Imidazopyridinyl inhibitors of plasma kallikrein

Abstract

The present invention provides compounds and compositions thereof that are useful as inhibitors of plasma kallikrein and that exhibit desirable properties therefor.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No. 63 / 162,494, filed March 17, 2021, which is incorporated by reference herein in its entirety. [Background technology]

[0002] I. Background technology 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 cascade of blood coagulation. Mechanisms that lead to activation of this pathway in vivo include interaction with polyphosphates released from activated platelets and deficiency of C1-inhibitor (C1-INH), the major 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.

[0003] PKa is also associated with a number of disorders, including hereditary angioedema (HAE), an autosomal dominant disease characterized by painful, unpredictable, recurrent attacks of inflammation affecting the hands, limbs, 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 deficient (type I) or dysfunctional (type II) levels of C1-INH, which inhibits PKa, bradykinin, and other serine proteases in the blood. Individuals with hereditary angioedema (HAE) are deficient in C1-INH, resulting in the production of excess bradykinin, which in turn causes painful, debilitating, and potentially fatal attacks of swelling. Left untreated, HAE can result in a mortality rate as high as 40%, primarily due to upper airway obstruction. Summary of the Invention

[0004] 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 plasma kallikrein and effectively inhibit its activity.Therefore, compounds and their uses for targeting plasma kallikrein and / or treating plasma kallikrein-mediated diseases and disorders are provided herein, as well as novel intermediates and processes for preparing the compounds disclosed herein.The present disclosure also extends to pharmaceutical compositions comprising any one of them, and the use of the compounds or compositions herein for treatment, particularly for the treatment of autoimmune diseases, such as HAE.

[0005] In some embodiments, the present invention provides a compound of formula (I): [ka] or a pharma- ceutically acceptable salt thereof, A , Cy B , L, L', R 3 , R 4 , R 5 , R 6 , R 7 , and R 8each of which is defined and described in classes and subclasses herein, both alone and in combination. In certain embodiments, the invention provides compounds of formulae (I)-(VI-c), as defined and described in classes and subclasses herein.

[0006] In some embodiments, the present invention also provides methods of using the compounds of Formulae (I)-(VI-c).

[0007] Advantageously, the compounds of the present disclosure have therapeutic activity and a suitable level of bioavailability and / or suitable half-life for use as therapeutic agents. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0008] III. MODE FOR CARRYING OUT THE DISCLOSURE A.Definition Compounds of the invention include those generally described above, and are further exemplified by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise indicated. For purposes of the present 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 according to Ed. Also, the general principles of organic chemistry are described 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] Abbreviations used herein have their ordinary 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 term "aliphatic" or "aliphatic group," as used herein, means 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"), having 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, is not aromatic, and has a single point of attachment to the remainder 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 one or more of 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 heterocycle, e.g., N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR +(including N-substituted pyrrolidinyl).

[0012] As used herein, the term "unsaturated" 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., -(CH2) 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 group hydrogen atoms are 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 5-10 ring members, where at least one ring of the system is aromatic and each ring of the system has 3-7 ring members. The term "aryl" may be used interchangeably with the term "aryl ring." In some embodiments, the 8-10 membered bicyclic aryl group is an optionally substituted naphthyl ring. In certain embodiments of the invention, "aryl" refers to an aromatic ring system that may have one or more substituents, including, but not limited to, phenyl, biphenyl, naphthyl, anthracyl, and the like. As used herein, the term "aryl" also includes within its scope groups in which an aromatic ring is fused to one or more non-aromatic rings, such as, for example, indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl.

[0016] The terms "heteroaryl" and "heteroar-" refer to groups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms, having 6, 10, or 14 pi electrons shared in a cyclic arrangement, and having 1 to 5 heteroatoms in addition to the 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, benzothiazolyl, 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" may 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 "heterocycle" are used interchangeably and refer to a stable 5-7 membered monocyclic or 7-10 membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated and has, in addition to carbon atoms, one or more, preferably one to four, heteroatoms as defined above. In this context, the term "nitrogen" when used in reference to a ring atom includes substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 0-3 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 may be NR (as in N-substituted pyrrolidinyl).

[0018] The heterocycle may be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure, and any of the ring atoms may be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl. The terms "heterocyclyl," "heterocyclyl ring," "heterocyclic group," "heterocyclic moiety," and "heterocyclic radical" are used interchangeably herein and 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, where 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 moieties independently are optionally substituted.

[0019] As used herein, the term "partially unsaturated" refers to a ring moiety that contains 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 describe the divalent version of that moiety. For example, a divalent carbocycle is a "carbocyclylene", 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. In general, the term "substituted," whether preceded by the term "optionally," means that one or more hydrogens at the specified moiety are 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" groups). Unless otherwise specified, an "optionally substituted" group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituents may be the same or different at all positions. 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 substantially unchanged 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°;-(CH2) 0-4 Ph (optionally substituted with R°); -(CH2) 0-4 O(CH2) 0-1 Ph (optionally substituted with R°); -CH=CHPh (optionally substituted with R°); -(CH2) 0-4 O(CH2) 0-1 -pyridyl (optionally substituted by R°); -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;-(C 1-4 Linear or branched alkylene)ON(R°)2; or -(C 1-4 linear or branched alkylene)C(O)ON(R°), where each R° is optionally substituted as defined below and is independently 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 optionally substituted as defined below.

[0023] Suitable monovalent substituents on R° (or the ring formed by 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 S.R. ● , -(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 ● And each R ● is unsubstituted or, if preceded by "halo", is substituted with one or more halogens only; C 1-4Aliphatic, -CH2Ph, -O(CH2) 0-1 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 the following: =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-included, R * Each independent occurrence of is hydrogen, C which may be substituted as defined below 1-6 Aliphatic or unsubstituted 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Preferred divalent substituents attached to adjacent substitutable carbons of an "optionally substituted" group include -O(CR * 2) 2-3 Contains O- and R * Each independent occurrence of is hydrogen, C which may be substituted as defined below 1-6 It is selected from 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 groups include halogen, -R ● , -(Halo R ● ), -OH, -OR ● , -O(HaloR ● ), -CN, -C(O)OH, -C(O)OR ● , -NH2, -NHR ● , -NR● 2, or -NO2, 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)CH2C(O)R † , -S(O)2R † , -S(O)NR † 2. -C(S)NR † 2. -C(NH)NR † 2, or -N(R † )S(O)2R † Each R † are independently hydrogen, optionally substituted as defined below, 1-6 an aliphatic, unsubstituted -OPh, or an unsubstituted 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or, notwithstanding the above definitions, R † two independent occurrences of 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 groups are independently halogen, -R ● , -(Halo R ● ), -OH, -OR ● , -O(HaloR ● ), -CN, -C(O)OH, -C(O)OR● , -NH2, -NHR ● , -NR ● 2, or -NO2, where 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 "pharmaceutical acceptable salt" refers to a salt that is suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, etc., within the scope of sound medical judgment, and is commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S.M. Berge et al. describe pharmaceutical acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, which is 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, hi some embodiments, the parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents.

[0030] Unless otherwise stated, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Thus, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the compounds of the invention 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. In addition, 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, replacement of hydrogen by deuterium or tritium, or 13 C-enriched carbon or 14 Compounds having the structure of the present invention, including the replacement of carbon with C-enriched carbon, are within the scope of the present invention. Such compounds are useful, for example, as analytical tools in biological assays, as probes, or as therapeutic agents according to the present invention. In some embodiments, the compounds of the present disclosure are provided as single enantiomers or single diastereoisomers. Single enantiomers refer to an enantiomeric excess of 80% or more, for example, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99%. Single diastereomeric excess refers to an excess of 80% or more, for example, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99%.

[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 remainder of a 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 two or more) that are administered individually to a subject, typically spaced apart by a period of 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 is comprised of multiple doses, each spaced apart by the same length of time from each other, and in some embodiments, a dosing regimen is comprised of multiple doses, with at least two different periods separating the individual doses.

[0035] As will be understood from the context, a "reference" compound is one that is sufficiently similar to the particular compound of interest to allow for a relevant comparison. In some embodiments, the information about the reference compound is obtained at the same time as the information about the particular compound. In some embodiments, the information about the reference compound is historical. In some embodiments, the information about the reference compound is stored, for example, on a computer readable medium. In some embodiments, the comparison of the particular compound of interest to the reference compound establishes an identity, similarity, or difference between the particular compound of interest compared to 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 the 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 shows signs of or feels the effect). In particular, "therapeutically effective amount" refers to an amount of a therapeutic agent that is effective to treat, ameliorate, or prevent a desired disease or condition, or to exhibit a therapeutic or prophylactic effect that is detectable, for example, by improving symptoms associated with the disease, preventing or delaying the onset of the disease, and / or reducing the severity or frequency of symptoms of the disease. Therapeutically effective amounts are generally administered in a dosing regimen that may be composed of multiple unit doses. For any particular therapeutic agent, the therapeutically effective amount (and / or the appropriate unit dose within an effective dosing regimen) may vary depending, for example, on the route of administration, combination with other pharmaceutical agents. In addition, the therapeutically effective amount (and / or unit dose) specific to any particular subject may 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, 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 known in the medical arts.

[0038] As used herein, the term "treatment" (also "treat" or "treating") refers to any administration of a substance (e.g., a provided composition) that partially or completely relieves, ameliorates, alleviates, inhibits, delays the onset of, reduces the severity of, and / or reduces the incidence 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 symptoms of the relevant disease, disorder, and / or condition and / or of subjects who exhibit only early symptoms of the disease, disorder, and / or condition. Alternatively or additionally, such treatment may be of subjects who exhibit one or more established symptoms of the relevant disease, disorder, and / or condition. In some embodiments, treatment may be of subjects who have been diagnosed as suffering from the relevant disease, disorder, and / or condition. In some embodiments, treatment may be of subjects who are known to have one or more susceptibility factors that are statistically correlated with an increased risk of developing the relevant disease, disorder, and / or condition.

[0039] B. Compound In some embodiments, provided compounds have Formula I: [ka] or a pharma- ceutically acceptable salt thereof, Cy A is phenylene or a 5- to 6-membered monocyclic heteroarylene having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, or a 7- 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; 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, or 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur; Each R is independently hydrogen or an optionally substituted C 1-6 is an aliphatic group; Cy B is selected from phenyl, 8-10 membered bicyclic aryl, 5-6 membered heteroaryl having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, or 7-10 membered heteroaryl having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur; Cy B 0 to 5 -R B is substituted with a group; Each R B is oxo, halogen, haloalkyl, -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 a 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from aliphatic, oxygen, nitrogen, or sulfur, or a 5-6 membered heteroaryl having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur; L is an optionally substituted C 1-3 A hydrocarbon chain, wherein 1 to 3 methylene units are optionally and independently -O-, -NR zor L is an optionally substituted 5-6 membered saturated or partially unsaturated heterocyclene having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur; Each R z is hydrogen, -(CH2) 0-3 OR, -(CH2) 0-3 C(O)OR or any substituted C 1-6 independently selected from aliphatic groups; X is -O- or -NR y - and; R y is hydrogen or an optionally substituted C 1-6 is an aliphatic group; L' is a covalent bond or an optionally substituted C 1-3 is a hydrocarbon chain, and the carbon of L' is R y may optionally form a 3- to 7-membered heterocyclic ring; Each R 3 , R 4 , R 5 , R 6 , and R 7 is hydrogen or -L C -R C are independently selected from Each L C is a covalent bond or an optionally substituted C 1-6 one to three methylene units independently selected from the hydrocarbon chain are optionally and independently replaced with -O- or -NR-; Each R C means halogen, haloalkyl, -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, Cy C , or C 1-6 independently selected from optionally substituted groups selected from aliphatic; Each Cy Care independently selected from a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 2 heteroatoms independently selected from oxygen, nitrogen, or sulfur, a 5- to 6-membered monocyclic heteroaryl having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, a 6- to 12-membered saturated or partially unsaturated fused bicyclic heterocyclyl having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, or sulfur, a bridged bicyclic ring, or a 6- to 12-membered saturated or partially unsaturated bicyclic spiroheterocyclyl having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, or sulfur; C 0 to 4 -L D -R D is substituted with a group; Each L D is a covalent bond or an optionally substituted C 1-6 one to three methylene units independently selected from the hydrocarbon chain are optionally and independently replaced with -O- or -NR-; Each R D is oxo, halogen, haloalkyl, -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, or 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur; R 8 is hydrogen, -OR, or an optionally substituted C 1-6 aliphatic groups).

[0040] It is understood that "oxo" refers to an oxygen replacement of a double bond on a carbon, "C=O," that is part of a structure or group in which the carbon atom is replaced by oxo. For example, CyC Ga-L D -R D and L D is a covalent bond, and R D is oxo, the carbon atom substituted with oxo (i.e., the carbon at C=O) is C (e.g., -L at position 2) D -R D Cy is a cyclopentyl substituted with C The structure of (L D is a covalent bond, and R D is oxo) is [ka] Corresponds to.

[0041] In some embodiments, Cy A is phenylene, and Cy A 0 to 4 -R A In some embodiments, Cy is substituted with a A is phenylene, and Cy A 0 to 2 -R A is substituted with a group.

[0042] 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 is 0 to 4 R A is substituted with a group.

[0043] 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 is 0 to 4 R A In some embodiments, Cy is substituted with a A is a 6-membered monocyclic heteroarylene having 1 to 3 nitrogen heteroatoms; Cy A is 0 to 4 R AIn some embodiments, Cy is substituted with a A is 0 to 1 R A In some embodiments, Cy is a pyridinediyl substituted with a pyridine group. A is 0 to 1 R A In some embodiments, Cy is a pyrimidinediyl substituted with a pyrimidinediyl group. A is 0 to 1 R A In some embodiments, Cy is a pyridazinediyl substituted with a pyridazine group. A is 0 to 1 R A In some embodiments, Cy is a triazinediyl substituted with a cy group. A is unsubstituted pyridinediyl. In some embodiments, Cy A is unsubstituted pyrimidinediyl.

[0044] 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 is 0 to 2 R A In some embodiments, Cy is substituted with a A is unsubstituted thiadiazoldiyl. In some embodiments, Cy A is unsubstituted oxadiazoldiyl. In some embodiments, Cy A is an unsubstituted triazoldiyl.

[0045] In some embodiments, Cy A is a 7- to 12-membered bicyclic heteroarylene having 1 to 4 heteroatoms independently selected from oxygen, nitrogen, and sulfur; Cy A is 0 to 4 R A In some embodiments, Cy is substituted with a A is a 9-membered bicyclic heteroarylene having 3 to 4 heteroatoms independently selected from oxygen and nitrogen; Cy A is 0 to 1 R A In some embodiments, Cy is substituted with a Ais a 10-membered bicyclic heteroarylene having 3 to 4 heteroatoms independently selected from oxygen and nitrogen; Cy A is 0 to 1 R A In some embodiments, Cy is substituted with a A is 0 to 1 -R A In some embodiments, Cy is a triazolopyridinediyl substituted with a cyi group. A is 0 to 1 -R A In some embodiments, Cy is an imidazopyridinediyl substituted with a Cy group. A is 0 to 1 -R A The triazolopyrazinediyl is substituted with a group.

[0046] In some embodiments, Cy A teeth, [ka] where * represents the point of attachment to L.

[0047] In some embodiments, Cy A teeth, [ka] where * represents the point of attachment to L.

[0048] In some embodiments, Cy A teeth, [ka] where * represents the point of attachment to L.

[0049] In some embodiments, Cy A teeth, [ka] where * represents the point of attachment to L.

[0050] In some embodiments, each R A is oxo, halogen, -CN, -C(O)2R, -N(R)2, -OR, -SR, -S(O)R, -S(O)2R, or C 1-6 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.

[0051] 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 described in the classes and subclasses herein.

[0052] In some embodiments, R A A single example of R is oxo. A A single example of R is halogen. A A single example of is -CN. In some embodiments, R A A single example of is -C(O)R. In some embodiments, R A A single example of is -N(R). In some embodiments, R A A single example of R is -OR. A A single example of is -SR. In some embodiments, R A A single example of is -SR, where R is an optionally substituted C 1-6 In some embodiments, R A A single example of is -S(O)R. In some embodiments, R A A single example of is -S(O)R, where R is an optionally substituted C 1-6 In some embodiments, R AA single example of is -S(O)R. In some embodiments, R A A single example of is -S(O)R, where R is an optionally substituted C 1-6 It is aliphatic.

[0053] It is understood that references herein to embodiments in which a "single instance" of a substituent is defined are not limited to monosubstituted embodiments. For example, "in some embodiments, R A A single example of is oxo' A At least one instance of is oxo, and one or more additional R A

[0033] Embodiments are included that may include groups.

[0054] In some embodiments, R A A single example of is halogen-substituted C 1-6 In some embodiments, R A A single example of is -(CH2) 0-4 C replaced by OR° 1-6 aliphatic, R is hydrogen or C 1-6 In some embodiments, R A A single example of is -(CH2) 0-4 C substituted with N(R°)2 1-6 aliphatic, each R° is hydrogen or C 1-6 is independently selected from aliphatic.

[0055] In some embodiments, R A A single example of R is an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl. A A single example of is optionally substituted cyclopropyl.

[0056] In some embodiments, R A A single example of R is an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur. AA single example of R is an optionally substituted 3-7 membered saturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen and nitrogen. A A single example of R is optionally substituted oxetanyl. A A single example of is halogen or -(CH2) 0-4 In some embodiments, R is oxetanyl optionally substituted with OR°. A A single example of is pyrrolidinyl.

[0057] In some embodiments, Cy B is selected from 5- to 6-membered heteroaryl having 1 to 3 heteroatoms independently selected from phenyl, oxygen, nitrogen, and sulfur, or 7- to 10-membered heteroaryl having 1 to 4 heteroatoms independently selected from oxygen, nitrogen, and sulfur; Cy B 0 to 4 -R B is substituted with a group.

[0058] In some embodiments, Cy B is selected from phenyl and 5-6 membered heteroaryl having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur; Cy B 0 to 4 -R B is substituted with a group.

[0059] In some embodiments, Cy B is phenyl, and Cy B 0 to 4 -R B In some embodiments, Cy is substituted with a B is phenyl, and Cy B 0 to 3 -R B is substituted with a group.

[0060] In some embodiments, Cy B is a 6-membered heteroaryl having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur; Cy B 0 to 4 -R BIn some embodiments, Cy is substituted with a B is a 6-membered heteroaryl having 1 to 3 nitrogen atoms; Cy B 0 to 4 -R B In some embodiments, Cy is substituted with a B 0 to 2 -R B In some embodiments, Cy is a pyrimidinyl group substituted with a pyrimidinyl group. B 0 to 2 -R B In some embodiments, Cy is a pyridinyl group substituted with a pyridinyl group. B is 0 to 1 -R B In some embodiments, Cy is a pyrazinyl group substituted with a pyrazinyl group. B is 0 to 1 -R B In some embodiments, Cy is a pyridazinyl group substituted with a pyridazinyl group. B is 0 to 1 -R B The aryl group is a 1,3,5-triazinyl group substituted with a aryl group.

[0061] In some embodiments, Cy B is a 5-membered heteroaryl having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur; Cy B 0 to 4 -R B In some embodiments, Cy is substituted with a B is a 5-membered heteroaryl having 1 to 2 heteroatoms independently selected from sulfur and nitrogen; Cy B 0 to 4 -R B In some embodiments, Cy is substituted with a B 0 to 2 -R B In some embodiments, Cy is a thienyl group substituted with a thienyl group. B is 0 to 1 -R B In some embodiments, Cy is a thiazolyl group substituted with a thiazolyl group. B is 0 to 1 -R B A thiadiazolyl group substituted with a group.

[0062] In some embodiments, Cy B teeth, [ka] is selected from the group consisting of:

[0063] In some embodiments, Cy B teeth, [ka] is selected from the group consisting of:

[0064] In some embodiments, Cy B teeth, [ka] is selected from the group consisting of:

[0065] In some embodiments, each R B is oxo, halogen, -CN, -NO2, -N(R)2, -N(R)C(O)2R, -OR, or C 1-6 In some embodiments, each R is independently selected from an optionally substituted group selected from aliphatic or 5-membered heteroaryl having 1 to 4 heteroatoms independently selected from oxygen, nitrogen, and sulfur. B is independently selected from halogen, -OR, or an optionally substituted 5-membered heteroaryl having 1 to 4 heteroatoms independently selected from oxygen, nitrogen, and sulfur.

[0066] In some embodiments, optionally substituted R B Substituents on the group include oxo, halogen, and -(CH2) 0-4 is independently selected from OR°, where R° is defined above and as described in classes and subclasses herein.

[0067] In some embodiments, R B A single example of R is oxo. B A single example of R is halogen.B A single example of R is fluorine. B A single example of R is chlorine. B A single example of is -CN. In some embodiments, R B A single example of is -NO2. In some embodiments, R B A single example of is -N(R). In some embodiments, R B A single example of is -N(R)C(O)R. In some embodiments, R B A single example of R is -OR. B A single example of is -OMe.

[0068] In some embodiments, R B A single example of is the arbitrarily substituted C 1-6 In some embodiments, R B A single example of is halogen-substituted C 1-6 It is aliphatic.

[0069] In some embodiments, R B A single example of is -N(R)C(O)R, where each R is hydrogen or -(CH) 0-4 C optionally substituted with R° 1-6 is independently selected from aliphatic.

[0070] In some embodiments, R B A single example of is -OR, where each R is hydrogen or halogen, -(CH2) 0-4 OR°, or (CH2) 0-4 C optionally substituted with C(O)OR° 1-6 is independently selected from aliphatic.

[0071] In some embodiments, R B A single example of R is a 5-membered heteroaryl having 1 to 4 heteroatoms independently selected from oxygen, nitrogen, and sulfur. B A single example of is tetrazolyl.

[0072] In some embodiments, L is optionally substituted C 1-3 A hydrocarbon chain with 1 to 3 methylene units, -O-, -NR z In some embodiments, L is optionally substituted with -, -S-, or -SO2-. 1-3 A hydrocarbon chain in which one methylene unit is -O- or -NR z - has been optionally replaced.

[0073] In some embodiments, L is an optionally substituted C1 hydrocarbon chain.

[0074] In some embodiments, L is an optionally substituted C1 hydrocarbon chain, in which one methylene unit is -(CH2) 0-4 It is replaced by a 5-membered saturated or partially unsaturated heterocyclene having one nitrogen heteroatom, optionally substituted with OR°, where R° is as defined above and described in the classes and subclasses herein.

[0075] In some embodiments, L is -CH-. In some embodiments, L is optionally substituted [ka] (In the formula, * represents Cy A In some embodiments, L is an optionally substituted [ka] (In the formula, * represents Cy A In some embodiments, L is an optionally substituted [ka] (In the formula, * represents Cy A In some embodiments, L is [ka] (In the formula, * represents Cy A In some embodiments, L is [ka] (In the formula, * represents Cy A In some embodiments, L is [ka] (In the formula, * represents Cy A represents the attachment point to

[0076] In some embodiments, L is an optionally substituted C2 hydrocarbon chain in which one methylene unit is -NR z In some embodiments, L is an optionally substituted C2 hydrocarbon chain and Cy is optionally substituted with - or -O-. A The methylene unit connected to is -NR z In some embodiments, L is an optionally substituted C2 hydrocarbon chain and Cy is replaced with -O-. A The methylene unit connected to is -NR z In some embodiments, L is an optionally substituted C2 hydrocarbon chain and Cy is replaced with -. A is replaced with -O-. In some embodiments, L is *-NHCH(Me)-, where * is Cy A In some embodiments, L is [ka] (In the formula, * represents Cy A In some embodiments, L is [ka] (In the formula, * represents Cy AIn some embodiments, L is *-NHCH2-, where * represents the point of attachment to Cy. A In some embodiments, L is *-N(CH3)CH2-, where * represents the point of attachment to Cy. A In some embodiments, L is [ka] (In the formula, * represents Cy A In some embodiments, L is [ka] (In the formula, * represents Cy A In some embodiments, L is *-OCH(Me)-, where * represents the point of attachment to Cy. A In some embodiments, L is *-OCH2-, where * represents the point of attachment to Cy A In some embodiments, L is a Cy A and [ka] A two-atom spacer is included between the

[0077] In some embodiments, L is an optionally substituted 5-6 membered saturated or partially unsaturated heterocyclene having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, L is an optionally substituted 5 membered saturated or partially unsaturated heterocyclene having one heteroatom independently selected from oxygen, nitrogen, and sulfur. In some embodiments, L is an optionally substituted pyrrolidinediyl group.

[0078] In some embodiments, the optional substituents on L are -(CH2) 0-4 R°, -(CH2) 0-4 OR°, -(CH2) 0-4 OC(O)R° and -(CH2) 0-4N(R°)2, where each R° is independently as defined above and described in the classes and subclasses herein.

[0079] In some embodiments, X is -O-. In some embodiments, X is -NR y -It is.

[0080] In some embodiments, R y is hydrogen. In some embodiments, R y is an arbitrarily substituted C 1-6 It is an aliphatic group.

[0081] In some embodiments, L' is a covalent bond. In some embodiments, L' is an optionally substituted C 1-3 In some embodiments, L' is -CH2-. In some embodiments, L' is -CH(CH3)-. In some embodiments, L' is [ka] (In the formula, * represents Cy B In some embodiments, L' is [ka] (In the formula, * represents Cy B In some embodiments, L' is -(CH2) 0-4 R° or -(CH2) 0-4 A methylene unit optionally substituted with OR°, where R° is independently as defined above and as described in the classes and subclasses herein. In some embodiments, R° is hydrogen or C 1-6 It is aliphatic.

[0082] In certain embodiments, the carbon of L′ is optionally selected from R z and together with R may form a 3- to 7-membered heterocyclic ring. In certain embodiments, a carbon of L' may optionally be joined with Ry may be taken together with to form a four-membered heterocyclic ring.

[0083] In some embodiments, R 3 , R 4 , R 5 , R 6 , and R 7 Each of C -R C Each L C is a covalent bond or an optionally substituted C 1-6 wherein 1 to 3 methylene units are independently selected from the hydrocarbon chain and are optionally and independently replaced with -O- or -NR-; C are halogen, -CN, -C(O)R, -C(O)2R, -C(O)N(R)2, -N(R)2, -N(R)C(O)R, -N(R)C(O)2R, -N(R)S(O)2R, -S(O)2R, -S(O)2N(R)2, Cy C or an optionally substituted group selected from C1-6 aliphatic.

[0084] In some embodiments, R 3 is hydrogen or L C -R C Selected from L C is a covalent bond, and R C is halogen. In some embodiments, R 3 is hydrogen.

[0085] In some embodiments, R 4 is hydrogen or L C -R C Selected from L C is a covalent bond or an optionally substituted C 1-6 a hydrocarbon chain, in which 1 to 3 methylene units are optionally and independently replaced by -O- or -NR-; R C are halogen, -CN, -C(O)R, -C(O)2R, -C(O)N(R)2, -N(R)2, -N(R)C(O)R, -N(R)C(O)2R, -N(R)S(O)2R, -OR, -S(O)2R, -S(O)2N(R)2, CyC or an optionally substituted group selected from C1-6 aliphatic.

[0086] In some embodiments, R 4 is hydrogen or L C -R C Selected from L C is a covalent bond, and R C are halogen, -CN, -C(O)R, -C(O)2R, -C(O)N(R)2, -N(R)2, -N(R)C(O)R, -N(R)C(O)2R, -N(R)S(O)2R, -OR, -S(O)2R, -S(O)2N(R)2, Cy C , or C 1-6 In some embodiments, R 4 is hydrogen.

[0087] In some embodiments, R 4 teeth, [ka] is selected from the group consisting of:

[0088] R 4 In some embodiments of the present invention, 1-6 Optional substituents on an aliphatic group are -(CH2) 0-4 R°, -(CH2) 0-4 OR°, -CN, -(CH2) 0-4 N(R°)2 and -(CH2) 0-4 C(O)OR°, where each R° is independently as defined above and described in classes and subclasses herein.

[0089] R 4 In some embodiments, Cy Cis selected from a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 2 heteroatoms independently selected from oxygen, nitrogen, or sulfur, a 5- to 6-membered monocyclic heteroaryl having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, a 6- to 12-membered saturated or partially unsaturated fused bicyclic heterocyclyl having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, or sulfur, a bridged bicyclic ring, or a 6- to 12-membered saturated or partially unsaturated bicyclic spiroheterocyclyl having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, or sulfur; C 0 to 4 -L D -R D It is substituted with the R group. 4 In some embodiments, Cy C is a 5-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 2 heteroatoms selected from oxygen, nitrogen, or sulfur.

[0090] R 4 In some embodiments, Cy C teeth, [ka] is selected from the group consisting of:

[0091] R 4 In some embodiments of the present invention, R D is oxo, halogen, -C(O)2R, -N(R)2, -OR, or C 1-6 It is selected from optionally substituted groups selected from aliphatic, phenyl, 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.

[0092] R 4 R D In some embodiments of the group, R D The optional substituents on the above are halogen, -(CH2) 0-4 R°, -(CH2) 0-4 OR°, -(CH2)0-4 N(R°)2, -(CH2) 0-4 and -O(O)(OR°)2, where each R° is independently as defined above and as described in classes and subclasses herein.

[0093] R 4 In some embodiments of the present invention, L D is a covalent bond.

[0094] In some embodiments, R 5 is hydrogen.

[0095] In some embodiments, R 5 L C -R C And L C is a covalent bond, and R C Cy C In some embodiments, Cy C is a cyclopropyl group.

[0096] In some embodiments, R 6 is hydrogen or L C -R C Selected from L C is a covalent bond, and R C is halogen, -N(R)2, -OR, Cy C , or any substituted C 1-6 In some embodiments, R 6 is hydrogen.

[0097] R 6 In some embodiments, Cy C 0 to 4 L D -R D R is a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl substituted with a group. 6 In some embodiments, Cy C 0 to 4 L D -R D In some embodiments, L is a cyclopropyl group substituted with a cyclopropyl group.D is a covalent bond, and R D is halogen and optionally substituted C 1-6 aliphatic. R 6 In some embodiments, Cy C is an unsubstituted cyclopropyl group.

[0098] In some embodiments, R 7 is hydrogen or L C -R C Selected from L C is a covalent bond, and R C Cy C It is.

[0099] In some embodiments, R 7 is hydrogen.

[0100] R 7 In some embodiments, Cy C teeth, [ka] It is.

[0101] In some embodiments, R 8 is hydrogen.

[0102] In some embodiments, R 8 is -OR or an optionally substituted C 1-6 The alkyl group is selected from aliphatic groups.

[0103] In some embodiments, provided compounds have formula II-a or II-b: [ka] or a pharma- ceutically acceptable salt thereof, A , Cy B , L, L', R y , R 3 , R 4 , R 5 , R 6 , and R 7Each of the following is defined and described herein in classes and subclasses, both alone and in combination:

[0104] Unless otherwise specified or prohibited by the preceding definitions of formula II-a or II-b, the variables Cy, as defined above and described in the classes and subclasses herein, A , Cy B , L, L', R y , R 3 , R 4 , R 5 , R 6 , and R 7 It is understood that this embodiment also applies to compounds of formula II-a or II-b, both alone and in combination.

[0105] In some embodiments, provided compounds have formula III-a-1, III-b-1, III-a-2, III-b-2, III-a-3, or III-b-3: [ka] or a pharma- ceutically acceptable salt thereof, A , R B , L, L', R y , R 3 , R 4 , R 5 , R 6 , and R 7 Each of the following is defined and described herein in classes and subclasses, both alone and in combination:

[0106] Unless otherwise specified or prohibited by the preceding definitions of formula III-a-1, III-b-1, III-a-2, III-b-2, III-a-3, or III-b-3, the variables Cy, as defined above and described in the classes and subclasses herein, A , Cy B , L, L', R y , R 3 , R 4 , R 5 , R 6 , and R7 It is understood that this embodiment also applies to compounds of formula III-a-1, III-b-1, III-a-2, III-b-2, III-a-3, or III-b-3, both alone and in combination.

[0107] In some embodiments, provided compounds have formula IV-a-1, IV-b-1, IV-a-2, or IV-b-2 [ka] or a pharma- ceutically acceptable salt thereof, A , Cy B , L, L', R y , R 3 , R 4 , R 5 , R 6 , and R 7 Each of the following is defined and described herein in classes and subclasses, both alone and in combination:

[0108] Unless otherwise specified or prohibited by the preceding definitions of formula IV-a-1, IV-b-1, IV-a-2, or IV-b-2, the variable R is defined above and described in classes and subclasses herein. A , Cy B , L, L', R y , R 3 , R 4 , R 5 , R 6 , and R 7 It is understood that this embodiment also applies to compounds of formula IV-a-1, IV-b-1, IV-a-2, or IV-b-2, both alone and in combination.

[0109] In some embodiments, provided compounds have formula V: [ka] or a pharma- ceutically acceptable salt thereof, A , Cy B , L, R 3 , R4 , R 5 , R 6 , and R 7 Each of the following is defined and described herein in classes and subclasses, both alone and in combination:

[0110] Unless otherwise specified or prohibited by the preceding definition of Formula V, the variables Cy, as defined above and described in the classes and subclasses herein, A , Cy B , L, R 3 , R 4 , R 5 , R 6 , and R 7 It is understood that this embodiment also applies to compounds of formula V, both alone and in combination.

[0111] In some embodiments, provided compounds have formula VI-a, VI-b, or VI-c: [ka] or a pharma- ceutically acceptable salt thereof, A , Cy B ,X,L',R°,R z , R 3 , R 4 , R 5 , R 6 , and R 7 Each of the following is defined and described herein in classes and subclasses, both alone and in combination:

[0112] Unless otherwise specified or prohibited by the preceding definitions of Formula VI-a, VI-b, or VI-c, the variables Cy, as defined above and described in the classes and subclasses herein, A , Cy B ,X,L',R°,R 3 , R 4 , R 5 , R 6 , and R 7It is understood that this embodiment also applies to compounds of formula VI-a, VI-b, or VI-c, both alone and in combination.

[0113] In certain embodiments, provided compounds are 3-Chlorobenzyl(6-(((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)amino)pyrimidin-4-yl)carbamate (I-1); (R)-1-(3-chlorophenyl)ethyl(6-(((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)amino)pyrimidin-4-yl)carbamate (I-2); (S)-1-(3-chlorophenyl)ethyl(6-(((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)amino)pyrimidin-4-yl)carbamate (I-3); 3-Methoxybenzyl(6-(((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)amino)pyrimidin-4-yl)carbamate (I-4); 1-(3-chlorobenzyl)-3-(6-(((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)amino)pyrimidin-4-yl)-1-methylurea (I-5); 1-(3-chlorophenyl)propyl(6-(((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)amino)pyrimidin-4-yl)carbamate (I-6); 1-(3-chloro-2-fluorophenyl)ethyl(6-(((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)amino)pyrimidin-4-yl)carbamate (I-7); 5-Chloro-2-(1H-tetrazol-1-yl)benzyl (6-(((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)amino)pyrimidin-4-yl)carbamate (I-8); 2-(3-chlorophenyl)-2-hydroxyethyl(6-(((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)amino)pyrimidin-4-yl)carbamate (I-9); 1-(5-chloro-2-(1H-tetrazol-1-yl)benzyl)-3-(4-(((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)amino)pyridin-2-yl)urea (I-10); 5-Chloro-2-(1H-tetrazol-1-yl)benzyl(4-(((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)amino)pyridin-2-yl)carbamate (I-11); 5-Chloro-2-(1H-tetrazol-1-yl)benzyl (4-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methoxy)pyridin-2-yl)carbamate (I-12); 3-Chlorobenzyl(4-(((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)amino)pyridin-2-yl)carbamate (I-13); 3-Chlorobenzyl(3-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-[1,2,4]triazolo[4,3-a]pyrazin-6-yl)carbamate (I-14); 1-(3-chlorophenyl)ethyl(4-(((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)amino)pyridin-2-yl)carbamate (I-15); 3-Chlorobenzyl(1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-imidazo[4,5-c]pyridin-6-yl)carbamate (I-16); 1-(3-chlorophenyl)ethyl(1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-imidazo[4,5-c]pyridin-6-yl)carbamate (I-17); 3-Chlorobenzyl(1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazolo[4,3-c]pyridin-4-yl)carbamate (I-18); 3-Chlorobenzyl(2-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazolo[4,3-c]pyridin-4-yl)carbamate (I-19); 3-Chlorobenzyl(1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)carbamate (I-20); 1-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)ethyl(4-(((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)amino)pyridin-2-yl)carbamate (I-21); 5-Chloro-2-(1H-tetrazol-1-yl)benzyl(2-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)carbamate (I-22); 5-Chloro-2-(1H-tetrazol-1-yl)benzyl(1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-imidazo[4,5-c]pyridin-6-yl)carbamate (I-23); 1-(3-chlorobenzyl)-3-(6-(((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)amino)pyrimidin-4-yl)urea (I-24); 3-(3-chlorophenyl)-N-(6-(((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)amino)pyrimidin-4-yl)azetidine-1-carboxamide (I-25); (4-chloropyridin-2-yl)methyl(6-(((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)amino)pyrimidin-4-yl)carbamate (I-26); 1-((4-chloropyridin-2-yl)methyl)-3-(6-(((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)amino)pyrimidin-4-yl)urea (I-27); (4-chloropyridin-2-yl)methyl(6-((2R,4S)-2-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)-4-hydroxypyrrolidin-1-yl)pyrimidin-4-yl)carbamate (I-28); 1-((4-chloropyrimidin-2-yl)methyl)-3-(6-(((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)amino)pyrimidin-4-yl)urea (I-29); 1-(6-(((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)amino)pyrimidin-4-yl)-3-((4-methoxypyrimidin-2-yl)methyl)urea (I-30); N-(6-((2R,4S)-2-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)-4-hydroxypyrrolidin-1-yl)pyrimidin-4-yl)-3-phenylazetidine-1-carboxamide (I-31); 1-(4-chlorobicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)-3-(6-(((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)amino)pyrimidin-4-yl)urea (I-32); N-(6-((2R,4S)-2-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)-4-hydroxypyrrolidin-1-yl)pyrimidin-4-yl)-3-(pyrimidin-2-yl)azetidine-1-carboxamide (I-33); and (4-Methylpyrimidin-2-yl)methyl(6-(((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)amino)pyrimidin-4-yl)carbamate (I-34); or a pharma- ceutically acceptable salt thereof.

[0114] Compounds explicitly disclosed herein may be claimed as individual compounds, including where no reference to stereochemistry is made.

[0115] C. Pharmaceutical Compositions In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the disclosure, including Formulas (I)-(VI-c), or a compound of Formulas (I)-(VI-c) or an exemplified compound, in combination with a pharma- ceutically acceptable excipient (e.g., a carrier).

[0116] The pharmaceutical composition comprises an optical isomer, diastereomer, or pharma- ceutically acceptable salt of the inhibitor disclosed herein. The compound of formula (I)-(VI-c) contained in the pharmaceutical composition may be covalently bound to a carrier moiety as described above. Alternatively, the compound of formula (I)-(VI-c) contained in the pharmaceutical composition is not covalently bound to a carrier moiety.

[0117] As used herein, "pharmaceutical acceptable carrier" refers to a pharmaceutical excipient, e.g., a pharmaceutically, physiologically acceptable organic or inorganic carrier substance suitable for enteral or parenteral application that does not adversely react with the active agent. Suitable pharmaceutically acceptable carriers include water, salt solutions (e.g., Ringer's solution), alcohol, oils, gelatin, and carbohydrates such as lactose, amylose, or starch, fatty acid esters, hydroxymethylcellulose, and polyvinylpyrrolidine. Such preparations may be sterilized and, if necessary, may be mixed with auxiliary agents, e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring agents, and / or flavoring agents that do not adversely react with the compounds of the present invention.

[0118] The compounds of the present invention can be administered to a subject alone or simultaneously. Simultaneous administration is intended to include simultaneous or sequential administration of the compounds individually or in combination (two or more compounds).The preparation can also be combined with other agents as needed (e.g., to reduce metabolic degradation).

[0119] 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 compounds provided.

[0120] 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., intravenously, intramuscularly, intradermally, subcutaneously, intraduodenally, or intraperitoneally). In some embodiments, the compounds of the present disclosure are administered orally. The compounds described herein can also be administered by inhalation, for example, intranasally. In addition, the compounds of the present invention can be administered transdermally. It is also envisioned that multiple routes of administration (e.g., intramuscularly, orally, transdermally) can be used to administer the compounds of the present invention. Thus, the present invention also provides pharmaceutical compositions comprising a pharma- ceutically acceptable carrier or excipient and one or more compounds of the present invention.

[0121] For preparing pharmaceutical compositions from the compounds of the present invention, pharma-ceutically acceptable carriers can be solid or liquid.Solid preparations include powder, tablets, pills, capsules, cachets, suppositories, and dispersible granules.Solid carriers can be one or more substances that can also function as diluents, flavorings, binders, preservatives, tablet disintegrating agents or encapsulating materials.

[0122] 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 the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.

[0123] 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 wax, cocoa butter, and the like. The term "preparation" is intended to include a blend of the active compound with an encapsulating material as a carrier, where the active ingredient is surrounded by a carrier, with or without other carriers, thereby providing a capsule in which the carrier is associated with the active ingredient. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.

[0124] 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 solidify.

[0125] Liquid 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.

[0126] When parenteral application is required or desired, the particularly suitable mixture for the compound of the present invention is an injectable sterile solution, preferably an oily or aqueous solution, as well as a suspension, an emulsion, or an implant, including a suppository.In particular, carriers for parenteral administration include an aqueous solution of dextrose, saline, pure water, ethanol, glycerol, propylene glycol, peanut oil, sesame oil, polyoxyethylene block polymer, and the like.Ampoules are convenient unit doses.The compound of the present invention can also be incorporated into liposomes or administered via a transdermal pump or patch.The pharmaceutical mixtures suitable for use in the present invention include, for example, 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.

[0127] Aqueous solutions suitable for oral use can be prepared by dissolving the active ingredient in water and adding suitable colorants, flavors, stabilizers, and thickeners, if desired. Aqueous suspensions suitable for oral use can be made by dispersing finely divided active ingredients in water with viscous materials, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well-known suspending agents.

[0128] Also included are solid form preparations that are intended to be converted immediately 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.

[0129] Pharmaceutical preparations are preferably in unit dosage form.In such form, the preparation is divided into unit doses containing appropriate amounts of active ingredient.The unit dosage form can be a packaged preparation, the package containing discrete amounts of the preparation, for example, packaged tablets, capsules, and powders in vials or ampoules.Or, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in package form.

[0130] 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.

[0131] Some compounds may have limited solubility in water and therefore may require a surfactant or other suitable co-solvent in the composition. Such co-solvents include: polysorbate 20, 60, and 80; Pluronic F-68, F-84, and P-103; cyclodextrin; and polyoxyl 35 castor oil. Such co-solvents are typically used at levels between about 0.01% and about 2% by weight.

[0132] A viscosity greater than that of a simple aqueous solution may be desirable to reduce variability in dispensing the formulation, to reduce physical separation of the suspension or emulsion components of the formulation, and / or to otherwise improve the formulation. Such viscosity enhancing agents include, for example, polyvinyl alcohol, polyvinylpyrrolidone, methylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, carboxymethylcellulose, hydroxypropylcellulose, chondroitin sulfate and its salts, hyaluronic acid and its salts, and combinations of the foregoing. Such agents are typically used at levels between about 0.01% and about 2% by weight.

[0133] The compositions of the present invention may additionally comprise components that provide sustained release and / or comfort. Such components include high molecular weight anionic mucus-mimetic polymers, gelling polysaccharides, and micronized drug carrier substrates. These components are described in more detail in U.S. Patent Nos. 4,911,920; 5,403,841; 5,212,162; and 4,861,760. The entire contents of these patents are incorporated herein by reference in their entirety for all purposes.

[0134] E. Effective Dosage The pharmaceutical compositions provided by the present invention include compositions in which active ingredients are contained in a therapeutically effective amount, i.e., in an amount effective to achieve the intended purpose.The actual amount effective for a particular application depends, inter alia, on the pathology to be treated.For example, when administered in a method for treating HAE, such compositions contain an amount of active ingredients effective to achieve the desired result (e.g., inhibit PKa and / or reduce the amount of bradykinin in a subject).

[0135] The dosage and frequency of the administered compound (single or multiple doses) may 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 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 may be used in conjunction with the methods and compounds of the present invention.

[0136] For any provided compound or test agent, the therapeutically effective amount can be initially determined by cell culture assays. The target concentration is the concentration of active compound(s) capable of reducing PKa enzyme activity, for example, as measured using the methods described.

[0137] The therapeutically effective amount used in humans can be determined from animal models.For example, the dose for humans can be formulated to achieve the concentration that is known to be effective in animals.The dosage in humans can be adjusted by monitoring PKa inhibition and adjusting the dosage upward or downward as described above.

[0138] Dosage may vary depending on the patient's needs and the compound being used. In the context of the present invention, the dose administered to a patient should be sufficient to effect a beneficial therapeutic response in the patient over time. The size of the dose is also determined by the existence, nature, and extent of any adverse side effects. In some embodiments, the compound of the present disclosure or a pharmaceutical composition comprising the same is provided as a unit dose.

[0139] In one aspect, 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.

[0140] F. Treatment Method The present disclosure provides compounds and pharmaceutical compositions comprising the same for use in medicine, i.e., for use in treatment. The present disclosure further provides the use of any of the compounds described herein to inhibit the activity of PKa, which would be beneficial in the treatment of PKa-mediated diseases and conditions. Exemplary PKa-mediated disorders include edema, which refers to swelling in the subject's body or in a portion 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 (e.g., diabetic macular edema (DME)). The present disclosure provides methods of inhibiting the activity of PKa. In certain embodiments, the application provides methods of 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 application provides methods of 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.

[0141] In certain embodiments, the method comprises administering to a subject in need thereof (e.g., a subject having edema, e.g., a human patient) any of the compounds described herein, or a pharma- ceutically acceptable salt thereof. In certain embodiments, the method comprises administering to a subject in need thereof a compound of Formula (I)-(VI-c), or a pharma- ceutically acceptable salt or composition thereof. In some embodiments, the method comprises administering to a subject in need thereof a pharmaceutical composition comprising a compound of Formula (I)-(VI-c), or a pharma- ceutically acceptable salt thereof.

[0142] In some embodiments, the subject treated by any of the methods described herein is a human patient who has, suspects, or is at risk of having edema, such as HAE or diabetic macular edema (DME).Subjects with edema can be identified by routine medical examination, such as clinical examination.Subjects suspected of having edema can show one or more symptoms of disease / disorder.Subjects at risk of edema can have one or more of the risk factors associated with disease, such as C1-INH deficiency for HAE.

[0143] In certain embodiments, provided herein is a method for alleviating one or more symptoms of HAE in a human patient suffering from an HAE attack. Such a patient can be identified by routine medical procedures. An effective amount of one or more of the provided compounds can be administered to a human patient by 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®).

[0144] In another embodiment, a method is provided herein for reducing the risk of HAE attacks in human HAE patients in remission. 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 of the present invention can be administered to a human patient by 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®).

[0145] In some embodiments, provided herein is a preventive treatment of HAE in a human patient at risk for an HAE attack using one or more of the compounds described herein. In some embodiments, a patient suitable for preventive treatment of HAE is a human subject suffering from HAE (e.g., having a history of HAE attacks). In some embodiments, a patient suitable for such preventive treatment is a human subject whose HAE attack history is determined by a physician to require a preventive approach (e.g., a human subject experiencing more than a certain average number of attacks over a given period of time, including, as non-limiting examples, 1, 2, or more attacks per month). Alternatively, a patient suitable for preventive treatment may be a human subject who does not have a history of HAE attacks, but has one or more risk factors for HAE (e.g., family history, genetic defects in the C1-INH gene, etc.). Such preventive treatment may require a compound described herein as the only active agent, or may require an additional anti-HAE agent, such as those described herein.

[0146] In certain embodiments, provided herein is a method 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 patient who has, is suspected of having, or is at risk of having diabetic macular edema (DME). DME is a proliferative form of diabetic retinopathy characterized by swelling of the retinal layer, neovascularization, vascular leakage, and retinal thickening in diabetes due to leakage of fluid from blood vessels in the macula. To carry out this method, an effective amount of one or more of the compounds described herein or a pharma- ceutically 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 injection or intravitreal injection. The subject can be treated with the compounds 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, agents that target the VEGF pathway (e.g., Lucentis® (ranibizumab) or Eylea® (aflibercept)), and / or anti-PDGF agents.

[0147] In certain embodiments, the methods disclosed herein include administering to a subject an effective amount of a compound of Formula (I)-(VI-c), or a pharma- ceutically 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.

[0148] In certain embodiments, the subject being treated is an animal. The animal may be of either sex and at any stage of development. In certain embodiments, the subject is a mammal. In certain embodiments, the subject being treated is a human. In certain embodiments, the subject is a domesticated animal, e.g., a dog, cat, cow, pig, horse, sheep, or goat. In certain embodiments, the subject is a companion animal, e.g., a dog or cat. In certain embodiments, the subject is a livestock animal, e.g., a cow, pig, horse, sheep, or goat. In certain embodiments, the subject is a zoo animal. In another embodiment, the subject is a research animal, e.g., a rodent (e.g., mouse, rat), dog, pig, or non-human primate. In certain embodiments, the animal is a genetically engineered animal. In certain embodiments, the animal is a transgenic animal.

[0149] Certain methods described herein may include administering one or more additional pharmaceutical agent(s) in combination with the compounds described herein. The additional pharmaceutical agent(s) may be administered simultaneously with the compound of formula (I)-(VI-c) or at different times from the compound of formula (I)-(VI-c). For example, the compound of formula (I)-(VI-c) and any additional pharmaceutical agent(s) may be on the same administration schedule or different administration schedules. All or a portion of the dose of the compound of formula (I)-(VI-c) may be administered before administration of all or a portion of the additional pharmaceutical agent, after administration of all or a portion of the additional pharmaceutical agent, or a combination thereof, within the administration schedule of the additional pharmaceutical agent. The timing of administration of the compound of formula (I)-(VI-c) and the additional pharmaceutical agent may be different for different additional pharmaceutical agents.

[0150] 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.

[0151] Also provided is the use of a compound of the present disclosure for the manufacture of a medicament for the conditions / diseases disclosed herein.

[0152] In the context of this specification, "comprising" should be interpreted as "including". Embodiments of the invention comprising certain features / elements are also intended to extend to alternative embodiments "consisting of" or "consisting essentially of" the associated element / feature. Where technically appropriate, embodiments of the invention may be combined.

[0153] Technical references, such as patents and applications, are incorporated herein by reference.

[0154] Any embodiment specifically and explicitly described herein may form the basis of a disclaimer, either alone or in combination with one or more additional embodiments.

[0155] The Background section of this specification contains relevant technical information and may be used as a basis for amendment. The subject headings in this specification are used to divide the document into sections and are not intended to be used to interpret the meaning of the disclosure provided herein.

[0156] This application claims priority to U.S. Provisional Application No. 63 / 162,494, filed March 17, 2021, which is incorporated herein by reference. This application may be used as a basis for any corrections of this specification, particularly with respect to the chemical structures disclosed therein. EXAMPLES

[0157] IV. Working Examples Synthesis of intermediates Synthesis of 1-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)-2,2,2-trifluoroethan-1-one [ka] Synthesis of 5-cyclopropylpyridin-2-amine. 5-Bromopyridin-2-amine (10 g, 58 mmol), cyclopropylboronic acid (12 g, 120 mmol), SPhos (2.4 g, 5.8 mmol) and K3PO4 (43 g, 200 mmol) were placed under N2 atmosphere and suspended in toluene (220 mL) and water (22 mL). The resulting suspension was degassed for 10 min and Pd(OAc)2 (0.65 g, 2.9 mmol) was added. The reaction mixture was stirred at 95 °C for 16 h under N2 atmosphere. The mixture was cooled to room temperature, diluted with water (30 mL) and extracted with ethyl acetate (3 x 30 mL). The organic phase was washed with brine (150 mL), passed through a hydrophobic frit and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with a gradient of 10-95% EtOAc in hexanes to give the title compound (5.3 g, 68%) as a red solid. ESI-MS (M+H)+: 135.0, 1H NMR (400 MHz, DMSO) δ 7.78 (d, J=2.5 Hz, 1H), 7.07 (dd, J=2.5, 8.6 Hz, 1H), 6.39 (d, J=8.4 Hz, 1H), 5.66 (s, 2H), 1.80-1.72 (m, 1H), 0.86-0.81 (m, 2H), 0.56-0.52 (m, 2H).

[0158] Synthesis of ethyl 6-cyclopropylimidazo[1,2-a]pyridine-2-carboxylate. A solution of 5-cyclopropylpyridin-2-amine (5.3 g, 40 mmol) and ethyl 3-bromo-2-oxopropanoate (5.9 mL, 47 mmol) in ethanol (110 mL) was stirred under reflux for 1 h. The mixture was cooled to room temperature and concentrated in vacuo. The residue was dissolved in DCM (100 mL), washed with Na2CO3 (sat. aq., 60 mL), passed through a hydrophobic frit and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with a gradient of 20-80% EtOAc in hexanes to give the title compound (5 g, 54%) as an orange solid. ESI-MS (M+H)+: 231.2, 1 H NMR (400 MHz, CDCl3) δ 8.10-8.09 (m, 1H), 7.91-7.89 (m, 1H), 7.57 (d, J=9.5 Hz, 1H), 6.99 (dd, J=1.6, 9.5 Hz, 1H), 4.45 (q, J=7.1 Hz, 2H), 1.94 - 1.86 (m, 1H), 1.44 (t, J=7.2 Hz, 3H), 1.03-0.97 (m, 2H), 0.73-0.68 (m, 2H).

[0159] Synthesis of (6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methanol. LiAlH4 (1M in THF, 42.99 mmol, 42.99 mL) was added to a solution of ethyl 6-cyclopropylimidazo[1,2-a]pyridine-2-carboxylate (21.50 mmol, 4.95 g) in THF (25 mL) cooled to 0° C. under N2. The mixture was stirred for 1 h and then EtOAc (5 mL) was added dropwise. The mixture was stirred at room temperature for 1 h and then washed with water (30 mL) and brine (30 mL). The organics were dried over MgSO4 and then concentrated in vacuo to give the title compound, which was used without further purification. 1 H NMR (400 MHz, CDCl3) δ 7.86 (s, 1H), 7.46-7.42 (m, 2H), 6.92 (dd, J=1.8, 9.4 Hz, 1H), 4.82 (s, 2H), 3.88-3.84 (m, 1H), 1.87 (s, 1H), 0.99-0.93 (m, 2H), 0.69-0.64 (m, 2H).

[0160] Synthesis of (6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methanamine [ka] Synthesis of 2-(bromomethyl)-6-cyclopropylimidazo[1,2-a]pyridine [ka] A mixture of 5-cyclopropylpyridin-2-amine (670 mg, 5.0 mmol) and 1,3-dibromopropan-2-one (1.61 g, 7.5 mmol) in DME (20.0 mL) was stirred at 90 °C under N2 for 16 h. The reaction mixture was cooled to room temperature, quenched with saturated NaHCO3 solution (50 mL), and extracted with EtOAc (3x50 ml). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, and concentrated in vacuo. The crude residue was purified by column chromatography (eluent: DCM / MeOH = 50 / 1 to 30 / 1) to give the product 2-(bromomethyl)-6-cyclopropylimidazo[1,2-a]pyridine (880 mg, 70%) as a yellow solid. ESI-MS [M+H] + :252.2.

[0161] Synthesis of 2-(azidomethyl)-6-cyclopropylimidazo[1,2-a]pyridine [ka] A mixture of 2-(bromomethyl)-6-cyclopropylimidazo[1,2-a]pyridine (753 mg, 3 mmol) and NaN3 (244 mg, 3.75 mmol) in DMF (10.0 mL) was stirred at room temperature under N2 for 16 h. The mixture was diluted with EtOAc (100 mL) and washed with brine (3x50 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo to give 2-(azidomethyl)-6-cyclopropylimidazo[1,2-a]pyridine (730 mg, crude) as a yellow solid, which was used for the next step without purification. ESI-MS [M+H] + :214.2.

[0162] Synthesis of (6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methanamine [ka] A mixture of 2-(azidomethyl)-6-cyclopropylimidazo[1,2-a]pyridine (730 mg, crude) and PPh3 (983 mg, 3.75 mmol) in MeOH (25 mL) was stirred under reflux for 2 h. The mixture was concentrated in vacuo and purified by preparative TLC (eluent: DCM / MeOH=10 / 1) to give (6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methanamine (450 mg, 81% (for 2 steps)) as a yellow oil. ESI-MS [M+H]+: 188.2.

[0163] Synthesis of 2-((2R,4S)-4-((tert-butyldimethylsilyl)oxy)pyrrolidin-2-yl)-6-cyclopropylimidazo[1,2-a]pyridine [ka] Synthesis of methyl (2R,4S)-4-hydroxypyrrolidine-2-carboxylate [ka] To a solution of (2R,4S)-4-hydroxypyrrolidine-2-carboxylic acid hydrochloride (5 g, 29.8 mmol) in MeOH (50 mL) was added SOCl2 (10.6 g, 89.4 mmol) slowly at 0 °C. After stirring at 80 °C for 12 h, the reaction was concentrated in vacuo to give methyl (2R,4S)-4-hydroxypyrrolidine-2-carboxylate (4 g, crude) as a grey solid. ESI-MS [M+H]+: 146.2.

[0164] Synthesis of 1-benzyl 2-methyl (2R,4S)-4-hydroxypyrrolidine-1,2-dicarboxylate [ka] To a solution of methyl (2R,4S)-4-hydroxypyrrolidine-2-carboxylate (4 g, 27.5 mmol) in THF (80 mL) was added saturated aqueous NaHCO3 (60 ml) followed by CbzCl (5.6 g, 33.1 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for another 1 h and then extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo to give the crude product, which was purified by silica gel chromatography (EtOAc / PE=1 / 5) to give 1-benzyl 2-methyl (2R,4S)-4-hydroxypyrrolidine-1,2-dicarboxylate (5.8 g, 75%) as a yellow oil. ESI-MS [M+H] + :280.1.

[0165] Synthesis of 1-benzyl 2-methyl(2R,4S)-4-((tert-butyldimethylsilyl)oxy)pyrrolidine-1,2-dicarboxylate [ka] A mixture of 1-benzyl 2-methyl(2R,4S)-4-hydroxypyrrolidine-1,2-dicarboxylate (4 g, 14.3 mmol), TMSCl (2.3 g, 21.5 mmol), and imidazole (1.9 g, 28.6 mmol) in DCM (40 mL) was stirred at room temperature for 12 h. The reaction was washed with water (50 mL) and then extracted with EtOAc (3x50 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to give the crude product, which was purified by silica gel chromatography (EtOAc / PE=1 / 3) to give 1-benzyl 2-methyl(2R,4S)-4-((tert-butyldimethylsilyl)oxy)pyrrolidine-1,2-dicarboxylate (4 g, 71%) as a yellow oil. ESI-MS [M+H] + :394.1.

[0166] Synthesis of (2R,4S)-1-((benzyloxy)carbonyl)-4-((tert-butyldimethylsilyl)oxy)pyrrolidine-2-carboxylic acid [ka] To a solution of 1-benzyl 2-methyl(2R,4S)-4-((tert-butyldimethylsilyl)oxy)pyrrolidine-1,2-dicarboxylate (4 g, 10.2 mmol) in THF (40 mL) was added LiOH (1.25 g, 30.6 mmol) and water (4 mL). The reaction mixture was stirred at room temperature for 2 h and then concentrated in vacuo to remove THF. The pH of the resulting residue was adjusted to 3-4 with HCl (1.0 M) and then the mixture was extracted with EtOAc (3x50 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to give crude (2R,4S)-1-((benzyloxy)carbonyl)-4-((tert-butyldimethylsilyl)oxy)pyrrolidine-2-carboxylic acid (3.3 g, 87%) as a yellow oil. ESI-MS [M+H] + :394.1.

[0167] Synthesis of benzyl (2R,4S)-4-((tert-butyldimethylsilyl)oxy)-2-(chlorocarbonyl)pyrrolidine-1-carboxylate [ka] To a solution of (2R,4S)-1-((benzyloxy)carbonyl)-4-((tert-butyldimethylsilyl)oxy)pyrrolidine-2-carboxylic acid (2 g, crude from previous step) in DCM (20 mL) was added DMF (2 drops) and (COCl)2 (1.0 g, 7.91 mmol) at 0° C. After stirring at room temperature for 1 h, the solution was concentrated in vacuo to give benzyl (2R,4S)-4-((tert-butyldimethylsilyl)oxy)-2-(chlorocarbonyl)pyrrolidine-1-carboxylate (2.1 g crude) as a yellow oil, which was used in the next step without further purification. ESI-MS [M+H] + :394.1.

[0168] Synthesis of benzyl (2R,4S)-2-(2-chloroacetyl)-4-hydroxypyrrolidine-1-carboxylate [ka] To a solution of benzyl (2R,4S)-4-((tert-butyldimethylsilyl)oxy)-2-(chlorocarbonyl)pyrrolidine-1-carboxylate (400 mg, 1 mmol) in DCM (20 mL) was added TMSCH2N2 (1 mL, 2.0 M in hexanes). After stirring at room temperature for 12 h, the solution was concentrated in vacuo to give the crude product, which was redissolved in DCM (10 mL) and then HCl (4.0 M in 1,4-dioxane, 0.5 mL) was added. After stirring at room temperature for another 10 min, the solution was concentrated in vacuo to give the crude product, which was purified by silica gel chromatography (eluent: EtOAc / PE=1 / 5) to give benzyl (2R,4S)-2-(2-chloroacetyl)-4-hydroxypyrrolidine-1-carboxylate (150 mg, 36%) as a yellow oil. ESI-MS [M+H] + :298.2.

[0169] Synthesis of benzyl (2R,4S)-4-((tert-butyldimethylsilyl)oxy)-2-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)pyrrolidine-1-carboxylate [ka] A solution of benzyl (2R,4S)-2-(2-chloroacetyl)-4-hydroxypyrrolidine-1-carboxylate (150 mg, 0.51 mmol), 5-cyclopropylpyridin-2-amine (134 mg, 1.0 mmol) and DIPEA (329 mg, 2.55 mmol) in 1,4-dioxane (10 mL) was stirred at 95° C. for 12 h. The resulting mixture was concentrated in vacuo to give a crude product, which was purified by silica gel chromatography (eluent: DCM / MeOH=15 / 1) to give benzyl (2R,4S)-4-((tert-butyldimethylsilyl)oxy)-2-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)pyrrolidine-1-carboxylate (150 mg, 58%) as a yellow solid. ESI-MS [M+H] +:492.1.

[0170] Synthesis of 2-((2R,4S)-4-((tert-butyldimethylsilyl)oxy)pyrrolidin-2-yl)-6-cyclopropylimidazo[1,2-a]pyridine [ka] A mixture of benzyl (2R,4S)-4-((tert-butyldimethylsilyl)oxy)-2-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)pyrrolidine-1-carboxylate (150 mg, 0.31 mmol) and Pd / C (20 mg) in MeOH (10 mL) was stirred at room temperature for 5 h under an H2 atmosphere. The reaction was filtered and then washed with MeOH (30 mL). The filtrate was concentrated in vacuo to give 2-((2R,4S)-4-((tert-butyldimethylsilyl)oxy)pyrrolidin-2-yl)-6-cyclopropylimidazo[1,2-a]pyridine (110 mg) as a yellow solid, which was used without further purification. ESI-MS [M+H] + :358.2.

[0171] Example 1 Synthesis of 3-chlorobenzyl (6-(((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)amino)pyrimidin-4-yl)carbamate (I-1) [ka] Synthesis of 6-chloro-N-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)pyrimidin-4-amine. A solution of 4,6-dichloropyrimidine (302 mg, 2.6 mmol), (6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methanamine hydrochloride (400 mg, 2.1 mmol) and DIPEA (0.93 mL, 5.3 mmol) in iPrOH (20 mL) was heated at 80° C. for 2 h. The reaction mixture was concentrated in vacuo and the residue triturated with Et2O. The crude solid was redissolved in DCM (35 mL) and washed with water. The combined organics were passed through a hydrophobic frit then concentrated in vacuo to give the title compound (560 mg, 87%) as a colourless oil. 1 H NMR (400 MHz, DMSO) δ 8.33-8.29 (m, 2H), 8.21-8.20 (m, 1H), 7.68 (s, 1H), 7.39 (d, J=9.3 Hz, 1H), 6.98 (dd, J=1.5, 9.3 Hz, 1H), 6.63 (s, 1H), 4.61 (s, 2H), 1.95 - 1.88 (m, 1H), 0.94 - 0.89 (m, 2H), 0.69 - 0.64 (m, 2H).

[0172] Synthesis of N-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-6-(methoxyamino)pyrimidin-4-amine. A solution of 6-chloro-N-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)pyrimidin-4-amine (1.6 g, 5.5 mmol) and O-methyl-hydroxylamine hydrochloride (6.9 g, 82 mmol) in ethanol (40 mL) was heated at 85° C. for 24 h. The reaction mixture was diluted with NaHCO3 (saturated aqueous) and extracted with EtOAc. The combined organics were dried over MgSO4, filtered and concentrated in vacuo to give the title compound (1.52 g, 90%) as a brown gum which was used without further purification. ESI-MS (M+H)+: 311, 1H NMR (400 MHz, DMSO) δ 9.56 (br s, 1H), 8.30 (s, 1H), 8.00 (s, 1H), 7.62 (s, 1H), 7.49-7.40 (m, 1H), 7.37 (d, J=9.3 Hz, 1H), 6.95 (dd, J=1.4, 9.2 Hz, 1H), 5.84 (s, 1H), 4.50 (s, 2H), 3.32 (s, 3H), 1.96-1.85 (m, 1H), 0.95-0.85 (m, 2H), 0.70-0.60 (m, 2H).

[0173] N 4 Synthesis of -((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)pyrimidine-4,6-diamine. A solution of N-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-6-(methoxyamino)pyrimidin-4-amine (1.5 g, 4.9 mmol) and iron powder (1.4 g, 24 mmol) in acetic acid (13 mL) and ethanol (80 mL) was heated at 70° C. for 2 h. The reaction mixture was cooled and filtered through a pad of Celite® eluting with EtOAc. The filtrate was concentrated and loaded onto an SCX column and washed with MeOH in DCM (1:9). The product was eluted with (7N NH3 in MeOH) in DCM (1:9) and concentrated in vacuo to give the title compound (1.2 g, 84%) as a brown solid. ESI-MS (M+H)+: 281. 1 H NMR (400 MHz, DMSO) δ 8.30-8.29 (m, 1H), 7.87 (s, 1H), 7.57 (s, 1H), 7.36 (d, J=9.3 Hz, 1H), 6.99 (t, J=5.8 Hz, 1H), 6.95 (dd, J=1.8, 9.3 Hz, 1H), 6.02 (s, 2H), 5.41 (s, 1H), 4.43 (d, J=5.5 Hz, 2H), 1.94-1.86 (m, 1H), 0.93-0.87 (m, 2H), 0.68-0.62 (m, 2H).

[0174] Synthesis of 3-chlorobenzyl (6-(((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)amino)pyrimidin-4-yl)carbamate. Phosgene (20% in toluene, 0.42 mL, 0.80 mmol) was added dropwise to a stirred solution of 3-chlorobenzyl alcohol (0.12 mL, 1.0 mmol) and DIPEA (0.44 mL, 2.5 mmol) in DCM (14 mL) at 0° C. The mixture was stirred at 0° C. for 30 min, then warmed to room temperature and stirred for 1 h. The resulting solution was dissolved in N 4 To a solution of -((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)pyrimidine-4,6-diamine (140 mg, 1.0 mmol) and DIPEA (0.35 mL, 2.0 mmol) was added over 1 h. The mixture was stirred at room temperature for 18 h, then K2CO3 (10% aqueous) was added and the phases were separated. The combined organics were dried over MgSO4 and then concentrated in vacuo. The residue was purified by silica gel chromatography eluting with a gradient of 1-10% MeOH in DCM followed by preparative HPLC to give the title compound (1.1 mg, 1%). ESI-MS (M+H)+: 449.2, 1 H NMR (400 MHz, DMSO) δ 10.18 (s, 1H), 8.29 (s, 1H), 8.16 (s, 1H), 7.82 (br s, 1H), 7.61 (s, 1H), 7.51 (s, 1H), 7.43-7.33 (m, 4H), 7.03-6.93 (m, 2H), 5.16 (s, 2H), 4.56 (br s, 2H), 1.94-1.86 (m, 1H), 0.94-0.88 (m, 2H), 0.68-0.62 (m, 2H).

[0175] Example 2 Synthesis of (R)-1-(3-chlorophenyl)ethyl (6-(((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)amino)pyrimidin-4-yl)carbamate (I-2) [ka] Synthesis of (R)-1-(3-chlorophenyl)ethyl carbamate. Trichloroacetyl isocyanate (46 μL, 0.38 mmol) was added dropwise to a stirred solution of (R)-1-(3-chlorophenyl)ethan-1-ol (50 mg, 0.32 mmol) in DCM (3 mL) at 0 °C. After stirring with cooling for 80 min, the reaction mixture was concentrated in vacuo. The residue was redissolved in MeOH (3.0 mL) and K2CO3 (8.8 mg, 0.064 mmol) was added. The reaction mixture was stirred at room temperature for 2 days and then diluted with DCM and water. The organic layer was separated, dried over MgSO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a gradient of 0-50% EtOAc in cyclohexane to give the title compound (36 mg, 57%) as a colorless oil, which was used directly in the next step.

[0176] Synthesis of (R)-1-(3-chlorophenyl)ethyl(6-(((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)amino)pyrimidin-4-yl)carbamate. A mixture of (R)-1-(3-chlorophenyl)ethyl carbamate (18 mg, 0.090 mmol), 6-chloro-N-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)pyrimidin-4-amine (27 mg, 0.090 mmol), tris(dibenzylideneacetone)dipalladium(0) (17 mg, 0.018 mmol), Xantphos (21 mg, 0.036 mmol) and CsCO (44 mg, 0.14 mmol) in 1,4-dioxane (1.0 mL) was degassed with nitrogen and then heated at 90 °C for 18 h. After cooling to room temperature, the reaction mixture was diluted with 10% MeOH in DCM, filtered through a pad of Celite®, and concentrated in vacuo. The residue was purified by preparative HPLC to give the title compound (4.7 mg, 11%). ESI-MS (M+H)+: 463.4, 1H NMR (400 MHz, DMSO) δ 10.12 (s, 1H), 8.28 (s, 1H), 8.15 (s, 1H), 7.77 (br s, 1H), 7.59 (s, 1H), 7.51 (s, 1H), 7.43-7.33 (m, 4H), 6.98-6.92 (m, 2H), 5.82-5.75 (m, 1H), 4.54 (s, 2H), 1.94-1.86 (m, 1H), 1.50 (d, J=6.6 Hz, 3H), 0.94-0.87 (m, 2H), 0.68-0.62 (m, 2H). The compounds in Table 1 were synthesized from 6-chloro-N-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)pyrimidin-4-amine and the appropriate alcohol coupling partner using a procedure similar to that for (R)-1-(3-chlorophenyl)ethyl (6-(((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)amino)pyrimidin-4-yl)carbamate. [Table 1-1] [Table 1-2]

[0177] Example 8 Synthesis of 5-chloro-2-(1H-tetrazol-1-yl)benzyl (6-(((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)amino)pyrimidin-4-yl)carbamate (I-8) [ka] Synthesis of tert-butyl (4-chloro-2-(hydroxymethyl)phenyl)carbamate. (2-amino-5-chlorophenyl)methanol (0.50 g, 3.2 mmol) was added to a solution of di-tert-butyl dicarbonate (0.83 g, 3.8 mmol) in THF (5.0 mL). The reaction mixture was stirred at 40° C. for 2 days. The solvent was removed in vacuo and the residue was purified by column chromatography on silica gel eluting with 0-30% EtOAc in cyclohexane to give the title compound, which was used directly in the next step. 1 H NMR (400 MHz, CDCl3) δ 7.83 (d, J=8.6 Hz, 1H), 7.65 (br s, 1H), 7.23 (dd, J=2.4, 8.7 Hz, 1H), 7.13-7.11 (m, 1H), 4.60 (d, J=5.6 Hz, 2H), 2.62 (t, J=5.6 Hz, 1H), 1.51 (s, 9H).

[0178] Synthesis of tert-butyl (2-((carbamoyloxy)methyl)-4-chlorophenyl)carbamate. The title compound was synthesized from tert-butyl (4-chloro-2-(hydroxymethyl)phenyl)carbamate trichloroacetylisocyanate in a similar manner to (R)-1-(3-chlorophenyl)ethylcarbamate (0.15 g, 86%). 1 H NMR (400 MHz, CDCl3) δ 7.83 (s, 1H), 7.76 (d, J=8.1 Hz, 1H), 6.79-6.74 (m, 2H), 5.09 (br s, 2H), 5.02 (s, 2H), 1.51 (s, 9H).

[0179] Synthesis of 2-((tert-butoxycarbonyl)amino)-5-chlorobenzyl (6-(((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)amino)pyrimidin-4-yl)carbamate. The title compound was synthesized starting from tert-butyl (2-((carbamoyloxy)methyl)-4-chlorophenyl)carbamate and 6-chloro-N-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)pyrimidin-4-amine in a similar manner to (R)-1-(3-chlorophenyl)ethyl (6-(((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)amino)pyrimidin-4-yl)carbamate, and then used directly in the next step (0.21 g, 74%).

[0180] Synthesis of 2-amino-5-chlorobenzyl(6-(((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)amino)pyrimidin-4-yl)carbamate. HCl (4.0 M in 1,4-dioxane, 20 μL, 0.080 mmol) was added to a solution of 2-((tert-butoxycarbonyl)amino)-5-chlorobenzyl-(6-(((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)amino)pyrimidin-4-yl)carbamate (60 mg, 0.053 mmol) in 1,4-dioxane (0.5 mL). The mixture was stirred at room temperature for 4 h, then quenched by addition of NaHCO3 (sat. aq.) and extracted with DCM. The combined organics were passed through a hydrophobic frit then concentrated in vacuo to give the title compound which was used in the next step without further purification.

[0181] Synthesis of 5-chloro-2-(1H-tetrazol-1-yl)benzyl (6-(((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)amino)pyrimidin-4-yl)carbamate. NaN3 (4.4 mg, 0.067 mmol) and triethyl orthoformate (29 μL, 0.17 mmol) were added to a solution of 2-amino-5-chlorobenzyl (6-(((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)amino)pyrimidin-4-yl)carbamate (25 mg, 0.054 mmol) in acetic acid (50 μL). The mixture was stirred at room temperature for 18 h. The reaction was diluted with water and extracted with EtOAc. The combined organics were passed through a hydrophobic frit and the solvent removed in vacuo. The residue was purified by preparative HPLC to give the title compound (11 mg, 39%). ESI-MS(M+H)+:517.3, 1 H NMR (400 MHz, DMSO) δ 10.22 (s, 1H), 9.89 (s, 1H), 8.29-8.29 (m, 1H), 8.16 (s, 1H), 7.91 (d, J=1.9 Hz, 1H), 7.84 (br s, 1H), 7.77-7.70 (m, 2H), 7.60 (s, 1H), 7.36 (d, J=9.4 Hz, 1H), 6.95 (dd, J=1.8, 9.3 Hz, 2H), 5.04 (s, 2H), 4.55 (s, 2H), 1.94-1.86 (m, 1H), 0.93-0.87 (m, 2H), 0.68-0.63 (m, 2H).

[0182] Example 9 Synthesis of 2-(3-chlorophenyl)-2-hydroxyethyl (6-(((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)amino)pyrimidin-4-yl)carbamate (I-9) [ka] Synthesis of 1-(3-chlorophenyl)ethane-1,2-diol. OsO4 (2.5% in tBuOH, 0.45 mL, 0.036 mmol) was added dropwise to a solution of 3-chlorostyrene (1.0 g, 7.2 mmol) and N-methyl-morpholine oxide (1.3 g, 11 mmol) in water (9.0 mL) and tBuOH (27 mL). The mixture was stirred at room temperature for 18 h. Na2SO3 (1.0 M aqueous, 20 mL) was added and the mixture was stirred for 30 min and then extracted with DCM. The combined organics were dried over MgSO4 and concentrated in vacuo to give the title compound, which was used without further purification. 1 H NMR (400 MHz, CDCl3) δ 7.38 (s, 1H), 7.33-7.21 (m, 3H), 4.79 (dd, J=3.4, 8.0 Hz, 1H), 3.76 (dd, J=3.4, 11.2 Hz, 1H), 3.70 (t, J=4.7 Hz, 1H), 3.65-3.59 (m, 1H), one exchangeable proton not visible.

[0183] Synthesis of 2-((tert-butyldimethylsilyl)oxy)-1-(3-chlorophenyl)ethan-1-ol. Imidazole (0.54 g, 7.9 mmol) and tert-butyldimethylsilyl chloride (1.2 g, 7.9 mmol) were added to a solution of 1-(3-chlorophenyl)ethane-1,2-diol (1.3 g, 7.2 mmol) in DCM (35 mL). The mixture was stirred at room temperature for 18 h. The mixture was filtered and then concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a gradient of 0-20% EtOAc in cyclohexane to give the title compound (1.5 g, 70%). 1H NMR (400 MHz, CDCl3) δ 7.38 (s, 1H), 7.31-7.20 (m, 3H), 4.72 (dd, J=3.5, 8.3 Hz, 1H), 3.76 (dd, J=3.5, 10.1 Hz, 1H), 3.52 (dd, J=8.5, 10.0 Hz, 1H), 0.91 (s, 9H), 0.06 (d, J=3.3 Hz, 6H), no exchangeable protons visible.

[0184] Synthesis of 2-((tert-butyldimethylsilyl)oxy)-1-(3-chlorophenyl)ethyl carbamate. The title compound was synthesized in a similar manner to (R)-1-(3-chlorophenyl)ethyl carbamate starting from 2-((tert-butyldimethylsilyl)oxy)-1-(3-chlorophenyl)ethan-1-ol and trichloroacetyl isocyanate (0.35 g, 61%). 1 H NMR (400 MHz, CDCl3) δ 7.34 (s, 1H), 7.29-7.18 (m, 3H), 5.69-5.64 (m, 1H), 4.68 (br s, 2H), 3.87-3.75 (m, 2H), 0.87-0.85 (m, 9H), 0.00 (d, J=1.9 Hz, 6H).

[0185] Synthesis of 2-((tert-butyldimethylsilyl)oxy)-1-(3-chlorophenyl)ethyl(6-(((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)amino)pyrimidin-4-yl)carbamate. The title compound was synthesized in a similar manner to (R)-1-(3-chlorophenyl)ethyl(6-(((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)amino)pyrimidin-4-yl)carbamate starting from 2-((tert-butyldimethylsilyl)oxy)-1-(3-chlorophenyl)ethylcarbamate and 6-chloro-N-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)pyrimidin-4-amine (0.25 g, quantitative). ESI-MS (M+H)+: 593.3.

[0186] Synthesis of 2-(3-chlorophenyl)-2-hydroxyethyl (6-(((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)amino)pyrimidin-4-yl)carbamate. TBAF (3.3 M in THF, 0.15 mL, 0.51 mmol) was added to a solution of 2-((tert-butyldimethylsilyl)oxy)-1-(3-chlorophenyl)ethyl (6-(((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)amino)pyrimidin-4-yl)carbamate (0.20 g, 0.10 mmol) in THF (2.0 mL). The mixture was stirred at room temperature for 1 h. Water was added and the mixture was extracted with DCM. The organic extract was passed through a hydrophobic frit and concentrated in vacuo. The residue was purified by reverse phase HPLC to give the product as an 85:15 mixture of isomers (3 mg, 6%). ESI-MS (M+H)+: 479.3. 1 H NMR (major isomer) (400 MHz, DMSO) δ 9.95 (s, 1H), 8.23-8.19 (m, 1H), 8.08 (s, 1H), 7.71 (s, 1H), 7.55-7.51 (m, 1H), 7.41-7.38 (m, 1H), 7.30-7.26 (m, 4H), 6.92-6.86 (m, 2H), 5.68 (s, 1H), 4.77-4.73 (m, 1H), 4.48 (s, 2H), 4.06 (d, J=5.6 Hz, 2H), 1.87-1.79 (m, 1H), 0.87-0.80 (m, 2H), 0.61-0.57 (m, 2H).

[0187] Example 10 Synthesis of 1-(5-chloro-2-(1H-tetrazol-1-yl)benzyl)-3-(4-(((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)amino)pyridin-2-yl)urea (I-10) [ka] Synthesis of 5-chloro-2-(1H-tetrazol-1-yl)benzoic acid [ka] To a mixture of 2-amino-5-chlorobenzoic acid (100 mg, 0.58 mmol) and NaN3 (38 mg, 0.58 mmol) in triethoxymethane (3 mL) was added PO5 (16 mg, 0.12 mmol). The mixture was stirred at 130 °C for 3 h. After the reaction was cooled to room temperature, water (20 mL) was added and then the mixture was extracted with EtOAc (20 mL x 3). The combined organics were dried over Na2SO4 and concentrated in vacuo to give the crude product, which was purified by recrystallization from DCM to give 5-chloro-2-(1H-tetrazol-1-yl)benzoic acid (55 mg, 42%) as a yellow solid. ESI-MS [M+H]+: 225.1.

[0188] Synthesis of 5-chloro-2-(1H-tetrazol-1-yl)benzamide [ka] To a solution of 5-chloro-2-(1H-tetrazol-1-yl)benzoic acid (55 mg, 0.24 mmol), NH4Cl (26 mg, 0.49 mmol), HOBt (66 mg, 0.49 mmol), and EDCI (94 mg, 0.49 mmol) in DMF (5 mL) was added DIPEA (127 mg, 0.98 mmol). The mixture was stirred at 25 °C for 16 h, then water (30 mL) was added. The mixture was extracted with EtOAc (20 mL x 3) and the combined organics were dried over Na2SO4, filtered, and concentrated in vacuo to give 5-chloro-2-(1H-tetrazol-1-yl)benzamide (40 mg, 73%) as a yellow oil. ESI-MS [M+H]+: 224.0.

[0189] Synthesis of 5-chloro-2-(1H-tetrazol-1-yl)benzonitrile [ka] To a mixture of 5-chloro-2-(1H-tetrazol-1-yl)benzamide (40 mg, 0.18 mmol) in DMF (2 mL) was added POCl3 (165 mg, 1.08 mmol) at 0° C. The mixture was stirred at 25° C. for 16 h. Water (20 mL) was added and then the mixture was extracted with DCM (10 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo to give 5-chloro-2-(1H-tetrazol-1-yl)benzonitrile (30 mg, 81%) as an oil. ESI-MS [M+H]+: 206.1.

[0190] Synthesis of (5-chloro-2-(1H-tetrazol-1-yl)phenyl)methanamine [ka] To a mixture of 5-chloro-2-(1H-tetrazol-1-yl)benzonitrile (30 mg, 0.15 mmol) in NH3 in MeOH (2 mL, 7 M in MeOH) was added RaNi (30 mg). The mixture was stirred under H2 at 25° C. for 1 h whereupon it was filtered and the filter cake was washed with MeOH (10 mL). The filtrate was concentrated in vacuo to give (5-chloro-2-(1H-tetrazol-1-yl)phenyl)methanamine (21 mg, 67%) as a yellow oil, which was used in the next step without purification. ESI-MS [M+H]+: 210.1.

[0191] Synthesis of 2-bromo-N-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)pyridin-4-amine [ka] A mixture of (6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methanamine (935 mg, 5 mmol), 2-bromo-4-fluoropyridine (1.1 g, 6.25 mmol) and DIPEA (1.29 g, 10 mmol) in iPrOH (30 mL) was stirred at 100° C. for 12 h. The reaction was cooled to room temperature and then concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography (eluent: PE / EtOAc=1 / 1) to give 2-bromo-N-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)pyridin-4-amine (1 g, 58%) as a yellow solid. ESI-MS [M+H]+: 344.2.

[0192] Synthesis of N-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-2-((diphenylmethylene)amino)pyridin-4-amine [ka] A mixture of 2-bromo-N-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)pyridin-4-amine (1 g, 2.9 mmol), diphenylmethanimine (1.1 g, 5.8 mmol), Pd2(dba)3 (265 mg, 0.29 mmol), BINAP (360 mg, 0.58 mmol), and tBuONa (835 mg, 8.7 mmol) in toluene (25 mL) was stirred at 90° C. for 12 h. The reaction was diluted with water (40 mL) and then extracted with EtOAc (40 mL×3). The combined organic layers were washed with brine (40 mL), dried over anhydrous Na2SO4, and concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography (eluent: PE / EtOAc=2 / 1) to give N-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-2-((diphenylmethylene)amino)pyridin-4-amine (760 mg, 59%) as a yellow solid. ESI-MS [M+H]+: 444.1.

[0193] N 4Synthesis of -((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)pyridine-2,4-diamine [ka] To a solution of N-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-2-((diphenylmethylene)amino)pyridin-4-amine (443 mg, 1 mmol) in MeOH (10 mL) was added HCl (2 mL, 4 M solution in MeOH) at 0° C. The resulting reaction was stirred at room temperature for 1 h. The reaction was concentrated in vacuo to give the crude product, which was neutralized with NH3 (5 mL, 7 M solution in MeOH) and concentrated in vacuo. The crude product was purified by silica gel column chromatography (eluent: DCM / MeOH=10 / 1) to give N 4 -((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)pyridine-2,4-diamine (260 mg, 93%) was obtained as a yellow solid. ESI-MS [M+H]+: 280.2.

[0194] Synthesis of 1-(5-chloro-2-(1H-tetrazol-1-yl)benzyl)-3-(4-(((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)amino)pyridin-2-yl)urea [ka] N in DCM (1.0 mL) 4A solution of -((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)pyridine-2,4-diamine (28 mg, 0.1 mmol), di(1H-imidazol-1-yl)methanone (32 mg, 0.2 mmol), and triethylamine (50 mg, 0.5 mmol) was stirred at room temperature for 3 h. Then a solution of (5-chloro-2-(1H-tetrazol-1-yl)phenyl)methanamine (42 mg, 0.2 mmol) in DCM (0.5 mL) was added. The mixture was stirred at room temperature for another 2 h. The reaction mixture was concentrated in vacuo to give the crude product, which was purified by preparative TLC (eluent: DCM / MeOH=20 / 1) to give 1-(5-chloro-2-(1H-tetrazol-1-yl)benzyl)-3-(4-(((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)amino)pyridin-2-yl)urea (10.9 mg, 21%) as a white solid. ESI-MS [M+H] + :515.2. 1 H NMR (400 MHz, DMSO) δ 9.85 (s, 1H), 9.35 (s, 1H), 8.96 (s, 1H), 8.27 (s, 1H), 7.60-7.57 (m, 5H), 7.35 (d, J = 9.3 Hz, 1H), 7.10 (s, 1H), 6.94 (dd, J = 9.3, 1.6 Hz, 1H), 6.27-6.21 (m, 2H), 4.29-4.23 (m, 4H), 1.91-1.85 (m, 1H), 0.88-0.85 (m, 2H), 0.65-0.61 (m, 2H).

[0195] Example 11 Synthesis of 5-chloro-2-(1H-tetrazol-1-yl)benzyl (4-(((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)amino)pyridin-2-yl)carbamate (I-11) [ka] Synthesis of (2-amino-5-chlorophenyl)methanol [ka] To a solution of 2-amino-5-chlorobenzaldehyde (0.50 g, 3.2 mmol) in THF (10 mL) was added NaBH4 (0.18 g, 4.8 mmol) and the resulting mixture was stirred at room temperature for 3 h. The reaction mixture was quenched with water (30 mL), extracted with EtOAc (30 mLx3), and washed with brine (40 mLx2). The combined organic phase was dried over Na2SO4 and concentrated in vacuo to give the crude product, which was purified by column chromatography (eluent: PE / EtOAc=2 / 1) to give (2-amino-5-chlorophenyl)methanol (0.40 g, 80%) as a yellow solid. ESI-MS: [M+H]+, 156.1.

[0196] Synthesis of (5-chloro-2-(1H-tetrazol-1-yl)phenyl)methanol [ka] To a solution of (2-amino-5-chlorophenyl)methanol (0.36 g, 2.3 mmol) in trimethoxymethane (5 mL) was added NaN3 (0.37 g, 5.7 mmol) at 0° C. The mixture was stirred at 0° C. for 40 min. Then, acetic acid (0.05 mL) was added and the mixture was stirred at 80° C. for 16 h. The reaction mixture was quenched with water (20 mL), extracted with EtOAc (20 mL×3), and washed with brine (30 mL×2). The combined organic phase was dried over Na2SO4 and concentrated in vacuo to give the crude product, which was purified by column chromatography (eluent: PE / EtOAc=1 / 1) to give (5-chloro-2-(1H-tetrazol-1-yl)phenyl)methanol (0.21 g, 43%) as a yellow solid. ESI-MS: [M+H]+, 211.1.

[0197] Synthesis of 5-chloro-2-(1H-tetrazol-1-yl)benzyl (4-(((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)amino)pyridin-2-yl)carbamate [ka] N in DCM (1.5 mL) 4 A solution of -((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)pyridine-2,4-diamine (35 mg, 0.13 mmol), di(1H-imidazol-1-yl)methanone (41 mg, 0.25 mmol), and triethylamine (64 mg, 0.63 mmol) was stirred at room temperature for 3 h. Then a solution of (5-chloro-2-(1H-tetrazol-1-yl)phenyl)methanol (53 mg, 0.25 mmol) in DCM (0.5 mL) was added. The mixture was stirred at room temperature for an additional 2 h. The reaction mixture was concentrated in vacuo to give the crude product, which was purified by preparative TLC (eluent: DCM / MeOH=12 / 1) to give 5-chloro-2-(1H-tetrazol-1-yl)benzyl (4-(((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)amino)pyridin-2-yl)carbamate (11.9 mg, 18%) as a white solid. ESI-MS [M+H] + :516.2, 1 H NMR (400 MHz, DMSO) δ 9.94-9.80 (m, 2H), 8.28 (s, 1H), 7.88 (s, 1H), 7.73-7.68 (m, 3H), 7.60 (s, 1H), 7.35 (d, J = 9.3 Hz, 1H), 7.12 (t, J = 5.5 Hz, 1H), 7.03 (s, 1H), 6.94 (dd, J = 9.3, 1.4 Hz, 1H), 6.28 (dd, J = 5.7, 1.8 Hz, 1H), 4.98 (s, 2H), 4.32 (d, J = 5.5 Hz, 2H), 1.91-1.85 (m, 1H), 0.90-0.85 (m, 2H), 0.65-0.61 (m, 2H).

[0198] Example 12 Synthesis of 5-chloro-2-(1H-tetrazol-1-yl)benzyl (4-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methoxy)pyridin-2-yl)carbamate (I-12) [ka] Synthesis of 2-(((2-bromopyridin-4-yl)oxy)methyl)-6-cyclopropylimidazo[1,2-a]pyridine [ka] To a solution of (6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methanol (0.50 g, 2.7 mmol) in DMF (5 mL) was added NaH (0.32 g, 60% in mineral oil, 8.0 mmol) at 0° C., and the mixture was stirred at 0° C. for 0.5 h. Then a solution of 2-bromo-4-fluoropyridine (0.93 g, 5.3 mmol) in DMF (1 mL) was added, and the mixture was stirred at room temperature for 3 h. The reaction was quenched with water (50 mL) and extracted with EtOAc (50 mL×3). The combined organic phase was washed with brine (30 mL x 2), dried over anhydrous Na2SO4, and concentrated in vacuo to give the crude product, which was purified by column chromatography (eluent: DCM / MeOH = 50 / 1) to give 2-(((2-bromopyridin-4-yl)oxy)methyl)-6-cyclopropylimidazo[1,2-a]pyridine (0.65 g, 70%) as a yellow oil. ESI-MS: [M+H] + , 344.1.

[0199] Synthesis of 4-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methoxy)-N-(4-methoxybenzyl)pyridin-2-amine [ka] A mixture of 2-(((2-bromopyridin-4-yl)oxy)methyl)-6-cyclopropylimidazo[1,2-a]pyridine (0.65 g, 1.9 mmol), (4-methoxyphenyl)methanamine (0.78 g, 5.9 mmol), Pd-PEPPSI-IPentCl2-MePy (0.16 g, 0.19 mmol), and Cs2CO3 (1.9 g, 5.9 mmol) in NMP (10 mL) was stirred at 100° C. for 18 h under N2. The reaction mixture was filtered through Celite® and the filter cake was washed with DCM / MeOH (10 / 1, 100 mL). The filtrate was concentrated in vacuo to give the crude product, which was purified by column chromatography (eluent: DCM / MeOH=25 / 1) to give 4-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methoxy)-N-(4-methoxybenzyl)pyridin-2-amine (0.70 g, 92%) as a yellow oil. ESI-MS: [M+H] + , 401.2.

[0200] Synthesis of 4-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methoxy)pyridin-2-amine [ka] To a solution of 4-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methoxy)-N-(4-methoxybenzyl)pyridin-2-amine (0.70 g, 1.8 mmol) in DCM (10 mL) was added TFA (10 mL) at 0° C., and the mixture was stirred at room temperature for 2 h. The reaction was quenched with saturated aqueous NaHCO3 (50 mL), extracted with EtOAc (30 mL×3), and washed with brine (100 mL×2). The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo to give the crude product, which was purified by column chromatography (eluent: DCM / MeOH=10 / 1) to give 4-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methoxy)pyridin-2-amine (0.50 g, quantitative) as a brown solid. ESI-MS: [M+H] + , 281.2.

[0201] Synthesis of 5-chloro-2-(1H-tetrazol-1-yl)benzyl (4-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methoxy)pyridin-2-yl)carbamate [ka] A mixture of 4-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methoxy)pyridin-2-amine (50 mg, 0.18 mmol), di(1H-imidazol-1-yl)methanone (43 mg, 0.27 mmol), and triethylamine (54 mg, 0.54 mmol) in DCM (5 mL) was stirred at room temperature for 5 h, then (5-chloro-2-(1H-tetrazol-1-yl)phenyl)methanol (75 mg, 0.36 mmol) was added and stirred at room temperature for 16 h. The reaction mixture was concentrated in vacuo to give the crude product, which was purified by preparative TLC (eluent: DCM / MeOH=10 / 1) to give 5-chloro-2-(1H-tetrazol-1-yl)benzyl (4-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methoxy)pyridin-2-yl)carbamate (10 mg, 11%) as a white solid. ESI-MS: [M+H] + , 517.2; 1 H NMR (400 MHz, DMSO) δ 10.31 (s, 1H), 9.90 (s, 1H), 8.35 (s, 1H), 8.10 (d, J = 5.8 Hz, 1H), 7.93 (d, J = 1.8 Hz, 1H), 7.88 (s, 1H), 7.78 - 7.70 (m, 2H), 7.45-7.41 (m, 2H), 7.03-6.99 (m, 1H), 6.83-6.79 (m, 1H), 5.23 (s, 2H), 5.06 (s, 2H), 1.96-1.91 (m, 1H), 0.96-0.89 (m, 2H), 0.72-0.66 (m, 2H).

[0202] Example 13 Synthesis of 3-chlorobenzyl (4-(((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)amino)pyridin-2-yl)carbamate (I-13) [ka] Synthesis of 3-chlorobenzyl (2,2,2-trichloroacetyl)carbamate [ka] To a solution of (3-chlorophenyl)methanol (0.8 g, 5.6 mmol) in DCM (10 mL) was added 2,2,2-trichloroacetyl isocyanate (1.27 g, 6.8 mmol) at room temperature and the mixture was stirred at room temperature for 18 h. The mixture was quenched with water (50 mL) and extracted with EtOAc (30 mLx3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, and concentrated in vacuo to give 3-chlorobenzyl (2,2,2-trichloroacetyl)carbamate (1.5 g, crude) as a white solid, which was used directly in the next step. ESI-MS [M+H]+: 329.9.

[0203] Synthesis of 3-chlorobenzyl carbamate [ka] A mixture of 3-chlorobenzyl (2,2,2-trichloroacetyl)carbamate (1.5 g, crude) and K2CO3 (1.9 g, 13.8 mmol) in MeOH (10 mL) was stirred at room temperature for 2 h. The mixture was quenched with water (50 mL) and extracted with EtOAc (30 mLx3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography (eluent: EtOAc / PE (0-30%)) to give 3-chlorobenzylcarbamate (700 mg, 67% (for two steps)) as a white solid. ESI-MS [M+H]+: 186.0.

[0204] Synthesis of 1-(3-chlorophenyl)ethyl (4-(((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)amino)pyridin-2-yl)carbamate [ka] A mixture of 3-chlorobenzylcarbamate (65 mg, 0.35 mmol), 2-bromo-N-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)pyridin-4-amine (120 mg, 0.35 mmol), Pd2(dba)3 (32 mg, 0.035 mmol), Xantphos (40 mg, 0.070 mmol), and Cs2CO3 (228 mg, 0.70 mmol) in 1,4-dioxane (5 mL) was degassed with N2 and stirred at 90 °C for 16 h. The mixture was filtered through Celite® and the filter cake was washed with DCM / MeOH (10 / 1, 50 mL). The filtrate was concentrated in vacuo to give the crude product, which was purified by preparative TLC (eluent: DCM / MeOH=20 / 1) to give 1-(3-chlorophenyl)ethyl (4-(((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)amino)pyridin-2-yl)carbamate (20 mg, 13% yield) as a white solid. ESI-MS [M+H]+: 448.1, 1 H NMR (400 MHz, DMSO) δ 9.79 (s, 1H), 8.30 (s, 1H), 7.73 (d, J = 5.8 Hz, 1H), 7.63 (s, 1H), 7.50 (s, 1H), 7.43-7.34 (m, 4H), 7.15-7.08 (m, 2H), 6.96 (dd, J = 9.3, 1.7 Hz, 1H), 6.30 (dd, J = 5.8, 2.0 Hz, 1H), 5.13 (s, 2H), 4.35 (d, J = 5.8 Hz, 2H), 1.92-1.85 (m, 1H), 0.97-0.79 (m, 2H), 0.70-0.61 (m, 2H).

[0205] Example 14 Synthesis of 3-chlorobenzyl (3-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-[1,2,4]triazolo[4,3-a]pyrazin-6-yl)carbamate (I-14) [ka] Synthesis of ethyl 2-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)acetate [ka] A mixture of ethyl 4-chloro-3-oxobutanoate (3.0 g, 18 mmol) and 5-cyclopropylpyridin-2-amine (2.0 g, 15 mmol) in ethanol (30 mL) was stirred at 90° C. for 24 h. The reaction mixture was then concentrated in vacuo and the resulting residue was purified by column chromatography on silica gel (eluting with 20-60% EtOAc / PE) to give ethyl 2-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)acetate (1.3 g, 36%) as a white solid. ESI-MS [M+H]+: 245.1.

[0206] Synthesis of 2-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)acetic acid [ka] To a solution of ethyl 2-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)acetate (1.3 g, 5.3 mmol) in THF (15 mL) and water (5 mL) was added NaOH (0.32 g, 8.0 mmol). The mixture was heated to 90° C. for 1 h. After cooling to room temperature, the resulting mixture was acidified to pH=6 with HCl (2N in H2O). The resulting precipitate was collected by filtration and then dried in vacuum to give 2-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)acetic acid (850 mg, 74%) as a brown solid. ESI-MS [M+H]+: 217.1.

[0207] Synthesis of (E)-5-bromo-2-hydrazono-1,2-dihydropyrazine [ka] A mixture of 2,5-dibromopyrazine (1.6 g, 6.7 mmol) and hydrazine hydrate (1.7 g, 34 mmol) in i-PrOH (20 mL) was stirred at 65° C. for 16 h. The reaction mixture was quenched with NaHCO3 (saturated aqueous 30 mL) and extracted with EtOAc (40 mL×5). The combined organics were washed with brine (20 mL), dried over Na2SO4, and concentrated in vacuo to give (E)-5-bromo-2-hydrazono-1,2-dihydropyrazine (1.1 g, crude) as a yellow solid. ESI-MS [M+H] + :189.0.

[0208] Synthesis of (E)-N'-(5-bromopyrazin-2(1H)-ylidene)-2-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)acetohydrazide [ka] A mixture of (E)-5-bromo-2-hydrazono-1,2-dihydropyrazine (400 mg, 2.1 mmol), 2-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)acetic acid (550 mg, 2.5 mmol), EDCI (1.2 g, 6.4 mmol), HOBt (0.86 g, 6.4 mmol), and DIPEA (1.6 g, 12 mmol) in DMF (10 mL) was stirred at room temperature for 16 h. The reaction mixture was quenched with water (60 mL) and extracted with EtOAc (50 mL x 5). The combined organics were washed with brine (50 mL), dried over Na2SO4, and then concentrated in vacuo to give the crude product, which was purified by column chromatography (eluent: DCM / MeOH=10 / 1) to give (E)-N'-(5-bromopyrazin-2(1H)-ylidene)-2-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)acetohydrazide (450 mg, 56%) as a yellow solid. ESI-MS [M+H] + :387.0.

[0209] Synthesis of 6-bromo-3-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-[1,2,4]triazolo[4,3-a]pyrazine [ka] To a suspension of (E)-N'-(5-bromopyrazin-2(1H)-ylidene)-2-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)acetohydrazide (290 mg, 0.75 mmol), C2Cl6 (0.71 g, 3.0 mmol), and PPh3 (0.79 g, 3.0 mmol) in DCM (20 mL) was added Et3N (0.30 g, 3.0 mmol) at room temperature and the mixture was stirred at room temperature for 16 h under nitrogen. The reaction mixture was diluted with DCM (50 mL), washed with water (30 mL) and brine (30 mL), dried over Na2SO4, and concentrated in vacuo to give the crude product, which was purified by column chromatography (eluent: DCM / MeOH=0-10 / 1) to give 6-bromo-3-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-[1,2,4]triazolo[4,3-a]pyrazine (190 mg, 69%) as a yellow solid. ESI-MS [M+H] + :369.0.

[0210] Synthesis of 3-chlorobenzyl (3-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-[1,2,4]triazolo[4,3-a]pyrazin-6-yl)carbamate [ka] A mixture of 6-bromo-3-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-[1,2,4]triazolo[4,3-a]pyrazine (60 mg, 0.16 mmol), 3-chlorobenzylcarbamate (30 mg, 0.25 mmol), Pd2(dba)3 (15 mg, 0.016 mmol), Xantphos (19 mg, 0.033 mmol), and Cs2CO3 (0.16 g, 0.49 mmol) in 1,4-dioxane (8 mL) was stirred at 70° C. for 10 h under N2. The reaction mixture was filtered through Celite® and the filter cake was washed with DCM / MeOH (10 / 1, 100 mL). The filtrate was concentrated in vacuo to give the crude product, which was purified by column chromatography (eluent: DCM / MeOH=10 / 1) and preparative HPLC to give the desired product (2.5 mg, 3.3%) as a white solid. ESI-MS [M+H] + :474.1, 1 H NMR (400 MHz, MeOD) δ 9.11 (d, J = 1.4 Hz, 1H), 8.57 (s, 1H), 8.18 (s, 1H), 7.71 (s, 1H), 7.41 (s, 1H), 7.40-7.29 (m, 4H), 7.08 (d, J = 9.2 Hz, 1H), 5.15 (s, 2H), 4.72 (s, 2H), 1.97-1.91 (m, 1H), 1.00-0.93 (m, 2H), 0.73-0.67 (m, 2H).

[0211] Example 15 Synthesis of 1-(3-chlorophenyl)ethyl (4-(((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)amino)pyridin-2-yl)carbamate (I-15) [ka] Synthesis of 1-(3-chlorophenyl)ethyl (2,2,2-trichloroacetyl)carbamate [ka] To a solution of 1-(3-chlorophenyl)ethan-1-ol (1.0 g, 6.4 mmol) in DCM (10 mL) was added 2,2,2-trichloroacetyl isocyanate (1.37 g, 7.3 mmol) at room temperature, and the mixture was stirred at room temperature for 18 h. The mixture was quenched with water (50 mL) and extracted with EtOAc (30 mLx3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, and concentrated in vacuo to give 1-(3-chlorophenyl)ethyl (2,2,2-trichloroacetyl)carbamate (2 g, crude) as a white solid, which was used directly in the next step. ESI-MS [M+H]+: 343.9.

[0212] Synthesis of 1-(3-chlorophenyl)ethyl carbamate [ka] A mixture of 1-(3-chlorophenyl)ethyl (2,2,2-trichloroacetyl)carbamate (1.0 g, crude) and K2CO3 (1.2 g, 8.7 mmol) in MeOH (10 mL) was stirred at room temperature for 2 h. The mixture was quenched with water (50 mL) and extracted with EtOAc (30 mLx3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography (eluent: EtOAc / PE (0-30%)) to give 1-(3-chlorophenyl)ethylcarbamate (500 mg, 78% yield) as a white solid. ESI-MS [M+H]+: 200.0.

[0213] Synthesis of 1-(3-chlorophenyl)ethyl (4-(((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)amino)pyridin-2-yl)carbamate [ka] A mixture of 1-(3-chlorophenyl)ethyl carbamate (70 mg, 0.35 mmol), 2-bromo-N-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)pyridin-4-amine (120 mg, 0.35 mmol), Pd2(dba)3 (32 mg, 0.035 mmol), Xantphos (40 mg, 0.070 mmol), and Cs2CO3 (228 mg, 0.70 mmol) in 1,4-dioxane (5 mL) was degassed with N2 and stirred at 90° C. for 16 h. The mixture was filtered through Celite® and the filter cake was washed with DCM / MeOH (10 / 1, 50 mL). The filtrate was concentrated in vacuo to give the crude product, which was purified by column chromatography (eluent: DCM / MeOH=0-5%) to give 1-(3-chlorophenyl)ethyl (4-(((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)amino)pyridin-2-yl)carbamate (15 mg, 9% yield) as a white solid. ESI-MS [M+H]+: 462.2, 1 H NMR (400 MHz, DMSO) δ 9.73 (s, 1H), 8.30-8.27 (m, 1H), 7.72 (d, J = 5.8 Hz, 1H), 7.61 (s, 1H), 7.51-7.49 (m, 1H), 7.43-7.32 (m, 4H), 7.10-7.03 (m, 2H), 6.98-6.93 (m, 1H), 6.31-6.27 (m, 1H), 5.80-5.73(m, 1H), 4.33 (d, J = 5.8 Hz, 2H), 1.94-1.85 (m, 1H), 1.48 (d, J = 6.6 Hz, 3H), 0.93 - 0.87 (m, 2H), 0.68-0.63 (m, 2H).

[0214] Example 16 Synthesis of 3-chlorobenzyl (1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-imidazo[4,5-c]pyridin-6-yl)carbamate (I-16) [ka] Synthesis of 2-chloro-N-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-5-nitropyridin-4-amine [ka] A mixture of 2,4-dichloro-5-nitropyridine (1 g, 5.18 mmol), (6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methanamine (1.1 g, 6.22 mmol), and DIPEA (2 g, 15.54 mmol) in THF (20 mL) was stirred at 60 °C for 6 h. The mixture was quenched with NaHCO3 (saturated aqueous, 50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography (eluent: DCM / MeOH = 0-6%) to give 2-chloro-N-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-5-nitropyridin-4-amine (1.5 g, 84%) as a white solid. ESI-MS[M+H]+: 344.2.

[0215] 6-Chloro-N 4 Synthesis of -((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)pyridine-3,4-diamine [ka] To a mixture of 2-chloro-N-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-5-nitropyridin-4-amine (1.5 g, 4.37 mmol) and NH4Cl (2.3 g, 43.7 mmol) in EtOH / water (20 ml / 5 mL) was added Fe (2.4 g, 43.7 mmol). The resulting reaction mixture was stirred at 100 °C for 3 h under N2. After cooling to room temperature, the mixture was quenched with water (50 mL) and extracted with DCM (50 mL x 5). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, and concentrated in vacuum. The residue was purified by column chromatography (eluent: DCM / MeOH = 0-5%) to give 6-chloro-N 4-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)pyridine-3,4-diamine (1.2 g, 88%) was obtained as a yellow solid. ESI-MS [M+H] + :314.2.

[0216] Synthesis of 5-(2,2-difluorocyclopropyl)-N,N-bis(4-methoxybenzyl)pyridin-2-amine [ka] 6-Chloro-N in trimethoxymethane (5 ml) 4 A mixture of -((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)pyridine-3,4-diamine (1.2 g, 3.83 mmol) and PTSA (65.0 mg, 0.38 mmol) was stirred at 60° C. for 12 h. Water (50 mL) was added and the mixture was extracted with DCM (50 mL×3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, and concentrated in vacuo to give the crude product, which was purified by column chromatography (eluent: PE / EtOAc=20 / 1 to 2 / 1) to give 6-chloro-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-imidazo[4,5-c]pyridine (500 mg, 40%) as a yellow solid. ESI-MS [M+H]+: 324.2.

[0217] Synthesis of 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(4-methoxybenzyl)-1H-imidazo[4,5-c]pyridin-6-amine [ka] To a mixture of 6-chloro-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-imidazo[4,5-c]pyridine (500 mg, 1.55 mmol), PMBNH2 (318.5 mg, 2.32 mmol), and Cs2CO3 (1.5 g, 4.65 mmol) in DMF (10 mL) was added Pd-PEPPSI-iPent-Cl-o-picoline (134 mg, 0.16 mmol). The reaction mixture was stirred at 85 °C for 16 h under N2. Water (100 mL) was added and the mixture was extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, and concentrated in vacuo to give the crude material, which was purified by column chromatography (eluent: PE / EtOAc = 10 / 1 to 2 / 1) to give 6-chloro-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-imidazo[4,5-c]pyridine (300 mg, 46%) as a yellow solid. ESI-MS [M+H]+: 425.2.

[0218] Synthesis of 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-imidazo[4,5-c]pyridin-6-amine [ka] A solution of 6-chloro-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-imidazo[4,5-c]pyridine (300 mg, 0.71 mmol) in TFA (4 mL) was stirred at room temperature for 12 h. The mixture was concentrated in vacuo and the residue was diluted with NaHCO3 (sat. aq., 50 mL) and extracted with DCM (50 mLx3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4 and concentrated in vacuo. The residue was purified by preparative TLC (DCM / MeOH=20 / 1) to give 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-imidazo[4,5-c]pyridin-6-amine (140 mg, 65%) as a white solid. ESI-MS [M+H] + :305.2.

[0219] Synthesis of 3-chlorobenzyl (1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-imidazo[4,5-c]pyridin-6-yl)carbamate [ka] To a mixture of CDI (29 mg, 0.18 mmol) in THF (3 mL) was added 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-imidazo[4,5-c]pyridin-6-amine (50 mg, 0.16 mmol) at 0° C. and the mixture was stirred at room temperature for 2 h. Then (3-chlorophenyl)methanol (28 mg, 0.20 mmol) was added to it and the mixture was stirred at room temperature for another 18 h. The reaction was quenched with water (30 mL) and extracted with EtOAc (30 mL×3). The organic layer was washed with brine (30 mL), dried over Na2SO4 and concentrated in vacuum. The residue was purified by column chromatography (0 to 5% MeOH / DCM) to give 3-chlorobenzyl (1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-imidazo[4,5-c]pyridin-6-yl)carbamate (22 mg, 29%) as a white solid. ESI-MS [M+H] + :473.1, 1 H NMR (400 MHz, DMSO) δ 10.24 (s, 1H), 8.64 (d, J = 0.9 Hz, 1H), 8.39 (s, 1H), 8.32 (s, 1H), 7.97 (d, J = 0.9 Hz, 1H), 7.73 (s, 1H), 7.51 (s, 1H), 7.43-7.35 (m, 4H), 7.01-6.96 (m, 1H), 5.54 (s, 2H), 5.17 (s, 2H), 1.96-1.85 (m, 1H), 0.95-0.85 (m, 2H), 0.70-0.60 (m, 2H).

[0220] Example 17 Synthesis of 1-(3-chlorophenyl)ethyl (1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-imidazo[4,5-c]pyridin-6-yl)carbamate (I-17) [ka] Synthesis of 1-(3-chlorophenyl)ethyl (1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-imidazo[4,5-c]pyridin-6-yl)carbamate. To a mixture of CDI (29 mg, 0.18 mmol) in THF (3 mL) was added 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-imidazo[4,5-c]pyridin-6-amine (50 mg, 0.16 mmol) at 0° C., and the resulting mixture was stirred at room temperature for 2 h. Then 1-(3-chlorophenyl)ethan-1-ol (31 mg, 0.20 mmol) was added, and the mixture was stirred at room temperature for another 18 h. The reaction was quenched with water (30 mL) and extracted with EtOAc (30 mL×3). The organic layer was washed with brine (30 mL), dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (0 to 5% MeOH / DCM) to give 1-(3-chlorophenyl)ethyl (1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-imidazo[4,5-c]pyridin-6-yl)carbamate (35 mg, 45%) as a white solid. ESI-MS [M+H]+: 487.2. 1H NMR (400 MHz, DMSO) δ 10.19 (s, 1H), 8.64 (d, J = 0.9 Hz, 1H), 8.38 (s, 1H), 8.31 (s, 1H), 7.93 (d, J = 0.9 Hz, 1H), 7.70 (s, 1H), 7.52 (s, 1H), 7.43-7.32 (m, 4H), 7.00-6.95 (m, 1H), 5.83-5.78 (m, 1H), 5.52 (s, 2H), 1.95-1.84(m, 1H), 1.51 (d, J = 6.6 Hz, 3H), 0.92-0.87 (m, 2H), 0.67-0.62 (m, 2H).

[0221] Examples 18 and 19 Synthesis of 3-chlorobenzyl (1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazolo[4,3-c]pyridin-4-yl)carbamate (I-18) and 3-chlorobenzyl (2-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazolo[4,3-c]pyridin-4-yl)carbamate (I-19) [ka] Synthesis of 4-chloro-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazolo[4,3-c]pyridine [ka] To a solution of 2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine (673 mg, 3.26 mmol) in DMF (30 mL) was added 4-chloro-1H-pyrazolo[4,3-c]pyridine (500 mg, 3.26 mmol) and Cs2CO3 (2.13 g, 6.52 mmol) and the mixture was stirred at room temperature for 5 h. Water (100 mL) was added and the mixture was extracted with EtOAc (3x100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, and concentrated in vacuo to give the crude material, which was purified by preparative TLC (DCM / MeOH=50 / 1) to give 4-chloro-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazolo[4,3-c]pyridine and 4-chloro-2-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazolo[4,3-c]pyridine (900 mg, 85%, mixture) as a yellow solid. ESI-MS [M+H]+: 324.1.

[0222] Synthesis of 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(4-methoxybenzyl)-1H-pyrazolo[4,3-c]pyridin-4-amine [ka] To a solution of 4-chloro-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazolo[4,3-c]pyridine (350 mg, 1.08 mmol, mixture) in DMF (1 mL) and DME (1.6 mL) was added (4-methoxyphenyl)methanamine (222 mg, 1.62 mmol), Pd-PEPPSI-iPent-Cl o-picoline (42 mg, 0.05 mmol), and Cs2CO3 (1.05 g, 3.24 mmol). After degassing with N2 for 1 min, the reaction was irradiated at 95 °C in a microwave reactor for 2 h. The mixture was quenched with water (20 mL) and extracted with EtOAc (20 mL x 4). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography (eluent: DCM:MeOH=0-10%) to give 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(4-methoxybenzyl)-1H-pyrazolo[4,3-c]pyridin-4-amine and 2-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(4-methoxybenzyl)-2H-pyrazolo[4,3-c]pyridin-4-amine (300 mg, 66%, mixture) as a yellow oil. ESI-MS [M+H] + :425.2. Synthesis of 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazolo[4,3-c]pyridin-4-amine [ka] A solution of 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(4-methoxybenzyl)-1H-pyrazolo[4,3-c]pyridin-4-amine (300 mg, 0.71 mmol, mixture) in trifluoroacetic acid (10 mL) was stirred for 3 h at 70° C. The mixture was quenched with NaHCO3 (sat. aq., 100 mL) and extracted with EtOAc (30 mL×4). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, and concentrated in vacuo to give 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazolo[4,3-c]pyridin-4-amine and 2-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazolo[4,3-c]pyridin-4-amine (180 mg, 83% yield, mixture) as a yellow oil, which was used without purification. ESI-MS [M+H] + :305.1.

[0223] Synthesis of 3-chlorobenzyl (1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazolo[4,3-c]pyridin-4-yl)carbamate [ka] To a mixture of 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazolo[4,3-c]pyridin-4-amine (180 mg, 0.71 mmol, mixture) in DCM (8 mL) was added CDI (170 mg, 1.05 mmol) and Et3N (266 mg, 2.63 mmol) at room temperature and the mixture was stirred at room temperature for 2 h. (3-Chlorophenyl)methanol (150 mg, 1.05 mmol) was added and the mixture was stirred at room temperature for 16 h. The reaction was quenched with water (30 mL) and then extracted with EtOAc (30 mLx3). The organic layer was washed with brine (30 mL), dried over Na2SO4 and concentrated in vacuo. The residue was purified by preparative TLC (DCM:MeOH=25:1) to give 3-chlorobenzyl (1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazolo[4,3-c]pyridin-4-yl)carbamate (62.8 mg, 19% yield) as a white solid and 3-chlorobenzyl (2-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)carbamate (16.7 mg, 6%) as a white solid. 3-Chlorobenzyl(1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazolo[4,3-c]pyridin-4-yl)carbamate: ESI-MS [M+H]+: 473.1, 1 H NMR (400 MHz, DMSO) δ 10.54 (s, 1H), 8.28 (s, 1H), 8.25 (s, 1H), 8.04-7.97 (m, 1H), 7.62 (s, 1H), 7.53 (s, 1H), 7.49-7.43 (m, 1H), 7.41-7.37 (m, 3H), 7.32 (d, J = 9.3 Hz, 1H), 6.97-6.90 (m, 1H), 5.67 (s, 2H), 5.20 (s, 2H), 1.90-1.83 (m, 1H), 0.89-0.84 (m, 2H), 0.63-0.59 (m, 2H). 3-Chlorobenzyl (2-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)carbamate: ESI-MS [M+H] + :473.1. 1 H NMR (400 MHz, DMSO) δ 10.52 (s, 1H), 8.72 (s, 1H), 8.32 (s, 1H), 7.80 (s, 1H), 7.73 - 7.65 (m, 1H), 7.48 (s, 1H), 7.41-7.35 (m, 4H), 7.11-7.05 (m, 1H), 6.97 (dd, J = 9.4, 1.7 Hz, 1H), 5.68 (s, 2H), 5.15 (s, 2H), 1.92-1.87 m, 1H), 0.90-0.86 (m, 2H), 0.65-0.61 (m, 2H).

[0224] Example 20 Synthesis of 3-chlorobenzyl (1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)carbamate (I-20) [ka] Synthesis of 2-chloro-N-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-5-nitropyridin-4-amine [ka] A mixture of 2,4-dichloro-5-nitropyridine (1 g, 5.18 mmol), (6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methanamine (1.1 g, 6.22 mmol), and DIPEA (2 g, 15.54 mmol) in THF (20 mL) was stirred at 60 °C for 6 h. The mixture was quenched with NaHCO3 (saturated aqueous, 50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography (eluent: DCM / MeOH = 0-6%) to give 2-chloro-N-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-5-nitropyridin-4-amine (1.5 g, 84%) as a white solid. ESI-MS[M+H]+: 344.2.

[0225] 6-Chloro-N 4 Synthesis of -((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)pyridine-3,4-diamine [ka] To a mixture of 2-chloro-N-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-5-nitropyridin-4-amine (1.5 g, 4.37 mmol) and NH4Cl (2.3 g, 43.7 mmol) in EtOH / water (20 ml / 5 mL) was added Fe (2.4 g, 43.7 mmol). The resulting reaction mixture was stirred at 100 °C for 3 h under N2. After cooling to room temperature, the mixture was quenched with water (50 mL) and extracted with DCM (50 mL x 5). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, and concentrated. The residue was purified by column chromatography (eluent: DCM / MeOH = 0-5%) to give 6-chloro-N 4 -((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)pyridine-3,4-diamine (1.2 g, 88%) was obtained as a yellow solid. ESI-MS [M+H] + :314.2.

[0226] Synthesis of 6-chloro-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-[1,2,3]triazolo[4,5-c]pyridine [ka] 6-Chloro-N in AcOH (15 ml) 4 To a solution of -((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)pyridine-3,4-diamine (500 mg, 1.59 mmol) was added a solution of NaNO2 (165 mg, 2.38 mmol) in H2O (15 ml) at room temperature. The resulting solution was stirred at this temperature for 30 min and then extracted with ethyl acetate (30 ml x 3). The combined organic layers were evaporated in vacuum and the residue was purified by chromatography on silica gel (MeOH:DCM = 1:20) to give 6-chloro-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-[1,2,3]triazolo[4,5-c]pyridine (400 mg, 77%) as a yellow solid. ESI-MS [M+H] + :325.1.

[0227] Synthesis of 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(4-methoxybenzyl)-1H-[1,2,3]triazolo[4,5-c]pyridin-6-amine [ka] To a mixture of 6-chloro-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-[1,2,3]triazolo[4,5-c]pyridine (400 mg, 1.23 mmol), PMBNH2 (342 mg, 2. mmol), and Cs2CO3 (1.46 g, 4.5 mmol) in DMF (10 mL) was added Pd-PEPPSI-iPent-Cl-o-picoline (100 mg, 0.12 mmol). The reaction mixture was stirred at 85 °C for 16 h under N2. Water (100 mL) was added and the mixture was extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, and concentrated in vacuo to give the crude product, which was purified by column chromatography (eluent: PE / EtOAc = 10 / 1 to 2 / 1) to give 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(4-methoxybenzyl)-1H-[1,2,3]triazolo[4,5-c]pyridin-6-amine (300 mg, 56%) as a yellow solid. ESI-MS [M+H]+: 426.2.

[0228] Synthesis of 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-[1,2,3]triazolo[4,5-c]pyridin-6-amine [ka] A solution of 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(4-methoxybenzyl)-1H-[1,2,3]triazolo[4,5-c]pyridin-6-amine (300 mg, 0.71 mmol) in TFA (4 mL) was stirred at room temperature for 12 h. The mixture was concentrated and the residue was diluted with NaHCO3 (saturated aqueous, 50 mL) and extracted with DCM (50 mLx3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4 and concentrated in vacuo. The residue was purified by preparative TLC (DCM / MeOH=20 / 1) to give 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-[1,2,3]triazolo[4,5-c]pyridin-6-amine (140 mg, 65%) as a white solid. ESI-MS [M+H] + :306.2.

[0229] Synthesis of 3-chlorobenzyl (1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)carbamate [ka] A mixture of 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-[1,2,3]triazolo[4,5-c]pyridin-6-amine (35 mg, 0.11 mmol), CDI (37 mg, 0.22 mmol), and Et3N (364 mg, 3.6 mmol) in DCM (2 mL) was stirred at 45° C. for 16 h. (3-Chlorophenyl)methanol (196 mg, 1.38 mmol) was added and the mixture was stirred at 45° C. for an additional 2 h. The reaction was quenched with water (30 mL) and extracted with DCM (10 mL×3). The combined organic layers were washed with water (30 mL), dried over anhydrous Na2SO4 and concentrated to give the crude product, which was purified by preparative TLC (eluent: DCM / MeOH=10 / 1) to give 3-chlorobenzyl (1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)carbamate (14.3 mg, 28%) as a white solid. ESI-MS [M+H] + :474.1. 1 H NMR (400 MHz, DMSO) δ 10.64 (s, 1H), 9.17 (s, 1H), 8.31 (s, 1H), 8.08 (s, 1H), 7.80 (s, 1H), 7.50 (s, 1H), 7.42-7.31 (m, 4H), 6.95 (d, J = 8.5 Hz, 1H), 5.98 (s, 2H), 5.17 (s, 2H), 1.91-1.85 (m, 1H), 0.88-0.85 (m, 2H), 0.65-0.61 (m, 2H).

[0230] Example 21 Synthesis of 1-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)ethyl (4-(((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)amino)pyridin-2-yl)carbamate (I-21) [ka] Synthesis of 5-chloro-2-(1H-tetrazol-1-yl)benzaldehyde [ka] To a solution of (5-chloro-2-(1H-tetrazol-1-yl)phenyl)methanol (500 mg, 2.37 mmol) in DCM (20 mL) was added PCC (1.023 g, 4.75 mmol) at room temperature. The mixture was stirred at room temperature for 4 h. The reaction was concentrated to give the crude product, which was purified by silica gel chromatography (eluent: DCM / MeOH=20 / 1) to give 5-chloro-2-(1H-tetrazol-1-yl)benzaldehyde (423 mg, 86%) as a yellow oil. ESI-MS [M+H] + :209.0.

[0231] Synthesis of 1-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)ethan-1-ol [ka] To a solution of 5-chloro-2-(1H-tetrazol-1-yl)benzaldehyde (100 mg, 0.48 mmol) in THF (0.3 mL) was added methylmagnesium bromide (3M in THF, 0.32 mL, 0.96 mmol) at -78 °C under N2. The mixture was stirred at -78 °C for 2 h. The reaction was quenched with saturated aqueous NH4Cl (20 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, and concentrated in vacuo to give the crude product, which was purified by preparative TLC (eluent: DCM / MeOH = 20 / 1) to give 1-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)ethan-1-ol (32 mg, 30%) as a white solid. ESI-MS [M+H] + :225.0.

[0232] Synthesis of 1-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)ethyl (4-(((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)amino)pyridin-2-yl)carbamate [ka] N in DCM (1.5 mL) 4 To a solution of -((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)pyridine-2,4-diamine (20 mg, 0.071 mmol) was added CDI (23 mg, 0.142 mmol) and EtN (0.05 mL, 36 mg, 0.355 mmol) at room temperature. The mixture was stirred at 45° C. for 2 h. Then 1-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)ethan-1-ol (32 mg, 0.14 mmol) was added and the reaction mixture was stirred at 45° C. for 16 h. The reaction mixture was concentrated in vacuo to give the crude material, which was purified by silica gel chromatography (eluent: DCM / MeOH=20 / 1) to give 1-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)ethyl (4-(((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)amino)pyridin-2-yl)carbamate (5.9 mg, 16%) as a white solid. ESI-MS [M+H] + :530.2. 1 H NMR (400 MHz, DMSO) δ 9.91 (s, 1H), 9.78 (s, 1H), 8.29 (s, 1H), 7.87 (d, J = 2.1 Hz, 1H), 7.70-7.66 (m, 3H), 7.60 (s, 1H), 7.37 (d, J = 9.3 Hz, 1H), 7.10 (t, J = 5.5 Hz, 1H), 6.97-6.94 (m, 2H), 6.27 (dd, J = 5.8, 2.0 Hz, 1H), 5.39 (q, J = 6.5 Hz, 1H), 4.31 (d, J = 5.7 Hz, 2H), 1.92-1.87 (m, 1H), 1.43 (d, J = 6.6 Hz, 3H), 0.92-0.88 (m, 2H), 0.68-0.64 (m, 2H).

[0233] Example 22 Synthesis of 5-chloro-2-(1H-tetrazol-1-yl)benzyl (2-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)carbamate (I-22) [ka] Synthesis of 5-chloro-2-(1H-tetrazol-1-yl)benzyl (2-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)carbamate [ka] A mixture of 2-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-amine (10 mg, 0.033 mmol), CDI (16 mg, 0.1 mmol), and Et3N (10 mg, 0.1 mmol) in DCM (2 mL) was stirred at 45° C. for 16 h. (5-chloro-2-(1H-tetrazol-1-yl)phenyl)methanol (35 mg, 0.17 mmol) was added. The mixture was stirred at 45° C. for an additional 2 h. The reaction was quenched with water (30 mL) and extracted with DCM (10 mL×3). The combined organic layers were washed with water (30 mL), dried over anhydrous Na2SO4, and concentrated in vacuo to give the crude product, which was purified by preparative TLC (eluent: DCM / MeOH=10 / 1) to give 5-chloro-2-(1H-tetrazol-1-yl)benzyl (2-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)carbamate (1.6 mg, 9%) as a white solid. ESI-MS [M+H] + :541.1. 1H NMR (400 MHz, DMSO) δ 10.57 (s, 1H), 9.91 (s, 1H), 8.73 (s, 1H), 8.34 (s, 1H), 7.91-7.73 (m, 5H), 7.39 (d, J = 9.3 Hz, 1H), 7.30-6.99 (m, 2H), 5.71 (s, 2H), 5.08 (s, 2H), 1.95-1.89 (m, 1H), 0.94-0.89 (m, 2H), 0.69-0.65 (m, 2H).

[0234] Example 23 Synthesis of 5-chloro-2-(1H-tetrazol-1-yl)benzyl (1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-imidazo[4,5-c]pyridin-6-yl)carbamate (I-23) [ka] Synthesis of 5-chloro-2-(1H-tetrazol-1-yl)benzyl(1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-imidazo[4,5-c]pyridin-6-yl)carbamate. A mixture of 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-imidazo[4,5-c]pyridin-6-amine (49 mg, 0.16 mmol), CDI (162 mg, 1 mmol), and TEA (101 mg, 1 mmol) in THF (5 mL) was stirred at 45° C. for 16 h. (5-chloro-2-(1H-tetrazol-1-yl)phenyl)methanol (210 mg, 1 mmol) was added and the mixture was stirred at 45° C. for an additional 2 h. The reaction was quenched with water (30 mL) and extracted with EtOAc (10 mLx3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, and concentrated in vacuo to give the crude product, which was purified by preparative HPLC to give 5-chloro-2-(1H-tetrazol-1-yl)benzyl (1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-imidazo[4,5-c]pyridin-6-yl)carbamate (10 mg, 12%) as a white solid. ESI-MS [M+H]+: 541.2. 1 H NMR (400 MHz, DMSO) δ = 10.30 (s, 1H), 9.92 (s, 1H), 8.65 (s, 1H), 8.40 (s, 1H), 8.33 (s, 1H), 7.91 (s, 2H), 7.73 (s, 3H), 7.36 (d, J=9.4, 1H), 6.99-6.97 (m, 1H), 5.53 (s, 2H), 5.05 (s, 2H), 1.94-1.85 (m, 1H), 0.93-0.87 (m, 2H), 0.67-0.62 (m, 2H).

[0235] Example 24 Synthesis of 1-(3-chlorobenzyl)-3-(6-(((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)amino)pyrimidin-4-yl)urea (I-24) [ka] Synthesis of 6-chloro-N-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)pyrimidin-4-amine [ka] To a solution of (6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methanamine hydrochloride (4.6 g, 21 mmol) and 4,6-dichloropyrimidine (4.6 g, 31 mmol) in iPrOH (48 mL) was added DIPEA (8.0 g, 62 mmol). The mixture was stirred at 40° C. for 4 h. The reaction mixture was concentrated in vacuo and the residue was purified by silica gel column (eluting with 0-5% MeOH / DCM) to give 6-chloro-N-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)pyrimidin-4-amine (4.2 g, 67%) as a pale solid. ESI-MS [M+H] + :300.2.

[0236] N 4 Synthesis of -((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N6-(2,4-dimethoxybenzyl)pyrimidine-4,6-diamine [ka] A solution of 6-chloro-N-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)pyrimidin-4-amine (1.4 g, 4.7 mmol), (2,4-dimethoxyphenyl)methanamine (1.2 g, 7.2 mmol), and DIPEA (1.8 g, 14 mmol) in i-PrOH (5.0 mL) and 1-methylpyrrolidin-2-one (5.0 mL) was stirred in a sealed tube. After degassing with N2 for 1 min, the resulting mixture was irradiated in a microwave reactor at 160 °C for 8 h. The reaction mixture was then concentrated in vacuo to give the crude product, which was purified by column chromatography on silica gel eluting with 0-10% MeOH / DCM to give N. 4-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N6-(2,4-dimethoxybenzyl)pyrimidine-4,6-diamine (0.79 g, 39%) was obtained as a yellow solid. ESI-MS [M+H] + :431.2.

[0237] N 4 Synthesis of -((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)pyrimidine-4,6-diamine [ka] N in DCM (40 mL) 4 To a mixture of -((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N6-(2,4-dimethoxybenzyl)pyrimidine-4,6-diamine (0.79 g, 1.8 mmol) was added TFA (8.2 mL, 0.11 mol). After stirring at room temperature overnight, the resulting mixture was concentrated in vacuo to give the crude product. NH3 (7.0 N in MeOH) was added to adjust the pH to 12. The resulting mixture was concentrated in vacuo and the residue was purified by silica gel column chromatography eluting with 0-10% MeOH / DCM to give N 4 -((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)pyrimidine-4,6-diamine (0.35 g, 70%) was obtained as a pale solid. ESI-MS [M+H] + :281.1.

[0238] Synthesis of 1-(3-chlorobenzyl)-3-(6-(((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)amino)pyrimidin-4-yl)urea [ka] N in DCM (3.0 mL) 4To a solution of -((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)pyrimidine-4,6-diamine (0.10 g, 0.36 mmol) and CDI (0.29 g, 1.8 mmol) was added Et3N (0.36 g, 3.6 mmol) under nitrogen. After stirring at 40° C. for 2 h, a solution of (3-chlorophenyl)methanamine (0.25 g, 1.8 mmol) in DCM (3.0 mL) was added. The resulting mixture was stirred at room temperature overnight. The mixture was concentrated in vacuo and the residue was purified by preparative TLC (DCM / MeOH=10 / 1) to give 1-(3-chlorobenzyl)-3-(6-(((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)amino)pyrimidin-4-yl)urea (11 mg, 6.8%) as a pale solid. ESI-MS [M+H] + :448.1, 1 H NMR (400 MHz, DMSO) δ 9.13 (s, 1H), 8.28-8.21 (m, 2H), 8.13 (s, 1H), 7.72 (s, 1H), 7.59 (s, 1H), 7.34-7.24 (m, 5H), 6.95 (d, J = 10.9 Hz, 1H), 6.57 (s, 1H), 4.53 (d, J = 9.4 Hz, 2H), 4.35 (d, J = 6.0 Hz, 2H), 1.93-1.87 (m, 1H), 0.92-0.88 (m, 2H), 0.67-0.63 (m, 2H).

[0239] Example 25 Synthesis of 3-(3-chlorophenyl)-N-(6-(((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)amino)pyrimidin-4-yl)azetidine-1-carboxamide (I-25) [ka] Synthesis of tert-butyl 3-(3-chlorophenyl)azetidine-1-carboxylate [ka] To a solution of 3-chlorophenyl)boronic acid (936 mg, 6.0 mmol) and tert-butyl 3-iodoazetidine-1-carboxylate (1.7 g, 6.0 mmol) in IPA (20 mL) was added NiI2 (373 mg, 1.2 mmol). The reaction mixture was stirred at 80° C. for 16 h. The reaction was diluted with water (50 mL) and extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, and concentrated in vacuo to give tert-butyl 3-(3-chlorophenyl)azetidine-1-carboxylate (360 mg) as a light yellow solid, which was used without further purification. ESI-MS [M+H]+: 268.1.

[0240] Synthesis of 3-(3-chlorophenyl)azetidine [ka] To a solution of tert-butyl 3-(3-chlorophenyl)azetidine-1-carboxylate (360 mg) in DCM (10 mL) was added HCl (2.0 M solution in EtOH, 2 mL). The resulting mixture was stirred at room temperature for 16 h. The reaction was concentrated in vacuo to give 3-(3-chlorophenyl)azetidine as the hydrochloride salt (250 mg) as a white solid, which was used without further purification. ESI-MS [M+H] + :168.2.

[0241] Synthesis of 3-(3-chlorophenyl)-N-(6-(((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)amino)pyrimidin-4-yl)azetidine-1-carboxamide [ka] 3-(3-chlorophenyl)azetidine hydrochloride (50 mg, crude) in THF (10 mL), N 4To a solution of -((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)pyrimidine-4,6-diamine (50 mg, 0.18 mmol) and TEA (55 mg, 0.54 mmol) was added triphosgene (35 mg, 0.12 mmol). The reaction mixture was stirred at 60° C. for 16 h. After cooling to 25° C., water (50 mL) was added and the mixture was extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine (60 mL), dried over anhydrous Na2SO4 and concentrated in vacuo to give the crude product, which was purified by column chromatography (eluent: DCM / MeOH=20 / 1) to give 3-(3-chlorophenyl)-N-(6-(((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)amino)pyrimidin-4-yl)azetidine-1-carboxamide (15 mg, yield: 18%) as a white solid. ESI-MS [M+H] + :474.2. 1 H NMR (400 MHz, DMSO) δ 8.42 (s, 1H), 8.30 (s, 1H), 7.80 (s, 1H), 7.53 (s, 1H), 7.42-7.18 (t, J = 16.2 Hz, 5H), 6.36 (s, 1H), 4.94 (s, 2H), 4.20 (s, 2H), 3.77 (s, 3H), 2.05-1.94 (m, 1H), 0.99-0.93 (m, 2H), 0.75-0.65 (m, 2H).

[0242] Example 26 Synthesis of (4-chloropyridin-2-yl)methyl (6-(((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)amino)pyrimidin-4-yl)carbamate (I-26) [ka] Synthesis of (4-chloropyridin-2-yl)methylcarbamate [ka] To a mixture of (4-chloropyridin-2-yl)methanol (0.5 g, 3.5 mmol) in DCM (10 mL) was added 2,2,2-trichloroacetyl isocyanate (0.79 g, 4.2 mmol) at 0 °C. The mixture was stirred at 0 °C for 2 h. It was then concentrated in vacuum and the residue was redissolved in MeOH (10 mL). K2CO3 (1.4 g, 10.5 mmol) was added. The mixture was stirred at room temperature for 1 h. The mixture was diluted with water (50 mL) and extracted with EtOAc (30 mLx3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4 and concentrated in vacuum to give the crude product. The crude product was purified by column chromatography on silica gel (eluent: EtOAc / PE = 0-50%) to give (4-methylpyrimidin-2-yl)methylcarbamate (0.46 g, 71% yield) as a white solid. ESI-MS[M+H]+: 187.1.

[0243] Synthesis of (4-chloropyridin-2-yl)methyl (6-(((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)amino)pyrimidin-4-yl)carbamate [ka] A mixture of (4-chloropyridin-2-yl)methyl carbamate (75 mg, 0.40 mmol), 6-chloro-N-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)pyrimidin-4-amine (0.10 g, 0.33 mmol), Pd2(dba)3 (45 mg, 0.050 mmol), Xantphos (29 mg, 0.050 mmol), and Cs2CO3 (0.14 g, 1.0 mmol) in 1,4-dioxane (5 mL) was stirred at 80° C. for 6 h under N2. After cooling to room temperature, the mixture was filtered through Celite® and the filter cake was washed with DCM / MeOH (10 / 1, 50 mL). The filtrate was concentrated in vacuo to give the crude product, which was purified by preparative TLC (eluent: DCM / MeOH=8 / 1) to give (4-chloropyridin-2-yl)methyl (6-(((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)amino)pyrimidin-4-yl)carbamate (4.3 mg, 2.4% yield) as a pale yellow solid. ESI-MS [M+H]+: 450.2, 1 H NMR (400 MHz, DMSO) δ 10.30 (s, 1H), 8.54 (d, J = 5.3 Hz, 1H), 8.29 (s, 1H), 8.18 (s, 1H), 7.85 (s, 1H), 7.65 (s, 1H), 7.61 (s, 1H), 7.50 (dd, J = 5.3, 1.9 Hz, 1H), 7.36 (d, J = 9.3 Hz, 1H), 7.01 (s, 1H), 6.95 (dd, J = 9.3, 1.6 Hz, 1H), 5.21 (s, 2H), 4.56 (s, 2H), 1.94 - 1.87 (m, 1H), 0.93-0.87 (m, 2H), 0.67-0.64 (m, 2H).

[0244] Example 27 Synthesis of 1-((4-chloropyridin-2-yl)methyl)-3-(6-(((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)amino)pyrimidin-4-yl)urea (I-27) [ka] Synthesis of 1-((4-chloropyridin-2-yl)methyl)-3-(6-(((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)amino)pyrimidin-4-yl)urea. 4 To a solution of -((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)pyrimidine-4,6-diamine (50 mg, 0.18 mmol) was added di(1H-imidazol-1-yl)methanone (87 mg, 0.54 mmol) and EtN (0.11 g, 1.1 mmol). After stirring at 40° C. for 5 h, a solution of (4-chloropyridin-2-yl)methanamine (76 mg, 0.53 mmol) in DCM (1.0 mL) was added. The resulting mixture was stirred at room temperature overnight. The mixture was concentrated in vacuo and the residue was purified by preparative HPLC to give 1-((4-chloropyridin-2-yl)methyl)-3-(6-(((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)amino)pyrimidin-4-yl)urea (4.2 mg, 5.2%) as a white solid. ESI-MS [M+H] + :449.2. 1 H NMR (400 MHz, DMSO) δ = 9.22 (s, 1H), 8.50 (d, J=5.1 Hz, 1H), 8.40 (s, 1H), 8.29 (s, 1H), 8.14 (s, 1H), 7.72 (s, 1H), 7.60 (s, 1H), 7.48-7.39 (m, 2H), 7.37 - 7.35 (m, 1H), 6.95 (d, J = 10.0 Hz, 1H), 6.58 (s, 1H), 4.53 (s, 2H), 4.45 (d, J = 5.6 Hz, 2H), 1.94-1.87 (m, 1H), 0.93-0.84 (m, 2H), 0.69-0.60 (m, 2H).

[0245] Example 28 Synthesis of (4-chloropyridin-2-yl)methyl (6-((2R,4S)-2-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)-4-hydroxypyrrolidin-1-yl)pyrimidin-4-yl)carbamate (I-28) [ka] Synthesis of 2-((2R,4S)-1-(6-bromopyrimidin-4-yl)-4-((tert-butyldimethylsilyl)oxy)pyrrolidin-2-yl)-6-cyclopropylimidazo[1,2-a]pyridine [ka] To a solution of 2-((2R,4S)-4-((tert-butyldimethylsilyl)oxy)pyrrolidin-2-yl)-6-cyclopropylimidazo[1,2-a]pyridine (714 mg, 2 mmol) and 4,6-dibromopyrimidine (569 mg, 2.4 mmol) in iPrOH (10 mL) was added DIPEA (775 mg, 6 mmol). The mixture was stirred at 60° C. for 2 h. The reaction mixture was concentrated in vacuo and the residue was purified by column purification on silica gel (eluting with 0-5% MeOH / DCM) to give 2-((2R,4S)-1-(6-bromopyrimidin-4-yl)-4-((tert-butyldimethylsilyl)oxy)pyrrolidin-2-yl)-6-cyclopropylimidazo[1,2-a]pyridine (617 mg, 60%) as a yellow solid. ESI-MS [M+H] + :515.2.

[0246] Synthesis of (4-chloropyridin-2-yl)methyl (6-((2R,4S)-4-((tert-butyldimethylsilyl)oxy)-2-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)pyrrolidin-1-yl)pyrimidin-4-yl)carbamate [ka] To a solution of 2-((2R,4S)-1-(6-bromopyrimidin-4-yl)-4-((tert-butyldimethylsilyl)oxy)pyrrolidin-2-yl)-6-cyclopropylimidazo[1,2-a]pyridine (0.15 g, 0.29 mmol), (4-chloropyridin-2-yl)methyl carbamate (65 mg, 0.35 mmol), and CsCO (0.28 g, 0.86 mmol) in 1,4-dioxane (2.0 mL) was added Pd(dba) (26 mg, 0.028 mmol) and Xantphos (16 mg, 0.028 mmol). The reaction mixture was stirred at 80° C. for 2 h under nitrogen. The reaction mixture was filtered through Celite® and the filter cake was washed with DCM / MeOH (10 / 1, 20 mL). The filtrate was concentrated in vacuo to give the crude material, which was purified by column chromatography on silica gel eluting with 20-100% EA / PE to give (4-chloropyridin-2-yl)methyl (6-((2R,4S)-4-((tert-butyldimethylsilyl)oxy)-2-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)pyrrolidin-1-yl)pyrimidin-4-yl)carbamate (80 mg, 44%) as a yellow solid. ESI-MS [M+H] + :620.2.

[0247] Synthesis of (4-chloropyridin-2-yl)methyl (6-((2R,4S)-2-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)-4-hydroxypyrrolidin-1-yl)pyrimidin-4-yl)carbamate [ka] To a mixture of (4-chloropyridin-2-yl)methyl (6-((2R,4S)-4-((tert-butyldimethylsilyl)oxy)-2-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)pyrrolidin-1-yl)pyrimidin-4-yl)carbamate (0.25 g, 0.40 mmol) in 1,4-dioxane (1.0 mL) was added HCl (1.0 mL, 4N in 1,4-dioxane) at room temperature. After stirring at room temperature for 1 h, the resulting mixture was concentrated in vacuo and purified by preparative HPLC to give (4-chloropyridin-2-yl)methyl (6-((2R,4S)-2-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)-4-hydroxypyrrolidin-1-yl)pyrimidin-4-yl)carbamate (30 mg, yield: 15%) as a pale solid. ESI-MS [M+H] + :506.1, 1 H NMR (400 MHz, CD3OD ) δ 8.45 (d, J = 5.3 Hz, 1H), 8.24-8.10 (m, 2H), 7.63 (s, 1H), 7.51 (s, 1H), 7.42-7.35 (m, 2H), 7.08 (d, J = 8.4 Hz, 1H), 6.99 (s, 1H), 5.21 (s, 3H), 4.61-4.57 (m, 1H), 3.99-3.95 (m, 2H), 2.46-2.36 (m, 2H), 1.95-1.88 (m, 1H), 0.98-0.94 (m, 2H), 0.71-0.67 (m, 2H).

[0248] Example 29 Synthesis of 1-((4-chloropyrimidin-2-yl)methyl)-3-(6-(((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)amino)pyrimidin-4-yl)urea (I-29) [ka] Synthesis of tert-butyl (6-chloropyrimidin-4-yl)((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)carbamate [ka] A mixture of 6-chloro-N-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)pyrimidin-4-amine (1 g, 3.36 mmol), (Boc)2O (870 mg, 4 mmol), DMAP (81 mg, 0.66 mmol) and TEA (1.01 g, 10 mmol) in THF (30 mL) was stirred at 80° C. for 16 h. The mixture was concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography (DCM:MeOH=10:1) to give the product (1 g, 74.4% yield) as a white solid. ESI-MS [M+H] + :400.3.

[0249] Synthesis of tert-butyl (6-azidopyrimidin-4-yl)((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)carbamate [ka] A mixture of tert-butyl (6-chloropyrimidin-4-yl)((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)carbamate (800 mg, 2.0 mmol) and NaN3 (390 mg, 6.0 mmol) in DMF (30 mL) was stirred at 90° C. for 3 h. The mixture was diluted with H2O (60 mL) and then extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, and then concentrated to give the crude product (700 mg, crude), which was used in the next step without further purification. ESI-MS [M+H]+: 407.2.

[0250] Synthesis of tert-butyl (6-aminopyrimidin-4-yl)((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)carbamate [ka] A mixture of tert-butyl (6-azidopyrimidin-4-yl)((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)carbamate (700 mg, crude) and Pd / C (100 mg, 10%) in MeOH (10 mL) was stirred at room temperature for 10 min under H2. The mixture was filtered and concentrated in vacuo to give the crude product (600 mg, crude) as a white solid, which was used in the next step without further purification. ESI-MS [M+H]+: 381.2.

[0251] Synthesis of tert-butyl ((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl) (6-((phenoxycarbonyl)amino)pyrimidin-4-yl)carbamate [ka] To a mixture of tert-butyl (6-aminopyrimidin-4-yl)((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)carbamate (100 mg, crude) and DIPEA (170 mg, 1.31 mmol) in DCM (10 mL) was added phenyl carbonochloridate (82 mg, 0.525 mol) at −78° C. The mixture was allowed to warm to room temperature and stirred for 16 h. The mixture was concentrated in vacuo to give a crude residue which was purified by preparative TLC (PE:EtOAc=1:1) to give the product (100 mg, 60% for 3 steps) as a white solid.

[0252] Synthesis of tert-butyl (6-(3-((4-chloropyrimidin-2-yl)methyl)ureido)pyrimidin-4-yl)((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)carbamate [ka] To a mixture of tert-butyl ((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)(6-((phenoxycarbonyl)amino)pyrimidin-4-yl)carbamate (50 mg, 0.1 mmol) and DIPEA (28.7 mg, 0.77 mmol) in 1,4-dioxane (5 mL) was added (4-chloropyrimidin-2-yl)methanamine (28.7 mg, 0.2 mmol). The mixture was stirred at 70° C. for 16 h. The mixture was concentrated in vacuo to give the crude product, which was purified by preparative TLC (DCM:MeOH=10:1) to give the product (30 mg, 54.5%) as a white solid. ESI-MS [M+H]+: 550.2.

[0253] Synthesis of 1-((4-chloropyrimidin-2-yl)methyl)-3-(6-(((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)amino)pyrimidin-4-yl)urea [ka] To a solution of tert-butyl (6-(3-((4-chloropyrimidin-2-yl)methyl)ureido)pyrimidin-4-yl)((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)carbamate (25 mg, 0.045 mmol) in DCM (4 mL) was added TFA (1 mL). The resulting mixture was stirred at room temperature for 1 h and then concentrated in vacuo. The residue was purified by preparative TLC (DCM:MeOH=10:1) to give the product (12.3 mg, 60% yield) as a white solid. ESI-MS [M+H] + :450.1. 1H NMR (400 MHz, DMSO) δ 9.45-9.39 (m, 1H), 8.77 (d, J = 5.4 Hz, 1H), 8.64 (s, 1H), 8.21 (s, 2H), 7.99 (s, 2H), 7.79-7.73 (m, 1H), 7.64-7.62 (m, 2H), 6.73 (s, 1H), 4.71 (s, 2H), 4.56 (d, J = 5.7 Hz, 2H), 2.13-2.02 (m, 1H), 1.09-0.97 (m, 2H), 0.81-0.72 (m, 2H).

[0254] Example 30 Synthesis of 1-(6-(((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)amino)pyrimidin-4-yl)-3-((4-methoxypyrimidin-2-yl)methyl)urea (I-30) [ka] Synthesis of tert-butyl ((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl) (6-((phenoxycarbonyl)amino)pyrimidin-4-yl)carbamate [ka] A mixture of tert-butyl (6-aminopyrimidin-4-yl)((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)carbamate (20 mg, 0.05 mmol), phenyl carbonochloridate (15 mg, 0.10 mmol), and pyridine (20 mg, 0.25 mmol) in THF (10 mL) was stirred at 50° C. for 16 h. The mixture was concentrated in vacuo to give crude tert-butyl ((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)(6-((phenoxycarbonyl)amino)pyrimidin-4-yl)carbamate (60 mg, crude) as a colorless oil, which was used without further purification. ESI-MS [M+H] + :501.2.

[0255] Synthesis of tert-butyl ((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl) (6-(3-((4-methoxypyrimidin-2-yl)methyl)ureido)pyrimidin-4-yl)carbamate [ka] To a solution of tert-butyl ((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl) (6-((phenoxycarbonyl)amino)pyrimidin-4-yl)carbamate (60 mg, crude from previous step) in 1,4-dioxane (4.0 mL) was added a solution of (4-methoxypyrimidin-2-yl)methanamine (14 mg, 0.10 mmol) and DIPEA (0.13 g, 1.0 mmol) in 1,4-dioxane (2.0 mL). After stirring at 70° C. for 16 h, the resulting mixture was concentrated in vacuo to give the crude product, which was purified by preparative TLC (DCM / MeOH=10 / 1) to give tert-butyl ((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)(6-(3-((4-methoxypyrimidin-2-yl)methyl)ureido)pyrimidin-4-yl)carbamate (10 mg, 37%, 2 steps) as a white solid. ESI-MS [M+H] + :546.2.

[0256] Synthesis of 1-(6-(((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)amino)pyrimidin-4-yl)-3-((4-methoxypyrimidin-2-yl)methyl)urea [ka] To a mixture of tert-butyl ((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)(6-(3-((4-methoxypyrimidin-2-yl)methyl)ureido)pyrimidin-4-yl)carbamate (10 mg, 0.018 mmol) in 1,4-dioxane (4.0 mL) was added HCl (1.0 mL, 4N in 1,4-dioxane) at 0° C. After stirring at 25° C. for 2 h, the resulting mixture was concentrated in vacuo to give the crude product, which was purified by preparative TLC (DCM / MeOH=10 / 1) to give 1-(6-(((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)amino)pyrimidin-4-yl)-3-((4-methoxypyrimidin-2-yl)methyl)urea (1.3 mg, yield: 16%) as a white solid. ESI-MS [M+H] + :446.2. 1 H NMR (400 MHz, DMSO) δ 9.30 (s, 1H), 8.46 (d, J = 5.8 Hz, 1H), 8.28 (s, 1H), 8.13 (s, 1H), 7.75-7.66 (m, 1H), 7.58 (s, 1H), 7.35 (d, J = 9.3 Hz, 1H), 6.94 (dd, J = 9.3, 1.6 Hz, 1H), 6.81 (d, J = 5.8 Hz, 1H), 6.56-6.48 (m, 1H), 4.56-4.48 (m, 2H), 4.45 (d, J = 5.4 Hz, 2H), 3.92 (s, 3H), 1.94-1.85 (m, 1H), 0.93-0.86 (m, 2H), 0.68-0.62 (m, 2H).

[0257] Example 31 Synthesis of N-(6-((2R,4S)-2-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)-4-hydroxypyrrolidin-1-yl)pyrimidin-4-yl)-3-phenylazetidine-1-carboxamide (I-31) [ka] Synthesis of 2-(azetidin-3-yl)pyrimidine hydrochloride [ka] A mixture of tert-butyl 3-(pyrimidin-2-yl)azetidine-1-carboxylate (300 mg, 1.28 mmol) in HCl (4 M solution in 1,4-dioxane, 3 mL) was stirred at room temperature for 1 h. The reaction mixture was concentrated in vacuo to give 2-(azetidin-3-yl)pyrimidine hydrochloride (150 mg, crude) as a white solid. ESI-MS [M+H] + :136.2.

[0258] Synthesis of 4-nitrophenyl 3-(pyrimidin-2-yl)azetidine-1-carboxylate [ka] A mixture of 2-(azetidin-3-yl)pyrimidine hydrochloride (150 mg, crude), 4-nitrophenyl carbonochloridate (177 mg, 0.88 mmol), and DIPEA (568 mg, 4.4 mmol) in DCM (5 mL) was stirred at room temperature for 16 h. The reaction was concentrated in vacuo to give the crude product, which was purified by preparative TLC (eluent: DCM / MeOH=50 / 1) to give 4-nitrophenyl 3-(pyrimidin-2-yl)azetidine-1-carboxylate (200 mg, 76%) as a colorless oil. ESI-MS [M+H] + :301.2.

[0259] Synthesis of 6-((2R,4S)-4-((tert-butyldimethylsilyl)oxy)-2-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)pyrrolidin-1-yl)pyrimidin-4-amine [ka] A mixture of 2-((2R,4S)-4-((tert-butyldimethylsilyl)oxy)pyrrolidin-2-yl)-6-cyclopropylimidazo[1,2-a]pyridine (200 mg, 0.56 mmol), 6-chloropyrimidin-4-amine (72 mg, 0.56 mmol), and DIPEA (361 mg, 2.8 mmol) in i-PrOH (5 mL) was stirred in a sealed tube. After degassing with N2 for 1 min, the reaction was irradiated in a microwave reactor at 140 °C for 8 h. The reaction was concentrated in vacuo to give the crude product, which was purified by preparative TLC (eluent: DCM / MeOH=10 / 1) to give 6-((2R,4S)-4-((tert-butyldimethylsilyl)oxy)-2-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)pyrrolidin-1-yl)pyrimidin-4-amine (160 mg, 63%) as a yellow solid. ESI-MS [M+H] + :451.2.

[0260] Synthesis of N-(6-((2R,4S)-4-((tert-butyldimethylsilyl)oxy)-2-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)pyrrolidin-1-yl)pyrimidin-4-yl)-3-phenylazetidine-1-carboxamide [ka] To a solution of 6-((2R,4S)-4-((tert-butyldimethylsilyl)oxy)-2-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)pyrrolidin-1-yl)pyrimidin-4-amine (45 mg, 0.1 mmol) in dry DMF (3 mL) was added NaH (12 mg, 60% dispersion in mineral oil, 0.3 mmol) at 0° C. After the mixture was stirred at 0° C. for 0.5 h, a solution of 4-nitrophenyl 3-phenylazetidine-1-carboxylate (30 mg, 0.1 mmol) in dry DMF (2 mL) was added and the resulting mixture was stirred at room temperature for an additional 1 h. The reaction mixture was quenched with saturated aqueous NH4Cl (20 mL) and extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, and concentrated in vacuo to give the crude product, which was purified by preparative TLC (eluent: DCM / MeOH=20 / 1) to give N-(6-((2R,4S)-4-((tert-butyldimethylsilyl)oxy)-2-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)pyrrolidin-1-yl)pyrimidin-4-yl)-3-phenylazetidine-1-carboxamide (20 mg, 33%) as a yellow solid. ESI-MS [M+H] + :610.2.

[0261] Synthesis of N-(6-((2R,4S)-2-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)-4-hydroxypyrrolidin-1-yl)pyrimidin-4-yl)-3-phenylazetidine-1-carboxamide [ka] A solution of N-(6-((2R,4S)-4-((tert-butyldimethylsilyl)oxy)-2-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)pyrrolidin-1-yl)pyrimidin-4-yl)-3-phenylazetidine-1-carboxamide (20 mg, 0.033 mmol) in HCl (4 M solution in 1,4-dioxane, 2 mL) was stirred at room temperature for 1 h. The reaction mixture was concentrated in vacuo to give the crude product, which was purified by preparative HPLC to give N-(6-((2R,4S)-2-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)-4-hydroxypyrrolidin-1-yl)pyrimidin-4-yl)-3-phenylazetidine-1-carboxamide (5 mg, 31%) as a white solid. ESI-MS [M+H] + :496.2. 1 H NMR (400 MHz, CD3OD) δ 8.13 (s, 2H), 7.63 (s, 1H), 7.44-7.29 (m, 5H), 7.27 - 7.22 (m, 1H), 7.12-7.04 (m, 2H), 5.19 (s, 1H), 4.87 (s, 1H), 4.65-4.52 (m, 1H), 4.46-4.42 (m, 2H), 4.02-3.97 (m, 3H), 3.84-3.78 (m, 1H), 2.50-2.45 (m, 2H), 2.00-1.79 (m, 1H), 1.02-0.86 (m, 2H), 0.79-0.56 (m, 2H).

[0262] Example 32 Synthesis of 1-(4-chlorobicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)-3-(6-(((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)amino)pyrimidin-4-yl)urea (I-32) [ka] Synthesis of 2-carboxy-5-chlorobenzenediazonium chloride [ka] To a mixture of 2-amino-4-chlorobenzoic acid (5.0 g, 29.3 mmol) in EtOH (50 mL) and MTBE (50 mL) was added concentrated HCl (20 mL) at 0° C. Then isoamyl nitrite (3.4 g, 29.3 mmol) was added at 0° C. The reaction mixture was stirred at 0° C. for 1 h. The reaction was warmed to room temperature and filtered. The precipitate was dried in vacuum to give the product 2-carboxy-5-chlorobenzenediazonium chloride (4.0 g, 63%) as a white solid.

[0263] Synthesis of ethyl 4-chlorobicyclo[4.2.0]octa-1,3,5-triene-7-carboxylate [ka] A mixture of 4-chloro-2-(chlorodiazenyl)benzoic acid (4.0 g, 18.3 mmol), methyl acrylate (7.9 g, 91.5 mmol), and propylene (3.8 g, 91.5 mmol) in 1,2-dichloroethane (50.0 mL) was stirred at 60° C. for 2 h. The reaction was concentrated in vacuo to give the crude product, which was purified by column chromatography (eluent: DCM / MeOH=15 / 1) to give ethyl 4-chlorobicyclo[4.2.0]octa-1,3,5-triene-7-carboxylate (1.1 g, 28%) as a colorless oil. ESI-MS [M+H] + :211.2.

[0264] Synthesis of 4-chlorobicyclo[4.2.0]octa-1,3,5-triene-7-carboxamide [ka] To a mixture of ethyl 4-chlorobicyclo[4.2.0]octa-1,3,5-triene-7-carboxylate (1.0 g, 4.76 mmol) in THF (20 mL) was added NH4OH (20 mL) at 0°C. The reaction mixture was stirred at room temperature for 48 h. Water (30 mL) was added and extracted with EtOAc (50 mLx3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, and concentrated in vacuo to give 4-chlorobicyclo[4.2.0]octa-1,3,5-triene-7-carboxamide (700 mg, crude) as a yellow solid, which was used in the next step without further purification. ESI-MS [M+H] + :182.2.

[0265] Synthesis of 4-chlorobicyclo[4.2.0]octa-1,3,5-trien-7-amine [ka] To a mixture of 4-chlorobicyclo[4.2.0]octa-1,3,5-trien-7-carboxamide (350 mg, crude) in MeCN / H2O (10 mL / 5 mL) was added (CF3CO2)2PhI (1.63 g, 3.32 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 16 h. The reaction was quenched with water (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, and concentrated in vacuum to give the crude product, which was purified by silica gel column chromatography (eluent: DCM / MeOH = 20 / 1) to give 4-chlorobicyclo[4.2.0]octa-1,3,5-trien-7-amine (100 mg, 27%) as a yellow oil. ESI-MS [M+H] + :154.2.

[0266] Synthesis of 1-(4-chlorobicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)-3-(6-(((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)amino)pyrimidin-4-yl)urea [ka] 4-Chlorobicyclo[4.2.0]octa-1,3,5-trien-7-amine (31 mg, 0.2 mmol) in DCM (5 mL), N 4 A mixture of -((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)pyrimidine-4,6-diamine (56 mg, 0.2 mmol) and CDI (65 mg, 0.4 mmol) was stirred at room temperature for 5 h. The reaction was quenched with water (20 mL) and extracted with DCM (30 mLx3). 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 HPLC to give 1-(4-chlorobicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)-3-(6-(((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)amino)pyrimidin-4-yl)urea (5 mg, 5%) as a white solid. ESI-MS [M+H] + :460.2. 1 H NMR (400 MHz, DMSO) δ 9.01 (s, 1H), 8.42-8.30 (m, 2H), 8.12-8.10 (m, 1H), 7.75 (s, 1H), 7.64-7.60 (m, 1H), 7.38-7.20 (m, 3H), 6.97-6.94 (m, 1H), 6.62 (s, 1H), 5.25-5.20 (m, 1H), 4.53 (s, 2H), 3.64-3.55 (m, 1H), 3.02-2.95 (m, 1H), 1.94-1.87 (m, 1H), 0.93-0.88 (m, 2H), 0.68-0.64 (m, 2H).

[0267] Example 33 Synthesis of N-(6-((2R,4S)-2-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)-4-hydroxypyrrolidin-1-yl)pyrimidin-4-yl)-3-(pyrimidin-2-yl)azetidine-1-carboxamide (I-33) [ka] Synthesis of 2-(azetidin-3-yl)pyrimidine hydrochloride [ka] A mixture of tert-butyl 3-(pyrimidin-2-yl)azetidine-1-carboxylate (300 mg, 1.28 mmol) in HCl (4 M solution in 1,4-dioxane, 5 mL) was stirred at room temperature for 1 h. The reaction mixture was concentrated in vacuo to give 2-(azetidin-3-yl)pyrimidine as the hydrochloride salt (200 mg, crude) as a yellow solid. ESI-MS [M+H] + :136.2.

[0268] Synthesis of 4-nitrophenyl 3-(pyrimidin-2-yl)azetidine-1-carboxylate [ka] To a mixture of 2-(azetidin-3-yl)pyrimidine hydrochloride (200 mg, crude) and DIPEA (453 mg, 3.51 mmol) in DCM (10.0 mL) was added a solution of 4-nitrophenyl carbonochloridate (353 mg, 1.76 mmol) in DCM (5.0 mL) at 0° C. The reaction mixture was stirred at room temperature for 1 h. The reaction was quenched with water (20 mL) and extracted with DCM (20 mL×3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, and concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography (eluent: DCM / MeOH=50 / 1) to give 4-nitrophenyl 3-(pyrimidin-2-yl)azetidine-1-carboxylate (200 mg, 52% (for two steps)) as a yellow solid. ESI-MS [M+H] + :301.2.

[0269] Synthesis of N-(6-((2R,4S)-4-((tert-butyldimethylsilyl)oxy)-2-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)pyrrolidin-1-yl)pyrimidin-4-yl)-3-(pyrimidin-2-yl)azetidine-1-carboxamide [ka] To a solution of 6-((2R,4S)-4-((tert-butyldimethylsilyl)oxy)-2-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)pyrrolidin-1-yl)pyrimidin-4-amine (45 mg, 0.1 mmol) in dry DMF (2.0 mL) was added LiHMDS (1 M in THF, 0.3 mL) at 0° C. The resulting mixture was stirred at 0° C. for 0.5 h. Then a solution of 4-nitrophenyl 3-(pyrimidin-2-yl)azetidine-1-carboxylate (30 mg, 0.1 mmol) in dry DMF (1 mL) was added and stirred at room temperature for another 1 h. The reaction was quenched with saturated aqueous NH4Cl (20 mL) and extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, and concentrated in vacuo to give the crude product, which was purified by preparative TLC (eluent: DCM / MeOH=20 / 1) to give N-(6-((2R,4S)-4-((tert-butyldimethylsilyl)oxy)-2-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)pyrrolidin-1-yl)pyrimidin-4-yl)-3-(pyrimidin-2-yl)azetidine-1-carboxamide (30 mg, 49%) as a yellow solid. ESI-MS [M+H] + :612.2.

[0270] Synthesis of N-(6-((2R,4S)-2-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)-4-hydroxypyrrolidin-1-yl)pyrimidin-4-yl)-3-(pyrimidin-2-yl)azetidine-1-carboxamide [ka] A mixture of N-(6-((2R,4S)-4-((tert-butyldimethylsilyl)oxy)-2-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)pyrrolidin-1-yl)pyrimidin-4-yl)-3-(pyrimidin-2-yl)azetidine-1-carboxamide (30 mg, 0.05 mmol) in HCl (4 M solution in 1,4-dioxane, 2 mL) was stirred at room temperature for 1 h. The reaction mixture was concentrated in vacuo to give the crude material, which was purified by preparative HPLC to give N-(6-((2R,4S)-2-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)-4-hydroxypyrrolidin-1-yl)pyrimidin-4-yl)-3-(pyrimidin-2-yl)azetidine-1-carboxamide (12 mg, 48%) as a white solid. ESI-MS [M+H] + :498.2. 1 H NMR (400 MHz, CD3OD) δ 8.77 (d, J = 4.9 Hz, 2H), 8.13 (s, 2H), 7.62 (s, 1H), 7.37-7.33 (m, 2H), 7.17-6.96 (m, 2H), 5.16 (s, 1H), 4.59-4.56 (m, 1H), 4.54-4.21 (m, 4H), 4.20-3.84 (m, 3H), 2.44-2.43 (m, 2H), 1.99-1.83 (m, 1H), 1.05-0.83 (m, 2H), 0.78-0.51 (m, 2H).

[0271] Example 34 Synthesis of (4-methylpyrimidin-2-yl)methyl (6-(((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)amino)pyrimidin-4-yl)carbamate (I-34) [ka] Synthesis of 6-bromo-N-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)pyrimidin-4-amine [ka] To a solution of (6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methanamine hydrochloride (446 mg, 2 mmol) and 4,6-dibromopyrimidine (569 mg, 2.4 mmol) in iPrOH (10 mL) was added DIPEA (775 mg, 6 mmol). The mixture was stirred at 60° C. for 4 h. The reaction mixture was concentrated in vacuo and the residue was purified by silica gel column (eluting with 0-5% MeOH / DCM) to give 6-bromo-N-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)pyrimidin-4-amine (475 mg, 69%) as a yellow solid. ESI-MS [M+H]+: 345.2.

[0272] Synthesis of (4-methylpyrimidin-2-yl)methylcarbamate [ka] To a solution of (4-methylpyrimidin-2-yl)methanol (500 mg, 4 mmol) in DCM (15 mL) was added 2,2,2-trichloroacetyl isocyanate (1.5 g, 8 mmol) at 0° C. The resulting mixture was stirred at 0° C. for 1 h. The mixture was then concentrated in vacuo and then redissolved in MeOH (15 mL). K2CO3 (1.67 g, 12 mmol) was added and the mixture was stirred at room temperature for 3 h. The mixture was diluted with water (50 mL) and extracted with EtOAc (20 mL×3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, and then concentrated in vacuo to give the crude product. The crude product was purified by preparative TLC (DCM:MeOH=10:1) to give (4-methylpyrimidin-2-yl)methyl carbamate (150 mg, 22.5% yield) as a white solid. ESI-MS[M+H]+: 168.1.

[0273] Synthesis of (4-methylpyrimidin-2-yl)methyl (6-(((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)amino)pyrimidin-4-yl)carbamate [ka] A mixture of (4-methylpyrimidin-2-yl)methyl carbamate (100 mg, 0.60 mmol), 6-bromo-N-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)pyrimidin-4-amine (162 mg, 0.47 mmol), Pd2(dba)3 (110 mg, 0.12 mmol), Xantphos (139 mg, 0.24 mmol), and Cs2CO3 (587 mg, 1.8 mmol) in 1,4-dioxane (15 mL) was stirred at 70° C. for 16 h under N2. After cooling to room temperature, the mixture was filtered through Celite® and the filter cake was washed with DCM / MeOH (10 / 1, 50 mL). The filtrate was concentrated in vacuo to give the crude material, which was purified by preparative HPLC to give (4-methylpyrimidin-2-yl)methyl (6-(((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)amino)pyrimidin-4-yl)carbamate (29 mg, 14% yield) as a white solid. ESI-MS [M+H]+: 431.2, 1 H NMR (400 MHz, DMSO) δ 10.27 (s, 1H), 8.62 (d, J = 5.1 Hz, 1H), 8.32-8.26 (m, 1H), 8.17 (s, 1H), 7.78 (s, 1H), 7.59 (s, 1H), 7.38-7.29 (m, 2H), 6.99-6.91 (m, 2H), 5.23 (s, 2H), 4.55 (s, 2H), 2.45 (s, 3H)1.96 - 1.85 (m, 1H), 0.95-0.85 (m, 2H), 0.69-0.61 (m, 2H).

[0274] Example 35 Inhibitory activity of exemplary compounds against plasma kallikrein. Compounds were evaluated for inhibition of human activated kallikrein enzyme in two assay formats using a fluorescent peptide substrate. In one assay format, the concentrations of reagents were as follows: 20 mM Tris pH 7.5, 1 mM EDTA, 150 mM sodium chloride, 0.1% PEG-400, 0.1% Triton X-100, 500 pM activated kallikrein enzyme, 300 uM Pro-Phe-Arg-7-amido-4-methylcoumarin (PFR-AMC) substrate. The enzyme and inhibitor were pre-incubated for 30 minutes at room temperature before initiating the reaction with the substrate. After initiation with the substrate, the reaction was incubated for 10 minutes at room temperature and the fluorescence emission at 460 nm from 380 nm excitation was measured in a microplate reader. In another assay format, the concentrations of the reagents were as follows: 20 mM Tris pH 7.5, 1 mM EDTA, 150 mM sodium chloride, 0.1% PEG-400, 0.1% Triton X-100, 5 pM activated kallikrein enzyme, 300 uM PFR-AMC substrate. The enzyme and inhibitor were pre-incubated for 30 minutes at room temperature before initiating the reaction with the substrate. After initiation with the substrate, the reaction was incubated for 18 hours at room temperature and the fluorescence emission at 460 nm from 380 nm excitation was measured in a microplate reader.

[0275] Table 2 provides the results of the assay in a format using the 500 pM activated kallikrein assay. For the compounds listed in Table 2, the EC 50 Values ​​are reported according to the following ranges: A ≦ 5.0 nM; <B≦50nM;50nM<C≦500nM;500nM<D≦9000nM;9000nM<E。 [Table 2]

[0276] Example 36 Pure human and rat plasma assays To analyze the inhibition of plasma kallikrein in an ex vivo environment, the potency of compounds was measured in a contact pathway activation plasma assay. In a fluorescent peptide substrate assay, test compounds dissolved in DMSO were added to sodium citrate-collected human or rat plasma in a 96-well microplate. Alternatively, citrated plasma was collected from rats to which compounds were administered orally or IV. 10 nM human FXIIa (Enzyme Research Laboratories) diluted in PKa buffer (20 mM Tris-HCl, pH 7.5, 150 mM NaCl, 1 mM EDTA, 0.1% PEG-8000, and 0.1% Triton X-100) was added to the plasma, followed by 100 μM profluorescent synthetic plasma kallikrein substrate PFR-AMC (also diluted in PKa buffer). The final plasma concentration in the reaction was 78%. Fluorescence was immediately monitored in a microplate reader with excitation / emission wavelengths of 360 nm / 480 nm, respectively, over a time period of 5 minutes. The resulting linear increase in fluorescence emission (reflecting PKa proteolysis of the PFR-AMC substrate) was fitted to extract the proteolysis rate (fluorescence units over time), which was then plotted against compound inhibitor concentration. The resulting plot was fitted to a standard 4-parameter IC50 / IC90 equation to determine the minimum / maximum values, IC50 / 90, and slope. All experimental steps were performed at room temperature. Table 3 provides the results of the assay.

[0277] For the compounds listed in Table 3, IC 90 Values ​​are reported according to the following ranges: A≦2500 nM; <B≦7500nM;7500nM<C≦15000nM。 [Table 3]

[0278] While multiple embodiments of the invention have been described, it will be apparent that the basic examples may be modified to provide other embodiments that utilize the compounds and methods of the invention, and therefore, it will be understood that the scope of the invention is to be defined by the appended claims rather than by the specific embodiments set forth by way of example.

[0279] Exemplary Enumerated Embodiments 1. Compound of Formula I: [ka] or a pharma- ceutically acceptable salt thereof, Cy A is phenylene or a 5- to 6-membered monocyclic heteroarylene having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, or a 7- 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; 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, or 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur; Each R is independently hydrogen or an optionally substituted C 1-6 is an aliphatic group; Cy Bis selected from phenyl, 8-10 membered bicyclic aryl, 5-6 membered heteroaryl having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, or 7-10 membered heteroaryl having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur; Cy B 0 to 5 -R B is substituted with a group; Each R B is oxo, halogen, haloalkyl, -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 a 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from aliphatic, oxygen, nitrogen, or sulfur, or a 5-6 membered heteroaryl having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur; L is an optionally substituted C 1-3 A hydrocarbon chain, wherein 1 to 3 methylene units are optionally and independently -O-, -NR z or L is an optionally substituted 5-6 membered saturated or partially unsaturated heterocyclene having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur; Each R z is hydrogen, -(CH2) 0-3 OR, -(CH2) 0-3 C(O)OR or any substituted C 1-6 independently selected from aliphatic groups; X is -O- or -NR y - and; R y is hydrogen or an optionally substituted C 1-6 is an aliphatic group; L' is a covalent bond or an optionally substituted C 1-3A hydrocarbon chain, and the carbon of L' is optionally joined to R y may be taken together with to form a 3- to 7-membered heterocyclic ring; Each R 3 , R 4 , R 5 , R 6 , and R 7 is hydrogen or -L C -R C are independently selected from Each L C is a covalent bond or an optionally substituted C 1-6 one to three methylene units independently selected from the hydrocarbon chain are optionally and independently replaced with -O- or -NR-; Each R C means halogen, haloalkyl, -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, Cy C , or C 1-6 independently selected from optionally substituted groups selected from aliphatic; Each Cy C are independently selected from a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 2 heteroatoms independently selected from oxygen, nitrogen, or sulfur, a 5- to 6-membered monocyclic heteroaryl having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, a 6- to 12-membered saturated or partially unsaturated fused bicyclic heterocyclyl having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, or sulfur, a bridged bicyclic ring, or a 6- to 12-membered saturated or partially unsaturated bicyclic spiroheterocyclyl having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, or sulfur; C 0 to 4 -L D -R D is substituted with a group; Each L D is a covalent bond or an optionally substituted C 1-6one to three methylene units independently selected from the hydrocarbon chain are optionally and independently replaced with -O- or -NR-; Each R D is oxo, halogen, haloalkyl, -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, or 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur; R 8 is hydrogen, -OR, or an optionally substituted C 1-6 aliphatic groups).

[0280] 2. 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 The compound of embodiment 1, wherein the compound is substituted with a group.

[0281] 3. 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 The compound of embodiment 1 or 2, wherein the compound is substituted with a group.

[0282] 4. Cy A teeth, [ka] The compound of any one of embodiments 1-3, selected from the group consisting of: wherein * represents the point of attachment to L.

[0283] 5. Cy A is 0 to 1 R A The compound of any one of embodiments 1-3, wherein the compound is pyridinediyl substituted with a group.

[0284] 6. Cy A is 0 to 1 R A The compound of any one of embodiments 1-3, wherein the compound is pyrimidinediyl substituted with a group.

[0285] 7. Cy A is 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 The compound of embodiment 1, wherein the compound is substituted with a group.

[0286] 8. Cy A is triazolopyridinediyl, imidazopyridinediyl, or triazolopyrazinediyl, and Cy A is 0 to 1 -R A The compound of embodiment 7, wherein the compound is substituted with a group.

[0287] 9. Cy B is selected from phenyl and 5-6 membered heteroaryl having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur; Cy B 0 to 4 -R B The compound according to any one of the preceding embodiments, wherein the compound is substituted with a group.

[0288] 10. Cy B is phenyl, and Cy B 0 to 3 -R B The compound according to any one of the preceding embodiments, wherein the compound is substituted with a group.

[0289] 11. Cy B is a 6-membered heteroaryl having 1 to 3 nitrogen atoms; Cy B 0 to 4 -R BThe compound of any one of embodiments 1 to 9, wherein the compound is substituted with a group.

[0290] 12. Cy B 0 to 2 -R B The compound of any one of the preceding embodiments, wherein the pyrimidinyl group is substituted with a Cy group. B 0 to 2 -R B A pyridinyl group substituted with a group.

[0291] 13. Cy B teeth, [ka] The compound of any one of the preceding embodiments, selected from the group consisting of:

[0292] 14.Each R B is halogen, -OR, or C 1-6 The compound of any one of the preceding embodiments, wherein the optionally substituted group is selected from aliphatic, or a 5-membered heteroaryl having 1 to 4 heteroatoms independently selected from oxygen, nitrogen, and sulfur.

[0293] 15.L is an optionally substituted C 1-3 A hydrocarbon chain in which one methylene unit is -O- or -NR z The compound according to any one of the preceding embodiments, optionally replaced with -.

[0294] 16. L is an optionally substituted C2 hydrocarbon chain, one methylene unit of which is -NR z The compound according to any one of the preceding embodiments, optionally replaced with - or -O-.

[0295] 17. L is an optionally substituted C2 hydrocarbon chain; Cy A The methylene unit connected to is -NR z The compound according to any one of the preceding embodiments, wherein - or -O- is replaced.

[0296] 18. L is an optionally substituted C2 hydrocarbon chain; Cy A The methylene unit connected to is -NR z The compound according to any one of the preceding embodiments, wherein - is replaced with.

[0297] 19. L is an optionally substituted C2 hydrocarbon chain; Cy A is replaced with -O-.

[0298] 20.L is *-NHCH2- (where * is Cy A represents a point of attachment to

[0299] 21.L is *-OCH2- (wherein * is Cy A represents the point of attachment to

[0300] 22. The compound of any one of embodiments 1-14, wherein L is an optionally substituted 5-membered saturated or partially unsaturated heterocyclene having one heteroatom independently selected from oxygen, nitrogen, and sulfur. In some embodiments, L is an optionally substituted pyrrolidinediyl group.

[0301] 23. L is [ka] (In the formula, * represents Cy A 23. The compound of any one of embodiments 1-14 or 22, wherein:

[0302] 24.L is for Cy A and [ka] The compound of any one of the preceding embodiments, comprising a two atom spacer between:

[0303] 25. A compound according to any one of the preceding embodiments, wherein X is -O-.

[0304] 26.X is -NR y The compound of any one of the preceding embodiments, wherein

[0305] 27.R y is hydrogen.

[0306] 28.R y is an arbitrarily substituted C 1-6 The compound of embodiment 26, wherein the group is an aliphatic group.

[0307] 29. L' is an optionally substituted C 1-3 The compound of any one of the preceding embodiments, which is a hydrocarbon chain.

[0308] 30. The compound according to any one of the preceding embodiments, wherein L' is -CH(CH3)-.

[0309] 31.L' is [ka] (In the formula, * represents Cy B The compound of any one of the preceding embodiments, wherein

[0310] 32. L' is -(CH2) 0-4 R° or -(CH2) 0-4 A methylene unit optionally substituted with OR°, where R° is hydrogen or C 1-6 The compound of any one of the preceding embodiments, which is aliphatic.

[0311] 33. The compound according to any one of embodiments 1-28, wherein L' is CH2.

[0312] 34. The carbon of L' can be optionally R zThe compound according to any one of the preceding embodiments, which may be taken together with

[0313] 35. The carbon of L' is R y The compound of embodiment 34, wherein, together with

[0314] 36.R 3 The compound of any one of the preceding embodiments, wherein is hydrogen.

[0315] 37.R 4 The compound of any one of the preceding embodiments, wherein is hydrogen.

[0316] 38.R 5 The compound of any one of the preceding embodiments, wherein is hydrogen.

[0317] 39.R 6 is hydrogen or L C -R C Selected from L C is a covalent bond, and R C is halogen, -N(R)2, -OR, Cy C , or any substituted C 1-6 The compound of any one of the preceding embodiments, wherein the compound is selected from an aliphatic group.

[0318] 40. Cy C 0 to 4 L D -R D The compound according to embodiment 37, wherein the compound is a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl substituted with a group.

[0319] 41. Cy C 0 to 4 L D -R D The compound of embodiment 38, wherein the R is a cyclopropyl group substituted with a group.

[0320] 42. Cy C The compound of any one of the preceding embodiments, wherein is an unsubstituted cyclopropyl group.

[0321] 43.R 7 The compound of any one of the preceding embodiments, wherein is hydrogen.

[0322] 44.R 8 The compound of any one of the preceding embodiments, wherein is hydrogen.

[0323] 45. The compound has formula II-a or II-b: [ka] or a pharma- ceutically acceptable salt thereof.

[0324] 46. ​​The compound has the formula III-a-1, III-b-1, III-a-2, III-b-2, III-a-3, or III-b-3: [ka] or a pharma- ceutically acceptable salt thereof.

[0325] 47. The compound has the formula IV-a-1, IV-b-1, IV-a-2, or IV-b-2 [ka] or a pharma- ceutically acceptable salt thereof.

[0326] 48. The compound has formula V: [ka] or a pharma- ceutically acceptable salt thereof.

[0327] 49. The compound has the formula VI-a, VI-b, or VI-c: [ka] or a pharma- ceutically acceptable salt thereof.

[0328] 50. The compound of any one of the preceding embodiments, wherein the compound is selected from compounds I-1 to I-34, or a pharma- ceutically acceptable salt thereof.

[0329] 51. A pharmaceutical composition comprising a compound according to any one of the preceding embodiments.

[0330] 52. A pharmaceutical composition comprising a compound according to any one of the preceding embodiments, further comprising a pharma- ceutically acceptable excipient.

[0331] 53. The composition of embodiment 51 or 52, wherein the composition is suitable for oral administration.

[0332] 54. A method of treating a plasma kallikrein mediated disease or disorder using a compound or composition according to any one of the preceding embodiments.

[0333] 55. The method of embodiment 54, wherein the disease or disorder is hereditary angioedema.

[0334] 56. The method of embodiment 54, wherein the disease or disorder is diabetic macular edema.

[0335] 57. A method for treating hereditary angioedema, comprising administering to a patient in need thereof a compound or composition according to any one of the preceding embodiments.

[0336] 58. 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 embodiments.

[0337] 59. The method of any one of embodiments 55 or 57, wherein administration of the compound partially or completely inhibits, delays the onset of, reduces the severity of, and / or reduces the incidence of, one or more symptoms, characteristics, and / or causes of hereditary angioedema.

[0338] 60. The method of embodiment 59, wherein the compound is administered orally.

Claims

1. Compounds of Formula I: 【Chemistry 1】 or a pharma- ceutically acceptable salt thereof, Cy Ａ is phenylene or a 5- to 6-membered monocyclic heteroarylene having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, or a 7- to 12-membered bicyclic heteroarylene having 1 to 4 heteroatoms independently selected from oxygen, nitrogen, and sulfur; Cy is Ａ is 0 to 4 -R Ａ is 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 , and C １－６ independently selected from optionally substituted groups selected from aliphatic, phenyl, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, and 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, and sulfur; Each R is independently hydrogen or an optionally substituted C １－６ is an aliphatic group; Cy Ｂ is selected from phenyl, 8-10 membered bicyclic aryl, 5-6 membered heteroaryl having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, and 7-10 membered heteroaryl having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur; Cy Ｂ is 0 to 5 -R Ｂ is substituted with a group; Each R Ｂ is oxo, halogen, haloalkyl, -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 , and C １－６ independently selected from optionally substituted groups selected from 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from aliphatic, oxygen, nitrogen, and sulfur, and 5- or 6-membered heteroaryl having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur; L is an optionally substituted C １－３ is a hydrocarbon chain, 1 to 3 methylene units are optionally and independently -O-, -NR ｚ -, -S-, -SO-, or -SO ２ -; or L is an optionally substituted 5- or 6-membered saturated or partially unsaturated heterocyclene having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur; 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; X is -O- or -NR ｙ - and R ｙ is hydrogen or an optionally substituted C １－６ is an aliphatic group; L' is a covalent bond or an optionally substituted C １－３ is a hydrocarbon chain, and the carbon of L′ is optionally ｙ may be taken together with to form a 3- to 7-membered heterocyclic ring; Each R ３ , R ４ , R ５ , R ６ , and R ７ is hydrogen and -L Ｃ -R Ｃ are independently selected from Each L Ｃ represents a covalent bond and an optionally substituted C １－６ wherein 1 to 3 methylene units independently selected from the hydrocarbon chain are optionally and independently replaced with -O- or -NR-; Each R Ｃ is halogen, haloalkyl, -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 , Cy Ｃ , and C １－６ independently selected from optionally substituted groups selected from aliphatic; Each Cy Ｃ are independently selected from 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, and sulfur, 5- to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, 6- to 12-membered saturated or partially unsaturated fused bicyclic heterocyclyl having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, bridged bicyclic rings, and 6- to 12-membered saturated or partially unsaturated bicyclic spiroheterocyclyl having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur; Ｃ 0 to 4 -L Ｄ -R Ｄ is substituted with a group; Each L Ｄ represents a covalent bond and an optionally substituted C １－６ wherein 1 to 3 methylene units independently selected from the hydrocarbon chain are optionally and independently replaced with -O- or -NR-; Each R Ｄ is oxo, halogen, haloalkyl, -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, or 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur; R ８ is hydrogen, -OR, and optionally substituted C １－６ aliphatic groups).

2. Cy Ａ is a 5-6 membered monocyclic heteroarylene having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur; Cy Ａ is 0 to 4 -R Ａ The compound of claim 1 , which is substituted with a group.

3. Cy Ａ teeth, 【Chemistry 2】 3. The compound of claim 1 or 2, selected from the group consisting of: wherein * represents the point of attachment to L.

4. Cy Ａ is a 7-12 membered bicyclic heteroarylene having 1 to 4 heteroatoms independently selected from oxygen, nitrogen, and sulfur; Cy Ａ is 0 to 4 -R Ａ The compound of claim 1 , which is substituted with a group.

5. Cy Ａ is triazolopyridinediyl, imidazopyridinediyl, or triazolopyrazinediyl; Cy is Ａ is 0 to 1 -R Ａ The compound of claim 1 or 4, which is substituted with a group.

6. Cy Ｂ is selected from phenyl and 5-6 membered heteroaryl having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur; Cy Ｂ is 0 to 4 -R Ｂ The compound according to any one of claims 1 to 5, which is substituted with a group.

7. Cy Ｂ teeth, 【Chemistry 3】 The compound according to any one of claims 1 to 6, selected from the group consisting of:

8. Each R Ｂ is halogen, -OR, and C １－６ The compound according to any one of claims 1 to 7, wherein the optionally substituted group is selected from aliphatic, or a 5-membered heteroaryl having 1 to 4 heteroatoms independently selected from oxygen, nitrogen, and sulfur.

9. L is an optionally substituted C １－３ A hydrocarbon chain, each methylene unit being -O- or -NR ｚ A compound according to any one of claims 1 to 8, optionally replaced by -.

10. L is *-NHCH ２ - or *-OCH ２ - (wherein * represents Cy Ａ 10. The compound according to any one of claims 1 to 9, wherein

11. 9. The compound of any one of claims 1 to 8, wherein L is an optionally substituted 5-membered saturated or partially unsaturated heterocyclene having one heteroatom independently selected from oxygen, nitrogen, and sulfur.

12. L' is an optionally substituted C １－３ The compound according to any one of claims 1 to 11, which is a hydrocarbon chain.

13. L'は、-CH(CH ３ )-、CH ２ 、 【Chemistry 4】 (In the formula, * represents Cy Ｂ 13. The compound according to any one of claims 1 to 12, wherein

14. The carbon of L′ is optionally ｚ The compound according to any one of claims 1 to 11, which may be taken together with

15. The carbon of L′ is R ｙ 17. The compound of claim 16, which together with

16. R ３ The compound according to any one of claims 1 to 15, wherein is hydrogen.

17. R ４ The compound according to any one of claims 1 to 16, wherein is hydrogen.

18. R ５ The compound according to any one of claims 1 to 17, wherein is hydrogen.

19. R ６ is hydrogen or L Ｃ -R Ｃ is selected from L Ｃ is a covalent bond, R Ｃ is halogen, -N(R) ２ , -OR, Cy Ｃ and optionally substituted C １－６ The compound according to any one of claims 1 to 18, selected from aliphatic groups.

20. Cy Ｃ The compound according to any one of claims 1 to 19, wherein is an unsubstituted cyclopropyl group.

21. R ７ The compound according to any one of claims 1 to 20, wherein is hydrogen.

22. The compound has formula II-a or II-b: 【Chemistry 5】 2. The compound of claim 1, which is:

23. The compounds have the formula III-a-1, III-b-1, III-a-2, III-b-2, III-a-3, or III-b-3: 【Chemistry 6】 2. The compound of claim 1, which is:

24. The compound has the formula IV-a-1, IV-b-1, IV-a-2, or IV-b-2 【Chemistry 7】 2. The compound of claim 1, which is:

25. The compound has formula V: 【Chemistry 8】 2. The compound of claim 1, which is:

26. The compounds have formula VI-a, VI-b, or VI-c: 【Chemistry 9】 2. The compound of claim 1, which is:

27. The compound is 【Chemistry 10】 【change】 【change】 【change】 or a pharma- ceutically acceptable salt thereof.

28. A pharmaceutical composition comprising a compound according to any one of claims 1 to 27.

29. A compound or composition according to any one of claims 1 to 28 for use in the treatment of a plasma kallikrein mediated disease or disorder.

30. 30. The compound or composition of claim 29, wherein the disease or disorder is hereditary angioedema or diabetic macular edema.

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