Plasma kallikrein inhibitor and use thereof

Abstract

To provide a plasma kallikrein inhibitor and its use.SOLUTION: The present invention provides a compound and a composition thereof, which are useful as a plasma kallikrein inhibitor and exhibit desirable properties as the inhibitor.SELECTED DRAWING: None

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to and the benefit of U.S. Provisional Patent Application No. 62 / 902,353, filed September 18, 2019, entitled "Plasma Kallikrein Inhibitors and Uses Thereof," the entire disclosure of which is 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 Cy A , Cy B , L, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7Each of n and n is as defined and described in classes and subclasses herein. In certain embodiments, the invention provides compounds of Formulas (I)-(IV), 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)-(IV). DETAILED DESCRIPTION OF THE INVENTION

[0007] A.Definition Compounds of the invention include those generally described above and those further exemplified by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise specified. For purposes of this invention, chemical elements are defined as defined in the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed. In addition, general principles of organic chemistry are identified 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, with 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 an aromatic heterocycle is fused to one or more aryl, alicyclic, or heterocyclyl rings. Non-limiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzothiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-1,4-oxazin-3(4H)-one. Heteroaryl groups can be monocyclic or The term "heteroaryl" may be used interchangeably with the terms "heteroaryl ring," "heteroaryl group," or "heteroaromatic," any of which terms include rings that are optionally substituted.

[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. Heterocyclyl groups can be monocyclic or bicyclic. The term "heterocyclylalkyl" refers to an alkyl group substituted by a heterocyclyl, where the alkyl and heterocyclyl portions 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 are 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 may be the same or different at all positions. Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds. The term " "Stable," as used herein, refers to compounds that do not substantially change when subjected to conditions that allow for 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 o ;-(CH2) 0~4 OR o ;-O(CH2) 0~4 R o , -O(CH2) 0~4 C(O)OR o ;-O(CH2) 0~4 OR o ;-(CH2) 0~4 CH(OR o )2;-(CH2) 0~4 SR o ;R o may be substituted with -(CH2) 0~4 Ph;R o may be substituted with -(CH2) 0~4 O(CH2) 0~1 Ph;R o -CH=CHPh; R o may be substituted with -(CH2) 0~4 O(CH2) 0~1 -pyridyl; -NO2; -CN; -N3; ​​-(CH2) 0~4 N(R o )2;-(CH2) 0~4 N(R o )C(O)R o ;-N(R o )C(S)R o ;-(CH2) 0~4 N(R o )C(O)NR o 2;-N(R o )C(S)NR o 2;-(CH2) 0~4 N(R o )C(O)OR o ;-N(R o )N(R o )C(O)R o ;-N(R o )N(R o )C(O)NR o 2;-N(R o )N(R o )C(O)OR o ;-(CH2) 0~4 C(O)Ro ;-C(S)R o ;-(CH2) 0~4 C(O)OR o ;-(CH2) 0~4 C(O)SR o ;-(CH2) 0~4 C(O)OSiR o 3;-(CH2) 0~4 OC(O)R o ;-OC(O)(CH2) 0~4 SR o ;-SC(S)SR o ;-(CH2) 0~4 SC(O)R o ;-(CH2) 0~4 C(O)NR o 2;-C(S)NR o 2;-C(S)SR o ;-SC(S)SR o ;-(CH2) 0~4 OC(O)NR o 2;-C(O)N(OR o )R o ;-C(O)C(O)R o ;-C(O)CH2C(O)R o ;-C(NOR o )R o ;-(CH2) 0~4 SSR o ;-(CH2) 0~4 S(O)2R o ;-(CH2) 0~4 S(O)2OR o ;-(CH2) 0~4 OS(O)2R o ;-S(O)2NR o 2;-(CH2) 0~4 S(O)R o ;-N(R o )S(O)2NR o 2;-N(R o )S(O)2R o ;-N(OR o )R o ;-C(NH)NR o 2;-P(O)2R o ;-P(O)R o 2;-OP(O)R o 2;-OP(O)(OR o)2;SiR o 3;-(C 1~4 Linear or branched alkylene)ON(R o )2; or -(C 1~4 Straight or branched chain alkylene)C(O)ON(R o )2, wherein each R o are optionally substituted as defined below and independently represent 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, regardless of the above definitions, R o two independent occurrences of 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 optionally substituted as defined below.

[0022] R o The above suitable monovalent substituents (or R o The ring formed by two independent occurrences of (with the atoms between them) can be 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, -CH2Ph, -O(CH2) 0~1 Ph, or a 5-6 membered saturated, partially unsaturated, or alkyl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; independently selected from the reel rings. o Suitable divalent substituents on a saturated carbon atom of include ═O 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. 1~6 and an 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(C(R * )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 ● , -N(R ● )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 1~6an 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, etc., and is commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al. describe pharmaceutically acceptable salts 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 for 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, comparison of the particular sample of interest with the reference sample establishes identity, similarity, or difference between the particular sample of interest compared to the reference material.

[0035] As used herein, the term "sample" refers to a sample of interest, as described herein. A biological sample refers to a sample obtained or derived from a source. In some embodiments, the source of interest includes a living 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 can be or include bone marrow; blood, e.g., whole blood; blood cells; ascites; tissue or fine needle biopsy samples; 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. In some embodiments, the biological sample is or includes cells obtained from a subject. In some embodiments, the obtained cells are or include cells derived from the subject from whom the sample is obtained. In some embodiments, the sample is a "primary sample" obtained directly from a source of interest by any suitable means. For example, in some embodiments, the 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 the primary sample (e.g., by removing one or more components of the primary sample and / or adding one or more agents), for example, filtration using a semipermeable membrane. Such a "processed sample" can include, for example, nucleic acids or proteins extracted from the 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") refers to any administration of a substance (e.g., a provided composition) that partially or completely relieves, ameliorates, alleviates, inhibits, delays the onset of, reduces the severity of, and / or reduces the incidence of, one or more symptoms, characteristics, and / or causes of a particular disease, disorder, and / or condition. Such treatment may be given to subjects who do not show signs of the associated disease, disorder, and / or condition and / or who are at an early stage of the disease, disorder, and / or condition. Treatment may be for subjects who only exhibit symptoms. Alternatively or additionally, such treatment may be for subjects who exhibit one or more established symptoms of the associated disease, disorder, and / or condition. In some embodiments, treatment may be for subjects who have been diagnosed with the associated disease, disorder, and / or condition. In some embodiments, treatment may be for subjects known to have one or more susceptibility factors that statistically correlate with an increased risk of developing the associated disease, disorder, and / or condition.

[0039] B. Compound In some embodiments, provided compounds have formula (I): [ka] or a pharmaceutically acceptable salt thereof; During the ceremony: Cy A is selected from 5-membered monocyclic heteroarylene having 1 to 4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, and 7-10-membered partially unsaturated bicyclic heterocyclylene having 1 to 4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein Cy is 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; Cy B is selected from phenyl, 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, and sulfur, 7-10 membered partially unsaturated bicyclic carbocyclyl, 10 membered bicyclic aryl, 7-10 membered bicyclic heterocyclyl having 1-4 heteroatoms selected from oxygen, nitrogen, and sulfur, 7-10 membered bicyclic heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, and sulfur, and 12 membered tricyclic heterocyclyl having 1-4 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein Cy is B is 0 to 5 R B is substituted with a group, Each R B is halogen, -CN, oxo, -C(R)=N(R), -C(O)R, -C(O)2R, -C(O)N(R)2, -C(=N(R))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 a 5- to 6-membered heteroaryl having 1 to 4 heteroatoms selected from aliphatic, phenyl, oxygen, nitrogen, or sulfur; a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl; oxygen, nitrogen, or sulfur; optionally substituted groups selected from 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, and sulfur; 7-10 membered bicyclic heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, and sulfur; and 8-10 membered spirocyclic heterocyclyl having 1-3 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)-, -C(O)NR-, -NRC(O)-, -S(O)NR-, -NRS(O)-, or -S(O)-; -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 1 and R 2 is hydrogen, halogen, -OR, -SR, -N(R)2, and optionally substituted C 1~6 independently selected from aliphatic, 1 is a monocyclic Cy A and R 3 , R 4 , R 5 , and R 7 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 C1~6 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; R 6 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 1~6 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; 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 are taken together with the atoms between them to 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, However, the following: (a)R 3 , R 4 , R 5 , R 6 and R 7 At least one of the 1~6 being aliphatic or halogen; (b) The compounds are N-[1-[(6-fluoroimidazo[1,2-a]pyridin-2-yl)methyl]-5-methyl-1H-pyrazol-3-yl]-3-pyridinecarboxamide, N-[1-[(6-chloroimidazo[1,2-a]pyridin-2-yl)methyl]-5-methyl-1H-pyrazol-3-yl]-3-pyridinecarboxamide, 3-chloro-4-[[5-[8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl]methyl]-5-methyl-1H-pyrazol-3-yl]-3-pyridinecarboxamide, 2-[(6,8-dichloroimidazo[1,2-a]pyridin-2-yl)methyl]-4-methyl-N-phenyl-5-thiazolecarboxamide, and N-(furan-2-ylmethyl)-N,3,5-trimethyl-1-((6-methylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-sulfonamide; This is subject to the following conditions.

[0040] In some embodiments, provided compounds, or pharmaceutically acceptable salts thereof, have the structure of Formula (I), wherein: B teeth, [ka] and R 3 , R 4 , R 5 , R 6 and R 7 At least one of the 1~6The compounds are aliphatic or halogenated and include N-[1-[(6-fluoroimidazo[1,2-a]pyridin-2-yl)methyl]-5-methyl-1H-pyrazol-3-yl]-3-pyridinecarboxamide, N-[1-[(6-chloroimidazo[1,2-a]pyridin-2-yl)methyl]-5-methyl-1H-pyrazol-3-yl]-3-pyridinecarboxamide, 3-chloro-4-[[5-[8-chloro-6-(trifluoromethyl)imidazo[1,2-a ]pyridin-2-yl]-1,3,4-oxadiazol-2-yl]amino]-benzenepropanoic acid, 2-[(6,8-dichloroimidazo[1,2-a]pyridin-2-yl)methyl]-4-methyl-N-phenyl-5-thiazolecarboxamide, and N-(furan-2-ylmethyl)-N,3,5-trimethyl-1-((6-methylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-sulfonamide.

[0041] In some embodiments, Cy A is selected from 5-membered monocyclic heteroarylene having 1 to 4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, and 7-10-membered partially unsaturated bicyclic heterocyclylene having 1 to 4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein Cy is A is 0 to 4 R A is substituted with a group.

[0042] In some embodiments, Cy A is a 5-membered monocyclic heteroarylene having 1 to 4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein Cy A is 0 to 3 R A In some embodiments, Cy is substituted with a group. A is a 5-membered monocyclic heteroarylene having 1 to 4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein Cy A is 0 to 2 R A In some embodiments, Cy is substituted with a group. Ais a 5-membered monocyclic heteroarylene having 1 to 4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein Cy A is non-substituted.

[0043] In some embodiments, Cy A is 1 to 4 atoms independently selected from oxygen and nitrogen. 5-membered heteroarylene having a hetero atom, wherein Cy A is 0 to 3 R A In some embodiments, Cy is substituted with a group. A is a 5-membered heteroarylene having 1 to 4 nitrogen atoms, where Cy A is 0 to 3 R A In some embodiments, Cy is substituted with a group. A is a 5-membered heteroarylene having 2 to 3 nitrogen atoms, where Cy A is 0 to 2 R A In some embodiments, Cy is substituted with a group. A is a 5-membered heteroarylene having one nitrogen atom, where Cy A is 0 to 3 R A In some embodiments, Cy is substituted with a group. A is a 5-membered heteroarylene having two nitrogen atoms, where Cy A is 0 to 2 R A In some embodiments, Cy is substituted with a group. A is a 5-membered heteroarylene having three nitrogen atoms, where Cy A is 0 to 1 R A In some embodiments, Cy is substituted with a group. A is an unsubstituted 5-membered heteroarylene having two nitrogen atoms and one oxygen atom. A is unsubstituted pyrrolediyl. In some embodiments, Cy A is 0 to 2 R A In some embodiments, Cy is a pyrazoldiyl substituted with a group. Ais unsubstituted imidazolediyl. In some embodiments, Cy A is unsubstituted triazolediyl. In some embodiments, Cy A is unsubstituted tetrazolediyl. In some embodiments, Cy A is unsubstituted oxadiazoldiyl.

[0044] In some embodiments, when n is 0, Cy A is a 7-10 membered saturated or partially unsaturated unsubstituted bicyclic heterocyclylene having 1 to 4 heteroatoms selected from oxygen, nitrogen, or sulfur.

[0045] In some embodiments, Cy A is a 7-10 membered partially unsaturated unsubstituted bicyclic heterocyclylene having 1-4 heteroatoms selected from oxygen, nitrogen, and sulfur. A is an 8-membered partially unsaturated bicyclic heterocyclylene having 1 to 4 heteroatoms selected from oxygen, nitrogen, and sulfur. A is an 8-membered partially unsaturated bicyclic heterocyclylene having 2-3 heteroatoms selected from oxygen, nitrogen, and sulfur. A is an 8-membered partially unsaturated bicyclic heterocyclylene having 2-3 heteroatoms selected from oxygen and nitrogen. A is an 8-membered partially unsaturated bicyclic heterocyclylene having two nitrogen atoms. A is an 8-membered partially unsaturated bicyclic heterocyclylene having three nitrogen atoms. A is an 8-membered partially unsaturated bicyclic heterocyclylene having two nitrogen atoms and one oxygen atom. In some embodiments, Cy A is unsubstituted pyrrolopyrazolediyl. In some embodiments, Cy Ais unsubstituted pyrroloimidazoldiyl. In some embodiments, Cy A is unsubstituted pyrrolotriazolediyl. In some embodiments, Cy A is unsubstituted dihydroimidazooxazoldiyl.

[0046] In some embodiments, Cy A is the following: [ka] wherein * represents the point of attachment to L.

[0047] In some embodiments, each R A is C 1~6 Independently 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.

[0048] In some embodiments, optionally substituted R A The substituents on the group are independently halogen, (CH2) 0~4 R o , -(CH2) 0~4 OR o ; and -(CH2) 0~4 C(O)OR o where each R o are 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.

[0049] In some embodiments, R A One example is halogen-substituted C 1~6 It is aliphatic.

[0050] In some embodiments, R A One example is -(CH2)0~4 OR o C replaced with 1~6 aliphatic, where R o is hydrogen or C 1~6 It is aliphatic.

[0051] In some embodiments, R A One example is -(CH2) 0~4 C(O)OR o C replaced with 1~6 aliphatic, where R o is hydrogen or C 1~6 It is aliphatic.

[0052] 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.

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

[0054] In some embodiments, each R A is the unsubstituted C 1~6 In some embodiments, each R A is independently selected from methyl, ethyl, n-propyl, iso-propyl, cyclopropyl, butyl, and cyclopentyl. A is independently selected from methyl and ethyl.

[0055] In some embodiments, Cy B is selected from phenyl, 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, and sulfur, 7-10 membered partially unsaturated bicyclic carbocyclyl, 10 membered bicyclic aryl, 7-10 membered bicyclic heterocyclyl having 1-4 heteroatoms selected from oxygen, nitrogen, and sulfur, 7-10 membered bicyclic heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, and sulfur, and 12 membered tricyclic heterocyclyl having 1-4 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein Cy is B is 0 to 5 R B is substituted with a group.

[0056] In some embodiments, Cy B is phenyl, where Cy B is 0 to 3 R B In some embodiments, Cy is substituted with a group. B is phenyl, where Cy B is three R B In some embodiments, Cy is substituted with a group. B is phenyl, where Cy B is two R B In some embodiments, Cy is substituted with a group. B is phenyl, where Cy B is one R B In some embodiments, Cy is substituted with a group. B is unsubstituted phenyl.

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

[0058] In some embodiments, Cy Bis a 5-membered monocyclic heteroaryl having 1 to 4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein Cy B is 0 to 3 R B In some embodiments, Cy is substituted with a group. B is a 5-membered monocyclic heteroaryl having 2-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein Cy B is 0 to 2 R B In some embodiments, Cy is substituted with a group. B is a 5-membered monocyclic heteroaryl having 2-3 heteroatoms independently selected from oxygen and nitrogen, wherein Cy B is 0 to 2 R B In some embodiments, Cy is substituted with a group. B is a 5-membered monocyclic heteroaryl having 2-3 heteroatoms independently selected from nitrogen and sulfur, wherein Cy B is 0 to 2 R B In some embodiments, Cy is substituted with a group. B is a 5-membered monocyclic heteroaryl having 2-3 nitrogen atoms, where Cy B is 0 to 2 R B In some embodiments, Cy is substituted with a group. B is one R B In some embodiments, Cy is an oxazoldiyl substituted with a group. B is one R B In some embodiments, Cy is a thiazoldiyl substituted with a thiazol-1-yl group. B is one R B In some embodiments, Cy is a triazolediyl substituted with a cysteine ​​group. B is one R B In some embodiments, Cy is an oxadiazole group substituted with a hydroxyl group. B is one R B and thiadiazoldiyl substituted with a group.

[0059] In some embodiments, Cy Bis a 6-membered monocyclic heteroaryl having 1 to 4 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein Cy B is 0 to 3 R B In some embodiments, Cy is substituted with a group. B is a 6-membered monocyclic heteroaryl having 1 to 4 nitrogen atoms, where Cy B is 0 to 3 R B substituted with a group In some embodiments, Cy B is a 6-membered monocyclic heteroaryl having 1-2 nitrogen atoms, where Cy B is 0 to 3 R B In some embodiments, Cy is substituted with a group. B is 2 to 3 R B In some embodiments, Cy is a pyridinediyl substituted with a methyl group. B is two R B In some embodiments, Cy is a pyridinediyl substituted with a methyl group. B is three R B It is a pyridinediyl substituted with a group.

[0060] In some embodiments, Cy B is a 7-10 membered partially unsaturated bicyclic carbocyclyl, where Cy B is 0 to 1 R B In some embodiments, Cy is substituted with a group. B is 0 to 1 R B and indenediyl substituted with a group.

[0061] In some embodiments, Cy B is a 10-membered bicyclic aryl, where Cy B is 0 to 1 R B In some embodiments, Cy is substituted with a group. B is one R B and naphthalenediyl substituted with a group.

[0062] In some embodiments, Cy Bis a 7-10 membered bicyclic heterocyclyl having 1-4 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein Cy B is 0 to 2 R B is substituted with a group.

[0063] In some embodiments, Cy B is a 7-10 membered bicyclic heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein Cy B is 0 to 3 R B In some embodiments, Cy is substituted with a group. B is a 9-10 membered bicyclic heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein Cy B is 0 to 3 R B In some embodiments, Cy is substituted with a group. B is a 9-10 membered bicyclic heteroaryl having 1-3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein Cy B is 0 to 3 R B In some embodiments, Cy is substituted with a group. B is a 9-membered bicyclic heteroaryl having 1 to 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein Cy B is 0 to 3 R B In some embodiments, Cy is substituted with a group. B is a 10-membered bicyclic heteroaryl having 1-2 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein Cy B is 0 to 3 R B is substituted with a group.

[0064] In some embodiments, Cy B is a 9-membered bicyclic heteroaryl having 1 to 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein Cy B is 0 to 3 R B In some embodiments, Cy is substituted with a group. B is 1 to 3 R BIn some embodiments, Cy is an indolediyl substituted with a group. B is 1 to 2 R B In some embodiments, Cy is a cyclopentapyridinediyl substituted with a cyclopentapyridinediyl group. B is 0 to 1 R B In some embodiments, Cy is benzothiophenediyl substituted with a benzothiophene group. B is 0 to 2 R B In some embodiments, Cy is a benzimidazole diyl substituted with a benzoimidazole group. B is 1 to 2 R B In some embodiments, Cy is an imidazopyridinediyl substituted with a group. B is three R B In some embodiments, Cy is a benzoisoxazolediyl substituted with a benzoisoxazole group. B is one R B In some embodiments, Cy is a benzisothiazol-1-yl group substituted with a benzoisothiazol-1-yl group. B is one R B In some embodiments, Cy is a thienopyridinediyl substituted with a thienopyridinediyl group. B is one R B It is a triazolopyridinediyl substituted with a group.

[0065] In some embodiments, Cy B is a 10-membered bicyclic heteroaryl having 1-2 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein Cy B is 0 to 3 R B In some embodiments, Cy is substituted with a group. B is one R B In some embodiments, Cy is an isoquinolinediyl substituted with a methyl group. B is three R B In some embodiments, Cy is a naphthyridinediyl substituted with a cysteine ​​group. B is 0 to 1 R B Based on It is a substituted quinolinonediyl.

[0066] In some embodiments, CyB is a 12-membered tricyclic heterocyclyl having 1 to 4 heteroatoms selected from oxygen, nitrogen, and sulfur, where Cy B is 0 to 1 R B In some embodiments, Cy is substituted with a group. B is one R B and dihydroimidazoquinolinediyl substituted with a group.

[0067] In some embodiments, Cy B is the following: [ka] [ka] is selected from the group consisting of:

[0068] In some embodiments, each R B is halogen, -CN, -OR, -N(R)2, -N(R)CN, -C(=N(R))N(R)2, -S(O)R, -S(O)2R, -S(O)2N(R)2, or C 1~6 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, 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur, 7-10 membered bicyclic heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, and sulfur, and 8-10 membered spirocyclic heterocyclyl having 1-3 heteroatoms selected from oxygen, nitrogen, or sulfur; wherein each R is independently selected from hydrogen or optionally substituted C 1~6 It is aliphatic.

[0069] In some embodiments, optionally substituted R B The substituents on the group are halogen, optionally halogen-substituted C 1~6Aliphatic, -(CH2) 0~4 C(O)OR o , and -(CH2) 0~4 N(R o )2, where each R o are independently hydrogen, C 1~6 Aliphatic or R o two independent occurrences of 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.

[0070] In some embodiments, R B One example of R is halogen. B One example of is -F. In some embodiments, R B One example of is -Cl. In some embodiments, R B One example of is -Br. In some embodiments, R B One example of is -CN. In some embodiments, R B One example of is -N(R)2, where R is hydrogen or C 1~6 In some embodiments, R B One example of is -OR, where R is hydrogen or C optionally substituted with halogen. 1~6 In some embodiments, R B One example is -N(R)CN, where R is hydrogen or C 1~6 In some embodiments, R B One example of is -C(=N(R))N(R)2, where each R is independently hydrogen or C 1~6 In some embodiments, R B One example is -C(=N(R))N(R)2, where R is hydrogen. In some embodiments, R B One example of is -S(O)R, where R is hydrogen or C 1~6 In some embodiments, RB One example is -S(O)R, where R is C 1~6 In some embodiments, R B One example of is -S(O)R, where R is methyl. In some embodiments, R B One example of is -S(O)R, where R is hydrogen or C 1~6 In some embodiments, R B One example is -S(O)R, where R is C 1~6 In some embodiments, R B One example of is -S(O)R, where R is methyl. In some embodiments, R B One example of is -S(O)2N(R)2, where R is hydrogen or C 1~6 In some embodiments, R B One example is -S(O)N(R), where R is C 1~6 In some embodiments, R B One example is -S(O)N(R), where R is methyl. In some embodiments, R B One example of is -S(O)N(R), where two independent occurrences of R, together with the atom(s) between them, form an optionally substituted 3-12 membered saturated ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R B One example of is -S(O)N(R), where two independent occurrences of R, together with the atom(s) between them, form an optionally substituted 5-6 membered saturated ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0071] In some embodiments, R B One example is halogen-substituted C 1~6 It is aliphatic.

[0072] In some embodiments, R B One example is -(CH2)0~4 N(R o )2 substituted C 1~6 aliphatic, where R o is hydrogen or C 1~6 In some embodiments, R B One example is -(CH2) 0~4 N(R o )2 substituted C1 aliphatic, where R o is hydrogen or C 1~6 In some embodiments, R B One example of this is -N(R o )2 substituted C1 aliphatic, where R o is hydrogen or C 1~6 In some embodiments, R B One example is -CHNH It is 2.

[0073] In some embodiments, R B One example of is a C substituted with a 7-10 membered bicyclic heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, and sulfur. 1~6 In some embodiments, R B One example of is a C substituted with a 9-membered bicyclic heteroaryl having 1-2 heteroatoms selected from oxygen, nitrogen, and sulfur. 1~6 In some embodiments, R B One example is the imidazopyridinediyl-substituted C 1~6 In some embodiments, R B One example is the imidazopyridinediyl-substituted C 1~6 It is aliphatic, which is C 1~6 In some embodiments, R B One example is the imidazopyridinediyl-substituted C 1~6 It is aliphatic and may be further substituted with cyclopropyl.

[0074] In some embodiments, R B One example of is optionally substituted phenyl. In some embodiments, R B One example is -(CH2) 0~4 C(O)OR o is phenyl substituted with R o is hydrogen or C 1~6 It is aliphatic.

[0075] In some embodiments, R B One example of is an optionally substituted 5-6 membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur.

[0076] In some embodiments, R B One example of is an optionally substituted 5-membered heteroaryl having 1 to 4 heteroatoms selected from oxygen, nitrogen, and sulfur. In some embodiments, R B One example of is an optionally substituted 5-membered heteroaryl having 1 to 4 heteroatoms selected from oxygen and nitrogen. In some embodiments, R B One example of is an optionally substituted 5-membered heteroaryl having 1 to 4 nitrogen atoms. In some embodiments, R B One example of is optionally substituted pyrazoldiyl. In some embodiments, R B One example of an optionally halogen-substituted C 1~6 In some embodiments, R is an aliphatic substituted pyrazoldiyl. B One example of this is C 1~6 In some embodiments, R is an aliphatic substituted pyrazoldiyl. B One example of is unsubstituted pyrazoldiyl. In some embodiments, R B One example of is optionally substituted imidazolediyl. In some embodiments, R B One example of is unsubstituted imidazolediyl. In some embodiments, R B One example of is optionally substituted triazoldiyl. In some embodiments, R BOne example of R is triazoldiyl substituted with halogen. B One example of an optionally halogen-substituted C 1~6 In some embodiments, R is an aliphatic substituted triazolediyl. B One example of is unsubstituted triazoldiyl. In some embodiments, R B One example of is optionally substituted tetrazolediyl. In some embodiments, R B One example of is unsubstituted tetrazolediyl. In some embodiments, R B One example of is optionally substituted oxadiazoldiyl. In some embodiments, R B One example of is unsubstituted oxadiazoldiyl.

[0077] In some embodiments, R B One example of R is an optionally substituted 6-membered heteroaryl having 1 to 4 heteroatoms selected from oxygen, nitrogen, or sulfur. B One example of is an optionally substituted 6-membered heteroaryl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur. In some embodiments, R B One example of is an optionally substituted 6-membered heteroaryl having 1-2 nitrogen atoms. In some embodiments, R B One example of is optionally substituted pyridinediyl. In some embodiments, R B One example of R is pyridinediyl substituted with halogen. B One example is unsubstituted pyridinediyl. In some embodiments, R B One example of is optionally substituted pyridazinediyl. In some embodiments, R B One example of is unsubstituted pyridazinediyl. In some embodiments, R B One example of is optionally substituted pyrimidinediyl. In some embodiments, R B One example is -(CH2)0~4 C(O)OR o pyrimidinediyl substituted with R o is hydrogen or C 1~6 It is aliphatic.

[0078] In some embodiments, R B One example of is an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, R B One example of is optionally substituted cyclopropyl. In some embodiments, R B One example of is unsubstituted cyclopropyl.

[0079] In some embodiments, R B One example of is an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur.

[0080] In some embodiments, R B One example of R is an optionally substituted 7-10 membered bicyclic heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, and sulfur. B One example of is an optionally substituted 9-membered bicyclic heteroaryl having 1 to 4 heteroatoms selected from oxygen, nitrogen, and sulfur. In some embodiments, R B One example of is an optionally substituted 9-membered bicyclic heteroaryl having 1-2 nitrogen atoms. In some embodiments, R B One example of is optionally substituted pyrazolopyridinediyl. In some embodiments, R B One example of is unsubstituted pyrazolopyridinediyl. In some embodiments, R B One example of is optionally substituted imidazopyridinediyl. In some embodiments, R B One example of is unsubstituted imidazopyridinediyl.

[0081] In some embodiments, RB One example of is an optionally substituted 8-10 membered spirocyclic heterocyclyl having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, R B One example of is unsubstituted oxazaspiroheptyl.

[0082] In some embodiments, L is optionally substituted C 1~6 a hydrocarbon chain in which one to three methylene units are independently replaced by -O-, -NR-, -C(O)-, -C(O)NR-, -NRC(O)-, -S(O)NR-, -NRS(O)-, or -S(O)-, where each R is independently hydrogen or a C optionally substituted with halogen. 1~6 In some embodiments, L is -(C(R)2). m NR(C(R)2) m -#, -(C(R)2) m NRC(O)(C(R)2) m -#, -(C(R)2) m C(O)NR(C(R)2) m -#, -NRC(O)NR-#, -(C(R)2) m OC(O)NR(C(R)2) m -#, -O(C(R)2) m NRC(O)-#, -O(C(R)2) m NRS(O)2-#, -(C(R)2) m S(O)2NR(C(R)2) m -# and -(C(R)2) m NRS(O)2(C(R)2) m -#, where each R is independently hydrogen or C 1~6 aliphatic, each m is independently 0, 1, or 2, and # is Cy AIn some embodiments, L represents a point of attachment to -NR-#, -C(R)NR-#, -C(R)NRC(R)-#, -NRC(O)-#, -C(R)NRC(O)-#, -C(R)C(R)NRC(O)-#, -C(O)NRC(R)-#, -C(R)C(O)NR-#, -C(R)C(O)NRC(R)-#, -NRC and -C(R)2C(R)2NRS(O)2-#, wherein each R is independently selected from hydrogen or C 1~6 aliphatic, and # is Cy A In some embodiments, L represents a point of attachment to -NR-#, -C(R)NR-#, -C(R)NRC(R)-#, -NRC(O)-#, -C(R)NRC(O)-#, -C(R)C(R)NRC(O)-#, -C(O)NRC(R)-#, -C(R)C(O)NR-#, -C(R)C(O)NRC(R)-#, -NRC(O)NR- #, -C(R)2OC(O)NR-#, -OC(R)2C(R)2NRC(O)-#, -OC(R)2C(R)2NRS(O)2-#, -S(O)2NRC(R)2-#, -C(R)2NRS(O)2-#, and -C(R)2C(R)2NRS(O)2-#, wherein each R is independently hydrogen or methyl; and # is selected from Cy A Represents a point of attachment to

[0083] In some embodiments, L is -NH-#, -CHNH-#, -CHNHCH-#, -C(CF)HNHCH-#, -NHC(O)-#, -CHNHC(O)-#, -CH(CH)NHC(O)-#, -CHN(CH)C(O)-#, CHCHNHC(O)-#, -CHC(O)NH-#, -C(CH)HC(O)NH-#, -C(O)NHCH-#, -CHC(O)NHCH 2-#, -NHC(O)NH-#, -CHOC(O)NH-#, -C(CH)HOC(O)NH-#, -S(O)NHCH-#, S(O)NHC(CH)H-#, -CHNHS(O)-#, -C(CH)HNHS(O)-#, -CHCHNHS(O)-#, -OCHCHNHC(O)-#, and -OCHCHNHS(O)-#, wherein # is selected from the group consisting of Cy A Represents a point of attachment to

[0084] In some embodiments, L is selected from -NRC(O)-#, -C(R)2NRC(O)-#, -C(R)2NRC(R)2-#, and -C(R)2NRSO2-#, where each R is selected from hydrogen and C 1~6 independently selected from aliphatic and # is Cy A In some embodiments, L is selected from -NRC(O)-#, -C(R)2NRC(O)-#, -C(R)2NRC(R)2-#, and -C(R)2NRSO2-#, where each R is independently selected from hydrogen and methyl, and # represents a point of attachment to Cy. A In some embodiments, L is selected from -NRC(O)-# and -C(R)2NRC(O)-#, where each R is selected from hydrogen and C 1~6 independently selected from aliphatic and # is Cy A In some embodiments, L is selected from -NRC(O)-# and -C(R)2NRC(O)-#, where each R is independently selected from hydrogen and methyl, and # represents a point of attachment to Cy. A Represents a point of attachment to

[0085] In some embodiments, R 1 and R 2are each hydrogen. In some embodiments, R 2 is hydrogen and R 1 is a monocyclic Cy A and taken together 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 and R 2 is hydrogen and R 1 is a monocyclic Cy A and taken together 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 and R 2 is hydrogen and R 1 is a monocyclic Cy A taken together to form a fused 8-membered saturated or partially unsaturated bicyclic heterocyclylene having 1 to 4 heteroatoms selected from oxygen, nitrogen, or sulfur.

[0086] In some embodiments, R 1 and R 2 is hydrogen, halogen, -OR, -SR, -N(R)2, and optionally substituted C 1~6 aliphatic, where each R is hydrogen and C 1~6 In some embodiments, R 1 and R 2 represents hydrogen, fluorine, -OH, -SH, -NH2, and -(CH2) 0~4 C(O)OR o C replaced with 1~6 independently selected from aliphatic, o is hydrogen or C 1~6 In some embodiments, R 1 and R 2 is hydrogen, fluorine, -OH, and - (CH2) 0~4 C(O)OR o C replaced with 1~6 independently selected from aliphatic, ois hydrogen, methyl or ethyl.

[0087] In some embodiments, R 3 , R 4 , R 5 , and R 7 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 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. 3 , R 4 , R 5 , and R 7 is hydrogen, -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.

[0088] In some embodiments, optionally substituted R 3 , R 4 , R 5 , and R 7 The above substituents are each independently selected from halogen, -CN, (CH2) 0~4 R o , -(CH2) 0~4 OR o , -(CH2) 0~4 N(Ro )2, -(CH2) 0~4 O(CH2) 1~4 N(R o )2 and -(CH2) 0~4 C(O)OR o where each R o are 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.

[0089] In some embodiments, optionally substituted R 3 , R 4 , R 5 , and R 7 The above substituents are each independently -F, -CN, -R o , -OR o , -N(R o )2, -COOR o , or -OC(R o )2C(R o )2N(R o )2, where each R o are 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 3 , R 4 , R 5 , and R 7 The above substituents are -F, -CN, -CH3, -OH, -NH2, -COOH, -COOCH2CH2, -OCH2CH2NH2, -OCH2CH2N(CH3)2, and [ka] are independently selected from

[0090] In some embodiments, R 4 is hydrogen, halogen, -CN, -C(O)2R, -C(O)N(R)2, -N(R)2, -OR, -SR, -S(O)2N(R)2, or C 1~6In 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. 4 is hydrogen, halogen, -CN, -C(O)R, or C 1~6 5-6 membered heteroaryl having 1-4 heteroatoms selected from aliphatic, oxygen, nitrogen, or sulfur, and and optionally substituted groups selected from 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyls having 1 to 2 heteroatoms selected from yellow.

[0091] In some embodiments, optionally substituted R 4 The above substituents are -F, -CN, -R o , -OR o , -N(R o )2, -COOR o , or -OC(R o )2C(R o )2N(R o )2, where each R o are 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 4 The above substituents are -F, -CN, -CH3, -OH, -NH2, -COOH, -COOCH2CH2, -OCH2CH2NH2, -OCH2CH2N(CH3)2, and [ka] is selected from.

[0092] In some embodiments, each R is independently hydrogen or an optionally substituted C 1~6It is aliphatic, or two R groups on the same carbon or nitrogen are taken together with the atoms between them to 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.

[0093] In some embodiments, n is 0. In some embodiments, n is 1.

[0094] In some embodiments, provided compounds have formula (II): [ka] or a pharmaceutically acceptable salt thereof, wherein Cy A , Cy B , R 1 , R 2 , R 4 , R 6 , R, and n are each defined and described in classes and subclasses herein; Q is selected from -C(R)-, -C(O)-, and -S(O)-; p is 0, 1, or 2; provided that the compound is other than N-(furan-2-ylmethyl)-N,3,5-trimethyl-1-((6-methylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-sulfonamide and 2-[(6,8-dichloroimidazo[1,2-a]pyridin-2-yl)methyl]-4-methyl-N-phenyl-5-thiazolecarboxamide.

[0095] Unless otherwise specified or prohibited by the preceding definition of formula (II), the variable Cy is defined above and described in classes and subclasses herein. A , Cy B , R 1 , R 2 , R 4 , R6 It will be understood that the embodiments of R and n also apply to compounds of formula (II), both alone and in combination.

[0096] In some embodiments, Q is -C(R)- and p is 1. In some embodiments, Q is -C(O)- and p is 1. In some embodiments, Q is -C(O)- and p is 0. In some embodiments, Q is -S(O)- and p is 1.

[0097] In some embodiments, provided compounds have formula (III): [ka] wherein: [ka] represents a single or double bond, X is selected from C and N; Each W is a CR A , CH, N, and O; R A , Cy B , L, R 1 , R 2 , R 4 , and R 6 each of which is defined and described in classes and subclasses herein; provided that the compound is other than N-(furan-2-ylmethyl)-N,3,5-trimethyl-1-((6-methylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-sulfonamide.

[0098] In some embodiments, provided compounds, or pharmaceutically acceptable salts thereof, have the structure of Formula (III-a), (III-b), (III-c), (III-d), (III-e), (III-f), or (III-g): [ka] In the formula, R A , Cy B , L, R 4 , and R 6 Each of the is defined and described in classes and subclasses herein, provided that the compound is other than N-(furan-2-ylmethyl)-N,3,5-trimethyl-1-((6-methylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-sulfonamide.

[0099] In some embodiments, provided compounds, or pharmaceutically acceptable salts thereof, have the structure of Formula (III-ai), (III-bi), (III-ci), (III-di), (III-ei), (III-fi), (III-gi), [ka] wherein Q is selected from —C(R)—, —C(O)—, and —S(O)—; p is 0, 1, or 2; R A , Cy B , L, R 4 , R 6 and R are each defined and described in classes and subclasses herein; provided that the compound is other than N-(furan-2-ylmethyl)-N,3,5-trimethyl-1-((6-methylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-sulfonamide.

[0100] In some embodiments, Q is -C(R)- and p is 1. In some embodiments, Q is -C(O)- and p is 1. In some embodiments, Q is -C(O)- and p is 0. In some embodiments, Q is -S(O)- and p is 1.

[0101] Unless otherwise specified or prohibited by the preceding definition of formula (III), the variable moiety R is defined above and described in classes and subclasses herein. A , Cy B , R 1 , R 2 , R 6 , and R 7 It will be understood that this embodiment also applies to compounds of formula (III-a), (III-b), (III-c), (III-d), (III-e), (III-f), and (III-g) and compounds of formula (III-ai), (III-bi), (III-ci), (III-di), (III-ei), (III-fi), and (III-gi), both alone and in combination.

[0102] In some embodiments, R 1 However, monocyclic Cy A and taken together to form an optionally substituted fused ring, the compound has formula (IV): [ka] wherein: [ka] represents a single or double bond, each X is independently N or C; Each Y is independently a CR A , CH, or N; Z is CH2 or O; R A , Cy B , L, R 4 , and R 6 Each of the following is defined and described in classes and subclasses herein.

[0103] In some embodiments, provided compounds, or pharmaceutically acceptable salts thereof, have the structure of Formula (IV-a), Formula (IV-b), Formula (IV-c), and Formula (IV-d): [ka] In the formula, Cy B , L, R 4 , and R 6 Each of the following is defined and described in classes and subclasses herein.

[0104] In some embodiments, provided compounds, or pharmaceutically acceptable salts thereof, have the structure of Formula (IV-ai), Formula (IV-bi), Formula (IV-ci), and Formula (IV-di): [ka] wherein Q is selected from —C(R)—, —C(O)—, and —S(O)—; p is 0, 1, or 2; Cy B , R 4 , R 6 Each of R and R is defined and described in classes and subclasses herein.

[0105] In some embodiments, Q is -C(R)2- and p is 1. In some embodiments, Q is -C(O)- and p is 1. In some embodiments, Q is -C(O)- and p is 0. In some embodiments, Q is -S(O)- and p is 1.

[0106] Unless otherwise specified or prohibited by the preceding definition of formula (IV), the variable moiety R is defined above and described in classes and subclasses herein. A ,L,Cy B , R 4 , R 6 It will be understood that the embodiments of R also apply to compounds of formula (IV-a), (IV-b), (IV-c), and (IV-d), and compounds of formula (IV-ai), (IV-bi), (IV-ci), and (IV-di), both alone and in combination.

[0107] In some embodiments, provided compounds are those listed in Table I: [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] or a pharmaceutically acceptable salt thereof.

[0108] C. Pharmaceutical Compositions In another aspect, the present invention provides a pharmaceutical composition comprising a compound of Formula (I)-(IV) or a compound of Formula (I)-(IV) in combination with a pharmaceutically acceptable excipient (e.g., carrier).

[0109] The pharmaceutical composition comprises an optical isomer, diastereomer, or pharmaceutically acceptable salt of the inhibitor disclosed herein. The compound of Formulas (I)-(IV) contained in the pharmaceutical composition can be covalently bound to a carrier moiety as described above. Alternatively, the compound of Formulas (I)-(IV) contained in the pharmaceutical composition is not covalently bound to a carrier moiety.

[0110] As used herein, "pharmaceutically acceptable carrier" refers to a pharmaceutical excipient, e.g., a pharmaceutically and physiologically acceptable organic or inorganic carrier substance suitable for enteral or parenteral administration that does not adversely react with the active agent. Suitable pharmaceutically acceptable carriers include water, salt solutions (e.g., Ringer's solution), alcohol, oils, gelatin, and carbohydrates such as lactose, amylose, or starch, fatty acid esters, hydroxymethylcellulose, and polyvinylpyrrolidine. Such preparations may be sterilized and, if necessary, may be mixed with auxiliary agents, 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.

[0111] The compounds of the present invention can be administered to a subject alone or in combination. Co-administration is intended to include simultaneous or sequential administration of the compounds individually or in combination (two or more compounds). Also, the preparation can be combined with other active substances, if necessary (for example, to reduce metabolic degradation).

[0112] 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.

[0113] D. Formulation The compounds of the present invention can be prepared in and administered in a wide variety of oral, parenteral, and topical dosage forms. Thus, the compounds of the present invention can be administered by injection (e.g., intravenously, intramuscularly, intracutaneously, subcutaneously, intraduodenally, or intraperitoneally). 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 routes of administration (e.g., intramuscular, oral, transdermal) can be used to administer the compounds of the present invention. Accordingly, the present invention also provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier or excipient and one or more compounds of the present invention.

[0114] 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.

[0115] 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.

[0116] 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.

[0117] 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.

[0118] 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.

[0119] 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.

[0120] 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.

[0121] 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.

[0122] 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.Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge alone, or the appropriate number of any of these in packaged form.

[0123] 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.

[0124] 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.

[0125] 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.

[0126] The compositions of the present invention may additionally contain ingredients that provide sustained release and / or comfort. Such ingredients include high molecular weight anionic mucus-mimetic polymers, gelling polysaccharides, and micronized drug carrier substrates. These ingredients are described in more detail in U.S. Patent Nos. 4,911,920; 5,403,841; 5,212,162; and 4,861,760. The entire contents of these patents are incorporated herein by reference in their entirety for all purposes.

[0127] 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).

[0128] The dosage and frequency (single or multiple doses) of the compound administered will depend on the route of administration; the size, age, sex, health, weight, body mass index, and diet of the recipient; the disease being treated; The nature and severity of symptoms (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 may vary depending on a variety of factors. Other therapeutic regimens or agents may be used in conjunction with the methods and compounds of the invention.

[0129] 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.

[0130] 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.

[0131] Dosages 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.

[0132] 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.

[0133] 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 occurs in the eye (e.g., diabetic macular edema (DME)). 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 via a suitable route.

[0134] In certain embodiments, the methods comprise 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 methods comprise administering a compound of Formula (I)-(IV) or a pharmaceutically acceptable salt or composition thereof to a subject in need thereof. In some embodiments, the methods comprise administering a pharmaceutical composition comprising a compound of Formula (I)-(IV) or a pharmaceutically acceptable salt thereof to a subject in need thereof.

[0135] In certain embodiments, a subject treated by any of the methods described herein The subject is a human patient who has, suspects to have, or is at risk of having edema, such as HAE or diabetic macular edema (DME). The subject with edema can be identified by routine medical examination, for example, clinical examination. The subject suspected of having edema can show one or more symptoms of disease / disorder. The subject at risk of edema can have one or more of the risk factors related to disease, for example, C1-INH deficiency for HAE.

[0136] 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®).

[0137] 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®).

[0138] In yet another embodiment, 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 a compound described herein as the sole active agent, or may require an additional anti-HAE agent, such as those described herein.

[0139] 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.

[0140] In certain embodiments, the methods disclosed herein include administering to a subject an effective amount of a compound of Formula (I)-(IV) or a pharmaceutically acceptable salt thereof, or a composition thereof. In some embodiments, the effective amount is a therapeutically effective amount. In some embodiments, the effective amount is a prophylactically effective amount.

[0141] 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.

[0142] Certain methods described herein may include administering one or more additional pharmaceutical agents(s) in combination with a compound described herein. The additional pharmaceutical agent(s) may be administered simultaneously with the compound of Formula (I)-(IV) or at a different time than the compound of Formula (I)-(IV). For example, the compound of Formula (I)-(IV) and any additional pharmaceutical agent(s) may be on the same administration schedule or different administration schedules. All or a portion of the dose of the compound of Formula (I)-(IV) 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 administration schedule of the additional pharmaceutical agent, or a combination thereof. The timing of administration of the compound of Formula (I)-(IV) and the additional pharmaceutical agent may vary depending on the additional pharmaceutical agent.

[0143] In certain embodiments, the additional pharmaceutical agent comprises an agent useful in the treatment of edema, e.g., HAE or DME. Examples of such agents are provided herein.

[0144] V. Illustrative Embodiments The present disclosure contemplates, among other things, the following numbered embodiments:

[0145] 1. Formula (I): [ka] or a pharmaceutically acceptable salt thereof, During the ceremony: Cy A is selected from 5-membered monocyclic heteroarylene having 1 to 4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, and 7-10-membered partially unsaturated bicyclic heterocyclylene having 1 to 4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein Cy is A is 0 to 4 R A is substituted with a group, Each R A are halogens, -CN, -C(R)=N(R), -C(O)R, -C(O)R, -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; Cy Bis selected from phenyl, 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, and sulfur, 7-10 membered partially unsaturated bicyclic carbocyclyl, 10 membered bicyclic aryl, 7-10 membered bicyclic heterocyclyl having 1-4 heteroatoms selected from oxygen, nitrogen, and sulfur, 7-10 membered bicyclic heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, and sulfur, and 12 membered tricyclic heterocyclyl having 1-4 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein Cy is B is 0 to 5 R B is substituted with a group, Each R B is halogen, -CN, oxo, -C(R)=N(R), -C(O)R, -C(O)2R, -C(O)N(R)2, -C(=N(R))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 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, 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur, 7-10 membered bicyclic heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, and sulfur, and 8-10 membered spirocyclic heterocyclyl having 1-3 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)-, -C(O)NR-, -NRC(O)-, -S(O)NR-, -NRS(O)-, or -S(O)-; -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 1 and R 2 is hydrogen, halogen, -OR, -SR, -N(R)2, and optionally substituted C 1~6 independently selected from aliphatic, 1 is a monocyclic Cy A and R 3 , R 4 , R 5 , and R 7 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 a 5- to 6-membered heteroaryl having 1 to 4 heteroatoms selected from aliphatic, phenyl, oxygen, nitrogen, or sulfur; a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl; and a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl having 1 to 2 heteroatoms selected from oxygen, nitrogen, or sulfur. an optionally substituted group selected from 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 7 heteroatoms; R 6is 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 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; 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 are taken together with the atoms between them to 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, However, the following: (a)R 3 , R 4 , R 5 , R 6 and R 7 At least one of the 1~6 being aliphatic or halogen; (b) The compound is selected from the group consisting of N-[1-[(6-fluoroimidazo[1,2-a]pyridin-2-yl)methyl]-5-methyl-1H-pyrazol-3-yl]-3-pyridinecarboxamide, N-[1-[(6-chloroimidazo[1,2-a]pyridin-2-yl)methyl]-5-methyl-1H-pyrazol-3-yl]-3-pyridinecarboxamide, 3-chloro-4-[[5-[8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl]methyl]-5-methyl-1H-pyrazol-3-yl]-3-pyridinecarboxamide, [6,8-dichloroimidazo[1,2-a]pyridin-2-yl]methyl]-4-methyl-N-phenyl-5-thiazolecarboxamide, and N-(furan-2-ylmethyl)-N,3,5-trimethyl-1-((6-methylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-sulfonamide; or a pharmaceutically acceptable salt thereof, provided that:

[0146] 2. Cy A is selected from 5-membered heteroarylene having 1 to 4 heteroatoms independently selected from oxygen and nitrogen, and 8-membered partially unsaturated bicyclic heterocyclylene having 2 to 3 heteroatoms independently selected from oxygen and nitrogen, wherein Cy is A is 0 to 3 R A The compound of embodiment 1, wherein the compound is substituted with a group.

[0147] 3. Cy A is a 5-membered heteroarylene having 1 to 4 heteroatoms independently selected from oxygen and nitrogen, wherein Cy A is 0 to 3 R A The compound of embodiment 1, wherein the compound is substituted with a group.

[0148] 4. Cy A is an 8-membered partially unsaturated bicyclic heterocyclylene having 2-3 heteroatoms selected from oxygen and nitrogen, wherein Cy A is 0 to 3 R A Based on 2. The compound of embodiment 1, wherein

[0149] 5. Cy A is the following: [ka] wherein * represents the point of attachment to L.

[0150] 6.R 3 , R 5 , and R 7

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

[0151] 7. The compound has the formula (III): [ka] or a pharmaceutically acceptable salt thereof; During the ceremony: [ka] represents a single or double bond, X is selected from C and N; Each W is a CR A , CH, N, and O; R 4 is hydrogen, halogen, -CN, -C(O)OR, or C 1~6 optionally substituted groups selected from a 5- to 6-membered heteroaryl having 1 to 4 heteroatoms selected from aliphatic, oxygen, nitrogen, or sulfur, and a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 2 heteroatoms selected from oxygen, nitrogen, or sulfur; R 6 is C 1~6 selected from aliphatic or halogen; Each R is independently hydrogen or C 1~6 is an optionally substituted group selected from aliphatic or two R groups on the same carbon or nitrogen atom are taken together with the atoms between them to 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; The compound of embodiment 1, provided that the compound is other than N-(furan-2-ylmethyl)-N,3,5-trimethyl-1-((6-methylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-sulfonamide.

[0152] 8.R 1 is a monocyclic Cy A taken together to 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.

[0153] 9. The compound is of formula (IV): [ka] During the ceremony, [ka] represents a single or double bond, each X is independently N or C; Each Y is independently a CR A , CH, or N; Z is CH2 or O; R A is C 1~6 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; R 4is hydrogen, halogen, -CN, -C(O)OR, or C 1~6 5- to 6-membered heteroaryl having 1 to 4 heteroatoms selected from aliphatic, oxygen, nitrogen, or sulfur, and 3- to 7-membered heteroaryl having 1 to 2 heteroatoms selected from oxygen, nitrogen, or sulfur. an optionally substituted group selected from saturated or partially unsaturated monocyclic heterocyclyl of R 6 is C 1~6 The compound of embodiment 1 or 8, wherein the compound is selected from aliphatic or halogen.

[0154] 10. The compound has formula (III-a), formula (III-b), formula (III-c), formula (III-d), formula (III-e), formula (III-f), or formula (III-g): [ka] or a pharmaceutically acceptable salt thereof; During the ceremony: R A is C 1~6 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; R 4 is hydrogen, halogen, -CN, -C(O)OR, or C 1~6 optionally substituted groups selected from a 5- to 6-membered heteroaryl having 1 to 4 heteroatoms selected from aliphatic, oxygen, nitrogen, or sulfur, and a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 2 heteroatoms selected from oxygen, nitrogen, or sulfur; R 6 is C 1~6 selected from aliphatic or halogen; The compound of embodiment 1 or 7, with the proviso that the compound is other than N-(furan-2-ylmethyl)-N,3,5-trimethyl-1-((6-methylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-sulfonamide.

[0155] 11. The compound has formula (IV-a), formula (IV-b), formula (IV-c), or formula (IV-d): [ka] or a pharmaceutically acceptable salt thereof; During the ceremony: R 4 is hydrogen, halogen, -CN, -C(O)OR, or C 1~6 optionally substituted groups selected from a 5- to 6-membered heteroaryl having 1 to 4 heteroatoms selected from aliphatic, oxygen, nitrogen, or sulfur, and a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 2 heteroatoms selected from oxygen, nitrogen, or sulfur; R 6 is C 1~6 The compound of embodiment 1 or 9, wherein the alkyl is selected from aliphatic or halogen.

[0156] 12.L is -(C(R)2) m NR(C(R)2) m -#, -(C(R)2) m NRC(O)(C(R)2) m -#, -(C(R)2) m C(O)NR(C(R)2) m -#, -NRC(O)NR-#, -(C(R)2) m OC(O)NR(C(R)2) m -#, -O(C(R)2) m NRC(O)-#, -O(C(R)2) m NRS(O)2-#, -(C(R)2) m S(O)2NR(C(R)2) m -# and -(C(R)2) m NRS(O)2(C(R)2)m -#, where each R is independently hydrogen or optionally substituted C 1~6 aliphatic, each m is independently 0, 1, or 2, and # is Cy A The compound of any one of the preceding embodiments, wherein the compound represents a point of attachment to

[0157] 13.L is -NR-#, -C(R)2NR-#, -C(R)2NRC(R)2-#, -NRC(O)-#, -C(R)2NRC(O)-#, -C(R)2C(R)2NRC(O)-#, -C(O)NRC(R)2-#, -C(R)2C(O)NR-#, -C(R) and -C(R)C(R)NRC(R)-#, -NRC(O)NR-#, -C(R)OC(O)NR-#, -OC(R)C(R)NRC(O)-#, -OC(R)C(R)NRS(O)-#, -S(O)NRC(R)-#, -C(R)NRS(O)-#, and -C(R)C(R)NRS(O)-#, wherein each R is independently selected from hydrogen or an optionally substituted C 1~6 aliphatic, and # is Cy A The compound of any one of the preceding embodiments, wherein the compound represents a point of attachment to

[0158] 14. L is selected from -NRC(O)-#, -C(R)2NRC(O)-#, -C(R)2NRC(R)2-#, and -C(R)2NRSO2-#, where each R is selected from hydrogen and optionally substituted C 1~6 independently selected from aliphatic and # is Cy A The compound of any one of the preceding embodiments, wherein the compound represents a point of attachment to

[0159] 15. L is selected from -NRC(O)-# and -C(R)2NRC(O)-#, where each R is hydrogen and optionally substituted C 1~6 independently selected from aliphatic and # is Cy A The compound of any one of the preceding embodiments, wherein the compound represents a point of attachment to

[0160] 16. The compound has the formula (II): [ka] or a pharmaceutically acceptable salt thereof; During the ceremony: Cy A is selected from 5-membered monocyclic heteroarylene having 1 to 4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, and 7-10-membered partially unsaturated bicyclic heterocyclylene having 1 to 4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein Cy is A is 0 to 4 R A is substituted with a group, R A is C 1~6 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; Q is selected from -C(R)-, -C(O)-, and -S(O)-; Cy B is selected from phenyl, 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, and sulfur, 7-10 membered partially unsaturated bicyclic carbocyclyl, 10 membered bicyclic aryl, 7-10 membered bicyclic heterocyclyl having 1-4 heteroatoms selected from oxygen, nitrogen, and sulfur, 7-10 membered bicyclic heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, and sulfur, and 12 membered tricyclic heterocyclyl having 1-4 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein Cy is B is 0 to 5 R B is substituted with a group, R B is halogen, -CN, -OR, -N(R)2, -N(R)CN, -C(=N(R))N(R)2, -S(O)R, -S(O)2R, -S(O)2N(R)2, or C 1~6 aliphatic, phenyl, 5-6 membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur; 3-7 membered saturated or partially unsaturated monocyclic carbocyclic and optionally substituted groups selected from: 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur; 7-10 membered bicyclic heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, and sulfur; and 8-10 membered spirocyclic heterocyclyl having 1-3 heteroatoms selected from oxygen, nitrogen, or sulfur; wherein each R is independently hydrogen or an optionally substituted C 1~6 is aliphatic, R 1 and R 2 is hydrogen, halogen, -OR, -SR, -N(R)2, and optionally substituted C 1~6 independently selected from aliphatic, 1 is a monocyclic Cy A and R 4 is hydrogen, halogen, -CN, -C(O)OR, or C 1~6 optionally substituted groups selected from a 5- to 6-membered heteroaryl having 1 to 4 heteroatoms selected from aliphatic, oxygen, nitrogen, or sulfur, and a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 2 heteroatoms selected from oxygen, nitrogen, or sulfur; R 6 is C 1~6 selected from aliphatic or halogen; Each R is independently hydrogen or C 1~6 is an optionally substituted group selected from aliphatic or two R groups on the same carbon or nitrogen atom are taken together with the atoms between them to 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, p is 0, 1, or 2; The compound of embodiment 1, provided that the compound is other than N-(furan-2-ylmethyl)-N,3,5-trimethyl-1-((6-methylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-sulfonamide and 2-[(6,8-dichloroimidazo[1,2-a]pyridin-2-yl)methyl]-4-methyl-N-phenyl-5-thiazolecarboxamide.

[0161] 17. Cy A is selected from 5-membered heteroarylene having 1 to 4 heteroatoms independently selected from oxygen and nitrogen, and 8-membered partially unsaturated bicyclic heterocyclylene having 2 to 3 heteroatoms independently selected from oxygen and nitrogen, wherein Cy is A is 0 to 3 R A 17. The compound of embodiment 16, wherein the compound is substituted with a group.

[0162] 18. Cy A is a 5-membered heteroarylene having 1 to 4 heteroatoms independently selected from oxygen and nitrogen, wherein Cy A is 0 to 3 R A 17. The compound of embodiment 16, wherein the compound is substituted with a group.

[0163] 19. Cy A is an 8-membered partially unsaturated bicyclic heterocyclylene having 2-3 heteroatoms selected from oxygen and nitrogen, wherein Cy A is 0 to 3 R A 17. The compound of embodiment 16, wherein the compound is substituted with a group.

[0164] 20. Cy A is the following: [ka] wherein * represents the point of attachment to L.

[0165] 21. The compound is represented by the formula (III-ai), the formula (III-bi), the formula (III-ci), the formula (III-di), the formula (III-ei), the formula (III-fi), the formula (III-gi): [ka] or a pharmaceutically acceptable salt thereof; During the ceremony: Q is selected from -C(R)-, -C(O)-, and -S(O)-; R A is C 1~6 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; R 4 is hydrogen, halogen, -CN, -C(O)OR, or C 1~6 optionally substituted groups selected from a 5- to 6-membered heteroaryl having 1 to 4 heteroatoms selected from aliphatic, oxygen, nitrogen, or sulfur, and a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 2 heteroatoms selected from oxygen, nitrogen, or sulfur; R 6 is C 1~6 selected from aliphatic or halogen; p is 0, 1, or 2; However, the compound is N-(furan-2-ylmethyl)-N,3,5-trimethyl-1- The compound of embodiment 1, provided that it is other than ((6-methylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-sulfonamide.

[0166] 22. The compound is represented by the formula (IV-ai), the formula (IV-bi), the formula (IV-ci), the formula (IV-di), the formula (IV-ei), the formula (IV-fi), the formula (IV-gi): [ka] or a pharmaceutically acceptable salt thereof; During the ceremony: Q is selected from -C(R)-, -C(O)-, and -S(O)-; p is 0, 1, or 2; R 4 is hydrogen, halogen, -CN, -C(O)OR, or C 1~6 optionally substituted groups selected from a 5- to 6-membered heteroaryl having 1 to 4 heteroatoms selected from aliphatic, oxygen, nitrogen, or sulfur, and a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 2 heteroatoms selected from oxygen, nitrogen, or sulfur; R 6 is C 1~6 The compound of embodiment 8, wherein the alkyl group is selected from aliphatic or halogen.

[0167] 23. The compound according to any one of embodiments 16-22, wherein Q is -C(R)2- and p is 1.

[0168] 24. The compound according to any one of embodiments 16-22, wherein Q is —C(O)— and p is 1.

[0169] 25. The compound according to any one of embodiments 16-22, wherein Q is —C(O)— and p is 0.

[0170] 26. The compound according to any one of embodiments 16-22, wherein Q is -S(O)2- and p is 1.

[0171] 27. Cy B is a 5- to 6-membered monocyclic heteroaryl having 1 to 4 heteroatoms selected from phenyl, oxygen, nitrogen, and sulfur; a 7- to 10-membered partially unsaturated bicyclic aryl; and 12-membered tricyclic heterocyclyl having 1 to 4 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein Cy is selected from 10-membered bicyclic aryl, 7-10-membered bicyclic heterocyclyl having 1 to 4 heteroatoms selected from oxygen, nitrogen, and sulfur, 7-10-membered bicyclic heteroaryl having 1 to 4 heteroatoms selected from oxygen, nitrogen, and sulfur, and 12-membered tricyclic heterocyclyl having 1 to 4 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein Cy is selected from 10-membered bicyclic aryl, 7-10-membered bicyclic heteroaryl having 1 to 4 heteroatoms selected from oxygen, nitrogen, and sulfur, and 12-membered tricyclic heterocyclyl having 1 to 4 heteroatoms selected from oxygen, nitrogen, and sulfur, B is 0 to 5 R B The compound of any one of the preceding embodiments, wherein the compound is substituted with a group.

[0172] 28. Cy B is 0 to 5 R B 28. The compound of embodiment 27, wherein the R is phenyl substituted with a group.

[0173] 29. Cy B is a 5-membered monocyclic heteroaryl having 2-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein Cy B is 0 to 2 R B 28. The compound of embodiment 27, wherein the compound is substituted with a group.

[0174] 30. Cy B is a 6-membered monocyclic heteroaryl having 1-2 nitrogen atoms, where Cy B is 0 to 3 R B 28. The compound of embodiment 27, wherein the compound is substituted with a group.

[0175] 31. Cy B is a 9-10 membered bicyclic heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein Cy B is 0 to 3 R B 28. The compound of embodiment 27, wherein the compound is substituted with a group.

[0176] 32. Cy B is the following: [ka] 28. The compound of embodiment 27, selected from the group consisting of:

[0177] 33. Cy B teeth, [ka] The compound of any one of the preceding embodiments, wherein

[0178] 34.R 6 is C 1~6 The compound of any one of the preceding embodiments, wherein the compound is aliphatic.

[0179] 35.R 6 is C 1~6 The compound of any one of the preceding embodiments, wherein the compound is cycloalkyl.

[0180] 36.R 6 The compound of any one of the preceding embodiments, wherein is cyclopropyl.

[0181] 37. The compound of any one of the preceding embodiments, wherein the compound is any one of compounds I-1 to I-137 shown in Table I, or a pharmaceutically acceptable salt thereof.

[0182] 38. The compound of any one of the preceding embodiments, wherein the compound is any one of compounds I-1 to I-125 and I-128 to I-137 shown in Table I, or a pharmaceutically acceptable salt thereof.

[0183] 39. A pharmaceutical composition comprising a compound according to any one of the preceding embodiments, and further comprising a pharmaceutically acceptable excipient.

[0184] 40. 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.

[0185] 41. A method of treating hereditary angioedema or diabetic macular edema, comprising administering to a patient in need thereof a compound of any one of the preceding embodiments. [Example]

[0186] Example 1 General Procedure A for Amide Synthesis: Scheme 1 [ka] 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.

[0187] 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.

[0188] 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.

[0189] 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.

[0190] General procedure A for amide coupling. To a solution of 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylic acid (60 mg, 0.21 mmol), amine (0.32 mmol), and HATU (120 mg, 0.31 mmol) in DMF (8 mL) was added DIPEA (81 mg, 0.63 mmol). The reaction mixture was stirred at room temperature for 12 hours. Water (25 mL) was added, and the mixture was extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the crude product, which was purified by preparative TLC, preparative HPLC, or silica gel chromatography to give the desired product.

[0191] The following compounds were synthesized according to general procedure A starting from 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylic acid and the required amine: N-((3-amino-5,7-dimethylbenzo[d]isoxazol-6-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (I-134), N-((7-bromonaphthalen-1-yl)methyl)-1-((6-cyclopropyl N-(3-bromophenethyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (I-133), N-(3-bromophenethyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (I-132), N-((7-chloroisoquinolin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (I-131), N-(2-(3-chlorophenoxy) N-((5-chlorobenzo[b]thiophen-3-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (I-129), N-((5-chlorobenzo[b]thiophen-3-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (I-128), N-((5-chlorobenzo[d]isothiazol-3-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole N-((6-chloro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (I-126), N-(5-chloro-2-(1H-tetrazol-1-yl)benzyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (I-125), 1-((6-cyclopropylimidazo[1,2-a]pyridin-3-yl)methyl)-1H-pyrazole-4-carboxamide (I-126), N-((3-chloro-4,6-dimethyl-1H-indol-5-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (I-124), N-((3-chloro-4,6-dimethyl-1H-indol-5-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (I-123), N-((6-bromo-2-oxo-1,2-dihydroquinolin-4-yl)methyl)-1-((6-cyclopropylimidazo[1,N-(3-chlorobenzyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (I-122), N-(3-chlorobenzyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (I-121), N-((6-chloro-8-fluoroimidazo[1,5-a]pyridin-3-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (I-137), 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (I-138), )methyl)-N-((2-oxo-1,2-dihydroquinolin-4-yl)methyl)-1H-pyrazole-4-carboxamide (I-120), N-(6-cyano-2-fluoro-3-methoxybenzyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (I-119), and N-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)benzyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (I-116).

[0192] Example 2 N-((3-amino-5,7-dimethylbenzo[d]isoxazol-6-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (I-134) Scheme 2 [ka] Synthesis of N-((3-amino-5,7-dimethylbenzo[d]isoxazol-6-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide. N-((3-amino-5,7-dimethylbenzo[d]isoxazol-6-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide was synthesized according to General Procedure A starting from 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylic acid and 6-(aminomethyl)-5,7-dimethylbenzo[d]isoxazol-3-amine hydrochloride. The crude product was purified by preparative TLC (DCM / MeOH=10 / 1) to give the product (17 mg, yield: 26.7%) as a white solid. ESI-MS [M+H] + : 456.2. 1 H NMR (400 MHz, DMSO) δ 8.49 (t, J = 5.3 Hz, 1H), 8.34 (s, 1H), 8.23 ​​(s, 1H), 7.88 (s, 1H), 7.75 (s, 1H), 7.40 (d, J = 9.3 Hz, 1H), 7.00 (d, J = 9.3 Hz, 1H), 6.87 (s, 1H), 5.85 (s, 2H), 5.40 (s, 2H), 4.43 (d, J = 5.4 Hz, 2H), 2.50 (s, 3H), 2.32 (s, 3H), 1.95-1.89 (m, 1H), 0.92 (d, J = 6.7 Hz, 2H), 0.67 (d, J = 4.6 Hz, 2H).

[0193] Example 3 N-((7-bromonaphthalen-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (I-133) Scheme 3 [ka] Synthesis of N-((7-bromonaphthalen-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide. N-((7-bromonaphthalen-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide can be prepared according to general procedure A from 1-((6-cyclopropylimidazo[ The synthesis was started from 1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylic acid and 6-(7-bromonaphthalen-1-yl)methanamine. The crude product was purified by preparative TLC (DCM / MeOH=10 / 1) to give the product (6 mg, yield: 20%) as a white solid. ESI-MS [M +H]+: 500.1. 1 H NMR (400 MHz, MeOD) δ 8.32 (s, 1H), 8.16 (d, J = 6.4 Hz, 2H), 7.95 (s, 1H), 7.81 (d, J = 8.6 Hz, 2H), 7.70 (s, 1H), 7.62 - 7.51 (m, 2H), 7.50 - 7.43 (m, 1H), 7.37 (d, J = 9.3 Hz, 1H), 7.12 - 7.06 (m, 1H), 5.44 (s, 2H), 4.92 (s, 2H), 1.98 - 1.88 (m, 1H), 1.00 - 0.94 (m, 2H), 0.73 - 0.67 (m, 2H).

[0194] Example 4 N-(3-Bromophenethyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (I-132) Scheme 4 [ka] Synthesis of N-(3-bromophenethyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide). N-(3-bromophenethyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide was synthesized according to General Procedure A starting from 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylic acid and 2-(3-bromophenyl)ethan-1-amine. The crude product was purified by preparative TLC (DCM / MeOH=10 / 1) to give the product (35 mg, yield: 42.7%) as a pale pink solid. ESI-MS [M +H]: 464.1. 1 H NMR (400 MHz, DMSO) δ 8.34 (s, 1H), 8.15 (s, 2H), 7.81 (s, 1H), 7.74 (s, 1H), 7.47 - 7.35 (m, 3H), 7.27 - 7.17 (m, 2H), 7.02-6.97 (m, 1H), 5.39 (s, 2H), 3.43-3.31 (m, 2H), 2.78 (t, J = 7.2 Hz, 2H), 1.95-1.87 (m, 1H), 0.95 - 0.88 (m, 2H), 0.70 - 0.64 (m, 2H).

[0195] Example 5 N-((7-chloroisoquinolin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (I-131) Scheme 5 [ka] Synthesis of N-((7-chloroisoquinolin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide. N-((7-chloroisoquinolin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide was synthesized according to General Procedure A starting from 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylic acid and (7-chloroisoquinolin-1-yl)methanamine. The crude product was purified by preparative TLC (DCM / MeOH=10 / 1) to give the product (12 mg, yield: 12.5%) as a white solid. ESI-MS [M+H] + : 457.2. 1 H NMR (400 MHz, DMSO) δ 8.71 (t, J = 5.7 Hz, 1H), 8.47 - 8.46 (m, 2H), 8.33 (s, 1H), 8.26 (s, 1H), 8.05 (d, J = 8.8 Hz, 1H), 7.90 (s, 1H), 7.82 - 7.79 (m, 2H), 7.74 (s, 1H), 7.40 (d, J = 9.3 Hz, 1H), 7.02-6.97 (m, 1H), 5.40 (s, 2H), 5.01 (d, J = 5.7 Hz, 2H), 1.93 - 1.59 (m, 1H), 0.94 - 0.90 (m, 2H), 0.68 - 0.64 (m, 2H).

[0196] Example 6 N-(2-(3-chlorophenoxy)ethyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (I-129) Scheme 6 [ka] Synthesis of N-(2-(3-chlorophenoxy)ethyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide. N-(2-(3-chlorophenoxy)ethyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide was synthesized according to general procedure A starting from 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylic acid and 2-(3-chlorophenoxy)ethan-1-amine. The crude product was purified by preparative HPLC. The product (38 mg, yield: 25%) was obtained as a pale yellow solid. [M +H]+: 436.2. 1 H NMR (400 MHz, DMSO) δ 8.34 (s, 1H), 8.30 (t, J = 5.5 Hz, 1H), 8.20 (s, 1H), 7.85 (s, 1H), 7.74 (s, 1H), 7.40 (d, J = 9.3 Hz, 1H), 7.29 (t, J = 8.2 Hz, 1H), 7.05 - 6.90 (m, 4H), 5.40 (s, 2H), 4.07 (t, J = 5.8 Hz, 2H), 3.57-3.49 (m, 2H), 1.98 - 1.85 (m, 1H), 0.97 - 0.87 (m, 2H), 0.71 - 0.62 (m, 2H).

[0197] Example 7 N-((5-chlorobenzo[b]thiophen-3-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (I-128) Scheme 7 [ka] Synthesis of N-((5-chlorobenzo[b]thiophen-3-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide. N-((5-chlorobenzo[b]thiophen-3-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide was synthesized according to General Procedure A starting from 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylic acid and (5-chlorobenzo[b]thiophen-3-yl)methanamine. The crude product was purified by preparative TLC (DCM:MeOH=20:1) to give the product (18.8 mg, yield: 27%) as a white solid. ESI-MS [M +H]+: 462.2. 1 H NMR (400 MHz, DMSO) δ 8.63 (t, J = 5.7 Hz, 1H), 8.32 (s, 1H), 8.23 ​​(s, 1H), 8.03 - 7.99 (m, 2H), 7.88 (s, 1H), 7.73 (s, 1H), 7.65 (s, 1H), 7.41 - 7.37 (m, 2H), 7.01-6.96 (m, 1H), 5.40 (s, 2H), 4.60 (d, J = 5.7 Hz, 2H), 1.94 - 1.88(m, 1H), 0.94 - 0.86 (m, 2H), 0.70 - 0.62 (m, 2H).

[0198] Example 8 N-((7-chloronaphthalen-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (I-130) Scheme 8 [ka] Synthesis of N-((7-chloronaphthalen-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide. To a solution of methyl 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate (100 mg, 0.354 mmol) in anhydrous DMF (5 mL) was added DIPEA (200 mg, 1.55 mmol). The mixture was stirred at room temperature for 1 hour. Then, (7-chloronaphthalen-1-yl)methanamine (1100 mg, 0.522 mmol) was added. The final mixture was stirred at room temperature for 16 hours. Quenched with water (50 mL) and extracted with EA (30 mL × 3). The combined organic layer was washed with brine (30 mL), dried over NaSO, and concentrated. The residue was purified by preparative TLC (DCM / MeOH=10 / 1) to give N-((7-chloronaphthalen-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (40 mg, yield: 24.8%) as a brown solid. ESI-MS [M +H]: 456.2. Purity: 96.2 (214 nm), 97.0 (254 nm). 1 H NMR (400 MHz, DMSO) δ 8.65 (t, J = 5.8 Hz, 1H), 8.33 (s, 1H), 8.28 - 8.20 (m, 2H), 8.00 (d, J = 8.8 Hz, 1H), 7.93 - 7.83 (m, 2H), 7.75 (s, 1H), 7.60 - 7.45 (m, 3H), 7.40 (d, J = 9.3 Hz, 1H), 7.02-6.95 (m, 1H), 5.41 (d, J = 4.8 Hz, 2H), 4.82 (d, J = 5.8 Hz, 2H), 1.95-1.85 (m, 1H), 0.97 - 0.86 (m, 2H), 0.72 - 0.60 (m, 2H).

[0199] Example 9 N-((5-chlorobenzo[d]isothiazol-3-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (I-127) Scheme 9 [ka] Synthesis of N-((5-chlorobenzo[d]isothiazol-3-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide. (6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide was synthesized according to general procedure A starting from 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylic acid and (5-chlorobenzo[d]isothiazol-3-yl)methanamine. The crude product was purified by preparative TLC (DCM / MeOH=10 / 1) to give the product (10 mg, yield: 18%) as a white solid. ESI-MS [M +H]: 463.1. 1 H NMR (400 MHz, DMSO) δ 8.82 (t, J = 5.9 Hz, 1H), 8.38 - 8.30 (m, 2H), 8.26-8.22 (m, 2H), 7.89 (s, 1H), 7.74 (s, 1H), 7.66-7.62 (m, 1H), 7.40 (d, J = 9.3 Hz, 1H), 7.01- 6.98 (m, 1H), 5.41 (s, 2H), 4.85 (d, J = 5.9 Hz, 2H), 1.95 - 1.87 (m, 1H), 0.96 - 0.87 (m, 2H), 0.69 - 0.62 (m, 2H).

[0200] Example 10 N-((6-chloro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (I-126) Scheme 10 [ka] Synthesis of N-((6-chloro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide. N-((6-chloro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide was synthesized according to General Procedure A starting from 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylic acid and (6-chloro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methanamine hydrobromide. The crude product was purified by preparative TLC (DCM / MeOH=10 / 1) to give the product (15 mg, yield: 16%) as a white solid. ESI-MS [M +H] + : 447.1. 1 H NMR (400 MHz, DMSO) δ 8.90 (t, J = 5.8 Hz, 1H), 8.86-8.84 (m, 1H), 8.34 (s, 1H), 8.24 (s, 1H), 7.88 (s, 1H), 7.84-7.81 (m, 1H), 7.74 (s, 1H), 7.44-7.39 (m, 2H), 7.03-6.98 (m, 1H), 5.41 (s, 2H), 4.91 (d, J = 5.8 Hz, 2H), 1.96 - 1.88 (m, 1H), 0.95 - 0.86 (m, 2H), 0.71 - 0.62 (m, 2H).

[0201] Example 11 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1 H-Pyrazole-4-carboxamide Scheme 11 [ka] Synthesis of 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide. To a mixture of 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylic acid (100 mg, 0.35 mmol), NH4Cl (187 mg, 3.5 mmol), HOBT (94.5 mg, 0.7 mmol), and EDCI (134.4 mg, 0.7 mmol) in DMF (5 mL) was added DIPEA (225.8 mg, 1.76 mmol). The reaction mixture was stirred at room temperature for 18 hours, then diluted with water (50 mL) and extracted with EtOAc (30 mL × 5). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by preparative HPLC to give 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (15 mg, yield: 15.2%) as a white solid. ESI-MS [M+H] + : 282.2. 1 H NMR (400 MHz, DMSO) δ 8.34 (s, 1H), 8.16 (S, 1H), 7.82 (s, 1H), 7.74 (s, 1H), 7.54 (s, 1H), 7.40 (d, J = 9.3 Hz, 1H), 7.03 - 6.95 (m, 2H), 5.39 (s, 2H), 1.96 - 1.89 (m, 1H), 0.94 - 0.91 (m, 2H), 0.73 - 0.66 (m, 2H).

[0202] Example 12 N-(5-chloro-2-(1H-tetrazol-1-yl)benzyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (I-125) Scheme 12 [ka] Synthesis of N-(5-chloro-2-(1H-tetrazol-1-yl)benzyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide. N-(5-chloro-2-(1H-tetrazol-1-yl)benzyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide was prepared according to general procedure A from 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylic acid and (5-chloro-2-(1H-tetrazol-1-yl)benzyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide. The crude product was purified by preparative TLC (DCM / MeOH=10 / 1) to give the product (10 mg, yield: 21%) as a yellow solid. ESI-MS [M +H]+: 474.2. 1 H NMR (400 MHz, DMSO) δ 9.87 (s, 1H), 8.59 (t, J = 5.7 Hz, 1H), 8.34 (s, 1H), 8.19 (s, 1H), 7.82 (s, 1H), 7.76 (s, 1H), 7.63 (d, J = 1.3 Hz, 2H), 7.58 (s, 1H), 7.40 (d, J = 9.4 Hz, 1H), 7.00 (d, J = 9.4 Hz, 1H), 5.41 (s, 2H), 4.22 (d, J = 5.7 Hz, 2H), 1.96-1.89 (m, 1H), 0.93-0.89 (m, 2H), 0.69-0.65 (m, 2H).

[0203] Example 13 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-((4,6-dimethyl-1H-indol-5-yl)methyl)-1H-pyrazole-4-carboxamide (I-124) Scheme 13 [ka] Synthesis of 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-((4,6-dimethyl-1H-indol-5-yl)methyl)-1H-pyrazole-4-carboxamide. 1-((6-Cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-((4,6-dimethyl-1H-indol-5-yl)methyl)-1H-pyrazole-4-carboxamide was synthesized according to General Procedure A starting from 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylic acid and (4,6-dimethyl-1H-indol-5-yl)methanamine. The crude product was purified by preparative HPLC to give the product (25 mg, yield: 25%) as a white solid. ESI-MS [M +H]+: 439.2. 1 H NMR (400 MHz, DMSO) δ 10.84 (s, 1H), 8.31 (s, 1H), 8.24 (s, 1H), 7.90-7.84 (m, 2H), 7.71 (s, 1H), 7.38 (d, J = 9.3 Hz, 1H), 7.24 - 7.16 (m, 1H), 7.05 (s, 1H), 7.00-6.95 (m, 1H), 6.40 (s, 1H), 5.36 (s, 2H), 4.49 (d, J = 4.4 Hz, 2H), 2.47 (s, 3H), 2.37 (s, 3H), 1.95-1.86 (m, 1H), 0.96 - 0.84 (m, 2H), 0.71 - 0.61 (m, 2H).

[0204] Example 14 N-((3-chloro-4,6-dimethyl-1H-indol-5-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (I-123) Scheme 14 [ka] Synthesis of N-((3-chloro-4,6-dimethyl-1H-indol-5-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide. N-((3-chloro-4,6-dimethyl-1H-indol-5-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide was synthesized according to General Procedure A starting from 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylic acid and (3-chloro-4,6-dimethyl-1H-indol-5-yl)methanamine. The crude product was purified by preparative HPLC to give the product (15 mg, yield: 8.6%) as a white solid. ESI-MS [M +H]+: 473.2. 1 H NMR (400 MHz, DMSO) δ 11.14 (s, 1H), 8.32 (s, 1H), 8.24 (s, 1H), 7.91-7.84 (m, 2H), 7.72 (s, 1H), 7.41-7.32 (m, 2H), 7.06 (s, 1H), 6.98 (d, J = 9.1 Hz, 1H), 5.37 (s, 2H), 4.47 (d, J = 4.0 Hz, 2H), 2.71 (s, 3H), 2.37 (s, 3H), 1.92-01.87 (m, 1H), 0.94-0.86 (m, 2H), 0.69-0.62 (m, 2H).

[0205] Example 15 N-((6-bromo-2-oxo-1,2-dihydroquinolin-4-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (I-122) Scheme 15 [ka] Synthesis of N-((6-bromo-2-oxo-1,2-dihydroquinolin-4-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide. N-((6-bromo-2-oxo-1,2-dihydroquinolin-4-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide was prepared according to general procedure A from 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylic acid and 4-(aminomethyl)-6- The synthesis was started from bromoquinolin-2(1H)-one. The crude product was purified by preparative TLC (MeOH / DCM=1 / 10) to give the product (17.6 mg, yield: 16%) as a white solid. ESI-MS [M +H]+: 517.1. 1 H NMR (400 MHz, DMSO) δ 11.82 (s, 1H), 8.66 (t, J = 5.7 Hz, 1H), 8.34 (s, 1H), 8.27 (s, 1H), 8.01 (d, J = 1.8 Hz, 1H), 7.91 (s, 1H), 7.76 (s, 1H), 7.69-7.65 (m, 1H), 7.41 (d, J = 9.3 Hz, 1H), 7.27 (d, J = 8.8 Hz, 1H), 7.02-6.97 (m, 1H), 6.36 (s, 1H), 5.42 (s, 2H), 4.59 (d, J = 5.6 Hz, 2H), 1.95 - 1.89 (m, 1H), 0.94 - 0.88 (m, 2H), 0.71 - 0.63 (m, 2H).

[0206] Example 16 N-(3-chlorobenzyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (I-121) Scheme 16 [ka] Synthesis of N-(3-chlorobenzyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide. N-(3-chlorobenzyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide was synthesized according to general procedure A starting from 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylic acid and (3-chlorophenyl)methanamine. The crude product was purified by preparative HPLC to give the product (55 mg, yield: 27%) as a white solid. ESI-MS [M +H]: 406.1. 1 H NMR (400 MHz, DMSO) δ 8.66 (t, J = 6.0 Hz, 1H), 8.34 (s, 1H), 8.23 ​​(s, 1H), 7.88 (s, 1H), 7.75 (s, 1H), 7.49 - 7.13 (m, 5H), 7.00 (dd, J = 9.4, 1.8 Hz, 1H), 5.41 (s, 2H), 4.39 (d, J = 6.0 Hz, 2H), 2.05 - 1.78 (m, 1H), 1.05 - 0.80 (m, 2H), 0.82 - 0.37 (m, 2H).

[0207] Example 17 N-((6-chloro-8-fluoroimidazo[1,5-a]pyridin-3-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (I-137) Scheme 17 [ka] Synthesis of N-((6-chloro-8-fluoroimidazo[1,5-a]pyridin-3-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide. N-((6-chloro-8-fluoroimidazo[1,5-a]pyridin-3-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide was synthesized according to General Procedure A starting from 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylic acid and (6-chloro-8-fluoroimidazo[1,5-a]pyridin-3-yl)methanamine hydrochloride. The crude product was purified by preparative TLC (DCM / MeOH=10 / 1) to give the product (20 mg, yield: 21%) as a white solid. ESI-MS [M +H]+: 464.1. 1 H NMR (400 MHz, DMSO) δ 8.81 (t, J = 5.7 Hz, 1H), 8.55 (s, 1H), 8.33 (s, 1H), 8.23 ​​(s, 1H), 7.87 (s, 1H), 7.73 (s, 1H), 7.57 (s, 1H), 7.39 (d, J = 9.3 Hz, 1H), 7.01-6.98 (m, 1H), 6.94-6.90 (m, 1H), 5.39 (s, 2H), 4.80 (d, J = 5.7 Hz, 2H), 1.95 - 1.87 (m, 1H), 0.95 - 0.86 (m, 2H), 0.71 - 0.62 (m, 2H).

[0208] Example 18 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-((2-oxo-1,2-dihydroquinolin-4-yl)methyl)-1H-pyrazole-4-carboxamide (I-120) Scheme 18 [ka] Synthesis of 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-((2-oxo-1,2-dihydroquinolin-4-yl)methyl)-1H-pyrazole-4-carboxamide. 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-((2-oxo-1,2-dihydroquinolin-4-yl)methyl)-1H-pyrazole-4-carboxamide was synthesized according to General Procedure A starting from 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylic acid and 4-(aminomethyl)quinolin-2(1H)-one. The crude product was purified by preparative HPLC to give the product (10 mg, yield: 10%) as a white solid. ESI-MS [M +H]+: 439.2. 1 H NMR (400 MHz, DMSO) δ 11.68 (s, 1H), 8.65 (t, J = 5.8 Hz, 1H), 8.35 (s, 1H), 8.28 (s, 1H), 7.92 (s, 1H), 7.82 (d, J = 7.9 Hz, 1H), 7.76 (s, 1H), 7.55 - 7.48 (m, 1H), 7.41 (d, J = 9.3 Hz, 1H), 7.33 (d, J = 7.6 Hz, 1H), 7.19 (t, J = 7.6 Hz, 1H), 7.03-6.98 (m, 1H), 6.33 (s, 1H), 5.43 (s, 2H), 4.63 (d, J = 5.6 Hz, 2H), 1.97-1.88(m, 1H), 0.95-0.88 (m, 2H), 0.74 - 0.63 (m, 2H).

[0209] Example 19 N-(6-cyano-2-fluoro-3-methoxybenzyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (I-119) Scheme 19 [ka] Synthesis of N-(6-cyano-2-fluoro-3-methoxybenzyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide. N-(6-cyano-2-fluoro-3-methoxybenzyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide was synthesized according to General Procedure A starting from 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylic acid and 2-(aminomethyl)-3-fluoro-4-methoxybenzonitrile. The crude product was purified by silica gel column chromatography (DCM / MeOH=10 / 1) to give the product (3.2 mg, yield: 0.5%) as a white solid. ESI-MS [M+H] + : 445.2. 1 H NMR (400 MHz, DMSO) δ 8.56 (s, 1H), 8.33 (s, 1H), 8.19 (s, 1H), 7.83 (s, 1H), 7.73 (s, 1H), 7.66 (d, J = 8.6 Hz, 1H), 7.40 (d, J = 9.3 Hz, 1H), 7.27 (t, J = 8.4 Hz, 1H), 6.99 (d, J = 9.2 Hz, 1H), 5.39 (s, 2H), 4.50 (d, J = 4.3 Hz, 2H), 3.91 (s, 3H), 1.93 - 1.83 (m, 1H), 0.91 (d, J = 7.1 Hz, 2H), 0.66 (d, J = 4.6 Hz, 2H).

[0210] Example 20 N-(5-chloro-2-(2H-tetrazol-5-yl)benzyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (I-117) Scheme 20 [ka] Synthesis of N-(5-chloro-2-(2H-tetrazol-5-yl)benzyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide. A mixture of 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylic acid (209 mg, 0.740 mmol), (5-chloro-2-(1H-tetrazol-5-yl)phenyl)methanamine (222 mg, 1.06 mmol), EDCI (203 mg, 1.06 mmol), HOBT (143 mg, 1.06 mmol), and EtN (226 mg, 2.23 mmol) in DMF (6 mL) was stirred at room temperature for 16 hours. The reaction mixture was concentrated and purified by preparative HPLC to give N-(5-chloro-2-(2H-tetrazol-5-yl)benzyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (38 mg, yield: 11%) as a white solid. ESI-MS [M + H] + : 474.2. 1 H NMR (400 MHz, DMSO) δ 8.74 (t, J = 5.8 Hz, 1H), 8.35 (s, 1H), 8.24 (s, 1H), 7.90 - 7.82 (m, 2H), 7.76 (s, 1H), 7.51 (dd, J = 8.3, 1.9 Hz, 1H), 7.47 - 7.37 (m, 2H), 7.01 (d, J = 9.4 Hz, 1H), 5.43 (s, 2H), 4.70 (d, J = 5.8 Hz, 2H), 1.96 - 1.89 (m, 1H), 0.92 (m, 2H), 0.72 - 0.63 (m, 2H).

[0211] Example 21 N-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)benzyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (I-116) Scheme 21 [ka] Synthesis of N-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)benzyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide. N-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)benzyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide was synthesized according to general procedure A starting from 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylic acid and (3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)methanamine. The crude product was purified by flash chromatography (DCM / MeOH=10 / 1) to give the product (14.5 mg, yield: 13.4%) as a white solid. ESI-MS [M +H]+: 491.9. 1 H NMR (400 MHz, HDMSO) δ 9.84 (s, 1H), 8.47-8.45 (t, J = 5.0 Hz, 1H), 8.33 (s, 1H), 8.10 (s, 1H), 7.86-7.82 (t, J = 8.2 Hz, 1H), 7.72 (s, 2H), 7.50 (dd, J = 8.7, 1.1 Hz, 1H), 7.39 (d, J = 9.3 Hz, 1H), 6.99 (dd, J = 9.4, 1.7 Hz, 1H), 5.37 (s, 2H), 4.26 (d, J = 4.8 Hz, 2H), 1.94-1.88 (m, J = 13.5, 8.4, 5.1 Hz, 2H), 0.94 - 0.89 (m, 2H), 0.68 - 0.64 (m, 2H).

[0212] Example 22 N-(3-chloro-2-fluoro-6-(2-oxa-6-azaspiro[3.3]heptan-6-yl)benzyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (I-114) Scheme 22 [ka] Synthesis of N-(6-bromo-3-chloro-2-fluorobenzyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide. To a solution of (6-bromo-3-chloro-2-fluorophenyl)methanamine hydrochloride (600 mg, 2.2 mmol) in DMF (5 mL) was added 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylic acid (568 mg, 2.0 mmol), HOBT (335 mg, 2.50 mmol), EDCI (483 mg, 2.52 mmol), and DIPEA (1.1 g, 8.4 mmol). The reaction mixture was stirred at room temperature for 3 hours. Water (30 mL) was added, and the mixture was extracted with EtOAc (30 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 flash chromatography to give N-(6-bromo-3-chloro-2-fluorobenzyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (362 mg, yield: 43%) as a white solid. ESI-MS [M+H]+: 502.2.

[0213] Synthesis of N-(3-chloro-2-fluoro-6-(2-oxa-6-azaspiro[3.3]heptan-6-yl)benzyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide. To a mixture of N-(6-bromo-3-chloro-2-fluorobenzyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide (50 mg, 0.099 mmol) in 1,4-dioxane (15 mL) was added 2-oxa-6-azaspiro[3.3]heptane (15 mg, 0.149 mmol), Pd(dba) (20 mg, 0.022 mmol), Xantphos (20 mg, 0.035 mmol), and CsCO (0.5 mmol, 163 mmol). The reaction mixture was stirred at 100 °C under N for 3 h. The mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC to give N-(3-chloro-2-fluoro-6-(2-oxa-6-azaspiro[3.3]heptan-6-yl)benzyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide (22.9 mg, yield: 44%) as a yellow solid. ESI-MS [M +H]: 520.9. Purity: 98.0 (214 nm), 98.1 (254 nm). 1 H NMR (400 MHz, DMSO) δ 8.33 (s, 1H), 8.26 (s, 1H), 8.12 (t, J = 4.1 Hz, 1H), 7.88 (s, 1H), 7.75 (s, 1H), 7.40 (d, J = 9.3 Hz, 1H), 7.31 (t, J = 8.7 Hz, 1H), 6.99 (dd, J = 9.4, 1. 8 Hz, 1H), 6.33 - 6.27 (m, 1H), 5.39 (s, 2H), 4.66 (s, 4H), 4.30 (d, J = 1.8 Hz, 2H), 4.12 (s, 4H), 1.96 - 1.86 (m, 1H), 0.93-0.85 (m, 2H), 0.71 - 0.62 (m, 2H).

[0214] Example 23 N-(4-Carbamimidoyl-2,6-dimethylbenzyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (I-103) Scheme 23 [ka] Synthesis of N-(4-cyano-2,6-dimethylbenzyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide. To a solution of 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylic acid (150.0 mg crude), 4-(aminomethyl)-3,5-dimethylbenzonitrile (82 mg, 0.51 mmol), 1-hydroxybenzotriazole (71 mg, 0.44 mmol), and EDCI (101 mg, 0.53 mmol) in DMF (10 mL) was added triethylamine (214 mg, 2.12 mmol). After stirring at room temperature for 2 hours, the reaction was quenched with saturated aqueous ammonium chloride (20 mL) and extracted with ethyl acetate (20 × 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (DCM / MeOH=20 / 1) to give N-(4-cyano-2,6-dimethylbenzyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (50 mg, 22%). ESI-MS [M + H]: 425.1.

[0215] Synthesis of N-(4-carbamimidoyl-2,6-dimethylbenzyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide. HCl (gas) was bubbled through a solution of N-(4-cyano-2,6-dimethylbenzyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (50 mg, 0.11 mmol) in anhydrous MeOH (8 mL) at 0° C. for 1 hour. The reaction mixture was then stirred at room temperature for 3 hours. The reaction was concentrated under reduced pressure, redissolved in MeOH (6 mL), and NH4HCO3 (220 mg, 2.78 mmol) was slowly added. The resulting mixture was stirred at room temperature for 16 hours and then concentrated under reduced pressure to give a crude product which was purified by reverse phase flash chromatography (Biotage SNAP C18, 12 g) with 0.1% formic acid Purification by elution with an acetonitrile gradient in water (0–25% over 10 column volumes) gave N-(4-carbamimidoyl-2,6-dimethylbenzyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (20 mg, 41%). ESI-MS [M + H]: 442.1. 1 H NMR (400 MHz, DMSO, ppm) δ 11.49 (bs, 1H), 8.89 (bs, 0.7H), 8.44 (s, 1.62H), 8.33 (s, 1H), 8.22 (s, 1H), 8.18 (t, J = 4.8 Hz, 1H), 7.83 (d, J = 15.3 Hz, 1H), 7.74 (s, 1H), 7.49 (s, 2H), 7.38 (d, J = 9.3 Hz, 1H), 6.99 (dd, J = 9.4, 1.7 Hz, 1H), 5.40 (d, J = 14.0 Hz, 2H), 4.45 (d, J = 4.8 Hz, 2H), 2.41 (s, 6H), 1.99 -1.84 (m, 1H), 0.97 -0.87 (m, 2H), 0.71 -0.62 (m, 2H).

[0216] Example 24 N-(6-cyano-2-fluoro-3-methoxybenzyl)-1-((8-cyano-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (I-118) Scheme 24 [ka] Synthesis of 2-amino-5-cyclopropylnicotinonitrile. To a mixture of 2-amino-5-bromonicotinonitrile (1 g, 5.1 mmol), cyclopropylboronic acid (647 mg, 7.6 mmol), and KPO (3.78 g, 17.85 mmol) in toluene / HO (20 mL / 2 mL) was added Pd(OAc) (114 mg, 0.51 mmol) and S-Phos (209 mg, 0.51 mmol). The mixture was stirred at 95 °C for 16 h. The reaction was cooled to room temperature, and the mixture was filtered. The filtrate was concentrated to give the crude product, which was purified by silica gel chromatography (EtOAc / PE = 4 / 1) to give 2-amino-5-cyclopropylnicotinonitrile (570 mg, 71% yield) as a yellow solid. ESI-MS [M+H] + : 160.1.

[0217] Synthesis of 2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-carbonitrile. To a solution of 2-amino-5-cyclopropylnicotinonitrile (570 mg, 3.58 mmol) in EtOH (20 mL) was added 1,3-dichloropropan-2-one (1.37 g, 10.75 mmol). The reaction mixture was stirred at 85 °C for 16 h. The reaction was concentrated, and the residue was diluted with NaHCO (aq, 20 mL) and extracted with EtOAc (50 mL × 3). The combined organic layers were concentrated to give the crude product, which was purified by silica gel chromatography (EtOAc / PE = 2 / 1) to give 2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-carbonitrile (500 mg, yield: 58%) as a yellow solid. ESI-MS [M+H] +: 232.1.

[0218] Synthesis of ethyl 1-((8-cyano-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-8-carbonitrile (500 mg, 2.15 mmol) in DMF (10 mL) was added ethyl 1H-pyrazole-4-carboxylate (331 mg, 2.36 mmol) and CsCO (1.4 g, 4.3 mmol). The reaction mixture was stirred at room temperature for 12 hours. 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 a crude product, which was purified by silica gel chromatography (DCM / MeOH=20 / 1) to give ethyl 1-((8-cyano-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate (433 g, yield: 60%) as a white solid. ESI-MS [M+H]+: 336.2.

[0219] Synthesis of 1-((8-cyano-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylic acid. To a solution of 1-((8-cyano-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylic acid (400 mg, 1.19 mmol) in THF (15 mL) and HO (5 mL) was added LiOH (464 mg, 146 mmol). The mixture was stirred at room temperature for 16 h. Most of the THF was removed under reduced pressure, and the mixture was adjusted to pH 4-5 by adding HCl (1 M). The resulting precipitate was collected and dried to give 1-((8-cyano-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylic acid as a white solid (300 g, 82%). ESI-MS [M+H] + : 308.2.

[0220] Synthesis of N-(6-cyano-2-fluoro-3-methoxybenzyl)-1-((8-cyano-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide. A solution of 1-((8-cyano-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylic acid (100 mg, 0.326 mmol) in SOCl (0.5 mL) was stirred at room temperature for 1 hour. After concentration under reduced pressure, a solution of 2-(aminomethyl)-3-fluoro-4-methoxybenzonitrile (70 mg, 0.39 mmol) in THF (2 mL) was added, followed by LiHMDS (1 M in THF, 1.3 mL). The reaction mixture was stirred at room temperature for 2 hours. The reaction was quenched with saturated aqueous ammonium chloride (10 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated to give a residue, which was purified by preparative TLC (MeOH / DCM = 1 / 10) to give N-(6-cyano-2-fluoro-3-methoxybenzyl)-1-((8-cyano-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (8 mg, yield: 5%) as a white solid. ESI-MS [M +H]+: 470.1. 1 H NMR (400 MHz, DMSO) δ 8.68 (d, J = 1.4 Hz, 1H), 8.59 (t, J = 5.0 Hz, 1H), 8.24 (s, 1H), 7.87 (s, 2H), 7.78 (d, J = 1.6 Hz, 1H), 7.67 (dd, J = 8.6, 1.3 Hz, 1H), 7.28 (t, J = 8.4 Hz, 1H), 5.48 (s, 2H), 4.51 (d, J = 4.7 Hz, 2H), 3.92 (s, 3H), 1.97 (ddd, J = 13.5, 8.5, 5.1 Hz, 1H), 0.99 - 0.90 (m, 2H), 0.79 - 0.71 (m, 2H).

[0221] Example 25 General procedure for amide synthesis B-1: Scheme 25 [ka] 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.

[0222] 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.

[0223] 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. Washing, drying over NaSO, and concentration under reduced pressure gave 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.

[0224] 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.

[0225] Synthesis of 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid. A mixture of ethyl 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate (29 g, 93.2 mmol) and LiOH (6.7 g, 279.6 mmol, in 50 mL of HO) in THF / EtOH (150 mL / 150 mL) was stirred at 50° C. for 2 hours. The reaction was concentrated to remove most of the solvent. The pH of the residue was adjusted to 4 with 2 N HCl, resulting in the precipitation of a pale pink solid. The mixture was filtered and the filter cake was dried to give 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid (20 g, 77%) as a pale pink solid. ESI-MS [M+H] + : 284.1.

[0226] General synthesis of amide compounds (Procedure B-1). To a solution of 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid (60 mg, 0.21 mmol), amine (0.32 mmol), and HATU (120 mg, 0.31 mmol) in DMF (8 mL) was added DIPEA (81 mg, 0.63 mmol). The reaction mixture was stirred at room temperature for 12 hours. Water (25 mL) was added, and the mixture was extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the crude product, which was purified by preparative TLC, preparative HPLC, or silica gel chromatography to give the desired product.

[0227] The following compounds were synthesized according to general procedure B-1 starting from 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid and the required amine: N-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)benzyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide (I-106), 1-((6-cyclopropylimidazo[1,2- a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(1H-tetrazol-1-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide (I-105), 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxybenzyl)-1H-1,2,3-triazole-4-carboxamide (I-100), N-(6-chloro-8,9-dihydro-7H-imidazo[4,5,1-ij]quinolin-9-yl)-1-((6-cyclo 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-6-(1H-tetrazol-1-yl)-3-(trifluoromethoxy)benzyl)-1H-1,2,3-triazole-4-carboxamide (I-98), 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methyl I-96), 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(1H-pyrazol-1-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide (I-95), N-(3-bromo-2-fluoro-6-(1H-tetrazol-1-yl)benzyl)-1-((6-cyclopropylimidazo[ 1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide (IX), 2'-((1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide)methyl)-3'-fluoro-4'-methoxy-[1,1'-biphenyl]-4-carboxylate (I-87), 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(pyridazin-2-yl)methyl)- 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-ethyl-2-fluoro-6-(1H-tetrazol-1-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide (I-86), 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-ethyl-2-fluoro-6-(1H-tetrazol-1-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide (I-83), N-(3-chloro-6-(difluoromethyl)-2-fluorobenzyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-Triazole-4-carboxamide (I-79), N-(3-cyclopropyl-2-fluoro-6-(1H-tetrazol-1-yl)benzyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide (I-78), 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(imidazo[1,2-a]pyridin-6-ylmethyl)-1H-1,2,3-triazole-4-carboxamide (I-136), 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)- 1-(2-((1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(1H-1,2,3-triazol-1-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide (I-76), 5-(2-((1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide)methyl)-3-fluoro-4-methoxyphenyl)pyrimidine-2-carboxylate (I-75), 1-((6-cyclopropylimidazo[1, 2-a]pyridin-2-yl)methyl)-N-(6-(3,4-dimethyl-1H-pyrazol-1-yl)-2-fluoro-3-methoxybenzyl)-1H-1,2,3-triazole-4-carboxamide (I-73), 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-6-(imidazo[1,2-a]pyridin-2-yl)-3-methoxybenzyl)-1H-1,2,3-triazole-4-carboxamide (I-70), 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-6-(imidazo[1,2-a]pyridin-2-yl)-3-methoxybenzyl)-1H-1,2,3-triazole-4-carboxamide (I-71), 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(1H-tetrazol-1-yl)benzyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide (I-67), 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(1H-tetrazol-1-yl)benzyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide (I-66), N-((3-chloro-1H-indol-5-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide (I-65), 1-((6-cyclopropylimide, 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(pyrazolo[1,5-a]pyridin-2-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide (I-63), 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide (I-52), 1-((6-cyclopropyl 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(1-(2-fluoro-3-methoxy-6-(1H-tetrazol-1-yl)phenyl)ethyl)-1H-1,2,3-triazole-4-carboxamide (I-49), 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(1-(2-fluoro-3-methoxy-6-(1H-tetrazol-1-yl)phenyl)ethyl)-1H-1,2,3-triazole-4-carboxamide (I-31), N-((6-amino-2,4-dimethylpyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(1H-tetrazol-1-yl)phenyl)ethyl)-1H-1,2,3-triazole-4-carboxamide (I-32), N-((5-amino-1,3,4-thiadiazol-2-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide (I-26), N-((5-amino-1,3,4-thiadiazol-2-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide (I-20), N-((5-amino-1,3,4-oxadiazol-2-yl)methyl)-1-((6-cyclopropylimidazo[1,2- N-((2-aminothiazol-5-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide (I-19), N-((2-aminothiazol-5-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide (I-18), and N-(6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluoro-3-methoxybenzyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide (I-19).3-Triazole-4-carboxamide (I-1).

[0228] Example 26 General procedure for amide synthesis B-2: Scheme 26 [ka] General synthesis of amide compounds (Procedure B-2). To a solution of 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid (150 mg, 0.53 mmol), amine (1.01 mmol), HOBT (130 mg, 0.96 mmol), and EDCI (184 mg, 0.96 mmol) in DMF (10 mL) was added DIPEA (413 mg, 3.2 mmol). The reaction mixture was stirred at room temperature for 12 hours. Water (20 mL) was added, and the mixture was extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the crude product, which was purified by preparative TLC, preparative HPLC, or silica gel chromatography to give the desired product.

[0229] The following compounds were synthesized according to general procedure B-2 starting from 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid and the required amine: 4-((4-carbamimidoyl -2,6-dimethylbenzyl)amino)-6-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methoxy)pyrimidine-2-carboxylic acid (I-115), N-(6-bromo-2-fluoro-3-methoxybenzyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide (I-102), 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6 -(pyridin-4-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide (I-101), N-(benzo[b]thiophen-5-ylmethyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide (I-84), 7-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)-N-(2-fluoro-3-methoxy-6-(1H-tetrazol-1-yl)benzyl)-6,7-dihydro-5H-pyrrolo[ 1,2-b][1,2,4]triazole-2-carboxamide (I-82), N-(3-chloro-2-methyl-6-(1H-tetrazol-1-yl)benzyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide (I-80), N-((6-chlorobenzo[b]thiophen-2-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide boxamide (I-77), N-((5-cyano-3-fluoro-2-methoxypyridin-4-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide (I-72), 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2,6-difluoro-3-methoxybenzyl)-1H-1,2,3-triazole-4-carboxamide (I-64), 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide (I-62), N-benzyl-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide (I-60), 1-((6-cyclopropylimidazo[1, 2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(methylsulfinyl)benzyl)-1H-1,2,3-triazole-4-carboxamide (I-58), 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(6-(N,N-dimethylsulfamoyl)-2-fluoro-3-methoxybenzyl)-1H-1,2,3-triazole-4-carboxamide (I-57), 1-(( 6-Cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-(methylsulfonyl)benzyl)-1H-1,2,3-triazole-4-carboxamide (I-51), 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(morpholinosulfonyl)benzyl)-1H-1,2,3-triazole-4-carboxamide (I-48), N-(1-amino -6,7-Dihydro-5H-cyclopenta[c]pyridin-5-yl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide (I-23), N-((5-amino-4H-1,2,4-triazol-3-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide (I-21), N-(1-amino-3-methyl-6,7-dihydro-5H-cyclopenta[c]pyridin-5-yl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide (I-16), N-((4-chlorothieno[3,2-c]pyridin-2-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide (I-11), 1-((6-cyclohexyl)methyl)-1H-1,2,3-triazole-4-carboxamide (I-12), N-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)benzyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-((3-fluoro-4-methoxypyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide (I-7), and N-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)benzyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide (I-3).

[0230] Example 27 4-((4-Carbamimidoyl-2,6-dimethylbenzyl)amino)-6-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methoxy)pyrimidine-2-carboxylic acid (I-115) Scheme 27 [ka] Synthesis of N-(4-cyano-2,6-dimethylbenzyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide. N-(4-cyano-2,6-dimethylbenzyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide was synthesized according to general procedure B-2 starting from 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid and 4-(aminomethyl)-3,5-dimethylbenzonitrile hydrochloride. The crude product was purified by preparative TLC (DCM / MeOH=15 / 1) to give the product (100 mg, yield: 44.3%) as a yellow solid. ESI-MS [M+H] + : 426.1.

[0231] Synthesis of N-(4-carbamimidoyl-2,6-dimethylbenzyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide. HCl (g) was bubbled through a solution of N-(4-cyano-2,6-dimethylbenzyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide (100 mg, 0.24 mmol) in MeOH (10 mL) for 4 hours. The reaction mixture was concentrated under reduced pressure, and MeOH (15 mL) and NH4HCO3 (182 mg, 2.3 mmol) were added. The resulting mixture was stirred at room temperature for 13 hours. The reaction was concentrated under reduced pressure to give the crude material, which was purified by preparative HPLC to give N-(4-carbamimidoyl-2,6-dimethylbenzyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide as a white solid. ESI-MS [M + H] + : 443.0 1 H NMR (400 MHz, DMSO) δ 11.07 (s, 1H), 8.88 (s, 1H), 8.71 (t, J = 5.3 Hz, 1H), 8.55 (s, 1H), 8.43 (s, 1H), 8.35 (s, 1H), 7.84 (s, 1 H), 7.46 (s, 2H), 7.40 (d, J = 9.3 Hz, 1H), 7.01 (dd, J = 9.4, 1.7 Hz, 1H), 5.72 (s, 2H), 4.51 (d, J = 5.3 Hz, 2H), 2.44 (s, 6H), 1.98 - 1.89 (m, 1H), 0.94 - 0.90 (m, 2H), 0.69 - 0.65 (m, 2H).

[0232] Example 28 N-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)benzyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide (I-106) Scheme 28 [ka] Synthesis of N-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)benzyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide. N-(4-cyano-2,6-dimethylbenzyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide was synthesized according to general procedure B-1 starting from 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid and (3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)methanamine. The crude product was purified by flash chromatography (DCM / MeOH=10 / 1) to give the product (40 mg, yield: 45%) as a white solid. ESI-MS [M +H]+: 493.1. Purity: 99.32 (214 nm), 100.00 (254 nm). 1 H NMR (400 MHz, DMSO) δ 9.85 (s, 1H), 8.90 (t, J = 5.4 Hz, 1H), 8.49 (s, 1H), 8.34 (s, 1H), 7.86-7.82 (m, 2H), 7.50 (dd, J = 8.7 Hz, 1.3 Hz, 1H), 7.40 (d, J = 9.3 Hz, 1H), 7.00 (dd, J = 9.4 Hz, 1.7 Hz, 1H), 5.70 (s, 2H), 4.37 (d, J = 5.1 Hz, 2H), 1.94 - 1.90 (m, 1H), 0.93 - 0.90 (m, 2H), 0.69 - 0.65 (m, 2H).

[0233] Example 29 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(1H-tetrazol-1-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide (I-105) Scheme 29 [ka] Synthesis of 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(1H-tetrazol-1-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide. 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(1H-tetrazol-1-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide was synthesized according to general procedure B-1 starting from 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid and (2-fluoro-3-methoxy-6-(1H-tetrazol-1-yl)phenyl)methanamine. The crude product was purified by preparative TLC (DCM / MeOH=13 / 1) to give the product (14.3 mg, yield: 21%) as a white solid. ESI-MS [M +H]+: 489.2. 1 H NMR (400 MHz, DMSO) δ 9.74 (s, 1H), 8.76 (t, J = 5.4 Hz, 1H), 8.49 (s, 1H), 8.36 (s, 1H), 7.84 (s, 1H), 7.44-7.32 (m, 3H), 7.06-7.03 (m, 1H), 5.72 (s, 2H), 4.29 (d, J = 5.2 Hz, 2H), 3.92 (s, 3H), 1.93-1.90 (m, 1H), 0.93-0.90 (m, 2H), 0.70-0.67 (m, 2H).

[0234] Example 30 N-(6-bromo-2-fluoro-3-methoxybenzyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide (I-102) Scheme 30 [ka] Synthesis of N-(6-bromo-2-fluoro-3-methoxybenzyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide. 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(1H-tetrazol-1-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide was prepared according to general procedure B-2. The synthesis was started from (6-bromo-2-fluoro-3-methoxyphenyl)methanamine and (6-bromo-2-fluoro-3-methoxyphenyl)methanamine. The crude product was purified by preparative TLC (DCM / MeOH = 20 / 1) to give the product (390 mg, yield: 84%) as a white solid. ESI-MS [M + H] + : 499.1. 1 H NMR (400 MHz, DMSO) δ 8.68 - 8.61 (m, 1H), 8.55 (s, 1H), 8.35 (s, 1H), 7.83 (s, 1H), 7.42 - 7.39 (m, 2H), 7.09 (t, J = 8.7 Hz, 1H), 7.01 (d, J = 9.3 Hz, 1H), 5.72 (s, 2H), 4.55 (d, J = 2.8 Hz, 2H), 3.83 (s, 3H), 1.95 - 1.89 (m, 1H), 0.93 - 0.91 (m, 2H), 0.68 - 0.67 (m, 2H).

[0235] Example 31 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-6-(1H-imidazol-1-yl)-3-methoxybenzyl)-1H-1,2,3-triazole-4-carboxamide (I-104) Scheme 31 [ka] Synthesis of 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-6-(1H-imidazol-1-yl)-3-methoxybenzyl)-1H-1,2,3-triazole-4-carboxamide. A mixture of N-(6-bromo-2-fluoro-3-methoxybenzyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide (75 mg, 0.15 mmol), 1H-imidazole (81 mg, 1.19 mmol), KCO (245 mg, 1.78 mmol), and CuI (33 mg, 0.17 mmol) in DMF (2 mL) was stirred at 150 °C in a microwave for 1 h. The reaction mixture was diluted with HO (20 mL) and extracted with EtOAc (30 mL × 3). The organic layer was concentrated to give the crude product, which was purified by preparative TLC (DCM:MeOH = 20:1) to give 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-6-(1H-imidazol-1-yl)-3-methoxybenzyl)-1H-1,2,3-triazole-4-carboxamide (26.1 mg, yield: 36%) as a white solid. ESI-MS [M + H] + : 487.1. Purity: 99.51% (214 nm), 100.00% (254 nm). 1 H NMR (400 MHz, DMSO) δ 8.72 (t, J = 4.9 Hz, 1H), 8.52 (s, 1H), 8.35 (s, 1H), 7.82 (d, J = 5.0 Hz, 2H), 7.42 - 7.39 (m, 2H), 7.24 (t, J = 8.8 Hz, 1H), 7.16 (d, J = 9.0 Hz, 1H), 7.04 - 7.00 (m, 2H), 5.72 (s, 2H), 4.23 (d, J = 4.7 Hz, 2H), 3.88 (s, 3H), 1.96 - 1.89 (m, 1H), 0.92 - 0.89 (m, 2H), 0.69 - 0.65 (m, 2H).

[0236] Example 32 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide (I-97) Scheme 32 [ka] Synthesis of methyl 2-((1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide)methyl)-3-fluoro-4-methoxybenzoate. A solution of N-(6-bromo-2-fluoro-3-methoxybenzyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide (100 mg, 0.20 mmol), Pd(dppf)Cl (33 mg, 0.045 mmol), and EtN (76 mg, 0.75 mmol) in MeOH (10 mL) was stirred at 90 °C under CO for 72 h. The solution was filtered, and the filtrate was extracted with EtOAc (50 mL × 2). The combined organic layers were concentrated and purified by preparative TLC (DCM / MeOH=15:1) to give methyl 2-((1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamido)methyl)-3-fluoro-4-methoxybenzoate (35 mg, yield: 36.6%) as a white solid. ESI-MS [M+H] + : 479.1.

[0237] Synthesis of 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-6-(hydrazinecarbonyl)-3-methoxybenzyl)-1H-1,2,3-triazole-4-carboxamide. A solution of methyl 2-((1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide)methyl)-3-fluoro-4-methoxybenzoate (35 mg, 0.073 mmol) and hydrazine hydrate (purity: 80%) (0.25 mL) in EtOH (1 mL) was stirred at 90° C. for 16 hours. The mixture was concentrated under reduced pressure and purified by preparative TLC (DCM / MeOH=12:1) to give 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-6-(hydrazinecarbonyl)-3-methoxybenzyl)-1H-1,2,3-triazole-4-carboxamide (15 mg, yield: 43%) as a white solid. ESI-MS [M+H] + : 479.2.

[0238] Synthesis of 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide. 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-6-(hydrazinecarbonyl)-3-methoxybenzyl)-1H-1,2,3-triazole-4-carboxamide (15 mg, 0.03 mmol), triethoxymethyl A solution of methylpropane (0.25 mL) and NH4Cl (10 mg, 0.15 mmol) in EtOH (1 mL) was stirred at 80° C. for 16 h. The reaction mixture was concentrated under reduced pressure and purified by preparative TLC (DCM / MeOH=10:1) to give 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide as a white solid (2.9 mg, yield: 20%). ESI-MS [M +H]+: 489.2. 1 H NMR (400 MHz, DMSO) δ 9.37 (s, 1H), 8.75 (t, J = 5.7 Hz, 1H), 53 (s, 1H), 8.33 (s, 1H), 7.79 (s, 1H), 7.74 (d, J = 8.8 Hz, 1H), 7.38 - 7.31 (m, 2H), 7.00 (d, J = 9.2 Hz, 1H), 5.70 (s, 2H), 4.88 (d, J = 5.1 Hz, 2H), 3.92 (s, 3H), 1.94 - 1.88 (m, 1H), 0.94 - 0.90 (m, 2H), 0.68 - 0.66 (m, 2H).

[0239] Example 33 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(pyridin-4-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide (I-101) Scheme 33 [ka] Synthesis of 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(pyridin-4-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide. 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(pyridin-4-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide was synthesized according to general procedure B-2 starting from 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid and (2-fluoro-3-methoxy-6-(pyridin-4-yl)phenyl)methanamine. The crude product was purified by preparative TLC (DCM / MeOH=10 / 1) to give the product (7 mg, yield: 18%) as a white solid. ESI-MS [M + H]+: 498.2. 1 H NMR (400 MHz, DMSO) δ 8.65 (t, J = 4.9 Hz, 1H), 8.58 - 8.57 (m, 2H), 8.51 (s, 1H), 8.35 (s, 1H), 7.83 (s, 1H), 7.43 - 7.40 (m, 3H), 7.23 (t, J = 8.6 Hz, 1H), 7.08 (d, J = 8.6 Hz, 1H), 7.01 (dd, J = 9.4, 1.7 Hz, 1H), 5.71 (s, 2H), 4.40 (d, J = 4.5 Hz, 2H), 3.87 (s, 3H), 1.96 - 1.89 (m, 1H), 0.93 - 0.90 (m, 2H), 0.65 - 0.69 (m, 2H).

[0240] Example 34 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxybenzyl)-1H-1,2,3-triazole-4-carboxamide (I-100) Scheme 34 [ka] Synthesis of 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxybenzyl)-1H-1,2,3-triazole-4-carboxamide. 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxybenzyl)-1H-1,2,3-triazole-4-carboxamide was synthesized according to General Procedure B-1 starting from 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid and (2-fluoro-3-methoxyphenyl)methanamine. The crude product was purified by preparative HPLC to give the product (2 mg, yield: 7%) as a white solid. ESI-MS [M + H] + : 421.2. 1 H NMR (400 MHz, DMSO) δ 8.98 (t, J = 6.1 Hz, 1H), 8.52 (s, 1H), 8.32 - 8.30 (m, 1H), 7.79 (s, 1H), 7.35 (d, J = 9.3 Hz, 1H), 7.00 - 6.94 (m, 3H), 6.82 - 6.79 (m, 1H), 5.68 (s, 2H), 4.41 (d, J = 6.1 Hz, 2H), 3.76 (s, 3H), 1.89 - 1.84 (m, 1H), 0.89 - 0.84 (m, 2H), 0.64 - 0.60 (m, 2H).

[0241] Example 35 N-(6-chloro-8,9-dihydro-7H-imidazo[4,5,1-ij]quinolin-9-yl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide (I-135) Scheme 35 [ka] Synthesis of N-(6-chloro-8,9-dihydro-7H-imidazo[4,5,1-ij]quinolin-9-yl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide. N-(6-chloro-8,9-dihydro-7H-imidazo[4,5,1-ij]quinolin-9-yl) -1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide was synthesized according to general procedure B-1 starting from 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid and 6-chloro-8,9-dihydro-7H-imidazo[4,5,1-ij]quinolin-9-amine hydrochloride. The crude product was purified by preparative HPLC to give the product (18.3 mg, yield: 19.4%) as a white solid. ESI-MS [M + H] + : 473.1. 1 H NMR (400 MHz, DMSO) δ 8.59 (s, 1H), 8.56 (d, J = 8.4 Hz, 1H), 8.35 (s, 1H), 8.27 (s, 1H), 8.17 (d, J = 7.4 Hz, 1H), 7.83 (s, 1H), 7.41 (d, J = 9.3 Hz, 1H), 7.01 (dd, J = 9.3, 1.6 Hz, 1H), 6.65 (d, J = 7.4 Hz, 1H), 5.73 (s, 2H), 5.50 - 5.35 (m, 1H), 2.93 - 2.89 (m, 2H), 2.18 - 2.08 (m, 2H), 1.96 - 1.89 (m, 1H), 1.00 - 0.85 (m, 2H), 0.76 - 0.61 (m, 2H).

[0242] Example 36 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-6-(1H-tetrazol-1-yl)-3-(trifluoromethoxy)benzyl)-1H-1,2,3-triazole-4-carboxamide (I-98) Scheme 36 [ka] Synthesis of 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-6-(1H-tetrazol-1-yl)-3-(trifluoromethoxy)benzyl)-1H-1,2,3-triazole-4-carboxamide. 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-6-(1H-tetrazol-1-yl)-3-(trifluoromethoxy)benzyl)-1H-1,2,3-triazole-4-carboxamide was synthesized according to general procedure B-1 starting from 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid and (2-fluoro-6-(1H-tetrazol-1-yl)-3-(trifluoromethoxy)phenyl)methanamine. The crude product was purified by preparative TLC (DCM / MeOH=10:1) to give the product (70 mg, yield: 33%) as a white solid. ESI-MS [M + H] + : 543.20. 1 H NMR (400 MHz, DMSO-d6) δ 9.86 (s, 1H), 8.91 (t, J = 5.3 Hz, 1H), 8.49 (s, 1H), 8.34 (s, 1H), 7.88 - 7.80 (m, 2H), 7.60 (m, 1H), 7.40 (d, J = 9.3 Hz, 1H), 7.01 (m, 1H), 5.71 (s, 2H), 4.40 (d, J = 5.2 Hz, 2H), 1.97 - 1.87 (m, 1H), 0.96 - 0.87 (m, 2H), 0.70 - 0.6 3 (m, 2H).

[0243] Example 37 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(4H-1,2,4-triazol-4-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide (I-96) Scheme 37 [ka] Synthesis of 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(4H-1,2,4-triazol-4-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide. 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(4H-1,2,4-triazol-4-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide was synthesized according to general procedure B-1 starting from 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid and (2-fluoro-3-methoxy-6-(4H-1,2,4-triazol-4-yl)phenyl)methanamine. The crude product was purified by preparative TLC (DCM / MeOH=10:1) to give the product (46 mg, yield: 28.6%) as a yellow solid. ESI-MS [M +H]: 488.1. 1 H NMR (400 MHz, DMSO) δ 8.83 (t, J = 5.2 Hz, 1H), 8.74 (s, 1H), 8.52 (s, 1H), 8.35 (d, J = 0.7 Hz, 1H), 7.82 (s, 1H), 7.41 (d, J = 9.3 Hz, 1H), 7.26 (dt, J = 18.9, 9.3 Hz, 2H), 7.01 (dd, J = 9.4, 1.8 Hz, 1H), 5.72 (s, 2H), 4.21 (d, J = 5.0 Hz, 2H), 3.89 (s, 3H), 1.99 - 1.83 (m, 1H), 0.98 - 0.83 (m, 2H), 0.75 - 0.55 (m, 2H).

[0244] Example 38 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(1H-pyrazol-1-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide (I-95) Scheme 38 [ka] Synthesis of 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(1H-pyrazol-1-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide. 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(1H-pyrazol-1-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide was synthesized according to general procedure B-1 starting from 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid and (2-fluoro-3-methoxy-6-(1H-pyrazol-1-yl)phenyl)methanamine. The crude product was purified by preparative TLC (DCM / MeOH=10:1) to give the product (33 mg, yield: 39.8%) as a white solid. ESI-MS [M+H] + : 487.2. 1 H NMR (400 MHz, DMSO) δ 8.55 (s, 1H), 8.47 (t, J = 5.6 Hz, 1H), 8.34 (s, 1H), 8.09 (d, J = 2.2 Hz, 1H), 7.81 (s, 1H), 7.77 (d, J = 1.6 Hz, 1H), 7.41 (d, J = 9.2 Hz, 1H), 7.28 - 7.22 (m, 2H), 7.02 - 6.99 (m, 1H), 6.51 (t, J = 2.1 Hz, 1H), 5.71 (s, 2H), 4.38 (d, J = 4.7 Hz, 2H), 3.88 (s, 3H), 1.96 - 1.89 (m, 1H), 0.93 - 0.89 (m, 2H), 0.69 - 0.65 (m, 2H).

[0245] Example 39 N-(3-bromo-2-fluoro-6-(1H-tetrazol-1-yl)benzyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide (I-90) Scheme 39 [ka] Synthesis of N-(3-bromo-2-fluoro-6-(1H-tetrazol-1-yl)benzyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide. N-(3-bromo-2-fluoro-6-(1H-tetrazol-1-yl)benzyl)-1-((6-cyclopropyl 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide was synthesized according to general procedure B-1 starting from 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid and (3-bromo-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)methanamine. The crude product was purified by preparative TLC (DCM / MeOH=10:1) to give the product as a white solid (72 mg, yield: 24.4%). ESI-MS [M +H]: 538.2. 1H NMR (400 MHz, DMSO) δ 9.85 (s, 1H), 8.89 (t, J = 5.4 Hz, 1H), 8.49 (s, 1H), 8.36 (s, 1H), 7.95 (dd, J = 8.5, 7.3 Hz, 1H), 7.83 (s, 1H), 7.44 - 7.40 (m, 2H), 7.03 (dd, J = 9.4, 1.7 Hz, 1H), 5.71 (s, 2H), 4.37 (d, J = 5.1 Hz, 2H), 1.96 - 1.90 (m, 1H), 0.95 - 0.90 (m, 2H), 0.69 - 0.65 (m, 2H).

[0246] Example 40 2'-((1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamido)methyl)-3'-fluoro-4'-methoxy-[1,1'-biphenyl]-4-carboxylate (I-87) Scheme 40 [ka] Synthesis of methyl 2'-((1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamido)methyl)-3'-fluoro-4'-methoxy-[1,1'-biphenyl]-4-carboxylate. Methyl 2'-((1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamido)methyl)-3'-fluoro-4'-methoxy-[1,1'-biphenyl]-4-carboxylate was synthesized according to general procedure B-1 starting from 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid and methyl 2'-(aminomethyl)-3'-fluoro-4'-methoxy-[1,1'-biphenyl]-4-carboxylate. The crude product was purified by preparative HPLC to give the product (27.7 mg, yield: 35.7%) as a white solid. ESI-MS [M + H]+ : 555.2. 1 H NMR (400 MHz, DMSO) δ 8.58 (t, J = 4.8 Hz, 1H), 8.51 (s, 1H), 8.35 (s, 1H), 7.97 (d, J = 8.1 Hz, 2H), 7.82 (s, 1H), 7.53 (d, J = 8.1 Hz, 2H), 7.41 (d, J = 9.4 Hz, 1H), 7.21 (t, J = 8.5 Hz, 1H), 7.07 (d, J = 8.5 Hz, 1H), 7.01 (d, J = 9.0 Hz, 1H), 5.71 (s, 2H), 4.38 (d, J = 4.4 Hz, 2H), 3.87 (d, J = 4.2 Hz, 6H), 1.92-1.91 (m, 1H), 0.96 - 0.88 (m, 2H), 0.67 (m, 2H).

[0247] Example 41 2'-((1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamido)methyl)-3'-fluoro-4'-methoxy-[1,1'-biphenyl]-4-carboxylic acid (I-88) Scheme 41 [ka] Synthesis of 2'-((1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamido)methyl)-3'-fluoro-4'-methoxy-[1,1'-biphenyl]-4-carboxylic acid. A solution of methyl 2'-((1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamido)methyl)-3'-fluoro-4'-methoxy-[1,1'-biphenyl]-4-carboxylate (20 mg, 0.036 mmol) and LiOH—HO (7.6 mg, 0.18 mmol) in THF / MeOH / water (1 mL / 1 mL / 1 mL) was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure and purified by preparative HPLC to give 2'-((1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamido)methyl)-3'-fluoro-4'-methoxy-[1,1'-biphenyl]-4-carboxylic acid (7.6 mg, yield: 40%) as a white solid. ESI-MS [M + H] + : 541.2. 1 H NMR (400 MHz, DMSO) δ 8.55 (t, J = 4.7 Hz, 1H), 8.52 (s, 1H), 8.35 (s, 1H), 8.31 (s, 1H), 7.94 (d, J = 7.8 Hz, 2H), 7.82 (s, 1H), 7.46 - 7.40 (m,,3H), 7.20 (t, J = 8.6 Hz, 1H), 7.06 (d, J = 8.4 Hz, 1H), 7.01 (d, J = 8.0 Hz, 1H), 5.71 (s, 2H), 4.39 (d, J = 4.1 Hz, 2H), 3.87 (s, 3H), 1.94 - 1.89 (m, 1H), 0.94 - 0.89 (m, 2H), 0.71 - 0.65 (m, 2H).

[0248] Example 42 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(pyridazin-4-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide (I-86) Scheme 42 [ka] Synthesis of 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(pyridazin-4-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide. 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(pyridazin-4-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide was synthesized according to General Procedure B-1 starting from 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid and (2-fluoro-3-methoxy-6-(pyridazin-4-yl)phenyl)methanamine. The crude product was purified by preparative HPLC to give the product (21 mg, yield: 32.4%) as a white solid. ESI-MS [M + H] + : 499.2. 1 H NMR (400 MHz, DMSO) δ 9.31 - 9.23 (m, 1H), 9.20 (dd, J = 5.3, 0.9 Hz, 1H), 8.73 (t, J = 5.1 Hz, 1H), 8.45 (s, 1H), 8.32 (s, 1H), 7.79 (s, 1H), 7.72 (dd, J = 5.3, 2.4 Hz, 1H), 7.38 (d, J = 9.4 Hz, 1H), 7.24 (t, J = 8.5 Hz, 1H), 7.13 (d, J = 8.6 Hz, 1H), 6.98 (dd, J = 9.4, 1.7 Hz, 1H), 5.68 (s, 2H), 4.38 (d, J = 4.9 Hz, 2H), 3.86 (s, 3H), 1.94 - 1.84 (m, 1H), 0.96 - 0.87 (m, 2H), 0.70 - 0.62 (m, 2H).

[0249] Example 43 N-(benzo[b]thiophen-5-ylmethyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide (I-84) Scheme 43 [ka] Synthesis of N-(benzo[b]thiophen-5-ylmethyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide. N-(benzo[b]thiophen-5-ylmethyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1 ,2,3-Triazole-4-carboxamide was synthesized according to general procedure B-2 starting from 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid and benzo[b]thiophen-5-ylmethanamine hydrochloride. The crude product was purified by preparative TLC (MeOH / DCM=1 / 10) to give the product (40 mg, yield: 52%) as a white solid. ESI-MS [M +H]+: 429.1. 1 H NMR (400 MHz, DMSO) δ 9.16 (t, J = 6.2 Hz, 1H), 8.58 (s, 1H), 8.36 (s, 1H), 7.93 (d, J = 8.3 Hz, 2H), 7.85 (s, 1H), 7.78 (s, 1H), 7.73 (d, J = 5.4 Hz, 1H), 7.46 - 7.38 (m, 2H), 7.33 (dd, J = 8.3, 1.2 Hz, 1H), 7.02 (dd, J = 9.4, 1.6 Hz, 1H), 5.74 (s, 2H), 4.55 (d, J = 6.3 Hz, 2H), 1.95 - 1.91 (m, 1H), 0.98 - 0.87 (m, 2H), 0.75 - 0.65 (m, 2H).

[0250] Example 44 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-ethyl-2-fluoro-6-(1H-tetrazol-1-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide (I-83) Scheme 44 [ka] Synthesis of 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-ethyl-2-fluoro-6-(1H-tetrazol-1-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide. 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-ethyl-2-fluoro-6-(1H-tetrazol-1-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide was synthesized according to general procedure B-1 starting from 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid and 3-ethyl-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)methanamine. The crude product was purified by preparative TLC (MeOH / DCM=1 / 10) to give the product (114 mg, yield: 65.1%) as a white solid. ESI-MS [M +H]+: 487.1. 1 H NMR (400 MHz, DMSO) δ 9.80 (s, 1H), 8.76 (t, J = 5.5 Hz, 1H), 8.49 (s, 1H), 8.34 (s, 1H), 7.82 (s, 1H), 7.51 (t, J = 8.0 Hz, 1H), 7.37 (dd, J = 20.4, 8.8 Hz, 2H), 7.01 (dd, J = 9.4, 1.8 Hz, 1H), 5.70 (s, 2H), 4.32 (d, J = 5.3 Hz, 2H), 2.72 (q, J = 7.5 Hz, 2H), 1.92-1.89 (m, 1H), 1.21 (t , J = 7.6 Hz, 3H), 0.94 - 0.89 (m, 2H), 0.69 - 0.65 (m, 2H).

[0251] Example 45 7-(6-Cyclopropylimidazo[1,2-a]pyridin-2-yl)-N-(2-fluoro-3-methoxy-6-(1H-tetrazol-1-yl)benzyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide (I-82) Scheme 45 [ka] Synthesis of 7-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)-N-(2-fluoro-3-methoxy-6-(1H-tetrazol-1-yl)benzyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide. N-(benzo[b]thiophen-6-ylmethyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide was synthesized according to general procedure B-2 starting from 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid and benzo[b]thiophen-6-ylmethanamine. The crude product was purified by preparative TLC (7% MeOH / DCM) to give the product (20 mg, yield: 26%) as a white solid. ESI-MS [M +H]+: 429.1. 1 H NMR (400 MHz, DMSO) δ 9.20 (t, J = 6.3 Hz, 1H), 8.63 (s, 1H), 8.54 (s, 1H), 8.05 (s, 1H), 7.88 (s, 1H), 7.81 (d, J = 8.2 Hz, 1H), 7.71 (d, J = 5.4 Hz, 1H), 7.61 (d, J = 9.4 Hz, 1H), 7.41 (d, J = 5.4 Hz, 1H), 7.37 - 7.34 (m, 2H), 5.88 (s, 2H), 4.56 (d, J = 6.2 Hz, 2H), 2.05-1.95 (m, 1H), 1.03 - 0.93 (m, 2H), 0.75 - 0.69 (m, 2H).

[0252] Example 46 N-(3-chloro-2-methyl-6-(1H-tetrazol-1-yl)benzyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide (I-80) Scheme 46 [ka] Synthesis of N-(3-chloro-2-methyl-6-(1H-tetrazol-1-yl)benzyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide. N-(3-chloro-2-methyl-6-(1H-tetrazol-1-yl)benzyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide was synthesized according to general procedure B-2 starting from 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid and (3-chloro-2-methyl-6-(1H-tetrazol-1-yl)phenyl)methanamine. The crude product was purified by preparative TLC (MeOH / DCM=1 / 10) to give the product (35 mg, yield: 20%). ESI-MS [M +H] +: 489.2. 1 H NMR (400 MHz, DMSO) δ 9.76 (s, 1H), 8.78 (t, J = 6.0 Hz, 1H), 8.52 (s, 1H), 8.34 (s, 1H), 7.82 (s, 1 H), 7.68 (d, J = 8.0 Hz, 1H), 7.44-7.39 (m, 2H), 7.02-6.99 (m, 1H), 5.71 (s, 2H), 4.22 (d, J = 8.0 Hz, 2 H), 2.47 (s, 3H), 1.96-1.89(m, 1H), 0.94-0.89 (m, 2H), 0.69-0.65 (m, 2H).

[0253] Example 47 N-(3-chloro-6-(difluoromethyl)-2-fluorobenzyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide (I-79) Scheme 47 [ka] Synthesis of N-(3-chloro-6-(difluoromethyl)-2-fluorobenzyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide. N-(3-chloro-6-(difluoromethyl)-2-fluorobenzyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide can be prepared according to general procedure B-1 from 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl). The synthesis was started from (pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid and (3-chloro-6-(difluoromethyl)-2-fluorophenyl)methanamine. The crude product was purified by preparative TLC (MeOH / DCM=1 / 10) to give the product (80 mg, 42%) as a white solid. ESI-MS [M +H]+: 475.1. 1 H NMR (400 MHz, DMSO) δ 9.10 (t, J = 5.5 Hz, 1H), 8.56 (s, 1H), 8.35 (s, 1H), 7.83 (s, 1H), 7.71 - 7.68 (m, 1H), 7.60 - 7.32 (m, 3H), 7.01 (dd, J = 9.4, 1.7 Hz, 1H), 5.72 (s, 2H), 4.58 (d, J = 5.2 Hz, 2H), 1.96 - 1.89 (m, 1H), 0.93 - 0.89 (m, 2H), 0.69 - 0.65 (m, 2H).

[0254] Example 48 N-(3-cyclopropyl-2-fluoro-6-(1H-tetrazol-1-yl)benzyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide (I-78) Scheme 48 [ka] Synthesis of N-(3-cyclopropyl-2-fluoro-6-(1H-tetrazol-1-yl)benzyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide. N-(3-cyclopropyl-2-fluoro-6-(1H-tetrazol-1-yl)benzyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide was synthesized according to General Procedure B-1 starting from 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid and (3-cyclopropyl-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)methanamine. The crude product was purified by preparative TLC (MeOH / DCM=1 / 10) to give the product (23.4 mg, yield: 13.69%) as a white solid. ESI-MS [M +H]+: 499.2. 1 H NMR (400 MHz, DMSO) d 9.78 (s, 1H), 8.77 (t, J = 5.5 Hz, 1H), 8.49 (s, 1H), 8.34 (s, 1H), 7.82 (s, 1H), 7.40 (d, J = 9.3 Hz, 1H), 7.30 (d, J = 8.4 Hz, 1H), 7.16 (t, J = 8.1 Hz, 1H), 7.01 (dd, J = 9.4, 1.7 Hz, 1H), 5.70 (s, 2H), 4.32 (d, J = 5.1 Hz, 2H), 2.18 - 2.10 (m, 1H), 1.96 - 1.88 (m, 1H), 1.09 - 1.01 (m, 2H), 0.95 - 0.88 (m, 2H), 0.85 - 0.78 (m, 2H), 0.70 - 0.64 (m, 2H).

[0255] Example 49 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(imidazo[1,2-a]pyridin-6-ylmethyl)-1H-1,2,3-triazole-4-carboxamide (I-136) Scheme 49 [ka] Synthesis of 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(imidazo[1,2-a]pyridin-6-ylmethyl)-1H-1,2,3-triazole-4-carboxamide. 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(imidazo[1,2-a]pyridin-6-ylmethyl)-1H-1,2,3-triazole-4-carboxamide was synthesized according to General Procedure B-1 starting from 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid and imidazo[1,2-a]pyridin-6-ylmethanamine hydrochloride. The crude product was purified by preparative TLC (MeOH / DCM=1 / 15) to give the product (6 mg, yield: 8%) as a white solid. ESI-MS [M + H]+: 413.2. 1 H NMR (400 MHz, DMSO) δ 9.16 (t, J = 6.0 Hz, 1H), 8.58 (s, 1H), 8.45 (s, 1H), 8.36 (s, 1H), 7.97 (s, 1H), 7.85 (s, 1H), 7.51 (s, 2H), 7.41 (d, J = 9.3 Hz, 1H), 7.23 (s, 1H), 7.01 (d, J = 9.1 Hz, 1H), 5.74 (s, 2H), 4.42 (d, J = 6.0 Hz, 2H), 1.98-1.87 (m Hz, 1H), 0.96-0.88 (m, 2H), 0.71-0.63 (m, 2H).

[0256] Example 50 N-((6-chlorobenzo[b]thiophen-2-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide (I-77) Scheme 50 [ka] Synthesis of N-((6-chlorobenzo[b]thiophen-2-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide. N-((6-chlorobenzo[b]thiophen-2-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridine- 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid and (6-chlorobenzo[b]thiophen-2-yl)methanamine were synthesized according to general procedure B-2. The crude product was purified by preparative HPLC (MeOH / DCM=1 / 15) to give the product (15 mg, yield: 12%) as a white solid. ESI-MS [M +H]: 462.7. 1 H NMR (400 MHz, DMSO) δ 9.31 (t, J = 5.6 Hz, 1H), 8.61 (s, 1H), 8.36 (s, 1H), 8.03 (s, 1H), 7.85 (s, 1H), 7.78 (d, J = 8.6 Hz, 1H), 7.41 (d, J = 9.4 Hz, 1H), 7.36 (d, J = 8.5 Hz, 1H), 7.29 (s, 1H), 7.01 (d, J = 9.5 Hz, 1H), 5.75 (s, 2H), 4.67 (d, J = 5.6 Hz, 2H), 1.96 - 1.90 (m, 1H), 0.93 - 0.91 (m, 2H), 0.68 - 0.67 (m, 2H).

[0257] Example 51 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(1H-1,2,3-triazol-1-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide (I-76) Scheme 51 [ka] Synthesis of 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(1H-1,2,3-triazol-1-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide. 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(1H-1,2,3-triazol-1-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide was synthesized according to general procedure B-1 starting from 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid and (2-fluoro-3-methoxy-6-(1H-1,2,3-triazol-1-yl)phenyl)methanamine. The crude product was purified by preparative HPLC (MeOH / DCM=1 / 15) to give the product (25 mg, 14%) as a pale pink solid. ESI-MS [M +H]: 488.2. 1H NMR (400 MHz, DMSO) δ 8.63 - 8.60 (m, 3H), 8.50 (d, J = 0.9 Hz, 1H), 8.14 (s, 1H), 7.93 (d, J = 0.9 Hz, 1H), 7.71 (d, J = 9.3 Hz, 1H), 7.55 (d, J = 9.5 Hz, 1H), 7.35 - 7.29 (m, 2H), 5.92 (s, 2H), 4.31 (d, J = 5.1 Hz, 2H), 3.91 (s, 3H), 2.09 - 2.03 (m, 1H), 1.05 - 1.01 (m, 2H), 0.78 - 0.74 (m, 2H).

[0258] Example 52 Methyl 5-(2-((1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamido)methyl)-3-fluoro-4-methoxyphenyl)pyrimidine-2-carboxylate (I-75) Scheme 52 [ka] Synthesis of methyl 5-(2-((1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamido)methyl)-3-fluoro-4-methoxyphenyl)pyrimidine-2-carboxylate. Methyl 5-(2-((1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamido)methyl)-3-fluoro-4-methoxyphenyl)pyrimidine-2-carboxylate was synthesized according to general procedure B-1 starting from 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid and methyl 5-(2-(aminomethyl)-3-fluoro-4-methoxyphenyl)pyrimidine-2-carboxylate. The crude product was purified by preparative HPLC (MeOH / DCM=1 / 10) to give the product (80 mg, yield: 48%) as a yellow solid. ESI-MS [M +H]+ : 557.2. 1 H NMR (400 MHz, DMSO) δ 9.00 (s, 2H), 8.79 (t, J = 5.2 Hz, 1H), 8.48 (s, 1H), 8.34 (s, 1H), 7.81 (s, 1H), 7.40 (d, J = 9.3 Hz, 1H), 7.28 (t, J = 8.5 Hz, 1H), 7.18 (d, J = 8.5 Hz, 1H), 7.01 (dd, J = 9.4, 1.7 Hz, 1H), 5.70 (s, 2H), 4.39 (d, J = 4.8 Hz, 2H), 3.92 (s, 3H), 3.89 (s, 3H),1.92 - 1.88 (m, 1H), 1.01 - 0.85 (m, 2H), 0.73 - 0.65 (m, 2H).

[0259] Example 53 5-(2-((1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamido)methyl)-3-fluoro-4-methoxyphenyl)pyrimidine-2-carboxylic acid (I-74) Scheme 53 [ka] Synthesis of 5-(2-((1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamido)methyl)-3-fluoro-4-methoxyphenyl)pyrimidine-2-carboxylic acid. A solution of methyl 5-(2-((1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamido)methyl)-3-fluoro-4-methoxyphenyl)pyrimidine-2-carboxylate (56 mg, 0.1 mmol) and LiOH—HO (21 mg, 0.5 mmol) in THF / MeOH / water (1 mL / 1 mL / 1 mL) was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure and purified by preparative HPLC to give 5-(2-((1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamido)methyl)-3-fluoro-4-methoxyphenyl)pyrimidine-2-carboxylic acid (12 mg, yield: 22%) as a pale yellow solid. ESI-MS [M + H] + : 543.2. 1 H NMR (400 MHz, DMSO) δ 13.57 (s, 1H), 8.96 (s, 2H), 8.80 (t, J = 5.1 Hz, 1H), 8.49 (s, 1H), 8.34 (s, 1H), 7.80 (s, 1H), 7.40 (d, J = 9.3 Hz, 1H), 7.27 (t, J = 8.5 Hz, 1H), 7.17 (d, J = 8.6 Hz, 1H), 7.01 (dd, J = 9.3, 1.6 Hz, 1H), 5.70 (s, 2H), 4.39 (d, J = 4.7 Hz, 2H), 3.89 (s, 3H), 1.95 - 1.91 (m, 1H), 0.95 - 0.81 (m, 2H), 0.75 - 0.65 (m, 2H).

[0260] Example 54 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(6-(3,4-dimethyl-1H-pyrazol-1-yl)-2-fluoro-3-methoxybenzyl)-1H-1,2,3-triazole-4-carboxamide (I-73) Scheme 54 [ka] Synthesis of 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(6-(3,4-dimethyl-1H-pyrazol-1-yl)-2-fluoro-3-methoxybenzyl)-1H-1,2,3-triazole-4-carboxamide. 6-(3,4-Dimethyl-1H-pyrazol-1-yl)-2-fluoro-3-methoxybenzyl)-1H-1,2,3-triazole-4-carboxamide was synthesized according to general procedure B-1 starting from 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid and (6-(3,4-dimethyl-1H-pyrazol-1-yl)-2-fluoro-3-methoxyphenyl)methanamine. The crude product was purified by preparative HPLC (MeOH / DCM=1 / 10) to give the product (37.6 mg, yield: 37%, 2 steps) as a yellow solid. ESI-MS [M + H] + : 515.2. 1 H NMR (400 MHz, DMSO) δ 8.80 (t, J = 5.8 Hz, 1H), 8.58 (s, 1H), 8.43 (s, 1H), 7.92 (s, 1H), 7.78 (s, 1H), 7.50 (d, J = 9.4 Hz, 1H), 7.21 - 7.16 (m, 3H), 5.79 (s, 2H), 4.42 (d, J = 4.9 Hz, 2H), 3.86 (s, 3H), 2.19 (s, 3H), 2.00 (s, 3H), 1.95 - 1.91 (m, 1H), 1.02 - 0.88 (m, 2H), 0.78 - 0.64 (m, 2H).

[0261] Example 55 N-((5-cyano-3-fluoro-2-methoxypyridin-4-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide (I-72) Scheme 55 [ka] Synthesis of N-((5-bromo-3-fluoro-2-methoxypyridin-4-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide. N-((5-bromo-3-fluoro-2-methoxypyridin-4-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide was synthesized according to general procedure B-2 starting from 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid and (5-bromo-3-fluoro-2-methoxypyridin-4-yl)methanamine. The crude product was purified by recrystallization with MeOH to give the product (160 mg, yield: 76%) as a white solid. ESI-MS [M +H]+: 500.1.

[0262] Synthesis of N-((5-cyano-3-fluoro-2-methoxypyridin-4-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide. A solution of (fluoro-2-methoxypyridin-4-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide (110 mg, 0.22 mmol), Zn(CN) (52 mg, 0.44 mmol), Pd(dppf)Cl (19.7 mg, 0.027 mmol), and Pd(dba) (25 mg, 0.027 mmol) in DMF (4 mL) was stirred at 110 °C for 50 min using a microwave. The reaction mixture was washed with water (30 mL) and extracted with EtOAc (50 mL × 2). The combined organic layer was washed with brine (30 mL), dried over NaSO, concentrated, and purified by preparative TLC (DCM / MeOH=15:1) to give N-((5-cyano-3-fluoro-2-methoxypyridin-4-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide (55.4 mg, yield: 56%) as a white solid. ESI-MS [M+H]: 447.1. 1 H NMR (400 MHz, DMSO) δ 9.18 (t, J = 5.3 Hz, 1H), 8.56 (s, 1H), 8.48 (s, 1H), 8.34 (s, 1H), 7.83 (s, 1H), 7.40 (d, J = 9.3 Hz, 1H), 7.00 (dd, J = 9.4, 1.4 Hz, 1H), 5.73 (s, 2H), 4.56 (d, J = 5.2 Hz, 2H), 4.00 (s, 3H), 1.95 - 1.88 (m, 1H), 0.91 - 0.88 (m, 2H), 0.68 - 0.64 (m, 2H).

[0263] Example 56 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-6-(imidazo[1,2-a]pyridin-2-yl)-3-methoxybenzyl)-1H-1,2,3-triazole-4-carboxamide (I-70) Scheme 56 [ka] Synthesis of 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(pyrazolo[1,5-a]pyridin-2-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide. 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-6-(imidazo[1,2-a]pyridin-2-yl)-3-methoxybenzyl)-1H-1,2,3-triazole-4-carboxamide was synthesized according to general procedure B-1 starting from 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid and (2-fluoro-6-(imidazo[1,2-a]pyridin-2-yl)-3-methoxyphenyl)methanamine. The crude product was purified by preparative HPLC to give the product (80 mg, 42% for two steps) as a white solid. ESI-MS [M +H]: 537.2. 1 H NMR (400 MHz, DMSO) δ 9.37 (s, 1H), 8.67 (d, J = 6.7 Hz, 1H), 8.52 (s, 1H), 8.41 (s, 1H), 8.32 (s, 1H), 7.89 (s, 1H), 7.67 (d, J = 8.9 Hz, 1H), 7.52 - 7.42 (m, 3H), 7.22 (t, J = 8.6 Hz, 1H), 7.16 - 7.11 (m, 2H), 5.75 (s, 2H), 4.67 (d, J = 5.5 Hz, 2H), 3.86 (s, 3H), 1.97 - 1.91 (m, 1H), 0.94 - 0.90 (m, 2H), 0.69 - 0.66 (m, 2H).

[0264] Example 57 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(1H-pyrazol-4-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide (I-67) Scheme 57 [ka] Synthesis of 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(1H-pyrazol-4-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide. 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(1H-pyrazol-4-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide was synthesized according to General Procedure B-1 starting from 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid and (2-fluoro-3-methoxy-6-(1H-pyrazol-4-yl)phenyl)methanamine. The crude product was purified by preparative HPLC to give the product (2.5 mg, yield: 2%) as a yellow solid. ESI-MS [M +H] + : 487.2. 1 H NMR (400 MHz, DMSO) δ 8.72 - 8.63 (m, 2H), 8.60 - 8.57 (m, 1H), 8.19 - 8.14 (m, 1H), 7.77 - 7.73 (m, 3H), 7.64 - 7.58 (m, 1H), 7.17 - 7.12 (m, 2H), 5.96 (s, 2H), 4.51 - 4.50 (m, 2H), 3.84 (s, 3H), 2.11 - 2.03 (m, 1H), 1.09 - 0.95 (m, 2H), 0.82 - 0.69 (m, 2H).

[0265] Example 58 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(1H-tetrazol-1-yl)benzyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide (I-66) Scheme 58 [ka] Synthesis of 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(1H-tetrazol-1-yl)benzyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide. 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(1H-tetrazol-1-yl)benzyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide was synthesized according to general procedure B-1 starting from 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid and 1-(2-fluoro-3-methoxy-6-(1H-tetrazol-1-yl)phenyl)-N-methylmethanamine. The crude product was purified by preparative TLC (DCM / MeOH=10:1) to give the product (30 mg, 15%) as a white solid. ESI-MS [M +H]: 503.2. 1 H NMR (400 MHz, DMSO) δ 9.72 (s, 1H), 8.45 - 8.35 (m, 2H), 7.84 (d, J = 11.1 Hz, 1H), 7.42 - 7.35 (m, 3H), 7.02 (d, J = 9.4 Hz, 1H), 5.71 (d, J = 10.4 Hz, 2H), 5.20 (s, 1H), 4.54 (s, 1H), 3.94 (s, 3H), 3.17 (s, 2H), 2.68 (s, 1H), 1.96 - 1.89 (m, 1H), 0.94 - 0.86 (m, 2H), 0.69 - 0.66 (m, 2H).

[0266] Example 59 N-((3-chloro-1H-indol-5-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide (I-65) Scheme 59 [ka] Synthesis of N-((3-chloro-1H-indol-5-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide. N-((3-chloro-1H-indol-5-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide can be prepared according to general procedure B-1 from 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide. The synthesis was started from (methyl)-1H-1,2,3-triazole-4-carboxylic acid and (3-chloro-1H-indol-5-yl)methanamine hydrochloride. The crude product was purified by preparative HPLC to give the product (20 mg, yield: 25%) as a pale yellow solid. ESI-MS [M + H] + : 445.8. 1 H NMR (400 MHz, MeOD) δ 8.51 (d, J = 4.0 Hz, 2H), 8.14 (s, 1H), 7.69 (d, J = 3.0 Hz,2H), 7.51 (s, 1H), 7.33 (d, J = 5.0 Hz,1H), 7.24 (s, 1H),7.21(d, J = 4.0 Hz,1H) 5.97 (s, 2H), 4.68 (s, 2H), 2.14-2.05 (m, 1H), 1.15 - 1.06 (m, 2H), 0.86 - 0.79 (m, 2H).

[0267] Example 60 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2,6-difluoro-3-methoxybenzyl)-1H-1,2,3-triazole-4-carboxamide (I-64) Scheme 60 [ka] Synthesis of 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2,6-difluoro-3-methoxybenzyl)-1H-1,2,3-triazole-4-carboxamide. 1-((6-Cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2,6-difluoro-3-methoxybenzyl)-1H-1,2,3-triazole-4-carboxamide was synthesized according to general procedure B-2 starting from 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid and (2,6-difluoro-3-methoxyphenyl)methanamine. The crude product was purified by flash column chromatography (0-4% MeOH in DCM) to give the product (90 mg, 62%) as a white solid. ESI-MS [M + H] + : 439.1. 1 H NMR (400 MHz, DMSO) δ 8.82 (t, J = 5.4 Hz, 1H), 8.54 (s, 1H), 8.34 (s, 1H), 7.82 (s, 1H), 7.40 (d, J = 9.3 Hz, 1H), 7.15 - 7.05 (m, 1H), 7.04 - 6.94 (m, 2H), 5.72 (s, 2H), 4.49 (d, J = 5.3 Hz, 2H), 3.80 (s, 3H), 1.97 - 1.86 (m, 1H), 0.97 - 0.86 (m, 2H), 0.71 - 0.61 (m, 2H).

[0268] Example 61 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(pyrazolo[1,5-a]pyridin-2-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide (I-63) Scheme 61 [ka] Synthesis of 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(pyrazolo[1,5-a]pyridin-2-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide. 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(pyrazolo[1,5-a]pyridin-2-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide was synthesized according to general procedure B-1 starting from 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid and (2-fluoro-3-methoxy-6-(pyrazolo[1,5-a]pyridin-2-yl)phenyl)methanamine. The crude product was purified by preparative HPLC to give the product (2.0 mg, 12.9%) as a white solid. ESI-MS [M +H]: 537.2. 1 H NMR (400 MHz, DMSO) δ 8.97 (t, J = 5.9 Hz, 1H), 8.64 (d, J = 6.9 Hz, 1H), 8.56 (s, 1H), 8.33 (s, 1H), 7.80 (s, 1H), 7.71 (d, J = 8.9 Hz, 1H), 7.53 (d, J = 8.7 Hz, 1H), 7.39 (d, J = 9.3 Hz, 1H), 7.24 (d, J = 8.8 Hz, 2H), 7.01 - 6.98 (m, 1H), 6.94 (d, J = 6.9 Hz, 1H), 6.91 (s, 1H), 5.71 (s, 2H), 4.73 (d, J = 4.9 Hz, 2H), 3.87 (s, 3H), 2.00 - 1.96 (m, 1H), 0.91- 0.89 (m, 2H), 0.67 - 0.64 (m, 2H).

[0269] Example 62 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide (I-62) Scheme 62 [ka] 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(3-(trifluoromethyl)-1H-pyrazoline) Synthesis of 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide. 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid and (2-fluoro-3-methoxy-6-(3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)methanamine according to General Procedure B-2. The crude product was purified by preparative TLC (DCM / MeOH=10 / 1) to give the product (29.1 mg, yield: 66%) as a white solid. ESI-MS [M +H]+: 555.1. 1H NMR (400 MHz, DMSO) δ 8.55 (t, J = 5.5 Hz, 1H), 8.51 (s, 1H), 8.34 (s, 1H), 8.31 (dd, J = 2.3 Hz, J = 0.9 Hz, 1H), 7.81 (s, 1H), 7.40 (d, J = 9.3 Hz, 1H), 7.33 - 7.25 (m, 2H), 7.01 (dd, J = 9.4 Hz, J = 1.8 Hz, 1H), 6.96 (d, J = 2.3 Hz, 1H), 5.70 (s, 2H), 4.34 (d, J = 5.2 Hz, 2H), 3.90 (s, 3H), 1.96 - 1.89 (m, 1H), 0.92 - 0.89 (m, 2H), 0.69 - 0.65 (m, 2H).

[0270] Example 63 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(1H-1,2,4-triazol-1-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide (I-61) Scheme 63 [ka] Synthesis of tert-butyl (6-(2-(diphenylmethylene)hydrazinyl)-2-fluoro-3-methoxybenzyl)carbamate. tert-Butyl (6-bromo-2-fluoro-3-methoxybenzyl)carbamate (333 mg, 1.0 mmol), (diphenylmethylene)hydrazine (245 mg, 1.25 mmol), Pd-PEPPSI-IPENT-Cl-(o-picoline) (42 mg, 0.05 mmol), and CsCO A mixture of 3 (652 mg, 2.0 mmol) in DME (15 mL) was stirred under N at 90 °C for 16 h. The reaction mixture was concentrated under reduced pressure and purified by silica gel chromatography (DCM / MeOH = 10 / 1) to give tert-butyl (6-(2-(diphenylmethylene)hydrazinyl)-2-fluoro-3-methoxybenzyl)carbamate (210 mg, 47%) as a yellow oil. ESI-MS [M + H] + : 450.1.

[0271] Synthesis of (6-(2-(diphenylmethylene)hydrazinyl)-2-fluoro-3-methoxyphenyl)methanamine hydrochloride. A mixture of tert-butyl (6-(2-(diphenylmethylene)hydrazinyl)-2-fluoro-3-methoxybenzyl)carbamate (200 mg, 0.445 mmol) in HCl (4 M in dioxane, 5.0 mL) was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to give (6-(2-(diphenylmethylene)hydrazinyl)-2-fluoro-3-methoxyphenyl)methanamine hydrochloride (160 mg, crude) as a yellow solid, which was used directly in the next step without further purification. ESI-MS [M + H] + : 350.1.

[0272] Synthesis of 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(6-(2-(diphenylmethylene)hydrazinyl)-2-fluoro-3-methoxybenzyl)-1H-1,2,3-triazole-4-carboxamide. 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(6-(2-(diphenylmethylene)hydrazinyl)-2-fluoro-3-methoxybenzyl)-1H-1,2,3-triazole-4-carboxamide was synthesized according to general procedure B-1 starting from 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid and (6-(2-(diphenylmethylene)hydrazinyl)-2-fluoro-3-methoxyphenyl)methanamine hydrochloride. The crude product was purified by preparative TLC (DCM / MeOH=20 / 1) to give the product (120 mg, yield: 44%, 2 steps) as a yellow solid. ESI-MS [M + H] + : 615.2.

[0273] Synthesis of 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-6-hydrazinyl-3-methoxybenzyl)-1H-1,2,3-triazole-4-carboxamide. A mixture of 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(6-(2-(diphenylmethylene)hydrazinyl)-2-fluoro-3-methoxybenzyl)-1H-1,2,3-triazole-4-carboxamide (122.8 mg, 0.2 mmol) in concentrated HCl / EtOH (2.0 mL / 4.0 mL) was stirred at 75° C. for 1 hour. The reaction mixture was concentrated under reduced pressure to give the desired product (90 mg, crude) as a yellow solid, which was used directly in the next step without further purification. ESI-MS [M +H] + : 451.1.

[0274] Synthesis of 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(1H-1,2,4-triazol-1-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide. A mixture of 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-6-hydrazinyl-3-methoxybenzyl)-1H-1,2,3-triazole-4-carboxamide (90 mg, crude) in formamide (3 mL) was stirred at 120° C. for 16 hours. The reaction mixture was diluted with EtOAc (50 mL) and washed with water (50 mL). The organic layer was separated, dried over Na2SO4, and concentrated under reduced pressure to give the crude product, which was purified by preparative HPLC to give 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(1H-1,2,4-triazol-1-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide (7.3 mg, yield: 7.5% for two steps) as a white solid. ESI-MS [M + H] + : 488.1. Purity: 95.8% (214 nm), 95.5% (254 nm). 1 H NMR (400 MHz, DMSO) δ 8.84 (s, 1H), 8.56 (t, J = 5.4 Hz, 1H), 8.51 (s, 1H), 8.34 (s, 1H), 8.22 (s, 1H), 7.81 (s, 1H), 7.40 (d, J = 9.3 Hz, 1H), 7.34 - 7.24 (m, 2H), 7.01 (dd, J = 9.4, 1.7 Hz, 1H), 5.71 (s, 2H), 4.36 (d, J = 4.9 Hz, 2H), 3.90 (s, 3H), 1.93 - 1.86 (m, 1H), 0.98 - 0.89 (m, 2H), 0.73 - 0.65 (m, 2H).

[0275] Example 64 N-Benzyl-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide (I-60) Scheme 64 [ka] Synthesis of N-benzyl-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide. N-benzyl-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide was synthesized according to General Procedure B-2, starting from 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid and benzylamine. The crude product was purified by preparative TLC (DCM / MeOH=10 / 1) to give the product (120 mg, yield: 45%) as a white solid. ESI-MS [M +H]: 373.2. 1 H NMR (400 MHz, DMSO) δ 9.08 (t, J = 6.3 Hz, 1H), 8.57 (s, 1H), 8.36 (s, 1H), 7.85 (s, 1H), 7.41 (d, J = 9.3 Hz, 1H), 7.34 - 7.27 (m, 4H), 7.25 - 7.17 (m, 1H), 7.04-7.00 (m, 1H), 5.75 (d, J = 7.0 Hz, 2H), 4.43 (d, J = 6.3 Hz, 2H), 1.97 - 1.87 (m, 1H), 0.96 - 0.87 (m, 2H), 0.72 - 0.63 (m, 2H).

[0276] Example 65 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(methylsulfinyl)benzyl)-1H-1, 2,3-Triazole-4-carboxamide (I-58) Scheme 65 [ka] Synthesis of 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(methylthio)benzyl)-1H-1,2,3-triazole-4-carboxamide. 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(methylthio)benzyl)-1H-1,2,3-triazole-4-carboxamide was synthesized according to general procedure B-2 starting from 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid and (2-fluoro-3-methoxy-6-(methylthio)phenyl)methanamine. The crude product was purified by preparative TLC (DCM / MeOH=10 / 1) to give the product (300 mg, 49.5%) as a yellow solid. ESI-MS [M +H] + : 467.1.

[0277] Synthesis of 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(methylsulfinyl)benzyl)-1H-1,2,3-triazole-4-carboxamide. To a solution of 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(methylthio)benzyl)-1H-1,2,3-triazole-4-carboxamide (100 mg, 0.21 mmol) in DCM (5 mL) was added 3-chloroperbenzoic acid (36 mg, 0.21 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 1 hour. The mixture diluted with DCM (15 mL) was washed with brine (30 mL), dried over Na2SO4, and concentrated under reduced pressure to give the crude product, which was purified by preparative TLC (DCM / MeOH=10 / 1) to give 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(methylsulfinyl)benzyl)-1H-1,2,3-triazole-4-carboxamide (20 mg, yield: 19.4%) as a white solid. ESI-MS [M + H] + : 483.1. Purity: 91.77 (214nm), 91.39 (254nm). 1 H NMR (400 MHz, CDCl3) δ = 8.27 (t, J = 6.4 Hz, 1H), 8.23 ​​(s, 1H), 7.85 (s, 1H), 7.53 (d, J = 8.0 Hz, 1H), 7.46 (s, 1H), 7.14 (t, J = 8.8 Hz, 1H), 7.01 (dd, J = 9.2, 1.6 Hz, 1H), 6.82 (dd, J = 9.2, 4.0 Hz, 1H), 5.75 (s, 2H), 5.12 (dd, J = 14.4, 6.4 Hz 1H), 4.91 (dd, J = 14.4, 6.4 Hz, 1H), 3.85 (s, 3H), 3.03 (s, 3H), 1.92 - 1.85 (m, 1H), 0.98 (dd, J = 14.0, 5.6 Hz, 2H), 0.67 (q, J = 5.6 Hz, 2H).

[0278] Example 66 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(methylsulfonyl)benzyl)-1H-1,2 ,3-Triazole-4-carboxamide (I-53) Scheme 66 [ka] Synthesis of 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(methylsulfonyl)benzyl)-1H-1,2,3-triazole-4-carboxamide. To a solution of 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(methylthio)benzyl)-1H-1,2,3-triazole-4-carboxamide (100 mg, 0.21 mmol) in DCM (5 mL) was added 3-chloroperbenzoic acid (72 mg, 0.42 mmol) at 0° C. The reaction mixture was stirred at room temperature for 1 hour. The mixture diluted with DCM (15 mL) was washed with brine (30 mL), dried over Na2SO4, and concentrated to give the crude product, which was purified by preparative HPLC to give 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(methylsulfonyl)benzyl)-1H-1,2,3-triazole-4-carboxamide (20 mg, yield: 19%) as a white solid. ESI-MS [M + H] + : 498.8. Purity: 99.79 (214 nm), 99.16 (254 nm).1 H NMR (400 MHz, CDCl3) δ = 8.37 (s, 1H), 8.12 (s, 1H), 8.04 (t, J = 6.4 Hz, 1H), 7.92 (d, J = 9.2 Hz, 1H), 7.77 (s, 1H), 7.44 (d, J = 9.2 Hz, 1H), 7.32 (t, J = 9.2 Hz, 1H), 7.02 (dd, J = 9.2, 4.0 Hz, 1H), 5.96 (s, 2H), 5.04 (d, J = 6.0 Hz, 2H), 3.96 (s, 3H), 3.34 (s, 3H), 2.02-1.95 (m, 1H), 1.1 (q, J = 6.4 Hz, 2H), 0.77 (q, J = 5.6 Hz, 2H).

[0279] Example 67 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(6-(N,N-dimethylsulfamoyl)-2-fluoro-3-methoxybenzyl)-1H-1,2,3-triazole-4-carboxamide (I-57) Scheme 67 [ka] 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(6-(N,N-dimethylsulfamoyl)-2-fluoro-3-methoxybenzyl Synthesis of 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(6-(N,N-dimethylsulfamoyl)-2-fluoro-3-methoxybenzyl)-1H-1,2,3-triazole-4-carboxamide was synthesized according to General Procedure B-2 starting from 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid and 2-(aminomethyl)-3-fluoro-4-methoxy-N,N-dimethylbenzenesulfonamide. The crude product was purified by preparative TLC (DCM / MeOH=10 / 1) to give the product (30 mg, yield: 20%) as a white solid. ESI-MS [M +H]+: 528.2. 1 H NMR (400 MHz, DMSO) δ 8.58 (s, 1H), 8.34 (s, 1H), 8.30 (t, J = 5.3 Hz, 1H), 7.82 (s, 1H), 7.67 (d, J = 8.9 Hz, 1H), 7.40 (d, J = 9.3 Hz, 1H), 7.33 (t, J = 8.5 Hz, 1H), 7.02-6.99 (m, 1H), 5.72 (s, 2H), 4.81 (d, J = 4.3 Hz, 2H), 3.93 (s, 3H), 2.71 (s, 6H), 1.96-1.90 (m, 1H), 0.96 - 0.85 (m, 2H), 0.73 - 0.64 (m, 2H).

[0280] Example 68 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide (I-52) Scheme 68 [ka] Synthesis of 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide. 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide was synthesized according to general procedure B-1 starting from 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid and (2-fluoro-3-methoxy-6-(3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl)phenyl)methanamine hydrochloride. The crude product was purified by preparative HPLC to give the product (27.8 mg, yield: 33%) as a yellow solid. ESI-MS [M +H]: 556.2. 1 H NMR (400 MHz, DMSO) δ 9.13 (s, 1H), 8.71(s, 1H), 8.48 (s, 1H), 8.34 (s, 1H), 7.81 (s, 1H), 7.40 (d, J = 9.2 Hz, 2H), 7.31 (t, J = 8.7 Hz, 1H), 7.01 (d, J = 9.2 Hz, 1H), 5.70 (s, 2H), 4.37 (d, J = 5.1 Hz, 2H), 3.91 (s, 3H), 2.00 - 1.82 (m, 1H), 1.02 - 0.83 (m, 2H), 0.76 - 0.58 (m, 2H).

[0281] Example 69 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-(methylsulfonyl)benzyl)-1H-1,2,3-triazole-4-carboxamide (I-51) Scheme 69 [ka] Synthesis of 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-(methylsulfonyl)benzyl)-1H-1,2,3-triazole-4-carboxamide. 1-((6-Cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-(methylsulfonyl)benzyl)-1H-1,2,3-triazole-4-carboxamide was synthesized according to General Procedure B-2, starting from 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid and (2-(methylsulfonyl)phenyl)methanamine. The crude product was purified by preparative TLC (DCM / MeOH=10 / 1) to give the product (30 mg, yield: 8%) as a white solid. ESI-MS [M +H]+: 451.2. 1 H NMR (400 MHz, DMSO) δ 9.22 (t, J = 6.1 Hz, 1H), 8.61 (s, 1H), 8.36 (s, 1H), 8.27(s, 1H),7.92 (d, J = 7.8 Hz, 1H), 7.86 (s, 1H), 7.68 (t, J = 7.5 Hz, 1H), 7.61 - 7.47 (m, 2H), 7.41 (d, J = 9.3 Hz, 1H), 7.01 (d, J = 9.4 Hz, 1H), 5.75 (s, 2H), 4.83 (d, J = 6.1 Hz, 2H), 3.37 (s, 3H), 1.96-1.91 (m, 1H), 0.98-0.92 (m, 2H), 0.74-0.66 (m, 2H).

[0282] Example 70 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(1H-1,2,3-triazol-4-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide (I-49) Scheme 70 [ka] Synthesis of 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(1H-1,2,3-triazol-4-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide. 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(1H-1,2,3-triazol-4-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide was synthesized according to general procedure B-1 starting from 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid and (2-fluoro-3-methoxy-6-(1H-1,2,3-triazol-4-yl)phenyl)methanamine hydrochloride. The crude product was purified by preparative HPLC to give the product (3.1 mg, yield: 3.2% for two steps) as a yellow solid. ESI-MS [M +H]: 488.2. 1 H NMR (400 MHz, DMSO) δ 8.81 (s, 1H), 8.55 (s, 1H), 8.43 (s, 2H), 8.33 (s, 1H), 8.16 (s, 1H), 7.79 (s, 1H), 7.52 - 7.31 (m, 2H), 7.20 - 7.18 (m, 1H), 7.00 (d, J = 9.2 Hz, 1H), 5.72 (s, 2H), 4.65 (s, 2H), 3.86 (s, 3H), 1.98 - 1.84 (m, 1H), 1.00 - 0.82 (m, 2H), 0.68 - 0.66 (m, 2H).

[0283] Example 71 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(morpholinosulfonyl)benzyl)-1H-1,2,3-triazole-4-carboxamide (I-48) Scheme 71 [ka] Synthesis of 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(morpholinosulfonyl)benzyl)-1H-1,2,3-triazole-4-carboxamide. 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(morpholinosulfonyl)benzyl)-1H-1,2,3-triazole-4-carboxamide The carboxamide was synthesized according to general procedure B-2 starting from 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid and (2-fluoro-3-methoxy-6-(morpholinosulfonyl)phenyl)methanamine. The crude product was purified by preparative TLC (DCM / MeOH=10 / 1) to give the product (30 mg, yield: 14%) as a white solid. ESI-MS [M +H]: 570.2. 1 H NMR (400 MHz, DMSO) δ 8.59 (s, 1H), 8.38-8.33 (m, 2H), 7.82 (s, 1H), 7.70 (d, J = 8.9 Hz, 1H), 7.42 - 7.31 (m, 2H), 7.04-6.95 (m, 1H), 5.73 (s, 2H), 4.83-4.79 (m, 2H), 3.95 (s, 3H), 3.62 - 3.55 (m, 4H), 3.04-2.95 (m, 4H), 1.93-1.88 (m, 1H), 0.95 - 0.85 (m, 2H), 0.71 - 0.60 (m, 2H).

[0284] Example 72 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(1-(2-fluoro-3-methoxy-6-(1H-tetrazol-1-yl)phenyl)ethyl)-1H-1,2,3-triazole-4-carboxamide (I-31) Scheme 72 [ka] Synthesis of 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(1-(2-fluoro-3-methoxy-6-(1H-tetrazol-1-yl)phenyl)ethyl)-1H-1,2,3-triazole-4-carboxamide. 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(1-(2-fluoro-3-methoxy-6-(1H-tetrazol-1-yl)phenyl)ethyl)-1H-1,2,3-triazole-4-carboxamide was synthesized according to general procedure B-1 starting from 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid and 1-(2-fluoro-3-methoxy-6-(1H-tetrazol-1-yl)phenyl)ethan-1-amine. The crude product was purified by preparative TLC (DCM / MeOH=18 / 1) to give the product (17.4 mg, 41%) as an off-white solid. ESI-MS [M + H] + : 503.2. 1 H NMR (400 MHz, DMSO) δ 9.78 (s, 1H), 8.77 (d, J = 6.4 Hz, 1H), 8.51 (s, 1H), 8.34 (s, 1H), 7.81 (s, 1H), 7.41 - 7.30 (m, 3H), 7.01 (d, J = 9.3 Hz, 1H), 5.71 (s, 2H), 4.47 - 4.43 (m, 1H), 3.90 (s, 3H), 1.95 - 1.89 (m, 1H), 1.56 (d, J = 7.0 Hz, 3H), 0.92 - 0.91 (m, 2H), 0.67 - 0.66 (m, 2H).

[0285] Example 73 N-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide (I-26) Scheme 73 [ka] Synthesis of N-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide. N-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide was synthesized according to general procedure B-1 starting from 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid and 5-(aminomethyl)-4,6-dimethylpyridin-2-amine hydrochloride. The crude product was purified by preparative TLC (DCM / MeOH=10 / 1) to give the product (50 mg, yield: 35%) as an off-white solid. ESI-MS [M +H]+: 417.2. 1 H NMR (400 MHz, DMSO) δ 8.55 (s, 1H), 8.35 (s, 1H), 8.31 (t, J = 5.1 Hz, 1H), 7.83 (s, 1H), 7.40 (d, J = 9.3 Hz, 1H), 7.02 - 7.00 (m, 1H), 6.09 (s, 1H), 5.71 (s, 2H), 5.65 (s, 2H), 4.32 (d, J = 5.2 Hz, 2H), 2.30 (s, 3H), 2.17 (s, 3H), 1.97-1.88 (m, 1H), 0.96 - 0.88 (m, 2H), 0.70 - 0.65 (m, 2H).

[0286] Example 74 N-(1-amino-6,7-dihydro-5H-cyclopenta[c]pyridin-5-yl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide (I-23) Scheme 74 [ka] Synthesis of N-(1-amino-6,7-dihydro-5H-cyclopenta[c]pyridin-5-yl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide. N-(1-amino-6,7-dihydro-5H-cyclopenta[c]pyridin-5-yl)-1-((6-cyclo Propylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide was synthesized according to general procedure B-2 starting from 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid and 6,7-dihydro-5H-cyclopenta[c]pyridine-1,5-diamine hydrochloride. The crude product was purified by preparative TLC (DCM / MeOH=10 / 1) to give the product (30 mg, 42%) as a white solid. ESI-MS [M + H] + : 415.2. 1H NMR (400 MHz, DMSO) δ 8.74 (d, J = 8.6 Hz, 1H), 8.59 (d, J = 6.2 Hz, 1H), 8.36 (s, 1H), 7.85 (s, 1H), 7.72 (d, J = 5.1 Hz, 1H), 7.41 (d, J = 9.3 Hz, 1H), 7.02 (dd, J = 9.4, 1.3 Hz, 1H), 6.39 (d, J = 5.1 Hz, 1H), 5.77 (s, 2H), 5.74 (s, 2H), 5.42 (q, J = 8.2 Hz, 1H), 2.79 - 2.73 (m, 1H), 2.58 - 2.50 (m, 1H), 2.41 - 2.34 (m, 1H), 2.05 - 1.90 (m, 2H), 0.95 - 0.90 (m, 2H), 0.69 - 0.66 (m, 2H).

[0287] Example 75 N-((5-amino-4H-1,2,4-triazol-3-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide (I-21) Scheme 75 [ka] Synthesis of N-((5-amino-4H-1,2,4-triazol-3-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide) N-((5-amino-4H-1,2,4-triazol-3-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide) was synthesized according to general procedure B-2 starting from 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid and 5-(aminomethyl)-4H-1,2,4-triazol-3-amine hydrochloride. The crude product was purified by trituration with DCM / MeOH (200 / 100 mL) to give the product (100 mg, 31%). ESI-MS [M + H] + : 379.2. 1 H NMR (400 MHz, DMSO) δ 11.71 (s, 1H), 8.56 (s, 1H), 8.45 (s, 1H), 8.34 (s, 1H), 7.83 (s, 1H), 7.40 (d, J = 9.4 Hz, 1H), 7.00 (dd, J = 9.4 Hz, 1.6 Hz, 1H), 5.86 (s, 2H), 5.72 (s, 2H), 4.25 (d, J = 4.9Hz, 2H), 1.94 - 1.90 (m, 1H), 0.92 - 0.90 (m, 2H), 0.68 - 0. 64 (m, 2H).

[0288] Example 76 N-((5-amino-1,3,4-thiadiazol-2-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide (I-20) Scheme 76 [ka] Synthesis of N-((5-amino-1,3,4-thiadiazol-2-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide. N-((5-amino-1,3,4-thiadiazol-2-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide was synthesized according to General Procedure B-1 starting from 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid and 5-(aminomethyl)-1,3,4-thiadiazol-2-amine hydrochloride. The crude product was purified by preparative TLC (MeOH / DCM=1 / 10) to give the product (40 mg, yield: 21%) as a white solid. ESI-MS [M +H]+: 396.1. 1 H NMR (400 MHz, DMSO) δ 9.26 (t, J = 5.9 Hz, 1H), 8.61 (s, 1H), 8.35 (s, 1H), 7.84 (s, 1H), 7.42 (d, J = 9.3 Hz, 1H), 7.10 - 6.97 (m, 3H), 5.74 (s, 2H), 4.53 (d, J = 5.9 Hz, 2H), 1.93 - 1.90 (m, 1H), 0.93 - 0.90 (m, 2H), 0.68 - 0.65 (m, 2H).

[0289] Example 77 N-((5-amino-1,3,4-oxadiazol-2-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide (I-19) Scheme 77 [ka] Synthesis of N-((5-amino-1,3,4-oxadiazol-2-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide. (Oxadiazol-2-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide was synthesized according to general procedure B-1 starting from 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid and 5-(aminomethyl)-1,3,4-oxadiazol-2-amine. The crude product was purified by preparative HPLC to give the product (29 mg, yield: 36.2%) as a white solid. ESI-MS [M +H]: 380.2. 1 H NMR (400 MHz, DMSO) δ = 9.11 (s, 1H), 8.61 (s, 1H), 8.37 (s, 1H), 7.85 (s, 1H), 7.42 - 7.40 (m, 1H), 7.03 - 6.95 (m, 3H), 5.75 (s, 2H), 4.46 (s, 2H), 1.95 - 1.90 (m, 1H), 0.95 - 0.91 (m, 2H), 0.69 -0.65 (m, 2H).

[0290] Example 78 N-((2-aminothiazol-5-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide (I-18) Scheme 78 [ka] Synthesis of N-((2-aminothiazol-5-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide. N-((2-aminothiazol-5-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide was synthesized according to General Procedure B-1 starting from 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid and 5-(aminomethyl)thiazol-2-amine. The crude product was purified by preparative HPLC to obtain the product (6.0 mg, yield: 7.5%) as a white solid. ESI-MS [M +H]+: 395.1. 1 H NMR (400 MHz, DMSO) δ 8.94 (t, J=6.0, 1H), 8.56 (s, 1H), 8.35 (s, 1H), 8.18 (s, 1H), 7.83 (s, 1H), 7.41 (d, J=9.4, 1H), 7.01-6.96 (m, 1H), 6.75 (d, J=4.9, 2H), 5.73 (s, 2H), 4.34 (d, J=6.0, 2H), 1.93-1.90 (m, 1H), 0.97 - 0.87 (m, 2H), 0.73 - 0.62 (m, 2H).

[0291] Example 79 N-(1-amino-3-methyl-6,7-dihydro-5H-cyclopenta[c]pyridin-5-yl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide (I-16) Scheme 79 [ka] Synthesis of N-(1-amino-3-methyl-6,7-dihydro-5H-cyclopenta[c]pyridin-5-yl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide. N-(1-amino-3-methyl-6,7-dihydro-5H-cyclopenta[c]pyridin-5-yl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide was synthesized according to general procedure B-2 starting from 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid and 3-methyl-6,7-dihydro-5H-cyclopenta[c]pyridine-1,5-diamine. The crude product was purified by preparative HPLC to give the product (8 mg, yield: 21%) as a white solid. ESI-MS [M +H]: 429.2. 1 H NMR (400 MHz, DMSO) δ 8.70 (d, J = 8.7 Hz, 1H), 8.58 (s, 1H), 8.36 (s, 1H), 7.85 (s, 1H), 7.42 (d, J = 9.3 Hz, 1H), 7.02 (d, J = 9.4 Hz, 1H), 6.25 (s, 1H), 5.74 (s, 2H), 5.77 (s, 2H), 5.38 (m, 1H), 2.65-2.75 (m, 1H), 2.46-2.50 (m, 1H), 2.42 - 2.30 (m, 1H), 2.18 (s, 3H), 1.90 - 2.03 (m, 2H), 0.96-0.88 (m, 2H), 0.71-0.68(m, 2H).

[0292] Example 80 N-((4-chlorothieno[3,2-c]pyridin-2-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide (I-11) Scheme 80 [ka] Synthesis of N-((4-chlorothieno[3,2-c]pyridin-2-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide. N-((4-chlorothieno[3,2-c]pyridin-2-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide The compound was synthesized according to general procedure B-2 starting from 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid and (4-chlorothieno[3,2-c]pyridin-2-yl)methanamine. The crude product was purified by preparative TLC (10% MeOH / DCM) to give the product (9.2 mg, yield: 2.6%) as an off-white solid. ESI-MS [M +H]: 464.1. 1 H NMR (400 MHz, DMSO) δ 9.40 (t, J = 6.1 Hz, 1H)., 8.62 (s, 1H), 8.35 (s, 1H), 8.19 (d, J = 5.5 Hz, 1H), 8.01 (d, J = 5.5 Hz, 1H), 7.85 (s, 1H), 7.44-7.38 (m, 2H), 7.05-6.98 (m, 1H), 5.75 (s, 2H), 4.75 (d, J = 6.0 Hz, 2H), 1.98-1.87 (m, 1H), 0.97 - 0.87 (m, 2H), 0.72-0.62 (m, 2H).

[0293] Example 81 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-((3-fluoro-4-methoxypyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide (I-7) Scheme 81 [ka] Synthesis of 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-((3-fluoro-4-methoxypyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide. 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-((3-fluoro-4-methoxypyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide was synthesized according to general procedure B-2 starting from 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid and (3-fluoro-4-methoxypyridin-2-yl)methanamine. The crude product was purified by preparative TLC (MeOH / DCM=1 / 10) to give the product (55 mg, 58.5%) as a white solid. ESI-MS: [M + H]+, 422.2. 1 H NMR (400 MHz, DMSO) δ 8.80 - 8.76 (m, 1H), 8.58 (s, 1H), 8.38 - 8.33 (m, 1H), 8.22 (d, J = 5.5 Hz, 1H), 7.84 (s, 1H), 7.41 (d, J = 9.3 Hz, 1H), 7.21 - 7.14 (m, 1H), 7.05 - 6.98 (m, 1H), 5.74 (s, 2H), 4.61 - 4.55 (m, 2H), 3.92 (s, 3H), 1.98 - 1.87 (m, 1H), 0.95 - 0.88 (m, 2H), 0.70 - 0.63 (m, 2H).

[0294] Example 82 N-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)benzyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl) (I-3)-1H-1,2,3-triazole-4-carboxamide Scheme 82 [ka] Synthesis of N-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)benzyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide. N-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)benzyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide was synthesized according to general procedure B-2, starting from 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid and (5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)methanamine. The crude product was purified by preparative TLC (DCM / MeOH=15 / 1) to give the product (50 mg, yield: 46%) as a white solid. ESI-MS [M + H] + : 508.1. 1 H NMR (400 MHz, MeOD) δ 8.45 (s, 1H), 8.37 (s, 1H), 8.21 - 8.19 (m, 1H), 7.80 (s, 1H), 7.62 (d, J = 2.2 Hz, 1H), 7.50 (dd, J = 8.5, 2.3 Hz, 1H), 7.46 (d, J = 8.5 Hz, 1H), 7.39 (d, J = 9.4 Hz, 1H), 7.11 (dd, J = 9.4, 1.7 Hz, 1H), 5.75 (s, 2H), 4.45 (s, 2H), 1.98 - 1.90 (m, 1H), 1.00 - 0.95 (m, 2H), 0.74 - 0.69 (m, 2H).

[0295] Example 83 N-(6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluoro-3-methoxybenzyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide (I-1) Scheme 83 [ka] Synthesis of N-(6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluoro-3-methoxybenzyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide. N-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)benzyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide was synthesized according to general procedure B-1 starting from 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid and (6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluoro-3-methoxyphenyl)methanamine. The crude product was purified by flash chromatography (PE / EtOAc=1 / 1) to give the product (30 mg, yield: 29.7%) as a white solid. ESI-MS [M +H]: 522.2. 1 H NMR (400 MHz, DMSO) δ 8.76 (s, 1H), 8.69-8.61 (m, 1H), 8.50 (s, 1H), 8.34 (s, 1H), 7.82 (s, 1H), 7.40 (d, J = 9.3 Hz, 1H), 7.45 - 7.28 (m, 2H), 7.05-6.97 (m, 1H), 5.71 (s, 2H), 4.35 (d, J = 5.2 Hz, 2H), 3.91 (s, 3H), 1.98-1.85 (m, 1H), 0.95 - 0.85 (m, 2H), 0.71 - 0.60 (m, 2H).

[0296] Example 84 Ethyl 3-(2-((4-((3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)benzyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)propanoate (I-113) Scheme 84 [ka] Synthesis of 3-bromo-5-cyclopropylpyridin-2-amine. To a solution of 5-cyclopropylpyridin-2-amine (10.00 g, 74.5 mmol) in MeCN (130 mL) was added 1-bromo-2,5-pyrrolidinedione (16 g, 89.4 mmol) at room temperature. The reaction mixture was stirred for 3 hours and then concentrated under reduced pressure to give 3-bromo-5-cyclopropylpyridin-2-amine (15.0 g, crude) as a yellow solid, which was used in the next reaction without further purification. ESI-MS [M + H] + : 213.0.

[0297] Synthesis of ethyl 3-(2-amino-5-cyclopropylpyridin-3-yl)acrylate. To a solution of 3-bromo-5-cyclopropylpyridin-2-amine (7.00 g, 32.85 mmol) in DMF (60 mL) was added EtN (15 mL), PPh (1.74 g, 16.43 mmol), Pd(OAc) (0.75 g, 3.3 mmol), and ethyl acrylate (6 mL, 65.7 mmol) at room temperature. The reaction mixture was heated to 95 °C and stirred for 16 h. The mixture was concentrated under reduced pressure and washed with EtOAc to give ethyl 3-(2-amino-5-cyclopropylpyridin-3-yl)acrylate (4 g, yield: 52.42%) as a yellow solid. ESI-MS [M+H] + : 233.1.

[0298] Synthesis of ethyl 3-(2-amino-5-cyclopropylpyridin-3-yl)propanoate. To a solution of ethyl 3-(2-amino-5-cyclopropylpyridin-3-yl)acrylate (5 g, 21.53 mmol) in EtOH (50 mL) / EtOAc (10 mL) was added Pd / C (500 mg). The mixture was stirred at room temperature under a hydrogen atmosphere for 16 hours. The mixture was filtered and concentrated under reduced pressure to give ethyl 3-(2-amino-5-cyclopropylpyridin-3-yl)propanoate (5.4 g, crude) as a yellow oil, which was used in the next step without further purification. ESI-MS [M +H]: 235.1.

[0299] Synthesis of ethyl 3-(2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)propanoate. To a solution of ethyl 3-(2-amino-5-cyclopropylpyridin-3-yl)propanoate (5.4 g, crude) in DMF (60 mL) was added 1,3-dichloropropan-2-one (11.7 g, 92.16 mmol) at room temperature. The reaction mixture was heated to 95° C. and stirred for 16 hours. The mixture was concentrated under reduced pressure and flash-eluted. Purification by column chromatography (0-60% EtOAc in PE) gave ethyl 3-(2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)propanoate (2.2 g, yield: 31.1%) as a red oil. ESI-MS [M+H]: 307.1.

[0300] Synthesis of ethyl 3-(2-(azidomethyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)propanoate. To a solution of ethyl 3-(2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)propanoate (2.2 g, 7.17 mmol) in DMF (30 mL) was added NaN (416 mg, 6.40 mmol). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with HO (30 mL) and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (50 mL) and concentrated under reduced pressure to give ethyl 3-(2-(azidomethyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)propanoate (1.6 g, crude) as a red oil, which was used in the next step without further purification. ESI-MS [M +H]+: 314.1.

[0301] Synthesis of benzyl 1-((6-cyclopropyl-8-(3-ethoxy-3-oxopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate. To a solution of ethyl 3-(2-(azidomethyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)propanoate (1.6 g, 5.11 mmol) in t-BuOH / HO (20 mL / 20 mL) was added benzyl propiolate (0.98 g, 6.13 mmol), sodium ascorbate (0.202 g, 1.02 mmol), and CuSO (0.163 g, 1.02 mmol) at room temperature. The mixture was stirred for 2 hours. The reaction was diluted with water (30 mL) and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (50 mL) and concentrated under reduced pressure to give benzyl 1-((6-cyclopropyl-8-(3-ethoxy-3-oxopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate (1.4 g, crude) as a red oil, which was used in the next step without further purification. ESI-MS [M +H]: 474.2.

[0302] Synthesis of 1-((6-cyclopropyl-8-(3-ethoxy-3-oxopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid. A mixture of benzyl 1-((6-cyclopropyl-8-(3-ethoxy-3-oxopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate (1.4 g, 2.97 mmol) and Pd / C (2 g) in EtOH / EtOAc (20 mL / 20 mL) was stirred under a hydrogen atmosphere at room temperature for 1 hour. The mixture was filtered and washed with MeOH (100 mL). The filtrate was concentrated under reduced pressure to give 1-((6-cyclopropyl-8-(3-ethoxy-3-oxopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid (600 mg, crude) as a white solid. ESI-MS [M +H]: 384.1.

[0303] Synthesis of ethyl 3-(2-((4-((3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)benzyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)propanoate. To a solution of 1-((6-cyclopropyl-8-(3-ethoxy-3-oxopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid (100 mg, 0.261 mmol) in DMF (3 mL) was added HATU (119.01 mg, 0.313 mmol), DIPEA (134.84 mg, 1.04 mmol), and (3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)benzyl)carbamoyl). )phenyl)methanamine (59.9 mg, 0.261 mmol) was added at room temperature. After stirring for 16 h, the reaction mixture was quenched with water (20 mL) and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, concentrated, and purified by preparative HPLC to give ethyl 3-(2-((4-((3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)benzyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)propanoate (95.4 mg, yield: 61.68%) as a white solid. ESI-MS [M + H]+: 593.2. 1 H NMR (400 MHz, DMSO) 9.84 (s, 1H), 8.93 (t, J = 5.3 Hz, 1H), 8.53 (s, 1H), 8.36 (s, 1H), 7.95 (s, 1H), 7.88 - 7.82 (m, 1H), 7.53 - 7.48 (m, 1H), 5.81 (s, 2H), 4.38 (d, J = 5.1 Hz, 2H), 4.04 (q, J = 7.1 Hz, 2H), 3.08 (t, J = 7.6 Hz, 2H), 2.77 (t, J = 7.7 Hz, 2H), 2.00 - 1.90 (m, 1H), 1.14 (t, J = 7.1 Hz, 3H), 1.00 - 0.90 (m, 2H), 0.75 - 0.65 (m, 2H).

[0304] Example 85 3-(2-((4-((3-chloro-6-cyanamid-2-fluorobenzyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)propanoic acid (I-110) and 3-(2-((4-((3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)benzyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)propanoic acid (I-109) Scheme 85 [ka] Synthesis of 3-(2-((4-((3-chloro-6-cyanamid-2-fluorobenzyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)propanoic acid and 3-(2-((4-((3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)benzyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)propanoic acid. To a solution of ethyl 3-(2-((4-((3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)benzyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)propanoate (80 mg, 0.135 mmol) in EtOH / HO (10 mL / 10 mL) was added LiOH·HO (10.8 mg, 0.27 mmol) at room temperature. The reaction mixture was stirred at room temperature for 0.5 h. The pH of the mixture was adjusted to 3 by adding HCl (1 M, aq.), and the mixture was extracted with EtOAc (20 mL × 3). The combined organic layer was concentrated under reduced pressure and purified by preparative HPLC to give 3-(2-((4-((3-chloro-6-cyanamido-2-fluoro)methyl)propanoate. (benzyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)propanoic acid (I-110, 32.4 mg, yield: 44.7%) was obtained as a white solid, and 3-(2-((4-((3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)benzyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)propanoic acid (I-109, 5.4 mg, yield: 7.1%) was obtained as a white solid. I-110: ESI-MS [M + H]: 537.1. 1H NMR (400 MHz, DMSO) d 12.16 (s, 1H), 10.20 (s, 1H), 9.22 (s, 1H), 8.62 (s, 1H), 8.20 (s, 1H), 7.78 (s, 1H), 7.53 (t, J = 8.4 Hz, 1H), 6.96 (d, J = 8.8 Hz, 1H), 6.85 (s, 1H), 5.75 (s, 2H), 4.44 (d, J = 4.7 Hz, 2H), 3.03 (t, J = 7.6 Hz, 2H), 2.69 (t, J = 7.6 Hz, 2H), 1.93 - 1.84 (m, 1H), 0.96 - 0.86 (m, 2H), 0.70 - 0.62 (m, 2H). I-109:ESI-MS [M +H]+: 565.1. 1 H NMR (400 MHz, DMSO) d 12.18 (s, 1H), 9.85 (s, 1H), 8.91 (d, J = 5.4 Hz, 1H), 8.49 (s, 1H), 8.20 (d, J = 1.2 Hz, 1H), 7.87 - 7.82 (m, 1H), 7.76 (s, 1H), 7.50 (dd, J = 8.7, 1.4 Hz, 1H), 6.84 (s, 1H), 5.71 (s, 2H), 4.37 (d, J = 4.9 Hz, 2H), 3.03 (t, J = 7.6 Hz, 2H), 2.70 - 2.66 (m, 2H), 1.91 - 1.85 (m, 1H), 0.94 - 0.86 (m, 2H), 0.68 - 0.60 (m, 2H).

[0305] Example 86 Ethyl 3-(2-((4-((6-cyano-2-fluoro-3-methoxybenzyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)propanoate (I-108) Scheme 86 [ka] Synthesis of ethyl 3-(2-((4-((6-cyano-2-fluoro-3-methoxybenzyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)propanoate. A mixture of 1-((6-cyclopropyl-8-(3-ethoxy-3-oxopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid (192 mg, 0.5 mmol) in SOCl (2 mL) was stirred at room temperature for 2 hours and then concentrated under reduced pressure. The residue was redissolved in THF (3 mL) and diluted with 2-(aminomethyl)-3-fluoro-4-methoxybenzonitrile (90 mg, 0.5 mmol) and LiHM. To a solution of DS (1 M in THF, 2 mL) in THF (5 mL) was added at 0° C. The resulting mixture was stirred at room temperature for 2 hours. The reaction was quenched with saturated aqueous NH4Cl (10 mL) and extracted with EtOAc (20×3 mL). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the crude product, which was purified by preparative HPLC to give ethyl 3-(2-((4-((6-cyano-2-fluoro-3-methoxybenzyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)propanoate (20 mg, yield: 7%) as an off-white solid. ESI-MS [M+H]+: 546.2. 1 H NMR (400 MHz, DMSO) δ 9.04 (t, J = 5.3 Hz, 1H), 8.55 (s, 1H), 8.22 (s, 1H), 7.78 (s, 1H), 7.65 (dd, J = 8.6, 1.3 Hz, 1H), 7.27 (t, J = 8.4 Hz, 1H), 6.84 (s, 1H), 5.74 (s, 2H), 4.58 (d, J = 5.1 Hz, 2H), 4.03 (q, J = 7.1 Hz, 2H), 3.91 (s, 3H), 3.07 (t, J = 7.6 Hz, 2H), 2.76 (t, J = 7.6 Hz, 2H), 1.91-1.85 (m, 1H), 1.14 (t, J = 7.1 Hz, 3H), 0.97 - 0.82 (m, 2H), 0.74 - 0.56 (m, 2H).

[0306] Example 87 3-(2-((4-((6-cyano-2-fluoro-3-methoxybenzyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)propanoic acid (I-107) Scheme 87 [ka] Synthesis of 3-(2-((4-((6-cyano-2-fluoro-3-methoxybenzyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)propanoic acid. A mixture of ethyl 3-(2-((4-((6-cyano-2-fluoro-3-methoxybenzyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)propanoate (55 mg, 0.1 mol) in TFA (2 mL) and EtSiH (1 mL) was stirred at 80° C. for 36 hours. The reaction mixture was concentrated under reduced pressure to give the crude product, which was purified by preparative HPLC to give 3-(2-((4-((6-cyano-2-fluoro-3-methoxybenzyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)propanoic acid (5 mg, yield: 10%) as a white solid. ESI-MS [M+H]: 518.2. 1 H NMR (400 MHz, DMSO) δ 12.17 (s, 1H), 9.04 (t, J = 5.4 Hz, 1H), 8.56 (s, 1H), 8.21 (s, 1H), 7.77 (s, 1H), 7.65 (dd, J = 8.6, 1.3 Hz, 1H), 7. 27 (t, J = 8.4 Hz, 1H), 6.84 (s, 1H), 5.74 (s, 2H), 4.58 (d, J = 5.2 Hz, 2H), 3.91 (s, 3H), 3.04 (t, J = 7.6 Hz, 2H), 2.68 (t, J = 7.6 Hz, 2H), 1.92-1.85 (m, 1H), 0.94 - 0.85 (m, 2H), 0.70 - 0.59 (m, 2H).

[0307] Example 88 Ethyl 3-(6-cyclopropyl-2-((4-((2-fluoro-3-methoxy-6-(1H-tetrazol-1-yl)benzyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-8-yl)propanoate (I-89) and 3-(6-cyclopropyl-2-((4-((2-fluoro-3-methoxy-6-(1H-tetrazol-1-yl)benzyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-8-yl)propanoic acid (I-92) Scheme 88 [ka] Synthesis of ethyl 3-(6-cyclopropyl-2-((4-((2-fluoro-3-methoxy-6-(1H-tetrazol-1-yl)benzyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-8-yl)propanoate. To a solution of 1-((6-cyclopropyl-8-(3-ethoxy-3-oxopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid (200 mg, 0.52 mmol), (2-fluoro-3-methoxy-6-(1H-tetrazol-1-yl)phenyl)methanamine (116 mg, 0.52 mmol), and HATU (257 mg, 0.678 mmol) in DMF (5 mL) was added DIPEA (335 mg, 2.6 mmol). The reaction mixture was stirred at room temperature for 14 hours. Water (20 mL) was added, and the mixture was extracted with EtOAc (20 mL × 3). The combined organic layer was concentrated under reduced pressure and purified by preparative TLC (DCM / MeOH=10 / 1) to give ethyl 3-(6-cyclopropyl-2-((4-((2-fluoro-3-methoxy-6-(1H-tetrazol-1-yl)benzyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-8-yl)propanoate as a white solid (150 mg, yield: 49%). ESI-MS [M +H]: 589.3. 1H NMR (400 MHz, DMSO) 9.74 (s, 1H), 8.77 (t, J = 5.4 Hz, 1H), 8.50 (s, 1H), 8.27 (s, 1H), 7.84 (s, 1H), 7.39 - 7.32 (m, 2H), 6.95 (s, 1H), 5.75 (s, 2H), 4.29 (d, J = 5.2 Hz, 2H), 4.03 (q, J = 7.1 Hz, 2H), 3.92 (s, 3H), 3.07 (t, J = 7.6 Hz, 2H), 2.76 (t, J = 7.6 Hz, 2H), 1.90 (d, J = 4.6 Hz, 1H), 1.14 (t, J = 7.1 Hz, 3H), 0.93 (d, J = 6.7 Hz, 2H), 0.67 (d, J = 5.3 Hz, 2H)。

[0308] Synthesis of 3-(6-cyclopropyl-2-((4-((2-fluoro-3-methoxy-6-(1H-tetrazol-1-yl)benzyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-8-yl)propanoic acid. To a solution of ethyl 3-(6-cyclopropyl-2-((4-((2-fluoro-3-methoxy-6-(1H-tetrazol-1-yl)benzyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-8-yl)propanoate (80 mg, 0.136 mmol) in THF / HO (5 mL / 1 mL) was added LiOH·HO (17 mg, 0.408 mmol). The reaction mixture was stirred at room temperature for 2 hours. The pH of the mixture was adjusted to 5 by adding HCl (1M, aq.), and the mixture was extracted with EtOAc (20 mL × 3). The combined organic layer was concentrated under reduced pressure and purified by preparative TLC (DCM / MeOH = 10 / 1) to give 3-(6-cyclopropyl-2-((4-((2-fluoro-3-methoxy-6-(1H-tetrazol-1-yl)benzyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-8-yl)propanoic acid as a white solid (28 mg, yield: 36.8%). ESI-MS [M +H]: 561.2. 1 H NMR (400 MHz, DMSO) δ 12.17 (s, 1H), 9.74 (s, 1H), 8.77 (t, J = 5.4 Hz, 1H), 8.50 (s, 1H), 8.23 ​​(s, 1H), 7.79 (s, 1H), 7.47 - 7.21 (m, 2H), 6.89 (s, 1H), 5.73 (s, 2H), 4.29 (d, J = 5.2 Hz, 2H), 3.92 (s, 3H), 3.03 (t, J = 7.6 Hz, 2H), 2.68 (t, J = 7.6 Hz, 2H), 1.97 - 1.83 (m, 1H), 0.94-0.89 (m, 2H), 0.68-0.65 (m, 2H).

[0309] Example 89 Ethyl 2-((4-((4-carbamimidoyl-2,6-dimethylbenzyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-carboxylate (I-112) and 2-((4-((4-carbamimidoyl-2,6-dimethylbenzyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-carboxylic acid (I-111) Scheme 89 [ka] Synthesis of ethyl 2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-carboxylate. A mixture of ethyl 2-amino-5-cyclopropylnicotinate (3 g, 14.55 mmol) and 1,3-dichloropropan-2-one (5.5 g, 43.32 mmol) in EtOH (100 mL) was stirred at 95 °C for 1 hour. The reaction mixture was concentrated under reduced pressure to remove EtOH. The residue was adjusted to pH 9 using saturated aqueous NaHCO and then extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine (150 mL), dried over NaSO, and concentrated under reduced pressure to give the crude product, which was purified by flash chromatography (PE / EtOAc = 1 / 1) to give ethyl 2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-carboxylate (2.5 g, yield: 61.7%). ESI-MS [M + H] + : 279.2.

[0310] Synthesis of ethyl 2-(azidomethyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-carboxylate. To a solution of ethyl 2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-carboxylate (2.5 g, 9 mmol) in 50 mL of DMF was added NaN (0.88 g, 13.5 mmol). The reaction mixture was stirred at room temperature for 3 hours. HO (100 mL) was added, and the mixture was extracted with EtOAc (150 mL × 2). The combined organic layers were washed with brine, dried over NaSO, and concentrated under reduced pressure to give crude ethyl 2-(azidomethyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-carboxylate as a brown solid, which was used in the next step without further purification (2.6 g crude). ESI-MS [M + H] + : 286.2.

[0311] Synthesis of ethyl 2-((4-((benzyloxy)carbonyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-carboxylate. To a solution of ethyl 2-(azidomethyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-carboxylate (2.6 g crude from the previous step) and benzyl propiolate (1.58 g, 9.9 mmol) in t-BuOH / HO (20 mL / 20 mL) was added CuSO (288 mg, 1.8 mmol) and sodium ascorbate. (356 mg, 1.8 mmol) was added. The reaction mixture was stirred at room temperature for 3 hours. HO (50 mL) was added, and the mixture was extracted with DCM (100 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 column chromatography (DCM / MeOH = 20 / 1) to give ethyl 2-((4-((benzyloxy)carbonyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-carboxylate (1.5 g, 38% for two steps). ESI-MS [M + H] + : 446.2.

[0312] Synthesis of ethyl 2-((4-((benzyloxy)carbonyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-carboxylate. A mixture of ethyl 2-((4-((benzyloxy)carbonyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-carboxylate (700 mg, 1.57 mmol) and Pd / C (300 mg) in MeOH (20 mL) was stirred at room temperature under an H atmosphere for 4 hours. The reaction mixture was filtered to give 1-((6-cyclopropyl-8-(ethoxycarbonyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid (300 mg, yield: 53.8%), which was used in the next step without further purification. ESI-MS [M + H] + : 356.2.

[0313] Synthesis of ethyl 2-((4-((4-cyano-2,6-dimethylbenzyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-carboxylate. To a solution of 1-((6-cyclopropyl-8-(ethoxycarbonyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid (300 mg, 0.84 mmol), 4-(aminomethyl)-3,5-dimethylbenzonitrile hydrochloride (215 mg, 1.34 mmol), HOBT (176 mg, 1.3 mmol), and EDCI (250 mg, 1.3 mmol) in DMF (20 mL) was added DIPEA (549 mg, 4.25 mmol). The reaction mixture was stirred at room temperature for 14 hours. HO (50 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 column chromatography (DCM / MeOH = 20 / 1) to give ethyl 2-((4-((4-cyano-2,6-dimethylbenzyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-carboxylate (250 mg, 59.8%) as a brown solid. ESI-MS [M + H] + : 498.2

[0314] Synthesis of ethyl 2-((4-((4-carbamimidoyl-2,6-dimethylbenzyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-carboxylate. HCl (g) was bubbled through a solution of ethyl 2-((4-((4-cyano-2,6-dimethylbenzyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-carboxylate (280 mg, 0.56 mmol) in MeOH (20 mL) for 3 hours. The reaction mixture was concentrated under reduced pressure. MeOH (20 mL) and NH4HCO3 (442 mg, 5.6 mmol) were added. The reaction mixture was stirred at room temperature for 14 hours. The mixture was concentrated under reduced pressure to give the crude product, which was purified by preparative HPLC to give ethyl 2-((4-((4-carbamimidoyl-2,6-dimethylbenzyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-carboxylate (140 mg, 48.6%) as a white solid. ESI-MS [M + H] + : 515.2. 1 H NMR (400 M Hz, DMSO) δ 10.20 (s, 2H), 9.02 (s, 1H), 8.74 (t, J = 5.4 Hz, 1H), 8.59 - 8.57 (m, 2H), 8.38 (s, 1H), 7.91 (s, 1H), 7.62 (d, J = 1.8 Hz, 1H), 7.46 (s, 2H), 5.78 (s, 2H), 4.52 (d, J = 5.3 Hz, 2H), 4.33 (q, J = 7.1 Hz, 2H), 2.45 (s, 6H), 2.01 - 1.98 (m, 1H), 1.31 (t, J = 7.1 Hz, 2H), 1.02 - 0.89 (m, 2H), 0.79 - 0.65 (m, 2H).

[0315] Synthesis of 2-((4-((4-carbamimidoyl-2,6-dimethylbenzyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-carboxylic acid. To a solution of ethyl 2-((4-((4-carbamimidoyl-2,6-dimethylbenzyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-carboxylate (90 mg, 0.17 mmol) in THF / HO (15 mL / 15 mL) was added LiOH (22 mg, 0.52 mmol). The reaction mixture was stirred at room temperature for 3 hours. The mixture was concentrated under reduced pressure to give the crude material, which was purified by preparative HPLC to give 2-((4-((4-carbamimidoyl-2,6-dimethylbenzyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-carboxylic acid (20 mg, 24%) as a white solid. ESI-MS [M + H] + : 487.2. 1 H NMR (400 MHz, DMSO) δ 9.20 (s, 2H), 8.92 (s, 2H), 8.80 (t, J = 5.4 Hz, 1H), 8.74 (s, 1H), 8.61 (s, 1H), 8.12 (s, 1H), 7.92 (s, 1H), 7.47 (s, 2H), 5.88 (s, 2H), 4.52 (d, J = 5.4 Hz, 2H), 2.45 (s, 6H), 2.19 - 2.04 (m, 1H), 1.05 - 1.00 (m, 2H), 0.79 - 0.75 (m, 2H).

[0316] Example 90 1-((6-cyclopropyl-8-fluoroimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(1H-tetrazol-1-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide (I-99) Scheme 90 [ka] Synthesis of 5-cyclopropyl-3-fluoropyridin-2-amine. A mixture of 5-chloro-3-fluoropyridin-2-amine (2 g, 13.65 mmol), cyclopropylboronic acid (1.76 g, 20.47 mmol), Pd(OAc) (306 mg, 1.365 mmol), SPhos (1.12 g, 2.73 mmol), and KPO (10.14 g, 47.78 mmol) in toluene (40 mL) and HO (10 mL) was stirred at 90 °C for 16 h under N. The reaction mixture was filtered and washed with EtOAc. The combined filtrate was washed with HO (100 mL) and brine (100 mL), dried over NaSO, concentrated, and purified by silica gel chromatography (EA / PE=1 / 2) to give 5-cyclopropyl-3-fluoropyridin-2-amine (2.2 g, yield: 100%) as a yellow syrup. ESI-MS [M+H] + : 153.2.

[0317] Synthesis of 2-(chloromethyl)-6-cyclopropyl-8-fluoroimidazo[1,2-a]pyridine. A mixture of 5-cyclopropyl-3-fluoropyridin-2-amine (2.2 g, 13.65 mmol) and 1,3-dichloropropan-2-one (5.5 g, 43.38 mmol) in EtOH (40 mL) was stirred at 85 °C for 16 h. The reaction mixture was concentrated. The residue was washed with aqueous NaHCO and extracted with EtOAc (100 mL × 3). The organic layer was washed with brine (100 mL), dried over NaSO, concentrated, and purified by silica gel chromatography (EA / PE = 1 / 2) to give 2-(chloromethyl)-6-cyclopropyl-8-fluoroimidazo[1,2-a]pyridine (1.8 g, 58%) as a yellow solid. ESI-MS [M+H] + : 225.1.

[0318] Synthesis of 2-(azidomethyl)-6-cyclopropyl-8-fluoroimidazo[1,2-a]pyridine. A mixture of 2-(chloromethyl)-6-cyclopropyl-8-fluoroimidazo[1,2-a]pyridine (1.8 g, 8.01 mmol) and NaN (625 mg, 9.61 mmol) in DMF (20 mL) was stirred at room temperature for 3 hours. The reaction mixture was poured into HO (100 mL) and extracted with EtOAc (80 mL × 2). The combined organic components were washed with brine (160 mL), concentrated, and dried under reduced pressure to give 2-(azidomethyl)-6-cyclopropyl-8-fluoroimidazo[1,2-a]pyridine (1.75 g, 95% yield) as a white solid. ESI-MS [M+H] + : 232.1.

[0319] 1-((6-cyclopropyl-8-fluoroimidazo[1,2-a]pyridine-2-yl) Synthesis of ethyl (methyl)-1H-1,2,3-triazole-4-carboxylate. A mixture of 2-(azidomethyl)-6-cyclopropyl-8-fluoroimidazo[1,2-a]pyridine (1.75 g, 7.57 mmol), ethyl propiolate (891 mg, 9.08 mmol), CuSO (362 mg, 2.27 mmol), and sodium ascorbate (750 mg, 3.79 mmol) in t-BuOH (20 mL) and HO (20 mL) was stirred at room temperature for 3 hours. HO (50 mL) was added to the reaction mixture, which was then extracted with EtOAc (100 mL × 3). The combined organic components were washed with brine (100 mL), dried over NaSO, and concentrated to give the crude product, which was purified by silica gel chromatography (EA / PE=1 / 2) to give ethyl 1-((6-cyclopropyl-8-fluoroimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate (1.0 g, yield: 40%) as a white solid. ESI-MS [M+H] + : 330.1.

[0320] Synthesis of 1-((6-cyclopropyl-8-fluoroimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid. To a solution of ethyl 1-((6-cyclopropyl-8-fluoroimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate (270 mg, 0.82 mmol) in methanol (4 mL), THF (4 mL), and HO (2 mL) was added lithium hydroxide monohydrate (138 mg, 3.28 mmol). The mixture was stirred at 40 °C for 2 h. MeOH and THF were removed. The residue was diluted in HO (20 mL) and acidified with HCl (1 N) to pH 5-6, resulting in the precipitation of a yellow solid. The mixture was filtered and dried under vacuum to give 1-((6-cyclopropyl-8-fluoroimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid (220 mg, 89%) as a yellow solid. ESI-MS [M+H] + : 302.1.

[0321] Synthesis of 1-((6-cyclopropyl-8-fluoroimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(1H-tetrazol-1-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide. A mixture of 1-((6-cyclopropyl-8-fluoroimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid (60 mg, 0.2 mmol), (2-fluoro-3-methoxy-6-(1H-tetrazol-1-yl)phenyl)methanamine (45 mg, 0.2 mmol), HATU (114 mg, 0.3 mmol), and DIPEA (155 mg, 1.2 mmol) in DMF (3 mL) was stirred at room temperature for 16 hours. The reaction mixture was poured into water (40 mL), and a white solid precipitated. The mixture was filtered, washed with water (30 mL), dried under reduced pressure, and purified by silica gel chromatography (DCM / MeOH=20 / 1) to give 1-((6-cyclopropyl-8-fluoroimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(1H-tetrazol-1-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide (40 mg, yield: 40%) as a white solid. ESI-MS [M + H] + : 507.2. 1 H NMR (400 MHz, DMSO) δ 9.75 (s, 1H), 8.77 (t, J = 5.5 Hz, 1H), 8.51 (s, 1H), 8.26 (d, J = 0.8 Hz, 1H), 7.94 (d, J = 3.0 Hz, 1H), 7.40 - 7.31 (m, 2H), 6.95 (dd, J = 12.4, 1.2 Hz, 1H), 5.73 (s, 2H), 4.29 (d, J = 5.1 Hz, 2H), 3.92 (s, 3H), 1.97 - 1.91 (m, 1H), 0.96 - 0.89 (m, 2H), 0.72 - 0.67 (m, 2H).

[0322] Example 91 1-((6-cyclopropyl-8-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(1H-tetrazol-1-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide (I-93) Scheme 91 [ka] Synthesis of 2-(chloromethyl)-6-cyclopropyl-8-(trifluoromethyl)imidazo[1,2-a]pyridine. A mixture of 5-cyclopropyl-3-(trifluoromethyl)pyridin-2-amine (600 mg, 2.97 mmol) and 1,3-dichloropropan-2-one (1.14 g, 8.98 mmol) in EtOH (5 mL) was stirred at 85 °C overnight. The reaction mixture was concentrated under reduced pressure, diluted with saturated aqueous NaHCO (50 mL), and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (50 mL), dried over NaSO, concentrated, and purified by silica gel chromatography (PE / EtOAc = 2 / 1) to give 2-(chloromethyl)-6-cyclopropyl-8-(trifluoromethyl)imidazo[1,2-a]pyridine (350 mg, yield: 43%) as a brown solid. ESI-MS [M + H] + : 275.1.

[0323] Synthesis of 2-(azidomethyl)-6-cyclopropyl-8-(trifluoromethyl)imidazo[1,2-a]pyridine. A mixture of 2-(chloromethyl)-6-cyclopropyl-8-(trifluoromethyl)imidazo[1,2-a]pyridine (350 mg, 1.27 mmol) and NaN3 (413 mg, 6.4 mmol) in DMF (10 mL) was stirred at room temperature for 3 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, and concentrated. This gave 2-(azidomethyl)-6-cyclopropyl-8-(trifluoromethyl)imidazo[1,2-a]pyridine (400 mg crude) as a yellow solid. ESI-MS [M + H]+ : 282.1.

[0324] Synthesis of ethyl 1-((6-cyclopropyl-8-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate. A mixture of 2-(azidomethyl)-6-cyclopropyl-8-(trifluoromethyl)imidazo[1,2-a]pyridine (400 mg, 1.4 mmol), ethyl propiolate (420 mg, 4.25 mmol), CuSO (115 mg, 0.7 mmol), and sodium ascorbate (125 mg, 0.7 mmol) in HO / t-BuOH (10 mL / 10 mL) was stirred at room temperature for 3 hours. The reaction mixture was concentrated, diluted with water (45 mL), and extracted with EtOAc (30 mL × 5). The combined organic layers were washed with brine (40 mL), dried over NaSO, and concentrated under reduced pressure to give a crude product, which was purified by silica gel chromatography (DCM / MeOH=15 / 1) to give ethyl 1-((6-cyclopropyl-8-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate (350 mg, yield: 66%) as a yellow solid. ESI-MS [M+H]: 380.1.

[0325] Synthesis of 1-((6-cyclopropyl-8-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid. A mixture of ethyl 1-((6-cyclopropyl-8-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate (350 mg, 0.9 mmol) and LiOH·HO (76 mg, 1.8 mmol) in THF / EtOH / HO (4 mL / 4 mL / 2 mL) was stirred at 50 °C for 3 h. The reaction mixture was concentrated under reduced pressure to give a residue, which was diluted with water (10 mL) and acidified to pH 2–3 with HCl (3 M). The resulting precipitate was collected by filtration and dried to give 1-((6-cyclopropyl-8-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid (300 mg, yield: 95%) as a white solid. ESI-MS [M +H]: 352.1.

[0326] Synthesis of 1-((6-cyclopropyl-8-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(1H-tetrazol-1-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide. A mixture of 1-((6-cyclopropyl-8-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid (35 mg, 0.1 mmol), (2-fluoro-3-methoxy-6-(1H-tetrazol-1-yl)phenyl)methanamine (25 mg, 0.11 mmol), HOBT (27 mg, 0.2 mmol), EDCI (38 mg, 0.2 mmol), and DIPEA (65 mg, 0.5 mmol) in DMF (2 mL) was stirred at room temperature for 16 hours. Water (20 mL) was added, and the mixture was extracted with EtOAc (20 mL × 3). The combined organic layer was washed with brine (30 mL), dried over NaSO, concentrated, and purified by silica gel chromatography (DCM / MeOH=10 / 1) to give 1-((6-cyclopropyl-8-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(1H-tetrazol-1-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide (24.8 mg, yield: 45%) as a white solid. ESI-MS [M+H]: 557.2. 1 H NMR (400 MHz, DMSO) δ 9.74 (s, 1H), 8.78 (t, J = 5.4 Hz, 1H), 8.60 (s, 1H), 8.51 (s, 1H), 7.92 (s, 1H), 7.50 (s, 1H), 7.50 - 7.32 (m, 2H), 5.78 (s, 2H), 4.29 (d, J = 5.2 Hz, 2H), 3.92 (s, 3H), 2.07 - 1.99 (m, 1H), 0.98 - 0.93 (m, 2H), 0.77 - 0.0.73 (m, 2H).

[0327] Example 92 1-((6-cyclopropyl-8-(3-fluorooxetan-3-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(1H-tetrazol-1-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide (I-91) Scheme 92 [ka] Synthesis of 3-(2-amino-5-chloropyridin-3-yl)oxetan-3-ol. To a solution of 3-bromo-5-chloropyridin-2-amine (5 g, 24 mmol) in THF (100 mL), n-BuLi (35 mL, 2.4 M solution in hexane, 84 mmol) was added dropwise at −78° C. After 5 minutes, oxetan-3-one (17 g, 240 mmol) in THF (50 mL) was added and stirred at −78° C. for 2 hours. The reaction was quenched with saturated aqueous NH4Cl (100 mL) and extracted with ethyl acetate (100 mL × 3). The combined organic layers were washed with brine (50 mL), dried over NaSO, and concentrated to give the crude product, which was purified by silica gel column chromatography (DCM / MeOH=15 / 1) to give 3-(2-amino-5-chloropyridin-3-yl)oxetan-3-ol (2.8 g, 58% yield) as a yellow solid. ESI-MS [M+H] + : 201.1. 1 H NMR (400 MHz, DMSO-d6) δ 7.93 (d, J = 2.5 Hz, 1H), 7.61 (d, J = 2.5 Hz, 1H), 6.49 (s, 1H), 5.81 (s, 2H), 4.84 (d, J = 7.4 Hz, 2H), 4.72 (d, J = 7.4 Hz, 2H).

[0328] Synthesis of 3-(2-amino-5-cyclopropylpyridin-3-yl)oxetan-3-ol. A mixture of 3-(2-amino-5-chloropyridin-3-yl)oxetan-3-ol (2.8 g, 14 mmol), cyclopropylboronic acid (2.4 g, 28 mmol), KPO (8.9 g, 42 mmol), SPhos (1.1 g, 2.7 mmol), and Pd(OAc) (0.3 g, 1.3 mmol) in toluene / HO (50 mL / 5 mL) was stirred at 90 °C for 16 h. The reaction mixture was filtered through Celite and washed with EtOAc (100 mL). The filtrate was concentrated to give the crude product, which was purified by silica gel column chromatography (DCM / MeOH=8 / 1) to give 3-(2-amino-5-cyclopropylpyridin-3-yl)oxetan-3-ol (2.1 g, 73% yield) as a yellow solid. ESI-MS [M+H] + : 207.2. 1 H NMR (400 MHz, DMSO-d6) δ 7.75 (d, J = 1.8 Hz, 1H), 7.17 (d, J = 2.1 Hz, 1H), 6.34 (s, 1H), 5.34 (s, 2H), 4.85 (d, J = 7.1 Hz, 2H), 4.70 (d, J = 7.2 Hz, 2H), 3.61 (s, 1H), 1.85-1.78 (m, 1H), 0.86-0.80 (m, 2H), 0.64-0.59 (m, 2H).

[0329] Synthesis of 3-(2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)oxetan-3-ol. A mixture of 3-(2-amino-5-cyclopropylpyridin-3-yl)oxetan-3-ol (2 g, 9.7 mmol), 1,3-dichloropropan-2-one (3.85 g, 31 mmol) in EtOH (50 mL) was stirred at 80° C. for 16 hours. The reaction was concentrated, and the residue was diluted with ethyl acetate (50 mL), washed with saturated aqueous NaHCO (30 mL), HO (30 mL), and brine (30 mL), dried over NaSO, and concentrated to give the crude product, which was purified by silica gel column chromatography (DCM / MeOH=8 / 1) to give 3-(2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)oxetan-3-ol (1.2 g, 44% yield) as a yellow solid. ESI-MS [M+H] + : 279.1. 1 H NMR (400 MHz, DMSO-d6) δ 8.54 (s, 1H), 8.15 (s, 1H), 7.54 (s, 1H), 5.10 (d, J = 6.5 Hz, 2H), 4.96 (s, 2H), 4.80 (d, J = 6.4 Hz, 2H), 2.07 (d, J = 4.7 Hz, 1H), 1.06-0.98 (m, 2H), 0.80 (d, J = 5.1 Hz, 2H).

[0330] Synthesis of ethyl 1-((6-cyclopropyl-8-(3-hydroxyoxetan-3-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate. A mixture of 3-(2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)oxetan-3-ol (500 mg, 1.8 mmol) and NaN (176 mg, 2.7 mmol) in DMF (15 mL) was stirred at room temperature for 3 hours. HO (30 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 Na2SO4, and concentrated under reduced pressure to give the crude product, which was purified by silica gel chromatography (EA / PE=1 / 1) to give 3-(2-(azidomethyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)oxetan-3-ol (420 mg, yield: 82%) as a yellow solid. ESI-MS [M+H] + : 286.1.

[0331] Synthesis of ethyl 1-((8-(3-hydroxyoxetan-3-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate. 3-(2-(azidomethyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)oxetan-3-ol (420 mg, 1.47 mmol) in t-BuOH To a solution in HCl / HO (10 mL / 10 mL) was added ethyl propiolate (158 mg, 1.6 mmol), CuSO (70 mg, 0.44 mmol), and sodium ascorbate (87 mg, 0.44 mmol). The resulting reaction was stirred at room temperature for 3 hours. The reaction was concentrated under reduced pressure to give a residue, which was purified by silica gel chromatography (EA / PE=1 / 1) to give ethyl 1-((8-(3-hydroxyoxetan-3-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate (400 mg, yield: 71%) as a yellow solid. ESI-MS [M+H] + : 383.2.

[0332] Synthesis of 1-((8-(3-hydroxyoxetan-3-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid. A mixture of ethyl 1-((8-(3-hydroxyoxetan-3-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate (400 mg, 1.05 mmol) and LiOH (140 mg, 5.8 mmol) in THF / HO (15 mL / 5 mL) was stirred at 50° C. for 3 hours. The reaction was concentrated under reduced pressure to give the crude product, which was purified by preparative HPLC to give 1-((8-(3-hydroxyoxetan-3-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid (220 mg, 58% yield) as a yellow solid. ESI-MS [M+H] + : 356.2.

[0333] Synthesis of 1-((6-cyclopropyl-8-(3-hydroxyoxetan-3-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(1H-tetrazol-1-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide. To a solution of 1-((6-cyclopropyl-8-(3-hydroxyoxetan-3-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid (125 mg, 0.35 mmol), (2-fluoro-3-methoxy-6-(1H-tetrazol-1-yl)phenyl)methanamine hydrochloride (178 mg, 0.70 mmol), EDCI (102 mg, 0.53 mmol), and HOBT (72 mg, 0.53 mmol) in DMF (10 mL) was added DIPEA (135 mg, 1.05 mmol). The reaction mixture was stirred at room temperature for 12 hours. HO (30 mL) was added, and the mixture was extracted with EtOAc (30 mL × 3). The combined organic layer was washed with brine (30 mL), 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-((6-cyclopropyl-8-(3-hydroxyoxetan-3-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(1H-tetrazol-1-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide (20 mg, yield: 10%) as a white solid. ESI-MS [M+H]: 561.2.

[0334] Synthesis of 1-((6-cyclopropyl-8-(3-fluorooxetan-3-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(1H-tetrazol-1-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide. To a solution of 1-((6-cyclopropyl-8-(3-hydroxyoxetan-3-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(1H-tetrazol-1-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide (20 mg, 0.036 mmol) in DCM (5 mL) was added DAST (11 mg, 0.072 mmol) under nitrogen at −78° C. The mixture was stirred at -20 °C for 3 h. The reaction was quenched with saturated aqueous NaHCO (15 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over NaSO, and concentrated under reduced pressure to give the crude product, which was Purification by silica gel chromatography (DCM / MeOH=10 / 1) gave 1-((6-cyclopropyl-8-(3-fluorooxetan-3-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(1H-tetrazol-1-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide (10 mg, yield: 49%) as a white solid. ESI-MS [M +H] + : 563.2. 1 H NMR (400 MHz, DMSO) δ 9.74 (d, J = 2.6 Hz, 1H), 8.778-8.74 (m, 1H), 8.48 (d, J = 2.6 Hz, 1H), 8.42 (s, 1H), 7.81 (s, 1H), 7.39-7.35 (m, 2H), 7.17 (s, 1H), 5.75 (s, 2H), 5.33-5.25 (m, 2H), 4.99-4.91 (m, 2H), 4.29 (s, 2H), 3.93 (s, 3H), 1.98-1.95 (m, 1H), 0.95-0.92 (m, 2H), 0.74-071 (m, 2H).

[0335] Example 93 Ethyl 3-(6-cyclopropyl-2-((4-((2-fluoro-3-methoxy-6-(1H-tetrazol-1-yl)benzyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-8-yl)-2,2-dimethylpropanoate (I-85) Scheme 93 [ka] Synthesis of tert-butyl 1-((6-cyclopropyl-8-(hydroxymethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate. A mixture of (2-(azidomethyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)methanol (20 g, 82.38 mmol), tert-butyl propiolate (10.4 g, 82.38 mmol), CuSO (657 mg, 4.12 mmol), and sodium ascorbate (1.63 g, 8.24 mmol) in t-BuOH (100 mL) and HO (100 mL) was stirred at 25 °C for 16 h. Removal of t-BuOH gave a residue which was diluted in HO (100 mL) and diluted with DCM. The combined organic phase was washed with brine (300 mL), dried over NaSO, and concentrated to give the crude product, which was triturated with EtOAc and dried to give tert-butyl 1-((6-cyclopropyl-8-(hydroxymethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate (18 g, yield: 59%) as a light brown solid. ESI-MS [M+H] + : 370.1.

[0336] Synthesis of tert-butyl 1-((8-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate. To a stirred solution of tert-butyl 1-((6-cyclopropyl-8-(hydroxymethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate (2 g, 5.41 mmol) in DCM (30 mL) was added SOCl (1.29 g, 10.82 mmol) dropwise at 0° C. The mixture was stirred at 25° C. for 1 hour. The reaction mixture was concentrated, and the residue was dissolved in DCM (80 mL), washed with saturated aqueous NaHCO (80 mL) and brine, dried over NaSO, and concentrated to give the crude product, which was purified by silica gel chromatography (EtOAc / PE=1 / 1) to give tert-butyl 1-((8-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate (1.8 g, yield: 86%) as a light brown solid. ESI-MS [M+H] + : 388.1.

[0337] Synthesis of tert-butyl 1-((6-cyclopropyl-8-(3-ethoxy-2,2-dimethyl-3-oxopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate. To a stirred solution of ethyl isobutyrate (808 mg, 6.96 mmol) in THF (20 mL) was added LDA (3.7 mL, 2 M, 7.4 mmol) dropwise under N at −40° C. After 1 h, a solution of tert-butyl 1-((8-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate (1.8 g, 4.64 mmol) in THF (15 mL) was added to the above reaction at −78° C. over 30 min. The resulting mixture was stirred at −78° C. for an additional 1.5 hours. The reaction mixture was quenched with aqueous NH4Cl (100 mL) and extracted with EtOAc (100 mL × 3). The combined organic components were washed with brine (140 mL), dried over Na2SO4, and concentrated to give the crude product, which was purified by silica gel chromatography (EtOAc / PE=1 / 2) to give tert-butyl 1-((6-cyclopropyl-8-(3-ethoxy-2,2-dimethyl-3-oxopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate (1.24 g, yield: 57%) as a colorless syrup. ESI-MS [M+H] + : 468.2.

[0338] Synthesis of 1-((6-cyclopropyl-8-(3-ethoxy-2,2-dimethyl-3-oxopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid. A mixture of tert-butyl 1-((6-cyclopropyl-8-(3-ethoxy-2,2-dimethyl-3-oxopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate (1.24 g, 2.65 mmol) and HCl in dioxane (10 mL, 4N) was stirred at 25° C. for 18 hours. The reaction mixture was concentrated and dried under reduced pressure to give 1-((6-cyclopropyl-8-(3-ethoxy-2,2-dimethyl-3-oxopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid (1.3 g, yield: 100%) as a colorless syrup. ESI-MS [M+H] + : 412.2.

[0339] Synthesis of ethyl 3-(6-cyclopropyl-2-((4-((2-fluoro-3-methoxy-6-(1H-tetrazol-1-yl)benzyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-8-yl)-2,2-dimethylpropanoate. A mixture of 1-((6-cyclopropyl-8-(3-ethoxy-2,2-dimethyl-3-oxopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid (167 mg, 0.406 mmol), (2-fluoro-3-methoxy-6-(1H-tetrazol-1-yl)phenyl)methanamine (91 mg, 0.406 mmol), EDCI (156 mg, 0.812 mmol), HOBT (110 mg, 0.812 mmol), and DIPEA (525 mg, 4.06 mmol) in DMF (5 mL) was stirred at room temperature for 16 hours. The reaction mixture was poured into water (50 mL) and extracted with EtOAc / THF (50 mL x 2, 5 / 1). The combined organic layers were washed successively with water (100 mL × 3) and brine (100 mL × 1), dried over Na2SO4, concentrated under reduced pressure, and purified by preparative TLC (DCM / MeOH = 10 / 1) to give ethyl 3-(6-cyclopropyl-2-((4-((2-fluoro-3-methoxy-6-(1H-tetrazol-1-yl)benzyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-8-yl)-2,2-dimethylpropanoate as a pale white solid (100 mg, yield: 40%). ESI-MS [M + H] + : 617.2. 1 H NMR (400 MHz, DMSO) δ 9.71 (s, 1H), 8.72 (t, J = 5.4 Hz, 1H), 8.41 (s, 1H), 8.19 (s, 1H), 7.73 (s, 1H), 7.36 - 7.29 (m, 2H), 6.63 (s, 1H), 5.65 (s, 2H), 4.26 (d, J = 5.4 Hz, 2H), 3.94 - 3.88 (m, 5H), 3.05 (s, 2H), 1.87 - 1.82 (m, 1H), 1.08 - 1.03 (m, 9H), 0.90 - 0.85 (m, 2H), 0.60 - 0.55 (m, 2H).

[0340] Example 94 3-(6-cyclopropyl-2-((4-((2-fluoro-3-methoxy-6-(1H-tetrazol-1-yl)benzyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-8-yl)-2,2-dimethylpropanoic acid (I-81) Scheme 94 [ka] Synthesis of 3-(6-cyclopropyl-2-((4-((2-fluoro-3-methoxy-6-(1H-tetrazol-1-yl)benzyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-8-yl)-2,2-dimethylpropanoic acid. To a solution of ethyl 3-(6-cyclopropyl-2-((4-((2-fluoro-3-methoxy-6-(1H-tetrazol-1-yl)benzyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-8-yl)-2,2-dimethylpropanoate (75 mg, 0.122 mmol) in dioxane (3 mL) and H2O (1 mL) was added concentrated H2SO4 (1 mL). The reaction mixture was stirred at 75°C for 16 hours and then poured onto water (30 mL). The mixture was adjusted to pH 4-5 using saturated aqueous NaHCO3 and then extracted with EtOAc / THF (40 mL x 2, 5 / 1). The combined organic layers were washed with brine (80 mL), dried over Na2SO4, concentrated, and purified by preparative HPLC to give 3-(6-cyclopropyl-2-((4-((2-fluoro-3-methoxy-6-(1H-tetrazol-1-yl)benzyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-8-yl)-2,2-dimethylpropanoic acid as a white solid (30 mg, yield: 42%). ESI-MS [M + H] + : 589.2. 1 H NMR (400 MHz, DMSO) δ 12.34 (s, 1H), 9.74 (s, 1H), 8.76 (s, 1H), 8.45 (s, 1H), 8.21 (d, J = 1.4 Hz, 1H), 7.74 (s, 1H), 7.39 - 7.32 (m, 2H), 6.72 (d, J = 1.3 Hz, 1H), 5.70 (s, 2H), 4.29 (d, J = 5.2 Hz, 2H), 3.92 (s, 3H), 3.09 (s, 2H), 1.90 - 1.83 (m, 1H), 1.06 (s, 6H), 0.93 - 0.87 (m, 2H), 0.65 - 0.59 (m, 2H).

[0341] Example 95 1-((8-(2-cyano-2-methylpropyl)-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2,6-difluoro-3-methoxybenzyl)-1H-1,2,3-triazole-4-carboxamide (I-12) Scheme 95 [ka] Synthesis of ethyl 3-(6-cyclopropyl-2-((4-((2,6-difluoro-3-methoxybenzyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-8-yl)-2,2-dimethylpropanoate. 1-((6-cyclopropyl-8-(3-ethoxy-2,2-dimethyl-3-oxopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid (352 mg, crude), (2,6-difluoro-3-methoxyphenyl)methanamine hydrochloride (179 mg, 0.855 mmol), EDCI (328 mcg, 100 sq ft). A mixture of (6-cyclopropyl-2-(4-((2,6-difluoro-3-methoxybenzyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-8-yl)-2,2-dimethylpropanoate (320 mg, 66% yield, 2 steps) was obtained as a pale white solid. ESI-MS [M + H] + : 567.2.

[0342] Synthesis of 3-(6-cyclopropyl-2-((4-((2,6-difluoro-3-methoxybenzyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-8-yl)-2,2-dimethylpropanoic acid. To a solution of ethyl 3-(6-cyclopropyl-2-((4-((2,6-difluoro-3-methoxybenzyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-8-yl)-2,2-dimethylpropanoate (320 mg, 0.565 mmol) in methanol (6 mL), THF (6 mL), and water (4 mL) was added lithium hydroxide monohydrate (95 mg, 2.26 mmol). The reaction mixture was stirred at 40° C. for 2 hours. The MeOH and THF were removed under reduced pressure, and the mixture was diluted in water (40 mL) and extracted with EtOAc (40 mL). The organic layer was discarded. The aqueous layer was acidified to pH = 5-6 using HCl (2 M, aq.) and extracted with EtOAc (40 mL × 2). The combined organic components were washed with brine (80 mL), dried over Na2SO4, concentrated, and dried under reduced pressure to give 3-(6-cyclopropyl-2-((4-((2,6-difluoro-3-methoxybenzyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-8-yl)-2,2-dimethylpropanoic acid (270 mg, 88%) as a white solid. ESI-MS [M + H] + : 539.2.

[0343] Synthesis of 1-((8-(3-amino-2,2-dimethyl-3-oxopropyl)-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2,6-difluoro-3-methoxybenzyl)-1H-1,2,3-triazole-4-carboxamide. A mixture of 3-(6-cyclopropyl-2-((4-((2,6-difluoro-3-methoxybenzyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-8-yl)-2,2-dimethylpropanoic acid (270 mg, 0.501 mmol), NH4Cl (266 mg, 5.01 mmol), EDCI (192 mg, 1.0 mmol), HOBT (135 mg, 1.0 mmol), and DIPEA (324 mg, 2.51 mmol) in DMF (8 mL) was stirred at room temperature for 16 hours. The reaction mixture was poured into water (60 mL) and extracted with EtOAc (60 mL × 2). The combined organic components were washed with water (120 mL × 3) and brine (120 mL × 1), dried over Na2SO4, concentrated, and purified by silica gel chromatography (EtOAc / MeOH = 10 / 1) to give 1-((8-(3-amino-2,2-dimethyl-3-oxopropyl)-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2,6-difluoro-3-methoxybenzyl)-1H-1,2,3-triazole-4-carboxamide (240 mg, yield: 89%) as a pale white solid. ESI-MS [M + H] + : 538.2.

[0344] Synthesis of 1-((8-(2-cyano-2-methylpropyl)-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2,6-difluoro-3-methoxybenzyl)-1H-1,2,3-triazole-4-carboxamide. A mixture of N-(3-amino-2,2-dimethyl-3-oxopropyl)-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2,6-difluoro-3-methoxybenzyl)-1H-1,2,3-triazole-4-carboxamide (120 mg, 0.223 mmol) in POCl3 (4 mL) was stirred at 60 °C for 3 h. The reaction mixture was poured into water (30 mL). The mixture was adjusted to pH 9-10 with saturated aqueous NaHCO3 and extracted with EtOAc (30 mL × 2). The combined organic components were washed with brine (60 mL), dried over NaSO, concentrated, and purified by silica gel chromatography (EtOAc / PE=1 / 2) to give 1-((8-(2-cyano-2-methylpropyl)-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2,6-difluoro-3-methoxybenzyl)-1H-1,2,3-triazole-4-carboxamide (50 mg, 43%) as a white solid. ESI-MS [M + H]: 520.2. 1 H NMR (400 MHz, DMSO) δ 8.79 (t, J = 5.5 Hz, 1H), 8.49 (s, 1H), 8.31 (s, 1H), 7.81 (s, 1H), 7.15 - 7.06 (m, 1H), 7.02 - 6.94 (m, 2H), 5.72 (s, 2H), 4.48 (d, J = 5.4 Hz, 2H), 3.80 (s, 3H), 3.12 (s, 2H), 1.92 - 1.89 (m, 1H), 1.29 (s, 6H), 0.97 - 0.90 (m, 2H), 0.69 - 0.64 (m, 2H).

[0345] Example 96 1-((6-cyclopropyl-8-(4H-1,2,4-triazol-4-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(1H-tetrazol-1-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide (I-71) Scheme 96 [ka] 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 hours. HO (50 mL) was added to the reaction 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 2-(azidomethyl)-8-bromo-6-cyclopropylimidazo[1,2-a]pyridine. (1.1 g, crude) was obtained, which was used in the next step without further purification. ESI-MS [M+H] + : 292.0.

[0346] Synthesis of tert-butyl 1-((8-bromo-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate. To a solution of 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) was 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.

[0347] Synthesis of tert-butyl 1-((8-((tert-butoxycarbonyl)amino)-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate. To a solution of tert-butyl 1-((8-bromo-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate (1 g, 2 mmol) and tert-butyl carbamate (0.56 g, 4 mmol) in dioxane (10 mL) was added Pd(dba) (0.18 g, 0.2 mmol), Xantphos (0.23 g, 0.4 mmol), and CsCO (1.95 g, 6 mmol). The reaction mixture was stirred at 100 °C under N for 16 h. The reaction mixture was cooled to room temperature, and HO (50 mL) was added. The aqueous phase was extracted with ethyl acetate (100 mL × 3). The combined organic layers were dried over sodium sulfate and evaporated. The residue was purified by silica gel chromatography (DCM:MeOH = 15:1) to give tert-butyl 1-((8-((tert-butoxycarbonyl)amino)-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate (900 mg, 99%) as a yellow solid. ESI-MS [M+H] + : 455.2.

[0348] Synthesis of methyl 1-((8-amino-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate. A solution of tert-butyl 1-((8-((tert-butoxycarbonyl)amino)-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate (300 mg, 0.66 mmol) in MeOH (5 mL) and HCl in dioxane (4 M, 5 mL) was stirred at room temperature for 16 hours. LCMS showed the reaction was complete. Evaporation of the reaction mixture solvent gave the crude product (230 mg, 100% yield) as a yellow solid, which was used in the next step without further purification. ESI-MS [M+H] + : 313.3.

[0349] Synthesis of 1-((6-cyclopropyl-8-(4H-1,2,4-triazol-4-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(1H-tetrazol-1-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide. 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-triazole-4-carboxylic acid (120 mg, 0.34 mmol) in anhydrous DMF (3 mL) was added (2-fluoro-3-methoxy-6-(1H-tetrazol-1-yl)phenyl)methanamine (152 mg, 0.68 mmol), HATU( To the mixture were added 1-((6-cyclopropyl-8-(4H-1,2,4-triazol-4-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(1H-tetrazol-1-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide (80 mg, yield: 43%) as a white solid. ESI-MS [M + H] + : 556.2. 1 H NMR (400 MHz, HDMSO-d6) δ 9.74 (s, 1H), 9.39 (s, 2H), 8.77 (t, J = 5.4 Hz, 1H), 8.57 (s, 1H), 8.47 (s, 1H), 8.00 (s, 1H), 7.45 (d, J = 1.1 Hz, 1H), 7.42 - 7.32 (m, 2H), 5.77 (d, J = 6.9 Hz, 2H), 4.29 (d, J = 5.1 Hz, 2H), 3.90 (s, 3H), 2.01 - 1.93 (m, 1H), 1.03 - 0.93 (m, 2H), 0.86 - 0.77 (m, 2H).

[0350] Example 97 1-((6-cyclopropyl-8-(oxetan-3-ylmethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(1H-tetrazol-1-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide (I-68) Scheme 97 [ka] Synthesis of ethyl 1-((6-cyclopropyl-8-(hydroxymethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate. To a solution of 1-((6-cyclopropyl-8-(hydroxymethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid (800 mg, 2.56 mmol) in EtOH (50 mL) was added SOCl (10 mL). The resulting reaction was stirred at 70° C. for 14 hours. The reaction was concentrated under reduced pressure to provide ethyl 1-((6-cyclopropyl-8-(hydroxymethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate as a yellow solid (850 mg, 97.5%). ESI-MS [M+H] + : 342.2.

[0351] Synthesis of ethyl 1-((8-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate. To a solution of ethyl 1-((6-cyclopropyl-8-(hydroxymethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate (850 mg, 2.49 mmol) in DCM (25 mL) was added SOCl (3 mL) at 0° C. The resulting reaction was stirred at room temperature for 4 hours. The reaction was concentrated under reduced pressure to give ethyl 1-((8-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate as a yellow solid (900 mg crude). ESI-MS [M+H] + : 360.3.

[0352] Synthesis of ethyl 1-((6-cyclopropyl-8-((triphenyl-1,4-phosphanyl)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate. A mixture of ethyl 1-((8-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate (900 mg crude from the previous step) and PPh3 (720 mg, 2.74 mmol) in toluene (40 mL) was stirred at 110 °C for 12 h. The reaction was concentrated under reduced pressure to give ethyl 1-((6-cyclopropyl-8-((triphenyl-14-phosphanyl)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate as a yellow solid, which was used in the next step without further purification (1.62 g crude). ESI-MS [M+H] + : 586.1.

[0353] Synthesis of ethyl 1-((6-cyclopropyl-8-(oxetan-3-ylidenemethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate. A mixture of ethyl 1-((6-cyclopropyl-8-((triphenyl-14-phosphanyl)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate (1 g crude from the previous step), oxetan-3-one (369 mg, 5.1 mmol), and NaH (340 mg, 8.5 mmol, 60 wt% in oil) in THF (30 mL) was stirred at 65 °C for 14 h under N. The reaction was quenched with aqueous NH4Cl (50 mL) and 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 on silica gel (eluent: DCM / MeOH = 30 / 1) to give ethyl 1-((6-cyclopropyl-8-(oxetan-3-ylidenemethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate as a yellow solid (450 mg, 47.7% over three steps). ESI-MS [M+H] + : 380.2.

[0354] Synthesis of ethyl 1-((6-cyclopropyl-8-(oxetan-3-ylmethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate. A mixture of ethyl 1-((6-cyclopropyl-8-(oxetan-3-ylidenemethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate (450 mg, 1.19 mmol) and Pd / C (100 mg) in THF (25 mL) was stirred under an H atmosphere for 2 hours. The reaction was filtered and concentrated under reduced pressure to give ethyl 1-((6-cyclopropyl-8-(oxetan-3-ylmethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate as a yellow solid (180 mg, 40%). ESI-MS [M+H] + : 382.2.

[0355] 1-((6-cyclopropyl-8-(oxetan-3-ylmethyl)imidazo[1,2 Synthesis of 1-((6-cyclopropyl-8-(oxetan-3-ylmethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid. To a solution of ethyl 1-((6-cyclopropyl-8-(oxetan-3-ylmethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate (180 mg, 0.47 mmol) in THF / HO (8 mL / 8 mL) was added LiOH·HO (79 mg, 1.88 mmol). The resulting mixture was stirred at room temperature for 4 hours. The reaction was concentrated under reduced pressure to give the crude product, which was purified by preparative HPLC to give 1-((6-cyclopropyl-8-(oxetan-3-ylmethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid as a white solid (90 mg, 54%). ESI-MS [M+H] + : 354.2.

[0356] Synthesis of 1-((6-cyclopropyl-8-(oxetan-3-ylmethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(1H-tetrazol-1-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide. To a mixture of 1-((6-cyclopropyl-8-(oxetan-3-ylmethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid (50 mg, 0.14 mmol), HATU (80 mg, 0.21 mmol), and DIPEA (90 mg, 0.70 mmol) in DMF (10 mL) was added (2-fluoro-3-methoxy-6-(1H-tetrazol-1-yl)phenyl)methanamine (47 mg, 0.21 mmol). The reaction mixture was stirred at room temperature for 14 h and then quenched with HO (20 mL). The aqueous phase was extracted with EtOAc (20 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-((6-cyclopropyl-8-(oxetan-3-ylmethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(1H-tetrazol-1-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide (10 mg, 12.8%) as a white solid. ESI-MS [M +H]: 559.2. 1 H NMR (400 MHz, DMSO) δ 9.74 (s, 1H), 8.76 (t, J = 5.4 Hz, 1H), 8.47 (s, 1H), 8.19 (d, J = 1.3 Hz, 1H), 7.76 (s, 1H), 7.39 - 7.32 (m, 2H), 6.80 (s, 1H), 5.70 (s, 2H), 4.61 (dd, J = 7.7, 5.9 Hz, 2H), 4.36 (t, J = 6.0 Hz, 2H), 4.29 (d, J = 5.1 Hz, 2H), 3.92 (s, 3H), 3.42 - 3.37 (m, 1H), 3.15 (d, J = 7.7 Hz, 2H), 1.91 - 1.84 (m, 1H), 0.92 - 0.88 (m, 2H), 0.68 - 0.64 (m, 2H).

[0357] Example 98 1-((6-cyclopropyl-8-(hydroxy(oxetan-3-yl)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(1H-tetrazol-1-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide (I-27) Scheme 98 [ka] Synthesis of (2-amino-5-cyclopropylpyridin-3-yl)(oxetan-3-yl)methanol. To a solution of 3-bromo-5-cyclopropylpyridin-2-amine (500 mg, 2.35 mmol) in anhydrous THF (25 mL) was added n-BuLi (3.5 mL, 2.4 M solution in hexane, 8.4 mmol) at −60° C. The resulting mixture was stirred at −60° C. for 30 m...

Claims

[Claim 1] The invention described in the specification.

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