Heteroaryl plasma kallikrein inhibitor

Abstract

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

Description

Technical Field

[0001] Cross - reference to related applications This application claims the priority and benefit of U.S. Provisional Patent Application No. 62 / 902,333, entitled "HETEROARYL PLASMA KALLIKREIN INHIBITORS", filed on September 18, 2019, the entire content of which is incorporated herein by reference.

Background Art

[0002] Plasma kallikrein (pKal) is a serine protease zymogen in the blood that is converted to its catalytically active form by factor XIIa and contributes to innate inflammatory responses and the endogenous blood coagulation cascade. Mechanisms leading to activation of this pathway in vivo include interaction with polyphosphate released from activated platelets and deficiency of C1 inhibitor (C1 - INH), the major physiological inhibitor of pKal. Cleavage of high - molecular - weight kininogen mediated by pKal generates bradykinin (BK), a potent vasodilator and pro - inflammatory nonapeptide, which activates the bradykinin 2 receptor. Subsequent cleavage of BK by carboxypeptidase generates des - Arg9 - BK, which activates the B1 receptor. The B1 and B2 receptors are expressed by vascular, glial, and neuronal cell types, and maximal levels of retinal expression are detected in the ganglion cell layer and the inner and outer nuclear layers. Activation of the B1 and B2 receptors causes vasodilation and increases vascular permeability.

[0003] pKal is also associated with a number of disorders such as hereditary angioedema (HAE), an autosomal dominant disorder characterized by painful, unpredictable, recurrent episodes of inflammation affecting the hands, feet, face, abdomen, genitourinary tract, and larynx. The prevalence of HAE is uncertain but is estimated to be about 1 case per 50,000 people, with no known differences between ethnic groups. HAE is caused by a deficiency (type I) or dysfunction (type II) of C1-INH, which inhibits plasma kallikrein (pKal), bradykinin, and other serine proteases in the blood. Individuals with hereditary angioedema (HAE) are deficient in C1-INH, which results in the production of excessive bradykinin, which in turn causes painful, debilitating, and potentially life-threatening swelling attacks. Untreated, HAE can result in a high mortality rate of 40%, mainly 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 plasma kallikrein and efficiently inhibit its activity. Accordingly, compounds for targeting pKal and / or treating diseases or disorders mediated by pKal and their use are provided herein.

[0005] In some embodiments, the invention provides a compound of formula (I):

Chemical formula

[0006] In some embodiments, the present invention also provides methods of using the compounds of formulas (I)-(III-b).

DETAILED DESCRIPTION OF THE INVENTION

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

[0008] The abbreviations used herein have their ordinary meanings within the scope of the chemical and biological arts. The chemical structures and formulas described herein are constructed in accordance with the standard rules of chemical valency known in the chemical art.

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

[0010] The term "heteroatom" means one or more oxygen, sulfur, nitrogen, phosphorus or silicon (any oxidized form of nitrogen, sulfur, phosphorus, or silicon; any quaternized form of any basic nitrogen; or a replaceable nitrogen in a heterocycle, such as N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR + (as in N-substituted pyrrolidinyl)).

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

[0012] The term "alkylene" refers to a divalent alkyl group. An "alkylene chain" is a polymethylene group, i.e., -(CH2) n -, where n is a positive integer, preferably 1 to 6, 1 to 4, 1 to 3, 1 to 2, or 2 to 3. A substituted alkylene chain is a polymethylene group in which one or more methylene group hydrogen atoms are replaced by substituents. 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 systems having a total of 5 to 10 ring members, where at least one ring of the system is aromatic and each ring of the system has 3 to 7 ring members. The term "aryl" can 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 and includes, but is not limited to, phenyl, biphenyl, naphthyl, anthracyl, etc. As used herein, within the scope of the term "aryl" are also included groups in which an aromatic ring is fused to one or more non-aromatic rings, such as indanyl, phthalimidyl, naphthalimidyl, phenanthridinyl, or tetrahydronaphthyl.

[0015] The terms "heteroaryl" and "heteroar-" refer to a group having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms, having 6, 10, or 14 π electrons shared in a cyclic arrangement, and having 1 to 5 heteroatoms in addition to carbon atoms. Examples of 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 heterocyclic ring is fused to one or more aryl rings, cycloaliphatic rings, or heterocyclyl rings, where the radical or point of attachment is on the aromatic heterocyclic ring. Non-limiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzothiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-1,4-oxazin-3(4H)-one. A heteroaryl group can be monocyclic or bicyclic. The term "heteroaryl" can be used interchangeably with the terms "heteroaryl ring", "heteroaryl group" or "heterocyclic aromatic", and any of these terms includes 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 has, in addition to carbon atoms, one or more, preferably 1 to 4, of the heteroatoms as defined above. In this context, when used with respect to ring atoms, the term "nitrogen" includes substituted nitrogen. By way of example, in a saturated or partially unsaturated ring having 0 to 3 heteroatoms selected from oxygen, sulfur, or nitrogen, nitrogen can be N (such as in 3,4-dihydro-2H-pyrrolyl), NH (such as in pyrrolidinyl), or + NR (such as in N-substituted pyrrolidinyl).

[0017] The heterocycle can be attached by any heteroatom or carbon atom to its pendant group, which 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 also include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl, or alicyclic rings, such as indolinyl, 3H-indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl, where the radical or point of attachment is on the heterocyclyl ring. The heterocyclyl group can be monocyclic or bicyclic. The term "heterocyclylalkyl" refers to an alkyl group substituted by heterocyclyl, where the alkyl and heterocyclyl moieties are independently optionally substituted.

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

[0019] As used herein and unless otherwise specified, the suffix "-ene" is used to denote a divalent group. Thus, any of the above terms may be modified with the suffix "-ene" to describe the divalent version of that moiety. For example, a divalent carbocyclic ring is "carbocyclylene", a divalent aryl ring is "arylene", a divalent benzene ring is "phenylene", a divalent heterocyclic ring is "heterocyclylene", a divalent heteroaryl ring is "heteroarylene", a divalent alkyl chain is "alkylene", a divalent alkenyl chain is "alkenylene", a divalent alkynyl chain is "alkynylene", and so on.

[0020] As described herein, the compounds of the invention may contain "optionally substituted" moieties, when so specified. In general, whether following the term "optionally" or not, the term "substituted" means that one or more hydrogens of the designated moiety are replaced with suitable substituents. Unless otherwise specified, an "optionally substituted" group may have suitable substituents at each substitutable position of the group, and when two or more positions in any given structure may be substituted with two or more substituents selected from the designated group, the substituents may be the same or different at all positions. Combinations of substituents contemplated by the present invention preferably result in the formation of stable or chemically possible compounds. The term "stable", as used herein, refers to compounds that do not substantially change when subjected to conditions that allow for their generation, detection, and in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.

[0021] Suitable monovalent substituents on replaceable carbon atoms of the "optionally substituted" radical are, independently, halogen; -(CH2) 0~4 R°; -(CH2) 0~4 OR°; -O(CH2) 0~4 R°, -O(CH2) 0~4 C(O)OR°; -O(CH2) 0~4 OR°; -(CH2) 0~4 CH(OR°)2; -(CH2) 0~4 SR°; -(CH2) optionally substituted with R° 0~4 Ph; -(CH2) optionally substituted with R° 0~4 O(CH2) 0~1 Ph; -CH=CHPh optionally substituted with R°; -(CH2) optionally substituted with R° 0~4 O(CH2) 0~1 -pyridyl; -NO2; -CN; -N3; -(CH2) 0~4 N(R°)2; -(CH2) 0~4 N(R°)C(O)R°; -N(R°)C(S)R°; -(CH2) 0~4 N(R°)C(O)NR°2; -N(R°)C(S)NR°2; -(CH2) 0~4 N(R°)C(O)OR°; -N(R°)N(R°)C(O)R°; -N(R°)N(R°)C(O)NR°2; -N(R°)N(R°)C(O)OR°; -(CH2) 0~4 C(O)R°; -C(S)R°; -(CH2) 0~4 C(O)OR°; -(CH2) 0~4 C(O)SR°; -(CH2) 0~4 C(O)OSiR°3; -(CH2) 0~4 OC(O)R°; -OC(O)(CH2) 0~4 SR°、 -SC(S)SR°; -(CH2) 0~4 SC(O)R°; -(CH2) 0~4 C(O)NR°2; -C(S)NR°2; -C(S)SR°; -SC(S)SR°, -(CH2) 0~4 OC(O)NR°2; -C(O)N(OR°)R°; -C(O)C(O)R°; -C(O)CH2C(O)R°; -C(NOR°)R°; -(CH2) 0~4 SSR°; -(CH2) 0~4S(O)2R°;-(CH2) 0~4 S(O)2OR°;-(CH2) 0~4 OS(O)2R°;-S(O)2NR°2;-(CH2) 0~4 S(O)R°;-N(R°)S(O)2NR°2;-N(R°)S(O)2R°;-N(OR°)R°;-C(NH)NR°2;-P(O)2R°;-P(O)R°2;-OP(O)R°2;-OP(O)(OR°)2;SiR°3;-(C 1~4 linear or branched alkylene)O-N(R°)2; or -(C 1~4 linear or branched alkylene)C(O)O-N(R°)2, wherein each R° may be substituted as defined below and is independently hydrogen, C 1~6 aliphatic, -CH2Ph, -O(CH2) 0~1 Ph, -CH2-(5- to 6-membered heteroaryl ring), or a 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, regardless of the above definition, two independent occurrences of R° together with the atom(s) intervening between them form a 3- to 12-membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below.

[0022] Suitable monovalent substituents on R° (or the ring formed by two independent occurrences of R° together with the atom(s) intervening between them) are independently halogen, -(CH2) 0~2 R ● , -(haloR ● ), -(CH2) 0~2 OH, -(CH2) 0~2 OR ● , -(CH2) 0~2 CH(OR ● )2; -O(haloR ● ), -CN, -N3, -(CH2) 0~2 C(O)R ● , -(CH2) 0~2 C(O)OH, -(CH2) 0~2 C(O)OR● 、 -(CH2) 0~2 SR ● 、 -(CH2) 0~2 SH, -(CH2) 0~2 NH2, -(CH2) 0~2 NHR ● 、 -(CH2) 0~2 NR ● 2, -NO2, -SiR ● 3, -OSiR ● 3, -C(O)SR ● 、 -(C 1~4 linear or branched alkylene)C(O)OR ● 、 or -SSR ● and, in the formula, each R ● is unsubstituted or, when "halo" precedes, is substituted with only one or more halogens, C 1~4 aliphatic, -CH2Ph, -O(CH2) 0~1 Ph, or a 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on the saturated carbon atoms of R° include =O and =S.

[0023] Suitable divalent substituents on the saturated carbon atoms of an "optionally substituted" group are as follows: =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-, and, in the formula, each R * appearing independently is hydrogen, C optionally substituted as defined below 1~6Selected from an aliphatic, or an unsubstituted 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents bonded to an adjacent substitutable carbon of an "optionally substituted" group include -O(CR * 2) 2~3 O-, wherein each R * appearing independently is hydrogen, C 1~6 aliphatic which may be substituted as defined below, or an unsubstituted 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0024] R * Suitable substituents on the aliphatic group of are halogen, -R ● , -(haloR ● ), -OH, -OR ● , -O(haloR ● ), -CN, -C(O)OH, -C(O)OR ● , -NH2, -NHR ● , -NR ● 2, or -NO2, wherein each R ● is unsubstituted or, when preceded by "halo", substituted with only one or more halogens and independently is C 1~4 aliphatic, -CH2Ph, -O(CH2) 0~1 Ph, or a 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 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)CH2C(O)R † , -S(O)2R † , -S(O)2NR † 2, -C(S)NR †2. -C(NH)NR † 2. or -N(R † )S(O)2R † is exemplified, where each R † is independently hydrogen, C 1~6 aliphatic optionally substituted as defined below, unsubstituted -OPh, or an unsubstituted 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or regardless of the above definition, two independent occurrences of R † together with the intervening atom(s) form an unsubstituted 3- to 12-membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0026] R † Preferred substituents on the aliphatic group of R ● are independently halogen, -R ● , -(haloR ● ), -OH, -OR ● , -O(haloR ● ), -CN, -C(O)OH, -C(O)OR ● , -NH2, -NHR ● , -NR ● 2, or -NO2, where each R 1~4 is unsubstituted or, when "halo" precedes, is substituted only with one or more halogens and is independently C 0~1 aliphatic, -CH2Ph, -O(CH2)

[0027] As used herein, the term "pharmaceutically acceptable salt" refers to salts that are suitable for use in contact with the tissues of humans and lower animals within the scope of sound medical judgment, without undue toxicity, irritation, allergic response, etc., and that 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 form of the compound is regenerated by contacting the salt with a base or acid and isolating the parent compound by conventional methods. In some embodiments, the parent form of the compound has certain physical properties, such as solubility in polar solvents, that differ from those of the various salt forms.

[0029] Unless otherwise specified, the structures described herein include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each chiral center, the (Z) and (E) double bond isomers, and the (Z) and (E) conformational isomers. Thus, single stereochemical isomers of the compounds of the invention, as well as mixtures of enantiomers, mixtures of diastereomers, and geometric (or conformational) mixtures are within the scope of the invention. Unless otherwise specified, all tautomeric forms of the compounds of the invention are within the scope of the invention. In addition, unless otherwise specified, the structures described herein also mean that compounds that differ only in the presence of one or more isotope-enriched atoms are included. For example, replacement of hydrogen by deuterium or tritium, or 13 C-enriched carbon or 14 compounds having the structure of the invention that include replacement of carbon by

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

[0031] The symbol " [Chem.] " is used to indicate the point of attachment of a chemical moiety to the remainder of a molecule or chemical formula, except when used as a bond to indicate an unknown stereochemistry or a mixture of stereochemistries.

[0032] The articles "a" and "an" are used herein to refer to one or more than one (i.e., at least one) of the grammatical objects of the article. By way of example, "an element" means one element or more than one element.

[0033] A "regimen" (or "optimal treatment regimen"), as the term is used herein, is typically a set of unit doses (typically two or more) that are administered individually to a subject at intervals over a period of time. In some embodiments, a given therapeutic agent has a recommended regimen that requires more than one dose. In some embodiments, a regimen consists of a plurality of doses, each separated from the others by the same length of period. In some embodiments, a regimen consists of a plurality of doses, with individual doses separated at least two different periods.

[0034] As will be understood from the context, a "reference" sample or subject is a sample or subject that is sufficiently similar to a particular sample or subject of interest to enable a relevant comparison. In some embodiments, information regarding the reference sample is obtained simultaneously with information regarding the particular sample. In some embodiments, information regarding the reference sample is a medical history. In some embodiments, information regarding the reference sample is stored, for example, on a computer-readable medium. In some embodiments, the comparison of a particular sample of interest to a reference sample establishes the identity, similarity, or difference of the particular sample of interest compared to a reference substance.

[0035] As used herein, the term "sample" refers to a biological sample obtained from or derived from a source of interest, as described herein. In some embodiments, the source of interest includes an organism such as an animal or a human. In some embodiments, the biological sample includes biological tissue or biofluid. 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; cell-free floating nucleic acids; sputum; saliva; urine; cerebrospinal fluid, peritoneal fluid; pleural fluid; feces; lymph fluid; gynecological fluids; skin swabs; vaginal swabs; oral swabs; nasal swabs; lavage or wash 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 from or including them. 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 which the sample is obtained. In some embodiments, the sample is a "primary sample" obtained directly from the 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., needle aspiration or tissue biopsy), surgery, collection of body fluids (e.g., blood (e.g., whole blood), lymph fluid, feces, etc.). In some embodiments, as apparent 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 by 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 mRNA amplification or reverse transcription, isolation and / or purification of specific components.

[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 the amount of a therapeutic agent that, at a reasonable benefit / risk ratio applicable to any medical treatment, confers a therapeutic effect on a subject being treated. The therapeutic effect can be objective (i.e., measurable by some test or marker) or subjective (i.e., the subject shows signs of, or feels, the effect). In particular, a "therapeutically effective amount" refers to an amount of a therapeutic agent effective to treat, ameliorate, or prevent a desired disease or condition, or detectable therapeutic or prophylactic effects, for example, by ameliorating 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 dosing regimen that may consist of a plurality of unit doses. For any particular therapeutic agent, the therapeutically effective amount (and / or appropriate unit dose within an effective dosing regimen) can vary, for example, depending on the route of administration, combination with other pharmaceuticals. Also, the therapeutically effective amount (and / or unit dose) specific to any particular subject can depend on various factors including the disorder being treated and the severity of the disorder; the activity of the particular therapeutic agent being used; the particular composition being used; the age, weight, health status, gender, and diet of the subject; the time of administration, route of administration, and / or rate of excretion or metabolism of the particular therapeutic agent being used; the duration of the treatment; as well as similar factors known in the medical arts.

[0038] As used herein, the term "treatment" (similarly, "treating" or "treatment of") refers to the administration of any substance (e.g., the provided composition) that partially or completely alleviates, ameliorates, mitigates, inhibits, delays the onset of, reduces the severity of, and / or reduces the incidence of one or more symptoms, features, and / or causes of a particular disease, disorder, and / or condition. Such treatment can be of a subject who does not exhibit symptoms of the relevant disease, disorder, and / or condition, and / or of a subject who exhibits only the initial symptoms of the disease, disorder, and / or condition. Alternatively or additionally, such treatment can be of a subject who exhibits one or more established symptoms of the relevant disease, disorder, and / or condition. In some embodiments, the treatment can be of a subject diagnosed as having the relevant disease, disorder, and / or condition. In some embodiments, the treatment can be of a subject known to have one or more susceptibility factors that are statistically correlated with an increased risk of developing the relevant disease, disorder, and / or condition.

[0039] B. Compound In some embodiments, the provided compound has the formula (I):

Chemical formula

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

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

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

[0043] In some embodiments, Het A is a 6-membered heteroarylene having 1 to 4 heteroatoms selected from oxygen, nitrogen, or sulfur, wherein Het A is substituted with 0 to 3 R A groups. In some embodiments, Het A is a 6-membered heteroarylene having 1 nitrogen, wherein Het A is substituted with 0 to 3 R A groups. In some embodiments, Het A is pyridinediyl. In some embodiments, Het A is

Chemical formula

[0044] In some embodiments, Het A is a 5-membered heteroarylene having 1 to 4 heteroatoms selected from oxygen or nitrogen. In some embodiments, Het A is a 5-membered heteroarylene having 1 to 4 nitrogens. In some embodiments, Het A is a 5-membered heteroarylene having 1 to 4 nitrogens, wherein, when Het A contains 3 nitrogens, it is not 1,2,4-triazolediyl. In some embodiments, Het A is a 5-membered heteroarylene having 1 to 3 nitrogens. In some embodiments, Het A is a 5-membered heteroarylene having 1 to 2 nitrogens. In some embodiments, Het A is a 5-membered heteroarylene having 1 nitrogen. In some embodiments, Het A is a 5-membered heteroarylene having 2 nitrogens. In some embodiments, Het A is a 5-membered heteroarylene having 3 nitrogens. In some embodiments, Het A is a 5-membered heteroarylene having 4 nitrogens.

[0045] In some embodiments, Het A is

Chemical formula

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

[0047] In some embodiments, Het A is pyrrolyldiyl substituted with 0 to 3 R A groups. In some embodiments, Het A is pyrazolyldiyl substituted with 0 to 2 R A groups. In some embodiments, Het A is triazolydiyl substituted with 0 to 1 R A groups. In some embodiments, Het A is thiazolydiyl substituted with 0 to 1 R A groups. In some embodiments, Het A is unsubstituted tetrazolydiyl. In some embodiments, Het A is unsubstituted oxadiazolydiyl. In some embodiments, Het A is unsubstituted thiadiazolydiyl. In some embodiments, Het A is imidazolydiyl substituted with 0 to 2 R A groups. In some embodiments, Het A is oxazolydiyl substituted with 0 to 1 R A groups. In some embodiments, Het A is isoxazolydiyl substituted with 0 to 1 R A groups. In some embodiments, Het A is unsubstituted pyrazolyldiyl. In some embodiments, Het Ais an unsubstituted 1,2,3-triazolediyl.

[0048] In some embodiments, Het A is

Chemical formula

[0049] In some embodiments, Het A is a 7- to 10-membered bicyclic heteroarylene having 1 to 4 heteroatoms selected from oxygen, nitrogen, or sulfur, where Het A is substituted with 0 to 4 R A groups. In some embodiments, Het A is a 9-membered bicyclic heteroarylene having 1 to 4 heteroatoms selected from oxygen, nitrogen, or sulfur, where Het A is substituted with 0 to 4 R A groups. In some embodiments, Het A is a 9-membered bicyclic heteroarylene having 2 nitrogens, where Het A is substituted with 0 to 4 R A groups. In some embodiments, Het A is pyrrolopyridinediyl substituted with 0 to 4 R A groups.

[0050] In some embodiments, Het A is

Chemical formula

Chemical formula

[0051] In some embodiments, each R A is C1~6 Independently selected from optionally substituted groups selected from aliphatic, saturated or partially unsaturated monocyclic carbocyclic groups having 3 to 7 members, and saturated or partially unsaturated monocyclic heterocyclic groups having 3 to 7 members and having 1 to 2 heteroatoms selected from oxygen, nitrogen, or sulfur.

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

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

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

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

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

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

[0058] In certain embodiments, L is selected from -C(R)2NRC(O)-#, -C(R)2C(O)NRC(R)2-#, -C(R)2NRC(R)2-#, -C(R)2C(R)2NRC(R)2-#, -C(O)NRC(R)2-#, -C(R)2C(O)NR-#, -NRC(O)C(R)2-#, -CR2C(O)NRC(R)2-#, -SO2NRC(R)2-#, and -C(R)2NRSO2-#, where # represents the point of attachment to Het A represents the point of attachment.

[0059] In certain embodiments, L is selected from -C(R)2NRC(O)-#, -C(R)2C(O)NRC(R)2-#, -C(R)2NRC(R)2-#, -C(R)2C(R)2NRC(R)2-#, -C(O)NRC(R)2-#, -C(R)2C(O)NR-#, -CR2C(O)NRC(R)2-#, -SO2NRC(R)2-#, and -C(R)2NRSO2-#, where # represents the point of attachment to Het A represents the point of attachment.

[0060] In certain embodiments, L is selected from -C(R)2C(O)NRC(R)2-, -C(R)2NRC(R)2-, -C(R)2C(R)2NRC(R)2-, -C(O)NRC(R)2-, -C(R)2C(O)NRC(R)2-, -SO2NRC(R)2-, and -C(R)2NRSO2-, where # represents the point of attachment to Het A represents the point of attachment to

[0061] In some embodiments, L is other than -C(R)2NRC(O)- or -C(R)2C(O)NR-. In some embodiments, L is other than -CH2NRC(O)- or -CH2C(O)NR-.

[0062] In some embodiments, when L is -C(R)2NRC(O)- or -C(R)2C(O)NR-, any one of the following (a), (b), or (c): (a) n is 0, (b) at least one of R 5 , R 6 , R 7 , R 8 , and R 9 is CN, or (c) R 1is an optionally substituted saturated monocyclic heterocyclic ring containing 1 to 3 nitrogen atoms, provided that the compound is N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(2-oxopyrrolidin-1-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide, N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-morpholinoimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide, N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(2-oxopyrrolidin-1-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide, N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(2-oxooxazolidin-3-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide, or 4-(2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)morpholine-2-carboxylic acid does not apply.

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

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

[0065] In some embodiments, when L is -CH2NRC(O)-# or -CH2C(O)NR-#, R’ is a monocyclic Het A which, together with, forms an optionally substituted fused 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclylene having 1 to 4 heteroatoms selected from oxygen, nitrogen, or sulfur.

[0066] In certain embodiments, when L is -(CR2) m NRC(O)- and m is 0 to 2 (e.g., 0 or 2), any one of the following (a), (b), or (c): (a) n is 0, (b) at least one of R 5 , R 6 , R 7 , R 8 , and R 9 is CN, or (c) R 1is an optionally substituted saturated monocyclic heterocyclic ring containing 1 to 3 nitrogen atoms, provided that the compound is not N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(2-oxopyrrolidin-1-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide, N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-morpholinoimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide, N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(2-oxopyrrolidin-1-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide, N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(2-oxooxazolidin-3-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide, or 4-(2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)morpholine-2-carboxylic acid.

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

[0068] In certain embodiments, L is -(CR2) m NRC(O)- and when m is 0 to 2 (e.g., 0 or 2), R’ is monocyclic HetA Together with, it forms an optionally substituted fused 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclylene having 1 to 4 heteroatoms selected from oxygen, nitrogen, or sulfur.

[0069] In some embodiments, L is -C(R)2C(O)NRC(R)2-#, where each R is independently hydrogen or C optionally substituted with halogen 1~3 and is aliphatic. In some embodiments, L is -CH2C(O)NHCH(CF3)-#. In some embodiments, L is -CH2C(O)NHCH(CH3)-#.

[0070] In some embodiments, L is -C(R)2NRC(R)2-#, where each R is independently hydrogen or C optionally substituted with halogen 1~3 and is aliphatic. In some embodiments, L is -CH2NHCH(CF3)-#. In some embodiments, L is -CH2NHCH2-#. In some embodiments, L is -CH2NHCH(CH3)-#. In some embodiments, L is -CH(CF3)NHCH2-#.

[0071] In certain embodiments, L is -C(R)2NRSO2-#, where each R is independently hydrogen or C optionally substituted with halogen 1~3 and is aliphatic. In certain embodiments, L is -CH2NHSO2-#.

[0072] In some embodiments, L is -SO2NRC(R)2-#, where each R is independently hydrogen or C optionally substituted with halogen 1~3 and is aliphatic. In some embodiments, L is -SO2NHCH2-#. In some embodiments, L is -SO2NHCH(CH3)-#.

[0073] In some embodiments, L is -C(O)NRC(R)2-#, where each R is independently hydrogen or C optionally substituted with halogen1~3 It is aliphatic. In some embodiments, L is -C(O)NHCH2-.

[0074] In certain embodiments, L is -C(R)2C(O)NRC(R)2-, where each R is independently hydrogen or C optionally substituted with halogen 1~3 It is aliphatic. In certain embodiments, L is -CH2C(O)NHCH2-.

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

[0076] In some embodiments, R’ and R’’ are independently selected from hydrogen, halogen, -OR, -SR, -NR2, and optionally substituted C 1~6 aliphatic, where each R is independently hydrogen and C 1~6 aliphatic. In some embodiments, R’ and R’’ are hydrogen, fluorine, -OH, -SH, -NH2, and -(CH2) 0~4 C substituted with C(O)OR°, 1~6 aliphatic, where R° is hydrogen or C 1~6 aliphatic. In some embodiments, R’ and R’’ are hydrogen, fluorine, -OH, and -(CH2)0~4 C substituted with C(O)OR° 1~6 independently selected from aliphatic, where R° is hydrogen, methyl or ethyl.

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

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

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

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

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

Chemical formula

[0082] In some embodiments, R 1 , R 2 , R 3 , and R 4 each independently is selected from hydrogen, halogen, -CN, -C(O)R, -C(O)2R, -N(R)2, -OR, or C 1~6 aliphatic, a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic, and an optionally substituted group selected from 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 2 heteroatoms selected from oxygen, nitrogen, or sulfur, where each R is independently hydrogen or C 1~6 aliphatic.

[0083] In some embodiments, the substituent on the optionally substituted R 1 , R 2 , R 3 , or R 4 group is independently selected from halogen, -(CH2) 0~4 OR, -O(CH2) 0~4 OR, -(CH2) 0~4 C(O)OR, and -(CH2) 0~4 N(R)2, where each R is independently hydrogen, C 1~6 aliphatic, or two independent occurrences of R, together with the atom(s) intervening therebetween, form an optionally substituted 3- to 12-membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be further substituted.

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

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

Chemical formula

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

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

[0088] In some embodiments, R 6 is selected from halogen or optionally substituted C 1~6 aliphatic. In some embodiments, R 6 is halogen. In some embodiments, R 6 is F. In some embodiments, R 6 is Cl. In some embodiments, R 6 is Br. In some embodiments, R 6 is I. In some embodiments, R 6 is optionally substituted C 1~6 aliphatic. In some embodiments, R 6 is optionally substituted C 1~5 aliphatic. In some embodiments, R 6 is optionally substituted C 1~4 aliphatic. In some embodiments, R 6 is optionally substituted C 1~3 aliphatic. In some embodiments, R 6 is optionally substituted C 1~2It is aliphatic. In some embodiments, R 6 is alkynyl.

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

[0090] In some embodiments, R 9 is hydrogen, R 6 is -F, -Cl, or -Br, and R 5 , R 7 , and R 8 are 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 1~6Independently selected from optionally substituted groups selected from 5- to 6-membered heteroaryl having 1 to 4 heteroatoms selected from aliphatic, phenyl, oxygen, nitrogen, or sulfur, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic, and 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic having 1 to 2 heteroatoms selected from oxygen, nitrogen, or sulfur.

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

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

[0093] In some embodiments, R 5 and R 6 are each independently halogen. In some embodiments, R 5 is F, and R6 is Cl. In some embodiments, R 6 is Cl. In some embodiments, R 6 is CN.

[0094] In some embodiments, the provided compound, or a pharmaceutically acceptable salt thereof, has the structure of formula (I-a), formula (I-b), formula (I-c), or formula (I-d):

Chemical formula

[0095] Unless otherwise specified or prohibited by the foregoing definition of formula (I), the variable moieties L, R A , Het A , R’, R’’, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 embodiments are also understood to apply, both singly and in combination, to compounds of formula (I-a), formula (I-b), formula (I-c), formula (I-d), formula (II), formula (II-a), formula (II-b), formula (III), formula (III-a), and formula (III-b).

[0096] In some embodiments, the provided compound, or a pharmaceutically acceptable salt thereof, has the structure of formula (II):

Chemical formula

[0097] In some embodiments, the provided compound, or a pharmaceutically acceptable salt thereof, has the structure of formula (II-a) or formula (II-b):

Chemical formula

[0098] In some embodiments, in the provided compound or a pharmaceutically acceptable salt thereof, R’ forms an optionally substituted fused ring with monocyclic Het A and the compound has the structure of formula (III):

Chemical formula

[0099] In some embodiments, the provided compound, or a pharmaceutically acceptable salt thereof, has a structure of formula (III-a) or formula (III-b):

Chemical formula

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

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

[0102] The pharmaceutical composition includes optical isomers, diastereomers, or pharmaceutically acceptable salts of the inhibitors disclosed herein. The compounds of formula (I)-(III-b) included in the pharmaceutical composition may be covalently bonded to the carrier moiety as described above. Alternatively, the compounds of formula (I)-(III-b) included in the pharmaceutical composition are not covalently bonded to the carrier moiety.

[0103] As used herein, "pharmaceutically acceptable carrier" refers to a pharmaceutical excipient, i.e., an organic or inorganic carrier substance that is pharmaceutically and physiologically acceptable for enteral or parenteral application and does not cause a harmful reaction 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 can be sterilized and, if necessary, mixed with adjuvants such as lubricants, preservatives, stabilizers, wetting agents, emulsifying agents, salts for influencing osmotic pressure, buffers, colorants, and / or fragrances, etc., which do not cause a harmful reaction with the compounds of the present invention.

[0104] The compounds of the present invention can be administered alone or can be co-administered. Co-administration is intended to include administering the compounds individually or in combination (two or more compounds) simultaneously or sequentially. Also, the preparations can, if necessary, be combined with other agents (e.g., to reduce metabolic degradation).

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

[0106] D. Formulations The compounds of the present invention can be prepared in a wide variety of oral, parenteral, and topical dosage forms and can be administered in a wide variety of oral, parenteral, and topical dosage forms. Thus, the compounds of the present invention can be administered by injection (e.g., intravenously, intramuscularly, intradermally, subcutaneously, intraduodenally, or intraperitoneally). Also, the compounds described herein can be administered by inhalation, e.g., 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 a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and one or more compounds of the present invention.

[0107] To prepare a pharmaceutical composition from the compounds of the present invention, the pharmaceutically acceptable carrier can be solid or liquid. Solid preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. The solid carrier can be one or more substances that can also function as a diluent, flavoring agent, binder, preservative, tablet disintegrant, or encapsulating material.

[0108] In powders, the carrier is a micronized solid in a mixture with the micronized active ingredient. In tablets, the active ingredient is mixed with a carrier having the necessary binding properties in a suitable ratio and compressed into the desired shape and size.

[0109] Powders and tablets preferably contain 5% to 70% of the active compound. Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, low melting wax, cocoa butter, and the like. The term "preparation" is intended to include formulations of the active compound with the encapsulating material as a carrier which provides capsules in which the active ingredient is surrounded by the carrier, either with or without other carriers, whereby the carrier is associated with the active ingredient. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.

[0110] To prepare suppositories, a mixture of low melting waxes such as fatty acid glycerides or cocoa butter is first melted, and the active ingredient is uniformly dispersed therein by stirring or the like. The melted homogeneous mixture is then poured into molds of convenient size and allowed to cool, thereby solidifying.

[0111] Preparations in liquid form include solutions, suspensions, and emulsions, such as water or water / propylene glycol solutions. In the case of parenteral injections, the liquid preparation can be formulated into a solution in an aqueous polyethylene glycol solution.

[0112] If parenteral administration is required or desired, particularly suitable mixtures for the compounds of the present invention include injectable sterile solutions, preferably oily or aqueous solutions, and suspensions, emulsions, or inserts such as suppositories. In particular, carriers for parenteral administration include aqueous solutions of dextrose, physiological saline, pure water, ethanol, glycerol, propylene glycol, peanut oil, sesame oil, polyoxyethylene block polymers, and the like. Ampoules are a convenient unit dose. Also, the compounds of the present invention can be incorporated into liposomes or administered via a transdermal pump or patch. Suitable pharmaceutical mixtures for use in the present invention include, for example, those described in Pharmaceutical Sciences (17th Ed., Mack Pub. Co., Easton, PA) and WO96 / 05309, the teachings of both of which are incorporated herein by reference.

[0113] Aqueous solutions suitable for oral use can be prepared by dissolving the active ingredient in water and adding, if desired, suitable colorants, flavorants, stabilizers, and thickeners. Aqueous suspensions suitable for oral use can be made by dispersing the micronized active ingredient in water with a viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well-known suspending agents.

[0114] Also included are solid preparations intended to be converted into liquid preparations for oral administration immediately before use. Such liquid forms include solutions, suspensions, and emulsions. These preparations can contain, in addition to the active ingredient, colorants, flavorants, stabilizers, buffers, artificial and natural sweeteners, dispersing agents, thickeners, solubilizing agents, and the like.

[0115] The pharmaceutical preparation is preferably in unit dosage form. In such form, the preparation is subdivided into unit doses containing the active ingredient in a suitable amount. The unit dosage form can be a packaged preparation, and the package contains an individual quantity of the preparation, for example, a packaged tablet, capsule, and powder in a vial or an ampoule. The unit dosage form can be a capsule, tablet, cachet, or lozenge alone, or can be a form in which a suitable number of any of these are packaged.

[0116] The amount of the active ingredient in the unit dosage preparation can be varied or adjusted from 0.1 mg to 10,000 mg, more generally from 1.0 mg to 1000 mg, and most generally from 10 mg to 500 mg, depending on the particular use and efficacy of the active ingredient. The composition can also contain other compatible therapeutic agents, if necessary.

[0117] Some compounds can have limited solubility in water and thus may require a surfactant or other suitable co-solvent in the composition. Examples of such co-solvents include: polysorbate 20, 60, and 80; pluronic® F-68, F-84, and P-103; cyclodextrin; and polyoxyl 35 castor oil. Such co-solvents are usually used at levels between about 0.01% and about 2% by weight.

[0118] To reduce variability in dispensing the preparation, to reduce physical separation of the components of a suspension or emulsion that is the preparation, and / or to improve the preparation in other respects, a greater viscosity than that of a simple aqueous solution may be desirable. Examples of such viscosity increasing 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 usually used at levels between about 0.01% and about 2% by weight.

[0119] The composition of the present invention may additionally contain components that provide sustained release and / or comfort. Such components include high molecular weight anionic mucin-mimicking polymers, gelling polysaccharides, and micronized drug carrier matrices. These components are described in more detail in U.S. Patent Nos. 4,911,920; 5,403,841; 5,212,162; and 4,861,760. The entire contents of these patents are hereby incorporated by reference in their entirety for all purposes.

[0120] E. Effective dosage The pharmaceutical compositions provided by the present invention include compositions in which the active ingredient is contained in a therapeutically effective amount, i.e., an amount effective to achieve the intended purpose of its use. The actual amount effective for a particular use depends, inter alia, on the condition being treated. For example, when administered in a method for treating HAE, such a composition contains an amount of the active ingredient effective to achieve the desired results (e.g., inhibiting pKal in a subject and / or reducing the amount of bradykinin).

[0121] The dosage and frequency (single or multiple doses) of the compound administered can vary depending on a variety of factors including the route of administration; the size, age, sex, health status, weight, body mass index, and diet of the recipient; the nature and extent of the symptoms of the disease being treated (e.g., a disease responsive to pKal inhibition); the presence of other diseases or other health-related problems; the type of co-treatment; and complications due to any disease or treatment regimen. Other treatment regimens or agents can be used in combination with the methods and compounds of the present invention.

[0122] For any given compound or test agent, a therapeutically effective amount can first be determined by cell culture assays. The target concentration is, for example, the concentration of the active compound(s) capable of reducing pKal enzyme activity as measured using the methods described.

[0123] The therapeutically effective amount for use in humans can be determined from animal models. For example, the dosage for humans can be formulated to achieve a concentration known to be effective in animals. The dosage in humans can be adjusted, as described above, by monitoring pKal inhibition and adjusting the dosage up or down.

[0124] The dosage can vary depending on the requirements of the patient and the compound used. In the context of the present invention, the dosage administered to a patient must be sufficient to produce a beneficial therapeutic response in the patient over time. The size of the dosage is also determined by the presence, nature, and extent of any adverse side effects. Generally, treatment is initiated at a lower dosage, less than the optimal dosage of the compound. Thereafter, the dosage is increased in small increments until the optimal effect under the circumstances is achieved. In some embodiments, the dosage range is 0.001 to 10 w / v%. In some embodiments, the dosage range is 0.1 to 5 w / v%.

[0125] The dosage and interval can be adjusted individually to provide an effective level of the compound being administered for the particular clinical indication being treated. This provides a treatment regimen appropriate to the severity of the individual disease state.

[0126] F. Method of Treatment The present disclosure provides compounds for use in pharmaceuticals. The present disclosure further provides the use of any of the compounds described herein for inhibiting the activity of pKal, which is beneficial for the treatment of pKal-mediated diseases and conditions. Exemplary disorders mediated by pKal include edema, which refers to swelling in the whole body or a part of a subject, caused by inflammation or injury when small blood vessels become leaky and release body fluid into the surrounding tissue. In some embodiments, 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 a method for inhibiting the activity of pKal in vitro by contacting any of the compounds described herein with a pKal molecule in a sample, e.g., a biological sample. In certain embodiments, the present application provides a method for inhibiting the activity of pKal in vivo by delivering an effective amount of any of the compounds described herein to a subject in need of treatment by a suitable route.

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

[0128] In certain embodiments, the subject to be treated by any of the methods described herein is a human patient having, suspected of having, or at risk for edema, such as HAE or diabetic macular edema (DME). Subjects having edema can be identified by standard medical tests, such as clinical examinations. Subjects suspected of having edema can exhibit one or more symptoms of the disease / disorder. Subjects at risk for edema can be, for example, subjects having a deficiency in C1-INH for HAE, one or more of the risk factors associated with the disease.

[0129] In certain embodiments, methods are provided herein for reducing one or more symptoms of HAE in a human patient suffering from an HAE attack. Such patients can be identified by standard medical procedures. An effective amount of one or more of the provided compounds can be administered to the human patient by a suitable route, such as those described herein. The compounds described herein can be used alone or in combination with other anti-HAE agents, such as C1-esterase inhibitors (e.g., Cinryze® or Berinert®), pKal inhibitors (e.g., ecallantide or lanadelumab), or bradykinin B2 receptor antagonists (e.g., Firazyr®).

[0130] In other embodiments, methods are provided herein for reducing the risk of an HAE attack in a human HAE patient during a quiescent period. 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 invention can be administered to the human patient by a suitable route, such as those described herein. The compounds described herein can be used alone or in combination with other anti-HAE agents, such as C1-esterase inhibitors (e.g., Cinryze® or Berinert®), pKal inhibitors (e.g., ecallantide or lanadelumab), or bradykinin B2 receptor antagonists (e.g., Firazyr®).

[0131] In yet other embodiments, prophylactic treatment of HAE in human patients at risk of HAE attacks using one or more of the compounds described herein is provided herein. Suitable patients for such prophylactic treatment can be human subjects having a history of HAE attacks (e.g., human subjects who have experienced more than two attacks per month). Alternatively, suitable patients for prophylactic treatment can be human subjects who do not have a history of HAE attacks but have one or more risk factors for HAE (e.g., family history, genetic defects in the C1-INH gene, etc.). Such prophylactic treatment may require one of the compounds described herein as the sole active agent or may require additional anti-HAE agents, such as those described herein.

[0132] In certain embodiments, methods for preventing or reducing edema in the eye of a subject (e.g., a human patient) are provided herein. In some examples, the human patient is a diabetic patient who has, is suspected of having, or is at risk of having diabetic macular edema (DME). DME is a proliferative diabetic retinopathy characterized by swelling of the retinal layers, neovascularization, vascular leakage, and retinal thickening in diabetes, which is caused by leakage of body fluids from blood vessels in the macula. To carry out this method, an effective amount of one or more of the compounds described herein or a 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 intravitreal injection or subretinal injection. The subject can be treated with the compounds described herein either as the sole active agent or in combination with another treatment method for DME. Non-limiting examples of treatment methods for DME include laser photocoagulation, steroids, agents that target the VEGF pathway (e.g., Lucentis® (ranibizumab) or Eylea® (aflibercept)), and / or anti-PDGF agents.

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

[0134] In certain embodiments, the subject being treated is an animal. The animal can be of either sex and at any stage of development. In certain embodiments, the subject is a mammal. In certain embodiments, the subject being treated is a human. In certain embodiments, the subject is a domesticated animal 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 farm animal such as a cow, pig, horse, sheep, or goat. In certain embodiments, the subject is a zoo animal. In another embodiment, the subject is a research animal such as a rodent (e.g., mouse, rat), dog, pig, or non-human primate. In certain embodiments, the animal is a genetically engineered animal. In certain embodiments, the animal is a transgenic animal.

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

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

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

[0138] 1. A compound of formula (I):

Chemical formula

[0139] 2. When L is -(CR2) m NRC(O)- and m is 0 to 2 (for example, 0 or 2), any of the following (a), (b), or (c): (a) n is 0, (b) R 5 、R 6 、R 7 、R8 and R 9 at least one of which is CN, or (c) R 1 is an optionally substituted saturated monocyclic heterocyclic ring containing 1 to 3 nitrogen atoms, provided that the compound is N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(2-oxopyrrolidin-1-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide, N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-morpholinoimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide, N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(2-oxopyrrolidin-1-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide, N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(2-oxooxazolidin-3-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide, or 4-(2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)morpholine-2-carboxylic acid does not apply, the compound according to Embodiment 1

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

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

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

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

[0144] 7. A compound according to any one of the preceding embodiments, wherein L is other than -CH2NRC(O)-# or -CH2C(O)NR-#

[0145] When L is -C(R)2NRC(O)- or -C(R)2C(O)NR-, any one of the following (a), (b), or (c): (a) n is 0, (b) at least one of R 5 , R 6 , R 7 , R 8 , and R 9 is CN, or (c) R 1 is an optionally substituted saturated monocyclic heterocyclic ring containing 1 to 3 nitrogen atoms, provided that the compound is not N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(2-oxopyrrolidin-1-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide, N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-morpholinoimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide, N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(2-oxopyrrolidin-1-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide, N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(2-oxooxazolidin-3-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide, or 4-(2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)morpholine-2-carboxylic acid, corresponding to any one of the compounds described in any one of the preceding embodiments.

[0146] 9. When L is -C(R)2NRC(O)-# or -C(R)2C(O)NR-#, n is 0, and the compound is as described in any one of the preceding embodiments.

[0147] 10. When L is -C(R)2NRC(O)-# or -C(R)2C(O)NR-#, R’ is monocyclic Het A Together with, an optionally substituted fused 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclylene having 1 to 4 heteroatoms selected from oxygen, nitrogen, or sulfur, and the compound is as described in any one of the preceding embodiments.

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

[0149] 12. When L is -(CR2) m NRC(O)- and m is 0, 1, or 2, n is 0, and the compound is as described in any one of the preceding embodiments.

[0150] 13. When L is -(CR2) m NRC(O)- and m is 0 to 2 (for example, 0 or 2), R’ is monocyclic Het A Together with, an optionally substituted fused 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclylene having 1 to 4 heteroatoms selected from oxygen, nitrogen, or sulfur, and the compound is as described in any one of the preceding embodiments.

[0151] 14. When L is -C(R)2C(O)NRC(R)2-#, where each R is independently hydrogen or C optionally substituted with halogen 1~3 Aliphatic, and the compound is as described in any one of the preceding embodiments.

[0152] 15. The compound according to any one of the preceding embodiments, wherein L is -CH2C(O)NHCH(CF3)-#.

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

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

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

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

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

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

[0159] 22. The compound according to any one of the preceding embodiments, wherein L is -C(R)2NRSO2-#, where each R is independently hydrogen or C optionally substituted with halogen 1~3 and is aliphatic.

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

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

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

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

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

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

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

[0167] 30. The compound according to any one of the preceding embodiments, wherein L is -CH2C(O)NHCH2-.

[0168] 31. The compound according to any one of the preceding embodiments, wherein the compound has the structure of formula (I-a), formula (I-b), formula (I-c), formula (I-d) [Chemical formula] or a pharmaceutically acceptable salt thereof.

[0169] 32. The compound according to any one of the preceding embodiments, wherein the compound has the structure of formula (II): [Chemical formula] or a pharmaceutically acceptable salt thereof.

[0170] 33. The compound has a structure of formula (II-a) or formula (II-b):

Chemical formula

[0171] 34. R’ condenses with monocyclic Het A to form an optionally substituted fused ring, and the compound has a structure of formula (III):

Chemical formula

[0172] 35. The compound has a structure of formula (III-a) or formula (III-b):

Chemical formula

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

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

[0175] 38.Het A is pyrazolediyl substituted with 0 to 2 R A groups, and is a compound according to any one of the preceding embodiments.

[0176] 39.Het A is triazolediyl substituted with 0 to 1 R A groups, and is a compound according to any one of the preceding embodiments.

[0177] 40.Het A is unsubstituted pyrazolediyl, and is a compound according to any one of the preceding embodiments.

[0178] 41.Het A is unsubstituted 1,2,3-triazolediyl, and is a compound according to any one of the preceding embodiments.

[0179] 42.Het A is as follows:

Chemical formula

[0180] 43.R A One example of is C substituted with halogen 1~6 and is aliphatic, and is a compound according to any one of the preceding embodiments.

[0181] 44. R’ and R’’ are each hydrogen, and is a compound according to any one of the preceding embodiments.

[0182] 45. R’’ is hydrogen, and R’ is monocyclic Het AA compound according to any one of the preceding embodiments, which together forms a fused 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclylene having 1 to 4 heteroatoms selected from oxygen, nitrogen, or sulfur.

[0183] 46. n is 1, R’’ is hydrogen, and R’ is monocyclic Het A A compound according to any one of the preceding embodiments, which together forms a fused 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclylene having 1 to 4 heteroatoms selected from oxygen, nitrogen, or sulfur.

[0184] 47. n is 1, R’’ is hydrogen, and R’ is monocyclic Het A A compound according to any one of the preceding embodiments, which together forms a fused 8-membered saturated or partially unsaturated bicyclic heterocyclylene having 1 to 4 heteroatoms selected from oxygen, nitrogen, or sulfur.

[0185] 48. When n is 0, Het A is a 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclylene having 1 to 4 heteroatoms selected from oxygen, nitrogen, or sulfur, a compound according to any one of the preceding embodiments.

[0186] 49. A compound according to any one of the preceding embodiments, where n is 0.

[0187] 50. A compound according to any one of the preceding embodiments, where n is 1.

[0188] 51. R 2 , R 3 , R 4 , R 5 , R 7 , R 8 and R 9 each being hydrogen, a compound according to any one of the preceding embodiments.

[0189] 52. R 1 , R2 , R 3 , R 4 , R 7 , R 8 , and R 9 Each of which is hydrogen, the compound according to any one of the preceding embodiments.

[0190] 53. R 1 , R 2 , R 3 , R 4 , R 5 , R 7 , R 8 , and R 9 Each of which is hydrogen, the compound according to any one of the preceding embodiments.

[0191] 54. R 1 is an optionally substituted group selected from a 5- to 6-membered heteroaryl having 1 to 4 heteroatoms selected from 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, the compound according to any one of the preceding embodiments.

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

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

[0194] 57. R 1 is an optionally substituted C 1~6 aliphatic, the compound according to any one of the preceding embodiments.

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

[0196] 59. R 5 and R 6 are each independently halogen, a compound according to any one of the preceding embodiments.

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

[0198] 61. R 6 is Cl or CN, a compound according to any one of the preceding embodiments.

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

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

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

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

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

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

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

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

Example

[0207] Synthesis of Intermediate Synthesis of 2-(7-chloroimidazo[1,5-a]pyridin-1-yl)acetic acid

Chemical formula

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

[0209] Synthesis of butyl 3-amino-3-(4-chloropyridin-2-yl)propanoate. A solution of hydrochloric acid (4 M in 1,4-dioxane, 10 mL, 40 mmol) was added to a solution of butyl 3-(4-chloropyridin-2-yl)-3-(1,1-dimethylethylsulfinamide)propanoate (3.5 g, 9.7 mmol) in 1,4-dioxane (30 mL). The mixture was stirred at room temperature for 4 hours and then concentrated to give a crude oil (4.3 g), which was used in the next step without purification. LCMS RT = 1.187 min [M + H] + 257, 80% purity.

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

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

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

[0213] Synthesis of Methyl 2-(7-chloroimidazo[1,5-a]pyridin-1-yl)acetate

Chem.

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

[0215] Synthesis of 2-(7-chloroimidazo[1,5-a]pyridin-1-yl)acetamide

Chem.

[0216] 1 H NMR (400 MHz, DMSO): δ, ppm 8.36 - 8.33 (2H,m), 7.79 - 7.77 (1H, m), 7.45 - 7.38 (1H, m), 6.99 - 6.92 (1H, m), 6.68 (1H, dd,J = 2.0, 7.3 Hz), 3.66 (2H, s).

[0217] Synthesis of ethyl 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate Synthesis of 5-cyclopropylpyridin-2-amine. A mixture of 5-bromopyridin-2-amine (100 g, 585 mmol), cyclopropylboronic acid (60 g, 701 mmol), Pd(AcO)2 (6.5 g, 29 mmol), SPhos (24 g, 58.5 mmol) and K3PO4 (372 g, 1.755 mol) in toluene / H2O (1.2 L / 0.12 L) was stirred at 90 °C for 14 h under N2. The reaction mixture was concentrated under reduced pressure to give a crude product, which was purified by silica gel chromatography (PE / EA = 1 / 2) to afford 5-cyclopropylpyridin-2-amine (61 g, yield: 78%) as a yellow solid. ESI-MS [M+H] + : 135.1.

[0218] Synthesis of 2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine. A mixture of 5-cyclopropylpyridin-2-amine (61 g, 455 mmol) and 1,3-dichloropropan-2-one (172 g, 1365 mmol) in EtOH (1 L) was stirred at 95 °C for 13 h. The reaction mixture was concentrated to remove EtOH. The pH of the residue was adjusted to 9 by adding aqueous NaHCO3 and extracted with EtOAc (1 L × 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 (EA) to afford 2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine (40 g, yield: 42%) as a yellow solid. ESI-MS [M+H] + : 207.1.

[0219] Synthesis of 2-(azidomethyl)-6-cyclopropylimidazo[1,2-a]pyridine. To a solution of 2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine (40 g, 193 mmol) in DMF (600 mL) was added NaN3 (18.8 g, 290 mmol). The resulting reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with H2O (500 mL) and extracted with EtOAc (500 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 (PE / EA = 2 / 1) to afford 2-(azidomethyl)-6-cyclopropylimidazo[1,2-a]pyridine (35 g, yield: 85%) as a yellow solid. ESI-MS [M+H] + : 214.1.

[0220] Synthesis of ethyl 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate. A mixture of 2-(azidomethyl)-6-cyclopropylimidazo[1,2-a]pyridine (35 g, 163.5 mmol), ethyl propiolate (17.6 g, 180 mmol), CuSO4 (2.6 g, 16.35 mmol), and sodium ascorbate (3.3 g, 16.35 mmol) in H2O / t-BuOH (150 mL / 150 mL) was stirred at room temperature for 3 h. After 3 h, a yellow solid precipitated and the mixture was filtered. The cake was dried to give ethyl 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate (29 g, yield: 57%) as a yellow solid, which was used in the next step without further purification. ESI-MS [M+H] + : 312.1.

[0221] Synthesis of 7-chloro-8-fluoroimidazo[1,5-a]pyridine-1-carbaldehyde Synthesis of 4-chloro-3-fluoropicolin aldehyde. To a solution of 2,2,6,6-tetramethylpiperidine (35.4 g, 250.88 mmol) in 200 mL of THF was added dropwise n-butyllithium (2.4 M in hexane, 100 mL, 240 mmol) at 0 °C. After stirring at 0 °C for 1 h, the reaction mixture was cooled to -78 °C, and a solution of 4-chloro-3-fluoropyridine (30.0 g, 228.08 mmol) in THF (100 mL) was added dropwise. The resulting reaction mixture was stirred at -78 °C for 2 h, a solution of DMF (17.5 g, 239.48 mmol) in THF (50 mL) was added dropwise, and the resulting reaction mixture was stirred at -78 °C for an additional 1 h. The reaction was quenched with H2O (50 mL) and extracted with ethyl acetate (200 mL × 3). The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to give 4-chloro-3-fluoropicolin aldehyde (26.0 g, yield: 71%). ESI-MS [M+H] + : 160.1.

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

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

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

[0225] Synthesis of 7-chloro-8-fluoroimidazo[1,5-a]pyridine. To a solution of N-((4-chloro-3-fluoropyridin-2-yl)methyl)formamide (crude, about 126.89 mmol) in anhydrous acetonitrile (200 mL) was added phosphoryl trichloride (18 mL, 1.5 equiv), and the resulting reaction mixture was stirred for 3 hours while refluxing. After the reaction was complete, the reaction mixture was cooled to room temperature and then carefully poured into H2O (200 mL). The pH was adjusted to 8 with saturated sodium bicarbonate, and then the resulting mixture was extracted with ethyl acetate (200 mL × 3). The combined organic phases were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate) to obtain 7-chloroimidazo[1,5-a]pyridine (12.0 g, yield: 56%) as a white solid. ESI-MS [M+H] + : 171.1.

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

[0227] Synthesis of 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylic acid Synthesis of 5-cyclopropylpyridin-2-amine. A solution of 5-bromopyridin-2-amine (5 g, 29.1 mmol), cyclopropylboronic acid (3.75 g, 43.6 mmol), Pd(OAc)2 (651 mg, 2.91 mmol), SPhos (1.19 g, 2.91 mmol), and K3PO4 (18.5 g, 87.3 mmol) in toluene / H2O (100 mL / 10 mL) was stirred at 95 °C for 12 h under nitrogen. Then the reaction mixture was quenched with H2O (50 mL) and extracted with DCM (200 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to obtain a crude residue, which was purified by silica gel chromatography (PE / EtOAc = 1 / 1) to obtain 5-cyclopropylpyridin-2-amine as a yellow solid (3.8 g, 97.4% yield). ESI-MS [M+H] + : 135.2.

[0228] Synthesis of 2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine. To a solution of 5-cyclopropyl-4-methylpyridin-2-amine (500 mg, 3.70 mmol) in DMF (10 mL) was added 1,3-dichloropropan-2-one (1409 mg, 11.1 mmol) at room temperature. The resulting reaction mixture was stirred at 85 °C for 2 h. The solution was quenched with H2O (60 mL), adjusted to pH 8 by adding saturated NaHCO3 solution, 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 a crude product, which was purified by preparative TLC (PE / EtOAc = 1 / 1) to afford 2-(chloromethyl)-6-cyclopropyl-7-methylimidazo[1,2-a]pyridine (300 mg, yield: 39%) as a pale yellow oil. ESI-MS [M+H] + : 207.2。

[0229] Synthesis of ethyl 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate. To a solution of 2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine (2 g, 9.70 mmol) in DMF (20 mL) were added ethyl 1H-pyrazole-4-carboxylate (906 mg, 6.46 mmol) and Cs2CO3 (6.32 g, 19.38 mmol) at room temperature. The resulting reaction mixture was stirred at room temperature for 12 h. H2O (150 mL) was added to the reaction mixture, 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 a crude product, which was purified by silica gel chromatography (DCM / MeOH = 20 / 1) to afford ethyl 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate (1.5 g, yield: 75%) as a white solid. ESI-MS [M+H] + : 311.2。

[0230] Synthesis of 1 - ((6 - cyclopropylimidazo[1,2 - a]pyridin - 2 - yl)methyl)-1H - pyrazole - 4 - carboxylic acid. To a solution of ethyl 1 - ((6 - cyclopropylimidazo[1,2 - a]pyridin - 2 - yl)methyl)-1H - pyrazole - 4 - carboxylate (1.2 g, 3.87 mmol) in THF (20 mL) and H2O (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, yield: 91%). ESI - MS [M + H] + : 283.2。

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

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

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

[0234] Synthesis of ethyl 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate Synthesis of 5-cyclopropylpyridin-2-amine. A mixture of 5-bromopyridin-2-amine (100 g, 585 mmol), cyclopropylboronic acid (60 g, 701 mmol), Pd(AcO)2 (6.5 g, 29 mmol), SPhos (24 g, 58.5 mmol) and K3PO4 (372 g, 1.755 mol) in toluene / H2O (1.2 L / 0.12 L) was stirred at 90 °C for 14 h under N2. The reaction mixture was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel chromatography (PE / EA = 1 / 2) to give 5-cyclopropylpyridin-2-amine (61 g, yield: 78%) as a yellow solid. ESI-MS [M+H] + : 135.1。

[0235] Synthesis of 2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine. A mixture of 5-cyclopropylpyridin-2-amine (61 g, 455 mmol) and 1,3-dichloropropan-2-one (172 g, 1365 mmol) in EtOH (1 L) was stirred at 95 °C for 13 h. The reaction mixture was concentrated to remove EtOH. The pH of the residue was adjusted to 9 by adding aqueous NaHCO3, and the mixture was extracted with EtOAc (1 L × 3). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated under reduced pressure to obtain a crude product, which was purified by silica gel chromatography (EA) to give 2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine (40 g, yield: 42%) as a yellow solid. ESI-MS [M+H] + : 207.1。

[0236] Synthesis of 2-(azidomethyl)-6-cyclopropylimidazo[1,2-a]pyridine. To a solution of 2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine (40 g, 193 mmol) in DMF (600 mL) was added NaN3 (18.8 g, 290 mmol). The resulting reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with H2O (500 mL) and extracted with EtOAc (500 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure to obtain a crude product, which was purified by silica gel chromatography (PE / EA = 2 / 1) to give 2-(azidomethyl)-6-cyclopropylimidazo[1,2-a]pyridine (35 g, yield: 85%) as a yellow solid. ESI-MS [M+H] + : 214.1.

[0237] Synthesis of ethyl 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate. A mixture of 2-(azidomethyl)-6-cyclopropylimidazo[1,2-a]pyridine (35 g, 163.5 mmol), ethyl propiolate (17.6 g, 180 mmol), CuSO4 (2.6 g, 16.35 mmol), and sodium ascorbate (3.3 g, 16.35 mmol) in H2O / t-BuOH (150 mL / 150 mL) was stirred at room temperature for 3 h. After 3 h, a yellow solid precipitated and the mixture was filtered. The cake was dried to give ethyl 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate (29 g, yield: 57%) as a yellow solid, which was used in the next step without further purification. ESI-MS [M+H] + : 312.1.

[0238] Synthesis of (7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride Synthesis of 4-chloro-3-fluoropicolin aldehyde. To a solution of 2,2,6,6-tetramethylpiperidine (35.4 g, 250.88 mmol) in 200 mL of THF was added dropwise n-butyllithium (2.4 M in hexane, 100 mL, 240 mmol) at 0 °C. After stirring at 0 °C for 1 hour, the reaction mixture was cooled to -78 °C, and a solution of 4-chloro-3-fluoropyridine (30.0 g, 228.08 mmol) in THF (100 mL) was added dropwise. The resulting reaction mixture was stirred at -78 °C for 2 hours, a solution of DMF (17.5 g, 239.48 mmol) in THF (50 mL) was added dropwise, and the resulting reaction mixture was stirred at -78 °C for an additional 1 hour. The reaction was quenched with H2O (50 mL) and extracted with ethyl acetate (200 mL × 3). The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to give 4-chloro-3-fluoropicolin aldehyde (26.0 g, yield: 71%). ESI-MS [M+H] + : 160.1.

[0239] Synthesis of N-((4-chloro-3-fluoropyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide. To a solution of 4-chloro-3-fluoropicolinaldehyde (26.0 g, mixture, 163.0 mmol) in DCM (100 mL) were added cesium carbonate (96.0 g, 293.3 mmol) and 2-methylpropane-2-sulfinamide (19.8 g, 163.0 mmol) at room temperature. The reaction mixture was stirred at room temperature for 3 hours. After the reaction was completed, the reaction mixture was filtered and washed three times with DCM. MeOH (40 mL) was added to the combined mixture, and then the resulting mixture was cooled to 0 °C in an ice-water bath. Sodium borohydride (15.5 g, 409.0 mmol) was added slowly in several portions. The reaction mixture was warmed to room temperature and stirred at this temperature for 2 hours. The reaction was carefully quenched with H2O. The resulting mixture was extracted with DCM (100 mL × 3), and the combined organic solvents were dried over sodium sulfate, filtered, and concentrated to obtain crude N-((4-chloro-3-fluoropyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide (43.3 g, crude product) as a yellow solid. ESI-MS [M+H] + : 265.1。

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

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

[0242] Synthesis of 7-chloro-8-fluoroimidazo[1,5-a]pyridine. To a solution of N-((4-chloro-3-fluoropyridin-2-yl)methyl)formamide (crude, about 126.89 mmol) in anhydrous acetonitrile (200 mL) was added phosphoryl trichloride (18 mL, 1.5 equiv), and the resulting reaction mixture was stirred for 3 hours while refluxing. After the reaction was complete, the reaction mixture was cooled to room temperature and then carefully poured into H2O (200 mL). The pH was adjusted to 8 with saturated sodium bicarbonate, and then the resulting mixture was extracted with ethyl acetate (200 mL × 3). The combined organic phases were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate) to obtain 7-chloroimidazo[1,5-a]pyridine (12.0 g, yield: 56%) as a white solid. ESI-MS [M+H] + : 171.1.

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

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

[0245] Synthesis of N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-2-methylpropane-2-sulfinamide. To a solution of (E)-N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methylene)-2-methylpropane-2-sulfinamide (7.77 g, 25.75 mmol) in MeOH (200 mL) was slowly added sodium borohydride (2.44 g, 64.37 mmol). The resulting reaction mixture was stirred at room temperature for 3 h. After the reaction was complete, the reaction was quenched with H2O (50 mL). The resulting mixture was extracted with ethyl acetate (200 mL × 3), and the combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-2-methylpropane-2-sulfinamide (7.77 g, 99%) as a white solid. ESI-MS [M+H] + : 304.1.

[0246] (7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride synthesis. A mixture of N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-2-methylpropane-2-sulfinamide (7.77 g, 25.5 mmol) and hydrochloric acid in ethyl acetate (3 M, 100 mL) was stirred at room temperature for 2 h, then the reaction mixture was filtered to obtain the crude product, which was washed with ethyl acetate and dried under vacuum to give (7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride (6.03 g, quantitative) as a white solid. ESI-MS [M-NH2] + :182.9. 1 1H NMR (400 MHz, DMSO): δ 8.64 (d, J = 2.0 Hz, 1H), 8.44 (br, 3H), 8.33 (d, J = 7.2 Hz, 1H), 6.92 (t, J = 6.8 Hz, 1H), 4.26 - 4.22 (m, 2H).

[0247] Synthesis of Ethyl 1-((6-Cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate Synthesis of 5-Cyclopropylpyridin-2-amine. A solution of 5-Bromopyridin-2-amine (5 g, 29.1 mmol), cyclopropylboronic acid (3.75 g, 43.6 mmol), Pd(OAc)2 (651 mg, 2.91 mmol), SPhos (1.19 g, 2.91 mmol), and K3PO4 (18.5 g, 87.3 mmol) in toluene / H2O (100 mL / 10 mL) was stirred at 95 °C for 12 h under nitrogen. The reaction mixture was then quenched with H2O (50 mL) and extracted with DCM (200 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to give a crude residue, which was purified by silica gel chromatography (PE / EtOAc = 1 / 1) to afford 5-Cyclopropylpyridin-2-amine as a yellow solid (3.8 g, 97.4% yield). ESI-MS [M+H] + : 135.2.

[0248] Synthesis of 2-(Chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine. To a solution of 5-Cyclopropyl-4-methylpyridin-2-amine (500 mg, 3.70 mmol) in DMF (10 mL) was added 1,3-Dichloropropan-2-one (1409 mg, 11.1 mmol) at room temperature. The resulting reaction was stirred at 85 °C for 2 h. The solution was quenched with H2O (60 mL), adjusted to pH 8 by adding saturated NaHCO3 solution, and extracted with EtOAc (50 mL x 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 preparative TLC (PE / EtOAc = 1 / 1) to afford 2-(Chloromethyl)-6-cyclopropyl-7-methylimidazo[1,2-a]pyridine (300 mg, yield: 39%) as a pale yellow oil. ESI-MS [M+H] + : 207.2.

[0249] Synthesis of ethyl 1 - ((6 - cyclopropylimidazo[1,2 - a]pyridin - 2 - yl)methyl)-1H - pyrazole - 4 - carboxylate. To a solution of 2-(chloromethyl)-6 - cyclopropylimidazo[1,2 - a]pyridine (2 g, 9.70 mmol) in DMF (20 mL) were added ethyl 1H - pyrazole - 4 - carboxylate (906 mg, 6.46 mmol) and Cs2CO3 (6.32 g, 19.38 mmol) at room temperature. The resulting reaction mixture was stirred at room temperature for 12 h. H2O (150 mL) was added to the reaction mixture, 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 obtain a crude product, which was purified by silica gel chromatography (DCM / MeOH = 20 / 1) to give ethyl 1 - ((6 - cyclopropylimidazo[1,2 - a]pyridin - 2 - yl)methyl)-1H - pyrazole - 4 - carboxylate (1.5 g, yield: 75%) as a white solid. ESI - MS [M + H] + : 311.2。

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

[0251] Synthesis of 8-bromo-2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine. A solution of 3-bromo-5-cyclopropylpyridin-2-amine (8.23 g, 38.6 mmol) and 1,3-dichloropropan-2-one (7.46 g, 57.9 mmol) in EtOAc (80 mL) was stirred at 70 °C for 48 h. The reaction mixture was diluted with EtOAc (300 mL) and washed with saturated aqueous NaHCO3 (100 mL). The organic layer was washed with brine, dried over Na2SO4, and concentrated under reduced pressure to give a crude product, which was purified using silica gel (EtOAc / PE = 1 / 2) to give (8 g, yield: 72.3%) as a yellow solid. ESI-MS [M+H] + : 284.8

[0252] Synthesis of 2-(azidomethyl)-8-bromo-6-cyclopropylimidazo[1,2-a]pyridine. To a solution of 8-bromo-2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine (1 g, 3.5 mmol) in DMF (15 mL) was added NaN3 (230 mg, 3.5 mmol). The resulting mixture was stirred at 50 °C for 24 h under nitrogen. H2O (50 mL) was added to the reaction 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 2-(azidomethyl)-8-bromo-6-cyclopropylimidazo[1,2-a]pyridine (1.1 g, crude), which was used in the next step without further purification. ESI-MS [M+H] + : 292.0。

[0253] 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 product from the previous step) and tert-butyl propiolate (860 mg, 6.8 mmol) in t-BuOH / H2O (15 mL / 15 mL) were added CuSO4 (170 mg, 0.68 mmol) and sodium ascorbate (180 mg, 1.02 mmol). The reaction mixture was stirred at room temperature for 12 h. The mixture was concentrated under reduced pressure to give the crude product, which was purified by silica gel chromatography (PE / EtOAc = 1 / 2) to afford 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 2 steps) as a brown oil. ESI-MS [M+H] + : 417.7.

[0254] Example 1 2-(7-Chloroimidazo[1,5-a]pyridin-1-yl)-N-((1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methyl)acetamide (I-1) Scheme 1

Chem.

Chem.

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

[0256] Synthesis of (1 - ((6 - cyclopropylimidazo[1,2 - a]pyridin - 2 - yl)methyl)-1H - 1,2,3 - triazol - 4 - yl)methanamine

Chemical Structure

[0257] Synthesis of 2 - (7 - chloroimidazo[1,5 - a]pyridin - 1 - yl)-N - ((1 - ((6 - cyclopropylimidazo[1,2 - a]pyridin - 2 - yl)methyl)-1H - 1,2,3 - triazol - 4 - yl)methyl)acetamide (I - 1)

Chemical Structure

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

[0259] Example 2 1-(7-Chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)-N-((1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methyl)-2,2,2-trifluoroethan-1-amine (I-2) Scheme 2

Chem.

Chem.

[0260] Synthesis of 1-(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)-2,2,2-trifluoroethan-1-ol

Chem.

[0261] Synthesis of 7-chloro-1-(1-chloro-2,2,2-trifluoroethyl)-8-fluoroimidazo[1,5-a]pyridine

Chemical Structure

[0262] Synthesis of 1-(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)-N-((1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methyl)-2,2,2-trifluoroethan-1-amine

Chemical Structure

[0263] 1H NMR (400 MHz, DMSO) δ 8.39 (d, J = 7.5 Hz, 1H), 8.35 (s,1H), 7.86 (s, 1H), 7.78 (s, 1H), 7.60 (s, 1H), 7.40 (d, J = 9.3 Hz, 1H), 7.01 (d,J = 9.4 Hz, 1H), 6.89 (t, J = 7.0 Hz, 1H), 5.55 (s, 2H), 5.42 ― 5.34 (m, 1H), 3.82― 3.71 (m, 2H), 1.95 ― 1.90 (m, 1H), 0.93 ― 0.90 (m, 2H), 0.70 ― 0.66 (m, 2H).

[0264] Example 3 7-Chloro-N-((1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methyl)-8-fluoroimidazo[1,5-a]pyridine-1-carboxamide (I-3) Scheme 3

Chem.

Chem.

[0265] Synthesis of 7-chloro-N-((1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methyl)-8-fluoroimidazo[1,5-a]pyridine-1-carboxamide

Chem.

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

[0267] Example 4 N-((7-Chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-sulfonamide (I-4) Scheme 4

Chemical Structure

Chem.

[0268] Synthesis of 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(1H-tetrazol-1-yl)benzyl)-1H-pyrazole-4-sulfonamide

Chem.

[0269] 1H NMR (400 MHz, DMSO) δ 8.41 (d, J = 2.3 Hz, 1H), 8.35 (s,1H), 8.19 ― 8.17 (m, 2H), 7.78 ― 7.77 (m, 2H), 7.66 (s, 1H), 7.42 (d, J = 9.3 Hz,1H), 7.01 (dd, J = 9.4, 1.7 Hz, 1H), 6.75 (t, J = 8.0 Hz, 1H), 5.42 (s, 2H), 4.23(d, J = 5.5 Hz, 2H), 1.97 ― 1.87 (m, 1H), 0.95 ― 0.90 (m, 2H), 0.70 ― 0.66 (m, 2H).

[0270] Example 5 N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-sulfonamide (I-5) Scheme 5

Chemistry

Chemistry

[0271] Benzyl(ethynyl)sulfane synthesis

Chemistry

[0272] 1H NMR (400 MHz, CDCl3) δ 7.35 ― 7.26 (m, 5H), 3.96 (s, 2H), 2.82 (s, 1H). Synthesis of Benzyl(ethynyl)sulfane

Chem.

[0273] Synthesis of 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-sulfonyl chloride

Chem.

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

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

[0276] Example 6 7-Chloro-N-((1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methyl)-8-fluoroimidazo[1,5-a]pyridine-1-sulfonamide (I-6) Scheme 6

Chemical formula

Chemical formula

[0277] Synthesis of 7-chloro-8-fluoro-1-((4-methoxybenzyl)thio)imidazo[1,5-a]pyridine

Chemical formula

[0278] Synthesis of 7-chloro-8-fluoroimidazo[1,5-a]pyridine-1-sulfonyl chloride [Chemical formula] To a mixture of 7-chloro-8-fluoro-1-((4-methoxybenzyl)thio)imidazo[1,5-a]pyridine (644 mg, 2.0 mmol) in AcOH / H2O (4.5 mL / 1.5 mL) was added NCS (266 mg, 2.0 mmol). After stirring at room temperature for 2 hours, a second portion of NCS (266 mg, 2.0 mmol) was added. The reaction mixture was stirred at room temperature for an additional 2 hours. The reaction was quenched with saturated aqueous NaHCO3 (50 mL) and extracted with DCM (50 mL × 3). The combined organic layers were washed with brine (40 mL), dried over Na2SO4, and concentrated to give crude 7-chloro-8-fluoroimidazo[1,5-a]pyridine-1-sulfonyl chloride (700 mg, crude) as a brown oil, which was used directly in the next step without further purification. ESI-MS [M + H] + : 269.0.

[0279] Synthesis of 7-chloro-N-((1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methyl)-8-fluoroimidazo[1,5-a]pyridine-1-sulfonamide [Chemical formula] A mixture of 7-chloro-8-fluoroimidazo[1,5-a]pyridine-1-sulfonyl chloride (150 mg, 0.56 mmol), (1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methanamine (150 mg, 0.56 mmol) and DIPEA (217 mg, 1.68 mmol) in DMF (100 mL) was stirred at room temperature for 18 h. The reaction was quenched with saturated aqueous NaHCO3 (30 mL) and extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4 and concentrated to give a crude product, which was purified by preparative HPLC to afford 7-chloro-N-((1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methyl)-8-fluoroimidazo[1,5-a]pyridine-1-sulfonamide (11 mg, 4% yield) as a pale yellow solid. ESI-MS [M+H]+: 501.1.

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

[0281] Example 7 7-Chloro-N-(1-(1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)ethyl)-8-fluoroimidazo[1,5-a]pyridine-1-sulfonamide (I-7)

Chemical Structure

[0282] 1H NMR (400 MHz, DMSO) δ 8.52 (d, J = 2.1 Hz, 1H), 8.37 -8.35(m, 2H), 8.19 (d, J = 8.5 Hz, 1H), 7.81 (s, 1H), 7.67 (s, 1H), 7.45 (d, J = 9.4Hz, 1H), 7.07 - 7.01 (m, 2H), 5.62 - 5.46 (m, 2H), 4.59 - 4.53 (m, 1H), 1.97 - 1.91(m, 1H), 1.33 (d, J = 7.0 Hz, 3H), 0.94 -0.91 (m, 2H), 0.71 -0.67 (m, 2H).

Chem.

[0283] Synthesis of 1-(1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)ethan-1-ol

Chem.

[0284] 2-((4-(1-chloroethyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridine

Chem.

[0285] Synthesis of 2-((4-(1-azidoethyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridine

Chemical Structure

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

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

[0288] Synthesis of methyl 2-(3-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)-3-oxopropyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylate [Chemical formula] 1-(6-Cyclopropylimidazo[1,2-a]pyridin-2-yl)prop-2-en-1-ol (1.2 g, 5.6 mmol), methyl 2-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylate (2.25 g, 6.7 mmol), Pd(OAc)2 (125 mg, 0.56 mmol), (o-MeC6H4)3P (170 mg, 0.56 mmol) and DIPEA (2.2 g, 16.8 mmol) in DMA (20 mL) were degassed with N2 and stirred at 120 °C for 18 h. The reaction mixture was cooled to room temperature and water (100 mL) was added. The mixture was extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (50 mL) and concentrated under reduced pressure to give a crude product, which was purified by flash column chromatography (eluent: DCM / MeOH = 15 / 1) to give methyl 2-(3-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)-3-oxopropyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylate as an off-white solid (900 mg, yield: 34%). ESI-MS [M + H]+: 468.2. Synthesis of methyl 2-(3-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)-3-oxopropyl)-1H-imidazole-4-carboxylate

Chemical Structure

[0289] Synthesis of methyl 2-(3-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)-3-hydroxypropyl)-1H-imidazole-4-carboxylate

Chemical formula

[0290] Synthesis of methyl 5-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-2-carboxylate

Chemical Structure

[0291] Synthesis of 5-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-2-carboxylic acid

Chemical Structure

[0292] Synthesis of N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-5-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-2-carboxamide

Chemical Structure

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

[0294] Synthesis of Methyl 2-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylate (Compound 3)

Chemical Structure

[0295] Synthesis of methyl 2-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylate

Chemical formula

[0296] Example 9 N - ((7 - chloro - 8 - fluoroimidazo[1,5 - a]pyridin - 1 - yl)methyl)-5 - (6 - cyclopropylimidazo[1,2 - a]pyridin - 2 - yl)-6,7 - dihydro - 5H - pyrrolo[1,2 - a]imidazole - 3 - carboxamide (I - 9) Scheme 9

Chemical Structure

Chemical Structure

[0297] Synthesis of methyl 5-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-3-carboxylate

Chemical Structure

[0298] Synthesis of 5-(6-Cyclopropylimidazo[1,2-a]pyridin-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-3-carboxylic acid

Chem.

[0299] Synthesis of N-((7-Chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-5-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-2-carboxamide

Chem.

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

[0301] Example 10 N-((7-Cyanoimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (I-10)

Chemical Structure

[0302] 1H NMR (400 MHz, DMSO) δ 8.65 (t, J = 5.7 Hz, 1H), 8.50 (s,1H), 8.44 (s, 1H), 8.40-8.37 (m, 1H), 8.32 (s, 1H), 8.21 (s, 1H), 7.86 (s, 1H),7.72 (s, 1H), 7.39 (d, J = 9.3 Hz, 1H), 7.01-6.97 (m, 1H), 6.85-6.81 (m, 1H), 5.39(s, 2H), 4.63 (d, J = 5.7 Hz, 2H), 1.94 ― 1.88 (m, 1H), 0.93 ― 0.88 (m, 2H), 0.68― 0.64 (m, 2H).

[0303] Example 11 1-(7-Chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)-N-(((1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methyl)methanamine (I-11) Scheme 11

Chemical formula

Chemical formula

[0304] Synthesis of 1 - ((6 - cyclopropylimidazo[1,2 - a]pyridin - 2 - yl)methyl)-1H - 1,2,3 - triazole - 4 - carbaldehyde

Chemical Structure

[0305] Synthesis of 1-(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)-N-(((1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methyl)methanamine

Chemical Structure

[0306] 1H NMR (400 MHz, DMSO) δ 8.44 (d, J = 2.1 Hz, 1H), 8.34 (s,1H), 8.19 (d, J = 7.4 Hz, 1H), 7.92 (s, 1H), 7.79 (s, 1H), 7.41 (d, J = 9.3 Hz,1H), 7.00 (d, J = 9.4 Hz, 1H), 6.73 (t, J = 6.9 Hz, 1H), 5.62 (s, 2H), 3.92 (s,2H), 3.74 (s, 2H), 1.97-1.88 (m, 1H), 0.97 ― 0.87 (m, 2H), 0.72-0.62 (m, 2H).

[0307] Example 12 N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-(1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)ethane-1-amine (I-12) Scheme 12

Chemical formula

Chemical formula

[0308] 2-((4-(1-chloroethyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridine

Chemical Structure

[0309] Synthesis of 2-((4-(1-azidoethyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridine

Chem.

[0310] Synthesis of 1-(1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)ethan-1-amine

Chem.

[0311] Synthesis of N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-(1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)ethane-1-amine.

Chemical Structure

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

[0313] Example 13 2-(7-Chloroimidazo[1,5-a]pyridin-1-yl)-N-(1-(1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)ethyl)acetamide (I-13) Synthesis of 2-(7-Chloroimidazo[1,5-a]pyridin-1-yl)-N-(1-(1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)ethyl)acetamide

Chemical Structure

[0314] 1H NMR (400 MHz, DMSO) δ 8.45 (d, J = 8.2 Hz, 1H), 8.36 (s,1H), 8.31 ― 8.24 (m, 2H), 7.90 (s, 1H), 7.83 (s, 1H), 7.75 ― 7.70 (m, 1H), 7.42(d, J = 9.3 Hz, 1H), 7.05-6.98 (m, 1H), 6.65-6.58 (m, 1H), 5.62 (s, 2H), 5.06 ―4.97 (m, 1H), 3.65 (s, 2H), 1.98-1.89 (m, 1H), 1.39 (d, J = 7.0 Hz, 3H), 0.95 ―0.89 (m, 2H), 0.71 ― 0.65 (m, 2H).

[0315] Example 14 Methyl 2-((4-((((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)amino)methyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-carboxylate (I-14) Scheme 14

Chem.

Chem.

[0316] (Synthesis of (1-((8-bromo-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methanol

Chemical Structure

[0317] Synthesis of methyl 6-cyclopropyl-2-((4-(hydroxymethyl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridine-8-carboxylate

Chem.

[0318] Synthesis of methyl 6-cyclopropyl-2-((4-formyl-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridine-8-carboxylate

Chem.

[0319] Synthesis of methyl 2-((4-((((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)amino)methyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-carboxylate

Chemical formula

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

[0321] Example 15 2-((4-((((7-Chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)amino)methyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-carboxylic acid (I-15)

Chem.

[0322] 1 H NMR (400 MHz, DMSO) δ 8.59 (s, 1H), 8.48 (s, 1H),8.21 (d, J = 7.4 Hz, 1H), 8.16 (s, 1H), 8.08 (s, 1H), 7.92 (s, 1H), 7.66 (s, 1H),6.76 (t, J = 6.8 Hz, 1H), 5.75 (s, 2H), 4.04 (s, 2H), 3.89 (s, 2H), 2.06 ― 1.98(m, 1H), 1.00 ― 0.93 (m, 2H), 0.74 ― 0.68 (d, 2H).

[0323] Example 16 N-((7-Chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-(1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazol-4-yl)-2,2,2-trifluoroethan-1-amine (I-16) Scheme 16

Chem.

Chem.

[0324] Synthesis of 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carbaldehyde

Chem.

[0325] Synthesis of 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carbaldehyde

Chemical Structure

[0326] Synthesis of 2-((4-(1-chloro-2,2,2-trifluoroethyl)-1H-pyrazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridine [Chemical formula] To a mixture of 1-(1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazol-4-yl)-2,2,2-trifluoroethan-1-ol (430 mg, 1.27 mmol) in DCM (5 mL) was added SOCl2 (1.0 mL) at 0 °C. The reaction mixture was stirred at room temperature for 2 hours. The mixture was concentrated to give 2-((4-(1-chloro-2,2,2-trifluoroethyl)-1H-pyrazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridine (450 mg, crude), which was used directly in the next step without further purification. ESI-MS [M + H] + : 355.1.

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

[0328] Synthesis of 1-(1-((6-Cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazol-4-yl)-2,2,2-trifluoroethan-1-amine

Chem.

[0329] Synthesis of N-((7-Chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-(1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazol-4-yl)-2,2,2-trifluoroethan-1-amine

Chem.

[0330] 1H NMR (400 MHz, DMSO) δ 8.44 (d, J = 2.4 Hz, 1H), 8.34 (s,1H), 8.18 (d, J = 7.4 Hz, 1H), 7.81 (s, 1H), 7.69 (s, 1H), 7.48 (s, 1H), 7.41 (d,J = 9.3 Hz, 1H), 7.00 (dd, J = 9.4, 1.8 Hz, 1H), 6.78 ― 6.68 (m, 1H), 5.37 (s, 2H),4.48 - 4.40 (m, 1H), 3.97 - 3.87 (m, 2H), 2.73 ― 2.64 (m, 1H), 1.98 ― 1.86 (m, 1H),0.99 ― 0.86 (m, 2H), 0.75 ― 0.60 (m, 2H).

[0331] Example 17 Ethyl 3-(2-((4-((((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)amino)methyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)propanoate (I-17a) 3-(2-((4-((((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)amino)methyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)propanoic acid (I-17b) Scheme 17 [Chemical Structure] Synthesis of ethyl (E)-3-(6-cyclopropyl-2-((4-(hydroxymethyl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-8-yl)acrylate [Chemical Structure] (1 - ((8 - Bromo - 6 - cyclopropylimidazo[1,2 - a]pyridin - 2 - yl)methyl)-1H - 1,2,3 - triazol - 4 - yl)methanol (1.4 g, 4.0 mmol), ethyl acrylate (0.81 g, 8.1 mmol), Pd2(dba)3 (183 mg, 0.2 mmol), (o - MeC6H4)3P (365 mg, 1.2 mmol) and triethylamine (1.2 g, 12.0 mmol) in MeCN (20 mL) were stirred at 90 °C for 8 h. The reaction mixture was cooled to room temperature, diluted with water (100 mL) and extracted with EtOAc (50 mL × 4). The combined organic layers were washed with brine (50 mL), dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by flash column chromatography (PE / EtOAc 0 - 30%) to give ethyl (E)-3-(6 - cyclopropyl - 2 - ((4 - (hydroxymethyl)-1H - 1,2,3 - triazol - 1 - yl)methyl)imidazo[1,2 - a]pyridin - 8 - yl)acrylate (0.4 g, yield: 27%) as a brown solid.

[0332] Synthesis of ethyl 3-(6 - cyclopropyl - 2 - ((4 - formyl - 1H - 1,2,3 - triazol - 1 - yl)methyl)imidazo[1,2 - a]pyridin - 8 - yl)propanoate

Chemical formula

[0333] Synthesis of Ethyl 3-(2-((4-((((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)amino)methyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)propionate

Chemical Structure

[0334] 1H NMR (400 MHz, DMSO) δ 8.44 (d, J = 2.4 Hz, 1H), 8.21 (d,J = 1.3 Hz, 1H), 8.18 (d, J = 7.4 Hz, 1H), 7.93 (s, 1H), 7.74 (s, 1H), 6.83 (s,1H), 6.75-6.70 (m, 1H), 5.64 (s, 2H), 4.02 (q, J = 7.1 Hz, 2H), 3.92 (s, 2H), 3.74(s, 2H), 3.07 (t, J = 7.6 Hz, 2H), 2.77 (t, J = 7.7 Hz, 2H), 1.92-1.84 (m, 1H),1.13 (t, J = 7.1 Hz, 3H), 0.93 ― 0.87 (m, 2H), 0.68 ― 0.62 (m, 2H).

[0335] Synthesis of 3-(2-((4-((((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)amino)methyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)propanoic acid

Chemical formula

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

[0337] Example 18 1-(7-Chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)-N-(((1-((6-cyclopropyl-8-(4H-1,2,4-triazol-4-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methyl)methanamine (I-18) Scheme 18

Chem.

Chem.

[0338] Synthesis of (1 - ((8 - amino - 6 - cyclopropylimidazo[1,2 - a]pyridin - 2 - yl)methyl)-1H - 1,2,3 - triazol - 4 - yl)methanol

Chemical Structure

[0339] Synthesis of (1 - ((6 - cyclopropyl - 8-(4H - 1,2,4 - triazol - 4 - yl)imidazo[1,2 - a]pyridin - 2 - yl)methyl)-1H - 1,2,3 - triazol - 4 - yl)methanol

Chem.

[0340] Synthesis of 1 - ((6 - cyclopropyl - 8-(4H - 1,2,4 - triazol - 4 - yl)imidazo[1,2 - a]pyridin - 2 - yl)methyl)-1H - 1,2,3 - triazole - 4 - carbaldehyde

Chem.

[0341] Synthesis of 1-(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)-N-((1-((6-cyclopropyl-8-(4H-1,2,4-triazol-4-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methyl)methanamine

Chemical formula

[0342] 1H NMR (400 MHz, DMSO) δ 9.41 (s, 2H), 8.48 (s, 1H), 8.44 (s,1H), 8.26 (s, 1H), 8.18 (d, J = 7.4 Hz, 1H), 8.03 (s, 1H), 7.98 (s, 1H), 7.45 (d,J = 0.9 Hz, 1H), 6.73 (t, J = 6.9 Hz, 1H), 5.71 (s, 2H), 3.94 (s, 2H), 3.77 (s,2H), 2.01 - 1.96 (m, 1H), 1.80 ― 1.72 (m, 1H), 1.02 ― 0.95 (m, 2H), 0.86 ― 0.77(m, 2H).

[0343] Example 19 2-(7-Chloroimidazo[1,5-a]pyridin-1-yl)-N-(1-(1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazol-4-yl)-2,2,2-trifluoroethyl)acetamide (I-19) [Chemical formula] A mixture of 1-(1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazol-4-yl)-2,2,2-trifluoroethan-1-amine (50 mg, 0.15 mmol), 2-(7-chloroimidazo[1,5-a]pyridin-1-yl)acetic acid (31 mg, 0.15 mmol), EDCI (40.3 mg, 0.21 mmol), HOBt (28.4 mg, 0.21 mmol) and DIPEA (54.2 mg, 0.42 mmol) in DMF (3 mL) was stirred at room temperature for 16 h. The mixture was diluted with EtOAc (50 mL) and washed with brine (30 mL × 3). The organic layer was concentrated and the residue was purified by preparative HPLC to give 2-(7-chloroimidazo[1,5-a]pyridin-1-yl)-N-(1-(1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazol-4-yl)-2,2,2-trifluoroethyl)acetamide (23.9 mg, 30%) as a pale yellow solid. ESI-MS [M +H]+: 528.1.

[0344] 1H NMR (400 MHz, DMSO) δ 9.11 (d, J = 9.4 Hz, 1H), 8.35 (s,1H), 8.32 ― 8.25 (m, 2H), 7.92 (s, 1H), 7.74 (s, 1H), 7.73 ― 7.72 (m, 1H), 7.58(s, 1H), 7.41 (d, J = 9.4 Hz, 1H), 7.00 (dd, J = 9.4, 1.7 Hz, 1H), 6.63 (dd, J =7.5, 2.1 Hz, 1H), 5.80 ― 5.64 (m, 1H), 5.39 (s, 2H), 3.78 (s, 2H), 2.01 ― 1.87 (m,1H), 1.00 ― 0.85 (m, 2H), 0.79 ― 0.53 (m, 2H).

[0345] Example 20 N-((7-Chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(4-methylpiperazin-1-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide (I-20) Scheme 20

Chemical Structure

Chemical Structure

[0346] Synthesis of 2-(azidomethyl)-6-cyclopropyl-8-(4-methylpiperazin-1-yl)imidazo[1,2-a]pyridine

Chemical formula

[0347] Synthesis of tert-butyl 1-((6-cyclopropyl-8-(4-methylpiperazin-1-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate

Chemical formula

[0348] Synthesis of 1-((6-cyclopropyl-8-(4-methylpiperazin-1-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid

Chemical Structure

[0349] Synthesis of N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(4-methylpiperazin-1-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide

Chemical formula

[0350] 1H NMR (400 MHz, DMSO) δ 8.66 (t, J = 5.4 Hz, 1H), 8.47 (s,1H), 8.40 (d, J = 2.4 Hz, 1H), 8.16 (d, J = 7.4 Hz, 1H), 7.86 (s, 1H), 7.67 (s,1H), 6.75 ― 6.68 (m, 1H), 6.16 (s, 1H), 5.67 (s, 2H), 4.65 (d, J = 5.5 Hz, 2H),3.46 (s, 4H), 2.56 (s, 4H), 2.27 (s, 3H), 1.84 ― 1.80 (m, 1H), 0.84 ― 0.79 (m, 2H),0.64 ― 0.50 (m, 2H).

[0351] Example 21 Inhibitory activity of exemplary compounds against plasma kallikrein. Exemplary compounds were evaluated for inhibition of human active kallikrein enzyme in two assay formats using a fluorescent peptide substrate. In one assay format, the reagent concentrations were as follows: 20 mM Tris (pH 7.5), 1 mM EDTA, 150 mM sodium chloride, 0.1% PEG-400, 0.1% Triton X-100, 500 pM active kallikrein enzyme, 300 μM Pro-Phe-Arg-7-amido-4-methylcoumarin substrate. Before initiation of the reaction by the substrate, the enzyme and inhibitor were pre-incubated at room temperature for 30 minutes. After initiation by the substrate, the reaction was incubated at room temperature for 10 minutes and the fluorescence emission at 460 nm upon excitation at 380 nm was measured by a microplate reader. In the other assay format, the reagent concentrations were as follows: 20 mM Tris (pH 7.5), 1 mM EDTA, 150 mM sodium chloride, 0.1% PEG-400, 0.1% Triton X-100, 5 pM active kallikrein enzyme, 300 μM Pro-Phe-Arg-7-amido-4-methylcoumarin substrate. Before initiation of the reaction by the substrate, the enzyme and inhibitor were pre-incubated at room temperature for 30 minutes. After initiation by the substrate, the reaction was incubated at room temperature for 18 hours and the fluorescence emission at 460 nm upon excitation at 380 nm was measured by a microplate reader.

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

[0353] Numerous embodiments of the present invention have been described, but it is clear that these basic examples can be modified to provide other embodiments that utilize the compounds and methods of the present invention. Accordingly, it will be understood that the scope of the present invention is defined not by the specific embodiments presented as examples, but by the appended claims. The present invention provides, for example, the following items. (Item 1) A compound of formula (I):

Chemical formula

Chem.

Chem.

Claims

1. A compound of formula (I): 【Chemical 119】 or a pharmaceutically acceptable salt thereof (wherein: Het Ａ is selected from a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclylene having 1 to 2 heteroatoms selected from oxygen, nitrogen, or sulfur, a 5- to 6-membered monocyclic heteroarylene having 1 to 4 heteroatoms selected from oxygen, nitrogen, or sulfur, a 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclylene having 1 to 4 heteroatoms selected from oxygen, nitrogen, or sulfur, and a 7- to 10-membered bicyclic heteroarylene having 1 to 5 heteroatoms selected from oxygen, nitrogen, or sulfur, where Het Ａ is substituted with 0 to 4 R Ａ groups, each R Ａ is independently selected from halogen, -CN, -C(R)=N(R), -C(O)R, -C(O) ２ R, -C(O)N(R) ２ 、 -NO ２ 、 -N(R)-N(R) ２ 、 -N(R) ２ 、 -N(R)C(O)R, -N(R)C(O) ２ R, -N(R)C(O)N(R) ２ 、 -N(R)S(O) ２ R, -OR, -OC(O)R, -OC(O)N(R) ２ 、 -SR, -S(O)R, -S(O) ２ R, -S(O)N(R) ２ 、 -S(O) ２ N(R) ２ 、 or C １～６ is independently selected from an optionally substituted group selected from aliphatic, phenyl, a 5- to 6-membered heteroaryl having 1 to 4 heteroatoms selected from 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 heterocyclyl having 1 to 2 heteroatoms selected from oxygen, nitrogen, or sulfur, L is an optionally substituted C １～６ hydrocarbon chain, wherein 1 to 3 methylene units are independently -Cy-, -O-, -NR-, -C(O)-, -S(O) ２ -, -C(O)NR-, -NRC(O)-, -S(O) ２ NR-, and -NRS(O) ２ and are replaced by - -Cy- is a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclylene, a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclylene having 1 to 2 heteroatoms selected from oxygen, nitrogen, or sulfur, or a 5- to 6-membered heteroarylene having 1 to 4 heteroatoms selected from oxygen, nitrogen, or sulfur R' and R'' are independently selected from hydrogen, halogen, -OR, -NR ２ , -SR, and optionally substituted C １～６ aliphatic, wherein R' together with monocyclic Het Ａ may form an optionally substituted fused 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclylene having 1 to 4 heteroatoms selected from oxygen, nitrogen, or sulfur R １ , R ２ , R ３ , R ４ , R ５ , R ６ , R ７ , R ８ , and R ９ are independently selected from hydrogen, halogen, -CN, -C(R)=N(R), -C(O)R, -C(O) ２ R, -C(O)N(R) ２ , -NO ２ , -N(R)-N(R) ２ , -N(R) ２ , -N(R)C(O)R, -N(R)C(O) ２ R, -N(R)C(O)N(R) ２ , -N(R)S(O) ２ R, -OR, -OC(O)R, -OC(O)N(R) ２ , -SR, -S(O)R, -S(O) ２R, -S(O)N(R) ２ , -S(O) ２ N(R) ２ , or C １～６ independently selected from optionally substituted groups selected from 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 carbocyclic ring, and a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms selected from oxygen, nitrogen, or sulfur, each R is independently hydrogen, or C １～６ independently selected from optionally substituted groups selected from 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 carbocyclic ring, and a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms selected from oxygen, nitrogen, or sulfur, or two R groups on the same carbon or nitrogen, together with the atoms intervening between them, form a ring selected from a 3- to 7-membered saturated or partially unsaturated monocyclic ring having 0 to 2 heteroatoms selected from oxygen, nitrogen, or sulfur, and a 5- to 6-membered heteroaryl having 1 to 4 heteroatoms selected from oxygen, nitrogen, or sulfur, n is 0 or 1, and where, when L is -(CR₂)mNR C(O)- and m is 0 to 2, any of the following (a), (b), or (c): (a) n is 0, (b) at least one of R₅, R₆, R₇, R₈, and R₉ is CN, or (c) R1 is an optionally substituted saturated monocyclic heterocyclic ring containing 1 to 3 nitrogen atoms, provided that the compound is not N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(2-oxopyrrolidin-1-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide, N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-morpholinoimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide, N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(2-oxopyrrolidin-1-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide, N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(2-oxooxazolidin-3-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide, or 4-(2-(((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)morpholine-2-carboxylic acid). (corresponding to).

2. L is -C(R) ２ NRC(O)-#, -C(R) ２ C(O)NRC(R) ２ -#, -C(R) ２ NRC(O)C(R) ２ -#, -C(R) ２ NRC(R) ２ -#, -C(R) ２ C(R) ２ NRC(R) ２ -#, -C(O)NRC(R) ２ -#, -C(R) ２C(O)NR—#, —NRC(O)C(R) ２ —#, —CR ２ C(O)NRC(R) ２ —#, —SO ２ NRC(R) ２ —#, and —C(R) ２ NRSO ２ —# selected from the group consisting of, where # represents a point of attachment to Het Ａ The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

3. L is —C(R) ２ NRC(O)—# or —C(R) ２ Other than C(O)NR—# of the compound according to claim 1 or a pharmaceutically acceptable salt thereof.

4. L is —CH ２ NRC(O)—# or —CH ２ Other than C(O)NR—# of the compound according to claim 1 or a pharmaceutically acceptable salt thereof.

5. When L is —C(R) ２ NRC(O)—# or —C(R) ２ C(O)NR—#, any of the following (a), (b), or (c): (a) n is 0, (b) R ５ 、R ６ 、R ７ 、R ８ 、and R ９ At least one of is CN, or (c) R １is an optionally substituted saturated monocyclic heterocyclic ring containing 1 to 3 nitrogen atoms, provided that the compound is not N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(2-oxopyrrolidin-1-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide, N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-morpholinoimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide, N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(2-oxopyrrolidin-1-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide, N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(2-oxooxazolidin-3-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide, or 4-(2-(((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)morpholine-2-carboxylic acid The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which corresponds to .

6. L is -C(R) ２ NRC(O)-# or -C(R) ２ When C(O)NR-# is, n is 0, The compound according to any one of claims 1 to 3 or 5, or a pharmaceutically acceptable salt thereof.

7. L is -C(R) ２ NRC(O)-# or -C(R) ２ When C(O)NR-# is, R' is monocyclic Het Ａand together 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, or a pharma- ceutically acceptable salt thereof.

8. L is - (CR ２ ) ｍ 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, wherein NRC(O)-, and when m is 0, 1 or 2, n is 0.

9. L is - (CR ２ ) ｍ NRC(O)-, m is 0 to 2, and R' is a monocyclic Het Ａ and together 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, or a pharma- ceutically acceptable salt thereof.

10. L is -C(R) ２ C(O)NRC(R) ２ -#, where each R is independently hydrogen or C optionally substituted with halogen. １～３ 5. The compound according to claim 1 or 2 to 4, or a pharma- ceutically acceptable salt thereof, which is aliphatic.

11. L is -C(R) ２ NRC(R) ２ -#, where each R is independently hydrogen or C optionally substituted with halogen. １～３ 3. The compound of claim 1 or 2, or a pharma- ceutically acceptable salt thereof, which is aliphatic.

12. L is -C(R) ２ NRSO ２ -#, where each R is independently hydrogen or C optionally substituted with halogen. １～３ 3. The compound of claim 1 or 2, or a pharma- ceutically acceptable salt thereof, which is aliphatic.

13. L is -SO ２ NRC(R) ２ -#, where each R is independently hydrogen or C optionally substituted with halogen １～３ that is aliphatic, the compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof.

14. L is -C(O)NRC(R) ２ -#, where each R is independently hydrogen or C optionally substituted with halogen １～３ that is aliphatic, the compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof.

15. The compound has the structure of formula (I-a), formula (I-b), formula (I-c), formula (I-d) 【Chemical 120】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

16. The compound has the structure of formula (II): 【Chemical 121】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

17. The compound has the structure of formula (II-a) or formula (II-b): 【Chemical 122】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

18. R' together with monocyclic Het Ａ forms an optionally substituted fused ring, and the compound has the structure of formula (III): 【Chemical 123】 (wherein R ｆｕｓ is Het Ａ condensed to form a fused 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclylene having 1 to 4 heteroatoms selected from oxygen, nitrogen, or sulfur) The compound according to claim 1 or a pharmaceutically acceptable salt thereof having

19. wherein the compound has a structure of formula (III-a) or formula (III-b): 【Chemical Formula 124】 The compound according to claim 1 or a pharmaceutically acceptable salt thereof having

20. Het Ａ is a 5-membered monocyclic heteroarylene having 1 to 4 heteroatoms selected from oxygen, nitrogen, or sulfur, wherein Het Ａ is substituted with 0 to 2 R Ａ groups, the compound according to claims 1 to 5, 15 or 17, or a pharmaceutically acceptable salt thereof.

21. Het Ａ is as follows: 【Chemical Formula 125】 (wherein * represents the bonding point to L), selected from the compound according to claims 1 to 5, 15 or 17, or a pharmaceutically acceptable salt thereof.

22. R Ａ One example of is C substituted with halogen １～６ is aliphatic, the compound according to claims 1 to 5, 15 or 17, or a pharmaceutically acceptable salt thereof.

23. R' and R'' are each hydrogen, the compound according to claims 1 to 5 or 15 to 18, or a pharmaceutically acceptable salt thereof.

24. R'' is hydrogen and R' together with monocyclic Het Ａ forms a fused 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclylene having 1 to 4 heteroatoms selected from oxygen, nitrogen, or sulfur, the compound according to claim 1, or a pharmaceutically acceptable salt thereof.

25. When n is 0, Het Ａ The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein it is a 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclylene having 1 to 4 heteroatoms selected from oxygen, nitrogen, or sulfur. **Claim 26** The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein n is 0. **Claim 27** The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein n is 1. **Claim 28** R ２ R ３ R ４ R ５ R ７ R ８ and R ９ The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, 15 to 19 or 24, wherein each of them is hydrogen. **Claim 29** R １ R ２ R ３ R ４ R ７ R ８ and R ９ The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, 15 to 19 or 24, wherein each of them is hydrogen. **Claim 30** R １ R ２ R ３ R ４ R ５ R ７ R ８ and R ９ The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, 15 to 19 or 24, wherein each of them is hydrogen. **Claim 31** R １is an optionally substituted group selected from 5- to 6-membered heteroaryl having 1 to 4 heteroatoms selected from oxygen, nitrogen, or sulfur, and 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 2 heteroatoms selected from oxygen, nitrogen, or sulfur, the compound according to any one of claims 1 to 5, 15 to 19 or 24, or a pharmaceutically acceptable salt thereof.

32. R １ is an optionally substituted 5-membered heteroaryl having 2 to 4 heteroatoms selected from oxygen or nitrogen, the compound according to any one of claims 1 to 5, 15 to 19 or 24, or a pharmaceutically acceptable salt thereof.

33. R １ is optionally substituted C １～６ is aliphatic, the compound according to any one of claims 1 to 5, 15 to 19 or 24, or a pharmaceutically acceptable salt thereof.

34. The substituents on the optionally substituted R １ group are independently halogen, -(CH ２ ) ０～４ R°, -(CH ２ ) ０～４ OR°; and -(CH ２ ) ０～４ C(O)OR°, where each R° is independently hydrogen, C １～６ is aliphatic, or a 5- to 6-membered saturated ring, partially unsaturated ring, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, the compound according to any one of claims 1 to 5, 15 to 19 or 24, or a pharmaceutically acceptable salt thereof.

35. R ５ and R ６ are each independently halogen, the compound according to any one of claims 1 to 5, 15 to 19 or 24, or a pharmaceutically acceptable salt thereof.

36. R ６ is Cl or CN, the compound according to any one of claims 1 to 5, 15 to 19 or 24, or a pharmaceutically acceptable salt thereof.

37. wherein the compound is 【Chemical Formula 126】 【Chemical Formula 127】 【Chemical Formula 128】 【Chemical Formula 129】 【Chemical Formula 130】 the compound according to claim 1 or a pharmaceutically acceptable salt thereof, selected from

38. A pharmaceutical composition comprising the compound according to any one of claims 1 to 37 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

39. The pharmaceutical composition according to claim 38, wherein the composition is suitable for oral administration.

40. A composition comprising the compound according to any one of claims 1 to 37 or a pharmaceutically acceptable salt thereof for treating a disease or disorder mediated by plasma kallikrein.

41. The composition according to claim 40, wherein the disease or disorder is hereditary angioedema or diabetic macular edema.

42. A composition comprising the compound according to any one of claims 1 to 37 or a pharmaceutically acceptable salt thereof for treating the hereditary angioedema or the diabetic macular edema in a patient in need of treatment for hereditary angioedema or diabetic macular edema.

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