Heteroaryl plasma kallikrein inhibitors

Abstract

To provide heteroaryl plasma kallikrein inhibitors.SOLUTION: The present invention provides compounds and compositions which are useful as inhibitors of plasma kallikrein and which exhibit desirable characteristics as inhibitors. The present disclosure is based, at least in part, on the development of a number of compounds which bind to plasma kallikrein and effectively inhibit its activity. Accordingly, provided herein are compounds and uses thereof for targeting pKal and / or treating pKal-mediated diseases and disorders.SELECTED DRAWING: None

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application is a joint venture of "HETEROARYL PLASMA" filed on September 18, 2019. This application claims priority to and benefit of U.S. Provisional Patent Application No. 62 / 902,333, entitled "KALLIKREIN INHIBITORS," the entire contents of which are incorporated herein by reference. [Background technology]

[0002] Plasma kallikrein (pKal) is a serine protease zymogen in blood that is converted to its catalytically active form by coagulation factor XIIa and contributes to the innate inflammatory response and the intrinsic blood coagulation cascade. Mechanisms leading to activation of this pathway in vivo include interaction with polyphosphate released from activated platelets and the lack of C1 inhibitor (C1-INH), the main physiological inhibitor of pKal. pKal-mediated cleavage of high-molecular-weight kininogen generates bradykinin (BK), a potent vasodilator and pro-inflammatory nonapeptide, which activates the bradykinin 2 receptor. Subsequent cleavage of BK by carboxypeptidases generates des-Arg9-BK, which activates the B1 receptor. 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] pKal is also associated with numerous disorders, including hereditary angioedema (HAE), an autosomal dominant disease characterized by painful, unpredictable, recurrent inflammatory attacks affecting the hands, feet, face, abdomen, genitourinary tract, and larynx. The prevalence of HAE is uncertain but estimated to be approximately 1 case per 50,000 people, with no known differences between racial groups. HAE is caused by a deficiency (type I) or dysfunction (type II) of C1-INH, which inhibits pKal, bradykinin, and other serine proteases in the blood. Individuals with hereditary angioedema (HAE) lack C1-INH, resulting in excessive bradykinin production, which in turn leads to painful, debilitating, and potentially fatal swelling attacks. Left untreated, HAE can result in a mortality rate as high as 40%, primarily due to upper airway obstruction. Summary of the Invention [Means for solving the problem]

[0004] The present disclosure is based, at least in part, on the development of a number of compounds that bind to and effectively inhibit the activity of plasma kallikrein. Accordingly, provided herein are compounds and uses thereof for targeting pKal and / or treating diseases or disorders mediated by pKal.

[0005] In some embodiments, the present invention provides a compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof, wherein Het A , L, R', R'', R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9each of which is defined and described in classes and subclasses herein. In certain embodiments, the invention provides compounds of Formulas (I)-(III-b), as defined and described in classes and subclasses herein.

[0006] In some embodiments, the present invention also provides methods of using the compounds of Formulas (I)-(III-b). DETAILED DESCRIPTION OF THE INVENTION

[0007] A.Definition Compounds of the present invention include those generally described above and further exemplified by the classes, subclasses, and chemical species disclosed herein. As used herein, the following definitions shall apply unless otherwise specified. For purposes of the present invention, chemical elements are identified according to the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed. In addition, the general principles of organic chemistry are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry", 5th Ed., Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are incorporated herein by reference.

[0008] Abbreviations used herein have their ordinary meaning within the chemical and biological arts. The chemical structures and formulas set forth herein are constructed according to the standard rules of chemical valency known in the chemical arts.

[0009] As used herein, the term "aliphatic" or "aliphatic group" means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that may be fully saturated or may contain 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 a "carbocyclyl," "alicyclic," or "cycloalkyl"), and has a single point of attachment to the rest of the molecule. Unless otherwise specified, aliphatic groups contain 1-6 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms, and in yet other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms. In some embodiments, "alicyclic" (or "carbocyclyl" or "cycloalkyl"). ") refers to a monocyclic C3-C7 hydrocarbon that is fully saturated or contains one or more units of unsaturation, but is not aromatic, and has a single point of attachment to the rest of the molecule. Suitable aliphatic groups include, but are not limited to, straight-chain or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups, and hybrids thereof, such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl, or (cycloalkyl)alkenyl.

[0010] The term "heteroatom" refers to one or more 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).

[0011] As used herein, the term "unsaturated" means that a moiety has one or more units of unsaturation.

[0012] The term "alkylene" refers to a divalent alkyl group. An "alkylene chain" is a polymethylene group, i.e., -(CH) n -, where n is a positive integer, preferably 1 to 6, 1 to 4, 1 to 3, 1 to 2, or 2 to 3. A substituted alkylene chain is a polymethylene group in which one or more methylene group hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for substituted aliphatic groups.

[0013] The term "halogen" means F, Cl, Br, or I.

[0014] The term "aryl" refers to monocyclic and bicyclic ring systems having a total of 5 to 10 ring members, wherein at least one ring in the system is aromatic and each ring in the system has 3 to 7 ring members. The term "aryl" may be used interchangeably with the term "aryl ring." In some embodiments, an 8- to 10-membered bicyclic aryl group is an optionally substituted naphthyl ring. In certain embodiments of the present invention, "aryl" refers to 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, naphthalimidyl, phenanthridinyl, or tetrahydronaphthyl.

[0015] 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. As used herein, the terms "heteroaryl" and "heteroar-" 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. 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-oxazine-3 (4H)-one. Heteroaryl groups can be monocyclic or bicyclic. The term "heteroaryl" can be used interchangeably with the terms "heteroaryl ring," "heteroaryl group," or "heteroaromatic ring," any of which includes optionally substituted rings.

[0016] As used herein, the terms "heterocyclyl," "heterocyclic radical," and "heterocycle" are used interchangeably and refer to a stable 5- to 7-membered monocyclic or 7- to 10-membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated and that, in addition to carbon atoms, has one or more, preferably 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 to 3 heteroatoms selected from oxygen, sulfur, or nitrogen, the nitrogen can be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or + It may be NR (as in N-substituted pyrrolidinyl).

[0017] A heterocycle can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure, and any of the ring atoms can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, but are not limited to, tetrahydrofuranyl, 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.

[0018] As used herein, the term "partially unsaturated" refers to a ring moiety that includes at least one double or triple bond. The term "partially unsaturated" is intended to encompass rings with multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties, as defined herein.

[0019] As used herein, and unless otherwise stated, 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 a 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.

[0020] As described herein, the compounds of the invention may contain "optionally substituted" moieties when specified. In general, the term "substituted," whether preceded by the term "optionally," means that one or more hydrogens of the specified moiety have been replaced with a suitable substituent. 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 are the same at all positions. The substituents may be one or different. 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 remain 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.

[0021] 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°; optionally substituted with R° -(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; -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) 0~4S(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 straight or branched chain alkylene)ON(R°)2; or -(C 1~4 straight or branched chain alkylene)C(O)ON(R°)2, where each R° may be optionally substituted as defined below and independently represents hydrogen, C 1~6 Aliphatic, -CH2Ph, -O(CH2) 0~1 Ph, -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 the atom(s) between them form a 3-12 membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below.

[0022] Suitable monovalent substituents on R° (or the ring formed by two independent occurrences of R° together with the atoms interposed therebetween) are independently halogen, —(CH2), 0~2 R ● ,-(Halo R ● ), -(CH2) 0~2 OH, -(CH2) 0~2 OR ● , -(CH2) 0~2 CH(OR ● )2;-O(HaloR ● ), -CN, -N3, -(CH2) 0~2 C(O)R ● , -(CH2) 0~2 C(O)OH, -(CH2) 0~2 C(O)OR● , -(CH2) 0~2 SR ● , -(CH2) 0~2 SH, -(CH2) 0~2 NH2, -(CH2) 0~2 NHR ● , -(CH2) 0~2 NR ● 2, -NO2, -SiR ● 3. -OSiR ● 3. -C(O)SR ● , -(C 1~4 Straight or branched chain alkylene)C(O)OR ● , or -SSR ● where each R ● is unsubstituted or, if preceded by "halo", is substituted with one or more halogens only, and C 1~4 aliphatic, -C H2Ph, -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 =0 and =S.

[0023] 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-, wherein each R * is hydrogen, optionally substituted as defined below. 1~6An unsubstituted 5-6 membered saturated, partially unsaturated, or aryl ring having an aliphatic or 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Preferred divalent substituents attached to adjacent substitutable carbon atoms of an "optionally substituted" group include -O(CR * 2) 2~3 O-, wherein each R * is hydrogen, optionally substituted as defined below. 1~6 It is selected from an aliphatic or unsubstituted 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0024] R * Suitable substituents on the aliphatic group include halogen, -R ● ,-(Halo R ● ), -OH, -OR ● , -O(HaloR ● ), -CN, -C(O)OH, -C(O)OR ● , -NH2, -NHR ● , -NR ● 2, or -NO2, wherein each R ● is unsubstituted or, if preceded by "halo", is substituted with only one or more halogens, and independently represents C 1~4 Aliphatic, -CH2Ph, -O(CH2) 0~1 Ph, or a 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0025] Suitable substituents on a substitutable nitrogen of an "optionally substituted" group include -R † , -NR † 2. -C(O)R † , -C(O)OR † , -C(O)C(O)R † , -C(O)CHC(O)R † , -S(O)2R † , -S(O)NR † 2. -C(S)NR †2. -C(NH)NR † 2, or -N(R † )S(O)2R † wherein each R † are independently hydrogen, optionally substituted as defined below, C 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, regardless of the above definitions, R † two independent occurrences of together with the atom(s) between them 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.

[0026] R † Suitable substituents on the aliphatic group are independently halogen, —R ● ,-(Halo R ● ), -OH, -OR ● , -O(HaloR ● ), -CN, -C(O)OH, -C(O)OR ● , -NH2, -NHR ● , -NR ● 2, or -NO2, 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.

[0027] As used herein, the term "pharmaceutically acceptable salt" refers to a salt that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and that is commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al., ref. Pharmaceutically acceptable salts are described in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, which is incorporated herein by reference.

[0028] In certain embodiments, the neutral forms of the compounds are regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. In some embodiments, the parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents.

[0029] 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. Accordingly, 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. Additionally, unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, the replacement of hydrogen by deuterium or tritium, or 13 C-enriched carbon or 14 Compounds having the present structures including the replacement of a carbon with a 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.

[0030] As used herein, the term "oxo" means an oxygen that is double bonded to a carbon atom, thereby forming a carbonyl.

[0031] symbol" [ka] " indicates the point of attachment of a chemical moiety to the rest of the molecule or chemical formula, except when used as a bond to indicate unknown or mixed stereochemistry.

[0032] 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.

[0033] A "dosing regimen" (or "optimal treatment 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 requires one or more doses. In some embodiments, the dosing regimen is made up of multiple doses, each spaced apart by the same length of time from each other; in some embodiments, the dosing regimen is made up of multiple doses, with at least two different time periods separating the individual doses.

[0034] As understood from the context, a "reference" sample or subject is a sample or subject that is sufficiently similar to the particular sample or subject of interest to allow a relevant comparison. In some embodiments, information about the reference sample is obtained simultaneously with information about the particular sample. In some embodiments, the information about the reference sample is a medical history. In some embodiments, the information about the reference sample is stored, for example, on a computer-readable medium. In some embodiments, the comparison of the particular sample of interest with the reference sample involves determining the specific characteristics of the particular sample of interest compared to the reference material. Establish identity, similarity, or difference with the sample.

[0035] As used herein, the term "sample" refers to a biological sample obtained or derived from a source of interest, as described herein. In some embodiments, the source of interest includes an organism, such as an animal or a human. In some embodiments, the biological sample includes a biological tissue or biological fluid. In some embodiments, the biological sample may be or include bone marrow; blood, e.g., whole blood; blood cells; ascites; tissue or fine needle biopsy sample; cell-containing body fluids; free-floating nucleic acids; sputum; saliva; urine; cerebrospinal fluid, peritoneal fluid; pleural fluid; feces; lymphatic fluid; gynecological fluids; skin swabs; vaginal swabs; oral swabs; nasal swabs; washings or lavage fluids, such as ductal lavage or bronchoalveolar lavage; aspirates; scrapings; bone marrow specimens; tissue biopsy specimens; surgical specimens; feces, other body fluids, secretions, and / or excretions; and / or cells derived therefrom, etc. In some embodiments, a biological sample is or comprises cells obtained from a subject. In some embodiments, the obtained cells are or comprise cells derived from the subject from whom the sample is obtained. In some embodiments, a sample is a "primary sample" obtained directly from a source of interest by any suitable means. For example, in some embodiments, a primary biological sample is obtained by a method selected from the group consisting of biopsy (e.g., fine needle aspiration or tissue biopsy), surgery, collection of bodily fluids (e.g., blood (e.g., whole blood), lymph, feces, etc.), and the like. In some embodiments, as will be clear from the context, the term "sample" refers to a preparation obtained by processing a primary sample (e.g., by removing one or more components of the primary sample and / or adding one or more agents), such as filtration using a semipermeable membrane. Such a "processed sample" can include, for example, nucleic acids or proteins extracted from a sample or obtained by subjecting the primary sample to techniques such as, for example, amplification or reverse transcription of mRNA, isolation and / or purification of specific components, etc.

[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 gives an indication of or feels an effect). In particular, a "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. A therapeutically effective amount is generally administered in a dosage regimen that may consist of multiple unit doses. For any particular therapeutic agent, the therapeutically effective amount (and / or an appropriate unit dose within an effective dosage regimen) may vary depending, for example, on the route of administration and combination with other pharmaceutical agents. Additionally, the therapeutically effective amount (and / or unit dose) specific for 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") means to partially or completely alleviate, ameliorate, relieve, inhibit, delay the onset of, or reduce one or more symptoms, characteristics, and / or causes of a particular disease, disorder, and / or condition; "Treatment" refers to any administration of a substance (e.g., a provided composition) that reduces their severity and / or reduces their incidence. Such treatment may be of subjects who do not exhibit symptoms of the associated disease, disorder, and / or condition and / or 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 associated disease, disorder, and / or condition. In some embodiments, treatment may be of subjects who have been diagnosed with the associated disease, disorder, and / or condition. In some embodiments, treatment may be of subjects known to have one or more susceptibility factors statistically correlated with an increased risk of developing the associated disease, disorder, and / or condition.

[0039] B. Compound In some embodiments, provided compounds have formula (I): [ka] or a pharmaceutically acceptable salt thereof (In the formula: Het A is selected from 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclylene having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur, 5- to 6-membered monocyclic heteroarylene having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclylene having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, and 7- to 10-membered bicyclic heteroarylene having 1-5 heteroatoms selected from oxygen, nitrogen, or sulfur, wherein Het A is 0 to 4 R A is substituted with a group, Each R Ais halogen, -CN, -C(R)=N(R), -C(O)R, -C(O)2R, -C(O)N(R)2, -NO2, -N(R)-N(R)2, -N(R)2, -N(R)C(O)R, -N(R)C(O)2R, - N(R)C(O)N(R)2, -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, 5-6 membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 3-7 membered saturated or partially unsaturated monocyclic carbocyclyl, and 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur; L is an optionally substituted C 1~6 a hydrocarbon chain wherein one to three methylene units are independently replaced by -Cy-, -O-, -NR-, -C(O)-, -S(O)2-, -C(O)NR-, -NRC(O)-, -S(O)2NR-, and -NRS(O)2-; -Cy- is a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclylene, a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclylene having 1 to 2 heteroatoms selected from oxygen, nitrogen, or sulfur, or a group selected from oxygen, nitrogen, or sulfur. is a 5- or 6-membered heteroarylene having 1 to 4 heteroatoms, R' and R'' are hydrogen, halogen, -OR, -NR2, -SR, and optionally substituted C 1~6 aliphatic, wherein R' is a monocyclic Het A together with R 1 , R 2 , R 3 , R 4 , R 5 , R6 , R 7 , R 8 , and R 9 is hydrogen, halogen, -CN, -C(R)=N(R), -C(O)R, -C(O)2R, -C(O)N(R)2, -NO2, -N(R)-N(R)2, -N(R)2, -N(R)C(O)R, -N(R)C(O)2R, -N(R)C(O)N(R)2, -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, 5-6 membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 3-7 membered saturated or partially unsaturated monocyclic carbocyclyl, and 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur; Each R is independently hydrogen or C 1~6 an optionally substituted group selected from aliphatic, phenyl, 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 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, or sulfur; or two R groups on the same carbon or nitrogen atom together with the atoms between them form a ring selected from a 3-7 membered saturated or partially unsaturated monocyclic ring having 0-2 heteroatoms selected from oxygen, nitrogen, or sulfur, and a 5-6 membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur; and n is 0 or 1.

[0040] In some embodiments, Het Ais selected from the group consisting of 3-7 membered saturated or partially unsaturated monocyclic heterocyclylene having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur, 5-6 membered heteroarylene having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 7-10 membered saturated or partially unsaturated bicyclic heterocyclylene having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, and 7-10 membered bicyclic heteroarylene having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, wherein Het A is 0 to 4 R A is substituted with a group.

[0041] In some embodiments, Het A is selected from the group consisting of 5- to 6-membered heteroarylene having 1 to 4 heteroatoms selected from oxygen, nitrogen, or sulfur, and 7- to 10-membered bicyclic heteroarylene having 1 to 4 heteroatoms selected from oxygen, nitrogen, or sulfur, wherein Het A is 0 to 4 R A is substituted with a group.

[0042] In some embodiments, Het A is a 5- to 6-membered heteroarylene having 1 to 4 heteroatoms selected from oxygen, nitrogen, or sulfur.

[0043] In some embodiments, Het A is a 6-membered heteroarylene having 1 to 4 heteroatoms selected from oxygen, nitrogen, or sulfur, where Het A is 0 to 3 R A In some embodiments, the group is substituted with Het A is a 6-membered heteroarylene having one nitrogen atom, where Het A is 0 to 3 R A In some embodiments, the group is substituted with Het A is pyridinediyl. In some embodiments, Het A teeth, [ka] wherein * represents the point of attachment to L.

[0044] In some embodiments, Het A is a 5-membered heteroarylene having 1 to 4 heteroatoms selected from oxygen or nitrogen. A is a 5-membered heteroarylene having 1 to 4 nitrogen atoms. A is a 5-membered heteroarylene having 1 to 4 nitrogen atoms, where Het A When Het contains three nitrogens, it is not 1,2,4-triazolediyl. A is a 5-membered heteroarylene having 1 to 3 nitrogen atoms. A is a 5-membered heteroarylene having 1 to 2 nitrogen atoms. A is a 5-membered heteroarylene having one nitrogen atom. In some embodiments, Het A is a 5-membered heteroarylene having two nitrogen atoms. In some embodiments, Het A is a 5-membered heteroarylene having three nitrogen atoms. In some embodiments, Het A is a five-membered heteroarylene having four nitrogens.

[0045] In some embodiments, Het A teeth, [ka] wherein * represents the point of attachment to L.

[0046] In some embodiments, Het A is a 5-membered monocyclic heteroarylene having 1 to 4 heteroatoms selected from oxygen, nitrogen, or sulfur, where Het A is 0 to 2 R AIn some embodiments, the group is substituted with Het A is a 5-membered monocyclic heteroarylene having 1 to 3 heteroatoms selected from nitrogen, where Het A is 0 to 2 R A In some embodiments, the group is substituted with Het A is a 5-membered monocyclic heteroarylene having 2 to 3 heteroatoms selected from nitrogen, where Het A is 0 to 2 R A is substituted with a group.

[0047] In some embodiments, Het A is 0 to 3 R A In some embodiments, Het is a pyrrolediyl substituted with a Het group. A is 0 to 2 R A In some embodiments, Het is a pyrazoldiyl substituted with a Het group. A is 0 to 1 R A In some embodiments, Het is a triazolediyl substituted with a Het group. A is 0 to 1 R A In some embodiments, Het is a thiazoldiyl substituted with a Het group. A is unsubstituted tetrazolediyl. In some embodiments, Het A is an unsubstituted oxadiazolediyl In some embodiments, Het A is unsubstituted thiadiazoldiyl. In some embodiments, Het A is 0 to 2 R A In some embodiments, imidazolediyl is substituted with a Het group. A is 0 to 1 R A In some embodiments, Het is an oxazoldiyl substituted with a Het group. A is 0 to 1 R A In some embodiments, Het is an isoxazoldiyl substituted with a Het group. A is unsubstituted pyrazoldiyl. In some embodiments, Het Ais unsubstituted 1,2,3-triazolediyl.

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

[0049] In some embodiments, Het A is a 7-10 membered bicyclic heteroarylene having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, where Het A is 0 to 4 R A In some embodiments, the group is substituted with Het A is a 9-membered bicyclic heteroarylene having 1 to 4 heteroatoms selected from oxygen, nitrogen, or sulfur, where Het A is 0 to 4 R A In some embodiments, the group is substituted with Het A is a 9-membered bicyclic heteroarylene having two nitrogen atoms, where Het A is 0 to 4 R A In some embodiments, the group is substituted with Het A is 0 to 4 R A and pyrrolopyridinediyl substituted with a group.

[0050] In some embodiments, Het A teeth, [ka] [ka] wherein * represents the point of attachment to L.

[0051] In some embodiments, each R A is C 1~6Independently selected from optionally substituted groups selected from aliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, and 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 2 heteroatoms selected from oxygen, nitrogen, or sulfur.

[0052] In some embodiments, optionally substituted R A The substituents on the group are independently halogen, (CH2) 0~4 R°, -(CH2) 0~4 OR°; and -(CH2) 0~4 C(O)OR°, where each R° is independently hydrogen, C 1~6 an aliphatic or 5-6 membered saturated ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; It is a partially unsaturated ring or an aryl ring.

[0053] In some embodiments, R A One example is -(CH2) 0~4 C substituted with OR° 1~6 aliphatic, where R° is hydrogen or C 1~6 It is aliphatic.

[0054] In some embodiments, R A One example is -(CH2) 0~4 C substituted with C(O)OR° 1~6 aliphatic, where R° is hydrogen or C 1~6 It is aliphatic.

[0055] In some embodiments, R A One example of is a C substituted with a 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. 1~6 It is aliphatic.

[0056] In some embodiments, R A One example of is an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, RA One example of is optionally substituted cyclopropyl. In some embodiments, R A One example is -(CH2) 0~4 C(O)OR° substituted cyclopropyl, where R° is hydrogen or C 1~6 It is aliphatic.

[0057] In some embodiments, R A One example is halogen-substituted C 1~6 In some embodiments, R A is a halogen-substituted C 1~3 In some embodiments, R A is a C1 aliphatic substituted with a halogen. In some embodiments, R A is a fluorine-substituted C1 aliphatic. In some embodiments, R A is -CHF2.

[0058] In certain embodiments, L is selected from —C(R)2NRC(O)-#, —C(R)2C(O)NRC(R)2-#, —C(R)2NRC(O)C(R)2-#, —C(R)2NRC(R)2-#, —C(R)2C(R)2NRC(R)2-#, —C(O)NRC(R)2-#, —C(R)2C(O)NR-#, —NRC(O)C(R)2-#, —CR2C(O)NRC(R)2-#, —SONRRC(R)2-#, and —C(R)2NRSO2-#, where # is Het A Represents a point of attachment to

[0059] In certain embodiments, L is selected from —C(R)2NRC(O)—#, —C(R)2C(O)NRC(R)2-#, —C(R)2NRC(R)2-#, —C(R)2C(R)2NRC(R)2-#, —C(O)NRC(R)2-#, —C(R)2C(O)NR-#, —CR2C(O)NRC(R)2-#, —SONRRC(R)2-#, and —C(R)2NRSO2-#, where # is Het A Represents a point of attachment to

[0060] In certain embodiments, L is selected from —C(R)2C(O)NRC(R)2-#, —C(R)2NRC(R)2-#, —C(R)2C(R)2NRC(R)2-#, —C(O)NRC(R)2-#, —C(R)2C(O)NRC(R)2-#, —SONRC(R)2-#, and —C(R)2NRSO2-#, where # is Het A Represents a point of attachment to

[0061] In some embodiments, L is other than -C(R)NRC(O)-# or -C(R)C(O)NR-#. In some embodiments, L is other than -CHNRC(O)-# or -CHC(O)NR-#.

[0062] In some embodiments, when L is —C(R)2NRC(O)—# or —C(R)2C(O)NR—#, any of the following (a), (b), or (c): (a) n is 0, (b)R 5 , R 6 , R 7 , R 8 , and R 9 At least one of the is CN, or (c)R 1is an optionally substituted saturated monocyclic heterocycle containing 1 to 3 nitrogen atoms, with the proviso that the compounds are N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(2-oxopyrrolidin-1-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide, N-((7-chloro-8 -fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-morpholinoimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide, N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(2-oxo)imidazo[1,5-a]pyridin-1-yl)methyl)-1H-1,2,3-triazole-4-carboxamide N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(2-oxooxazolidin-3-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide, N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(2-oxooxazolidin-3-yl)imidazo[1,2-a]pyridin-2-yl)methyl)- 1H-1,2,3-triazole-4-carboxamide or 4-(2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)morpholine-2-carboxylic acid.

[0063] In some embodiments, when L is —C(R)2NRC(O)—# or —C(R)2C(O)NR—#, n is 0.

[0064] In some embodiments, when L is —C(R)2NRC(O)—# or —C(R)2C(O)NR—#, R′ is a monocyclic Het A together with the group consisting of: form an optionally substituted fused 7-10 membered saturated or partially unsaturated bicyclic heterocyclylene having 1 to 4 heteroatoms selected from oxygen, nitrogen, or sulfur.

[0065] In some embodiments, when L is —CH 2 NRC(O)—# or —CH 2 C(O)NR—#, R′ is a monocyclic Het A together with the group consisting of: form an optionally substituted fused 7-10 membered saturated or partially unsaturated bicyclic heterocyclylene having 1 to 4 heteroatoms selected from oxygen, nitrogen, or sulfur.

[0066] In certain embodiments, L is -(CR2) m When NRC(O)- and m is 0 to 2 (e.g., 0 or 2), any of the following (a), (b), or (c): (a) n is 0, (b)R 5 , R 6 , R 7 , R 8 , and R 9 At least one of the is CN, or (c)R 1 is an optionally substituted saturated monocyclic heterocycle containing 1 to 3 nitrogen atoms, with the proviso that the compounds are N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(2-oxopyrrolidin-1-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide, N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-morpholinoimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide, N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(2-oxopyrrolidin-1-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide, N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(2-oxooxazolidin-3-yl) imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide, or 4-(2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)morpholine-2-carboxylic acid.

[0067] In certain embodiments, L is -(CR2) m When NRC(O)- and m is 0, n is 0. In certain embodiments, L is -(CR2) m When NRC(O)- and m is 1, n is 0. In certain embodiments, L is -(CR2) m NRC(O)-, and when m is 2, n is 0.

[0068] In certain embodiments, L is -(CR2) m When m is 0 to 2 (e.g., 0 or 2), R' is a monocyclic Het A together with the group consisting of: form an optionally substituted fused 7-10 membered saturated or partially unsaturated bicyclic heterocyclylene having 1 to 4 heteroatoms selected from oxygen, nitrogen, or sulfur.

[0069] In some embodiments, L is —C(R)C(O)NR C(R)—, where each R is independently hydrogen or C optionally substituted with halogen. 1~3 In some embodiments, L is —CHC(O)NHCH(CF)—#. In some embodiments, L is —CHC(O)NHCH(CH)—#.

[0070] In some embodiments, L is —C(R)2NRC(R)2-#, where each R is independently hydrogen, or C optionally substituted with halogen. 1~3It is aliphatic. In some embodiments, L is -CHNHCH(CF)-#. In some embodiments, L is -CHNHCH-#. In some embodiments, L is -CHNHCH(CH)-#. In some embodiments, L is -CH(CF)NHCH-#.

[0071] In certain embodiments, L is —C(R)NRSO—, where each R is independently hydrogen, or C optionally substituted with halogen. 1~3 It is aliphatic. In certain embodiments, L is —CH 2 NHSO 2 —#.

[0072] In some embodiments, L is -SONRC(R)-#, where each R is independently hydrogen or C optionally substituted with halogen. 1~3 It is aliphatic. In some embodiments, L is -SO2NHCH2-#. In some embodiments, L is -SO2NHCH(CH3)-#.

[0073] In some embodiments, L is —C(O)NR—C(R)—, where each R is independently hydrogen or C optionally substituted with halogen. 1~3 In some embodiments, L is —C(O)NHCH—.

[0074] In certain embodiments, L is —C(R)C(O)NR C(R)—, where each R is independently hydrogen, or C optionally substituted with halogen. 1~3 It is aliphatic. In certain embodiments, L is —CH 2 C(O)NHCH 2 —#.

[0075] In some embodiments, R' and R" are each hydrogen. In some embodiments, R" is hydrogen and R' is a monocyclic Het Atogether form a fused 7-10 membered saturated or partially unsaturated bicyclic heterocyclylene having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur. In some embodiments, n is 1, R" is hydrogen, and R' is a monocyclic Het A and oxygen, nitrogen, or sulfur. In some embodiments, n is 1, R" is hydrogen, and R' is a monocyclic Het A together with the group consisting of: form a fused 8-membered saturated or partially unsaturated bicyclic heterocyclylene having 1 to 4 heteroatoms selected from oxygen, nitrogen, or sulfur.

[0076] In some embodiments, R′ and R″ are selected from hydrogen, halogen, —OR, —SR, —NR, and optionally substituted C 1~6 aliphatic, where each R is hydrogen and C 1~6 In some embodiments, R' and R'' are independently selected from hydrogen, fluorine, -OH, -SH, -NH2, and -(CH2). 0~4 C substituted with C(O)OR° 1~6 aliphatic, where R° is hydrogen or C 1~6 In some embodiments, R' and R'' are selected from the group consisting of hydrogen, fluorine, -OH, and -(CH) 0~4 C substituted with C(O)OR° 1~6 aliphatic, where R° is hydrogen, methyl, or ethyl.

[0077] In some embodiments, when n is 0, Het A is a 7-10 membered saturated or partially unsaturated bicyclic heterocyclylene having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur.

[0078] In some embodiments, n is 0. In some embodiments, n is 1.

[0079] In some embodiments, R 1 , R 2 , R 3 , and R 4 is hydrogen, halogen, -CN, -C(R)=N(R), -C(O)R, -C(O)2R, -C(O)N(R)2, -NO2, -N(R)-N(R)2, -N(R)2, -N(R)C(O)R, -N(R)C(O)2R, -N(R)C(O)N(R)2, -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 In some embodiments, R is independently selected from optionally substituted groups selected from aliphatic, phenyl, 5-6 membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 3-7 membered saturated or partially unsaturated monocyclic carbocyclyl, and 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur. 1 , R 2 , R 3 , and R 4 is hydrogen, halogen, -CN, -C(O)R, or C 1~6 and optionally substituted groups selected from aliphatic, 5-6 membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, and 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur.

[0080] In some embodiments, optionally substituted R 1 , R 2 , R 3 , and R 4 The above substituents are each independently selected from halogen, -CN, (CH2) 0~4 R°, -(CH2) 0~4 OR°, -(CH2) 0~4 N(R°)2, -(CH2) 0~4 O(CH2) 1~4 N(R°)2 and -(CH2)0~4 C(O)OR°, where each R° is independently hydrogen, C 1~6 It is an aliphatic or 3-5 membered saturated, partially unsaturated, or aryl ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0081] In some embodiments, optionally substituted R 1 , R 2 , R 3 , and R 4 The above substituents are each independently -F, -CN, -R°, -OR°, -N(R°), -COOR°, or -OC(R°)C(R°)N(R°), where each R° is independently hydrogen, C 1~6 It is an aliphatic or 4-membered saturated ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, optionally substituted R 1 , R 2 , R 3 , and R 4 The above substituents are -F, -CN, -CH3, -OH, -NH2 , -COOH, -COOCH2CH2, -OCH2CH2NH2, -OCH2CH2N(CH3)2, and [ka] are each independently selected from

[0082] In some embodiments, R 1 , R 2 , R 3 , and R 4 each of which is hydrogen, halogen, -CN, -C(O)R, -C(O)2R, -N(R)2, -OR, or C 1~6 and optionally substituted groups selected from aliphatic, 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, or sulfur, wherein each R is independently selected from hydrogen or C 1~6 It is aliphatic.

[0083] In some embodiments, optionally substituted R 1 , R 2 , R 3 , or R 4 The substituents on the group are halogen, -(CH2) 0~4 OR, -O(CH2) 0~4 OR, -(CH2) 0~4 C(O)OR and -(CH2) 0~4 N(R)2, where each R is independently selected from hydrogen, C 1~6 aliphatic, or two independent occurrences of R together with the atom(s) between them form an optionally substituted 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 further substituted.

[0084] In some embodiments, R 1 is hydrogen, halogen, -CN, -C(O)2R, -C(O)N(R)2, -N(R)2, -OR, -SR, -S(O)2N(R)2, or C 1~6 In some embodiments, R is selected from an optionally substituted group selected from aliphatic, phenyl, 5-6 membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 3-7 membered saturated or partially unsaturated monocyclic carbocyclyl, and 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur. 1 is hydrogen, halogen, -CN, -C(O)R, or C 1~6 It is selected from optionally substituted groups selected from aliphatic, 5-6 membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, and 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur.

[0085] In some embodiments, optionally substituted R1 The above substituents are -F, -CN, -R°, -OR°, -N(R°), -COOR°, or -OC(R°)C(R°)N(R°), where each R° is independently hydrogen, C 1~6 It is an aliphatic or 4-membered saturated ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, optionally substituted R 1 The above substituents are -F, -CN, -CH3, -OH, -NH2, -COOH, -COOCH2CH2, -OCH2CH2NH2, -OCH2CH2N(CH3)2, and [ka] is selected from.

[0086] In some embodiments, R 5 , R 6 , R 7 , R 8 , and R 9 is hydrogen, halogen, -CN, -N(R)2, -OR, or C 1~6 and optionally substituted groups selected from aliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, where each R is independently hydrogen or C 1~6 In some embodiments, R 7 , R 8 , and R 9 is hydrogen.

[0087] In some embodiments, R 5 is selected from hydrogen or halogen. In some embodiments, R 5 is hydrogen. In some embodiments, R 5 is halogen. In some embodiments, R 5 is F. In some embodiments, R 5 is Cl. In some embodiments, R 5 is Br. In some embodiments, R 5 is I.

[0088] In some embodiments, R 6 is a halogen or an optionally substituted C 1~6 In some embodiments, R 6 is halogen. In some embodiments, R 6 is F. In some embodiments, R 6 is Cl. In some embodiments, R 6 is Br. In some embodiments, R 6 is I. In some embodiments, R 6 is an arbitrarily substituted C 1~6 In some embodiments, R 6 is an arbitrarily substituted C 1~5 In some embodiments, R 6 is an arbitrarily substituted C 1~4 In some embodiments, R 6 is an arbitrarily substituted C 1~3 In some embodiments, R 6 is an arbitrarily substituted C 1~2 In some embodiments, R 6 is alkynyl.

[0089] In certain embodiments, R 1 , R 2 , R 3 , R 4 , R 5 , R 7 , R 8 , and R 9 Each of R is hydrogen. 1 , R 2 , R 3 , R 4 , R 7 , R 8 , and R 9 Each of R is hydrogen. 2 , R 3 , R 4 , R 5 , R 7 , R 8 , and R 9 Each of is hydrogen.

[0090] In some embodiments, R 9 is hydrogen and R 6 is -F, -Cl, or -Br, and R 5 , R 7 , and R 8 is hydrogen, halogen, -CN, -C(R)=N(R), -C(O)R, -C(O)2R, -C(O)N(R)2, -NO2, -N(R)-N(R)2, -N(R)2, -N(R)C(O)R, -N(R)C(O)2R, -N(R)C(O)N(R)2, -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 and optionally substituted groups selected from aliphatic, phenyl, 5-6 membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 3-7 membered saturated or partially unsaturated monocyclic carbocyclyl, and 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur.

[0091] In some embodiments, R 1 is an optionally substituted group selected from 5-6 membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, and 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur. In some embodiments, R 1 is an optionally substituted 5-membered heteroaryl having 2-4 heteroatoms selected from oxygen or nitrogen. In some embodiments, R 1 is optionally substituted piperidinyl. In some embodiments, R 1 is an optionally substituted triazolyl.

[0092] In some embodiments, R 1 is an arbitrarily substituted C 1~6In some embodiments, optionally substituted R 1 The substituents on the group are independently halogen, (CH2)0 ~4 R°, -(CH2) 0~4 OR°; and -(CH2) 0~4 C(O)OR°, where each R° is independently hydrogen, C 1~6 It is an aliphatic or 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0093] In some embodiments, R 5 and R 6 are each independently a halogen. In some embodiments, R 5 is F and R 6 is Cl. In some embodiments, R 6 is Cl. In some embodiments, R 6 is CN.

[0094] In some embodiments, provided compounds, or pharmaceutically acceptable salts thereof, have the structure of Formula (Ia), Formula (Ib), Formula (Ic), or Formula (Id): [ka] wherein L, R A , R', R'', R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 Each of the following, both alone and in combination, is defined and described herein in classes and subclasses.

[0095] Unless otherwise specified or prohibited by the preceding definition of formula (I), the variables L, R, and R are defined above and described in classes and subclasses herein. A , Het A , R', R'', R 1 , R2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 It is understood that the above embodiments also apply to compounds of formula (Ia), formula (Ib), formula (Ic), formula (Id), formula (II), formula (II-a), formula (II-b), formula (III), formula (III-a), and formula (III-b), both alone and in combination.

[0096] In some embodiments, provided compounds, or pharmaceutically acceptable salts thereof, have the structure of Formula (II): [ka] wherein L, Het A , R', R 1 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 Each of the following, both alone and in combination, is defined and described herein in classes and subclasses.

[0097] In some embodiments, provided compounds, or pharmaceutically acceptable salts thereof, have the structure of Formula (II-a) or Formula (II-b): [ka] wherein L, R A , R', R 1 , R 3 , R 4 , R 5 , and R 6 Each of the following, both alone and in combination, is defined and described herein in classes and subclasses.

[0098] In some embodiments, in provided compounds or pharmaceutically acceptable salts thereof, R' is a monocyclic Het Aand forming an optionally substituted fused ring, the compound having the structure of formula (III): [ka] wherein R fus Het A to form a fused 7-10 membered saturated or partially unsaturated bicyclic heterocyclylene having 1 to 4 heteroatoms selected from oxygen, nitrogen, or sulfur; L, Het A , R 1 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 Each of the following, both alone and in combination, is defined and described herein in classes and subclasses.

[0099] In some embodiments, provided compounds, or pharmaceutically acceptable salts thereof, have the structure of Formula (III-a) or Formula (III-b): [ka] In the formula, R A , Cy B , R 1 , R 2 , R 6 Each of R, R, and R7 is defined and described in classes and subclasses herein.

[0100] In some embodiments, provided compounds include 2-(7-chloroimidazo[1,5-a]pyridin-1-yl)-N-((1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methyl)acetamide (I-1), 1-(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)-N-((1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methyl)-2,2,2-trifluoroacetamide (I-2), Tan-1-amine (I-2), 7-chloro-N-((1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methyl)-8-fluoroimidazo[1,5-a]pyridine-1-carboxamide (I-3), N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-sulfonamide (I-4), N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-sulfonamide I-5), 7-chloro-N-((1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-sulfonamide (I-6), 7-chloro-N-((1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-yl)methyl)-8-fluoroimidazo[1,5-a]pyridine-1-sulfonamide (I-7), 7-chloro-N-((1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-yl)methyl)-8-fluoroimidazo[1,5-a]pyridine-1-sulfonamide (I-8), )methyl)-1H-1,2,3-triazol-4-yl)ethyl)-8-fluoroimidazo[1,5-a]pyridine-1-sulfonamide (I-7), N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-5-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-2-carboxamide (I-8), N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-5-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-3-carboxamide (I-9), N-((7-cyanoimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (I-10), 1-(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)-N-((1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methyl)methanamine (I-11), N-(, (7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-(1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)ethan-1-amine (I-12), 2-(7-chloroimidazo[1,5-a]pyridin-1-yl)-N-(1-(1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)ethyl)acetamide (I-13), 2-((4-(((7- Methyl chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)amino)methyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-carboxylate (I-14), 2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)amino)methyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-carboxylic acid (I-15), N-((7-chloro-8 -fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-(1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazol-4-yl)-2,2,2-trifluoroethan-1-amine (I-16), 3-(2-((4-((((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)amino)methyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)ethyl propanoate (I-1 7a), 3-(2-((4-((((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)amino)methyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)propanoic acid (I-17b), 1-(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)-N-((1-((6-cyclopropyl-8-(4H-1,2,4-triazol-4-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methyl)methanamine (I-18), 2-(7-chloroimidazo[1,5-a]pyridin-1-yl)-N-(1-(1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazol-4-yl)-2,2,2-trifluoroethyl)acetamide (I-19), N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(4-methylpiperazin-1-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide (I-20), or a pharmaceutically acceptable salt thereof.

[0101] C. Pharmaceutical Compositions In another aspect, the present invention provides a pharmaceutical composition comprising a compound of Formula (I)-(III-b), or a compound of Formula (I)-(III-b), in combination with a pharmaceutically acceptable excipient (e.g., carrier).

[0102] The pharmaceutical composition comprises an optical isomer, diastereomer, or pharmaceutically acceptable salt of the inhibitor disclosed herein. The compound of Formula (I)-(III-b) contained in the pharmaceutical composition can be covalently bound to a carrier moiety as described above. Alternatively, the compound of Formula (I)-(III-b) contained in the pharmaceutical composition is not covalently bound to a carrier moiety.

[0103] As used herein, "pharmaceutically 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, The pharmaceutical compositions may be mixed with auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring agents, and / or flavoring agents, which do not adversely react with the compounds of the present invention.

[0104] The compounds of the present invention can be administered singly or simultaneously. Simultaneous administration is intended to include simultaneous or sequential administration of the compounds individually or in combination (two or more compounds). The preparations can also be combined with other agents, if necessary (e.g., to reduce metabolic degradation).

[0105] In some embodiments, test agents as described herein can be incorporated into pharmaceutical compositions for administration by methods known to those of skill in the art and described herein for the provided compounds.

[0106] D. Formulation The compounds of the present invention can be prepared into a wide variety of oral, parenteral, and topical dosage forms and can be administered in a wide variety of oral, parenteral, and topical dosage forms. Thus, the compounds of the present invention can be administered by injection (e.g., intravenously, intramuscularly, intradermally, subcutaneously, intraduodenally, or intraperitoneally). 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 contemplated that multiple administration routes (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 pharmaceutically acceptable carrier or excipient and one or more compounds of the present invention.

[0107] For preparing pharmaceutical compositions from the compounds of the present invention, pharmaceutically 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, flavoring agents, binders, preservatives, tablet disintegrating agents or encapsulating materials.

[0108] In powders, the carrier is a finely divided solid in admixture with the finely divided active ingredient. In tablets, the active ingredient is mixed with a carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.

[0109] Powders and tablets preferably contain 5% to 70% of the active compound. Suitable carriers include magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, low-melting waxes, cocoa butter, and the like. The term "preparation" is intended to include a combination of the active compound with an encapsulating material as a carrier, in which 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.

[0110] 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.

[0111] Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water / propylene glycol solutions.For parenteral injection, liquid preparations can be formulated in solution in aqueous polyethylene glycol solution.

[0112] When parenteral administration is required or desired, particularly suitable mixtures for the compounds of the present invention are injectable sterile solutions, preferably oily or aqueous solutions, and suspensions, emulsions, or inserts, including suppositories. Particularly, carriers for parenteral administration include aqueous solutions of dextrose, saline, pure water, ethanol, glycerol, propylene glycol, peanut oil, sesame oil, polyoxyethylene block polymers, etc. Ampoules are convenient unit doses. The compounds of the present invention can also be incorporated into liposomes or administered via transdermal pumps or patches. Suitable pharmaceutical mixtures for use in the present invention include, 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.

[0113] 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 the finely divided active ingredient in water together with viscous materials, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well-known suspending agents.

[0114] Also included are solid preparations intended to be converted immediately before use into liquid 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.

[0115] Pharmaceutical preparations are preferably in unit dosage form.In this form, the preparation is subdivided into unit doses containing appropriate amounts of active ingredient.The unit dosage form can be a packaged preparation, the package containing discrete amounts of preparation, for example, packaged tablets, capsules, and powders in vials or ampoules.The unit dosage form can be a capsule, tablet, cachet, or lozenge alone, or the appropriate number of any of these in packaged form.

[0116] The quantity of active ingredient in a unit dose preparation may be varied or adjusted from 0.1 mg to 10,000 mg, more usually from 1.0 mg to 1,000 mg, and most usually from 10 mg to 500 mg, depending on the particular use and potency of the active ingredient. The composition may also contain other compatible therapeutic agents, if desired.

[0117] 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: polysorbates 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.

[0118] 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 components of a suspension or emulsion formulation, and / or to otherwise improve the formulation. Examples of such viscosity-enhancing agents include 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.

[0119] The compositions of the present invention may additionally contain ingredients that provide sustained release and / or comfort. The components include a high molecular weight anionic mucus-mimetic polymer, a gelling polysaccharide, and a micronized drug carrier matrix. 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 which are incorporated herein by reference in their entirety for all purposes.

[0120] E. Effective Dosage Pharmaceutical compositions provided by the present invention include compositions containing an active ingredient in a therapeutically effective amount, i.e., an amount effective to achieve its intended purpose. The actual amount effective for a particular application will depend, inter alia, on the condition being treated. For example, when administered in a method for treating HAE, such compositions will contain an amount of active ingredient effective to achieve the desired result (e.g., inhibiting pKal and / or reducing the amount of bradykinin in a subject).

[0121] The dosage and frequency (single or multiple doses) of the compound administered can vary depending on a variety of factors, including the route of administration; the size, age, sex, health, weight, body mass index, and diet of the recipient; the nature and extent of symptoms of the disease being treated (e.g., a disease responsive to pKal inhibition); the presence of other diseases or other health-related problems; the type of concomitant 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 invention.

[0122] 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) that can reduce pKal enzyme activity, for example, as measured using the methods described.

[0123] The therapeutically effective amount for use in humans can be determined from animal models. For example, a human dose can be formulated to achieve a concentration that has been found to be effective in animals. The human dosage can be adjusted by monitoring pKal inhibition and adjusting the dosage upward or downward, as described above.

[0124] Dosage may vary depending on the patient's needs and the compound being used. In the context of this invention, the dosage administered to a patient should be sufficient to effect a beneficial therapeutic response in the patient over time. The size of the dose will also be determined by the existence, nature, and extent of any adverse side effects. Generally, treatment is initiated with lower dosages that are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached. In some embodiments, the dosage range is 0.001-10% w / v. In some embodiments, the dosage range is 0.1-5% w / v.

[0125] Dosage amount and interval may be adjusted individually to provide effective levels of the compound being administered for the particular clinical indication being treated, thereby providing a treatment regimen commensurate with the severity of the individual disease state.

[0126] F. Treatment Method The present disclosure provides compounds for use in medicine. The present disclosure further provides the use of any compound described herein to inhibit the activity of pKal, which is beneficial in treating diseases and conditions mediated by pKal. Exemplary disorders mediated by pKal include edema, which refers to swelling in a subject's entire body or part of it due to inflammation or injury when small blood vessels become leaky and release fluid into surrounding tissues. In some examples, the edema is HAE. In other examples, the edema is a condition in the eye (e.g., diabetic macular edema ( DME) occurs. The present disclosure provides methods for inhibiting the activity of pKal. In certain embodiments, the present application provides methods for inhibiting the activity of pKal in vitro by contacting any of the compounds described herein with pKal molecules in a sample, e.g., a biological sample. In certain embodiments, the present application provides methods for inhibiting the activity of pKal in vivo by delivering an effective amount of any of the compounds described herein to a subject in need of treatment by a suitable route.

[0127] In certain embodiments, the method comprises administering any of the compounds described herein, or a pharmaceutically acceptable salt thereof, to a subject in need thereof (e.g., a subject, such as a human patient, having edema). In certain embodiments, the method comprises administering a compound of Formula (I)-(III-b), or a pharmaceutically acceptable salt or composition thereof, to a subject in need thereof. In some embodiments, the method comprises administering a pharmaceutical composition comprising a compound of Formula (I)-(III-b), or a pharmaceutically acceptable salt thereof, to a subject in need thereof.

[0128] In certain embodiments, the subject treated by any of the methods described herein is a human patient who has, is suspected of having, 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, for example, 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, for example, C1-INH deficiency for HAE.

[0129] In certain embodiments, provided herein are methods for alleviating one or more symptoms of HAE in a human patient suffering from an HAE attack. Such patients can be identified through routine medical procedures. An effective amount of one or more of the provided compounds can be administered to a human patient 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®), pKal inhibitors (e.g., ecallantide or lanadelumab), or bradykinin B2 receptor antagonists (e.g., Firazyr®).

[0130] In another embodiment, provided herein is a method for reducing the risk of HAE attacks in human HAE patients in a quiescent state. 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®), pKal inhibitors (e.g., ecallantide or lanadelumab), or bradykinin B2 receptor antagonists (e.g., Firazyr®).

[0131] In yet other embodiments, provided herein is the prophylactic treatment of HAE in human patients at risk for HAE attacks using one or more of the compounds described herein. Patients suitable for such prophylactic treatment may be human subjects with a history of HAE attacks (e.g., human subjects experiencing more than two attacks per month). Alternatively, patients suitable for prophylactic treatment may be human subjects without a history of HAE attacks but with one or more risk factors for HAE (e.g., family history, genetic defects in the C1-INH gene, etc.). Such prophylactic treatment may require the compounds described herein as the sole active agent or may require the use of additional anti-HAE compounds. HAE medications, such as those described herein, may be required.

[0132] In certain embodiments, provided herein are methods for preventing or reducing edema in the eye of a subject (e.g., a human patient). In some examples, the human patient is a diabetic patient who has, is suspected of having, or is at risk for diabetic macular edema (DME). DME is a proliferative form of diabetic retinopathy characterized by swelling of the retinal layers, neovascularization, vascular leakage, and retinal thickening in diabetes due to leakage of fluid from blood vessels in the macula. To practice this method, an effective amount of one or more compounds described herein, or a pharmaceutically acceptable salt thereof, can be delivered to the eye of a subject in need of treatment. For example, the compounds of the present invention can be delivered by intraocular or intravitreal injection. The subject can be treated with a compound described herein either as the sole active agent or in combination with another treatment for DME. Non-limiting examples of treatments for DME include laser photocoagulation, steroids, drugs that target the VEGF pathway (e.g., Lucentis® (ranibizumab) or Eylea® (aflibercept)), and / or anti-PDGF drugs.

[0133] In certain embodiments, the methods disclosed herein include administering to a subject an effective amount of a compound of Formula (I)-(III-b) or a pharmaceutically acceptable salt or composition thereof. In some embodiments, the effective amount is a therapeutically effective amount. In some embodiments, the effective amount is a prophylactically effective amount.

[0134] In certain embodiments, the subject to be 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 to be treated is a human. In certain embodiments, the subject is a domesticated animal, such as a dog, cat, cow, pig, horse, sheep, or goat. In certain embodiments, the subject is a companion animal, such as a dog or cat. In certain embodiments, the subject is a livestock animal, such as a cow, pig, horse, sheep, or goat. In certain embodiments, the subject is a zoo animal. In other embodiments, the subject is a research animal, such as a rodent (e.g., mouse, rat), dog, pig, or non-human primate. In certain embodiments, the animal is a genetically engineered animal. In certain embodiments, the animal is a transgenic animal.

[0135] Certain methods described herein may include administering one or more additional pharmaceutical agents in combination with a compound described herein. The additional pharmaceutical agent(s) may be administered simultaneously with the compound of Formula (I)-(III-b) or at a different time than the compound of Formula (I)-(III-b). For example, the compound of Formula (I)-(III-b) and any additional pharmaceutical agent(s) may be on the same or different dosing schedules. All or a portion of the dose of the compound of Formula (I)-(III-b) may be administered before all or a portion of the dose of the additional pharmaceutical agent, after all or a portion of the dose of the additional pharmaceutical agent, within the dosing schedule of the additional pharmaceutical agent, or a combination thereof. The timing of administration of the compound of Formula (I)-(III-b) and the additional pharmaceutical agent may vary depending on the type of additional pharmaceutical agent.

[0136] In certain embodiments, the additional pharmaceutical agent comprises an agent useful in the treatment of edema, eg, HAE or DME.

[0137] Illustrative Embodiments The present disclosure contemplates, among other things, the following numbered embodiments:

[0138] 1. Compounds of formula (I): [ka] or a pharmaceutically acceptable salt thereof (In the formula: Het A is selected from 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclylene having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur, 5- to 6-membered monocyclic heteroarylene having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclylene having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, and 7- to 10-membered bicyclic heteroarylene having 1-5 heteroatoms selected from oxygen, nitrogen, or sulfur, wherein Het A is 0 to 4 R A is substituted with a group, Each R A is halogen, -CN, -C(R)=N(R), -C(O)R, -C(O)2R, -C(O)N(R)2, -NO2, -N(R)-N(R)2, -N(R)2, -N(R)C(O)R, -N(R)C(O)2R, - N(R)C(O)N(R)2, -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 1~6independently selected from optionally substituted groups selected from aliphatic, phenyl, 5-6 membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 3-7 membered saturated or partially unsaturated monocyclic carbocyclyl, and 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur; L is an optionally substituted C 1~6 a hydrocarbon chain wherein one to three methylene units are independently replaced by -Cy-, -C(R)2-O-, -NR-, -C(O)-, -S(O)2-, -C(O)NR-, -NRC(O)-, -S(O)2NR-, and -NRS(O)2-; -Cy- is a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclylene, a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclylene having 1 to 2 heteroatoms selected from oxygen, nitrogen, or sulfur, or a 5- to 6-membered heteroarylene having 1 to 4 heteroatoms selected from oxygen, nitrogen, or sulfur; R' and R'' are hydrogen, halogen, -OR, -NR2, -SR, and optionally substituted C 1~6 aliphatic, wherein R' is a monocyclic Het A together with R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9is hydrogen, halogen, -CN, -C(R)=N(R), -C(O)R, -C(O)2R, -C(O)N(R)2, -NO2, -N(R)-N(R)2, -N(R)2, -N(R)C(O)R, -N(R)C(O)2R, -N(R)C(O)N(R)2, -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 5-6 membered heteroaryl having 1-4 heteroatoms selected from aliphatic, phenyl, oxygen, nitrogen, or sulfur; 3-7 membered saturated or partially unsaturated monocyclic carbocyclyl; and oxygen, nitrogen, or or sulfur, Each R is independently hydrogen or C 1~6 an optionally substituted group selected from aliphatic, phenyl, 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 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, or sulfur; or two R groups on the same carbon or nitrogen atom together with the atoms between them form a ring selected from a 3-7 membered saturated or partially unsaturated monocyclic ring having 0-2 heteroatoms selected from oxygen, nitrogen, or sulfur, and a 5-6 membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur; n is 0 or 1).

[0139] 2.L is -(CR2) m When NRC(O)- and m is 0 to 2 (e.g., 0 or 2), any of the following (a), (b), or (c): (a) n is 0, (b)R 5 , R 6 , R7 , R 8 , and R 9 At least one of the is CN, or (c)R 1 is an optionally substituted saturated monocyclic heterocycle containing 1 to 3 nitrogen atoms, with the proviso that the compounds are N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(2-oxopyrrolidin-1-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide, N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide, N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-morpholinoimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide, N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(2-oxopyrrolidine N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(2-oxooxazolidin-3-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide The compound of embodiment 1, wherein the compound is not triazole-4-carboxamide or 4-(2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)morpholine-2-carboxylic acid.

[0140] 3. L is selected from the group consisting of -C(R)2NRC(O)-#, -C(R)2C(O)NRC(R)2-#, -C(R)2NRC(O)C(R)2-#, -C(R)2NRC(R)2-#, -C(R)2C(R)2NRC(R)2-#, -C(O)NRC(R)2-#, -C(R)2C(O)NR-#, -NRC(O)C(R)2-#, -CR2C(O)NRC(R)2-#, -SO2NRC(R)2-#, and -C(R)2NRSO2-#, wherein # is Het A The compound of any one of the preceding embodiments, wherein the compound represents a point of attachment to

[0141] 4. L is the group consisting of -C(R)2NRC(O)-#, -C(R)2C(O)NRC(R)2-#, -C(R)2NRC(R)2-#, -C(R)2C(R)2NRC(R)2-#, -C(O)NRC(R)2-#, -C(R)2C(O)NR-#, -CR2C(O)NRC(R)2-#, -SO2NRC(R)2-#, and -C(R)2NRSO2-# where # is selected from Het A The compound of any one of the preceding embodiments, wherein the compound represents a point of attachment to

[0142] 5. L is selected from the group consisting of -C(R)2C(O)NRC(R)2-#, -C(R)2NRC(R)2-#, -C(R)2C(R)2NRC(R)2-#, -C(O)NRC(R)2-#, -C(R)2C(O)NRC(R)2-#, -SO2NRC(R)2-#, and -C(R)2NRSO2-#, wherein # is Het A The compound of any one of the preceding embodiments, wherein the compound represents a point of attachment to

[0143] 6. The compound of any one of the preceding embodiments, wherein L is other than —C(R)2NRC(O)—# or —C(R)2C(O)NR—#.

[0144] 7. The compound of any one of the preceding embodiments, wherein L is other than —CH 2 NRC(O)—# or —CH 2 C(O)NR—#.

[0145] 8. When L is -C(R)2NRC(O)-# or -C(R)2C(O)NR-#, either (a), (b), or (c) below: (a) n is 0, (b)R 5 , R 6 , R 7 , R 8 , and R 9 At least one of the is CN, or (c)R 1 is an optionally substituted saturated monocyclic heterocycle containing 1 to 3 nitrogen atoms, with the proviso that the compounds are N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(2-oxopyrrolidin-1-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide, N-((7-chloro-8-fluoro imidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-morpholinoimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide, N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(2-oxopyrrolidin-1-yl)methyl)- N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(2-oxooxazolidin-3-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide 4-(2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)morpholine-2-carboxylic acid.

[0146] 9. The compound of any one of the preceding embodiments, wherein when L is —C(R)2NRC(O)—# or —C(R)2C(O)NR—#, then n is 0.

[0147] 10. When L is -C(R)2NRC(O)-# or -C(R)2C(O)NR-#, R' is a monocyclic Het A together with 1 to 4 heteroatoms selected from oxygen, nitrogen, or sulfur to form an optionally substituted fused 7 to 10 membered saturated or partially unsaturated bicyclic heterocyclylene.

[0148] 11. When L is -CH2NRC(O)-# or -CH2C(O)NR-#, R' is a monocyclic Het A and an optionally substituted fused 7-10 membered saturated or partially unsaturated bicyclic ring having 1 to 4 heteroatoms selected from oxygen, nitrogen, or sulfur. The compound of any one of the preceding embodiments, which forms the formula heterocyclylene.

[0149] 12.L is -(CR2) m The compound of any one of the preceding embodiments, wherein NRC(O)—, and when m is 0, 1, or 2, then n is 0.

[0150] 13.L is -(CR2) m When m is 0 to 2 (e.g., 0 or 2), R' is a monocyclic Het A together with 1 to 4 heteroatoms selected from oxygen, nitrogen, or sulfur to form an optionally substituted fused 7 to 10 membered saturated or partially unsaturated bicyclic heterocyclylene.

[0151] 14. L is -C(R)2C(O)NR C(R)2-#, where each R is independently hydrogen, or C optionally substituted with halogen. 1~3 The compound of any one of the preceding embodiments, which is aliphatic.

[0152] 15. The compound of any one of the preceding embodiments, wherein L is —CH 2 C(O)NHCH(CF 3 )—#.

[0153] 16. The compound of any one of the preceding embodiments, wherein L is —CH2C(O)NHCH(CH3)—#.

[0154] 17. L is -C(R)2NRC(R)2-#, where each R is independently hydrogen, or C optionally substituted with halogen. 1~3 The compound of any one of the preceding embodiments, which is aliphatic.

[0155] 18. The compound of any one of the preceding embodiments, wherein L is —CH2NHCH(CF3)—#.

[0156] 19. The compound of any one of the preceding embodiments, wherein L is -CH2NHCH2-#.

[0157] 20. The compound of any one of the preceding embodiments, wherein L is —CH2NHCH(CH3)—#.

[0158] 21. The compound of any one of the preceding embodiments, wherein L is —CH(CF3)NHCH2—#.

[0159] 22. L is -C(R)NRSO-#, where each R is independently hydrogen, or C optionally substituted with halogen. 1~3 The compound of any one of the preceding embodiments, which is aliphatic.

[0160] 23. The compound of any one of the preceding embodiments, wherein L is —CH2NHSO2—#.

[0161] 24. L is -SO2NRC(R)2-#, where each R is independently hydrogen, or C optionally substituted with halogen. 1~3 The compound of any one of the preceding embodiments, which is aliphatic.

[0162] 25. The compound of any one of the preceding embodiments, wherein L is -SO2NHCH2-#.

[0163] 26. The compound of any one of the preceding embodiments, wherein L is -SO2NHCH(CH3)-#.

[0164] 27. L is -C(O)NR C(R)2-#, where each R is independently hydrogen or C optionally substituted with halogen. 1~3 The compound of any one of the preceding embodiments, which is aliphatic.

[0165] 28. The compound of any one of the preceding embodiments, wherein L is -C(O)NHCH2-#.

[0166] 29. L is -C(R)2C(O)NR C(R)2-#, where each R is independently hydrogen, or C optionally substituted with halogen. 1~3 The compound of any one of the preceding embodiments, which is aliphatic.

[0167] 30. The compound of any one of the preceding embodiments, wherein L is —CH 2 C(O)NHCH 2 —#.

[0168] 31. The compound has the structure of formula (Ia), formula (Ib), formula (Ic), or formula (Id): [ka] or a pharmaceutically acceptable salt thereof.

[0169] 32. The compound has the structure of formula (II): [ka] or a pharmaceutically acceptable salt thereof.

[0170] 33. The compound has the structure of formula (II-a) or formula (II-b): [ka] or a pharmaceutically acceptable salt thereof.

[0171] 34. R' is a monocyclic Het A to form an optionally substituted fused ring, said compound having the structure of formula (III): [ka] (In the formula, R fus Het A together with, form a fused 7-10 membered saturated or partially unsaturated bicyclic heterocyclylene having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur. or a pharmaceutically acceptable salt thereof.

[0172] 35. The compound has the structure of formula (III-a) or formula (III-b): [ka] or a pharmaceutically acceptable salt thereof.

[0173] 36. Het A is a 5-membered monocyclic heteroarylene having 1 to 4 heteroatoms selected from oxygen, nitrogen, or sulfur, wherein Het A is 0 to 2 R A The compound of any one of the preceding embodiments, wherein the compound is substituted with a group.

[0174] 37.Het A is a 5-membered monocyclic heteroarylene having 2 to 3 heteroatoms selected from nitrogen, wherein Het A is 0 to 2 R AThe compound of any one of the preceding embodiments, wherein the compound is substituted with a group.

[0175] 38.Het A However, 0 to 2 R A The compound of any one of the preceding embodiments, wherein the compound is a pyrazoldiyl substituted with a group.

[0176] 39. Het A However, there are 0 to 1 R A The compound of any one of the preceding embodiments, wherein the compound is a triazolediyl substituted with a group.

[0177] 40.Het A The compound of any one of the preceding embodiments, wherein is unsubstituted pyrazoldiyl.

[0178] 41. Het A The compound of any one of the preceding embodiments, wherein is unsubstituted 1,2,3-triazolediyl.

[0179] 42.Het A But the following: [ka] The compound of any one of the preceding embodiments, wherein the compound is selected from:

[0180] 43.R A One example is halogen-substituted C 1~6 The compound of any one of the preceding embodiments, which is aliphatic.

[0181] 44. The compound according to any one of the preceding embodiments, wherein R' and R'' are each hydrogen.

[0182] 45. R'' is hydrogen and R' is a monocyclic Het Atogether with 1 to 4 heteroatoms selected from oxygen, nitrogen, or sulfur to form a fused 7 to 10 membered saturated or partially unsaturated bicyclic heterocyclylene.

[0183] 46. ​​n is 1, R'' is hydrogen, and R' is a monocyclic Het A together with 1 to 4 heteroatoms selected from oxygen, nitrogen, or sulfur to form a fused 7 to 10 membered saturated or partially unsaturated bicyclic heterocyclylene.

[0184] 47. n is 1, R'' is hydrogen, and R' is a monocyclic Het A together with 1 to 4 heteroatoms selected from oxygen, nitrogen, or sulfur to form a fused 8-membered saturated or partially unsaturated bicyclic heterocyclylene.

[0185] 48.If n is 0, then Het A is a 7-10 membered saturated or partially unsaturated bicyclic heterocyclylene having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur.

[0186] 49. The compound of any one of the preceding embodiments, wherein n is 0.

[0187] 50. The compound of any one of the preceding embodiments, wherein n is 1.

[0188] 51.R 2 , R 3 , R 4 , R 5 , R 7 , R 8 , and R 9

[0023] The compound of any one of the preceding embodiments, wherein each of is hydrogen.

[0189] 52.R 1 , R2 , R 3 , R 4 , R 7 , R 8 , and R 9

[0023] The compound of any one of the preceding embodiments, wherein each of is hydrogen.

[0190] 53.R 1 , R 2 , R 3 , R 4 , R 5 , R 7 , R 8 , and R 9

[0023] The compound of any one of the preceding embodiments, wherein each of is hydrogen.

[0191] 54.R 1 is an optionally substituted group selected from 5-6 membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, and 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur.

[0192] 55.R 1 The compound of any one of the preceding embodiments, wherein is an optionally substituted 5-membered heteroaryl having 2 to 4 heteroatoms selected from oxygen or nitrogen.

[0193] 56.R 1 The compound of any one of the preceding embodiments, wherein is optionally substituted piperidinyl or optionally substituted triazolyl.

[0194] 57.R 1 is arbitrarily substituted C 1~6 The compound of any one of the preceding embodiments, which is aliphatic.

[0195] 58. Optionally substituted R 1 The substituents on the group are independently halogen, (CH2) 0~4 R°, -(CH2)0~4 OR°; and -(CH2) 0~4 C(O)OR°, where each R° is independently hydrogen, C 1~6 The compound of any one of the preceding embodiments, which is an aliphatic or 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0196] 59.R 5 and R 6 is each independently halogen.

[0197] 60.R 5 is F and R 6 The compound of any one of the preceding embodiments, wherein is Cl.

[0198] 61.R 6 The compound of any one of the preceding embodiments, wherein is Cl or CN.

[0199] 62. The compound of any one of the preceding embodiments, wherein said compound is any of compounds I-1 to I-20, or a pharmaceutically acceptable salt thereof.

[0200] 63. A pharmaceutical composition comprising a compound according to any one of the preceding embodiments.

[0201] 64. A pharmaceutical composition comprising a compound according to any one of the preceding embodiments, further comprising a pharmaceutically acceptable excipient.

[0202] 65. The pharmaceutical composition according to any one of embodiments 63-64, wherein the composition is suitable for oral administration.

[0203] 66. The pharmaceutical composition according to any one of embodiments 63-64, wherein the composition is suitable for administration by injection.

[0204] 67. A method of treating a disease or disorder mediated by plasma kallikrein using a compound or composition according to any one of the preceding embodiments.

[0205] 68. The method of embodiment 67, wherein the disease or disorder is hereditary angioedema or diabetic macular edema.

[0206] 69. A method of treating hereditary angioedema or diabetic macular edema, comprising administering to a patient in need thereof a compound or composition according to any one of the preceding embodiments. [Example]

[0207] Synthesis of intermediates Synthesis of 2-(7-chloroimidazo[1,5-a]pyridin-1-yl)acetic acid [ka] Synthesis of N-((4-chloropyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide. To a stirred suspension of (S)-2-methylpropane-2-sulfinamide (5.00 g, 41.3 mmol) and cesium carbonate (20.2 g, 61.9 mmol) in dichloromethane (100 mL) was added dropwise over 10 minutes at room temperature to a solution of 4-chloropicolinaldehyde (5.84 g, 41.3 mmol) in dichloromethane (20 mL). The solution was stirred for 2 hours. The reaction mixture was diluted with water (100 mL) and extracted with dichloromethane (100 mL × 3). The combined organic layers were dried (MgSO4) and concentrated to give the product (N-((4-chloropyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide, 10.1 g, quantitative) as a brown oil. LCMSRT=1.738min[M+H] + 246.9, 95% purity.

[0208] Synthesis of 3-((tert-butylsulfinyl)amino)-3-(4-chloropyridin-2-yl)propanoate. To a stirred solution of lithium diisopropylamide (2 M in tetrahydrofuran, 43 mL, 86 mmol) in anhydrous tetrahydrofuran (100 mL) was added dropwise a solution of butyl acetate (9.40 g, 81 mmol) in tetrahydrofuran (20 mL) at −78° C. under a nitrogen atmosphere. After 30 minutes of stirring, a solution of N-((4-chloropyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide (10.0 g, 41 mmol) in tetrahydrofuran (30 mL) was added at the same temperature. After stirring for an additional 2 hours at −78° C., the reaction mixture was quenched with saturated aqueous ammonium chloride (100 mL) and allowed to warm to room temperature. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (100 mL × 3). The combined organic layers were dried (Na2SO4), concentrated, and purified by flash chromatography (eluent 50% petroleum ether / ethyl acetate) to give the product (butyl 3-((tert-butylsulfinyl)amino)-3-(4-chloropyridin-2-yl)propanoate, 9.0 g, 61%) as a white solid. LCMSRT=1.338 min [M + H] + 361, 95% purity.

[0209] Synthesis of butyl 3-amino-3-(4-chloropyridin-2-yl)propanoate. Solution of butyl 3-(4-chloropyridin-2-yl)-3-(1,1-dimethylethylsulfinamido)propanoate (3.5 g, 9.7 mmol) in 1,4-dioxane (30 mL). To this was added a solution of hydrochloric acid (4 M in 1,4-dioxane, 10 mL, 40 mmol). The mixture was stirred at room temperature for 4 hours and then concentrated to give a crude oil (4.3 g) which was used in the next step without purification. LCMSRT=1.187 min [M+ H] + twenty five 7, 80% purity.

[0210] Synthesis of butyl 3-(4-chloropyridin-2-yl)-3-formamidopropanoate. A solution of butyl 3-amino-3-(4-chloropyridin-2-yl)propanoate (2.6 g, 10.2 mmol) in formic acid (10 mL) was stirred at reflux for 4 hours. The reaction mixture was then concentrated to give the crude product as a dark oil (3.0 g), which was used in the next step without purification. LCMSRT=1.05 min [M+ H] + 285, 83% pure degree

[0211] Synthesis of butyl 2-(7-chloroimidazo[1,5-a]pyridin-1-yl)acetate. A solution of butyl 3-(4-chloropyridin-2-yl)-3-formamidopropanoate (500 mg, 1.76 mmol) in phosphorus oxychloride (V) (5.0 mL) was stirred at 80° C. for 1 hour. The mixture was evaporated, and the residue was dissolved in ethyl acetate (100 mL) and washed with saturated aqueous sodium bicarbonate (50 mL). The organic layer was separated, and the aqueous layer was extracted again with ethyl acetate (50 mL×3). The combined organic layers were combined and purified by flash chromatography (eluent 70% ethyl acetate / petroleum ether) to give the product (2-(7-chloroimidazo[1,5-a]pyridin-1-yl)butyl acetate, 290 mg, 62%). LCMSRT=1.18 min [M+ H] + 267, 95% purity.

[0212] Synthesis of 2-(7-chloroimidazo[1,5-a]pyridin-1-yl)acetic acid. To a stirred solution of butyl 2-(7-chloroimidazo[1,5-a]pyridin-1-yl)acetate (310 mg, 1.16 mmol) in tetrahydrofuran (3 mL) and water (1 mL), lithium hydroxide (139 mg, 5.8 mmol) was added, and the mixture was stirred at room temperature for 16 hours. The pH was adjusted to 6 by adding 1 M aqueous hydrochloric acid, and the mixture was extracted with dichloromethane / methanol (10 / 1, 50 mL × 5). The combined organic layers were dried and concentrated to give the product (2-(7-chloroimidazo[1,5-a]pyridin-1-yl)acetic acid, 200 mg, 82%), which was used in the next step without purification. LCMSRT=0.901 min [M+H] +211, 95% purity

[0213] Synthesis of methyl 2-(7-chloroimidazo[1,5-a]pyridin-1-yl)acetate [ka] Acetyl chloride (0.42 mL, 5.9 mmol) was added to a stirred solution of 2-(7-chloroimidazo[1,5-a]pyridin-1-yl)acetic acid (250 mg, 1.2 mmol) in methanol (5.0 mL) at 0° C., then allowed to warm to room temperature and stirred for 18 h. The mixture was concentrated under reduced pressure. The residue was dissolved in a mixture of saturated aqueous sodium bicarbonate (25 mL) and water (25 mL) and extracted with methanol / dichloromethane (1:9, 3×50 mL). The combined organic layers were dried (MgSO), filtered, and evaporated under reduced pressure to give the product (methyl 2-(7-chloroimidazo[1,5-a]pyridin-1-yl)acetate, 310 mg). g, quantitative) as a cream-colored solid.

[0214] 1 H NMR (400 MHz, DMSO): δ, ppm 9.23 (1H, s ), 8.52(1H, dd, J = 1.0, 7.5 Hz), 8.08 - 8.07 (1H, m), 7.03 (1H, dd, J = 2.0, 7.5 Hz),4.17 (2H, s), 3.67 (3H, s).

[0215] Synthesis of 2-(7-chloroimidazo[1,5-a]pyridin-1-yl)acetamide [ka] A mixture of 2-(7-chloroimidazo[1,5-a]pyridin-1-yl)acetic acid (500 mg, 2.4 mmol), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (550 mg, 2.9 mmol), 1-hydroxybenzotriazole hydrate (380 mg, 2.9 mmol), N,N-diisopropylethylamine (2.5 mL, 14 mmol), and ammonium carbonate (1.1 g, 12 mmol) in tetrahydrofuran (7.0 mL) and N,N-dimethylformamide (4.0 mL) was stirred at 60 °C for 18 h. The mixture was cooled, diluted with water (50 mL), and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with saturated aqueous sodium carbonate (100 mL), dried (MgSO), filtered, and evaporated under reduced pressure. The residue was triturated with diethyl ether:dichloromethane (9:1) to give the product (2-(7-chloroimidazo[1,5-a]pyridin-1-yl)acetamide, 0.20 g, 40%) as a yellow solid.

[0216] 1 H NMR (400 MHz, DMSO): δ, ppm 8.36 - 8.33 (2H,m), 7.79 - 7.77 (1H,m), 7.45 - 7.38 (1H , m), 6.99 - 6.92 (1H, m), 6.68 (1H, dd,J = 2 .0, 7.3 Hz), 3.66 (2H, s).

[0217] Synthesis of ethyl 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate Synthesis of 5-cyclopropylpyridin-2-amine. A mixture of 5-bromopyridin-2-amine (100 g, 585 mmol), cyclopropylboronic acid (60 g, 701 mmol), Pd(AcO) (6.5 g, 29 mmol), SPhos (24 g, 58.5 mmol), and KPO (372 g, 1.755 mol) in toluene / HO (1.2 L / 0.12 L) was stirred at 90 °C for 14 h under N. The reaction was concentrated under reduced pressure to give the crude product, which was purified by silica gel chromatography (PE / EA = 1 / 2) to give 5-cyclopropylpyridin-2-amine (61 g, 78% yield) as a yellow solid. ESI-MS [M+H] + : 135.1.

[0218] Synthesis of 2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine. A mixture of 5-cyclopropylpyridin-2-amine (61 g, 455 mmol) and 1,3-dichloropropan-2-one (172 g, 1365 mmol) in EtOH (1 L) was stirred at 95 °C for 13 h. The reaction was concentrated to remove EtOH. NaHCO3 aqueous solution The pH of the residue was adjusted to 9 by adding HCl and extracted with EtOAc (1 L x 3). The combined organic layers were washed with brine, dried over NaSO, and concentrated under reduced pressure to give the crude product, which was purified by silica gel chromatography (EA) to give 2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine (40 g, yield: 42%) as a yellow solid. ESI-MS [M+H] + : 207.1.

[0219] Synthesis of 2-(azidomethyl)-6-cyclopropylimidazo[1,2-a]pyridine. To a solution of 2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine (40 g, 193 mmol) in DMF (600 mL) was added NaN (18.8 g, 290 mmol). The resulting reaction was stirred at room temperature for 2 hours. The reaction was diluted with HO (500 mL) and extracted with EtOAc (500 mL × 3). The combined organic layers were washed with brine, dried over NaSO, and concentrated under reduced pressure to give the crude product, which was purified by silica gel chromatography (PE / EA = 2 / 1) to give 2-(azidomethyl)-6-cyclopropylimidazo[1,2-a]pyridine (35 g, yield: 85%) as a yellow solid. ESI-MS [M+H] + :214.1.

[0220] Synthesis of ethyl 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate. A mixture of 2-(azidomethyl)-6-cyclopropylimidazo[1,2-a]pyridine (35 g, 163.5 mmol), ethyl propiolate (17.6 g, 180 mmol), CuSO (2.6 g, 16.35 mmol), and sodium ascorbate (3.3 g, 16.35 mmol) in HO / t-BuOH (150 mL / 150 mL) was stirred at room temperature for 3 hours. After 3 hours, a yellow solid precipitated, and the mixture was filtered. The cake was dried to give ethyl 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate (29 g, yield: 57%) as a yellow solid, which was used in the next step without further purification. ESI-MS [M+H] + :312 .1.

[0221] Synthesis of 7-chloro-8-fluoroimidazo[1,5-a]pyridine-1-carbaldehyde Synthesis of 4-chloro-3-fluoropicolinaldehyde. To a solution of 2,2,6,6-tetramethylpiperidine (35.4 g, 250.88 mmol) in 200 mL of THF, n-butyllithium (2.4 M in hexane, 100 mL, 240 mmol) was added dropwise at 0 °C. After stirring at 0 °C for 1 hour, the reaction mixture was cooled to -78 °C, and a solution of 4-chloro-3-fluoropyridine (30.0 g, 228.08 mmol) in THF (100 mL) was added dropwise. The resulting reaction mixture was stirred at -78 °C for 2 hours, and a solution of DMF (17.5 g, 239.48 mmol) in THF (50 mL) was added dropwise, and the resulting reaction mixture was stirred at -78 °C for an additional 1 hour. The reaction was quenched with HO (50 mL) and extracted with ethyl acetate (200 mL × 3). The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to give 4-chloro-3-fluoropicolinaldehyde (26.0 g, yield: 71%). ESI-MS [M+H] + : 160.1.

[0222] Synthesis of N-((4-chloro-3-fluoropyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide. To a solution of 4-chloro-3-fluoropicolinaldehyde (26.0 g, mixture, 163.0 mmol) in DCM (100 mL) was added cesium carbonate (96.0 g, 293.3 mmol) and 2-methylpropane-2-sulfinamide (19.8 g, 163.0 mmol) at room temperature. The reaction mixture was stirred at room temperature for 3 hours. After the reaction was complete, the reaction mixture was filtered and washed three times with DCM. To the combined mixture was added MeOH (40 mL), and then the resulting mixture was cooled to 0° C. in an ice-water bath. Sodium borohydride (15.5 g, 409.0 mmol) was added slowly in several portions. The reaction mixture was allowed to warm to room temperature and stirred at this temperature for 2 hours. The reaction was carefully quenched with H2O. The resulting mixture was extracted with DCM (100 mL x 3), and the combined organic solvents were dried over sodium sulfate, filtered, and concentrated to give crude N-((4-chloro-3-fluoropyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide (43.3 g, crude) as a yellow solid. ESI-MS [M+H] + : 265.1.

[0223] Synthesis of (4-chloro-3-fluoropyridin-2-yl)methanamine hydrochloride. To a solution of N-((4-chloro-3-fluoropyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide (approximately 162.4 mmol) in ethyl acetate (100 mL) was added a solution of hydrochloric acid in ethyl acetate (3 M, 200 mL). The resulting reaction mixture was stirred at room temperature for 3 hours. After the reaction was completed, the reaction mixture was filtered to obtain the crude product, which was washed with ethyl acetate and dried under vacuum to obtain (4-chloro-3-fluoropyridin-2-yl)methanamine hydrochloride (25.0 g, 78%, mixture) as a pale pink solid. 1 HNMR (400 MHz, DMSO) δ 8.75 (br, 3H), 8.47 (d, J = 5.2 Hz, 1H), 7.80 (t, J = 5.6Hz, 1H), 4.28 - 4.26 (m, 2H).

[0224] Synthesis of N-((4-chloro-3-fluoropyridin-2-yl)methyl)formamide. To a solution of (4-chloro-3-fluoropyridin-2-yl)methanamine hydrochloride (25.0 g, mixture, 127.0 mmol) in THF (200 mL) was added triethylamine (38.5 g, 380.6 mmol) and ethyl formate (100 mL) at room temperature. The resulting reaction mixture was stirred at 70° C. overnight. After the reaction was complete, the reaction mixture was filtered, and the solid was washed three times with DCM. The combined organic solvents were washed with brine, dried over sodium sulfate, filtered, and concentrated to give N-((4-chloro-3-fluoropyridin-2-yl)methyl)formamide (crude), which was used directly in the next step without purification. ESI-MS [M+H] + : 189.1.

[0225] Synthesis of 7-chloro-8-fluoroimidazo[1,5-a]pyridine. To a solution of N-((4-chloro-3-fluoropyridin-2-yl)methyl)formamide (crude, approximately 126.89 mmol) in anhydrous acetonitrile (200 mL) was added phosphoryl trichloride (18 mL, 1.5 equivalents), and the resulting reaction mixture was stirred at reflux for 3 hours. After the reaction was complete, the reaction mixture was cooled to room temperature and then carefully poured into HO (200 mL). The pH was adjusted to 8 with saturated sodium bicarbonate, and the resulting mixture was extracted with ethyl acetate (200 mL × 3). The combined organic phases were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate) to give 7-chloroimidazo[1,5-a]pyridine (12.0 g, yield: 56%) as a white solid. ESI-MS [M+H] + : 171.1.

[0226] Synthesis of 7-chloro-8-fluoroimidazo[1,5-a]pyridine-1-carbaldehyde. A solution of 7-chloro-8-fluoroimidazo[1,5-a]pyridine (9.0 g, 52.6 mmol) in anhydrous DMF (12 mL) was cooled to 0-5 °C in an ice-water bath. Phosphorus oxychloride (7.4 g, 78.9 mmol, 1.5 equiv.) was added dropwise, and the reaction mixture was then stirred at 100 °C for 2 h. After the reaction was complete, the reaction mixture was cooled to room temperature and carefully poured into saturated aqueous sodium bicarbonate solution (200 mL). The resulting mixture was stirred at room temperature for 2 h and extracted with ethyl acetate (3 × 200 mL). The combined organic phase was washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by recrystallization (petroleum ether / ethyl acetate = 1 / 1) to give 7-chloroimidazo[1,5-a]pyridine-1-carbaldehyde (5.2 g, yield: 47%) as a brown solid. ESI-MS [M+H] + : 181.1.

[0227] Synthesis of 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylic acid Synthesis of 5-cyclopropylpyridin-2-amine. A solution of 5-bromopyridin-2-amine (5 g, 29.1 mmol), cyclopropylboronic acid (3.75 g, 43.6 mmol), Pd(OAc) (651 mg, 2.91 mmol), SPhos (1.19 g, 2.91 mmol), and KPO (18.5 g, 87.3 mmol) in toluene / HO (100 mL / 10 mL) was stirred at 95 °C for 12 h under nitrogen. The reaction mixture was then quenched with HO (50 mL) and extracted with DCM (200 mL). The combined organic layers were dried over NaSO and concentrated under reduced pressure to give the crude residue, which was purified by silica gel chromatography (PE / EtOAc = 1 / 1) to give 5-cyclopropylpyridin-2-amine as a yellow solid (3.8 g, 97.4% yield). ESI-MS [M+H] + : 135.2.

[0228] Synthesis of 2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine. To a solution of 5-cyclopropyl-4-methylpyridin-2-amine (500 mg, 3.70 mmol) in DMF (10 mL) was added 1,3-dichloropropan-2-one (1409 mg, 11.1 mmol) at room temperature. The resulting reaction mixture was stirred at 85 °C for 2 hours. The solution was quenched with HO (60 mL), adjusted to pH 8 by adding saturated NaHCO solution, and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine, dried over NaSO, and concentrated under reduced pressure to give the crude product, which was purified by preparative TLC (PE / EtOAc = 1 / 1) to give 2-(chloromethyl)-6-cyclopropyl-7-methylimidazo[1,2-a]pyridine (300 mg, yield: 39%) as a pale yellow oil. ESI-MS [M+H] + : 207.2.

[0229] Synthesis of ethyl 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate. To a solution of 2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine (2 g, 9.70 mmol) in DMF (20 mL) was added ethyl 1H-pyrazole-4-carboxylate (906 mg, 6.46 mmol) and CsCO (6.32 g, 19.38 mmol) at room temperature. The resulting reaction was stirred at room temperature for 12 hours. HO (150 mL) was added to the reaction, and then the mixture was extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure to give the crude product, which was purified by silica gel chromatography (DCM / MeOH=20 / 1) to give ethyl 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate (1.5 g, yield: 75%) as a white solid. ESI-MS [M+H] + : 311.2.

[0230] Synthesis of 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylic acid. To a solution of ethyl 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate (1.2 g, 3.87 mmol) in THF (20 mL) and HO (10 mL) was added LiOH (464 mg, 19.35 mmol). The mixture was stirred at room temperature for 16 h. Most of the THF was removed, and the pH was adjusted to 4-5 by adding HCl (1 M). The resulting precipitate was collected and dried to give 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylic acid as a white solid (1.0 g, 91% yield). ESI-MS [M+H] + :283.2.

[0231] Synthesis of 1-(aminomethyl)imidazo[1,5-a]pyridine-7-carbonitrile Synthesis of tert-butyl ((7-bromoimidazo[1,5-a]pyridin-1-yl)methyl)carbamate. To a solution of (7-bromoimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride (2 g, 7.66 mmol) in DCM (30 mL) was added triethylamine (4.3 mL, 30.6 mmol) and di-tert-butyl dicarbonate (3.5 mL, 15.3 mmol). The mixture was stirred at room temperature for 2 hours. TLC showed the reaction was complete. The mixture was concentrated, dissolved in ethyl acetate, and washed with saturated ammonium chloride. The organic layer was concentrated and purified by column chromatography (DCM / MeOH=10 / 1) to give tert-butyl ((7-bromoimidazo[1,5-a]pyridin-1-yl)methyl)carbamate (2 g, yield: 80%) as a yellow oil. ESI-MS [M+H] + : 326.1.

[0232] Synthesis of tert-butyl ((7-cyanoimidazo[1,5-a]pyridin-1-yl)methyl)carbamate. To a solution of tert-butyl ((7-bromoimidazo[1,5-a]pyridin-1-yl)methyl)carbamate (200 mg, 0.615 mmol) in DMF (3 mL) was added 1,1'-bis(diphenylphosphino)ferrocene (64 mg, 0.12 mmol), tris(dibenzylideneacetone)dipalladium (Pd2(dba)3, 55 mg, 0.06 mmol), and zinc cyanide (144 mg, 1.23 mmol). The mixture was stirred in a microwave reactor at 150 °C for 1 hour and concentrated. The residue was purified by column chromatography (DCM / MeOH=10 / 1) to give tert-butyl ((7-cyanoimidazo[1,5-a]pyridin-1-yl)methyl)carbamate (117 mg, yield: 70%) as a yellow oil. ESI-MS [M+H] + : 273.1.

[0233] Synthesis of 1-(aminomethyl)imidazo[1,5-a]pyridine-7-carbonitrile. A mixture of tert-butyl ((7-cyanoimidazo[1,5-a]pyridin-1-yl)methyl)carbamate (270 mg, 0.99 mmol) and hydrochloric acid (3 M, 20 mL) in ethyl acetate was stirred at room temperature for 2 hours, then filtered to give the crude product, which was washed with ethyl acetate and dried under vacuum to give 1-(aminomethyl)imidazo[1,5-a]pyridine-7-carbonitrile (201.3 mg, quantitative) as a yellow solid. ESI-MS [M-NH2] + :156.0. Purity: 96.3%.

[0234] Synthesis of ethyl 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate Synthesis of 5-cyclopropylpyridin-2-amine. A mixture of 5-bromopyridin-2-amine (100 g, 585 mmol), cyclopropylboronic acid (60 g, 701 mmol), Pd(AcO) (6.5 g, 29 mmol), SPhos (24 g, 58.5 mmol), and KPO (372 g, 1.755 mol) in toluene / HO (1.2 L / 0.12 L) was stirred at 90 °C for 14 h under N. The reaction was concentrated under reduced pressure to give the crude product, which was purified by silica gel chromatography (PE / EA = 1 / 2) to give 5-cyclopropylpyridin-2-amine (61 g, 78% yield) as a yellow solid. ESI-MS [M+H] + : 135.1.

[0235] Synthesis of 2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine. A mixture of 5-cyclopropylpyridin-2-amine (61 g, 455 mmol) and 1,3-dichloropropan-2-one (172 g, 1365 mmol) in EtOH (1 L) was stirred at 95 °C for 13 h. The reaction was concentrated to remove EtOH. The pH of the residue was adjusted to 9 by adding aqueous NaHCO and extracted with EtOAc (1 L × 3). The combined organic layers were washed with brine, dried over NaSO, and concentrated under reduced pressure to give the crude product, which was purified by silica gel chromatography (EA) to give 2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine (40 g, yield: 42%). %) as a yellow solid. ESI-MS [M+H] + : 207.1.

[0236] Synthesis of 2-(azidomethyl)-6-cyclopropylimidazo[1,2-a]pyridine. To a solution of 2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine (40 g, 193 mmol) in DMF (600 mL) was added NaN (18.8 g, 290 mmol). The resulting reaction was stirred at room temperature for 2 hours. The reaction was diluted with HO (500 mL) and extracted with EtOAc (500 mL × 3). The combined organic layers were washed with brine, dried over NaSO, and concentrated under reduced pressure to give the crude product, which was purified by silica gel chromatography (PE / EA = 2 / 1) to give 2-(azidomethyl)-6-cyclopropylimidazo[1,2-a]pyridine (35 g, yield: 85%) as a yellow solid. ESI-MS [M+H] + :214.1.

[0237] Synthesis of ethyl 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate. A mixture of 2-(azidomethyl)-6-cyclopropylimidazo[1,2-a]pyridine (35 g, 163.5 mmol), ethyl propiolate (17.6 g, 180 mmol), CuSO (2.6 g, 16.35 mmol), and sodium ascorbate (3.3 g, 16.35 mmol) in HO / t-BuOH (150 mL / 150 mL) was stirred at room temperature for 3 hours. After 3 hours, a yellow solid precipitated, and the mixture was filtered. The cake was dried to give ethyl 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate (29 g, yield: 57%) as a yellow solid, which was used in the next step without further purification. ESI-MS [M+H] + :312 .1.

[0238] Synthesis of (7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride Synthesis of 4-chloro-3-fluoropicolinaldehyde. To a solution of 2,2,6,6-tetramethylpiperidine (35.4 g, 250.88 mmol) in 200 mL of THF, n-butyllithium (2.4 M in hexane, 100 mL, 240 mmol) was added dropwise at 0 °C. After stirring at 0 °C for 1 hour, the reaction mixture was cooled to -78 °C, and a solution of 4-chloro-3-fluoropyridine (30.0 g, 228.08 mmol) in THF (100 mL) was added dropwise. The resulting reaction mixture was stirred at -78 °C for 2 hours, and a solution of DMF (17.5 g, 239.48 mmol) in THF (50 mL) was added dropwise, and the resulting reaction mixture was stirred at -78 °C for an additional 1 hour. The reaction was quenched with HO (50 mL) and extracted with ethyl acetate (200 mL × 3). The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to give 4-chloro-3-fluoropicolinaldehyde (26.0 g, yield: 71%). ESI-MS [M+H] + : 160.1.

[0239] Synthesis of N-((4-chloro-3-fluoropyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide. To a solution of 4-chloro-3-fluoropicolinaldehyde (26.0 g, mixture, 163.0 mmol) in DCM (100 mL) was added cesium carbonate (96.0 g, 293.3 mmol) and 2-methylpropane-2-sulfinamide (19.8 g, 163.0 mmol) at room temperature. The reaction mixture was stirred at room temperature for 3 hours. After the reaction was complete, the reaction mixture was filtered and washed three times with DCM. MeOH (40 mL) was added to the combined mixture, and then the resulting mixture was cooled to 0° C. in an ice-water bath. Sodium borohydride (15.5 g, 409.0 mmol) was added slowly in several portions. The reaction mixture was allowed to warm to room temperature and stirred at this temperature for 2 hours. The reaction was carefully quenched with HO. The resulting mixture was extracted with DCM (100 mL × 3), and the combined organic solvents were dried over sodium sulfate, filtered, and concentrated to give crude N-((4-chloro-N-methyl ... (3-fluoropyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide (43.3 g, crude) was obtained as a yellow solid. ESI-MS [M+H] + : 265.1.

[0240] Synthesis of (4-chloro-3-fluoropyridin-2-yl)methanamine hydrochloride. To a solution of N-((4-chloro-3-fluoropyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide (approximately 162.4 mmol) in ethyl acetate (100 mL) was added a solution of hydrochloric acid in ethyl acetate (3 M, 200 mL). The resulting reaction mixture was stirred at room temperature for 3 hours. After the reaction was completed, the reaction mixture was filtered to obtain the crude product, which was washed with ethyl acetate and dried under vacuum to obtain (4-chloro-3-fluoropyridin-2-yl)methanamine hydrochloride (25.0 g, 78%, mixture) as a pale pink solid. 1 HNMR (400 MHz, DMSO) δ 8.75 (br, 3H), 8.47 (d, J = 5.2 Hz, 1H), 7.80 (t, J = 5.6Hz, 1H), 4.28 - 4.26 (m, 2H).

[0241] Synthesis of N-((4-chloro-3-fluoropyridin-2-yl)methyl)formamide. To a solution of (4-chloro-3-fluoropyridin-2-yl)methanamine hydrochloride (25.0 g, mixture, 127.0 mmol) in THF (200 mL) was added triethylamine (38.5 g, 380.6 mmol) and ethyl formate (100 mL) at room temperature. The resulting reaction mixture was stirred at 70° C. overnight. After the reaction was complete, the reaction mixture was filtered, and the solid was washed three times with DCM. The combined organic solvents were washed with brine, dried over sodium sulfate, filtered, and concentrated to give N-((4-chloro-3-fluoropyridin-2-yl)methyl)formamide (crude), which was used directly in the next step without purification. ESI-MS [M+H] + : 189.1.

[0242] Synthesis of 7-chloro-8-fluoroimidazo[1,5-a]pyridine. To a solution of N-((4-chloro-3-fluoropyridin-2-yl)methyl)formamide (crude, approximately 126.89 mmol) in anhydrous acetonitrile (200 mL) was added phosphoryl trichloride (18 mL, 1.5 equivalents), and the resulting reaction mixture was stirred at reflux for 3 hours. After the reaction was complete, the reaction mixture was cooled to room temperature and then carefully poured into HO (200 mL). The pH was adjusted to 8 with saturated sodium bicarbonate, and the resulting mixture was extracted with ethyl acetate (200 mL × 3). The combined organic phases were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate) to give 7-chloroimidazo[1,5-a]pyridine (12.0 g, yield: 56%) as a white solid. ESI-MS [M+H] + : 171.1.

[0243] Synthesis of 7-chloro-8-fluoroimidazo[1,5-a]pyridine-1-carbaldehyde. A solution of 7-chloro-8-fluoroimidazo[1,5-a]pyridine (9.0 g, 52.6 mmol) in anhydrous DMF (12 mL) was cooled to 0-5 °C in an ice-water bath. Phosphorus oxychloride (7.4 g, 78.9 mmol, 1.5 equiv.) was added dropwise, and the reaction mixture was then stirred at 100 °C for 2 h. After the reaction was complete, the reaction mixture was cooled to room temperature and carefully poured into saturated aqueous sodium bicarbonate solution (200 mL). The resulting mixture was stirred at room temperature for 2 h and extracted with ethyl acetate (3 × 200 mL). The combined organic phase was washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by recrystallization (petroleum ether / ethyl acetate = 1 / 1) to give 7-chloroimidazo[1,5-a]pyridine-1-carbaldehyde (5.2 g, yield: 47%) as a brown solid. ESI-MS [M+H] + :181.1.

[0244] Synthesis of (Z)-N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methylene)-2-methylpropane-2-sulfinamide. To a solution of fluoroimidazo[1,5-a]pyridine-1-carbaldehyde (5.2 g, 26.19 mmol) and 2-methylpropane-2-sulfinamide (3.2 g, 26.71 mmol) in THF (200 mL) was added tetraethoxytitanium (15.0 g, 65.50 mol). The reaction mixture was stirred at reflux overnight. After completion of the reaction, the reaction mixture was concentrated, and the residue was purified by column chromatography (ethyl acetate) to give (E)-N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methylene)-2-methylpropane-2-sulfinamide (7.77 g, 98%) as a white solid. ESI-MS [M+H] + : 302.1.

[0245] Synthesis of N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-2-methylpropane-2-sulfinamide. To a solution of (E)-N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methylene)-2-methylpropane-2-sulfinamide (7.77 g, 25.75 mmol) in MeOH (200 mL) was added sodium borohydride (2.44 g, 64.37 mmol) slowly. The resulting reaction mixture was stirred at room temperature for 3 hours. After completion of the reaction, the reaction was quenched with HO (50 mL). The resulting mixture was extracted with ethyl acetate (200 mL x 3), and the combined organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-2-methylpropane-2-sulfinamide (7.77 g, 99%) as a white solid. ESI-MS [M+H] + : 304.1.

[0246] Synthesis of (7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride. A mixture of N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-2-methylpropane-2-sulfinamide (7.77 g, 25.5 mmol) and hydrochloric acid in ethyl acetate (3 M, 100 mL) was stirred at room temperature for 2 hours. The reaction mixture was then filtered to give the crude product, which was washed with ethyl acetate and dried under vacuum to give (7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride (6.03 g, quantitative) as a white solid. ESI-MS [M-NH2] + :182.9. 1 H NMR (400 MHz, DMSO): δ 8.64 (d,J = 2.0 Hz, 1H), 8.44 (br, 3H), 8.33 (d, J = 7.2 Hz, 1H), 6.92 (t, J = 6.8 Hz, 1H),4.2 6 - 4.22 (m, 2H).

[0247] Synthesis of ethyl 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate Synthesis of 5-cyclopropylpyridin-2-amine. A solution of 5-bromopyridin-2-amine (5 g, 29.1 mmol), cyclopropylboronic acid (3.75 g, 43.6 mmol), Pd(OAc) (651 mg, 2.91 mmol), SPhos (1.19 g, 2.91 mmol), and KPO (18.5 g, 87.3 mmol) in toluene / HO (100 mL / 10 mL) was stirred at 95 °C for 12 h under nitrogen. The reaction mixture was then quenched with HO (50 mL) and extracted with DCM (200 mL). The combined organic layers were dried over NaSO and concentrated under reduced pressure to give the crude residue, which was purified by silica gel chromatography (PE / EtOAc = 1 / 1) to give 5-cyclopropylpyridin-2-amine as a yellow solid (3.8 g, 97.4% yield). ESI-MS [M+H] + : 135.2.

[0248] Synthesis of 2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine. To a solution of 5-cyclopropyl-4-methylpyridin-2-amine (500 mg, 3.70 mmol) in DMF (10 mL) was added 1,3-dichloropropan-2-one (1409 mg, 11.1 mmol) at room temperature. The resulting reaction was stirred at 85° C. for 2 hours. The mixture was quenched with HO (60 mL), adjusted to pH 8 by adding saturated NaHCO solution, and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine, dried over NaSO, and concentrated under reduced pressure to give the crude product, which was purified by preparative TLC (PE / EtOAc = 1 / 1) to give 2-(chloromethyl)-6-cyclopropyl-7-methylimidazo[1,2-a]pyridine (300 mg, yield: 39%) as a pale yellow oil. ESI-MS [M+H] + : 207.2.

[0249] Synthesis of ethyl 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate. To a solution of 2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine (2 g, 9.70 mmol) in DMF (20 mL) was added ethyl 1H-pyrazole-4-carboxylate (906 mg, 6.46 mmol) and CsCO (6.32 g, 19.38 mmol) at room temperature. The resulting reaction was stirred at room temperature for 12 hours. HO (150 mL) was added to the reaction, and then the mixture was extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure to give the crude product, which was purified by silica gel chromatography (DCM / MeOH=20 / 1) to give ethyl 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate (1.5 g, yield: 75%) as a white solid. ESI-MS [M+H] + :311.2.

[0250] Synthesis of tert-butyl 1-((8-bromo-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate Synthesis of 3-bromo-5-cyclopropylpyridin-2-amine. To a solution of 5-cyclopropylpyridin-2-amine (8.08 g, 60 mmol) in MeCN (200 mL) was added NBS (11.72 g, 66 mmol) in portions over 30 min at 0 °C. The mixture was stirred at 0 °C for another 30 min and then concentrated to give the crude product, which was purified by silica gel chromatography (PE / EA = 5 / 1 to 4 / 1) to give 3-bromo-5-cyclopropylpyridin-2-amine as a white solid (8.23 g, yield: 64%). ESI-MS [M+H] + :212.8.

[0251] Synthesis of 8-bromo-2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine. A solution of 3-bromo-5-cyclopropylpyridin-2-amine (8.23 g, 38.6 mmol) and 1,3-dichloropropan-2-one (7.46 g, 57.9 mmol) in EtOAc (80 mL) was stirred at 70 °C for 48 h. The reaction mixture was diluted with EtOAc (300 mL) and washed with saturated aqueous NaHCO (100 mL). The organic layer was washed with brine, dried over NaSO, and concentrated under reduced pressure to give the crude product, which was purified using silica gel (EtOAc / PE = 1 / 2) to give (8 g, yield: 72.3%) as a yellow solid. ESI-MS [M+H] + :284.8

[0252] Synthesis of 2-(azidomethyl)-8-bromo-6-cyclopropylimidazo[1,2-a]pyridine. To a solution of 8-bromo-2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine (1 g, 3.5 mmol) in DMF (15 mL) was added NaN (230 mg, 3.5 mmol). The resulting mixture was stirred under nitrogen at 50 °C for 24 h. HO (50 mL) was added to the reaction mixture, which was then extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine, dried over NaSO, and concentrated under reduced pressure to give 2-(azidomethyl)-8-bromo-6-cyclopropylimidazo[1,2-a]pyridine (1.1 g, crude), which was used in the next step without further purification. ESI-MS [M+H] + :292.0.

[0253] 1-((8-bromo-6-cyclopropylimidazo[1,2-a]pyridin-2-yl Synthesis of tert-butyl 2-(azidomethyl)-8-bromo-6-cyclopropylimidazo[1,2-a]pyridine (1.1 g, crude from the previous step) and tert-butyl propiolate (860 mg, 6.8 mmol) in t-BuOH / HO (15 mL / 15 mL) were added CuSO (170 mg, 0.68 mmol) and sodium ascorbate (180 mg, 1.02 mmol). The reaction mixture was stirred at room temperature for 12 hours. The mixture was concentrated under reduced pressure to give the crude product, which was purified by silica gel chromatography (PE / EtOAc = 1 / 2) to give tert-butyl 1-((8-bromo-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate (500 mg, 34% over two steps) as a brown oil. ESI-MS [M+H] + :417.7.

[0254] Example 1 2-(7-chloroimidazo[1,5-a]pyridin-1-yl)-N-((1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methyl)acetamide (I-1) Scheme 1 [ka] Synthesis of (1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methanol [ka] To a solution of ethyl 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate (10.0 g, 33.7 mmol) in THF (100 mL) was added DIBAL-H (67.3 mL, 67.3 mmol) at −60° C. The mixture was stirred at room temperature for 3 h, then quenched with saturated aqueous NaHCO (300 mL) and extracted with EtOAc (150 mL × 3). The combined organic layers were washed with brine (200 mL), dried over NaSO, and concentrated under reduced pressure. The residue was purified by flash column chromatography (PE / EtOAc 0–80%) to give (1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate). )methyl)-1H-1,2,3-triazol-4-yl)methanol (7.5 g, yield: 82%) was obtained as an off-white solid. ESI-MS [M + H] + :270.1

[0255] Synthesis of 2-((4-(azidomethyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridine [ka] To a solution of (1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methanol (5 g, 18.6 mmol) and DPPA (10.2 g, 37.2 mmol) in DCM (80 mL) was added DBU (11.3 g, 74.4 mmol) dropwise at 0 °C. After stirring at room temperature for 18 h, the reaction was quenched with saturated aqueous NH4Cl (100 mL) and extracted with DCM (100 mL × 3). The combined organic layers were washed with brine (70 mL), dried over Na2SO4, and concentrated under reduced pressure to give the crude product, which was purified by silica gel chromatography (PE / EtOAc Purification by HCl (0-50%) gave 2-((4-(azidomethyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridine (2 g, yield: 36.6%) as a white solid. [M+H] + : 295.2

[0256] Synthesis of (1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methanamine [ka] A mixture of 2-((4-(azidomethyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridine (2 g, 6.8 mmol) and Pd / C (200 mg) in THF (80 mL) was stirred under an H atmosphere at room temperature for 18 hours. The reaction mixture was filtered and washed with MeOH (100 mL). The filtrate was concentrated under reduced pressure to give (1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methanamine (1 g, yield: 54.9%) as a yellow solid. [M+H]+: 269.2

[0257] Synthesis of 2-(7-chloroimidazo[1,5-a]pyridin-1-yl)-N-((1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methyl)acetamide (I-1) [ka] A mixture of 2-(7-chloro-1,8a-dihydroimidazo[1,5-a]pyridin-1-yl)acetic acid (40 mg, 0.19 mmol), HATU (110 mg, 0.29 mmol), DIPEA (74 mg, 0.57 mmol), and (1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methanamine (51 mg, 0.19 mmol) in DMF (3 mL) was stirred at room temperature for 18 hours. Water (30 mL) was added, and the mixture was extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (40 mL × 2), dried over NaSO, and concentrated under reduced pressure to give the crude product, which was purified by preparative TLC (DCM / MeOH = 20 / 1) to give 2-(7-chloroimidazo[1,5-a]pyridin-1-yl)-N-((1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methyl)acetamide (50 mg, yield: 57%) as a white solid. ESI-MS: [M+H] + 461.2.

[0258] 1H NMR (400 MHz, DMSO) δ 8.45 - 8.42 (m, 1H), 8.36 (s, 1H),8.29 - 8.27 (m, 2H),7.89 (s, 1H), 7.83 (s, 1H), 7.72 (s, 1H), 7.41 (d, J = 9.3Hz, 1H), 7.02 (d, J = 9.4 Hz, 1H), 6.63 ― 6.61 (m, 1H), 5.63 (s, 2H), 4.27 (d,J= 5.6 Hz, 2H), 3.66 (s, 2H), 1.97 ― 1.90 (m, 1H), 0.95 ―0.90 (m, 2H), 0.70 ― 0.66(m, 2H).

[0259] Example 2 1-(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)-N-((1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methyl)-2,2,2-trifluoroethan-1-amine (I-2) Scheme 2 [ka] Synthesis of 1-(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)-2,2,2-trifluoroethan-1-ol [ka] To a solution of 7-chloro-8-fluoroimidazo[1,5-a]pyridine (510 mg, 3 mmol) in DMF (15 mL) was added TFAA (1.58 g, 7.5 mmol) dropwise at 0 °C. The reaction mixture was stirred at 0 °C for 3 hours, then HO (50 mL) was added, and the mixture was extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (50 mL), dried over NaSO, and concentrated under reduced pressure to give the crude product, which was purified by silica gel column (PE / EtOAc = 1 / 1) to give 1-(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)-2,2,2-trifluoroethan-1-one (400 mg, yield: 50%) as a yellow solid. ESI-MS [M+H]: 267.0.

[0260] Synthesis of 1-(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)-2,2,2-trifluoroethan-1-ol [ka] To a solution of 1-(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)-2,2,2-trifluoroethan-1-one (50 mg, 0.19 mmol) in MeOH (10 mL) at 0 °C was added NaBH (29 mg, 0.77 mmol). The reaction mixture was stirred at room temperature for 2 hours, and then HO (20 mL) was added. The aqueous phase was extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (30 mL × 2), dried over NaSO, and concentrated under reduced pressure to give the crude product, which was purified by preparative TLC (DCM / MeOH = 10 / 1) to give 1-(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)-2,2,2-trifluoroethan-1-ol (46 mg, 90.2%) as a white solid. ESI-MS [M+H]+: 269.0.

[0261] Synthesis of 7-chloro-1-(1-chloro-2,2,2-trifluoroethyl)-8-fluoroimidazo[1,5-a]pyridine [ka] To a solution of 1-(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)-2,2,2-trifluoroethan-1-ol (46 mg, 0.17 mmol) in DCM (10 mL) was added SOCl (0.5 mL). The resulting mixture was heated to 50 °C and stirred for 12 h. The reaction mixture was concentrated under reduced pressure to give 7-chloro-1-(1-chloro-2,2,2-trifluoroethyl)-8-fluoroimidazo[1,5-a]pyridine (49 mg crude), which was used in the next step without further purification (49 mg crude). ESI-MS [M+H]: 288.1

[0262] Synthesis of 1-(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)-N-((1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methyl)-2,2,2-trifluoroethan-1-amine [ka] To a solution of (1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methanamine (46 mg, 0.17 mmol) and triethylamine (174 mg, 1.72 mmol) in DCM (5 mL) was added 7-chloro-1-(1-chloro-2,2,2-trifluoroethyl)-8-fluoroimidazo[1,5-a]pyridine (46 mg, 0.16 mmol) at 0° C. The reaction mixture was stirred at room temperature for 1 hour. The resulting mixture was poured into HO (20 mL) and extracted with DCM (25 mL × 3). The combined organic layers were washed with brine (30 mL × 2), dried over NaSO, and concentrated under reduced pressure to give the crude product, which was purified by preparative HPLC to give 1-(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)-N-((1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methyl)-2,2,2-trifluoroethan-1-amine as a white solid (6 mg, 7%). ESI-MS [M+H]: 519.1.

[0263] 1H NMR (400 MHz, DMSO) δ 8.39 (d, J = 7.5 Hz , 1H), 8.35 (s,1H), 7.86 (s, 1H), 7.78 (s, 1 H), 7.60 (s, 1H), 7.40 (d, J = 9.3 Hz, 1H), 7 .01 (d,J = 9.4 Hz, 1H), 6.89 (t, J = 7.0 Hz, 1H), 5.55 (s, 2H), 5.42 ― 5.34 (m, 1H), 3.82― 3.71 (m, 2H), 1.95 ― 1.90 (m, 1H), 0.93 - 0.90 (m, 2H), 0.70 - 0.66 (m,2H).

[0264] Example 3 7-chloro-N-((1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methyl)-8-fluoroimidazo[1,5-a]pyridine-1-carboxamide (I-3) Scheme 3 [ka] Synthesis of 7-chloro-8-fluoroimidazo[1,5-a]pyridine-1-carboxylic acid [ka] To a solution of 7-chloro-8-fluoroimidazo[1,5-a]pyridine-1-carbaldehyde (0.3 g, 1.5 mmol) in HO (5 mL) and t-BuOH (10 mL) was added NaHPO (0.4 g, 3.0 mmol) and NaClO (0.3 g, 3.0 mmol). The mixture was stirred at room temperature for 48 hours. Water (30 mL) was added, and the mixture was extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine, dried over NaSO, concentrated, and purified by silica gel chromatography (DCM / MeOH = 10 / 1) to give 7-chloro-8-fluoroimidazo[1,5-a]pyridine-1-carboxylic acid (0.15 g, yield: 46.6%) as a white solid. ESI-MS [M+H]: 215.0.

[0265] Synthesis of 7-chloro-N-((1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methyl)-8-fluoroimidazo[1,5-a]pyridine-1-carboxamide [ka] To a solution of 7-chloro-8-fluoroimidazo[1,5-a]pyridine-1-carboxylic acid (60 mg, 0.28 mmol) in DMF (5 mL) was added (1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methanamine (75 mg, 0.28 mmol), HOBt (56.7 mg, 0.42 mmol), EDCI (80.6 mg, 0.42 mmol), and DIPEA (108.4 mg, 0.84 mmol). The mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure to give the crude product, which was purified by preparative HPLC to give 7-chloro-N-((1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methyl)-8-fluoroimidazo[1,5-a]pyridine-1-carboxamide (30 mg, yield: 23.1%) as a white solid. ESI-MS [M+H]: 465.1.

[0266] 1H NMR (400 MHz, DMSO) δ 8.63 (t, J = 6.0 Hz , 1H), 8.58 (d,J = 1.5 Hz, 1H), 8.40 ― 8.31 ( m, 2H), 8.19 (s, 1H), 7.92 (s, 1H), 7.81 (s, 1H),7.40 (d, J = 9.3 Hz, 1H), 6.94― 7.06 (m, 2H), 5.63 (s, 2H), 4.50 (d, J = 6.0 Hz,2H),1.84 ― 1.98 (m, 1H), 0.97 ― 0.86 (m,2H), 0.73 - 0.62 (m, 2H).

[0267] Example 4 N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-sulfonamide (I-4) Scheme 4 [ka] Synthesis of N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-sulfonamide [ka] To a solution of (7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride (1.06 g, 5.3 mmol) and DIPEA (1.33 mL, 7.5 mmol) in THF (15 mL) was added a solution of 1H-pyrazole-4-sulfonyl chloride (250 mg, 1.5 mmol) in DMSO (5 mL) at 0° C. The reaction mixture was stirred at 0° C. for 1 hour. Water (30 mL) was added, and the mixture was extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure to give the crude product, which was purified by silica gel chromatography (eluent: DCM / MeOH=10 / 1) to give N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-sulfonamide as a yellow solid (70 mg, yield: 14.2%). ESI-MS [M+H]+: 330.2

[0268] Synthesis of 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(1H-tetrazol-1-yl)benzyl)-1H-pyrazole-4-sulfonamide [ka] A mixture of N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-sulfonamide (70 mg, 0.21 mmol), 2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine (43 mg, 0.21 mmol), and CsCO (205 mg, 0.63 mmol) in DMF (10 mL) was stirred at room temperature for 12 h. Water (25 mL) was added, and the mixture was extracted with EtOAc (40 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure to give the crude product, which was purified by preparative HPLC to give N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-sulfonamide as a white solid (7 mg, 6.7%). ESI-MS [M+H]+: 500.1, purity: 99.75% (214 nm), 99.89% (254 nm).

[0269] 1H NMR (400 MHz, DMSO) δ 8.41 (d, J = 2.3 Hz , 1H), 8.35 (s,1H), 8.19 - 8.17 (m, 2H), 7.7 8 ― 7.77 (m, 2H), 7.66 (s, 1H), 7.42 (d, J = 9.3 Hz,1H), 7.01 (dd, J = 9.4, 1.7Hz, 1H), 6.75 (t, J = 8.0 Hz, 1H), 5.42 (s, 2H), 4.23(d, J = 5.5 Hz, 2H), 1.97 ― 1.87 (m, 1H), 0.95 ― 0.90 (m, 2H), 0.70 - 0.66 (m, 2H).

[0270] Example 5 N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-sulfonamide (I-5) Scheme 5 [ka] ((benzylthio)ethynyl)trimethylsilane synthesis [ka] To a solution of ethynyltrimethylsilane (9.8 g, 100 mmol) in anhydrous EtO (150 mL) was added n-BuLi (42 mL, 2.4 M solution in hexane, 100.8 mmol) slowly at −78° C. The reaction was stirred at −78° C. for 15 min. S( Benzylthioethynyl)trimethylsilane (3.2 g, 100 mmol) was added and the reaction mixture was stirred at -78 °C for an additional 15 min. The reaction was allowed to warm to room temperature and stirred for 1 h until S was consumed, then cooled to 0 °C. BnBr (17.1 g, 100 mmol) was added and the resulting mixture was stirred at room temperature for 14 h. The reaction was concentrated under reduced pressure to give the crude product, which was purified by silica gel chromatography (eluent: PE) to give ((benzylthio)ethynyl)trimethylsilane as a yellow oil (20 g, 91%). 1H NMR (400 MHz, CDCl3) δ 7.25 - 7.13 (m, 5H), 3.80 (s, 2H), 0.00 (s, 9H).

[0271] Benzyl(ethynyl)sulfane synthesis [ka] To a solution of ((benzylthio)ethynyl)trimethylsilane (20 g, 90.9 mmol) in THF (50 mL) was added TBAF (75 mL, 1 M solution in THF, 75 mmol). The resulting solution was stirred at room temperature for 12 h. The reaction was quenched with saturated aqueous NH4Cl (100 mL) and extracted with Et2O (100 mL × 2). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure to give benzyl(ethynyl)sulfane, which was used in the next step without further purification (12 g, crude yield: 91%).

[0272] 1H NMR (400 MHz, CDCl3) δ 7.35 - 7.26 (m, 5H), 3.96 (s, 2H),2.82 (s, 1H). Benzyl(ethynyl)sulfane synthesis [ka] To a solution of benzyl(ethynyl)sulfane (4 g, 27 mmol) and 2-(azidomethyl)-6-cyclopropylimidazo[1,2-a]pyridine (6.9 g, 32.4 mmol) in tBuOH / HO (40 mL / 40 mL) was added CuSO (2.1 g, 13.2 mmol) and sodium ascorbate (2.61 g, 13.2 mmol). The reaction was stirred at room temperature for 12 h. HO (150 mL) was added, and the mixture was extracted with DCM (150 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure to give the crude product, which was purified by silica gel chromatography (DCM / MeOH=15 / 1) to give 2-((4-(benzylthio)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridine as a black solid. (3.5 g, 36%). ESI-MS [M+H]+: 3 62.2

[0273] Synthesis of 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-sulfonyl chloride [ka] To a solution of 2-((4-(benzylthio)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridine (500 mg, 1.39 mmol) in AcOH / HO (15 mL / 5 mL) was added NCS (197 mg, 1.39 mmol). The reaction was stirred at room temperature for 2 hours. Additional NCS (197 mg, 1.39 mmol) was added to the reaction. The resulting reaction mixture was stirred for an additional 3 hours. The mixture was concentrated under reduced pressure to give the crude product, which was used in the next step without further purification (650 mg crude). ESI-MS [M+H]: 338.0

[0274] Synthesis of N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-sulfonamide [ka] To a mixture of (7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride (100 mg, 0.42 mmol) and DIPEA (774 mg, 6 mmol) in anhydrous THF (15 mL) was added 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-sulfonyl chloride (650 mg crude from the previous step) in 5 mL THF at 0 °C. The reaction was stirred at room temperature for 1 h. Water (50 mL) was added, and the mixture was extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure to give the crude material, which was purified by preparative HPLC to give N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-sulfonamide as a white solid (18 mg, yield: 2.6% over two steps). ESI-MS [M+H]+: 501.1, purity: 99.78% (214 nm), 100% (254 nm).

[0275] 1H NMR (400 MHz, DMSO) δ 8.70 (s, 1H), 8.58 (s, 1H), 8.37 (s,1H), 7.88 (s, 1H),7.39 (d, J = 9.3 Hz, 1H), 7.20 ― 7.10 (m, 2H), 7.03 ― 7.00 (m,2H), 6.85 (d, J = 3.6 Hz, 1H), 5.85 ― 5.56 (m, 2H), 2.50 (s, 1H), 1.97 ― 1.92 (m, 2H), 1.23 ― 1.16 (m, 2H), 0.95 ― 0.87(m, 2H), 0.70 - 0.66 (m, 2H).

[0276] Example 6 7-Chloro-N-((1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methyl)-8-fluoroimidazo[1,5-a]pyridine-1-sulfonamide (I-6) Scheme 6 [ka] Synthesis of 7-chloro-8-fluoro-1-iodoimidazo[1,5-a]pyridine [ka] A mixture of 7-chloro-8-fluoroimidazo[1,5-a]pyridine (1.7 g, 10 mmol), NIS (2.5 g, 11 mmol), and TFA (342 mg, 3.0 mmol) in MeCN (15 mL) was stirred at 60 °C for 4 h. The reaction was cooled to 0 °C, quenched with saturated aqueous NaHCO (50 mL), and extracted with DCM (50 mL × 3). The combined organic layers were washed with brine (30 mL), dried over NaSO, and concentrated under reduced pressure. The residue was purified by flash column chromatography (MeOH / DCM = 1 / 20) to give 7-chloro-8-fluoro-1-iodoimidazo[1,5-a]pyridine (1.5 g, yield: 50%) as a yellow oil. ESI-MS [M+H] +: 2 97.0.

[0277] 7-chloro-8-fluoro-1-((4-methoxybenzyl)thio)imidazo[1,5 Synthesis of [-a]pyridine [ka] A mixture of 7-chloro-8-fluoro-1-iodoimidazo[1,5-a]pyridine (1.18 g, 4.0 mmol), (4-methoxyphenyl)methanethiol (0.74 g, 4.8 mmol), Xantphos (116 mg, 0.2 mmol), Pd(dba) (183 mg, 0.2 mmol), and DIPEA (1.03 g, 8.0 mmol) in dioxane (15 mL) was stirred at 100° C. for 18 h. The reaction was cooled to room temperature, diluted with water (50 mL), and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (50 mL), dried over NaSO, and concentrated under reduced pressure to give a crude product, which was purified by silica gel chromatography (eluent: MeOH / DCM=1 / 20) to give 7-chloro-8-fluoro-1-((4-methoxybenzyl)thio)imidazo[1,5-a]pyridine (1.2 g, yield: 93%) as a yellow oil. ESI-MS [M+H]: 323.0.

[0278] Synthesis of 7-chloro-8-fluoroimidazo[1,5-a]pyridine-1-sulfonyl chloride [ka] To a mixture of 7-chloro-8-fluoro-1-((4-methoxybenzyl)thio)imidazo[1,5-a]pyridine (644 mg, 2.0 mmol) in AcOH / HO (4.5 mL / 1.5 mL) was added NCS (266 mg, 2.0 mmol). After stirring at room temperature for 2 hours, a second portion of NCS (266 mg, 2.0 mmol) was added. The reaction mixture was stirred at room temperature for an additional 2 hours. The reaction was quenched with saturated aqueous NaHCO (50 mL) and extracted with DCM (50 mL × 3). The combined organic layers were washed with brine (40 mL), dried over NaSO, and concentrated to give crude 7-chloro-8-fluoroimidazo[1,5-a]pyridine-1-sulfonyl chloride (700 mg, crude) as a brown oil, which was used directly in the next step without further purification. ESI-MS [M+H ] + : 269.0.

[0279] Synthesis of 7-chloro-N-((1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methyl)-8-fluoroimidazo[1,5-a]pyridine-1-sulfonamide [ka] A mixture of 7-chloro-8-fluoroimidazo[1,5-a]pyridine-1-sulfonyl chloride (150 mg, 0.56 mmol), (1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methanamine (150 mg, 0.56 mmol), and DIPEA (217 mg, 1.68 mmol) in DMF (100 mL) was stirred at room temperature for 18 hours. The reaction was quenched with saturated aqueous NaHCO (30 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (30 mL), dried over NaSO, and concentrated to give the crude product, which was purified by preparative HPLC to give 7-chloro-N-((1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methyl)-8-fluoroimidazo[1,5-a]pyridine-1-sulfonamide (11 mg, 4% yield) as a pale yellow solid. ESI-MS [M+H]: 501.1.

[0280] 1H NMR (400 MHz, DMSO) δ 8.60 (s, 1H), 8.43 ― 8.34 (m, 2H),8.22 (s, 1H), 7.82 (d,J = 7.9 Hz, 2H), 7.43 (d, J = 9.2 Hz, 1H), 7.07 ― 7.01 (m, 2H), 5.57 (s, 2H), 4.18 (s, 2H),1.99 ― 1.92 (m, 1H), 0.95-0.89 (m, 2H), 0.72-0.68(m, 2H).

[0281] Example 7 7-Chloro-N-(1-(1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)ethyl)-8-fluoroimidazo[1,5-a]pyridine-1-sulfonamide (I-7) [ka] 7-chloro-N-(1-(1-((6-cyclopropylimidazo[1,2-a]pyridin Synthesis of (1H-1,2,3-triazol-4-yl)ethyl)-8-fluoroimidazo[1,5-a]pyridine-1-sulfonamide To a solution of 1-(1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)ethan-1-amine (70 mg, 0.248 mmol) and triethylamine (75 mg, 0.743 mmol) in DMF (3 mL) was added a solution of 7-chloro-8-fluoroimidazo[1,5-a]pyridine-1-sulfonyl chloride (100 mg, 0.373 mmol) in 3 mL of DMF at 0° C. The reaction mixture was stirred at room temperature for 8 hours. Water (30 mL) was added, and the mixture was extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, and concentrated to give the crude product, which was purified by preparative HPLC to give 7-chloro-N-(1-(1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)ethyl)-8-fluoroimidazo[1,5-a]pyridine-1-sulfonamide[1,5-a]pyridine-1-sulfonamide (5.4 mg, yield: 4.3%) as a white solid. ESI-MS: [M+H] + , 515.1, Purity: 97.25% (214nm); 98.25% ( 254nm).

[0282] 1H NMR (400 MHz, DMSO) δ 8.52 (d, J = 2.1 Hz , 1H), 8.37 -8.35(m, 2H), 8.19 (d, J = 8.5 Hz, 1H), 7.81 (s, 1H), 7.67 (s, 1H),7.45 (d, J = 9.4Hz, 1H), 7.07 - 7.01 (m, 2H), 5.62 - 5. 46 (m, 2H), 4.59 - 4.53 (m, 1H), 1.97 - 1.91(m, 1H), 1.33 (d, J = 7.0 Hz, 3H), 0.94-0.91 (m, 2H), 0.71 -0.67 (m, 2H). [ka]

[0283] Synthesis of 1-(1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)ethan-1-ol [ka] 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)- To a mixture of 1H-1,2,3-triazole-4-carbaldehyde (2.0 g, 7.5 mmol) in THF (30 mL) was added MeMgBr (30.0 mL, 30.0 mmol) at 0 °C. The mixture was stirred at 0 °C for 1 h. The reaction mixture was then quenched with saturated aqueous NH4Cl (50 mL) and extracted with EtOAc (30 mL × 5). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography (MeOH / DCM 0-5%) to give 1-(1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)ethan-1-ol (1.5 g, yield: 71%) as a yellow oil. ESI-MS [M+ H] + : 284.1

[0284] 2-((4-(1-chloroethyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridine [ka] To a mixture of 1-(1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)ethan-1-ol (500 mg, 1.77 mmol) in DCM (10 mL) was added SOCl (1.0 mL) at 0 °C, and the mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated to give crude 2-((4-(1-chloroethyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridine (600 mg, crude) as a yellow oil, which was used directly in the next step without further purification. ESI-MS [M+H] + : 302.1

[0285] Synthesis of 2-((4-(1-azidoethyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridine [ka] A mixture of 2-((4-(1-chloroethyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridine (600 mg, crude) and NaN3 (344 mg, 5.30 mmol) in DMF (10 mL) was stirred at room temperature for 16 h. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography (MeOH / DCM 0-3%) to give 2-((4-(1-azidoethyl)-1H-1,2,3 (1-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridine (250 mg, yield: 46% over two steps) was obtained as a yellow oil. + H]+ : 309.2.

[0286] Synthesis of 1-(1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)ethan-1-amine [ka] A mixture of 2-((4-(1-azidoethyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridine (250 mg, 0.81 mmol) and Pd / C (50 mg) in THF (10 mL) was stirred under a hydrogen atmosphere at room temperature for 18 hours. Upon completion, the reaction mixture was filtered and the filtrate was concentrated to give crude 1-(1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)ethan-1-amine (150 mg, 66% yield) as a yellow oil, which was used directly in the next step without further purification. ESI-MS [M+ H] + : 283.2

[0287] Example 8 N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-5-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-2-carboxamide (I-8) Scheme 8 [ka] Synthesis of 1-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)prop-2-en-1-ol [ka] To a mixture of 6-cyclopropylimidazo[1,2-a]pyridine-2-carbaldehyde (1.86 g, 10.0 mmol) in THF (30 mL) was added vinylmagnesium bromide (15 mL, 15.0 mmol) while maintaining the temperature below −60° C. The reaction mixture was stirred at −60° C. for 2 hours, then quenched with saturated aqueous NH4Cl (100 mL) and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, and concentrated to give the crude product, which was purified by flash column chromatography (eluent: DCM / MeOH = 10 / 1) to give 1-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)prop-2-en-1-ol (1.6 g, yield: 75%) as a pale yellow solid. ESI-MS [M+H]+: 215.2.

[0288] Synthesis of methyl 2-(3-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)-3-oxopropyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylate [ka] A mixture of 1-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)prop-2-en-1-ol (1.2 g, 5.6 mmol), methyl 2-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylate (2.25 g, 6.7 mmol), Pd(OAc) (125 mg, 0.56 mmol), (o-MeCH)P (170 mg, 0.56 mmol), and DIPEA (2.2 g, 16.8 mmol) in DMA (20 mL) was degassed with N and stirred at 120 °C for 18 h. The reaction mixture was cooled to room temperature, and water (100 mL) was added. The mixture was extracted with EtOAc (50 mL × 3). The combined organic layer was washed with brine (50 mL) and concentrated under reduced pressure to give a crude product, which was purified by flash column chromatography (eluent: DCM / MeOH=15 / 1) to give methyl 2-(3-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)-3-oxopropyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylate as an off-white solid (900 mg, yield: 34%). ESI-MS [M+H]: 468.2. Synthesis of methyl 2-(3-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)-3-oxopropyl)-1H-imidazole-4-carboxylate [ka] A mixture of methyl 2-(3-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)-3-oxopropyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylate (500 mg, 1.07 mmol) in TFA / DCM (3.5 mL / 10 mL) was stirred at 50° C. for 5 h. The reaction mixture was cooled to room temperature and concentrated to give a residue, which was diluted with saturated aqueous NaHCO (50 mL) and extracted with EtOAc (50 mL×3). The combined organic layer was washed with brine (50 mL), dried over NaSO, and concentrated under reduced pressure to give a crude product, which was purified by flash column chromatography (eluent: DCM / MeOH=15 / 1) to give methyl 2-(3-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)-3-oxopropyl)-1H-imidazole-4-carboxylate as a yellow solid (300 mg, yield: 83%). ESI-MS [M+H]: 338.1.

[0289] Synthesis of methyl 2-(3-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)-3-hydroxypropyl)-1H-imidazole-4-carboxylate [ka] To a solution of methyl 2-(3-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)-3-oxopropyl)-1H-imidazole-4-carboxylate (0.3 g, 0.89 mmol) in MeOH (15 mL) at 0 °C, NaBH (67 mg, 1.78 mmol) was slowly added. The reaction mixture was stirred at room temperature for 2 hours. Water (50 mL) was added, and the mixture was extracted with DCM / MeOH (10 / 1, 30 mL × 3). The combined organic layers were washed with brine (20 mL) and concentrated under reduced pressure to give the crude product, which was purified by flash column chromatography (eluent: DCM / MeOH = 8 / 1) to give methyl 2-(3-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)-3-hydroxypropyl)-1H-imidazole-4-carboxylate as a white solid (220 mg, yield: 73%). ESI-MS [M+H]+: 341.1.

[0290] Synthesis of methyl 5-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-2-carboxylate [ka] To a mixture of methyl 2-(3-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)-3-hydroxypropyl)-1H-imidazole-4-carboxylate (100 mg, 0.29 mmol) and PPh3 (152 mg, 0.58 mmol) in THF (5 mL) at 0 °C was added DIAD (118 mg, 0.58 mmol). The mixture was allowed to warm to room temperature and stirred for 3 h. The reaction was diluted with water (30 mL) and extracted with DCM / MeOH (10 / 1, 30 mL × 3). The combined organic layer was washed with brine (30 mL) and concentrated to obtain a crude product, which was purified by flash column chromatography (eluent: DCM / MeOH=10 / 1) to obtain methyl 5-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-2-carboxylate as a colorless oil (25 mg, yield: 26%). ESI-MS [M+H]: 323.1.

[0291] Synthesis of 5-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-2-carboxylic acid [ka] A mixture of methyl 5-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-2-carboxylate (25 mg, 0.078 mmol) and LiOH.HO (16 mg, 0.390 mmol) in EtOH / THF / HO (1.5 mL / 1.5 mL / 0.5 mL) was stirred at 35 °C for 18 h. The reaction mixture was adjusted to pH 5 by adding HCl (1 N) and concentrated to give 5-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-2-carboxylic acid (40 mg, crude) as a white solid, which was used in the next step without further purification. ESI-MS [M+H]: 309.2.

[0292] Synthesis of N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-5-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-2-carboxamide [ka] A mixture of 5-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-2-carboxylic acid (40 mg, 0.13 mmol crude), (7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride (30 mg, 0.13 mmol), HOBT (17.5 mg, 0.13 mmol), EDCI (25 mg, 0.13 mmol), and DIPEA (50 mg, 0.39 mmol) in DMF (1 mL) was stirred at room temperature for 18 hours. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (10 mL × 3). The combined organic layer was washed with brine (20 mL), dried over NaSO, and concentrated under reduced pressure to obtain crude material, which was purified by preparative HPLC to obtain N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-5-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-2-carboxamide as a white solid (10 mg, yield: 15.7%). ESI-MS [M+H]: 490.2.

[0293] 1H NMR (400 MHz, DMSO) δ 8.45 (d, J = 2.4 Hz , 1H), 8.32 (s,1H), 8.21 (d, J = 7.4 Hz, 1H), 7.96 (t, J = 5.4 Hz, 1H), 7.73 (s, 1H), 7.45 (s,1H), 7.41 (d, J = 9.3 Hz, 1H), 7.02-6.99 (m, 1H), 6.76 ― 6.74 (m, 1H), 5.58 -5.54(m, 1H), 4.66 (d, J = 5.4 Hz, 2H), 2.93 - 2.82 (m , 3H), 2.78-2.70 (m, 1H), 1.94-1.89(m, 1H), 0.92 - 0.89 (m, 2H), 0.70 - 0.65 (m, 2H).

[0294] Synthesis of methyl 2-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylate (compound 3) [ka] Synthesis of methyl 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylate To a stirred solution of methyl 1H-imidazole-4-carboxylate (4 g, 31.75 mmol) in anhydrous DMF (75 mL) was added NaH (1.46 g, 60% suspension in liquid paraffin, 36.5 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 30 minutes and then treated dropwise with (2-(chloromethoxy)ethyl)trimethylsilane (6.32 g, 38.1 mmol). The reaction was allowed to warm to room temperature and stirred for 18 hours. The reaction was quenched with ice water (80 mL) and extracted with EtOAc (80 mL×3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, and concentrated under reduced pressure to give a crude product, which was purified by silica gel chromatography (eluent: MeOH / DCM = 1 / 20) to give methyl 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylate (6.8 g, yield: 84%) as a white solid. ESI-MS [M +H]+: 257.2.

[0295] Synthesis of methyl 2-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylate [ka] To a stirred solution of methyl 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylate (5.0 g, 19.5 mmol) in carbon tetrachloride (50 mL) were added NBS (3.47 g, 19.5 mmol) and AIBN (160 mg, 5 mol%) at room temperature. The reaction mixture was heated at 60° C. for 3 h, then cooled to room temperature and filtered through a small pad of Celite. The filtrate was concentrated under reduced pressure to give a pale yellow colored residue, which was dissolved in EtOAc (100 mL) and washed with 10% aqueous NaHCO (100 mL). The organic layer was washed with brine (70 mL), dried over Na SO and concentrated to give the crude compound. The crude material was purified by silica gel chromatography (eluent: PE / EtOAc = 2 / 1) to give 2-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylate. Methyl)ethoxy)methyl)-1H-imidazole-4-carboxylate (4 g, yield: 61.5%) was obtained. ESI-MS [M +H]+: 355.2.

[0296] Example 9 N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-5-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-3-carboxamide (I-9) Scheme 9 [ka] Synthesis of methyl 2-(3-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)-3-((methylsulfonyl)oxy)propyl)-1H-imidazole-4-carboxylate [ka] To a solution of methyl 2-(3-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)-3-hydroxypropyl)-1H-imidazole-4-carboxylate (200 mg, 0.59 mmol) in DCM (4 mL) at 0° C. was added triethylamine (119.3 mg, 1.18 mmol) and MsCl (101.2 g, 0.88 mmol). After stirring at 0° C. for 2 h, the reaction was concentrated under reduced pressure to give methyl 2-(3-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)-3-((methylsulfonyl)oxy)propyl)-1H-imidazole-4-carboxylate (240 mg, 98% yield) as a black solid, which was used in the subsequent step without further purification. ESI-MS [M+H]: 419.1.

[0297] Synthesis of methyl 5-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-3-carboxylate [ka] A mixture of methyl 2-(3-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)-3-((methylsulfonyl)oxy)propyl)-1H-imidazole-4-carboxylate (240 mg, 0.57 mmol) and CsCO (557 mg, 1.71 mmol) in DMF (15 mL) was stirred at room temperature for 12 hours. Water (30 mL) was added, and the mixture was extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine, dried over NaSO, and concentrated under reduced pressure to give the crude product, which was purified by silica gel chromatography (EtOAc / PE=1 / 1) to give methyl 5-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-3-carboxylate (102 mg, yield: 55.7%) as a yellow solid. ESI-MS [M+H]+: 323.1.

[0298] Synthesis of 5-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-3-carboxylic acid [ka] To a solution of methyl 5-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-3-carboxylate (102 mg, 0.32 mmol) in MeOH (1 mL) and THF (1 mL) was added LiOH (31.6 mg, 1.32 mmol) and HO (0.5 mL). The reaction mixture was stirred at room temperature for 12 hours. The mixture was adjusted to pH 5 with 1N HCl and then extracted with EtOAc (30 mL × 3). The combined organic layers were concentrated to give 5-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-3-carboxylic acid (65 mg, yield: 67%) as a white solid, which was used in the subsequent reaction without further purification. ESI-MS [M+H]+: 309.1.

[0299] Synthesis of N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-5-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-2-carboxamide [ka] To a solution of 5-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-3-carboxylic acid (65 mg, 0.21 mmol) in DMF (2 mL) was added (7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride (64.7 mg, 0.27 mmol), HATU (102.6 mg, 0.27 mmol), and DIPEA (387 mg, 3.0 mmol). The reaction mixture was stirred at room temperature for 4 hours. Water (20 mL) was added, and the mixture was extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated to give the crude product, which was purified by preparative HPLC to give N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-5-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-2-carboxamide (32 mg, yield: 50%) as a white solid. ESI-MS [M+H ]+: 490.2. Purity: 98.98% (214nm), 99.54% (254nm) .

[0300] 1H NMR (400 MHz, DMSO) δ 8.48 (t, J = 5.3 Hz , 1H), 8.43 (d,J = 2.4 Hz, 1H), 8.26 (s, 1H), 8.19 (d, J = 7.4 Hz, 1H), 7.58 (s, 1H), 7.41 (s,1H), 7.34 (d, J = 9.3 Hz, 1H), 6.98-6.95 (m, 1H), 6.78 ― 6.71 (m, 1H), 5.86 (d,J = 7.6 Hz, 1H), 4.68-4.65 (m, 1H), 4.51-4.46 (m, 1H), 3.02-2.88 (m, 2H), 2.81 - 2.71 (m, 1H), 2.69 - 2.59 (m, 1H), 1.95-1.88 (m, 1H), 0.95-0.86 (m, 2H), 0.71 -0.62 (m, 2H).

[0301] Example 10 N-((7-cyanoimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (I-10) [ka] To a solution of 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylic acid (60 mg, 0.21 mmol), 1-(aminomethyl)imidazo[1,5-a]pyridine-7-carbonitrile (55 mg, 0.32 mmol), and HATU (120 mg, 0.31 mmol) in DMF (2 mL) was added DIPEA (81 mg, 0.63 mmol). The resulting reaction was stirred at room temperature for 12 h. HO (25 mL) was added, and the mixture was extracted with EtOAc (15 mL × 3). The combined organic layer was washed with brine (15 mL), dried over Na2SO4, and concentrated under reduced pressure to give the crude product, which was purified by preparative TLC (DMC / MeOH=10 / 1) to give N-((7-cyanoimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide as a white solid (22 mg, yield: 24%). ESI-MS [M+H]+: 437.2.

[0302] 1H NMR (400 MHz, DMSO) δ 8.65 (t, J = 5.7 Hz , 1H), 8.50 (s,1H), 8.44 (s, 1H), 8.40-8.37 (m, 1H), 8.32 (s, 1H), 8.21 (s, 1H),7.86 (s , 1H),7.72 (s, 1H), 7.39 (d, J = 9.3 Hz, 1H), 7.01-6.97 (m, 1H), 6.85-6.81 (m, 1H), 5.39 (s, 2H), 4.63 (d, J = 5.7 Hz, 2H), 1.94 ― 1.8 8 (m, 1H), 0.93 - 0.88 (m, 2H), 0.68 - 0.64 (m, 2H).

[0303] Example 11 1-(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)-N-((1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methyl)methanamine (I-11) Scheme 11 [ka] Synthesis of (1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methanol [ka] To a solution of ethyl 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate (10.0 g, 33.7 mmol) in THF (100 mL) was added DIBAL-H (67.3 mL, 67.3 mmol) at −60° C. The mixture was stirred at room temperature for 3 hours, then quenched with saturated aqueous NaHCO (300 mL) and extracted with EtOAc (150 mL×3). The combined organic layers were washed with brine (200 mL), dried over NaSO, and concentrated under reduced pressure. The residue was purified by flash column chromatography (PE / EtOAc 0-20%) to give (1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methanol (7.5 g, yield: 82%) as an off-white solid. ESI-MS [M+H] + : 270.1

[0304] Synthesis of 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carbaldehyde [ka] A mixture of (1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methanol (300 mg, 1.12 mmol) and MnO (963 mg, 11.2 mmol) in DCM (10 mL) was stirred at room temperature for 18 h. The reaction mixture was then filtered and concentrated under reduced pressure to give 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carbaldehyde (220 mg, 74% yield) as a yellow solid, which was used in the next step without purification. ESI-MS [M+H] + : 268.1

[0305] Synthesis of 1-(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)-N-((1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methyl)methanamine [ka] A mixture of 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carbaldehyde (100 mg, 0.37 mmol), (7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride (88 mg, 0.37 mmol), and triethylamine (37 mg, 0.37 mmol) in MeOH (5 mL) was stirred at room temperature for 16 h. NaBH(OAc) (157 mg, 0.74 mmol) was added, and the mixture was stirred at room temperature for an additional 2 h. The reaction was quenched with water (50 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic layers were washed with brine (30 mL), dried over NaSO, and concentrated under reduced pressure. The residue was purified by preparative TLC (MeOH / DCM=1 / 15) to give 1-(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)-N-((1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methyl)methanamine (5.5 mg, yield: 3.3%) as a white solid. ESI-MS [M+H]: 451.1.

[0306] 1H NMR (400 MHz, DMSO) δ 8.44 (d, J = 2.1 Hz , 1H), 8.34 (s,1H), 8.19 (d, J = 7.4 Hz, 1H), 7.92 (s, 1H), 7.79 (s, 1H), 7.41 (d, J = 9.3 Hz,1H), 7.00 (d, J = 9.4 Hz, 1H), 6.73(t, J = 6.9 Hz, 1H), 5.62 (s, 2H), 3.92 (s,2H), 3. 74 (s, 2H), 1.97-1.88 (m, 1H), 0.97 - 0.87 ( m, 2H), 0.72-0.62 (m, 2H).

[0307] Example 12 N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-(1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)ethan-1-amine (I-12) ) Scheme 12 [ka] Synthesis of 1-(1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)ethan-1-ol [ka] To a mixture of 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carbaldehyde (2.0 g, 7.5 mmol) in THF (30 mL) was added MeMgBr (30.0 mL, 30.0 mmol) at 0° C. The mixture was stirred at 0° C. for 1 h. The reaction mixture was then quenched with saturated aqueous NH4Cl (50 mL) and extracted with EtOAc (30 mL × 5). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography (MeOH / DCM 0-5%) to give 1-(1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)ethan-1-ol (1.5 g, yield: 71%) as a yellow oil. ESI-MS [M+ H] + : 284.1

[0308] 2-((4-(1-chloroethyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridine [ka] To a mixture of 1-(1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)ethan-1-ol (500 mg, 1.77 mmol) in DCM (10 mL) was added SOCl (1.0 mL) at 0 °C, and the mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated to give crude 2-((4-(1-chloroethyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridine (600 mg, crude) as a yellow oil, which was used directly in the next step without further purification. ESI-MS [M+H] + : 302.1

[0309] Synthesis of 2-((4-(1-azidoethyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridine [ka] A mixture of 2-((4-(1-chloroethyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridine (600 mg, crude) and NaN3 (344 mg, 5.30 mmol) in DMF (10 mL) was stirred at room temperature for 16 h. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography (MeOH / DCM 0–3%) to give 2-((4-(1-azidoethyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridine (250 mg, yield: 46% over two steps) as a yellow oil. ESI-MS [M + H] +: 309.2

[0310] Synthesis of 1-(1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)ethan-1-amine [ka] A mixture of 2-((4-(1-azidoethyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridine (250 mg, 0.81 mmol) and Pd / C (50 mg) in THF (10 mL) was stirred under a hydrogen atmosphere at room temperature for 18 hours. Upon completion, the reaction mixture was filtered and the filtrate was concentrated to give crude 1-(1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)ethan-1-amine (150 mg, 66% yield) as a yellow oil, which was used directly in the next step without further purification. ESI-MS [M+ H] + : 283.2

[0311] Synthesis of N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-(1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)ethan-1-amine. [ka] To a solution of 1-(1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)ethan-1-amine (80 mg, 0.284 mmol) in MeOH (4 mL) was added 7-chloro-8-fluoroimidazo[1,5-a]pyridine-1-carbaldehyde (51 mg, 0.256 mmol) and triethylamine (57.5 mg, 0.568 mmol). The mixture was stirred at room temperature for 4 h. NaBH (11 mg, 0.291 mmol) was added, and the reaction mixture was stirred at room temperature for another 3 h. Water (40 mL) was added, and the mixture was extracted with EA (30 mL × 3). The combined organic layers were washed with brine (20 mL), dried over NaSO, and concentrated. The crude product was purified by preparative TLC (DCM:MeOH=10:1) to give N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-(1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)ethan-1-amine (18 mg, yield: 13.6%) as a yellow solid. ESI-MS [M+ H]: 465.2

[0312] 1H NMR (400 MHz, DMSO) δ 8.42 (d, J = 2.4 Hz , 1H), 8.35 (s,1H), 8.17 (d, J = 7.4 Hz, 1H), 7.90 (s, 1H), 7.79 (s, 1H), 7.42 (d, J = 9.3 Hz,1H), 7.04-6.98 (m, 1H), 6.74 ― 6.69(m, 1) H), 5.62 (s, 2H), 3.96-3.89 (m, 1H), 3.86(s , 2H), 1.97-1.88 (m, 1H), 1.31 (d, J = 6.6 Hz, 3H), 0.95 ― 0.89 (m, 2H), 0.70― 0.64(m, 2H).

[0313] Example 13 2-(7-chloroimidazo[1,5-a]pyridin-1-yl)-N-(1-(1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)ethyl)acetamide (I-13) Synthesis of 2-(7-chloroimidazo[1,5-a]pyridin-1-yl)-N-(1-(1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)ethyl)acetamide [ka] A mixture of 1-(1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)ethan-1-amine (37.1 mg, 0.131 mmol), 2-(7-chloroimidazo[1,5-a]pyridin-1-yl)acetic acid (60 mg, 0.285 mmol), HATU (100.07 mg, 0.263 mmol), and DIPEA (114.2 mg, 0.885 mmol) in DMF (4 mL) was stirred at room temperature for 16 hours. Water (50 mL) was added, and the mixture was extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (30 mL) and concentrated. The residue was purified by preparative HPLC to give 2-(7-chloroimidazo[1,5-a]pyridin-1-yl)-N-(1-(1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)ethyl)acetamide (40 mg, yield: 47.7%) as a white solid. ESI-MS [M+H ]+: 475.2.

[0314] 1H NMR (400 MHz, DMSO) δ 8.45 (d, J = 8.2 Hz , 1H), 8.36 (s,1H), 8.31 ― 8.24 (m, 2H), 7.9 0 (s, 1H), 7.83 (s, 1H), 7.75 ― 7.70 (m, 1H), 7.42(d, J = 9.3 Hz, 1H), 7.05-6.98 (m, 1H), 6.65-6.58 (m, 1H), 5.62 (s, 2H), 5.06−4.97 (m, 1H), 3.65 (s, 2H), 1.98-1.89 (m, 1H), 1.39 (d, J = 7.0 Hz, 3H), 0.95 -0.89(m, 2H), 0 .71—0.65 (m, 2H).

[0315] Example 14 Methyl 2-((4-((((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)amino)methyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-carboxylate (I-14) Scheme 14 [ka] Synthesis of methyl 1-((8-bromo-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate [ka] To a stirred solution of tert-butyl 1-((8-bromo-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate (2.7 g, 6.45 mmol) in MeOH (50 mL) was added concentrated H2SO4 (1 mL) dropwise at room temperature. The mixture was heated to reflux for 16 h, then cooled to room temperature, diluted with water (50 mL), and concentrated under reduced pressure to remove MeOH. The residue was adjusted to pH 9-10 by adding saturated aqueous NaHCO3. The resulting precipitate was collected by filtration and dried under reduced pressure to give methyl 1-((8-bromo-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate (2.0 g, 82% yield) as a light brown solid. ESI-MS [M+H] +: 376.0.

[0316] Synthesis of (1-((8-bromo-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methanol [ka] To a stirred solution of methyl 1-((8-bromo-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate (600 mg, 1.59 mmol) in MeOH (10 mL) and THF (10 mL) was added NaBH (693 mg, 18.32 mmol) in several portions at 0 °C. The mixture was stirred at room temperature for 8 h, then quenched with saturated aqueous NH Cl (30 mL) and concentrated under reduced pressure to remove MeOH and THF. The residue was extracted with DCM (40 mL × 3). The combined organics were washed with brine (80 mL), dried over NaSO and concentrated to give (1-((8-bromo-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methanol (500 mg, yield: 91%) as a light brown solid, which was used directly in the next step without further purification. ESI-MS [M+H]: 348.0.

[0317] Synthesis of methyl 6-cyclopropyl-2-((4-(hydroxymethyl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridine-8-carboxylate [ka] A mixture of (1-((8-bromo-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methanol (500 mg, 1.44 mmol), Pd(dppf)Cl (105 mg, 0.143 mmol), and triethylamine (729 mg, 7.218 mmol) in MeOH (20 mL) was heated to reflux for 16 h, then cooled to room temperature and filtered. The filtrate was concentrated and purified by silica gel chromatography (DCM / MeOH = 20 / 1) to give methyl 6-cyclopropyl-2-((4-(hydroxymethyl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridine-8-carboxylate (400 mg, 85% yield) as a yellow solid. ESI-MS [M+H] + : 328.1.

[0318] Synthesis of methyl 6-cyclopropyl-2-((4-formyl-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridine-8-carboxylate [ka] A mixture of methyl 6-cyclopropyl-2-((4-(hydroxymethyl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridine-8-carboxylate (400 mg, 1.22 mmol) and MnO (2.12 g, 24.4 mmol) in DCM (15 mL) was stirred at room temperature for 16 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (DCM / MeOH=20 / 1) to give methyl 6-cyclopropyl-2-((4-formyl-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridine-8-carboxylate (180 mg, 45% yield) as a yellow solid. ESI-MS [M+H] + : 326.1.

[0319] Synthesis of methyl 2-((4-((((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)amino)methyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-carboxylate [ka] A mixture of methyl 6-cyclopropyl-2-((4-formyl-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridine-8-carboxylate (180 mg, 0.553 mmol) and (7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine (144 mg, 0.721 mmol) in MeOH (10 mL) was stirred at room temperature for 1 h. NaBHCN (174 mg, 2.77 mmol) was added, and the reaction mixture was stirred at room temperature for an additional 3 h. The reaction mixture was concentrated under reduced pressure, then diluted with water (40 mL), and extracted with DCM / MeOH (50 mL × 3, v / v 10 / 1). The combined organics were washed with brine (50 mL), dried over NaSO, and concentrated. The residue was purified by silica gel chromatography (DCM / MeOH=20 / 1) to give methyl 2-((4-((((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)amino)methyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-carboxylate (130 mg, yield: 46%) as a pale solid. ESI-MS [M+ H] + : 509.2.

[0320] 1 H NMR (400 MHz, DMSO) δ 8.58 (s, 1H), 8.47 (s, 1H),8.20 (d, J = 7.4Hz, 1H), 8.00 (s, 1H) ), 7.86 (s, 1H), 7.61 (d, J = 1.6 Hz, 1H),6.76 (t, J = 6.9 Hz, 1H), 5.70 (s, 2H),4.07 (s, 2H), 3.92 (s, 2H), 3.84 (s, 3H),2.03 ― 1.94 (m, 1H), 0.96 ― 0.90 (m, 2H), 0.71 ― 0.65 (m, 2H).

[0321] Example 15 2-((4-((((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)amino)methyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-carboxylic acid (I-15) [ka] To a solution of methyl 2-((4-((((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)amino)methyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-carboxylate (110 mg, 0.216 mmol) in THF (4 mL) and water (2 mL) was added lithium hydroxide monohydrate (18 mg, 0.429 mmol). The mixture was stirred at 40° C. for 1 h. The reaction mixture was diluted with water (20 mL), acidified to pH=5-6 by adding HCl (2 M), and concentrated under reduced pressure. The residue was purified by preparative HPLC to give 2-((4-((((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)amino)methyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-carboxylic acid (50 mg, yield: 47%) as a white solid. ESI-MS [M+ H] + : 495.1.

[0322] 1H NMR (400 MHz, DMSO) δ 8.59 (s, 1H), 8.48 (s, 1H),8.21 (d, J = 7.4Hz, 1H), 8.16 (s, 1H), 8.08 (s, 1H), 7.92 (s, 1H), 7.66 (s, 1H), 6.76 (t, J = 6.8 Hz, 1H), 5.75 (s, 2H), 4.04 (s, 2H), 3.89 (s, 2H), 2.06 ― 1.98(m, 1H), 1 .00 ― 0.93 (m, 2H), 0.74 ― 0.68 (d, 2H).

[0323] Example 16 N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-(1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazol-4-yl)-2,2,2-trifluoroethan-1-amine (I-16) Scheme 16 [ka] Synthesis of (1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazol-4-yl)methanol [ka] To a solution of ethyl 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate (600 mg, 1.94 mmol) in THF (20 mL) was added LiAlH (221 mg, 5.81 mmol) slowly at 0 °C under N. The mixture was stirred at 0 °C for 5 h. The mixture was quenched with NaSO-10H0 and diluted with EtOAc (50 mL). The resulting suspension was filtered, and the filtrate was concentrated under reduced pressure to give (1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazol-4-yl)methanol as a yellow solid (588 mg, crude), which was used directly in the next step without further purification. ESI-MS [M+H] + : 269.2.

[0324] Synthesis of 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carbaldehyde [ka] A mixture of (1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazol-4-yl)methanol (588 mg, 2.19 mmol) and MnO (1.7 g, 19.54 mmol) in DCM (20 mL) was stirred at room temperature for 72 hours. The mixture was filtered, and the filtrate was concentrated to give the crude product. The residue was purified by preparative TLC (DCM:MeOH=20:1) to give 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carbaldehyde as a yellow oil (365 mg, yield: 63%). ESI-MS [M+H] + : 267.1.

[0325] Synthesis of 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carbaldehyde [ka] To a solution of 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carbaldehyde (365 mg, 1.37 mmol) and CsF (584 mg, 3.845 mmol) in THF (10 mL) was added trimethyl(trifluoromethyl)silane (312 mg, 2.19 mmol) at room temperature. The mixture was stirred under nitrogen at 60° C. for 16 hours. The mixture was then diluted with EtOAc (50 mL) and washed with water (30 mL×3). The organic layer was dried over NaSO and concentrated to give 1-(1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazol-4-yl)-2,2,2-trifluoroethan-1-ol as a yellow solid (430 mg, yield: 93.5%), which was used directly in the next step without further purification. ESI-MS [M+H] + : 337.2.

[0326] Synthesis of 2-((4-(1-chloro-2,2,2-trifluoroethyl)-1H-pyrazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridine [ka] To a mixture of 1-(1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazol-4-yl)-2,2,2-trifluoroethan-1-ol (430 mg, 1.27 mmol) in DCM (5 mL) was added SOCl (1.0 mL) at 0 °C. The reaction mixture was stirred at room temperature for 2 h. The mixture was concentrated to give 2-((4-(1-chloro-2,2,2-trifluoroethyl)-1H-pyrazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridine (450 mg, crude) as a yellow solid, which was used directly in the next step without further purification. ESI-MS [M+H] + : 355.1.

[0327] Synthesis of 2-((4-(1-azido-2,2,2-trifluoroethyl)-1H-pyrazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridine [ka] A mixture of 2-((4-(1-chloro-2,2,2-trifluoroethyl)-1H-pyrazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridine (450 mg, 1.27 mmol) and NaN3 (165 mg, 2.54 mmol) in DMSO (5 mL) was stirred at 80 °C under N2 for 16 h. The reaction mixture was then diluted with EtOAc (50 mL) and washed with water (30 mL × 3). The organic layer was washed with brine (30 mL), dried over Na2SO4, and concentrated to give 2-((4-(1-azido-2,2,2-trifluoroethyl)-1H-pyrazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridine as a yellow solid (450 mg, crude), which was used directly in the next step without further purification. ESI-MS [M+H] + : 362.2.

[0328] Synthesis of 1-(1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazol-4-yl)-2,2,2-trifluoroethan-1-amine [ka] A mixture of 2-((4-(1-azido-2,2,2-trifluoroethyl)-1H-pyrazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridine (450 mg, 1.25 mmol) and Pd / C (50 mg) in anhydrous THF (10.0 mL) was stirred under H at room temperature for 16 hours. Upon completion, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to afford (1-(1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazol-4-yl)-2,2,2-trifluoroethan-1-amine (400 mg, crude) as a pale yellow oil, which was used directly in the next step without further purification. ESI-MS [M+H]: 336.1.

[0329] Synthesis of N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-(1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazol-4-yl)-2,2,2-trifluoroethan-1-amine [ka] A mixture of 1-(1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazol-4-yl)-2,2,2-trifluoroethan-1-amine (50 mg, 0.15 mmol) and 7-chloro-8-fluoroimidazo[1,5-a]pyridine-1-carbaldehyde (29.5 mg, 0.15 mmol) in MeOH / AcOH (5.0 mL / 0.1 mL) was stirred at room temperature for 4 hours. The reaction mixture was then cooled to 0 °C, and NaBH (8.6 mg, 0.227 mmol) was added. The reaction mixture was stirred at room temperature for an additional 1 hour, then concentrated under reduced pressure and purified by preparative HPLC to give N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-(1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazol-4-yl)-2,2,2-trifluoroethan-1-amine (19.8 mg, yield: 25.49%) as a pale yellow solid. ESI-MS [M+ H]+: 518.1.

[0330] 1H NMR (400 MHz, DMSO) δ 8.44 (d, J = 2.4 Hz , 1H), 8.34 (s,1H), 8.18 (d, J = 7.4 Hz, 1H), 7.81 (s, 1H), 7.69 (s, 1H), 7.48 (s, 1H), 7.41 (d,J = 9.3 Hz, 1H), 7.00 (dd, J =9.4, 1.8 Hz, 1H), 6.78 ― 6.68 (m, 1H), 5.37 (s, 2H),4 .48 - 4.40 (m, 1H), 3.97 - 3.87 (m, 2H), 2.73 ― 2.64 (m, 1H), 1.98 ― 1.86 (m, 1H),0.99 ― 0 .86 (m, 2H), 0.75 - 0.60 (m, 2H).

[0331] Example 17 Ethyl 3-(2-((4-((((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)amino)methyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)propanoate (I-17a) 3-(2-((4-((((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)amino)methyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)propanoic acid (I-17b) Scheme 17 [ka] Synthesis of ethyl (E)-3-(6-cyclopropyl-2-((4-(hydroxymethyl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-8-yl)acrylate [ka] (1-((8-bromo-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methanol (1.4 g, 4 A mixture of Pd(dba) (0.0 mmol), ethyl acrylate (0.81 g, 8.1 mmol), Pd(dba) (183 mg, 0.2 mmol), (o-MeC(H))P (365 mg, 1.2 mmol), and triethylamine (1.2 g, 12.0 mmol) in MeCN (20 mL) was stirred at 90 °C for 8 h. The reaction mixture was cooled to room temperature, diluted with water (100 mL), and extracted with EtOAc (50 mL × 4). The combined organic layers were washed with brine (50 mL), dried over NaSO, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (PE / EtOAc 0-30%) to give (£)-3-(6-cyclopropyl-2-((4-(hydroxymethyl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-8-yl)ethyl acrylate (0.4 g, yield: 27%) as a brown solid.

[0332] Synthesis of ethyl 3-(6-cyclopropyl-2-((4-formyl-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-8-yl)propanoate [ka] To a solution of (E)-3-(6-cyclopropyl-2-((4-(hydroxymethyl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-8-yl)ethyl acrylate (400 mg, 1.09 mmol) in MeOH (10 mL) was added CuCl (162 mg, 1.63 mmol) and NaBH (245 mg, 6.48 mmol) at 0 °C. The mixture was stirred at 0 °C for 1 h, then quenched with water (50 mL) and extracted with EtOAc (40 mL × 3). The combined organic layers were washed with brine (50 mL), dried over Na SO and concentrated under reduced pressure. The crude product was dissolved in DCM (10 mL). MnO (1.9 g, 21.8 mmol) was added, and the mixture was stirred at room temperature for 18 h, then filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (PE / EtOAc 0-20%) to give ethyl 3-(6-cyclopropyl-2-((4-formyl-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-8-yl)propanoate (160 mg, yield: 40%) as a colorless oil.

[0333] Synthesis of ethyl 3-(2-((4-((((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)amino)methyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)propanoate [ka] To a mixture of ethyl 3-(6-cyclopropyl-2-((4-formyl-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-8-yl)propanoate (160 mg, 0.44 mmol) and (7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride (87 mg, 0.44 mmol) in EtOH (10 mL) was added one drop of AcOH. The reaction mixture was stirred at room temperature for 18 h. NaBH (50 mg, 1.32 mmol) was added, and the mixture was stirred at room temperature for an additional 2 h. The reaction was quenched with saturated aqueous NH Cl (50 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (30 mL), dried over Na SO , and concentrated. The residue was purified by preparative HPLC to give ethyl 3-(2-((4-((((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)amino)methyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)propanoate (120 mg, yield: 50%) as a white solid. ESI-MS [M+H]: 551.2.

[0334] 1H NMR (400 MHz, DMSO) δ 8.44 (d, J = 2.4 Hz , 1H), 8.21 (d,J = 1.3 Hz, 1H), 8.18 (d, J = 7.4 Hz, 1H), 7.93 (s, 1H), 7.74 (s,1H), 6.83 (s,1H), 6.75-6.70 (m, 1H), 5.64 (s, 2H), 4. 02 (q, J = 7.1 Hz, 2H), 3.92 (s, 2H), 3.74(s, 2H), 3.07 (t, J = 7.6 Hz, 2H), 2.77 (t, J = 7 .7 Hz, 2H), 1.92-1.84 (m, 1H),1.13 (t, J = 7 .1 Hz, 3H), 0.93 ― 0.87 (m, 2H), 0.68 ― 0.62 (m, 2H).

[0335] Synthesis of 3-(2-((4-((((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)amino)methyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)propanoic acid [ka] A mixture of ethyl 3-(2-((4-((((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)amino)methyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)propanoate (90 mg, 0.16 mmol) and LiOH.HO (21 mg, 0.50 mmol) in EtOH / THF / HO (3 mL / 3 mL / 2 mL) was stirred at room temperature for 2 h. The reaction mixture was adjusted to pH 5 by adding HCl (2 M) and concentrated under reduced pressure. The residue was purified by preparative HPLC to give 3-(2-((4-((((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)amino)methyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)propanoic acid (60 mg, yield: 71.5%) as a white solid. ESI-MS [M+H]: 523.2. Purity: 95.01 (214 nm), 95.35 (254 nm).

[0336] 1H NMR (400 MHz, DMSO) δ 8.44 (d, J = 2.3 Hz , 1H), 8.18 (d,J = 7.4 Hz, 1H), 8.13 (s, 1H), 7.94 (s, 1H), 7.70 (s, 1H), 6.82 (s, 1H), 6.75 -6.69 (m, 1H), 5.63 (s, 2H), 3.92(s, 2H) , 3.73 (s, 2H), 2.99 (t, J = 7.7 Hz, 2H),2.36 (t, J = 7.7 Hz, 2H), 1.90-1.81 (m, 1H), 0.91 ― 0.85 (m, 2H), 0.67 ― 0.61 (m, 2H).

[0337] Example 18 1-(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)-N-((1-((6-cyclopropyl-8-(4H-1,2,4-triazol-4-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methyl)methanamine (I-18) Scheme 18 [ka] Synthesis of tert-butyl (6-cyclopropyl-2-((4-(hydroxymethyl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-8-yl)carbamate [ka] To a solution of (1-((8-bromo-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methanol (450 mg, 1.3 mmol) in dioxane (10 mL) was added NHBoc (227.6 mg, 1.95 mmol), Pd(OAc) (29.1 mg, 0.13 mmol), Xantphos (75.1 mg, 0.13 mmol), and CsCO (1.27 g, 3.9 mmol) at room temperature. The mixture was stirred at 95 °C under N for 16 h. The mixture was concentrated and purified by silica gel chromatography (DCM / MeOH=30 / 1) to give the product (6-cyclopropyl-2-((4-(hydroxymethyl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-8-yl)tert-butylcarbamate as a white solid (90 mg, yield: 18%). ESI-MS [M + H] + : 385.2.

[0338] Synthesis of (1-((8-amino-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methanol [ka] A solution of tert-butyl (6-cyclopropyl-2-((4-(hydroxymethyl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-8-yl)carbamate (90 mg, 0.23 mmol) in HCl (4 M in dioxane) (5.0 mL) was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure to give (1-((8-amino-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methanol (90 mg, crude) as a yellow solid, which was used directly in the next step without further purification. ESI-MS [M +H]+: 285.1.

[0339] Synthesis of (1-((6-cyclopropyl-8-(4H-1,2,4-triazol-4-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methanol [ka] To a solution of (1-((8-amino-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methanol (300 mg, 1.06 mmol) in pyridine (15 mL) was added N'-formylformohydrazide (280 mg, 3.18 mmol) and EtN (749 mg, 7.42 mmol) at room temperature. Then, TMSCl (1.72 g, 15.9 mmol) was added at 0 °C under N. The resulting solution was stirred at 100 °C for 18 h and then cooled to room temperature. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (DCM / MeOH=20 / 1 to 10 / 1) to give (1-((6-cyclopropyl-8-(4H-1,2,4-triazol-4-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methanol (150 mg, 42%) as a white solid. ESI-MS [M+H]: 337.1.

[0340] Synthesis of 1-((6-cyclopropyl-8-(4H-1,2,4-triazol-4-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carbaldehyde [ka] To a solution of (1-((6-cyclopropyl-8-(4H-1,2,4-triazol-4-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methanol (60 mg, 0.18 mmol) in DCM (5.0 mL) was added MnO (157 mg, 1.8 mmol) at room temperature. The reaction mixture was stirred at room temperature for 18 hours. Additional MnO (78 mg, 0.9 mmol) was added and the reaction mixture was stirred for an additional 3 hours. Upon completion, the mixture was filtered and the filtrate was concentrated to give 1-((6-cyclopropyl-8-(4H-1,2,4-triazol-4-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carbaldehyde (40 mg, crude) as a yellow solid, which was used directly in the next step without further purification. ESI-MS [M+H]: 335.1.

[0341] Synthesis of 1-(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)-N-((1-((6-cyclopropyl-8-(4H-1,2,4-triazol-4-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methyl)methanamine [ka] To a mixture of 1-((6-cyclopropyl-8-(4H-1,2,4-triazol-4-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carbaldehyde (40 mg, 0.12 mmol) and (7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine (30 mg, 0.15 mmol) in MeOH (5.0 mL) was added AcOH (0.1 mL) at room temperature. The reaction mixture was stirred at room temperature for 18 hours. NaBH (8.5 mg, 0.22 mmol) was then added, and the mixture was stirred at room temperature for an additional 4 hours. The mixture was then concentrated, and the residue was purified by preparative TLC (DCM / MeOH=15:1) to give 1-(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)-N-((1-((6-cyclopropyl-8-(4H-1,2,4-triazol-4-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methyl)methanamine (5 mg, 8%) as a pale yellow solid. ESI-MS [M+H]: 518.2.

[0342] 1H NMR (400 MHz, DMSO) δ 9.41 (s, 2H), 8.48 (s, 1H), 8.44 (s,1H), 8.26 (s, 1H),8.18 (d, J = 7.4 Hz, 1H), 8.03 (s, 1H), 7.98 (s, 1H), 7.45 (d,J = 0.9 Hz, 1H), 6.73 (t, J= 6.9 Hz, 1H), 5.71 (s, 2H), 3.94 (s, 2H), 3.77 (s,2H), 2.01 - 1.96 (m, 1H), 1.80― 1.72 (m, 1H), 1 .02 ― 0.95 (m, 2H), 0.86 ― 0.77(m, 2H).

[0343] Example 19 2-(7-chloroimidazo[1,5-a]pyridin-1-yl)-N-(1-(1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazol-4-yl)-2,2,2-trifluoroethyl)acetamide (I-19) [ka] 1-(1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazol-4-yl)-2,2,2-trifluoroethan-1-amine (50 mg, 0.15 mmol), 2-(7-chloroimidazo[1,5-a]pyridine-1 A mixture of 2-(7-chloroimidazo[1,5-a]pyridin-1-yl)-N-(1-(1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazol-4-yl)-2,2,2-trifluoroethyl)acetamide (23.9 mg, 30%) as a pale yellow solid. ESI-MS [M+H]: 528.1.

[0344] 1H NMR (400 MHz, DMSO) δ 9.11 (d, J = 9.4 Hz , 1H), 8.35 (s,1H), 8.32 - 8.25 (m, 2H), 7.9 2 (s, 1H), 7.74 (s, 1H), 7.73 ― 7.72 (m, 1H), 7.58(s, 1H), 7.41 (d, J = 9.4 Hz, 1H), 7.00 (dd, J = 9.4, 1.7 Hz, 1H), 6.63 (dd, J =7.5, 2.1 Hz, 1H), 5.80 ― 5.64 (m, 1H), 5.39 (s, 2H), 3.78 (s, 2H), 2.01 ― 1.87 (m, 1H),1.00 ― 0.85 (m, 2H), 0.79 ― 0.53 (m, 2H).

[0345] Example 20 N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(4-methylpiperazin-1-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide (I-20) Scheme 20 [ka] 2-(chloromethyl)-6-cyclopropyl-8-(4-methylpiperazin-1-yl) ) Synthesis of imidazo[1,2-a]pyridine [ka] To a mixture of 5-cyclopropyl-3-(4-methylpiperazin-1-yl)pyridin-2-amine (460 mg, 1.98 mmol) in DME (25 mL) was added 1,3-dichloropropan-2-one (620 mg, 5 mmol). The reaction was stirred at 90 °C for 16 h. The reaction mixture was concentrated under reduced pressure to give 2-(chloromethyl)-6-cyclopropyl-8-(4-methylpiperazin-1-yl)imidazo[1,2-a]pyridine (400 mg, yield: 32%, crude) as a yellow solid, which was used directly in the next step without further purification. ESI-MS [M+H]: 305.1.

[0346] Synthesis of 2-(azidomethyl)-6-cyclopropyl-8-(4-methylpiperazin-1-yl)imidazo[1,2-a]pyridine [ka] To a mixture of 2-(chloromethyl)-6-cyclopropyl-8-(4-methylpiperazin-1-yl)imidazo[1,2-a]pyridine (400 mg, 1.3 mmol) in DMF (5 mL) was added NaN (250 mg, 3.9 mmol). The reaction mixture was stirred at room temperature for 16 h. Water (50 mL) was added, and the mixture was extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (30 mL), dried over NaSO, and concentrated under reduced pressure. The residue was purified by flash column chromatography (MeOH / DCM 0–10%) to give 2-(azidomethyl)-6-cyclopropyl-8-(4-methylpiperazin-1-yl)imidazo[1,2-a]pyridine (100 mg, 25% yield) as a yellow solid. ESI-MS [M+H]: 312.1.

[0347] Synthesis of tert-butyl 1-((6-cyclopropyl-8-(4-methylpiperazin-1-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate [ka] To a mixture of 2-(azidomethyl)-6-cyclopropyl-8-(4-methylpiperazin-1-yl)imidazo[1,2-a]pyridine (100 mg, 0.32 mmol) in t-BuOH (5 mL) and HO (5 mL) was added tert-butyl propiolate (52 mg, 0.42 mmol), CuSO (25 mg, 0.16 mmol), and sodium ascorbate (31 mg, 0.16 mmol). The reaction mixture was stirred at room temperature for 2 hours. Water (30 mL) was added, and the mixture was extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine (20 mL), dried over NaSO, and concentrated under reduced pressure. The residue was purified by flash column chromatography (MeOH / DCM 0-10%) to give tert-butyl 1-((6-cyclopropyl-8-(4-methylpiperazin-1-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate (20 mg, yield: 14%) as a yellow solid. ESI-MS [M+H]: 438.2.

[0348] Synthesis of 1-((6-cyclopropyl-8-(4-methylpiperazin-1-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid [ka] A mixture of tert-butyl 1-((6-cyclopropyl-8-(4-methylpiperazin-1-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate (15 mg, 0.034 mmol) in anhydrous DCM (3 mL) and TFA (0.6 mL) was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure to give 1-((6-cyclopropyl-8-(4-methylpiperazin-1-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid (3 mg, yield: 23% crude) as a yellow solid, which was used directly in the next step without further purification. ESI-MS [M + H]: 382.1.

[0349] N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl) Synthesis of (6-cyclopropyl-8-(4-methylpiperazin-1-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide [ka] A mixture of 1-((6-cyclopropyl-8-(4-methylpiperazin-1-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid (20 mg, 0.05 mmol), (7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride (20 mg, 0.1 mmol), HOBT (10 mg, 0.074 mmol), EDCI (14 mg, 0.075 mmol), and DIPEA (32 mg, 0.25 mmol) in anhydrous DMF (5 mL) was stirred at room temperature for 16 hours. Water (50 mL) was added, and the mixture was extracted with EtOAc (20 mL × 3). The organic layer was washed with brine (20 mL), dried over NaSO, and concentrated under reduced pressure. The residue was purified by preparative TLC (MeOH / DCM=10%) to give N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(4-methylpiperazin-1-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide (1 mg, yield: 14%) as a yellow solid. ESI-MS [M+H] +: 5 63.1.

[0350] 1H NMR (400 MHz, DMSO) δ 8.66 (t, J = 5.4 Hz , 1H), 8.47 (s,1H), 8.40 (d, J = 2.4 Hz, 1H), 8.16 (d, J = 7.4 Hz, 1H), 7.86 (s, 1H), 7.67 (s,1H), 6.75 ― 6.68 (m, 1H), 6.16 (s,1H), 5 .67 (s, 2H), 4.65 (d, J = 5.5 Hz, 2H),3.46 (s, 4H), 2.56 (s, 4H), 2.27 (s, 3H),1.84 ― 1.80 (m, 1H), 0.84 ― 0.79 (m, 2H),0.64 ― 0.50 (m, 2H).

[0351] Example 21 Inhibitory activity of exemplary compounds against plasma kallikrein. Exemplary compounds were evaluated for inhibition of human active kallikrein enzyme in two assay formats using a fluorescent peptide substrate. In one assay format, the reagent concentrations 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 active kallikrein enzyme, and 300 μM Pro-Phe-Arg-7-amido-4-methylcoumarin substrate. Before initiation with the substrate, the enzyme and inhibitor were preincubated for 30 minutes at room temperature. After initiation with the substrate, the reaction was incubated for 10 minutes at room temperature, and fluorescence emission at 460 nm with excitation at 380 nm was measured using a microplate reader. In the other assay format, the reagent concentrations were as follows: The mixture was 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, and 300 μM Pro-Phe-Arg-7-amido-4-methylcoumarin substrate. The enzyme and inhibitor were preincubated for 30 minutes at room temperature before initiation with the substrate. After substrate initiation, the reaction was incubated for 18 hours at room temperature, and the fluorescence emission at 460 nm with excitation at 380 nm was measured using a microplate reader.

[0352] Table 1 provides the results of the assay in a format using 500 pM active kallikrein. For the compounds listed in Table 1, the EC 50Values ​​are reported according to the following ranges: A ≤ 50 nM; <B≦200nM;200nM<C≦1000nM;1000nM<D。 [Table 1]

[0353] While numerous embodiments of the present invention have been described, it will be apparent that these basic examples can be modified to provide other embodiments that utilize the compounds and methods of the present invention. It will therefore be appreciated that the scope of the present invention is defined by the appended claims rather than by the specific embodiments that have been represented by way of example. The present invention provides, for example, the following items. (Item 1) Compounds of formula (I): [ka] or a pharmaceutically acceptable salt thereof (In the formula: Het A is selected from 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclylene having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur, 5- to 6-membered monocyclic heteroarylene having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclylene having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, and 7- to 10-membered bicyclic heteroarylene having 1-5 heteroatoms selected from oxygen, nitrogen, or sulfur, wherein Het A is 0 to 4 R A is substituted with a group, Each R Ais halogen, -CN, -C(R)=N(R), -C(O)R, -C(O)2R, -C(O)N(R)2, -NO2, -N(R)-N(R)2, -N(R)2, -N(R)C(O)R, -N(R)C(O)2R, - N(R)C(O)N(R)2, -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, 5-6 membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 3-7 membered saturated or partially unsaturated monocyclic carbocyclyl, and 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur; L is an optionally substituted C 1~6 a hydrocarbon chain wherein one to three methylene units are independently replaced by -Cy-, -C(R)2-O-, -NR-, -C(O)-, -S(O)2-, -C(O)NR-, -NRC(O)-, -S(O)2NR-, and -NRS(O)2-; -Cy- is a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclylene, a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclylene having 1 to 2 heteroatoms selected from oxygen, nitrogen, or sulfur, or a 5- to 6-membered heteroarylene having 1 to 4 heteroatoms selected from oxygen, nitrogen, or sulfur; R' and R'' are hydrogen, halogen, -OR, -NR2, -SR, and optionally substituted C 1~6 aliphatic, wherein R' is a monocyclic Het A together with It is okay to R 1 , R 2 , R 3 , R 4 , R 5, R 6 , R 7 , R 8 , and R 9 is hydrogen, halogen, -CN, -C(R)=N(R), -C(O)R, -C(O)2R, -C(O)N(R)2, -NO2, -N(R)-N(R)2, -N(R)2, -N(R)C(O)R, -N(R)C(O)2R, -N(R)C(O)N(R)2, -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, 5-6 membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 3-7 membered saturated or partially unsaturated monocyclic carbocyclyl, and 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur; Each R is independently hydrogen or C 1~6 an optionally substituted group selected from aliphatic, phenyl, 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 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, or sulfur; or two R groups on the same carbon or nitrogen, together with the atoms between them, form a ring selected from a 3-7 membered saturated or partially unsaturated monocyclic ring having 0-2 heteroatoms selected from oxygen, nitrogen, or sulfur, and a 5-6 membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur; n is 0 or 1). (Item 2) L is -(CR2) m When NRC(O)- and m is 0 to 2 (e.g., 0 or 2), any of the following (a), (b), or (c): (a) n is 0, (b)R 5 , R 6 , R 7 , R 8 , and R 9 At least one of the is CN, or (c)R 1 is an optionally substituted saturated monocyclic heterocycle containing 1 to 3 nitrogen atoms, with the proviso that the compound is N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(2-oxopyrrolidin-1-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide, N-((7-chloro N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-morpholinoimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide, N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-( 2-oxopyrrolidin-1-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide, N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(2-oxooxazolidin-3-yl)imidazo[1,2-a]pyridin-2-yl) methyl)-1H-1,2,3-triazole-4-carboxamide or 4-(2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)morpholine-2-carboxylic acid The compound according to item 1, (Item 3) L is -C(R)2NRC(O)-#, -C(R)2C(O)NRC(R)2-#, -C(R)2NRC(O)C(R)2-#, -C(R)2NRC(R)2-#, -C(R)2C(R)2NRC(R)2-#, -C(O)NRC(R)2-#, -C(R)2C(O )NR-#, -NRC(O)C(R)2-#, -CR2C(O)NRC(R)2-#, -SO2NRC(R)2-#, and -C(R)2NRSO2-#, wherein # is Het A Item 1. The compound according to item 1, wherein the compound represents a point of attachment to (Item 4) When L is -C(R)2NRC(O)-# or -C(R)2C(O)NR-#, either (a), (b), or (c) below: (a) n is 0, (b)R 5 , R 6 , R 7 , R 8 , and R 9 At least one of the is CN, or (c)R 1is an optionally substituted saturated monocyclic heterocycle containing 1 to 3 nitrogen atoms, with the proviso that the compound is N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(2-oxopyrrolidin-1-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide, N-((7-chloro N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-morpholinoimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide, N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-( 2-oxopyrrolidin-1-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide, N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(2-oxooxazolidin-3-yl)imidazo[1,2-a]pyridin-2-yl) methyl)-1H-1,2,3-triazole-4-carboxamide or 4-(2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)morpholine-2-carboxylic acid The compound according to item 1, (Item 5) The compound has the structure of formula (Ia), formula (Ib), formula (Ic), or formula (Id). [ka] or a pharmaceutically acceptable salt thereof Item 1. The compound according to item 1, having the formula: (Item 6) The compound has the structure of formula (II): [ka] or a pharmaceutically acceptable salt thereof Item 1. The compound according to item 1, having the formula: (Item 7) The compound has the structure of formula (II-a) or formula (II-b): [ka] or a pharmaceutically acceptable salt thereof Item 1. The compound according to item 1, having the formula: (Item 8) R' is a monocyclic Het A together to form an optionally substituted fused ring, and said compound has the structure of formula (III): [ka] (In the formula, R fus Het A to form a fused 7-10 membered saturated or partially unsaturated bicyclic heterocyclylene having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur. or a pharmaceutically acceptable salt thereof Item 1. The compound according to item 1, having the formula: (Item 9) The compound has the structure of formula (III-a) or formula (III-b): [ka] or a pharmaceutically acceptable salt thereof Item 1. The compound according to item 1, having the formula: (Item 10) Het A is a 5-membered monocyclic heteroarylene having 1 to 4 heteroatoms selected from oxygen, nitrogen, or sulfur, wherein Het A is 0 to 2 R A Item 1. The compound according to item 1, substituted with a group. (Item 11) Het A But the following: [ka] wherein * represents the point of attachment to L; The compound according to item 1. (Item 12) RA One example is halogen-substituted C 1~6 Item 1. The compound according to item 1, which is aliphatic. (Item 13) 2. The compound according to item 1, wherein the compound is any one of compounds I-1 to I-20, or a pharmaceutically acceptable salt thereof. (Item 14) A pharmaceutical composition comprising the compound according to item 1 and a pharmaceutically acceptable excipient. (Item 15) 2. A method for treating a disease or disorder mediated by plasma kallikrein using the compound according to item 1. (Item 16) 16. The method of item 15, wherein the disease or disorder is hereditary angioedema or diabetic macular edema. (Item 17) 10. A method for treating hereditary angioedema or diabetic macular edema, comprising administering to a patient in need thereof a compound according to item 1.

Claims

[Claim 1] The invention described in the specification.

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