pyridazin-3-yl)amino)methyl)-5,7-dimethylisoquinolin-1-amine (I-444); 6-(((5-((6-((1H-pyrazol-1-yl)methyl)pyridin-3-yl)methoxy)pyridazin-3-yl)amino)methyl)-5,7-dimethylisoquinolin-1-amine (I-445); 6-(((5-((5-((1H-pyrazol-1-yl)methyl)pyridin-2-yl)methoxy)pyridazin-3-yl)amino)methyl)-5,7-dimethylisoquinolin-1-amine (I-446); N 5 -(4-((1H-pyrazol-1-yl)methyl)benzyl)-N 3 -((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)pyridazine-3,5-diamine (I-447); N 3 -((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N5-benzylpyridazine-3,5-diamine (I-448); 6-(((6-(benzyloxy)pyrimidin-4-yl)amino)methyl)-5,7-dimethylisoquinolin-1-amine (I-449); 6-(((5-((4-((1H-pyrazol-1-yl)methyl)benzyl)oxy)-6-(trifluoromethyl)pyridazin-3-yl)amino)methyl)-5,7-dimethylisoquinolin-1-amine (I-450); N 5 -(4-((1H-pyrazol-1-yl)methyl)benzyl)-N 3 -((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-6-(trifluoromethyl)pyridazine-3,5-diamine (I-451); 6-(((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)-4-((quinolin-6-ylmethyl)amino)pyridazine-3-carboxamide (I-452); 2-(((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyridin-4-yl)(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methanol (I-453); 6-(((4-((4-((1H-pyrazol-1-yl)methyl)benzyl)oxy)pyridin-2-yl)amino)methyl)-5,7-dimethylisoquinolin-1-amine (I-454); 6-(((2-((4-((1H-pyrazol-1-yl)methyl)benzyl)oxy)pyridin-4-yl)amino)methyl)-5,7-dimethylisoquinolin-1-amine (I-455); 1-(4-(((2-(((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)-5-chloropyridin-4-yl)oxy)methyl)benzyl)pyridin-2(1H)-one (I-456); 6-(((5-(4-((1H-pyrazol-1-yl)methyl)benzyl)-5H-pyrrolo[3,2-c]pyridazin-3-yl)amino)methyl)-5,7-dimethylisoquinolin-1-amine (I-457); 6-(((1-(4-((1H-pyrazol-1-yl)methyl)benzyl)-1H-pyrazolo[4,3-c]pyridin-6-yl)amino)methyl)-5,7-dimethylisoquinolin-1-amine (I-458); 6-(((2-(4-((1H-pyrazol-1-yl)methyl)benzyl)-2H-pyrazolo[4,3-c]pyridin-6-yl)amino)methyl)-5,7-dimethylisoquinolin-1-amine (I-459); 6-((6-(4-((1H-pyrazol-1-yl)methyl)phenethyl)pyrimidin-4-ylamino)methyl)-5,7-dimethylisoquinolin-1-amine (I-460); (4-(((6-(((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimidin-4-yl)amino)methyl)phenyl)methanol (I-461); 2-(4-(((5-(((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyridazin-3-yl)oxy)methyl)phenyl)-N,N-dimethylacetamide (I-462); 1-(4-(((6-(((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimidin-4-yl)amino)methyl)benzyl)-3,5-dichloropyridin-2(1H)-one (I-463); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-((2,3-dimethylquinoxalin-6-yl)methyl)-1H-pyrazole-4-carboxamide (I-464); 2-(4-(((6-(((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyridazin-4-yl)oxy)methyl)phenyl)-N,N-dimethylacetamide (I-465); 2-(4-(((6-(((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimidin-4-yl)oxy)methyl)phenyl)-N,N-dimethylacetamide (I-466); 2-(4-(((6-((6-(aminomethyl)-5,7-dimethylisoquinolin-1-yl)amino)pyrimidin-4-yl)oxy)methyl)phenyl)-N,N-dimethylacetamide (I-467); 4-((4-((1H-pyrazol-1-yl)methyl)benzyl)oxy)-6-(((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)-2-methylisoindolin-1-one (I-468); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-((4-bromophenyl)difluoromethyl)-1H-pyrazole-4-carboxamide (I-469); N-(6-(((5-((4-((1H-pyrazol-1-yl)methyl)benzyl)oxy)pyridazin-3-yl)amino)methyl)-5,7-dimethylisoquinolin-1-yl)acetamide (I-470); 1-(4-((4-(1-(((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)-2,2,2-trifluoroethyl)-1H-pyrazol-1-yl)methyl)benzyl)pyridin-2(1H)-one (I-471); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-(difluoro(phenyl)methyl)-1H-pyrazole-4-carboxamide (I-472); 6-((6-(4-((1H-pyrazol-1-yl)methyl)phenethyl)pyrimidin-4-ylamino)methyl)-5,7-dimethylisoquinolin-1-amine (I-473); 1-(4-(2-(3-azabicyclo[3.1.0]hexan-3-yl)-2-oxoethyl)-3-chlorobenzyl)-N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1H-pyrazole-4-carboxamide (I-474); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-(4-(1-methyl-2-oxopyrrolidin-3-yl)benzyl)-1H-pyrazole-4-carboxamide (I-475); N 2 -(4-((1H-pyrazol-1-yl)methyl)benzyl)-N 6 -((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)pyrazine-2,6-diamine (I-476); 1-(4-(2-(3-azabicyclo[3.1.0]hexan-3-yl)-2-oxoethyl)benzyl)-N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-3-fluoro-1H-pyrazole-4-carboxamide (I-477); 1-(4-(((2-(((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimidin-4-yl)oxy)methyl)benzyl)pyridin-2(1H)-one (I-478); 1-(4-(2-(3-azabicyclo[3.1.0]hexan-3-yl)-2-oxoethyl)benzyl)-N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-4-fluoro-1H-pyrrole-3-carboxamide (I-479); Ethyl (6-(((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimidin-4-yl)(4-((2-oxopyridin-1(2H)-yl)methyl)benzyl)carbamate (I-480); Ethyl (6-(((1-((ethoxycarbonyl)amino)-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimidin-4-yl)(4-((2-oxopyridin-1(2H)-yl)methyl)benzyl)carbamate (I-481); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-((6-cyclopropyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (I-482); (Z)-N 4 -(4-(1-(1H-pyrazol-1-yl)prop-1-en-1-yl)benzyl)-N 6 -((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)pyrimidine-4,6-diamine (I-483); N 4 -(4-(1-(1H-pyrazol-1-yl)propyl)benzyl)-N 6 -((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)pyrimidine-4,6-diamine (I-484); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide (I-485); 4-(((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)-6-((6-cyclopropyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)methoxy)pyrimidine-2-carboxylic acid (I-486); 4-(((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)-6-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methoxy)pyrimidine-2-carboxylic acid (I-487); 4-(((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)-6-((6-cyclopropylimidazo[1,2-a]pyrimidin-2-yl)methoxy)pyrimidine-2-carboxylic acid (I-488); Ethyl 4-(((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)-6-((6-cyclopropylimidazo[1,2-a]pyrimidin-2-yl)methoxy)pyrimidine-2-carboxylate (I-489); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-sulfonamide (I-490); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-sulfonamide (I-491); 6-(((4-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methoxy)pyrimidin-2-yl)amino)methyl)-5,7-dimethylisoquinolin-1-amine (I-492); 6-(((6-(1-(6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)ethoxy)pyrimidin-4-yl)amino)methyl)-5,7-dimethylisoquinolin-1-amine (I-493); 7-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-4-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methoxy)-2,7-diazabicyclo[4.2.0]octa-1,3,5-trien-8-one (I-494); 3-(((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)-5-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methoxy)picolinic acid (I-495); 7-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-4-(((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)amino)-2,7-diazabicyclo[4.2.0]octa-1,3,5-trien-8-one (I-496); 3-(((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)-5-(((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)amino)picolinic acid (I-497); 6-(((2-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-[1,2,4]triazolo[1,5-a]pyrazin-8-yl)amino)methyl)-5,7-dimethylisoquinolin-1-amine (I-498); 6-(((1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-imidazo[4,5-c]pyridin-6-yl)amino)methyl)-5,7-dimethylisoquinolin-1-amine (I-499); 6-(((2-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-3H-imidazo[4,5-c]pyridin-4-yl)amino)methyl)-5,7-dimethylisoquinolin-1-amine (I-500); 6-(((1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)amino)methyl)-5,7-dimethylisoquinolin-1-amine (I-501); 6-((l2-Azanyl)methyl)-N-(1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)-5,7-dimethylisoquinolin-1-amine (I-502); 6-(((1-((6-cyclopropyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)methyl)-1H-imidazo[4,5-c]pyridin-6-yl)amino)methyl)-5,7-dimethylisoquinolin-1-amine (I-503); 6-(((1-((5-cyclopropylthieno[2,3-b]pyridin-2-yl)methyl)-1H-imidazo[4,5-c]pyridin-6-yl)amino)methyl)-5,7-dimethylisoquinolin-1-amine (I-504); 2-((4-(((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)-6-oxopyrimidin-1(6H)-yl)methyl)-6-cyclopropylimidazo[1,2-c]pyrimidin-5(6H)-one (I-505); N 2 -((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N 3 -((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)pyridine-2,3-diamine (I-506); 1-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-3-(5-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methoxy)pyrimidin-4-yl)urea (I-507); 4-(2-(((6-(((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimidin-4-yl)oxy)methyl)-5-cyclopropylpyrazolo[1,5-a]pyridin-7-yl)-2-methylbutan-2-ol (I-508); 3-(2-(((6-(((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimidin-4-yl)oxy)methyl)-5-cyclopropylpyrazolo[1,5-a]pyridin-7-yl)-2,2-dimethylpropanamide (I-509); 3-(2-(((6-(((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimidin-4-yl)oxy)methyl)-5-cyclopropylpyrazolo[1,5-a]pyridin-7-yl)-2,2-dimethylpropanenitrile (I-510); N 3 -((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N 5 -((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1,2,4-thiadiazole-3,5-diamine (I-511); 6-(((6-((2R,4S)-4-((tert-butyldimethylsilyl)oxy)-2-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)pyrrolidin-1-yl)pyrimidin-4-yl)amino)methyl)-5,7-dimethylisoquinolin-1-amine (I-512); (3S,5R)-1-(6-(((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyrimidin-4-yl)-5-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)pyrrolidin-3-ol (I-513); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-2-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)isonicotinamide (I-514); 5,7-dimethyl-6-(((5-((2-methylquinolin-6-yl)methyl)-5H-pyrrolo[3,2-c]pyridazin-3-yl)amino)methyl)isoquinolin-1-amine (I-515); N 4 -((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-N 6-((6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)methyl)-N6-(2,2,2-trifluoroethyl)pyrimidine-4,6-diamine (I-516); 5,7-dimethyl-6-(((1-(quinolin-6-ylmethyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)amino)methyl)isoquinolin-1-amine (I-517); 6-(((1-((3-chloroquinolin-6-yl)methyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)amino)methyl)-5,7-dimethylisoquinolin-1-amine (I-518); 6-(((3-((3-chloroquinolin-6-yl)methyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)amino)methyl)-5,7-dimethylisoquinolin-1-amine (I-519); 6-(((3-((3-chloroquinolin-6-yl)methyl)imidazo[1,5-a]pyridin-6-yl)amino)methyl)-5,7-dimethylisoquinolin-1-amine (I-520); (6-(((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)imidazo[1,2-a]pyridin-3-yl)(naphthalen-2-yl)methanol (I-521); 5,7-dimethyl-6-(((3-(naphthalen-2-ylmethyl)imidazo[1,2-a]pyridin-6-yl)amino)methyl)-isoquinolin-1-amine (I-522); 5,7-dimethyl-6-(((3-(naphthalen-2-ylmethyl)imidazo[1,5-a]pyrazin-6-yl)amino)methyl)isoquinolin-1-amine (I-523); 5,7-dimethyl-6-(((1-methyl-3-(naphthalen-2-ylmethyl)-1H-pyrrolo[2,3-c]pyridin-5-yl)amino)methyl)isoquinolin-1-amine (I-524); 5,7-dimethyl-6-(((2-(naphthalen-2-ylmethyl)imidazo[1,2-a]pyrazin-8-yl)amino)methyl)isoquinolin-1-amine (I-525); 5,7-dimethyl-6-(((3-(naphthalen-2-ylmethyl)-1H-pyrrolo[2,3-c]pyridin-5-yl)amino)methyl)isoquinolin-1-amine (I-526); 5,7-dimethyl-6-(((3-(naphthalen-2-ylmethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)amino)methyl)isoquinolin-1-amine (I-527); 5,7-dimethyl-6-(((1-(quinolin-6-ylmethyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)amino)methyl)isoquinolin-1-amine (I-528); 6-(((6-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)fluoromethyl)pyrimidin-4-yl)amino)methyl)-5,7-dimethylisoquinolin-1-amine (I-529); 6-(((6-((4-((1H-pyrazol-1-yl)methyl)benzyl)oxy)pyridazin-4-yl)amino)methyl)-5,7-dimethylisoquinolin-1-amine (I-530); 6-(((1-((3-chloroquinolin-6-yl)methyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)amino)methyl)-5,7-dimethylisoquinolin-1-amine (I-531); 6-(((2-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methoxy)pyridin-4-yl)amino)methyl)-5,7-dimethylisoquinolin-1-amine (I-532); 6-(((6-((4-((1H-pyrazol-1-yl)methyl)benzyl)oxy)pyrimidin-4-yl)amino)methyl)-5-methylisoquinolin-1-amine (I-533); 6-(((6-((4-((1H-pyrazol-1-yl)methyl)benzyl)oxy)pyrimidin-4-yl)amino)methyl)-7-methylisoquinolin-1-amine. (I-534); 6-(((6-((4-((1H-pyrazol-1-yl)methyl)benzyl)oxy)pyrimidin-4-yl)amino)methyl)-7-(trifluoromethyl)isoquinolin-1-amine (I-535); 1-(4-(((6-(((1-amino-5-methylisoquinolin-6-yl)methyl)amino)pyridazin-4-yl)amino)methyl)benzyl)pyridin-2(1H)-one (I-536); 1-(4-(((5-(((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)amino)pyridazin-3-yl)amino)methyl)benzyl)pyridin-2(1H)-one (I-537); N-((1-amino-5,7-dimethylisoquinolin-6-yl)methyl)-2-((3-chloroquinolin-6-yl)methyl)oxazolo[5,4-d]pyrimidin-7-amine (I-538); 6-(((8-((3-chloroquinolin-6-yl)methyl)-9-methyl-9H-purin-6-yl)amino)methyl)-5,7-dimethylisoquinolin-1-amine (I-539); 5,7-dimethyl-6-(((6-(naphthalen-2-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)isoquinolin-1-amine (I-540); 6-(((6-((4-((1H-pyrazol-1-yl)methyl)benzyl)oxy)pyrimidin-4-yl)amino)methyl)-4-fluoroisoquinolin-1-amine; or 6-(((6-((4-((1H-pyrazol-1-yl)methyl)benzyl)oxy)pyrimidin-4-yl)amino)methyl)isoquinolin-1-amine; or a pharmaceutically acceptable salt thereof.

[0246] In some embodiments, the compound is [ka] or a pharmaceutically acceptable salt thereof.

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

[0248] The pharmaceutical composition includes an optical isomer, diastereomer, or pharmaceutically acceptable salt of the inhibitor disclosed herein. The compound of Formula (I)-(XVI-c) included in the pharmaceutical composition can be covalently linked to a carrier moiety, as described above. Alternatively, the compound of Formula (I)-(XVI-c) included in the pharmaceutical composition is not covalently linked to a carrier moiety.

[0249] As used herein, "pharmaceutically acceptable carrier" refers to a pharmaceutical excipient suitable for enteral or parenteral use that does not deleteriously react with the active agent, e.g., a pharmaceutically, physiologically acceptable organic or inorganic carrier substance. Suitable pharmaceutically acceptable carriers include water, salt solutions (e.g., Ringer's solution), alcohols, oils, gelatin, and carbohydrates such as lactose, amylose, or starch, fatty acid esters, hydroxymethylcellulose, and polyvinylpyrrolidine. Such preparations are sterilized and, if desired, may be mixed with auxiliary substances such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring agents, and / or aromatic substances that do not deleteriously react with the compounds of the present invention.

[0250] The compound of the present invention can be administered alone or co-administered to the subject.Co-administration means to include simultaneous or sequential administration of the compound individually or in combination (multiple compounds).Preparation can also be combined with other active substances (for example, to reduce metabolic degradation) if desired.

[0251] In some embodiments, the test agents described herein can be incorporated into pharmaceutical compositions for administration by methods known to those of skill in the art and described herein for the provided compounds.

[0252] D. Formulation The compounds of the present invention can be prepared and administered in a variety of oral, parenteral, and topical dosage forms. Thus, the compounds of the present invention can be administered by injection (e.g., intravenous, intramuscular, intradermal, subcutaneous, intraduodenal, or intraperitoneal). The compounds described herein can also be administered by inhalation, for example, intranasally. The compounds of the present invention can also be administered transdermally. It is also contemplated that multiple routes of administration (e.g., intramuscular, oral, transdermal) can be used to administer the compounds of the present invention. Accordingly, the present invention also provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier or excipient and one or more compounds of the present 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 powder, tablets, pills, capsules, cachets, suppositories and dispersible granules.Solid carriers can be one or more substances that can also act as diluents, flavoring agents, binders, preservatives, tablet disintegrating agents or encapsulating materials.

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

[0255] Powders and tablets preferably contain 5% to 70% of the active compound. Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, low-melting waxes, cocoa butter, and the like. The term "preparation" is intended to include formulations of the active compound with an encapsulating agent as a carrier, in which the active ingredient is surrounded by a carrier, with or without other carriers, thus providing a capsule in association with it. Cachets and lozenges are also 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 ingredient is dispersed homogeneously therein as by stirring, etc. 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 administration is necessary or desired, particularly suitable mixtures for the compounds of the present 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 present invention can also be incorporated into liposomes or administered via transdermal pumps or patches. Suitable pharmaceutical mixtures for use in the present invention include those described in Pharmaceutical Sciences (17th Ed., Mack Pub. Co., Easton, PA) and WO96 / 05309 (the teachings of both of which are incorporated herein by reference).

[0259] Aqueous solutions suitable for oral use can be prepared by dissolving the active ingredient 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 ingredient in water with a viscous substance, such as a well-known suspending agent.

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

[0261] Pharmaceutical preparations are preferably in unit dosage form.In this form, the preparation is subdivided into unit doses containing appropriate amounts of active ingredients.The unit dosage form can be a packaged preparation, a package containing individual amounts of preparation, for example, packed 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 packaged forms.

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

[0263] E. Effective Dosage The pharmaceutical compositions provided by the present invention include compositions containing an active ingredient in a therapeutically effective amount, i.e., an amount effective to achieve its intended purpose. The actual amount effective for a particular application will depend, among other things, on the condition being treated. For example, when administered in a method for treating HAE, such a composition will contain an amount of active ingredient effective to achieve the desired result (e.g., inhibiting PKa and / or reducing the amount of bradykinin in the subject).

[0264] The dosage and frequency (single or multiple doses) of the compound administered can vary depending on a variety of factors, including the route of administration; the size, age, sex, health, weight, body mass index, and diet of the recipient; the nature and extent of the symptoms of the disease being treated (e.g., a disease responsive to PKa inhibition); the presence of other diseases or other health-related problems; the type 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. The target concentration will be the concentration of active compound(s) capable of reducing PKa enzyme activity, for example, as measured using the methods described.

[0266] The therapeutically effective amount for human use can be determined from animal models.For example, the dose for human can be formulated to achieve the concentration found to be effective in animals.The dosage for human can be adjusted by monitoring PKa inhibition and adjusting the dosage upward or downward as described above.

[0267] Dosage can be varied depending on 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 will also be determined by the existence, nature, and extent of any adverse side effects.

[0268] In one embodiment, the compounds provided herein exhibit one or more improved pharmacokinetic (PK) properties (e.g., C max , t max , C min , t 1 / 2 , AUC, CL, bioavailability, etc.). In some embodiments, the reference compound is a PKa inhibitor known in the art. In some embodiments, the reference compound is a PKa inhibitor selected from those disclosed in PCT Publication No. WO2019 / 178129.

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

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

[0271] In some embodiments, the subject treated by any of the methods described herein is a human patient who has, suspects to have, or is at risk of having edema, for example, HAE or diabetic macular edema (DME).The subject who has edema can be identified by routine medical examination, for example, laboratory test.The subject who is suspected to have edema may show one or more symptoms of disease / disorder.The subject who is at risk of edema can be the subject who has one or more risk factors related to disease, for example, C1-INH deficiency for HAE.

[0272] In certain embodiments, provided herein are methods for alleviating one or more symptoms of HAE in a human patient suffering from an HAE attack. Such patients can be identified through routine medical procedures. An effective amount of one or more of the provided compounds can be administered to a human patient via a suitable route, such as those described herein. The compounds described herein can be used alone or in combination with other anti-HAE agents, such as C1 esterase inhibitors (e.g., Cinryze® or Berinert®), PKa inhibitors (e.g., ecallantide or lanadelumab), or bradykinin B2 receptor antagonists (e.g., Firazyr®).

[0273] In some embodiments, provided herein are methods for reducing the risk of HAE attacks in quiescent human HAE patients. Such patients can be identified based on various factors, including a history of HAE attacks. An effective amount of one or more of the compounds can be administered to a human patient via a suitable route, such as those described herein. The compounds described herein can be used alone or in combination with other anti-HAE agents, such as C1 esterase inhibitors (e.g., Cinryze® or Berinert®), PKa inhibitors (e.g., ecallantide or lanadelumab), or bradykinin B2 receptor antagonists (e.g., Firazyr®).

[0274] In some embodiments, provided herein is prophylactic treatment of HAE in human patients at risk for HAE attacks with one or more of the compounds described herein. In some embodiments, a patient suitable for prophylactic treatment of HAE is a human subject suffering from HAE (e.g., with a history of HAE attacks). In some embodiments, a patient suitable for such prophylactic treatment is a human subject whose history of HAE attacks indicates that a preventative approach is warranted by a physician (e.g., a human subject experiencing more than a certain average number of attacks over a period of time, including, by way of non-limiting example, one, two, or more attacks per month). Alternatively, a patient suitable for prophylactic treatment may be a human subject without a history of HAE attacks but who possesses one or more risk factors for HAE (e.g., a family history, a genetic defect in the C1-INH gene, etc.). Such prophylactic treatment may involve a compound described herein as the sole active agent, or may involve an additional anti-HAE agent, such as those described herein.

[0275] In certain embodiments, provided herein are methods for preventing or reducing edema in the eye of a subject (e.g., a human patient). In some examples, the human patient is a diabetic with, suspected of having, or at risk for diabetic macular edema (DME). DME is a proliferative form of diabetic retinopathy characterized by swelling of the retinal layers, neovascularization, vascular leakage, and retinal thickening in diabetes due to leakage of fluid from blood vessels in the macula. To practice this method, an effective amount of one or more compounds described herein, or a pharmaceutically acceptable salt thereof, can be delivered to the eye of a subject in need of treatment. For example, the compound can be delivered locally by intraocular or intravitreal injection. The subject can be treated with a compound described herein either as the sole active agent or in combination with another treatment for DME. Non-limiting examples of treatments 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 include administering to a subject an effective amount of a compound of Formula (I)-(VI-b), or a pharmaceutically acceptable salt or composition thereof. In some embodiments, the effective amount is a therapeutically effective amount. In some embodiments, the effective amount is a prophylactically effective amount.

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

[0278] Certain methods described herein may include administering one or more additional pharmaceutical agent(s) in combination with a compound described herein. The additional pharmaceutical agent(s) may be administered simultaneously with the compound of Formula (I)-(XVI-c) or at a different time than the compound of Formula (I)-(XVI-c). For example, the compound of Formula (I)-(XVI-c) and any additional pharmaceutical agent(s) may be on the same dosing schedule or different dosing schedules. All or a portion of the dose of the compound of Formula (I)-(XVI-c) may be administered before all or a portion of the dose of the additional pharmaceutical agent, after all or a portion of the dose of the additional pharmaceutical agent, within the dosing schedule of the additional pharmaceutical agent, or a combination thereof. The timing of administration of the compound of Formula (I)-(XVI-c) and the additional pharmaceutical agent may differ for different additional pharmaceutical agents.

[0279] In certain embodiments, the additional pharmaceutical agent comprises an agent useful in the treatment of edema, e.g., HAE or DME. Examples of such agents are provided herein. Exemplary Enumerated Embodiments 1. Compounds of formula (I): [ka] or a pharmaceutically acceptable salt thereof (In the formula, Cy A is a 5- to 6-membered monocyclic heteroarylene having 1 to 3 heteroatoms independently selected from phenylene, oxygen, nitrogen, and sulfur, a 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclene having 1 to 4 heteroatoms independently selected from oxygen, nitrogen, or sulfur, an 8- to 12-membered bicyclic heteroarylene having 1 to 4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, or an 8- to 10-membered bicyclic arylene; and Cy is A 0 to 4 -R A substituted with a group; Each R A is 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 C 1-6 independently selected from optionally substituted groups selected from aliphatic, phenyl, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur, or 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 C 1-6 is an aliphatic group; L' is a covalent bond or an optionally substituted C1-4 The hydrocarbon chain (1 to 3 methylene units are optionally and independently -O-, -C(O)-, -NR z -, -S-, -SO-, -SO2-, -S(NH)(O)-, or cyclopropylene); Each R z is hydrogen, -(CH2) 0-3 OR, -(CH2) 0-3 C(O)OR or optionally substituted C 1-6 independently selected from aliphatic groups; Cy B teeth, [ka] (In the formula, R B1 and R B2 each independently represents hydrogen or C 1-6 an optionally substituted group selected from aliphatic or 3- to 7-membered saturated or partially unsaturated monocyclic carboxyl; R B3 is hydrogen or C 1-6 It is aliphatic; R B4 is -N(R x )2; Each R x is hydrogen, -C(O)R, -C(O)R, or an optionally substituted C 1-6 independently selected from aliphatic, R B1 or R B2 At most one of the atoms is hydrogen) and Cy B teeth, [ka] (In the formula, R B5 is hydrogen or C 1-6 an aliphatic or optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic carboxyl; R B6 and R B7 each independently represents hydrogen or an optionally substituted C1-6 aliphatic) and; L is an optionally substituted C 1-3 The hydrocarbon chain (1 to 3 methylene units may optionally and independently be -C(O)-, -O-, -NR z -, -N(NO)-, -S-, -SO-, -SO2-, optionally substituted cyclopropylene, or optionally substituted 5- to 6-membered saturated or partially unsaturated heterocyclene having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur; Cy C is selected from a 5- to 6-membered heteroaryl having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, phenyl, an 8- to 10-membered bicyclic aryl, a 7- to 10-membered heteroaryl having 1 to 4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, or a 6- to 12-membered saturated or partially unsaturated fused bicyclic heterocyclyl having 1 to 4 heteroatoms independently selected from oxygen, nitrogen, or sulfur; and Cy C 0 to 6 -L C -R C substituted with a group; Each L C is a covalent bond or an optionally substituted C 1-6 independently selected from hydrocarbon chains (wherein 1 to 3 methylene units are optionally and independently replaced with -C(O)-, -O-, or -NR-); Each R C is 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 C 1-6and optionally substituted groups selected from aliphatic, phenyl, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, 5- or 6-membered heteroaryl having 1-3 heteroatoms selected from oxygen, nitrogen, or sulfur; 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur; 6- to 12-membered saturated or unsaturated bicyclic heterocyclyl having 1-3 heteroatoms selected from oxygen, nitrogen, or sulfur; 5- to 12-membered saturated or unsaturated bicyclic carbocyclyl; or 7- to 10-membered heteroaryl having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur). 2. The compound has the formula (II-a): [ka] or a pharmaceutically acceptable salt thereof. 3. The compound has the formula (III-a), (III-b), (III-c), or (III-d): [ka] or a pharmaceutically acceptable salt thereof. 4. The compound has the formula (III-a-1), (III-a-2), or (III-a-3): [ka] or a pharmaceutically acceptable salt thereof. 5. The compound has the formula (III-b-1), (III-b-2), or (III-b-3): [ka] or a pharmaceutically acceptable salt thereof. 6. The compound has the formula (IV), (IV-a), (IV-b), or (IV-c): [ka] or a pharmaceutically acceptable salt thereof. 7. The compound has the formula (Va), (Vb), or (Vc): [ka] or a pharmaceutically acceptable salt thereof. 8. The compound has the formula (VI-a), (VI-b), or (VI-c): [ka] or a pharmaceutically acceptable salt thereof. 9. The compound has formula (VII-a), (VII-b), or (VII-c): [ka] or a pharmaceutically acceptable salt thereof. 10. The compound has formula (VIII-a), (VIII-b), or (VIII-c): [ka] or a pharmaceutically acceptable salt thereof. 11. The compound has the formula (IX-a), (IX-b), or (IX-c): [ka] or a pharmaceutically acceptable salt thereof. 12. The compound has the formula (Xa), (Xb), or (Xc): [ka] or a pharmaceutically acceptable salt thereof. 13. The compound has the formula (XI-a), (XI-b), or (XI-c): [ka] or a pharmaceutically acceptable salt thereof. 14. The compound has the formula (XII-a), (XII-b), or (XII-c): [ka] or a pharmaceutically acceptable salt thereof. 15. The compound has the formula (XIII-a), (XIII-b), or (XIII-c): [ka] or a pharmaceutically acceptable salt thereof. 16. The compound has the formula (XIV-a), (XIV-b), or (XIV-c): [ka] or a pharmaceutically acceptable salt thereof. 17. The compound has the formula (XV-a), (XV-b), or (XV-c): [ka] or a pharmaceutically acceptable salt thereof. 18. The compound has formula (XVI-a), (XVI-b), or (XVI-c): [ka] or a pharmaceutically acceptable salt thereof. 19.R B1 is hydrogen or C 1-6 The compound of any one of embodiments 1-3, 5, or 7-18, which is aliphatic. 20.R B1 The compound of any one of embodiments 1-3, 5, or 7-19, wherein is hydrogen. 21.R B1 is C 1-6 The compound of any one of embodiments 1-3, 5, or 7-19, which is aliphatic. 22.R B1 The compound of any one of embodiments 1-3, 5, 7-19, or 21, wherein is methyl. 23.R B2 is hydrogen or C 1-6 The compound of any one of embodiments 1-4 or 7-22, which is aliphatic. 24.R B2 The compound of any one of embodiments 1-4 or 7-23, wherein is hydrogen. 25.R B2 is methyl, ethyl, -CF3, or [ka] The compound of any one of embodiments 1-4 or 7-23, wherein 26.R B2 The compound of any one of embodiments 1-4, 7-23, or 25, wherein is methyl. 27.R B3 The compound of any one of embodiments 1-3, 6, or 19-26, wherein is hydrogen. 28.R B3 The compound of any one of embodiments 1-3, 6, or 19-26, wherein is methyl. 29.Each R x The compound of any one of embodiments 1-6 or 19-26, wherein is hydrogen. 30.Each R xis -C(O)R, -C(O)R, or an optionally substituted C 1-6 The compound of any one of embodiments 1-6 or 19-26, independently selected from aliphatic. 31. One R x is hydrogen and the other is —C(O)R, —C(O)R, or an optionally substituted C 1-6 The compound of any one of embodiments 1-6 or 19-26, wherein the compound is selected from aliphatic. 32. Cy B teeth, [ka] The compound of embodiment 1 or 2, selected from the group consisting of: 33. The compound has the formula (II-b): [ka] or a pharmaceutically acceptable salt thereof. 34.R B5 is C 1-6 The compound of embodiment 1 or 33, which is an aliphatic or optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic carbocyl. 35.R B6 is an arbitrarily substituted C 1-6 The compound of any one of embodiments 1 or 33-34, which is aliphatic. 36.R B7 is C 1-6 The compound of any one of embodiments 1 or 33-35, which is aliphatic. 37. Cy A is phenylene, and Cy A 0 to 4 -R A The compound of any one of embodiments 1-6 or 10-36, wherein the compound is substituted with a group. 38. Cy A is a 5- to 6-membered monocyclic heteroarylene having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur; Cy A 0 to 4 -R AThe compound of any one of embodiments 1-6 or 10-36, wherein the compound is substituted with a group. 39. Cy A is selected from the group consisting of phenylene, thiazoldiyl, pyridinediyl, pyrazinediyl, pyrimidinediyl, pyridazinediyl, triazinediyl, thiadiazolediyl, oxadiazolediyl, triazolediyl, pyrrolediyl, pyrazolediyl, and imidazolediyl; A 0 to 4 -R A The compound of any one of embodiments 1-6, 10-36, or 38, substituted with a group. 40. Cy A is an 8- to 12-membered bicyclic heteroarylene having 1 to 4 heteroatoms independently selected from oxygen, nitrogen, and sulfur; Cy A 0 to 4 -R A The compound of any one of embodiments 1-6 or 10-36, wherein the compound is substituted with a group. 41. Cy A is an 8-membered bicyclic heteroarylene having 1-2 nitrogen heteroatoms, and Cy A 0 to 4 -R A The compound of any one of embodiments 1-6, 10-36, or 40, substituted with a group. 42. Cy A is a 9-membered bicyclic heteroarylene having 1 to 4 nitrogen heteroatoms, and Cy A 0 to 4 -R A The compound of any one of embodiments 1-6, 10-36, or 40, substituted with a group. 43. Cy A is a 10-membered bicyclic heteroarylene having 1-2 nitrogen heteroatoms, and Cy A 0 to 4 -R A The compound of any one of embodiments 1-6, 10-36, or 40, substituted with a group. 44. Cy A is a 7- to 12-membered bicyclic heteroarylene having 1 to 4 heteroatoms independently selected from oxygen, nitrogen, and sulfur; Cy A0 to 4 -R A The compound of any one of embodiments 1-6 or 10-36, wherein the compound is substituted with a group. 45. Cy A is a 9-membered bicyclic heteroarylene having 3 to 4 heteroatoms independently selected from oxygen and nitrogen, and Cy A is 0 to 1 -R A The compound of any one of embodiments 1-6, 10-36, or 44, substituted with a group. 46. ​​Cy A is a 10-membered bicyclic heteroarylene having 3 to 4 heteroatoms independently selected from oxygen and nitrogen, and Cy A is 0 to 1 -R A The compound of any one of embodiments 1-6, 10-36, or 44, substituted with a group. 47. Cy A teeth, [ka] [ka] The compound of any one of embodiments 1-6 or 10-36, selected from the group consisting of: wherein * represents the point of attachment to L'. 48.Each R A is oxo, halogen -C(O)R, -OR, -C(O)N(R), or optionally substituted C 1-6 The compound of any one of embodiments 1-47, independently selected from aliphatic. 49.L' is an optionally substituted C 1-4 The hydrocarbon chain (1 to 3 methylene units are optionally and independently -O-, -C(O)-, -NR z The compound of any one of embodiments 1-9 or 12-48, wherein the aryl group is -, -S-, -SO-, -SO2-, -S(NH)(O)-, or cyclopropylene. 50.L' is [ka] (Wherein, # represents Cy B 50. The compound of any one of embodiments 1-9 or 12-49, wherein R is an integer from 1 to 49, ... and R is an integer from 1 to 49. 51.L' is [ka] (Wherein, # represents Cy B The compound of any one of embodiments 1-9 or 12-50, wherein R is an integer from 1 to 50, and .... 52.L is an optionally substituted C 1-3 The hydrocarbon chain (1 to 3 methylene units may optionally and independently be -C(O)-, -O-, -NR z -, -N(NO)-, -S-, -SO-, -SO2-, optionally substituted cyclopropylene, or -(CH2) 0-4 and a 5-membered saturated or partially unsaturated heterocyclene having one nitrogen heteroatom optionally substituted with -OR° or -OSiR°3, wherein each R° is independently selected from the group consisting of C 1-6 The compound of any one of embodiments 1-11 or 14-51, wherein R is an aliphatic hydrogen. 53.L is an optionally substituted C 1-3 The hydrocarbon chain (1 to 3 methylene units are optionally and independently -C(O)-, -O-, -NR z -, or -S-). 54.L is [ka] (wherein % is Cy C 53. The compound of any one of embodiments 1-11 or 14-52, wherein R represents a point of attachment to R. 55.L is [ka] (wherein % is Cy C55. The compound of any one of embodiments 1-11, 14-52, or 54, wherein: 56. Cy C is phenyl and Cy C 0 to 5 -L C -R C The compound of any one of embodiments 1-13 or 19-55, wherein the compound is substituted with a group. 57. Cy C is a 5- to 6-membered heteroaryl having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur; Cy C 0 to 6 -L C -R C The compound of any one of embodiments 1-13 or 19-55, wherein the compound is substituted with a group. 58. Cy C is pyrazolyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl, and Cy C 0 to 4 -L C -R C The compound of any one of embodiments 1-13 or 19-55, wherein the compound is substituted with a group. 58. Cy C teeth, [ka] 59. The compound of any one of embodiments 1-13, 19-55, or 58, selected from the group consisting of: 59. Cy C is an 8- to 10-membered bicyclic aryl, and Cy C 0 to 6 -L C -R C The compound of any one of embodiments 1-13 or 19-55, wherein the compound is substituted with a group. 60. Cy C 0 to 6 -L C -R C60. The compound of any one of embodiments 1-13, 19-55, or 59, which is an indazolyl, benzotriazolyl, naphthalenyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, tetrahydro-2H-benzo[b][1,4]oxazinyl, or dihydro-2H-benzo[b][1,4]oxazinonyl substituted with a group. 61. Cy C is a 7- to 10-membered heteroaryl having 1 to 4 heteroatoms independently selected from oxygen, nitrogen, and sulfur; Cy C 0 to 6 -L C -R C The compound of any one of embodiments 1-13 or 19-55, wherein the compound is substituted with a group. 62. Cy C is imidazopyridinyl, pyrazolopyridinyl, indazolyl, pyrrolopyridinyl, benzimidazolyl, triazolopyridinyl, imidazopyridazinyl, imidazopyrimidinyl, imidazopyrimidinonyl, benzotriazolyl, triazolopyrimidinyl, triazolopyridazinyl, benzothiophenyl, benzothiozolyl, thienopyridinyl, benzofuranyl, benzoxazolyl, pyrazolopyrimidinyl, imidazopyrazinyl, quinolinyl, isoquinolinyl, quinazolinyl, naphthyridinyl, and Cy C 0 to 6 -L C -R C The compound of any one of embodiments 1-13, 19-55, or 61, substituted with a group. 63. Cy C teeth, [ka] The compound of any one of embodiments 1-13 or 19-55, selected from the group consisting of: 64. Cy C teeth, [ka] The compound of any one of embodiments 1-13 or 19-55, wherein 65.L Care *-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)- (where * is Cy C 65. The compound of any one of embodiments 1-64, wherein: 66.Each R C is oxo, halogen, -CN, -C(O)2R, -C(O)N(R)2, or C 1-6 66. The compound of any one of embodiments 1-65, wherein the optionally substituted group is selected from: 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. 67. The compound of any one of the preceding embodiments, wherein the compound is selected from compounds I-1 to I-540, or a pharmaceutically acceptable salt thereof. 68. A pharmaceutical composition comprising a compound according to any one of the preceding embodiments. 69. A pharmaceutical composition comprising a compound according to 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 according to 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 according to 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 according to 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 the onset of, reduces the severity of, and / or reduces the frequency of occurrence of one or more symptoms, characteristics, and / or causes of hereditary angioedema. 77. The method of embodiment 76, wherein the compound is administered orally. [Example]

[0280] IV. Working Examples In certain embodiments, the examples describe compounds containing one or more stereocenters, where a particular stereocenter is designated as "S*" or "R*." In both cases, the designation "*" typically indicates that the exact configuration is unknown (e.g., for a compound with a single stereocenter, the designation R*- or S*- indicates that either the R- or S-isomer has been isolated, but the configuration at the stereocenter of the particular isomer isolated has not been determined).

[0281] It will be understood that the compounds described in the examples may contain multiple stereocenters. As noted above, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or stereo) mixtures of the present compounds are within the scope of the present invention. Within a particular compound name where multiple "S*" or "R*" appear within a single parenthetical pair (e.g., "(1S*,2S*)"), it is understood that the S* and / or R* configurations are relative to one another. For example, a compound designated "(1S*,2S*)-" or "(1R*,2R*)-" will be understood to specifically refer to either the "(1S,2S)-" or "(1R,2R)-" isomer, but not the "(1S,2R)-" or "(1R,2S)-" isomer. Furthermore, compounds designated "rac-(1S*,2S*)-" or "rac-(1R*,2R*)-" will be understood to include a racemic mixture of the "(1S,2S)-" and "(1R,2R)-" isomers. Similarly, compounds designated "(1S*,2R*)-" or "(1R*,2S*)-" will be understood to specifically refer to either the "(1R,2S)-" or "(1S,2R)-" isomer, but not the "(1S,2S)-" or "(1R,2R)-" isomer. Also, compounds designated "rac-(1R*,2S*)-" or "rac-(1S*,2R*)-" will be understood to include a racemic mixture of the "(1R,2S)-" and "(1S,2R)-" isomers.

[0282] In certain embodiments, the examples include schemes showing compounds with one or more stereocenters. In some embodiments, the symbol "&" followed by a number appears adjacent to the 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 stereogenic center. In such cases, either the "R-" or "S-" isomer is indicated, although it is understood that the particular isomer has not been determined.

[0284] In some embodiments, a number following the symbol "&" or the term "or" refers to the relationship of one stereocenter to another in the compound. For example, when two stereocenters in a compound are each designated with the same number (e.g., two occurrences of "&1"), it is understood that the configurations are relative to one another (e.g., when a structure is designated as (S,S) and both stereocenters are designated with "&1", it is understood that the configurations include a mixture of (S,S) and (R,R) isomers, rather than just (S,R) or (R,S) isomers). However, when each stereocenter is designated with a different number (e.g., one occurrence of "&1" and one occurrence of "&2"), it is understood that the configurations can be independent of one another (e.g., when a structure is designated as (S,S) and one stereocenter is designated with "&1" and one stereocenter is designated with "&2", it is understood that the configurations include a mixture of (S,S), (S,R), (R,S), and (R,R) isomers).

[0285] Synthesis of intermediates Synthesis of (4-cyclopropyl-3-methoxyphenyl)methanol [ka] Synthesis of methyl 4-cyclopropyl-3-methylbenzoate. To a solution of methyl 4-bromo-3-methylbenzoate (700 mg, 3.1 mmol) in toluene / HO (10 mL) (1:1) was added KPO (1.95 g, 9.2 mmol), Pd(dba) (283 mg, 0.31 mmol), and Xantphos (359 mg, 0.62 mmol). The mixture was stirred at 90 °C for 16 h under N. After cooling to room temperature, the reaction was quenched with NHCl (saturated aqueous solution, 80 mL) and then extracted with DCM (100 mL × 3). The combined organic layers were washed with brine (200 mL), dried over NaSO, and concentrated in vacuo to give a residue which was purified by column chromatography on silica gel eluting with 0-70% EtOAc in PE to give methyl 4-cyclopropyl-3-methylbenzoate (390 mg, yield: 66%) as a yellow oil. ESI-MS [M+H]: 191.1.

[0286] Synthesis of (4-cyclopropyl-3-methoxyphenyl)methanol. To a solution of methyl 4-cyclopropyl-3-methylbenzoate (390 mg, 2.1 mmol) in THF (6 mL) was slowly added dropwise LiAlH (1 M in THF, 6.3 mL, 6.3 mmol) at 0 °C. The mixture was stirred at 0 °C for 2 h. The reaction mixture was quenched with NH Cl (saturated aqueous solution, 40 mL) at 0 °C and then extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine (100 mL), dried over Na SO , and concentrated in vacuo to give a residue, which was purified by column chromatography on silica gel eluting with 0–80% EtOAc in PE to give (4-cyclopropyl-3-methoxyphenyl)methanol (214 mg, yield: 63%) as a colorless oil. ESI-MS [M+H]: 163.1.

[0287] Synthesis of (6-methylimidazo[1,2-a]pyridin-2-yl)methanol [ka] Synthesis of ethyl 6-methylimidazo[1,2-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, NaHCO (saturated aqueous solution, 80 mL) was added, and the reaction was extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine, dried over NaSO, and concentrated in vacuo to give the crude product, which was purified by column chromatography on silica gel (PE / EtOAc = 5 / 1) to give ethyl 6-methylimidazo[1,2-a]pyridine-2-carboxylate (300 mg, yield: 32%). ESI-MS [M+H]: 205.2.

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

[0289] Synthesis of (6-methyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)methanol [ka] Synthesis of 2-imino-5-methylpyridin-1(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 hours. The reaction was concentrated to give 2-imino-5-methylpyridin-1(2H)-amine (16.2 g, crude) as a yellow solid, which was used directly in the next step. ESI-MS [M+H]: 124.1

[0290] Synthesis of ethyl 6-methyl-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylate. A mixture of 2-imino-5-methylpyridin-1(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 hours. After the reaction was cooled to room temperature, the mixture was concentrated. The residue was diluted with NaHCO (saturated aqueous solution, 100 mL) and extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine (50 mL), dried over NaSO, and concentrated in vacuo to give the crude material, which was purified by column chromatography (eluent: 0 to 50% EtOAc / PE) to give ethyl 6-methyl-[1,2,4]triazolo[1,5-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-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylate. To a solution of ethyl 6-methyl-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylate (710 mg, 3.46 mmol) in THF / EtOH (30 mL / 5 mL) was added LiBH (440 mg, 20.0 mmol) at 0 °C. The mixture was stirred at room temperature for 3 h and then quenched with NH Cl (saturated aqueous solution, 50 mL). The mixture was extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (50 mL), dried over NaSO, and concentrated in vacuo to give the crude material, which was purified by column chromatography (eluent: 0-100% EtOAc / PE) to give ethyl 6-methyl-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylate (450 mg, 80%) as a white solid. ESI-MS [M+H]: 164.2.

[0292] Synthesis of (2-methylquinazolin-7-yl)methanol [ka] 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 DIBAL-H (1 M in hexane, 12.5 mL, 12.5 mmol) dropwise 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 an additional 0.5 h. The reaction mixture was quenched with NaOH (1 M aqueous solution, 20 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (20 mL), dried over NaSO, and concentrated to give a residue that 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. ESI-MS [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 TBSCl (351 mg, 2.33 mmol). The mixture was stirred at room temperature for 2 hours. Water (20 mL) was added and extracted with ethyl acetate (20 mL × 3). The organic layer was dried over sodium sulfate, filtered, and concentrated to give the crude product, 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. ESI-MS [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 CsCO (1.49 g, 4.56 mmol) at room temperature under a N atmosphere. The mixture was stirred at 70 °C for 1 h, after which the mixture was cooled to room temperature and filtered. The filter cake was washed with DCM / MeOH (v / v = 3 / 1, 30 mL). The filtrate was concentrated in vacuo, and the residue was diluted with water (20 mL) and extracted with EtOAc (30 mL × 2). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, and concentrated to give a 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. ESI-MS [M+H]+: 289.2

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

[0296] Synthesis of (N-(1-(4-(hydroxymethyl)phenyl)cyclopropyl)acetamide [ka] Synthesis of methyl 4-(1-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 the 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 (1.57 mL, 12.7 mmol) was added in one portion. After stirring the reaction mixture at the same temperature for 2 h, the reaction was quenched by the addition of HCl (2 M aqueous solution, 20 mL). The reaction mixture was filtered. The aqueous phase was separated, and the organic layer was washed with water (30 mL × 3). The combined aqueous layers were basified with NaOH (2 M aqueous solution) to adjust the pH to 8. The mixture was then extracted with EtOAc (100 mL × 3). The combined organic layers were washed, dried over Na2SO4, and concentrated in vacuo to give the crude product, which was purified by column chromatography on silica gel eluting with 0-50% EtOAc in PE to give methyl 4-(1-aminocyclopropyl)benzoate (290 mg, yield: 24.4%) as a white solid. ESI-MS [M+H]+: 192.1.

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

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

[0299] Synthesis of 2-(4-(hydroxymethyl)-2,6-dimethylphenyl)-N,N-dimethylacetamide. [ka] 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 NaBH (38 mg, 1 mmol). The mixture was stirred at room temperature for 2 h. The reaction was quenched with HO (0.5 mL) and concentrated in vacuo to give the crude product, which was purified by preparative TLC (DCM / MeOH = 20 / 1) to give (4-bromo-3,5-dimethylphenyl)methanol (80 mg, yield: 75%) as a yellow solid. ESI-MS (M+H): 214.1.

[0300] Synthesis of 5-((benzyloxy)methyl)-2-bromo-1,3-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 for 15 h. The reaction was then quenched with NH Cl (saturated aqueous solution, 20 mL) and extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na SO , and concentrated in vacuo to give the crude product, which was purified by preparative TLC (PE / EtOAc = 1 / 1) to give 5-((benzyloxy)methyl)-2-bromo-1,3-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-dimethylphenyl)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-1,3-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 through Celite®. The filter cake was washed with THF (20 mL), and the filtrate was concentrated in vacuo to give a residue, which was purified by preparative TLC (PE / EtOAc=3 / 1) to give 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 NaHCO3 (saturated aqueous solution). The reaction mixture was extracted with DCM (20 mL × 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 minutes. Then dimethylamine (8 mg, 0.17 mmol) and DIPEA (66 mg, 0.51 mmol) were added. The reaction was stirred at room temperature for an additional 16 hours. The reaction was quenched with water (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were concentrated in vacuo, and the residue was purified by preparative TLC (PE / EtOAc=1 / 1) to give 2-(4-((benzyloxy)methyl)-2,6-dimethylphenyl)-N,N-dimethylacetamide (40 mg, yield: 80% for two 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). The reaction was stirred at room temperature under H for 1 h, and then the mixture was filtered through Celite®. The filter cake was washed with MeOH (15 mL), and the filtrate was concentrated to give the crude product, which was purified by preparative TLC (PE / EtOAc=1 / 2) to give 2-(4-(hydroxymethyl)-2,6-dimethylphenyl)-N,N-dimethylacetamide (24 mg, yield: 84%) as a pale solid. ESI-MS (M+H): 222.3.

[0305] Synthesis of N-(4-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)-N-methylpyrrolidine-1-carboxamide [ka] Synthesis of tert-butyldimethyl((4-nitrobenzyl)oxy)silane. To a solution of (4-nitrophenyl)methanol (5.0 g, 32.65 mmol) in DMF (10 mL) was added imidazole (6.7 g, 98.41 mmol) and TBSCl (4.9 g, 32.51 mmol) at 0 °C. After stirring the mixture at 0 °C for 1 h, the reaction was quenched with HO (100 mL) and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (30 mL), dried over NaSO, and concentrated in vacuo to give a 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. ESI-MS [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, and the mixture was stirred at this temperature under an H atmosphere for 14 h. The mixture was then filtered through Celite, the filter cake was washed with MeOH (20 mL), and the filtrate was concentrated to give the crude product, 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. ESI-MS [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 NaOCH3 (1.7 g, 32 mmol). The mixture was stirred at 80 °C for 3 h. After cooling to room temperature, NaBH4 (1.2 g, 32 mmol) was added to the solution, and the mixture was stirred at room temperature for an additional 1 h. Water (50 mL) was added, and the reaction was extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous NaSO, and concentrated in vacuo to give the crude product, 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, 24.9% yield) as a 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 hours. Water (50 mL) was added and the reaction was extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine (50 mL), dried over anhydrous NaSO, and concentrated in vacuo to give the crude product, 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-1-carboxamide (120 mg, yield: 43%) as a white solid. ESI-MS [M+H]: 349.2

[0309] Synthesis of 1-(4-(hydroxymethyl)phenyl)-1,3,3-trimethylurea [ka] 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 × 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous NaSO, and concentrated in vacuo to give the crude product, 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-1-carboxamide (126 mg, 31% yield) as a white solid. ESI-MS[M+H]+:323.2

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

[0311] Synthesis of (2,3-dimethylquinoxalin-6-yl)methanol [ka] Synthesis of methyl 3-methylquinoxaline-6-carboxylate. To a solution of methyl 3,4-diaminobenzoate (180 mg, 1.08 mmol) in MeOH (5 mL) was added oxopropanal (117 mg, 1.62 mmol). The resulting mixture was stirred at 25 °C for 24 h, after which the reaction was concentrated in vacuo. The residue was diluted with HO (25 mL) and extracted with DCM (20 mL × 3). The combined organics were washed with brine (20 mL), dried over NaSO, 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, 45.8% yield) as a white solid. ESI-MS [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 DIBAL-H (1 M in THF, 1.38 mL, 1.38 mmol) dropwise 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 an additional 0.5 h. The reaction mixture was quenched with NaOH (1 M aqueous solution, 5 mL) and water (15 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (50 mL), dried over NaSO, 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)methanol (40 mg, yield: 46.2%) as a white solid. ESI-MS[M+H]+:189.1

[0313] Synthesis of ethyl (4-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)(methyl)carbamate [ka] 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 × 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous NaSO, and concentrated in vacuo to give the crude product, 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 a white solid. ESI-MS [M+H]: 324.2

[0314] Synthesis of 2-(4-(hydroxymethyl)-2-methoxyphenyl)-N,N-dimethylacetamide [ka] Synthesis of (4-bromo-3-methoxyphenyl)methanol. To a solution of 4-bromo-3-methylbenzaldehyde (100 mg, 0.5 mmol) in EtOH (4 mL) was added NaBH (38 mg, 1 mmol). The mixture was stirred at room temperature for 2 h. The reaction was quenched with HO (1 mL) and concentrated in vacuo to give the crude product, which was purified by preparative TLC (DCM / MeOH = 20 / 1) to give (4-bromo-3-methoxyphenyl)methanol (80 mg, yield: 80%) as a yellow solid. ESI-MS (M+H): 201.1.

[0315] Synthesis of 4-((benzyloxy)methyl)-1-bromo-2-methylbenzene. To a solution of (4-bromo-3-methoxyphenyl)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 with NH4Cl (saturated aqueous solution, 20 mL) and extracted with 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 product, which was purified by preparative TLC (PE / EtOAc = 1 / 1) to give 4-((benzyloxy)methyl)-1-bromo-2-methylbenzene (84 mg, yield: 72%) as a yellow oil. ESI-MS(M+H)+:291.1.

[0316] Synthesis of tert-butyl 2-(4-((benzyloxy)methyl)-2-methoxyphenyl)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)-1-bromo-2-methylbenzene (84 mg, 0.29 mmol), Pd(dba) (27 mg, 0.03 mmol), and X-Phos (28 mg, 0.06 mmol). The mixture was stirred at 70 °C for 4 h under N, after which the mixture was cooled to room temperature and then filtered through Celite®. The filter cake was washed with THF (20 mL), and the filtrate was concentrated in vacuo to give a residue, which was purified by preparative TLC (PE / EtOAc=3 / 1) to give tert-butyl 2-(5-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)acetate (56 mg, yield: 59%) as a yellow oil. ESI-MS (M+H): 327.1.

[0317] Synthesis of 2-(4-((benzyloxy)methyl)-2-methoxyphenyl)acetic acid. To a solution of tert-butyl 2-(4-((benzyloxy)methyl)-2-methoxyphenyl)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 NaHCO3 (saturated aqueous solution). The reaction was extracted with DCM (20 mL × 3). The combined organics were concentrated in vacuo to give 2-(4-((benzyloxy)methyl)-2-methoxyphenyl)acetic acid (60 mg, crude) as a yellow solid. ESI-MS (M+H): 271.2.

[0318] Synthesis of 2-(4-((benzyloxy)methyl)-2-methoxyphenyl)-N,N-dimethylacetamide. To a solution of 2-(4-((benzyloxy)methyl)-2-methoxyphenyl)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 an additional 16 h. The reaction was quenched with HO (20 mL) and extracted with EtOAc (20 mL × 3). The combined organics were concentrated in vacuo, and the residue was purified by preparative TLC (PE / EtOAc=1 / 1) to give 2-(4-((benzyloxy)methyl)-2-methoxyphenyl)-N,N-dimethylacetamide (40 mg, yield: 80%) as a yellow oil. ESI-MS (M+H): 298.2.

[0319] Synthesis of 2-(4-(hydroxymethyl)-2-methoxyphenyl)-N,N-dimethylacetamide. To a solution of 2-(4-((benzyloxy)methyl)-2-methoxyphenyl)-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 under H for 1 h. The mixture was filtered through Celite®. The filter cake was washed with MeOH (10 mL), and the filtrate was concentrated and purified by preparative TLC (PE / EtOAc = 1 / 2) to give 2-(4-(hydroxymethyl)-2-methoxyphenyl)-N,N-dimethylacetamide (24 mg, yield: 88%) as a pale solid. ESI-MS (M+H): 208.3.

[0320] Synthesis of (2-methylquinolin-7-yl)methanol [ka] Synthesis of 7-bromo-2-methylquinoline. A mixture of 3-bromoaniline (500 mg, 2.91 mmol) and 2,4,6-trimethyl-1,3,5-trioxane (3.46 g, 26.19 mmol) in HCl (conc., 5 mL) was stirred at room temperature for 1 h and then heated to reflux for 3 h. After cooling to 0 °C, a solution of NaOH (saturated aqueous, 10 mL) was slowly added, 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 product, which was purified by flash column chromatography on silica gel eluting with 0–10% EtOAc / PE to give 7-bromo-2-methylquinoline (100 mg, yield: 15%) as a 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 slowly added n-BuLi (0.66 mL, 2 M in hexane, 1.32 mmol) at −78 °C under CO. After the mixture was stirred at −78 °C for 3 h, the reaction was quenched with NH4Cl (saturated aqueous solution, 10 mL) and extracted with EtOAc (20 mL × 3). The combined organic layers were dried over Na2SO4 and concentrated to give the crude product, which was purified by preparative TLC (PE / EtOAc = 1 / 1) 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 BH3-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 with NH4Cl (saturated aqueous solution, 10 mL) and extracted with EtOAc (20 mL × 3). The combined organic layers were dried over Na2SO4 and concentrated to give the crude product, which was purified by preparative TLC (MeOH / DCM = 1:20) to give (2-methylquinolin-7-yl)methanol (30 mg, yield: 33%) as a pale solid. ESI-MS (M+H): 174.1.

[0323] Synthesis of 3-(4-(hydroxymethyl)benzyl)-1-methylpyridin-2(1H)-one [ka] 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(PPh) (509 mg, 0.44 mmol), and NaCO (1.6 g, 13.11 mmol). The mixture was stirred at 115 °C for 2 h under N. After cooling to room temperature, the reaction was diluted with HO (50 mL) and extracted with EtOAc (50 mL × 3). The combined organic layers were dried over Na2SO4 and concentrated to give the crude product, 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-1,2-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 N. After cooling to room temperature, the reaction was concentrated, and the residue was diluted with water (20 mL), neutralized with NaHCO (saturated aqueous solution) to adjust the pH to 6, and then extracted with 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-1,2-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-((1-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzoate. To a solution of 4-((2-oxo-1,2-dihydropyridin-3-yl)methyl)benzoic acid (98 mg, 0.43 mmol) in DMF (3 mL) was added MeI (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 hours. Water (10 mL) was added, and the reaction was extracted with EtOAc (10 mL × 3). The combined organic layers were concentrated in vacuo, and the residue was purified by column chromatography on silica gel, eluting with 0 to 60% EtOAc in PE, to give methyl 4-((1-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzoate (80 mg, yield: 72%) as a yellow oil. ESI-MS(M+H)+:258.1.

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

[0327] Synthesis of (3-cyclopropylphenyl)methanol [ka] Synthesis of 3-cyclopropylbenzoic acid. To a solution of 1-bromo-3-cyclopropylbenzene (400 mg, 2.05 mmol) in THF (5 mL) was added n-BuLi (2 M in THF, 2 mL, 4 mmol) slowly at −78 °C under CO. After the mixture was stirred at −78 °C for 3 h, the reaction was quenched with NH4Cl (saturated aqueous solution, 20 mL) and extracted with EtOAc (20 mL × 3). The combined organic layers were dried over Na2SO4 and concentrated to give the crude product, which was purified by preparative TLC (PE / EtOAc = 1 / 1) 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 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 with NH4Cl (saturated aqueous solution, 20 mL) and extracted with EtOAc (20 mL × 3). The combined organic layers were dried over Na2SO4 and concentrated to give the crude product, which was purified by preparative TLC (MeOH / DCM = 1:20) to give (3-cyclopropylphenyl)methanol (150 mg, yield: 82%) as a pale solid. ESI-MS (M+H): 149.2.

[0329] Synthesis of (S)-1-phenylethan-1-ol [ka] To a solution of acetophenone (1 g, 8.32 mmol) in MeOH (10 mL) was added NaBH (629 mg, 16.64 mmol) at 0 °C. The mixture was stirred at room temperature for 1 h. The reaction was quenched with NH Cl (saturated aqueous solution, 20 mL) and extracted with 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-1-ol (800 mg, yield: 79%) as a pale solid. ESI-MS (M+H): 123.2.

[0330] Synthesis of 4-(chloromethyl)-1-methyl-2-(trifluoromethyl)benzene [ka] To a solution of 4-methyl-3-(trifluoromethyl)benzoic acid (500 mg, 2.45 mmol) in THF (10 mL) was added 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 with HCl (1 M aqueous solution, 10 mL) and extracted with EtOAc (20 mL × 3). The combined organic layers were dried over Na2SO4 and concentrated to give the crude product, which was purified by preparative TLC (MeOH / DCM = 1:20) to give 4-(chloromethyl)-1-methyl-2-(trifluoromethyl)benzene (400 mg, yield: 86%) as a pale solid. ESI-MS (M+H): 191.1.

[0331] Synthesis of (4-((1,3,4-oxadiazol-2-yl)methyl)phenyl)methanol [ka] 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% aqueous solution) 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 give 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-((1,3,4-oxadiazol-2-yl)methyl)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, it was quenched with NaHCO (saturated aqueous solution, 15 mL) and extracted with EtOAc (20 mL × 2). The combined organic layers were concentrated and purified by preparative TLC (EtOAc / PE = 2 / 1) to give (4-((1,3,4-oxadiazol-2-yl)methyl)phenyl)methanol (80 mg, yield: 75%) as a white solid. ESI-MS [M+H]: 191.2

[0333] Synthesis of 5'-(hydroxymethyl)-2H-[1,2'-bipyridin]-2-one [ka] Synthesis of ethyl 2-oxo-2H-[1,2'-bipyridine]-5'-carboxylate. To a solution of ethyl 6-chloronicotinate (650 mg, 3.51 mmol) and pyridin-2(1H)-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 cooling the reaction mixture to room temperature, it 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-[1,2'-bipyridine]-5'-carboxylate (550 mg, 64% yield) as a yellow solid. ESI-MS [M+H]+: 245.2

[0334] Synthesis of 5'-(hydroxymethyl)-2H-[1,2'-bipyridin]-2-one. To a solution of 2-oxo-2H-[1,2'-bipyridine]-5'-carboxylate (280 mg, 1.15 mmol) in EtOH (5 mL) was added NaBH4 (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-[1,2'-bipyridin]-2-one (210 mg, 91% yield) as a white solid. ESI-MS [M+H]+: 203.2

[0335] Synthesis of (4-(2-(1H-pyrazol-1-yl)ethyl)phenyl)methanol [ka] 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 concentrated H2SO4 (2 mL), and the mixture was refluxed for 12 h. After cooling the reaction to room temperature, the reaction mixture was concentrated, and the residue was diluted with water (50 mL), neutralized with Na2CO3 (saturated aqueous solution, 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, 92% yield) as a yellow solid. ESI-MS [M+H]+: 213.2

[0336] Synthesis of ethyl 4-(2-(1H-pyrazol-1-yl)ethyl)benzoate. To a solution of ethyl 4-(2-chloroethyl)benzoate (1.0 g, 4.72 mmol) in DMF (10 mL) was added CsCO (4.6 g, 14.16 mmol), NaI (2.1 g, 14.16 mmol), and 1H-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 mixture was extracted with EtOAc (80 mL × 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-(1H-pyrazol-1-yl)ethyl)benzoate (550 mg, 48% yield) as a yellow solid. ESI-MS[M+H]+:245.2

[0337] Synthesis of (4-(2-(1H-pyrazol-1-yl)ethyl)phenyl)methanol. To a solution of ethyl 4-(2-(1H-pyrazol-1-yl)ethyl)benzoate (50 mg, 0.20 mmol) in MeOH (1 mL) and THF (1 mL) was added LiBH4 (13 mg, 0.60 mmol), and the mixture was stirred at room temperature for 2 h. The reaction was concentrated and purified by preparative TLC (PE / EtOAc = 1 / 1) to give (4-(2-(1H-pyrazol-1-yl)ethyl)phenyl)methanol (30 mg, yield: 73%) as a white solid. ESI-MS [M+H]+: 203.2

[0338] Synthesis of 1-(4-(hydroxymethyl)phenethyl)pyridin-2(1H)-one [ka] Synthesis of ethyl 4-(2-(2-oxopyridin-1(2H)-yl)ethyl)benzoate. To a solution of ethyl 4-(2-chloroethyl)benzoate (106 mg, 0.50 mmol) in DMF (5 mL), CsCO (489 mg, 1.50 mmol), NaI (225 mg, 1.50 mmol), and pyridin-2-ol (71 mg, 0.75 mmol) were added, and the mixture was stirred at 90 °C for 16 h. After the reaction mixture was cooled to room temperature, it was quenched with HO (25 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were concentrated and purified by preparative TLC (PE / EtOAc = 1 / 1) to give ethyl 4-(2-(2-oxopyridin-1(2H)-yl)ethyl)benzoate (71 mg, yield: 52%) as a yellow solid. ESI-MS[M+H]+:272.2

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

[0340] Synthesis of (7-chloroquinolin-3-yl)methanol [ka] 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 EtN (487 mg, 4.82 mmol) at -20 °C, and the mixture was stirred at -20 °C for 20 min. After warming the mixture to 0 °C, NaBH (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 × 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, 26% yield) as a yellow solid. ESI-MS [M+H]: 194.1

[0341] Synthesis of 2-(4-(hydroxymethyl)phenyl)-N,N-dimethylacetamide [ka] To a solution of 2-(4-(hydroxymethyl)phenyl)acetic acid (500 mg, 3.01 mmol) in DMF (10 mL) was added dimethylamine (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 × 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, 81% yield) as a yellow solid. ESI-MS [M+H]: 194.2

[0342] Synthesis of (1-(difluoromethyl)-1H-benzo[d]imidazol-2-yl)methanol [ka] To a solution of (1H-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), and 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 × 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, 75% yield) as a yellow solid. ESI-MS [M+H]: 199.2

[0343] Synthesis of (6-bromoquinolin-2-yl)methanol [ka] Synthesis of 6-bromoquinoline-2-carbaldehyde. SeO (103 mg, 1.2 mmol, 1.3 equiv.) suspended 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 h. 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-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) and extracted with EtOAc (20 mL×3). The combined organic layers were concentrated and purified by preparative TLC (EtOAc / PE=1 / 1) to give (6-bromoquinolin-2-yl)methanol (120 mg, yield: 56% for two steps) as a white solid. ESI-MS [M+H]+: 238.2

[0345] Synthesis of (8-methylquinolin-3-yl)methanol [ka] 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 NaBH4 (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 × 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-chloro-8-methylquinolin-3-yl)methanol (200 mg, yield: 97%) as a white solid. ESI-MS [M+H]+: 208.2

[0346] Synthesis of (8-methylquinolin-3-yl)methanol. To a solution of (2-chloro-8-methylquinolin-3-yl)methanol (200 mg, 0.97 mmol) in THF (5 mL) was added Pd(dppf)Cl (139 mg, 0.19 mmol), TMEDA (337 mg, 2.91 mmol), and NaBH (110 mg, 2.91 mmol), and the mixture was stirred at room temperature for 12 h under N. Water (30 mL) was added, and the reaction was extracted with EtOAc (30 mL × 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 (8-methylquinolin-3-yl)methanol (105 mg, 62.5% yield) as a yellow solid. ESI-MS [M+H]: 174.2

[0347] Synthesis of quinoxalin-6-ylmethanol [ka] To a solution of quinoxaline-6-carboxylic acid (200 mg, 1.15 mmol) in THF (5 mL) was added LiAlH (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 × 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

[0348] Synthesis of (3-chloroquinolin-6-yl)methanol [ka] 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 cooling to room temperature, the reaction was quenched with NaHCO (saturated aqueous solution, 150 mL) and extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine (100 mL), dried over NaSO, and concentrated in vacuo to give the crude product, which was purified by 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 LiBH (202 mg, 9.2 mmol). The mixture was stirred at 50 °C for 12 h. After cooling to room temperature, the reaction was quenched with NH Cl (saturated aqueous solution, 50 mL) and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (80 mL), dried over Na SO , and concentrated in vacuo to give the crude product, which was purified by 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

[0350] Synthesis of (7-chloroquinolin-3-yl)methanol [ka] 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 EtN (487 mg, 4.82 mmol) at -20 °C, and the mixture was stirred at -20 °C for 20 min. After warming the mixture to 0 °C, NaBH (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 × 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, 26% yield) as a yellow solid. ESI-MS [M+H]: 194.1

[0351] Synthesis of 2-(4-(hydroxymethyl)phenyl)-N,N-dimethylacetamide [ka] To a solution of 2-(4-(hydroxymethyl)phenyl)acetic acid (500 mg, 3.01 mmol) in DMF (10 mL) was added dimethylamine (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 × 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, 81% yield) as a yellow solid. ESI-MS [M+H]: 194.2

[0352] Synthesis of (1-(difluoromethyl)-1H-benzo[d]imidazol-2-yl)methanol [ka] To a solution of (1H-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), and 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 × 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, 75% yield) as a yellow solid. ESI-MS [M+H]: 199.2.

[0353] Synthesis of (6-bromoquinolin-2-yl)methanol [ka] Synthesis of 6-bromoquinoline-2-carbaldehyde. SeO (103 mg, 1.2 mmol, 1.3 equiv.) suspended 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 h. 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 h. The reaction was quenched with water (20 mL) and extracted with EtOAc (20 mL × 3). The combined organic layers were concentrated and purified by preparative TLC (EtOAc / PE = 1 / 1) to give (6-bromoquinolin-2-yl)methanol (120 mg, yield: 56% for two steps) as a white solid. ESI-MS [M+H]: 238.2.

[0355] Synthesis of (8-methylquinolin-3-yl)methanol [ka] 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 NaBH4 (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 × 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-chloro-8-methylquinolin-3-yl)methanol (200 mg, 97% yield) as a white solid. ESI-MS [M+H]+: 208.2.

[0356] Synthesis of (8-methylquinolin-3-yl)methanol. To a solution of (2-chloro-8-methylquinolin-3-yl)methanol (200 mg, 0.97 mmol) in THF (5 mL) was added Pd(dppf)Cl (139 mg, 0.19 mmol), TMEDA (337 mg, 2.91 mmol), and NaBH (110 mg, 2.91 mmol), and the mixture was stirred at room temperature for 12 h under N. Water (30 mL) was added, and the reaction was extracted with EtOAc (30 mL × 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 (8-methylquinolin-3-yl)methanol (105 mg, 62.5% yield) as a yellow solid. ESI-MS [M+H]: 174.2.

[0357] Synthesis of quinoxalin-6-ylmethanol [ka] To a solution of quinoxaline-6-carboxylic acid (200 mg, 1.15 mmol) in THF (5 mL) was added LiAlH (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 × 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.

[0358] Synthesis of (3-chloroquinolin-6-yl)methanol [ka] 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 cooling to room temperature, the reaction was quenched with NaHCO (saturated aqueous solution, 150 mL) and extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine (100 mL), dried over NaSO, and concentrated in vacuo to give the crude product, which was purified by 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.

[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 LiBH (202 mg, 9.2 mmol). The mixture was stirred at 50 °C for 12 h. After cooling to room temperature, the reaction was quenched with NH Cl (saturated aqueous solution, 50 mL) and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (80 mL), dried over Na SO , and concentrated in vacuo to give the crude product, which was purified by 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.

[0360] Synthesis of methyl 3-chloroquinoline-6-carboxylate [ka] 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 cooling to room temperature, the reaction was quenched with NaHCO (saturated aqueous solution, 150 mL) and extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine (100 mL), dried over NaSO, and concentrated in vacuo to give the crude product, which was purified by 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.

[0361] Synthesis of (3-chloroquinolin-6-yl)methanol [ka] To a solution of methyl 3-chloroquinoline-6-carboxylate (500 mg, 2.3 mmol) in THF / MeOH (20 mL / 4 mL) was added LiBH (202 mg, 9.2 mmol). The mixture was stirred at 50 °C for 12 h. After cooling to room temperature, the reaction was quenched with NH Cl (saturated aqueous solution, 50 mL) and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (80 mL), dried over Na SO , and concentrated in vacuo to give the crude product, which was purified by 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.

[0362] Synthesis of (6-chloroimidazo[1,2-a]pyridin-2-yl)methanol [ka] To a solution of ethyl 6-chloroimidazo[1,2-a]pyridine-2-carboxylate (200 mg, 0.9 mmol) in THF (10 mL) was slowly added DIBAL-H (1 M in THF, 2.7 mL, 2.7 mmol) at -20 °C under N . After stirring the reaction mixture at -20 °C for 1 h, Na SO ·10H O (2 g) was added, and the mixture was stirred at room temperature for 10 min. The reaction mixture was then filtered through Celite, 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 (6-chloroimidazo[1,2-a]pyridin-2-yl)methanol (50 mg, yield: 30%) as a yellow solid. ESI-MS [M+H]: 183.2.

[0363] Synthesis of (6,7-dimethylimidazo[1,2-a]pyridin-2-yl)methanol [ka] Synthesis of ethyl 6,7-dimethylimidazo[1,2-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), and the mixture was stirred at 95 °C for 12 h. After the reaction was cooled to room temperature, NaHCO (30 mL, 10%) was added, and the reaction was extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine, dried over NaSO, and concentrated in vacuo to give the crude product, which was purified by Combiflash chromatography using PE / EtOAc (5 / 1) to give ethyl 6,7-dimethylimidazo[1,2-a]pyridine-2-carboxylate (300 mg, 33%) as a yellow solid. ESI-MS [M+H] + :219.2.

[0364] Synthesis of (6,7-dimethylimidazo[1,2-a]pyridin-2-yl)methanol. To a solution of ethyl 6,7-dimethylimidazo[1,2-a]pyridine-2-carboxylate (300 mg, 1.38 mmol) in THF (10 mL) was added LiAlH (1 M in THF, 2.8 mL, 2.8 mmol) slowly at 0 °C under N. The reaction mixture was allowed to warm to room temperature and stirred for 1 h. The reaction was quenched with NaSO·10H O (3 g) and stirred at room temperature for 10 min. The reaction was then filtered, and the 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 (6,7-dimethylimidazo[1,2-a]pyridin-2-yl)methanol (200 mg, yield: 82%) as a brown solid. ESI-MS [M+H]+: 177.2.

[0365] Synthesis of (7-methylimidazo[1,2-a]pyridin-2-yl)methanol [ka] Synthesis of ethyl 7-methylimidazo[1,2-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, NaHCO (80 mL, 10% aqueous solution) was added, and the reaction was extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine, dried over NaSO, and concentrated in vacuo to give the crude product, which was purified by Combiflash chromatography using PE / EtOAc (5 / 1) to give ethyl 7-methylimidazo[1,2-a]pyridine-2-carboxylate (300 mg, 32% yield). ESI-MS [M+H] + :205.2.

[0366] Synthesis of (7-methylimidazo[1,2-a]pyridin-2-yl)methanol. To a solution of ethyl 7-methylimidazo[1,2-a]pyridine-2-carboxylate (300 mg, 1.5 mmol) in THF (10 mL) was added LiAlH (1 M in THF, 3.0 mL, 3 mmol) slowly at 0 °C under N. The reaction mixture was then allowed to warm to room temperature and stirred for 1 h. The reaction was quenched with NaSO·10H O (3 g) and stirred at room temperature for 10 min. The reaction was 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[1,2-a]pyridin-2-yl)methanol (220 mg, yield: 82%) as a brown solid. ESI-MS [M+H]+: 163.2.

[0367] Synthesis of (4-cyclopropylphenyl)methanol [ka] 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) (52 mg, 0.23 mmol), PPh (61 mg, 0.23 mmol), and KPO (1.5 g, 6.9 mmol) in dioxane / HO (25 mL / 2.5 mL) was stirred at 100 °C for 12 h under N. The reaction mixture was cooled to room temperature and concentrated. Water (40 mL) was added and extracted with EtOAc (50 mL × 3). The combined organic layers were concentrated to give the crude product, which was purified by 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 slowly added LiAlH (1 M in THF, 4.6 mL, 4.6 mol) at 0 °C under N. The reaction mixture was then gradually warmed to room temperature and stirred for 1 h. The reaction was quenched with NaSO 10H O (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 (6-cyclopropyl-5-methylimidazo[1,2-a]pyridin-2-yl)methanol [ka] Synthesis of ethyl 6-cyclopropyl-5-methylimidazo[1,2-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, NaHCO (50 mL, 10% aqueous solution) was added, and the reaction was extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine, dried over NaSO, and concentrated in vacuo to give the crude product, which was purified by column chromatography (eluent: PE / EtOAc = 5 / 1) to give ethyl 6-cyclopropyl-5-methylimidazo[1,2-a]pyridine-2-carboxylate (150 mg, yield: 31%) as a yellow solid. ESI-MS [M+H]+: 245.2.

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

[0371] Synthesis of (5-methylimidazo[1,2-a]pyridin-2-yl)methanol [ka] Synthesis of ethyl 6-chloro-5-methylimidazo[1,2-a]pyridine-2-carboxylate. A mixture of 5-chloro-6-methylpyridin-2...

Claims

1. Compounds of formula (I): 【Chemistry 501】 or a pharmaceutically acceptable salt thereof (In the formula, Cy Ａ is a 5- to 6-membered monocyclic heteroarylene having 1 to 3 heteroatoms independently selected from phenylene, oxygen, nitrogen, and sulfur, a 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclene having 1 to 4 heteroatoms independently selected from oxygen, nitrogen, or sulfur, an 8- to 12-membered bicyclic heteroarylene having 1 to 4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, or an 8- to 10-membered bicyclic arylene; and Cy is Ａ is 0 to 4 -R Ａ substituted with a group; Each R Ａ is oxo, halogen, -CN, -C(O)R, -C(O) ２ R, -C(O)N(R) ２ , -NO ２ , -N(R) ２ , -N(R)C(O)R, -N(R)C(O) ２ R, -N(R)S(O) ２ R, -OR, -OC(O)R, -OC(O)N(R) ２ , -SR, -S(O)R, -S(O) ２ R, -S(O)N(R) ２ , -S(O) ２ N (R) ２ , or C １－６ independently selected from optionally substituted groups selected from aliphatic, phenyl, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur, or 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 C １－６ is an aliphatic group; L' is a covalent bond or an optionally substituted C １－４ The hydrocarbon chain (1 to 3 methylene units are optionally and independently -O-, -C(O)-, -NR ｚ -, -S-, -SO-, -SO ２ -, -S(NH)(O)-, or cyclopropylene; Each R ｚ is hydrogen, -(CH ２ ) ０－３ OR, -(CH ２ ) ０－３ C(O)OR, or optionally substituted C １－６ independently selected from aliphatic groups; Cy Ｂ teeth, 【Chemistry 502】 (In the formula, R Ｂ１ and R Ｂ２ Each of is independently hydrogen or C １－６ an optionally substituted group selected from aliphatic or 3- to 7-membered saturated or partially unsaturated monocyclic carboxyl; R Ｂ３ is hydrogen or C １－６ is aliphatic; R Ｂ４ is -N(R ｘ ) ２ and Each R ｘ is hydrogen, -C(O)R, -C(O) ２ R, or optionally substituted C １－６ independently selected from aliphatic, R Ｂ１ or R Ｂ２ at most one of the groups is hydrogen) and Cy Ｂ teeth, 【Chemistry 503】 (In the formula, R Ｂ５ is hydrogen or C １－６ an aliphatic or optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic carboxyl; R Ｂ６ and R Ｂ７ Each of is independently hydrogen or an optionally substituted C １－６ aliphatic); L is an optionally substituted C １－３ The hydrocarbon chain (1 to 3 methylene units are optionally and independently —C(O)—, —O—, —NR ｚ -, -N(NO)- -S-, -SO-, -SO ２ -, optionally substituted cyclopropylene, or optionally substituted 5- to 6-membered saturated or partially unsaturated heterocyclene having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur; Cy Ｃ is selected from a 5- to 6-membered heteroaryl having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, phenyl, an 8- to 10-membered bicyclic aryl, a 7- to 10-membered heteroaryl having 1 to 4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, or a 6- to 12-membered saturated or partially unsaturated fused bicyclic heterocyclyl having 1 to 4 heteroatoms independently selected from oxygen, nitrogen, or sulfur; and Cy Ｃ is 0 to 6 -L Ｃ -R Ｃ substituted with a group; Each L Ｃ is a covalent bond or an optionally substituted C １－６ independently selected from hydrocarbon chains in which 1 to 3 methylene units are optionally and independently replaced with —C(O)—, —O—, or —NR—; Each R Ｃ is oxo, halogen, -CN, -C(O)R, -C(O) ２ R, -C(O)N(R) ２ , -NO ２ , -N(R) ２ , -N(R)C(O)R, -N(R)C(O) ２ R, -N(R)S(O) ２ R, -OR, -OC(O)R, -OC(O)N(R) ２ , -SR, -S(O)R, -S(O) ２ R, -S(O)N(R) ２ , -S(O) ２ N (R) ２ , or C １－６ and optionally substituted groups selected from aliphatic, phenyl, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, 5- or 6-membered heteroaryl having 1-3 heteroatoms selected from oxygen, nitrogen, or sulfur; 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur; 6- to 12-membered saturated or unsaturated bicyclic heterocyclyl having 1-3 heteroatoms selected from oxygen, nitrogen, or sulfur; 5- to 12-membered saturated or unsaturated bicyclic carbocyclyl; or 7- to 10-membered heteroaryl having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur.

2. The compound has the formula (II-a): 【Chemistry 504】 2. The compound of claim 1, wherein the compound is:

3. The compound has the formula (III-a), (III-b), (III-c), or (III-d): 【Chemistry 505】 3. The compound according to any one of claims 1 to 2, which is: or a pharmaceutically acceptable salt thereof.

4. The compound has the formula (III-a-1), (III-a-2), or (III-a-3): 【Chemistry 506】 3. The compound according to any one of claims 1 to 2, which is: or a pharmaceutically acceptable salt thereof.

5. The compound has the formula (III-b-1), (III-b-2), or (III-b-3): 【Chemistry 507】 4. The compound of claim 1, wherein the compound is:

6. The compound has the formula (IV), (IV-a), (IV-b), or (IV-c): 【Chemistry 508】 4. The compound of claim 1, wherein the compound is:

7. The compound has formula (V-a), (V-b), or (V-c): 【Chemistry 509】 7. The compound of any one of claims 1 to 6, which is: or a pharmaceutically acceptable salt thereof.

8. The compound has formula (VI-a), (VI-b), or (VI-c): 【Chemistry 510】 7. The compound of any one of claims 1 to 6, which is: or a pharmaceutically acceptable salt thereof.

9. The compound has formula (VII-a), (VII-b), or (VII-c): 【Chemistry 511】 7. The compound of any one of claims 1 to 6, which is: or a pharmaceutically acceptable salt thereof.

10. The compound has the formula (VIII-a), (VIII-b), or (VIII-c): 【Chemistry 512】 7. The compound of any one of claims 1 to 6, which is: or a pharmaceutically acceptable salt thereof.

11. The compound has formula (IX-a), (IX-b), or (IX-c): 【Chemistry 513】 7. The compound of any one of claims 1 to 6, which is: or a pharmaceutically acceptable salt thereof.

12. The compound has formula (X-a), (X-b), or (X-c): 【Chemistry 514】 7. The compound of any one of claims 1 to 6, which is: or a pharmaceutically acceptable salt thereof.

13. The compound has formula (XI-a), (XI-b), or (XI-c): 【Chemistry 515】 7. The compound of any one of claims 1 to 6, which is: or a pharmaceutically acceptable salt thereof.

14. The compound has formula (XII-a), (XII-b), or (XII-c): 【Chemistry 516】 7. The compound of any one of claims 1 to 6, which is: or a pharmaceutically acceptable salt thereof.

15. The compound has the formula (XIII-a), (XIII-b), or (XIII-c): 【Chemistry 517】 7. The compound of any one of claims 1 to 6, which is: or a pharmaceutically acceptable salt thereof.

16. The compound has the formula (XIV-a), (XIV-b), or (XIV-c): 【Chemistry 518】 7. The compound of any one of claims 1 to 6, which is: or a pharmaceutically acceptable salt thereof.

17. The compound has formula (XV-a), (XV-b), or (XV-c): 【Chemistry 519】 7. The compound of any one of claims 1 to 6, which is: or a pharmaceutically acceptable salt thereof.

18. The compound has the formula (XVI-a), (XVI-b), or (XVI-c): 【Chemistry 520】 7. The compound of any one of claims 1 to 6, which is: or a pharmaceutically acceptable salt thereof.

19. R Ｂ１ is hydrogen or C １－６ The compound of any one of claims 1 to 3, 5, or 7 to 18, which is aliphatic.

20. R Ｂ２ is hydrogen, methyl, ethyl, -CF ３ ,or 【Chemistry 521】 The compound according to any one of claims 1 to 4 or 7 to 19,

21. R Ｂ３ is hydrogen or methyl.

22. Each R ｘ The compound of any one of claims 1 to 6 or 19 to 20, wherein is hydrogen.

23. On the other hand, R ｘ is hydrogen, and the other is —C(O)R, —C(O) ２ R, or optionally substituted C １－６ 21. The compound according to any one of claims 1 to 6 or 19 to 20, selected from aliphatic.

24. Cy Ｂ teeth, 【Chemistry 522】 3. The compound of claim 1 or 2, selected from the group consisting of:

25. The compound has the formula (II-b): 【Chemistry 523】 2. The compound of claim 1, wherein the compound is:

26. R Ｂ５ is C １－６ 26. The compound of claim 1 or 25, which is an aliphatic or optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic carboxyl.

27. R Ｂ６ is an optionally substituted C １－６ 27. The compound of any one of claims 1 or 25-26, which is aliphatic.

28. R Ｂ７ is C １－６ 28. The compound of any one of claims 1 or 25-27, which is aliphatic.

29. Cy Ａ teeth, 【Chemical Formula 524】 【Chemistry 525】 29. The compound of any one of claims 1-6 or 10-28, selected from the group consisting of: wherein * represents the point of attachment to L'.

30. Each R Ａ is oxo, halogen, -C(O) ２ R, -OR, -C(O)N(R) ２ or optionally substituted C １－６ 30. The compound of any one of claims 1 to 29, independently selected from aliphatic.

31. L' is an optionally substituted C １－４ A hydrocarbon chain (1 to 3 methylene units are optionally and independently -O-, -C(O)-, -NR ｚ -, -S-, -SO-, -SO ２ 31. The compound of any one of claims 1 to 9 or 12 to 30, wherein the aryl group is -, -S(NH)(O)-, or cyclopropylene.

32. L' is 【Chemistry 526】 (Wherein, # represents Cy Ｂ 32. The compound of any one of claims 1 to 9 or 12 to 31, selected from the group consisting of:

33. L is an optionally substituted C １－３ A hydrocarbon chain (1 to 3 methylene units are optionally and independently -C(O)-, -O-, -NR ｚ -, or -S-).

34. L is, 【Chemical 527】 (wherein % is Cy Ｃ 33. The compound of any one of claims 1-11 or 14-32, selected from the group consisting of:

35. Cy Ｃ teeth, 【Chemistry 528】 35. The compound of any one of claims 1 to 13 or 19 to 34, selected from the group consisting of:

36. Cy Ｃ teeth, 【Chemical 529】 35. The compound of any one of claims 1 to 13 or 19 to 34, selected from the group consisting of:

37. Cy Ｃ teeth, 【Chemistry 530】 The compound according to any one of claims 1 to 13 or 19 to 34,

38. L Ｃ *-NH-, *-NCH ３ -, *-O-, *-CH ２ -, *-CH ２ C(CH ３ ) ２ -, *-CH ２ CH ２ -, *-CH ２ C(O)N(CH ３ )-, *-CH ２ C(O)N(CH ３ ) CH ２ -, *-CF ２ -, *-CH(CH ３ )-, *-OCH ２ -, *-OCF ２ -, *-OC(CH ３ ) ２ -, *-CH ２ C(O)-, *-OCH ２ C(O)-, *-CH ２ C(O)NH-, *-CH ２ C(O)NHCH ２ -, *-N (CH ３ )C(O)-, *-C(CH ２ CH ３ )-, *-C(CHCH ３ )-, *-C(FCH ３ ) - (where * represents Cy Ｃ 38. The compound of any one of claims 1 to 37, selected from the group consisting of:

39. Each R Ｃ is oxo, halogen, -CN, -C(O) ２ R, -C(O)N(R) ２ , or C １－６ 39. The compound of any one of claims 1 to 38, wherein the optionally substituted groups are independently selected from: aliphatic, phenyl, a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, a 5- or 6-membered heteroaryl having 1 to 3 heteroatoms selected from oxygen, nitrogen, or sulfur; a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 2 heteroatoms selected from oxygen, nitrogen, or sulfur; a 6- to 12-membered saturated or unsaturated bicyclic heterocyclyl having 1 to 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 to 4 heteroatoms independently selected from oxygen, nitrogen, and sulfur.

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

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

42. 10. A pharmaceutical composition comprising a compound according to any one of the preceding claims, further comprising a pharmaceutically acceptable excipient.

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

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

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

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