Heteroaryl plasma kallikrein inhibitors

Abstract

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

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to and the benefit of U.S. Provisional Patent Application Serial No. 62 / 902,333, filed September 18, 2019, entitled “HETEROARYL PLASMA KALLIKREININHIBITORS,” the contents of which are incorporated herein by reference in their entirety. Background Art

[0003] Plasma kallikrein (pKal) is a serine protease zymogen in the blood that is converted to its catalytically active form by coagulation factor XIIa and contributes to the innate inflammatory response and the intrinsic coagulation cascade. Mechanisms leading to the activation of this pathway in vivo include interaction with polyphosphates released by activated platelets and deficiency of C1 inhibitor (C1-INH), the main physiological inhibitor of pKal. pKal-mediated cleavage of high molecular weight kininogen generates the potent vasodilator and proinflammatory nonapeptide bradykinin (BK), which activates the bradykinin 2 receptor. BK is subsequently cleaved by carboxypeptidases to generate des-Arg9-BK, which activates the B1 receptor. Both B1 and B2 receptors are expressed by vascular, glial, and neuronal cell types, with the highest levels of retinal expression detected in the ganglion cell layer and the inner and outer nuclear layers. Activation of the B1 and B2 receptors causes vasodilation and increases vascular permeability.

[0004] pKal is also associated with a variety of conditions, such as hereditary angioedema (HAE), an autosomal dominant disease characterized by painful, unpredictable, recurring inflammation that affects the hands, feet, face, abdomen, genitourinary tract, and larynx. The prevalence of HAE is uncertain but is estimated to be approximately 1 in 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 levels, which inhibits pKal, bradykinin, and other serine proteases in the blood. Individuals with hereditary angioedema (HAE) lack C1-INH and therefore produce excess bradykinin, which in turn causes painful, debilitating, and potentially fatal episodes of swelling. If untreated, HAE can lead to a mortality rate of up to 40%, primarily due to upper airway obstruction. Summary of the Invention

[0005] The present disclosure is based, at least in part, on the development of a variety of compounds that bind to plasma kallikrein and effectively inhibit its activity. Accordingly, provided herein are compounds and uses thereof for targeting pKal and / or treating pKal-mediated diseases and conditions.

[0006] In some embodiments, the present invention provides a compound of formula (I):

[0007]

[0008] or a pharmaceutically acceptable salt thereof, wherein Het A ,L,R′,R″,R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 and R 9 Each of which is defined and described in classes and subclasses herein. In certain embodiments, the invention provides compounds of Formula (I)-(III-b) as defined and described in classes and subclasses herein.

[0009] In some embodiments, the present invention also provides methods of using the compounds of Formula (I)-(III-b). DETAILED DESCRIPTION

[0010] A. Definition

[0011] The compounds of the present invention include those generally described above and are further illustrated by the classes, subclasses and species disclosed herein. As used herein, unless otherwise indicated, the following definitions will apply. 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 edition. In addition, the general principles of organic chemistry are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999 and "March's Advanced Organic Chemistry", 5th edition, ed.: Smith, MB and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are incorporated herein by reference.

[0012] Abbreviations used herein have their conventional meanings in the fields of chemistry and biology.The chemical structures and formulas shown herein are constructed according to standard rules of chemical valence known in the chemical arts.

[0013] As used herein, the term "aliphatic" or "aliphatic group" means a straight chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is fully saturated or contains one or more unsaturated units, or a monocyclic or bicyclic hydrocarbon (also referred to herein as "carbocyclyl," "alicyclic," or "cycloalkyl") that is fully saturated or contains one or more unsaturated units but is not aromatic, having a single point of attachment to the rest of the molecule. Unless otherwise specified, an aliphatic group contains 1-6 aliphatic carbon atoms. In some embodiments, an aliphatic group contains 1-5 aliphatic carbon atoms. In some embodiments, an aliphatic group contains 1-4 aliphatic carbon atoms. In some embodiments, an aliphatic group contains 1-3 aliphatic carbon atoms, and in yet other embodiments, an aliphatic group contains 1-2 aliphatic carbon atoms. In some embodiments, "alicyclic" (or "carbocyclyl" or "cycloalkyl") refers to a monocyclic C3-C7 hydrocarbon that is fully saturated or contains one or more unsaturated units but is not aromatic, having a single point of attachment to the rest of the molecule. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups, and hybrids thereof, such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl, or (cycloalkyl)alkenyl.

[0014] The term "heteroatom" means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including any oxidized form of nitrogen, sulfur, phosphorus, or silicon; a quaternized form of any basic nitrogen; a substitutable nitrogen of a heterocyclic ring, such as N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR + (as in N-substituted pyrrolidinyl)).

[0015] As used herein, the term "unsaturated" means a moiety having one or more units of unsaturation.

[0016] The term "alkylene" refers to a divalent alkyl group. An "alkylene chain" is a polymethylene group, i.e., -(CH2) n -, wherein n is a positive integer, preferably 1 to 6, 1 to 4, 1 to 3, 1 to 2, or 2 to 3. Substituted alkylene chains are polymethylene chains in which one or more methylene hydrogen atoms are replaced by substituents. Suitable substituents include those described below for substituted aliphatic groups.

[0017] The term "halogen" means F, Cl, Br or I.

[0018] The term "aryl" refers to monocyclic and bicyclic ring systems having a total of 5 to 10 ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains three to seven ring members. The term "aryl" can be used interchangeably with the term "aryl ring". In some embodiments, the 8-10 membered bicyclic aryl is an optionally substituted naphthyl ring. In certain embodiments of the present invention, "aryl" refers to an aromatic ring system that may carry one or more substituents, including but not limited to phenyl, biphenyl, naphthyl, anthracenyl, etc. Groups in which an aromatic ring is fused to one or more non-aromatic rings (such as indanyl, phthalimide, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl, etc.) are also included within the scope of the term "aryl" as used herein.

[0019] The terms "heteroaryl" and "heteroar-" refer to groups having 5 to 10 ring atoms, preferably 5, 6 or 9 ring atoms; having 6, 10 or 14 π electrons shared in the ring array; and having one to five heteroatoms other than carbon atoms. Heteroaryl includes, but is not limited to, thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl and pteridinyl. As used herein, the terms "heteroaryl" and "heteroar-" also include groups in which a heteroaromatic ring is fused to one or more aryl, alicyclic or heterocyclyl rings, wherein the radical or point of attachment is on the heteroaromatic ring. Non-limiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzothiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolyl, tetrahydroisoquinolyl and pyrido [2,3-b] -1,4-oxazin-3 (4H) -one. Heteroaryl can be monocyclic or bicyclic. The term "heteroaryl" can be used interchangeably with the term "heteroaryl ring", "heteroaryl group" or "heteroaromatic", any of which includes optionally substituted rings.

[0020] As used herein, the terms "heterocyclyl," "heterocyclic group," and "heterocycle" are used interchangeably and refer to a stable 5- to 7-membered monocyclic or 7- to 10-membered bicyclic heterocyclic moiety which may be saturated or partially unsaturated and which has, in addition to carbon atoms, one or more (preferably one to four) heteroatoms as defined above. The term "nitrogen" when used in the context of referring to a ring atom includes substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 0-3 heteroatoms selected from oxygen, sulfur, or nitrogen, the nitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or+ NR (as in N-substituted pyrrolidinyl).

[0021] The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure and any of the ring atoms may be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxane, dioxolane, diazepine, oxazolidinyl ... Oxazolin thiazolinone The terms "heterocyclic radical", "heterocyclic ring", "heterocyclic group", "heterocyclic moiety" and "heterocyclic radical" are used interchangeably herein and also include groups in which the heterocyclic ring is fused to one or more aryl, heteroaryl or alicyclic rings, such as indolinyl, 3H-indolyl, chromanyl, phenanthridinyl or tetrahydroquinolinyl, wherein the group or point of attachment is on the heterocyclic ring. The heterocyclic radical can be monocyclic or bicyclic. The term "heterocyclylalkyl" refers to an alkyl group substituted with a heterocyclic radical, wherein the alkyl moiety and the heterocyclic radical moiety are independently optionally substituted.

[0022] As used herein, the term "partially unsaturated" refers to a ring moiety that includes at least one double or triple bond. The term "partially unsaturated" is intended to encompass rings with multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties as defined herein.

[0023] As used herein and unless otherwise indicated, the prefix "sub" is used to describe a divalent group. Thus, any of the above terms can be modified with the prefix "sub" to describe the divalent form of the moiety. For example, a divalent carbocyclic ring is a "carbocyclylene," a divalent aromatic ring is an "arylene," a divalent benzene ring is a "phenylene," a divalent heterocyclic ring is a "heterocyclylene," a divalent heteroaromatic ring is a "heteroarylene," a divalent alkyl chain is an "alkylene," a divalent alkenyl chain is an "alkenylene," a divalent alkynyl chain is an "alkynylene," and the like.

[0024] As described herein, the compounds of the present invention may contain an "optionally substituted" portion when described. Typically, the term "substituted" means that one or more hydrogens of the designated portion are replaced by a suitable substituent, regardless of whether the term "optionally" is present. Unless otherwise indicated, an "optionally substituted" group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure can be substituted by more than one substituent selected from a specified group, the substituents at each position may be the same or different. The substituent combinations contemplated by the present invention are preferably those that allow the formation of stable or chemically feasible compounds. As used herein, the term "stable" refers to a compound that is substantially unchanged when subjected to conditions that allow compound preparation, detection, and in certain embodiments, its recovery, purification, and use for one or more purposes disclosed herein.

[0025] Suitable monovalent substituents on a substitutable carbon atom of an "optionally substituted" group 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) 0-4 Ph, which may be substituted by R°; -(CH2) 0-4 O(CH2) 0-1 Ph, which may be substituted by R°; -CH=CHPh, which may be substituted by R°; -(CH2) 0-4 O(CH2) 0-1 -pyridyl, which may be substituted by R°; -NO2; -CN; -N3; ​​-(CH2) 0-4 N(R°)2;-(CH2) 0-4 N(R°)C(O)R°;-N(R°)C(S)R°;-(CH2) 0-4 N(R°)C(O)NR°2;-N(R°)C(S)NR°2;-(CH2) 0-4 N(R°)C(O)OR°; -N(R°)N(R°)C(O)R°; -N(R°)N(R°)C(O)NR°2; -N(R°)N(R°)C(O)OR°; -(CH2) 0-4 C(O)R°;-C(S)R°;-(CH2) 0-4 C(O)OR°;-(CH2) 0-4 C(O)SR°;-(CH2) 0-4 C(O)OSiR°3;-(CH2)0-4 OC(O)R°; -OC(O)(CH2) 0-4 SR°;-SC(S)SR°;-(CH2) 0-4 SC(O)R°;-(CH2) 0-4 C(O)NR°2;-C(S)NR°2;-C(S)SR°;-SC(S)SR°;-(CH2) 0-4 OC(O)NR°2; -C(O)N(OR°)R°; -C(O)C(O)R°; -C(O)CH2C(O)R°; -C(NOR°)R°; -(CH2) 0-4 SSR°; -(CH2) 0-4 S(O)2R°;-(CH2) 0-4 S(O)2OR°;-(CH2) 0-4 OS(O)2R°;-S(O)2NR°2;-(CH2) 0-4 S(O)R°; -N(R°)S(O)2NR°2; -N(R°)S(O)2R°; -N(OR°)R°; -C(NH)NR°2; -P(O)2R°; -P(O)R°2; -OP(O)R°2; -OP(O)(OR°)2; SiR°3; -(C 1-4 linear or branched alkylene)ON(R°)2; or -(C 1-4 linear or branched alkylene) C(O)ON(R°)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-(5-6 membered heteroaryl ring), or a 5-6 membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or, notwithstanding the above definition, two independent occurrences of R° together with their intervening atom(s) form a 3-12 membered saturated, partially unsaturated or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, which may be substituted as defined below.

[0026] Suitable monovalent substituents on R° (or two independent occurrences of R° together with their intervening atoms to form a ring) are independently halogen, -(CH2) 0-2 R ● 、-(halogenated R ● ), -(CH2) 0-2 OH, -(CH2) 0-2 OR ● 、-(CH2) 0-2 CH(OR ● )2、-O(halogenated R ●)、-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 ● , where each R ● is unsubstituted or, in the case of "halo" preceding it, is substituted only with one or more halogens, and is independently selected from C 1-4 Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph, or a 5-6 membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur. ● Suitable divalent substituents on a saturated carbon atom of include =0 and =S.

[0027] Suitable divalent substituents on a saturated carbon atom of an "optionally substituted" group include the following: =0, =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-, where each independent occurrence of R * is selected from hydrogen, C which may be substituted as defined below 1-6 aliphatic, or an unsubstituted 5-6 membered saturated, partially unsaturated or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur. Suitable divalent substituents attached to adjacent substitutable carbons of an "optionally substituted" group include: -O(CR * 2) 2-3O-, where each independent occurrence of R * is selected from hydrogen, C which may be substituted as defined below 1-6 aliphatic, or unsubstituted 5-6 membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0028] R * Suitable substituents on the aliphatic group include halogen, -R ● 、-(halogenated R ● ), -OH, -OR ● 、-O(halogenated R ● )、-CN、-C(O)OH、-C(O)OR ● 、-NH2、-NHR ● 、-NR ● 2 or -NO2, where each R ● is unsubstituted or, when preceded by "halo," substituted only with one or more halogens, and is independently C 1-4 Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph, or a 5-6 membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0029] Suitable substituents on a substitutable nitrogen of an "optionally substituted" group include or Each of these is independently hydrogen, which may be substituted as defined below 1-6 aliphatic, unsubstituted -OPh, or an unsubstituted 5-6 membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or, although defined above, two independent occurrences of Together with its one or more intervening atoms, it forms a 3-12 membered saturated, partially unsaturated or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0030] Suitable substituents on the aliphatic group are independently halogen, -R ● 、-(halogenated R ● ), -OH, -OR ● 、-O(halogenated R ● )、-CN、-C(O)OH、-C(O)OR ● 、-NH2、-NHR ● 、-NR ● 2 or -NO2, where each R ●is unsubstituted or, when preceded by "halo," substituted only with one or more halogens, and is independently C 1-4 Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph, or a 5-6 membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0031] 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 without undue toxicity, irritation, allergic response, etc., within the scope of sound medical judgment, and commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, SM Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, which is incorporated herein by reference.

[0032] In certain embodiments, the neutral form of the compound is regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. In some embodiments, the parent form of the compound differs from the various salt forms in certain physical properties such as solubility in polar solvents.

[0033] Unless otherwise stated, structures depicted herein are also intended to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the compounds of the invention are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention. In addition, unless otherwise stated, structures depicted herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, structures having substitutions including hydrogen being replaced by deuterium or tritium or carbon being enriched by 13 C- or 14 Compounds of the present structures in which the carbon of C- is substituted are within the scope of the present invention. Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents according to the present invention.

[0034] As used herein, the term "oxo" refers to an oxygen double-bonded to a carbon atom, thereby forming a carbonyl group.

[0035] symbol Represents the point of attachment of a chemical moiety to the rest of a molecule or formula, except when used as a bond to depict unknown or mixed stereochemistry.

[0036] The articles "a" and "an" are used herein to refer to one or to more than one (ie, to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element.

[0037] As used herein, the term "dosing regimen" (or "therapeutic regimen") is a group of unit doses (usually more than one dose) that are administered to a subject individually, typically at intervals of time. In some embodiments, a given therapeutic agent has a recommended dosing regimen, which may involve one or more doses. In some embodiments, the dosing regimen comprises multiple doses, each separated by a time period of the same length; in some embodiments, the dosing regimen comprises multiple doses and at least two different time periods separating the individual doses.

[0038] As will be appreciated from the context, a "reference" sample or subject is a sample or subject that is sufficiently similar to a particular sample or subject that is of concern to allow for relevant comparison. In some embodiments, information about a reference sample is obtained simultaneously with information about a particular sample. In some embodiments, information about a reference sample is historical. In some embodiments, information about a reference sample is stored in, for example, a computer-readable medium. In some embodiments, the comparison of a particular sample of concern with a reference sample has established identity, similarity, or otherness of the particular sample of concern relative to the reference sample.

[0039] 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 a biological tissue or fluid. In some embodiments, the biological sample can be or include bone marrow; blood, such as whole blood; blood cells; ascites; tissue or fine needle biopsy samples; body fluids containing cells; free floating nucleic acids; sputum; saliva; urine; cerebrospinal fluid; peritoneal fluid; pleural effusion; feces; lymph fluid; gynecological fluid; cotton swabs; vaginal swabs; oral swabs; nasal swabs; washes or lavage fluids, such as duct lavage fluid or bronchoalveolar lavage fluid; aspirates; scrapings; bone marrow specimens; tissue biopsy specimens; surgical specimens; feces; other body fluids, secretions and / or excretions; and / or cells therefrom, etc. In some embodiments, the biological sample is or includes cells obtained from a subject. In some embodiments, the cells obtained are or include cells from the subject from whom the sample was obtained. In some embodiments, a sample is a "raw sample" obtained directly from a source of interest by any appropriate means. For example, in some embodiments, the raw biological sample is obtained by a method selected from the group consisting of: biopsy (e.g., fine needle aspiration or tissue biopsy), surgery, collection of body fluids (e.g., blood (e.g., whole blood), lymph, feces, etc.), etc. In some embodiments, as will be clear from the context, the term "sample" refers to a preparation obtained by processing the raw sample (e.g., by removing one or more components of the raw sample and / or by adding one or more agents to the raw sample). For example, filtering using a semipermeable membrane. Such a "processed sample" may include, for example, nucleic acids or proteins extracted from the sample, or nucleic acids or proteins obtained by subjecting the raw sample to techniques such as amplification or reverse transcription of mRNA, separation and / or purification of certain components.

[0040] As used herein, the phrase "therapeutic agent" refers to any agent that has a therapeutic effect and / or elicits a desired biological and / or pharmacological effect when administered to a subject.

[0041] As used herein, the term "therapeutically effective amount" refers to the amount of a therapeutic agent that produces a therapeutic effect on a subject treated at a reasonable benefit / risk ratio applicable to any medical treatment. The therapeutic effect can be objective (i.e., it can be measured by a certain test or marker) or subjective (i.e., the subject gives an indication or feeling of the effect). Specifically, "therapeutically effective amount" refers to an amount that effectively treats, improves or prevents a desired disease or illness, or shows a detectable therapeutic or preventive effect, such as by improving the symptoms associated with the disease, preventing or delaying the onset of the disease, and / or also by alleviating the severity or frequency of the disease symptoms. A therapeutically effective amount is typically administered in a dosage regimen that can include multiple unit doses. For any specific therapeutic agent, a therapeutically effective amount (and / or an appropriate unit dose in an effective dosage regimen) can, for example, vary according to route of administration, in combination with other agents. In addition, for any particular subject, a given therapeutically effective amount (and / or unit dose) may depend on a variety of factors, including the condition being treated and the severity of the condition; the activity of the given therapeutic agent employed; the given composition employed; the age, weight, general health, sex, and diet of the subject; the time of administration, route of administration, and / or rate of excretion or metabolism of the given therapeutic agent employed; the duration of treatment; and like factors well known in the medical arts.

[0042] As used herein, the term "treatment" (also referred to as "treat" or "treating") refers to any administration of a substance (e.g., a provided composition) that partially or completely alleviates, ameliorates, relieves, 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 may be directed to subjects who do not exhibit signs of the relevant disease, disorder, and / or condition, and / or to subjects who exhibit only early signs of the disease, disorder, and / or condition. Alternatively or in addition, such treatment may be directed to subjects who exhibit one or more established signs of the relevant disease, disorder, and / or condition. In some embodiments, treatment may be directed to subjects who have been diagnosed with the relevant disease, disorder, and / or condition. In some embodiments, treatment may be directed to subjects who are known to have one or more susceptibility factors that are statistically associated with an increased risk of developing the relevant disease, disorder, and / or condition.

[0043] B. Compounds

[0044] In some embodiments, provided compounds have Formula (I):

[0045]

[0046] or a pharmaceutically acceptable salt thereof,

[0047] in:

[0048] Het A is selected from 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclylene groups having 1-2 heteroatoms selected from oxygen, nitrogen or sulfur, 5- to 6-membered monocyclic heteroarylene groups having 1-4 heteroatoms selected from oxygen, nitrogen or sulfur, 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclylene groups having 1-4 heteroatoms selected from oxygen, nitrogen or sulfur, and 7- to 10-membered bicyclic heteroarylene groups having 1-5 heteroatoms selected from oxygen, nitrogen or sulfur, wherein Het A 0-4 R A group substitution;

[0049] Each R A independently selected from halogen, -CN, -C(R)=N(R), -C(O)R, -C(O)2R, -C(O)N(R), -NO, -N(R)-N(R), -N(R), -N(R)C(O)R, -N(R)C(O)2R, -N(R)C(O)N(R), -N(R)S(O)2R, -OR, -OC(O)R, -OC(O)N(R), -SR, -S(O)R, -S(O)2R, -S(O)N(R), -S(O)2N(R), or an optionally substituted group selected from: C 1-6 aliphatic, phenyl, 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen or sulfur, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic group, and 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic group having 1-2 heteroatoms selected from oxygen, nitrogen or sulfur;

[0050] L is an optionally substituted C 1-6 A hydrocarbon chain in which 1-3 methylene units are independently replaced by –Cy-, –O-, –NR-, –C(O)-, –S(O)2-, –C(O)NR-, –NRC(O)-, –S(O)2NR-, and –NRS(O)2-;

[0051] -Cy- is a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclylene group, a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclylene group having 1-2 heteroatoms selected from oxygen, nitrogen or sulfur, or a 5- to 6-membered heteroarylene group having 1-4 heteroatoms selected from oxygen, nitrogen or sulfur;

[0052] R' and R" are independently selected from hydrogen, halogen, -OR, -NR2, -SR and optionally substituted C 1-6 Aliphatic; wherein R' can be combined with a monocyclic Het A together forming an optionally substituted fused 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclylene having 1-4 heteroatoms selected from oxygen, nitrogen or sulfur;

[0053] R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 and R 9 independently selected from hydrogen, halogen, -CN, -C(R)=N(R), -C(O)R, -C(O)R, -C(O)N(R), -NO, -N(R)-N(R), -N(R), -N(R)C(O)R, -N(R)C(O)R, -N(R)C(O)N(R), -N(R)S(O)R, -OR, -OC(O)R, -OC(O)N(R), -SR, -S(O)R, -S(O)R, -S(O)R, -S(O)N(R), -S(O)N(R), or an optionally substituted group selected from: C 1-6 aliphatic, phenyl, 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen or sulfur, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic group, and 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic group having 1-2 heteroatoms selected from oxygen, nitrogen or sulfur; and

[0054] Each R is independently hydrogen or an optionally substituted group selected from: C 1-6 aliphatic, phenyl, 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen or sulfur, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic group, and 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic group having 1-2 heteroatoms selected from oxygen, nitrogen or sulfur;

[0055] or two R groups on the same carbon or nitrogen together with their intervening atoms form a ring selected from a 3- to 7-membered saturated or partially unsaturated monocyclic ring having 0-2 heteroatoms selected from oxygen, nitrogen or sulfur, and a 5- to 6-membered heteroaryl group having 1-4 heteroatoms selected from oxygen, nitrogen or sulfur;

[0056] n is 0 or 1.

[0057] In some embodiments, Het A is selected from the group consisting of a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclylene group having 1-2 heteroatoms selected from oxygen, nitrogen or sulfur, a 5- to 6-membered heteroarylene group having 1-4 heteroatoms selected from oxygen, nitrogen or sulfur, a 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclylene group having 1-4 heteroatoms selected from oxygen, nitrogen or sulfur, and a 7- to 10-membered bicyclic heteroarylene group having 1-4 heteroatoms selected from oxygen, nitrogen or sulfur, wherein Het A 0-4 RA Group substitution.

[0058] In some embodiments, Het A is selected from the group consisting of 5- to 6-membered heteroarylene groups having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, and 7- to 10-membered bicyclic heteroarylene groups having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, wherein Het A 0-4 R A Group substitution.

[0059] In some embodiments, Het A is a 5- to 6-membered heteroarylene group having 1 to 4 heteroatoms selected from oxygen, nitrogen or sulfur.

[0060] In some embodiments, Het A is a 6-membered heteroarylene group having 1 to 4 heteroatoms selected from oxygen, nitrogen or sulfur, wherein Het A 0-3 R A In some embodiments, Het A is a 6-membered heteroarylene group having one nitrogen atom, wherein Het A 0-3 R A In some embodiments, Het A In some embodiments, Het A Selected from:

[0061]

[0062] Where * indicates the connection point with L.

[0063] In some embodiments, Het A is a 5-membered heteroarylene group having 1-4 heteroatoms selected from oxygen or nitrogen. A is a 5-membered heteroarylene group having 1-4 nitrogen atoms. A is a 5-membered heteroarylene group having 1 to 4 nitrogen atoms, wherein when Het A When it contains 3 nitrogens, it is not 1,2,4-triazolediyl. In some embodiments, Het A is a 5-membered heteroarylene group having 1-3 nitrogen atoms. A is a 5-membered heteroarylene group having 1-2 nitrogen atoms. A is a 5-membered heteroarylene group having 1 nitrogen. In some embodiments, Het A is a 5-membered heteroarylene group having 2 nitrogen atoms. A is a 5-membered heteroarylene group having 3 nitrogen atoms.A It is a 5-membered heteroarylene group having 4 nitrogen atoms.

[0064] In some embodiments, Het A Selected from the group consisting of:

[0065]

[0066] Where * indicates the connection point with L.

[0067] In some embodiments, Het A is a 5-membered monocyclic heteroarylene group having 1 to 4 heteroatoms selected from oxygen, nitrogen or sulfur, wherein Het A 0-2 R A In some embodiments, Het A is a 5-membered bicyclic heteroarylene group having 1 to 3 heteroatoms selected from nitrogen, wherein Het A 0-2 R A In some embodiments, Het A is a 5-membered bicyclic heteroarylene group having 2-3 heteroatoms selected from nitrogen, wherein Het A 0-2 R A Group substitution.

[0068] In some embodiments, Het A Is 0-3 R A In some embodiments, Het A Is 0-2 R A In some embodiments, Het A Is 0-1 R A In some embodiments, Het A Is 0-1 R A In some embodiments, Het A is unsubstituted tetrazolyl. In some embodiments, Het A In some embodiments, Het A is unsubstituted thiadiazolediyl. In some embodiments, Het A Is 0-2 R A In some embodiments, Het A Is 0-1 R A In some embodiments, Het A Is 0-1 R A In some embodiments, HetA is unsubstituted pyrazolediyl. In some embodiments, Het A It is an unsubstituted 1,2,3-triazolediyl.

[0069] In some embodiments, Het A Selected from:

[0070]

[0071] Where * indicates the connection point with L.

[0072] In some embodiments, Het A is a 7- to 10-membered bicyclic heteroarylene group having 1-4 heteroatoms selected from oxygen, nitrogen or sulfur, wherein Het A 0-4 R A In some embodiments, Het A is a 9-membered bicyclic heteroarylene group having 1 to 4 heteroatoms selected from oxygen, nitrogen or sulfur, wherein Het A 0-4 R A In some embodiments, Het A is a 9-membered bicyclic heteroarylene group having two nitrogen atoms, wherein Het A 0-4 R A In some embodiments, Het A Is 0-4 R A A pyrrolopyridinediyl group substituted with a group.

[0073] In some embodiments, Het A Selected from the group consisting of:

[0074]

[0075]

[0076] Where * indicates the connection point with L.

[0077] In some embodiments, each R A Independently selected from optionally substituted groups, the optionally substituted groups are selected from C 1-6 aliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic group, and a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic group having 1-2 heteroatoms selected from oxygen, nitrogen or sulfur.

[0078] 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°, wherein each R° is independently hydrogen, C 1-6 aliphatic or a 5-6 membered saturated, partially unsaturated or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0079] In some embodiments, R A A single example is -(CH2) 0-4 OR° substituted C 1-6 Aliphatic, where R° is hydrogen or C 1-6 aliphatic.

[0080] In some embodiments, R A A single example is -(CH2) 0-4 C(O)OR° substituted C 1-6 Aliphatic, where R° is hydrogen or C 1-6 aliphatic.

[0081] In some embodiments, R A A single example is C substituted with a 5-6 membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur. 1-6 aliphatic.

[0082] In some embodiments, R A A single example of is an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, R A A single example of is optionally substituted cyclopropyl. In some embodiments, R A A single example is -(CH2) 0-4 C(O)OR° substituted cyclopropyl, and R° is hydrogen or C 1-6 aliphatic.

[0083] In some embodiments, R A A single example is a C substituted by a halogen 1-6 In some embodiments, R A is a C substituted by a halogen 1-3 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 It is -CHF2.

[0084] In certain embodiments, L is selected from -C(R)2NRC(O)-#, -C(R)2C(O)NRC(R)2-#, -C(R)2NRC(O)C(R)2-#, -C(R)2NRC(R)2-#, -C(R)2C(R)2NRC(R)2-#, -C(O)NRC(R)2-#, -C(R)2C(O)NR-#, -NRC(O)C(R)2-#, -CR2C(O)NRC(R)2-#, -SO2NRC(R)2-#, and -C(R)2NRSO2-#, wherein # represents the same A connection point.

[0085] 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-#, wherein # represents the same A connection point.

[0086] 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-#, wherein # represents the same A connection point.

[0087] In some embodiments, L is not -C(R)2NRC(O)-# or -C(R)2C(O)NR-#. In some embodiments, L is not -CH2NRC(O)-# or -CH2C(O)NR-#.

[0088] In some embodiments, when L is -C(R)2NRC(O)-# or -C(R)2C(O)NR-#, one of the following (a), (b), or (c) applies:

[0089] (a) n is 0;

[0090] (b)R 5 、R 6 、R 7 、R 8 and R 9 At least one of is CN; or

[0091] (c)R1 is an optionally substituted saturated monocyclic heterocycle 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-morpholinoimidazolo[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, -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.

[0092] In some embodiments, when L is -C(R)2NRC(O)-# or -C(R)2C(O)NR-#, n is 0.

[0093] In some embodiments, when L is -C(R)2NRC(O)-# or -C(R)2C(O)NR-#, R' is the same as the monocyclic Het A Together they form an optionally substituted fused 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclylene having 1-4 heteroatoms selected from oxygen, nitrogen or sulfur.

[0094] In some embodiments, when L is -CH2NRC(O)-# or -CH2C(O)NR-#, R' is the same as the monocyclic Het A Together they form an optionally substituted fused 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclylene having 1-4 heteroatoms selected from oxygen, nitrogen or sulfur.

[0095] In certain embodiments, when L is -(CR2) m NRC(O)—and m is 0 to 2 (e.g., 0 or 2), one of the following (a), (b), or (c) applies:

[0096] (a) n is 0;

[0097] (b)R 5 、R 6 、R 7 、R 8 and R 9 At least one of is CN; or

[0098] (c)R 1 is an optionally substituted saturated monocyclic heterocycle 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-morpholinoimidazolo[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, -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.

[0099] In certain embodiments, when L is -(CR2) m When NRC(O)- and m is 0, then n is 0. In certain embodiments, when L is -(CR2) m When NRC(O)- and m is 1, then n is 0. In certain embodiments, when L is -(CR2) m NRC(O)—and m is 2, then n is 0.

[0100] In certain embodiments, when L is -(CR2) m NRC(O)- and m is 0 to 2 (eg, 0 or 2), R' is the same as the monocyclic Het A Together they form an optionally substituted fused 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclylene having 1-4 heteroatoms selected from oxygen, nitrogen or sulfur.

[0101] In some embodiments, L is -C(R)2C(O)NRC(R)2-#, wherein each R is independently hydrogen or C(O) optionally substituted with halogen. 1-3 Aliphatic. In some embodiments, L is -CH2C(O)NHCH(CF3)-#. In some embodiments, L is -CH2C(O)NHCH(CH3)-#.

[0102] In some embodiments, L is -C(R)2NRC(R)2-#, wherein each R is independently hydrogen or C optionally substituted with halogen. 1-3 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-#.

[0103] In certain embodiments, L is -C(R)2NRSO2-#, wherein each R is independently hydrogen or C(R)2NRSO2-# optionally substituted with halogen. 1-3 In certain embodiments, L is -CH2NHSO2-.

[0104] In some embodiments, L is -SO2NRC(R)2-#, wherein each R is independently hydrogen or C optionally substituted with halogen. 1-3 In some embodiments, L is -SO2NHCH2-#. In some embodiments, L is -SO2NHCH(CH3)-#.

[0105] In some embodiments, L is -C(O)NRC(R)2-#, wherein each R is independently hydrogen or C optionally substituted with halogen. 1-3 In some embodiments, L is -C(O)NHCH2-#.

[0106] In certain embodiments, L is -C(R)2C(O)NRC(R)2-#, wherein each R is independently hydrogen or C(O) optionally substituted with halogen. 1-3 In certain embodiments, L is -CH2C(O)NHCH2-#.

[0107] In some embodiments, R' and R" are each hydrogen. In some embodiments, R" is hydrogen, and R' is in combination with the monocyclic Het A Together they form a fused 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclylene having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur. In some embodiments, n is 1, R" is hydrogen, and R' is the same as the monocyclic Het ATogether they form a fused 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclylene having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur. In some embodiments, n is 1, R" is hydrogen, and R' is the same as the monocyclic Het A Together they form a fused 8-membered saturated or partially unsaturated bicyclic heterocyclylene group having 1 to 4 heteroatoms selected from oxygen, nitrogen or sulfur.

[0108] In some embodiments, R' and R" are independently selected from hydrogen, halogen, -OR, -SR, -NR2, and optionally substituted C 1-6 aliphatic, wherein each R is independently selected from hydrogen and C 1-6 In some embodiments, R' and R" are independently selected from hydrogen, fluorine, -OH, -SH, -NH2 and -(CH2) 0-4 C(O)OR° substituted C 1-6 Aliphatic, where R° is hydrogen or C 1-6 In some embodiments, R' and R" are independently selected from hydrogen, fluorine, -OH and -(CH2) 0-4 C(O)OR° substituted C 1-6 Aliphatic, wherein R° is hydrogen, methyl or ethyl.

[0109] In some embodiments, when n is 0, Het A is a 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclylene group having 1 to 4 heteroatoms selected from oxygen, nitrogen or sulfur.

[0110] In some embodiments, n is 0. In some embodiments, n is 1.

[0111] In some embodiments, R 1 、R 2 、R 3 and R 4 independently selected from hydrogen, halogen, -CN, -C(R)=N(R), -C(O)R, -C(O)R, -C(O)N(R), -NO, -N(R)-N(R), -N(R), -N(R)C(O)R, -N(R)C(O)R, -N(R)C(O)N(R), -N(R)S(O)R, -OR, -OC(O)R, -OC(O)N(R), -SR, -S(O)R, -S(O)R, -S(O)R, -S(O)N(R), -S(O)N(R), or an optionally substituted group selected from: C 1-6 aliphatic, phenyl, 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen or sulfur, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic group, and 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic group having 1-2 heteroatoms selected from oxygen, nitrogen or sulfur. In some embodiments, R1 、R 2 、R 3 and R 4 independently selected from hydrogen, halogen, -CN, -C(O)2R or an optionally substituted group selected from: C 1-6 aliphatic, 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen or sulfur, and 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen or sulfur.

[0112] In some embodiments, optionally substituted R 1 、R 2 、R 3 and R 4 The substituents on each of the above groups are 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°, wherein each R° is independently hydrogen, C 1-6 aliphatic, or a 3- to 5-membered saturated, partially unsaturated or aromatic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0113] In some embodiments, optionally substituted R 1 、R 2 、R 3 and R 4 The substituents on the alkyl group are each independently -F, -CN, -R°, -OR°, -N(R°)2, -COOR° or -OC(R°)2C(R°)2N(R°)2, wherein each R° is independently hydrogen, C 1-6 aliphatic, or a 4-membered saturated ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. 1 、R 2 、R 3 and R 4 The substituents on the alkylene oxide are each independently selected from -F, -CN, -CH3, -OH, -NH2, -COOH, -COOCH2CH2, -OCH2CH2NH2, -OCH2CH2N(CH3)2 and

[0114] In some embodiments, R 1 、R 2 、R 3 and R 4are each independently selected from hydrogen, halogen, -CN, -C(O)R, -C(O)2R, -N(R)2, -OR or an optionally substituted group selected from: C 1-6 aliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic group, and 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic group having 1-2 heteroatoms selected from oxygen, nitrogen or sulfur, wherein each R is independently hydrogen or C 1-6 aliphatic.

[0115] In some embodiments, optionally substituted R 1 、R 2 、R 3 or R 4 The substituents on the group are 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, wherein each R° is independently hydrogen, C 1-6 aliphatic, or two independent occurrences of R° together with one or more intervening atoms thereof form an optionally substituted 3-12 membered saturated, partially unsaturated or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, which monocyclic or bicyclic ring may be further substituted.

[0116] In some embodiments, R 1 an optionally substituted group selected from hydrogen, halogen, -CN, -C(O)2R, -C(O)N(R)2, -N(R)2, -OR, -SR, -S(O)2N(R)2 or selected from: C 1-6 aliphatic, phenyl, 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen or sulfur, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic group, and 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic group having 1-2 heteroatoms selected from oxygen, nitrogen or sulfur. In some embodiments, R 1 is selected from hydrogen, halogen, -CN, -C(O)2R or an optionally substituted group selected from: C 1-6 aliphatic, 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen or sulfur, and 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen or sulfur.

[0117] In some embodiments, optionally substituted R 1 The substituents on the alkyl group are -F, -CN, -R°, -OR°, -N(R°)2, -COOR° or -OC(R°)2C(R°)2N(R°)2, wherein each R° is independently hydrogen, C 1-6aliphatic, or a 4-membered saturated ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. 1 The substituents on the amine group are selected from -F, -CN, -CH3, -OH, -NH2, -COOH, -COOCH2CH2, -OCH2CH2NH2, -OCH2CH2N(CH3)2 and

[0118] In some embodiments, R 5 、R 6 、R 7 、R 8 and R 9 independently selected from hydrogen, halogen, -CN, -N(R)2, -OR or an optionally substituted group selected from: C 1-6 an aliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic group, wherein each R is independently hydrogen or C 1-6 In some embodiments, R 7 、R 8 and R 9 It's hydrogen.

[0119] In some embodiments, R 5 In some embodiments, R 5 In some embodiments, R 5 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 It's I.

[0120] In some embodiments, R 6 is selected from halogen or optionally substituted C 1-6 In some embodiments, R 6 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 1. In some embodiments, R 6 is an optionally substituted C 1-6 In some embodiments, R 6 is an optionally substituted C 1-5 In some embodiments, R 6 is an optionally substituted C 1-4 In some embodiments, R 6is an optionally substituted C 1-3 In some embodiments, R 6 is an optionally substituted C 1-2 In some embodiments, R 6 It is an alkynyl group.

[0121] In certain embodiments, R 1 、R 2 、R 3 、R 4 、R 5 、R 7 、R 8 and R 9 In certain embodiments, R 1 、R 2 、R 3 、R 4 、R 7 、R 8 and R 9 In certain embodiments, R 2 、R 3 、R 4 、R 5 、R 7 、R 8 and R 9 Each is hydrogen.

[0122] In some embodiments, R 9 is hydrogen, R 6 is -F, -Cl, or –Br, and R 5 、R 7 and R 8 independently selected from hydrogen, halogen, -CN, -C(R)=N(R), -C(O)R, -C(O)R, -C(O)N(R), -NO, -N(R)-N(R), -N(R), -N(R)C(O)R, -N(R)C(O)R, -N(R)C(O)N(R), -N(R)S(O)R, -OR, -OC(O)R, -OC(O)N(R), -SR, -S(O)R, -S(O)R, -S(O)R, -S(O)N(R), -S(O)N(R), or an optionally substituted group selected from: C 1-6 aliphatic, phenyl, 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen or sulfur, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic group, and 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic group having 1-2 heteroatoms selected from oxygen, nitrogen or sulfur.

[0123] In some embodiments, R 1is an optionally substituted group selected from the group consisting of 5- to 6-membered heteroaryl groups having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, and 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl groups having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur. 1 is an optionally substituted 5-membered heteroaryl group having 2-4 heteroatoms selected from oxygen or nitrogen. 1 is an optionally substituted piperazinyl. In some embodiments, R 1 is an optionally substituted triazolyl group.

[0124] In some embodiments, R 1 is an optionally substituted C 1-6 In some embodiments, the optionally substituted R 1 The substituents on the group are independently halogen, (CH2) 0-4 R°, -(CH2) 0-4 OR° and -(CH2) 0-4 C(O)OR°, wherein each R° is independently hydrogen, C 1-6 aliphatic or a 5-6 membered saturated, partially unsaturated or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0125] In some embodiments, R 5 and R 6 are each independently halogen. In some embodiments, R 5 is F, and R 6 Is Cl. In some embodiments, R 6 Is Cl. In some embodiments, R 6 It is CN.

[0126] In some embodiments, provided compounds or pharmaceutically acceptable salts thereof have the structure of Formula (Ia), Formula (Ib), Formula (Ic), or Formula (Id),

[0127]

[0128] Among them, L, R A , R', R", R 1 、R 2 、R 3 、R 4 、R 5 and R 6 Each of the is defined and described herein, individually and in combination, in classes and subclasses.

[0129] It is understood that unless otherwise indicated or prohibited by the foregoing definition of formula (I), the variables L, R, andA 、Het A , R', R", R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 and R 8 The embodiments also apply, individually and in combination, to compounds of Formula (Ia), Formula (Ib), Formula (Ic), Formula (Id), Formula (II), Formula (II-a), Formula (II-b), Formula (III), Formula (III-a), and Formula (III-b).

[0130] In some embodiments, provided compounds or pharmaceutically acceptable salts thereof have the structure of Formula (II):

[0131]

[0132] Among them, L, Het A , R', R 1 、R 3 、R 4 、R 5 、R 6 、R 7 and R 8 Each of the is defined and described herein, individually and in combination, in classes and subclasses.

[0133] In some embodiments, provided compounds or pharmaceutically acceptable salts thereof have the structure of Formula (II-a) or Formula (II-b):

[0134]

[0135] Among them, L, R A , R', R 1 、R 3 、R 4 、R 5 and R 6 Each of the is defined and described herein, individually and in combination, in classes and subclasses.

[0136] In some embodiments, in the provided compounds or pharmaceutically acceptable salts thereof, wherein R' is identical to the monocyclic Het A Together they form an optionally substituted fused ring, the compound having the structure of formula (III):

[0137]

[0138] where R fus With Het Afused to form a fused 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclylene having 1-4 heteroatoms selected from oxygen, nitrogen or sulfur, and L, Het A 、R 1 、R 3 、R 4 、R 5 、R 6 、R 7 and R 8 Each of the is defined and described herein, individually and in combination, in classes and subclasses.

[0139] In some embodiments, provided compounds or pharmaceutically acceptable salts thereof have the structure of Formula (III-a) or Formula (III-b):

[0140]

[0141] Among them, L, R 1 、R 3 、R 4 、R 5 and R 6 Each of the is defined and described herein, individually and in combination, in classes and subclasses.

[0142] In some embodiments, the compound provided is selected from the group consisting 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), 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)acetamide (I-1), imidazo[1,5-a]pyridin-1-yl)methyl)-1H-1,2,3-triazol-4-yl)methyl)-8-fluoroimidazo[1,5-a]pyridin-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-triazole-4-sulfonamide [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), 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)methylamine (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-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazol-4-yl)-2,2,2-trifluoroethane-1-amine (I-16), 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-carboxylic acid (I-15), N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-(1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazol-4-yl)-2,2,2-trifluoroethane-1-amine (I-16), 3-(2-((4-(((( 7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)amino)methyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)propanoic acid ethyl ester (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)imidazole 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.

[0143] C. Pharmaceutical Compositions

[0144] In another aspect, the present invention provides a pharmaceutical composition comprising a compound of Formula (I)-(III-b) or a combination of a compound of Formula (I)-(III-b) and a pharmaceutically acceptable excipient (eg, carrier).

[0145] The pharmaceutical composition includes an optical isomer, diastereomer, or pharmaceutically acceptable salt of the inhibitor disclosed herein. The compound of formula (I)-(III-b) contained in the pharmaceutical composition can be covalently linked to a carrier moiety, as described above. Alternatively, the compound of formula (I)-(III-b) contained in the pharmaceutical composition is not covalently linked to a carrier moiety.

[0146] As used herein, "pharmaceutically acceptable carrier" refers to a pharmaceutical excipient, for example, a pharmaceutically, physiologically acceptable organic or inorganic carrier substance suitable for enteral or parenteral application that does not adversely react with the active agent. Suitable pharmaceutically acceptable carriers include water, saline solutions (such as Ringer's solution), alcohols, 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 auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts that affect osmotic pressure, buffers, coloring substances, and / or aromatic substances, which do not adversely react with the compounds of the present invention.

[0147] The compounds of the present invention may be administered alone or co-administered to a subject. Co-administration is intended to include administering the compounds alone or in combination (more than one compound), simultaneously or sequentially. Where desired, the preparation may also be combined with other active substances (e.g., to reduce metabolic degradation).

[0148] In some embodiments, the test agents described herein can be incorporated into pharmaceutical compositions that are administered by methods known to those skilled in the art and described herein for the provided compounds.

[0149] D. Preparation

[0150] The compounds of the present invention can be prepared and administered in a variety of oral, parenteral, and topical dosage forms. Thus, the compounds of the present invention can be administered by injection (e.g., intravenous, intramuscular, intradermal, subcutaneous, intraduodenal, or intraperitoneal injection). In addition, the compounds described herein can be administered, for example, intranasally, by inhalation. Additionally, the compounds of the present invention can be administered transdermally. It is also contemplated that a variety of routes of administration (e.g., intramuscular, oral, transdermal) can be used to administer the compounds of the present invention. Therefore, the present invention also provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier or excipient and one or more compounds of the present invention.

[0151] For preparing pharmaceutical compositions from the compounds of the present invention, pharmaceutically acceptable carriers can be solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid carrier can be one or more substances that may also act as a diluent, flavoring agent, binder, preservative, tablet disintegrating agent, or encapsulating material.

[0152] In powders, the carrier is a finely divided solid which is in a mixture with the finely divided active ingredient. In tablets, the active ingredient is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.

[0153] Powders and tablets preferably contain 5% to 70% active compound. Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, low melting waxes, cocoa butter, and the like. The term "preparation" is intended to encompass the formulation of the active compound with an encapsulating material as a carrier providing a capsule in which the active ingredient, with or without other carriers, is surrounded by a carrier, which is thereby associated with it. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.

[0154] To prepare suppositories, a low melting wax such as a mixture of fatty acid glycerides or cocoa butter is first melted and the active ingredient is dispersed uniformly therein, as by stirring. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool, and thereby solidify.

[0155] Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water / propylene glycol solutions. For parenteral injection, liquid preparations can be formulated in solution in aqueous polyethylene glycol solution.

[0156] When parenteral application is needed or desired, particularly suitable admixtures of the compounds of the present invention are injectable sterile solutions, preferably oily or aqueous solutions, and suspensions, emulsions or implants, including suppositories. Specifically, carriers for parenteral administration include aqueous solutions of glucose, saline, pure water, ethanol, glycerol, propylene glycol, peanut oil, sesame oil, polyoxyethylene-block polymers, etc. Ampoules are suitable unit doses. The compounds of the present invention can also be incorporated into liposomes or administered by transdermal pumps or patches. Suitable drug admixtures for the present invention include those described in, for example, Pharmaceutical Sciences (17th edition, Mack Pub. Co., Easton, PA) and WO 96 / 05309, the teachings of which are incorporated herein by reference.

[0157] Aqueous solutions suitable for oral use can be prepared by dissolving the active ingredient in water and adding suitable colorants, flavorings, stabilizers, and thickeners as needed. Aqueous suspensions suitable for oral use can be prepared by dispersing the finely divided active ingredient in water with a viscous material such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well-known suspending agents.

[0158] Also included are solid form preparations that are intended to be converted into liquid form preparations for oral administration immediately before use. Such liquid forms include solutions, suspensions, and emulsions. These preparations may contain, in addition to the active ingredient, colorants, flavorings, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizers, and the like.

[0159] The pharmaceutical preparation is preferably in unit dosage form. In this form, the preparation is subdivided into unit doses containing appropriate quantities of the active ingredient. The unit dosage form can be a packaged preparation containing discrete quantities of the preparation, such as packaged tablets, capsules, and powders in vials or ampoules. Furthermore, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these unit dosage forms in packaged form.

[0160] The quantity of active ingredient in a unit dose preparation may be varied or adjusted from 0.1 mg to 10000 mg, more typically 1.0 mg to 1000 mg, most typically 10 mg to 500 mg, depending on the specific application and potency of the active ingredient. If desired, the composition may also contain other compatible therapeutic agents.

[0161] Some compounds may have limited solubility in water and therefore may require a surfactant or other appropriate co-solvent in the composition. Such co-solvents include: polysorbate 20, 60, and 80; Pluronic F-68, F-84, and P-103; cyclodextrins; and polyoxyl 35 castor oil. Such co-solvents are typically employed at levels between about 0.01% and about 2% by weight.

[0162] Viscosity greater than that of a simple aqueous solution may be desirable to reduce variability in dispersing the formulation, to reduce physical separation of components of the formulation's suspension or emulsion, and / or to otherwise improve the formulation. Such viscosity building agents include, for example, polyvinyl alcohol, polyvinyl pyrrolidone, methylcellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, carboxymethyl cellulose, hydroxypropyl cellulose, chondroitin sulfate and salts thereof, hyaluronic acid and salts thereof, and combinations thereof. Such agents are typically employed at levels between about 0.01% and about 2% by weight.

[0163] The compositions of the present invention may further include components to provide sustained release and / or comfort. Such components include high molecular weight anionic permeability polymers, curdlan, and finely dispersed drug carrier matrices. These components are discussed in more detail in U.S. Patent Nos. 4,911,920; 5,403,841; 5,212,162; and 4,861,760. The entire contents of these patents are incorporated herein by reference in their entirety for all purposes.

[0164] E. Effective dose

[0165] The pharmaceutical compositions provided herein include compositions comprising a therapeutically effective amount (i.e., an amount effective to achieve its intended purpose) of an active ingredient. The actual amount effective for a particular application will depend, among other things, on the condition being treated. For example, when administered in a method for treating HAE, such a composition will contain an amount of the active ingredient effective to achieve the desired result (e.g., inhibiting pKal and / or reducing the amount of bradykinin in a subject).

[0166] The dosage and frequency (single or multiple doses) of the compound administered may vary depending on a variety of factors, including the route of administration; the size, age, sex, health, weight, body mass index, and diet of the recipient; the nature and extent of 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 concurrent treatment; and complications from any disease or treatment regimen. Other treatment regimens or agents may be used in conjunction with the methods and compounds of the present invention.

[0167] For any provided compound or test agent, a therapeutically effective amount can be initially determined from cell culture assays.The target concentration will be the concentration of one or more active compounds capable of reducing pKal enzyme activity, for example, as measured using the described methods.

[0168] The therapeutically effective amount for humans can be determined from animal models. For example, a dose for humans can be formulated to achieve a concentration found to be effective in animals. The dose for humans can be adjusted by monitoring pKal inhibition and adjusting the dose upward or downward, as described above.

[0169] The dosage may vary depending on the patient's needs and the compound being used. In the context of the present invention, the dosage administered to the patient should be sufficient to achieve a beneficial therapeutic response in the patient over time. The size of the dosage will also be determined by the presence, nature, and extent of any adverse side effects. Generally, treatment is initiated with a smaller dose that is lower than the optimal dose of the compound. Thereafter, the dosage is increased in small increments until the optimal effect is achieved under the circumstances. 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).

[0170] Dosage amount and interval can be gradually adjusted to provide a level of the administered compound that is effective for the particular clinical indication being treated. This will provide a treatment regimen that is commensurate with the severity of the individual's disease state.

[0171] F. Treatment Methods

[0172] The present disclosure provides compounds for use in medicine. The present disclosure also provides the use of any compound described herein for inhibiting the activity of pKal, which will be beneficial to the treatment of pKal-mediated diseases and illnesses. Exemplary pKal-mediated conditions include edema, which refers to swelling of the whole body or part of a subject due to inflammation or damage when small blood vessels leak and release fluid into nearby tissues. In some instances, edema is HAE. In other instances, edema occurs in the eye, for example, diabetic macular edema (DME). The present disclosure provides methods for inhibiting the activity of pKal. In certain embodiments, the application provides a method for inhibiting the activity of pKal in vitro by contacting any one of the compounds described herein with a pKal molecule in a sample (such as a biological sample). In certain embodiments, the application provides a method for inhibiting the activity of pKal in vivo by delivering any one of the compounds described herein to a subject in need of treatment through a suitable route.

[0173] In certain embodiments, the method comprises administering any one of the compounds described herein, or a pharmaceutically acceptable salt thereof, to a subject in need thereof (e.g., a subject such as a human patient suffering from edema). In certain embodiments, the method comprises administering a compound of Formula (I)-(III-b), or a pharmaceutically acceptable salt or composition thereof, to a subject in need thereof. In some embodiments, the method comprises administering a pharmaceutical composition comprising a compound of Formula (I)-(III-b), or a pharmaceutically acceptable salt thereof, to a subject in need thereof.

[0174] In certain embodiments, the subject to be treated by any of the methods described herein is a human patient suffering from, suspected of having, or at risk of developing edema (e.g., HAE or diabetic macular edema (DME)). A subject suffering from edema can be identified by routine medical examinations, such as laboratory tests. A subject suspected of having edema may exhibit one or more symptoms of the disease / disorder. A subject at risk of edema can be a subject having one or more risk factors associated with the disease (e.g., C1-INH deficiency for HAE).

[0175] In certain embodiments, provided herein are methods for alleviating one or more symptoms of HAE in a human patient suffering from an attack of HAE. Such patients can be identified by conventional medical procedures. An effective amount of one or more of the provided compounds can be administered to the human patient by suitable routes such as those described herein. The compounds described herein can be used alone or in combination with other anti-HAE agents, such as, for example, C1 esterase inhibitors (e.g., or ), pKal inhibitors (e.g., ecallantide or lanadelumab), or bradykinin B2 receptor antagonists (e.g., ).

[0176] In other embodiments, provided herein are methods for reducing the risk of HAE attacks in human HAE patients who are in the quiescent phase. Such patients can be identified based on various factors, including a history of HAE attacks. An effective amount of one or more compounds can be administered to a human patient by suitable routes, such as those described herein. The compounds described herein can be used alone or in combination with other anti-HAE agents, such as, for example, C1 esterase inhibitors (e.g., or ), pKal inhibitors (e.g., ecallantide or lanadelumab), or bradykinin B2 receptor antagonists (e.g., ).

[0177] In other embodiments, provided herein is a prophylactic treatment of HAE in a human patient at risk of HAE attack with one or more compounds as described herein. Patients suitable for such prophylactic treatment can be human subjects with a history of HAE attacks (e.g., human subjects who experience more than 2 attacks per month). Alternatively, patients suitable for prophylactic treatment can be human subjects who do not have a history of HAE attacks but carry one or more HAE risk factors (e.g., family history, genetic defects of the C1-INH gene, etc.). Such prophylactic treatment may involve a compound as described herein as the sole active agent, or may involve additional anti-HAE agents, such as those described herein.

[0178] In certain embodiments, provided herein are methods for preventing or reducing edema in the eyes of subjects (e.g., human patients). In some instances, the human patient is a diabetic patient suffering from, suspected of suffering from, or at risk of diabetic macular edema (DME). DME is a proliferative form of diabetic retinopathy, characterized by swelling of the retinal layers, neovascularization, vascular leakage, and retinal thickening in diabetes caused by fluid leakage in the blood vessels within the macula. To implement this method, an effective amount of one or more compounds as described herein, or a pharmaceutically acceptable salt thereof, can be delivered to the eye of a subject in need of treatment. For example, the compound can be delivered by intraocular injection or intravitreal injection. The subject can be treated with a compound as described herein as the sole active agent or in combination with another treatment for DME. Non-limiting examples of treatments for DME include laser photocoagulation, steroids, VEGF pathway targeting agents (e.g., (ranibizumab) or (aflibercept) and / or anti-PDGF agents.

[0179] In certain embodiments, the methods disclosed herein comprise 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 prophylactic effective amount.

[0180] In certain embodiments, the subject being treated is an animal. The animal can be of either sex and can be 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 domestic animal, such as a dog, cat, cattle, pig, horse, sheep, or goat. In certain embodiments, the subject is a companion animal, such as a dog or cat. In certain embodiments, the subject is a livestock animal, such as a cattle, 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.

[0181] Certain methods described herein may include administering one or more additional agents in combination with a compound described herein. One or more additional agents may be administered simultaneously with the compound of formula (I)-(III-b) or at a different time than the compound of formula (I)-(III-b). For example, the compound of formula (I)-(III-b) and any one or more additional agents may be in the same dosing regimen or a different dosing regimen. All or some doses of the compound of formula (I)-(III-b) may be administered before all or some doses of the additional agent, after all or some doses of the additional agent, within the dosing regimen of the additional agent, or in combination thereof. For different additional agents, the administration time of the compound of formula (I)-(III-b) and the additional agent may be different.

[0182] In certain embodiments, the additional agent includes an agent useful in treating edema, such as HAE or DME.

[0183] V. Exemplary Embodiments

[0184] Among other things, the present disclosure contemplates the following numbered embodiments:

[0185] 1. A compound of formula (I):

[0186]

[0187] or a pharmaceutically acceptable salt thereof,

[0188] in:

[0189] Het Ais selected from 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclylene groups having 1-2 heteroatoms selected from oxygen, nitrogen or sulfur, 5- to 6-membered monocyclic heteroarylene groups having 1-4 heteroatoms selected from oxygen, nitrogen or sulfur, 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclylene groups having 1-4 heteroatoms selected from oxygen, nitrogen or sulfur, and 7- to 10-membered bicyclic heteroarylene groups having 1-5 heteroatoms selected from oxygen, nitrogen or sulfur, wherein Het A 0-4 R A group substitution;

[0190] Each R A independently selected from halogen, -CN, -C(R)=N(R), -C(O)R, -C(O)2R, -C(O)N(R), -NO, -N(R)-N(R), -N(R), -N(R)C(O)R, -N(R)C(O)2R, -N(R)C(O)N(R), -N(R)S(O)2R, -OR, -OC(O)R, -OC(O)N(R), -SR, -S(O)R, -S(O)2R, -S(O)N(R), -S(O)2N(R), or an optionally substituted group selected from: C 1-6 aliphatic, phenyl, 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen or sulfur, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic group, and 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic group having 1-2 heteroatoms selected from oxygen, nitrogen or sulfur;

[0191] L is an optionally substituted C 1-6 a hydrocarbon chain in which 1-3 methylene units are independently replaced by –Cy-, –C(R)2-, –O-, –NR-, –C(O)-, –S(O)2-, –C(O)NR-, –NRC(O)-, –S(O)2NR-, and –NRS(O)2-;

[0192] -Cy- is a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclylene group, a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclylene group having 1-2 heteroatoms selected from oxygen, nitrogen or sulfur, or a 5- to 6-membered heteroarylene group having 1-4 heteroatoms selected from oxygen, nitrogen or sulfur;

[0193] R' and R" are independently selected from hydrogen, halogen, -OR, -NR2, -SR and optionally substituted C 1-6 Aliphatic; wherein R' can be combined with a monocyclic Het A together forming an optionally substituted fused 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclylene having 1-4 heteroatoms selected from oxygen, nitrogen or sulfur;

[0194] R 1 、R 2 、R3 、R 4 、R 5 、R 6 、R 7 、R 8 and R 9 independently selected from hydrogen, halogen, -CN, -C(R)=N(R), -C(O)R, -C(O)R, -C(O)N(R), -NO, -N(R)-N(R), -N(R), -N(R)C(O)R, -N(R)C(O)R, -N(R)C(O)N(R), -N(R)S(O)R, -OR, -OC(O)R, -OC(O)N(R), -SR, -S(O)R, -S(O)R, -S(O)R, -S(O)N(R), -S(O)N(R), or an optionally substituted group selected from: C 1-6 aliphatic, phenyl, 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen or sulfur, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic group, and 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic group having 1-2 heteroatoms selected from oxygen, nitrogen or sulfur; and

[0195] Each R is independently hydrogen or an optionally substituted group selected from: C 1-6 aliphatic, phenyl, 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen or sulfur, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic group, and 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic group having 1-2 heteroatoms selected from oxygen, nitrogen or sulfur;

[0196] or two R groups on the same carbon or nitrogen together with their intervening atoms form a ring selected from a 3- to 7-membered saturated or partially unsaturated monocyclic ring having 0-2 heteroatoms selected from oxygen, nitrogen or sulfur, and a 5- to 6-membered heteroaryl group having 1-4 heteroatoms selected from oxygen, nitrogen or sulfur;

[0197] n is 0 or 1.

[0198] 2. The compound according to embodiment 1, wherein when L is -(CR2) m NRC(O)—and m is 0 to 2 (e.g., 0 or 2), one of the following (a), (b), or (c) applies:

[0199] (a) n is 0;

[0200] (b)R 5 、R 6 、R 7 、R 8 and R 9 At least one of is CN; or

[0201] (c)R 1 is an optionally substituted saturated monocyclic heterocycle 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-morpholinoimidazolo[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, -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.

[0202] 3. A compound according to any one of the preceding embodiments, wherein L is selected from the group consisting of: -C(R)2NRC(O)-#, -C(R)2C(O)NRC(R)2-#, -C(R)2NRC(O)C(R)2-#, -C(R)2NRC(R)2-#, -C(R)2C(R)2NRC(R)2-#, -C(O)NRC(R)2-#, -C(R)2C(O)NR-#, -NRC(O)C(R)2-#, -CR2C(O)NRC(R)2-#, -SO2NRC(R)2-# and -C(R)2NRSO2-#, wherein # represents the same A connection point.

[0203] 4. A compound according to any one of the preceding embodiments, wherein 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-#, wherein # represents the sameA connection point.

[0204] 5. A compound according to any one of the preceding embodiments, wherein L is selected from the group consisting of: -C(R)2C(O)NRC(R)2-#, -C(R)2NRC(R)2-#, -C(R)2C(R)2NRC(R)2-#, -C(O)NRC(R)2-#, -C(R)2C(O)NRC(R)2-#, -SO2NRC(R)2-# and -C(R)2NRSO2-#, wherein # represents the same A connection point.

[0205] 6. A compound according to any one of the preceding embodiments, wherein L is not -C(R)2NRC(O)-# or -C(R)2C(O)NR-#.

[0206] 7. A compound according to any one of the preceding embodiments, wherein L is not -CH2NRC(O)-# or -CH2C(O)NR-#.

[0207] 8. A compound according to any one of the preceding embodiments, wherein when L is -C(R)2NRC(O)-# or -C(R)2C(O)NR-#, one of the following (a), (b) or (c) applies:

[0208] (a) n is 0;

[0209] (b)R 5 、R 6 、R 7 、R 8 and R 9 At least one of is CN; or

[0210] (c)R 1is an optionally substituted saturated monocyclic heterocycle 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-morpholinoimidazolo[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, -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.

[0211] 9. The compound according to any one of the preceding embodiments, wherein when L is -C(R)2NRC(O)-# or -C(R)2C(O)NR-#, n is 0.

[0212] 10. A compound according to any one of the preceding embodiments, wherein when L is -C(R)2NRC(O)-# or -C(R)2C(O)NR-#, R' is the same as the monocyclic Het A Together they form an optionally substituted fused 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclylene having 1-4 heteroatoms selected from oxygen, nitrogen or sulfur.

[0213] 11. A compound according to any one of the preceding embodiments, wherein when L is -CH2NRC(O)-# or -CH2C(O)NR-#, R' is the same as the monocyclic Het A Together they form an optionally substituted fused 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclylene having 1-4 heteroatoms selected from oxygen, nitrogen or sulfur.

[0214] 12. A compound according to any one of the preceding embodiments, wherein when L is -(CR2) m NRC(O)- and m is 0, 1 or 2, then n is 0.

[0215] 13. A compound according to any one of the preceding embodiments, wherein when L is -(CR2) m NRC(O)- and m is 0 to 2 (eg, 0 or 2), R' is the same as the monocyclic Het A Together they form an optionally substituted fused 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclylene having 1-4 heteroatoms selected from oxygen, nitrogen or sulfur.

[0216] 14. A compound according to any one of the preceding embodiments, wherein L is -C(R)2C(O)NRC(R)2-#, wherein each R is independently hydrogen or C(O) optionally substituted with halogen. 1-3 aliphatic.

[0217] 15. A compound according to any one of the preceding embodiments, wherein L is -CH2C(O)NHCH(CF3)-#.

[0218] 16. A compound according to any one of the preceding embodiments, wherein L is -CH2C(O)NHCH(CH3)-#.

[0219] 17. A compound according to any one of the preceding embodiments, wherein L is -C(R)2NRC(R)2-#, wherein each R is independently hydrogen or C optionally substituted by halogen. 1-3 aliphatic.

[0220] 18. A compound according to any one of the preceding embodiments, wherein L is -CH2NHCH(CF3)-#.

[0221] 19. A compound according to any one of the preceding embodiments, wherein L is -CH2NHCH2-#.

[0222] 20. A compound according to any one of the preceding embodiments, wherein L is -CH2NHCH(CH3)-#.

[0223] 21. A compound according to any one of the preceding embodiments, wherein L is -CH(CF3)NHCH2-#.

[0224] 22. A compound according to any one of the preceding embodiments, wherein L is -C(R)2NRSO2-#, wherein each R is independently hydrogen or C optionally substituted by halogen. 1-3 aliphatic.

[0225] 23. A compound according to any one of the preceding embodiments, wherein L is -CH2NHSO2-#.

[0226] 24. A compound according to any one of the preceding embodiments, wherein L is -SO2NRC(R)2-#, wherein each R is independently hydrogen or C optionally substituted by halogen. 1-3 aliphatic.

[0227] 25. A compound according to any one of the preceding embodiments, wherein L is -SO2NHCH2-#.

[0228] 26. A compound according to any one of the preceding embodiments, wherein L is -SO2NHCH(CH3)-#.

[0229] 27. A compound according to any one of the preceding embodiments, wherein L is -C(O)NRC(R)2-#, wherein each R is independently hydrogen or C optionally substituted by halogen. 1-3 aliphatic.

[0230] 28. A compound according to any one of the preceding embodiments, wherein L is -C(O)NHCH2-#.

[0231] 29. A compound according to any one of the preceding embodiments, wherein L is -C(R)2C(O)NRC(R)2-#, wherein each R is independently hydrogen or C(O) optionally substituted with halogen. 1-3 aliphatic.

[0232] 30. A compound according to any one of the preceding embodiments, wherein L is -CH2C(O)NHCH2-#.

[0233] 31. A compound according to any one of the preceding embodiments, wherein the compound has the structure of Formula (Ia), Formula (Ib), Formula (Ic), Formula (Id),

[0234]

[0235] or a pharmaceutically acceptable salt thereof.

[0236] 32. A compound according to any one of the preceding embodiments, wherein the compound has the structure of Formula (II):

[0237]

[0238] or a pharmaceutically acceptable salt thereof.

[0239] 33. A compound according to any one of the preceding embodiments, wherein the compound has a structure of Formula (II-a) or Formula (II-b):

[0240]

[0241] or a pharmaceutically acceptable salt thereof.

[0242] 34. A compound according to any one of the preceding embodiments, wherein R' is identical to the monocyclic Het A Together they form an optionally substituted fused ring, and the compound has the structure of formula (III):

[0243]

[0244] where R fus With Het A fused to form a fused 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclylene having 1-4 heteroatoms selected from oxygen, nitrogen or sulfur,

[0245] or a pharmaceutically acceptable salt thereof.

[0246] 35. A compound according to any one of the preceding embodiments, wherein the compound has the structure of Formula (III-a) or Formula (III-b):

[0247]

[0248] or a pharmaceutically acceptable salt thereof.

[0249] 36. A compound according to any one of the preceding embodiments, wherein Het A is a 5-membered monocyclic heteroarylene group having 1 to 4 heteroatoms selected from oxygen, nitrogen or sulfur, wherein Het A 0-2 R A Group substitution.

[0250] 37. A compound according to any one of the preceding embodiments, wherein Het A is a 5-membered monocyclic heteroarylene group having 2-3 heteroatoms selected from nitrogen, wherein Het A 0-2 R A Group substitution.

[0251] 38. A compound according to any one of the preceding embodiments, wherein Het A Is 0-2 R A A pyrazole diyl group substituted with a group.

[0252] 39. A compound according to any one of the preceding embodiments, wherein Het A Is 0-1 R A A triazolediyl group substituted with a group.

[0253] 40. A compound according to any one of the preceding embodiments, wherein Het A It is an unsubstituted pyrazolediyl.

[0254] 41. A compound according to any one of the preceding embodiments, wherein Het A It is an unsubstituted 1,2,3-triazolediyl.

[0255] 42. A compound according to any one of the preceding embodiments, wherein Het A Selected from:

[0256]

[0257] Where * indicates the connection point with L.

[0258] 43. A compound according to any one of the preceding embodiments, wherein R A A single example is a C substituted by a halogen 1-6 aliphatic.

[0259] 44. A compound according to any one of the preceding embodiments, wherein R' and R" are each hydrogen.

[0260] 45. A compound according to any one of the preceding embodiments, wherein R" is hydrogen and R' is a monocyclic Het A Together they form a fused 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclylene group having 1-4 heteroatoms selected from oxygen, nitrogen or sulfur.

[0261] 46. ​​A compound according to any one of the preceding embodiments, wherein n is 1, R" is hydrogen, and R' is identical to the monocyclic Het A Together they form a fused 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclylene group having 1-4 heteroatoms selected from oxygen, nitrogen or sulfur.

[0262] 47. A compound according to any one of the preceding embodiments, wherein n is 1, R" is hydrogen, and R' is identical to the monocyclic Het A Together they form a fused 8-membered saturated or partially unsaturated bicyclic heterocyclylene group having 1 to 4 heteroatoms selected from oxygen, nitrogen or sulfur.

[0263] 48. A compound according to any one of the preceding embodiments, wherein when n is 0, Het A is a 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclylene group having 1 to 4 heteroatoms selected from oxygen, nitrogen or sulfur.

[0264] 49. The compound according to any one of the preceding embodiments, wherein n is 0.

[0265] 50. The compound according to any one of the preceding embodiments, wherein n is 1.

[0266] 51. A compound according to any one of the preceding embodiments, wherein R 2 、R 3 、R 4 、R 5 、R 7 、R 8 and R 9 Each is hydrogen.

[0267] 52. A compound according to any one of the preceding embodiments, wherein R 1 、R 2 、R 3 、R 4 、R 7 、R 8 and R 9 Each is hydrogen.

[0268] 53. A compound according to any one of the preceding embodiments, wherein R 1 、R 2 、R 3 、R 4 、R 5 、R 7 、R 8 and R 9 Each is hydrogen.

[0269] 54. A compound according to any one of the preceding embodiments, wherein R 1 is an optionally substituted group selected from the group consisting of a 5- to 6-membered heteroaryl group having 1-4 heteroatoms selected from oxygen, nitrogen or sulfur, and a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl group having 1-2 heteroatoms selected from oxygen, nitrogen or sulfur.

[0270] 55. A compound according to any one of the preceding embodiments, wherein R 1 is an optionally substituted 5-membered heteroaryl group having 2 to 4 heteroatoms selected from oxygen or nitrogen.

[0271] 56. A compound according to any one of the preceding embodiments, wherein R 1 is optionally substituted piperazinyl or optionally substituted triazolyl.

[0272] 57. A compound according to any one of the preceding embodiments, wherein R 1 is an optionally substituted C 1-6 aliphatic.

[0273] 58. A compound according to any one of the preceding embodiments, wherein the optionally substituted R 1 The substituents on the group are independently halogen, (CH2) 0-4 R°, -(CH2) 0-4OR° and -(CH2) 0-4 C(O)OR°, wherein each R° is independently hydrogen, C 1-6 aliphatic, or a 5- to 6-membered saturated, partially unsaturated or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0274] 59. A compound according to any one of the preceding embodiments, wherein R 5 and R 6 are each independently halogen.

[0275] 60. A compound according to any one of the preceding embodiments, wherein R 5 is F and R 6 It's Cl.

[0276] 61. A compound according to any one of the preceding embodiments, wherein R 6 It is Cl or CN.

[0277] 62. The compound of any one of the preceding embodiments, wherein the compound is any one of compounds I-1 to I-20, or a pharmaceutically acceptable salt thereof.

[0278] 63. A pharmaceutical composition comprising a compound according to any one of the preceding embodiments.

[0279] 64. A pharmaceutical composition comprising a compound according to any one of the preceding embodiments, further comprising a pharmaceutically acceptable excipient.

[0280] 65. The pharmaceutical composition of any one of embodiments 63-64, wherein the composition is suitable for oral administration.

[0281] 66. The pharmaceutical composition of any one of embodiments 63-64, wherein the composition is suitable for administration by injection.

[0282] 67. A method of treating a plasma kallikrein-mediated disease or condition using a compound or composition according to any one of the preceding embodiments.

[0283] 68. The method of embodiment 67, wherein the disease or condition is hereditary angioedema or diabetic macular edema.

[0284] 69. A method of treating hereditary angioedema or diabetic macular edema, the method comprising administering to a patient in need thereof a compound or composition according to any one of the preceding embodiments.

[0285] Example

[0286] Synthesis of intermediates

[0287] Synthesis of 2-(7-chloroimidazo[1,5-a]pyridin-1-yl)acetic acid

[0288]

[0289] The synthesis of N-((4-chloropyridin-2-yl) methylene)-2-methylpropane-2-sulfinamide. At room temperature over the time period of 10 minutes to (S)-2-methylpropane-2-sulfinamide (5.00g, 41.3mmol) and cesium carbonate (20.2g, 61.9mmol) in dichloromethane (100mL) stirred solution dropwise add 4-chloropyridine carboxaldehyde (5.84g, 41.3mmol) in dichloromethane (20mL).Solution was stirred for 2 hours.Reactant mixture was diluted with water (100mL) and extracted with dichloromethane (100mL x 3).By the organic layer dried (MgSO4) merged and concentrated, obtain the product (N-((4-chloropyridin-2-yl) methylene)-2-methylpropane-2-sulfinamide, 10.1g, quantitative) in brown oil. LCMS RT=1.738min[M+H] + 246.9, 95% purity.

[0290] Synthesis of 3-((tert-butylsulfinyl)amino)-3-(4-chloropyridin-2-yl)propanoate. To a stirred solution of lithium diisopropylamide (2M in tetrahydrofuran, 43mL, 86mmol) in anhydrous tetrahydrofuran (100mL) was added dropwise a solution of butyl acetate (9.40g, 81mmol) in tetrahydrofuran (20mL) 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 (10.0g, 41mmol) in tetrahydrofuran (30mL) was added at this temperature. After stirring for another 2 hours at -78°C, the reaction mixture was quenched with saturated aqueous ammonium chloride solution (100mL) and warmed to room temperature. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (100mL x 3). The combined organic layers were dried (NaSO), concentrated, and purified by flash chromatography (eluent 50% petroleum ether / ethyl acetate) to give butyl (3-((tert-butylsulfinyl)amino)-3-(4-chloropyridin-2-yl)propanoate as a white solid, 9.0 g, 61%). LCMS RT = 1.338 min [M+H] + 361, 95% purity.

[0291] Synthesis of butyl 3-amino-3-(4-chloropyridin-2-yl)propanoate. To a solution of butyl 3-(4-chloropyridin-2-yl)-3-(1,1-dimethylethylsulfinamido)propanoate (3.5 g, 9.7 mmol) in 1,4-dioxane (30 mL) was added hydrochloric acid solution (4 M in 1,4-dioxane, 10 mL, 40 mmol). The mixture was stirred at room temperature for 4 hours and then concentrated to give a crude oil (4.3 g) which was used in the next step without purification. LCMS RT = 1.187 min [M + H] + 257, 80% purity.

[0292] Synthesis of butyl 3-(4-chloropyridin-2-yl)-3-formamidopropanoate. A solution of butyl 3-amino-3-(4-chloropyridin-2-yl)propanoate (2.6 g, 10.2 mmol) in formic acid (10 mL) was stirred at reflux for 4 hours. The reaction mixture was then concentrated to give the crude product (3.0 g) as a dark oil, which was used in the next step without purification. LCMS RT = 1.05 min [M+H] + 285, 83% purity

[0293] Synthesis of butyl 2-(7-chloroimidazo[1,5-a]pyridin-1-yl)acetate. A solution of butyl 3-(4-chloropyridin-2-yl)-3-formamidopropanoate (500mg, 1.76mmol) in phosphorus oxychloride (V) (5.0mL) was stirred at 80 ° C for 1 hour. The mixture was evaporated, and the residue was dissolved in ethyl acetate (100mL) and washed with saturated sodium bicarbonate aqueous solution (50mL). The organic layer was separated and the aqueous layer was extracted again with ethyl acetate (50mL x 3). The combined organic layers were concentrated and purified by flash chromatography (eluent 70% ethyl acetate / petroleum ether) to give the product (butyl 2-(7-chloroimidazo[1,5-a]pyridin-1-yl)acetate, 290mg, 62%). LCMS RT=1.18min[M+H] + 267, 95% purity.

[0294] Synthesis of 2-(7-chloroimidazo[1,5-a]pyridin-1-yl)acetic acid. To a stirred solution of 2-(7-chloroimidazo[1,5-a]pyridin-1-yl)butyl acetate (310 mg, 1.16 mmol) in tetrahydrofuran (3 mL) and water (1 mL) was added lithium hydroxide (139 mg, 5.8 mmol), and the mixture was stirred at room temperature for 16 hours. The pH was adjusted to 6 by adding 1 M aqueous hydrochloric acid solution and extracted with dichloromethane / methanol (10 / 1, 50 mL x 5). The combined organic layers were dried and concentrated to give the product (2-(7-chloroimidazo[1,5-a]pyridin-1-yl)acetic acid, 200 mg, 82%), which was used in the next step without purification. LCMS RT=0.901 min[M+H] + 211, 95% purity

[0295] Synthesis of methyl 2-(7-chloroimidazo[1,5-a]pyridin-1-yl)acetate

[0296]

[0297] Acetyl chloride (0.42mL, 5.9mmol) is added to a stirred solution of 2- (7- chloroimidazo [1,5-a] pyridin-1-yl) acetic acid (250mg, 1.2mmol) in methanol (5.0mL) at 0°C, then warmed to room temperature and stirred for 18 hours. The mixture is concentrated in a vacuum. The residue is dissolved in a mixture of saturated sodium bicarbonate aqueous solution (25mL) and water (25mL) and extracted with methanol / dichloromethane (1:9, 3x 50mL). The combined organic layer is dried (MgSO4), filtered and evaporated in a vacuum to give the product (2- (7- chloroimidazo [1,5-a] pyridin-1-yl) methyl acetate, 310mg, quantitative) as a beige solid.

[0298] 1H NMR (400MHz, 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).

[0299] Synthesis of 2-(7-chloroimidazo[1,5-a]pyridin-1-yl)acetamide

[0300]

[0301] A mixture of 2-(7-chloroimidazo[1,5-a]pyridin-1-yl)acetic acid (500 mg, 2.4 mmol), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (550 mg, 2.9 mmol), 1-hydroxybenzotriazole hydrate (380 mg, 2.9 mmol), N,N-diisopropylethylamine (2.5 mL, 14 mmol) and ammonium carbonate (1.1 g, 12 mmol) in tetrahydrofuran (7.0 mL) and N,N-dimethylformamide (4.0 mL) was stirred at 60 ° C for 18 hours. The mixture was cooled, diluted with water (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with saturated aqueous sodium carbonate solution (100 mL), dried (MgSO 4 ), filtered and evaporated in vacuo. The residue was triturated with diethyl ether: dichloromethane (9: 1) to give the product (2-(7-chloroimidazo[1,5-a]pyridin-1-yl)acetamide, 0.20 g, 40%) as a yellow solid.

[0302] 1H NMR (400MHz, 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=2.0,7.3Hz),3.66(2H,s).

[0303] Synthesis of ethyl 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate become

[0304] 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 under N2 for 14 hours. The reactants were concentrated in vacuo to give 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.

[0305] Synthesis of 2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine. A mixture of 5-cyclopropylpyridine-2-amine (61g, 455mmol) and 1,3-dichloropropane-2-one (172g, 1365mmol) in EtOH (1L) was stirred at 95 ° C for 13 hours. The reactant was concentrated to remove EtOH. The pH of the residue was adjusted to 9 by adding NaHCO3 aqueous solution and extracted with EtOAc (1L x3). The combined organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo to give a crude product, which was purified by silica gel chromatography (EA) to give 2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine (40g, yield: 42%) as a yellow solid. ESI-MS[M+H] + :207.1.

[0306] 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 reactant was stirred at room temperature for 2 hours. The reactant 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 in vacuo to give 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.

[0307] 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 hours. A yellow solid precipitated after 3 hours, and the mixture was filtered. The filter 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.

[0308] Synthesis of 7-chloro-8-fluoroimidazo[1,5-a]pyridine-1-carbaldehyde

[0309] Synthesis of 4-chloro-3-fluoropyridinecarboxaldehyde. At 0 ° C., n-butyl lithium (2.4M in hexane, 100 mL, 240 mmol) was added dropwise to a solution of 2,2,6,6-tetramethylpiperidine (35.4 g, 250.88 mmol) in 200 mL of THF. The reaction mixture was stirred at 0 ° C. for 1 hour and then 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 another 1 hour. The reactant was quenched with H2O (50 mL) and extracted with ethyl acetate (200 mL x 3). The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to give 4-chloro-3-fluoropicolinaldehyde (26.0 g, yield: 71%). ESI-MS [M+H] + :160.1.

[0310] Synthesis of N-((4-chloro-3-fluoropyridin-2-yl)methyl)-2-methylpropane-2-sulfenamide. To a solution of 4-chloro-3-fluoropicolinaldehyde (26.0 g, mixture, 163.0 mmol) in DCM (100 mL) was added Cesium carbonate To the 4- chloro-3-fluoropyridin-2-yl of 4- (4- chloro-3-fluoropyridin-2-yl) methyl) -2- methylpropane -2- sulfenamide (96.0g, 293.3mmol). 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 (40mL) was added to the combined mixture, and the resulting mixture was then cooled to 0 ° C by an ice-water bath. Sodium borohydride (15.5g, 409.0mmol) was slowly added in batches. The reaction mixture was warmed to room temperature and stirred at this temperature for 2 hours. The reactant was carefully quenched with H2O. The resulting mixture was extracted with DCM (100mL x 3), the combined organic solvent was dried over sodium sulfate, filtered and concentrated to give crude N- ((4- chloro-3-fluoropyridin-2-yl) methyl) -2- methylpropane -2- sulfenamide (43.3g, crude product) as a yellow solid. ESI-MS [M+H] + :265.1.

[0311] Synthesis of (4-chloro-3-fluoropyridin-2-yl)methylamine hydrochloride. 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 (3M, 200 mL). The resulting reaction mixture was stirred at room temperature for 3 hours. After the reaction was complete, the reaction mixture was filtered to obtain a crude product, which was washed with ethyl acetate and dried in vacuo to obtain (4-chloro-3-fluoropyridin-2-yl)methylamine hydrochloride (25.0 g, 78%, mixture) as a pink solid. 1 H NMR (400MHz, DMSO) δ8.75 (br, 3H), 8.47 (d, J = 5.2Hz, 1H), 7.80 (t, J = 5.6Hz, 1H), 4.28-4.26 (m, 2H).

[0312] Synthesis of N-((4-chloro-3-fluoropyridin-2-yl)methyl)formamide. To a solution of (4-chloro-3-fluoropyridin-2-yl)methylamine hydrochloride (25.0 g, mixture, 127.0 mmol) in THF (200 mL) was added triethylamine (38.5 g, 380.6 mmol) and ethyl formate (100 mL) at room temperature. The resulting reaction mixture was stirred at 70 ° C overnight. After the reaction was completed, the reaction mixture was filtered and the solid was washed three times with DCM. The combined organic solvents were washed with brine, dried over sodium sulfate, filtered and concentrated to give N-((4-chloro-3-fluoropyridin-2-yl)methyl)formamide (crude product), which was used directly in the next step without purification. ESI-MS [M+H] + :189.1.

[0313] 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 126.89mmol) in anhydrous acetonitrile (200mL) was added phosphorus oxychloride (18mL, 1.5 equivalents), and the resulting reaction mixture was refluxed and stirred for 3 hours. After the reaction was complete, the reaction mixture was cooled to room temperature and then carefully poured into H2O (200mL). The pH was adjusted to 8 with saturated sodium bicarbonate, and the resulting mixture was extracted with ethyl acetate (200mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate) to give 7-chloroimidazo[1,5-a]pyridine (12.0g, yield: 56%) as a white solid. ESI-MS[M+H] + :171.1.

[0314] Synthesis of 7-chloro-8-fluoroimidazo[1,5-a]pyridine-1-carboxaldehyde. 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 ° C -5 ° C with an ice-water bath. Phosphorus oxychloride (7.4 g, 78.9 mmol, 1.5 equivalents) was added dropwise, and the reaction mixture was stirred at 100 ° C for 2 hours. After the reaction was completed, the reaction mixture was cooled to room temperature and carefully poured into a saturated aqueous sodium bicarbonate solution (200 mL). The resulting mixture was stirred at room temperature for 2 hours and extracted with ethyl acetate (3 x 200 mL). The combined organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. 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.

[0315] Synthesis of 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylic acid

[0316] Synthesis of 5-cyclopropylpyridine-2-amine. A solution of 5-bromopyridine-2-amine (5g, 29.1mmol), cyclopropylboronic acid (3.75g, 43.6mmol), Pd(OAc)2(651mg, 2.91mmol), SPhos (1.19g, 2.91mmol) and K3PO4(18.5g, 87.3mmol) in toluene / HO (100mL / 10mL) was stirred at 95°C under nitrogen for 12 hours. The reaction mixture was then quenched with HO (50mL) and extracted with DCM (200mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo to give a crude residue, which was purified by silica gel chromatography (PE / EtOAc=1 / 1) to give 5-cyclopropylpyridine-2-amine (3.8g, 97.4% yield) as a yellow solid. ESI-MS[M+H] + :135.2.

[0317] Synthesis of 2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine. To a solution of 5-cyclopropyl-4-methylpyridin-2-amine (500mg, 3.70mmol) in DMF (10mL) was added 1,3-dichloropropane-2-one (1409mg, 11.1mmol) at room temperature. The resulting reactant was stirred at 85 ° C for 2 hours. The solution was quenched with H2O (60mL), adjusted to pH 8 by adding saturated NaHCO3, and extracted with EtOAc (50mL x 3). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo to give a crude product, which was purified by preparative TLC (PE / EtOAc=1 / 1) to give 2-(chloromethyl)-6-cyclopropyl-7-methylimidazo[1,2-a]pyridine (300mg, yield: 39%) as a light yellow oil. ESI-MS[M+H] + :207.2.

[0318] Synthesis of ethyl 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate. To a solution of 2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine (2 g, 9.70 mmol) in DMF (20 mL) was added ethyl 1H-pyrazole-4-carboxylate (906 mg, 6.46 mmol) and CsCO (6.32 g, 19.38 mmol) at room temperature. The resulting reactant was stirred at room temperature for 12 hours. HO (150 mL) was added to the reactant, and the mixture was then extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo to give 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.

[0319] 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 hours. Most of the THF was removed and the pH was adjusted to 4 to 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 (1.0 g, yield: 91%) as a white solid. ESI-MS [M+H] + :283.2.

[0320] Synthesis of 1-(Aminomethyl)imidazo[1,5-a]pyridine-7-carbonitrile

[0321] Synthesis of tert-butyl ((7-bromoimidazo[1,5-a]pyridin-1-yl)methyl)carbamate. To a solution of (7-bromoimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride (2 g, 7.66 mmol) in DCM (30 mL) was added triethylamine (4.3 mL, 30.6 mmol) and di-tert-butyl dicarbonate (3.5 mL, 15.3 mmol). The mixture was stirred at room temperature for 2 hours. TLC showed 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.

[0322] Synthesis of tert-butyl ((7-cyanoimidazo [1,5-a] pyridin-1-yl) methyl) carbamate. To a solution of tert-butyl ((7-bromoimidazo [1,5-a] pyridin-1-yl) methyl) carbamate (200 mg, 0.615 mmol) in DMF (3 mL) was added 1,1'-bis (diphenylphosphino) ferrocene (64 mg, 0.12 mmol), tris (dibenzylideneacetone) dipalladium (Pd2(dba)3, 55 mg, 0.06 mmol) and zinc cyanide (144 mg, 1.23 mmol). The mixture was stirred in a microwave reactor at 150 ° C for 1 hour and concentrated. The residue was purified by column chromatography (DCM / MeOH=10 / 1) to give tert-butyl ((7-cyanoimidazolo[1,5-a]pyridin-1-yl)methyl)carbamate (117 mg, yield: 70%) as a yellow oil. ESI-MS [M+H] + :273.1.

[0323] Synthesis of 1-(aminomethyl)imidazo[1,5-a]pyridine-7-carbonitrile. A mixture of tert-butyl ((7-cyanoimidazolo[1,5-a]pyridin-1-yl)methyl)carbamate (270 mg, 0.99 mmol) and hydrochloride in ethyl acetate (3M, 20 mL) was stirred at room temperature for 2 hours and then filtered to give a crude product, which was washed with ethyl acetate and dried in vacuo 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%.

[0324] Synthesis of ethyl 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate become

[0325] 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 under N2 for 14 hours. The reactants were concentrated in vacuo to give 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.

[0326] Synthesis of 2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine. A mixture of 5-cyclopropylpyridine-2-amine (61g, 455mmol) and 1,3-dichloropropane-2-one (172g, 1365mmol) in EtOH (1L) was stirred at 95 ° C for 13 hours. The reactant was concentrated to remove EtOH. The pH of the residue was adjusted to 9 by adding NaHCO3 aqueous solution and extracted with EtOAc (1L x3). The combined organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo to give a crude product, which was purified by silica gel chromatography (EA) to give 2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine (40g, yield: 42%) as a yellow solid. ESI-MS[M+H] + :207.1.

[0327] 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 reactant was stirred at room temperature for 2 hours. The reactant 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 in vacuo to give 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.

[0328] 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 hours. A yellow solid precipitated after 3 hours, and the mixture was filtered. The filter 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.

[0329] Synthesis of (7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methylamine hydrochloride

[0330] Synthesis of 4-chloro-3-fluoropicolinaldehyde. To a solution of 2,2,6,6-tetramethylpiperidine (35.4 g, 250.88 mmol) in 200 mL of THF was added dropwise at 0°C. n-Butyllithium (2.4M in hexane, 100mL, 240mmol). The reaction mixture was stirred at 0°C for 1 hour and then cooled to -78°C, and a solution of 4-chloro-3-fluoropyridine (30.0g, 228.08mmol) in THF (100mL) was added dropwise. The resulting reaction mixture was stirred at -78°C for 2 hours, a solution of DMF (17.5g, 239.48mmol) in THF (50mL) was added dropwise, and the resulting reaction mixture was stirred at -78°C for another 1 hour. The reactant was quenched with H2O (50mL) and extracted with ethyl acetate (200mL x 3). The combined organic layer was 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-fluoropyridinecarboxaldehyde (26.0g, yield: 71%). ESI-MS[M+H] + :160.1.

[0331] Synthesis of N-((4-chloro-3-fluoropyridin-2-yl)methyl)-2-methylpropane-2-sulfenamide. To a solution of 4-chloro-3-fluoropicolinaldehyde (26.0 g, mixture, 163.0 mmol) in DCM (100 mL) was added Cesium carbonate To the 4- chloro-3-fluoropyridin-2-yl of 4- (4- chloro-3-fluoropyridin-2-yl) methyl) -2- methylpropane -2- sulfenamide (96.0g, 293.3mmol). 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 (40mL) was added to the combined mixture, and the resulting mixture was then cooled to 0 ° C by an ice-water bath. Sodium borohydride (15.5g, 409.0mmol) was slowly added in batches. The reaction mixture was warmed to room temperature and stirred at this temperature for 2 hours. The reactant was carefully quenched with H2O. The resulting mixture was extracted with DCM (100mL x 3), the combined organic solvent was dried over sodium sulfate, filtered and concentrated to give crude N- ((4- chloro-3-fluoropyridin-2-yl) methyl) -2- methylpropane -2- sulfenamide (43.3g, crude product) as a yellow solid. ESI-MS [M+H] + :265.1.

[0332] Synthesis of (4-chloro-3-fluoropyridin-2-yl)methylamine hydrochloride. 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 (3M, 200 mL). The resulting reaction mixture was stirred at room temperature for 3 hours. After the reaction was complete, the reaction mixture was filtered to obtain a crude product, which was washed with ethyl acetate and dried in vacuo to obtain (4-chloro-3-fluoropyridin-2-yl)methylamine hydrochloride (25.0 g, 78%, mixture) as a pink solid. 1 H NMR (400MHz, DMSO) δ8.75 (br, 3H), 8.47 (d, J = 5.2Hz, 1H), 7.80 (t, J = 5.6Hz, 1H), 4.28-4.26 (m, 2H).

[0333] Synthesis of N-((4-chloro-3-fluoropyridin-2-yl)methyl)formamide. To a solution of (4-chloro-3-fluoropyridin-2-yl)methylamine hydrochloride (25.0 g, mixture, 127.0 mmol) in THF (200 mL) was added triethylamine (38.5 g, 380.6 mmol) and ethyl formate (100 mL) at room temperature. The resulting reaction mixture was stirred at 70 ° C overnight. After the reaction was completed, the reaction mixture was filtered and the solid was washed three times with DCM. The combined organic solvents were washed with brine, dried over sodium sulfate, filtered and concentrated to give N-((4-chloro-3-fluoropyridin-2-yl)methyl)formamide (crude product), which was used directly in the next step without purification. ESI-MS [M+H] + :189.1.

[0334] 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 126.89mmol) in anhydrous acetonitrile (200mL) was added phosphorus oxychloride (18mL, 1.5 equivalents), and the resulting reaction mixture was refluxed and stirred for 3 hours. After the reaction was complete, the reaction mixture was cooled to room temperature and then carefully poured into H2O (200mL). The pH was adjusted to 8 with saturated sodium bicarbonate, and the resulting mixture was extracted with ethyl acetate (200mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate) to give 7-chloroimidazo[1,5-a]pyridine (12.0g, yield: 56%) as a white solid. ESI-MS[M+H] + :171.1.

[0335] Synthesis of 7-chloro-8-fluoroimidazo[1,5-a]pyridine-1-carboxaldehyde. 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 ° C -5 ° C with an ice-water bath. Phosphorus oxychloride (7.4 g, 78.9 mmol, 1.5 equivalents) was added dropwise, and the reaction mixture was stirred at 100 ° C for 2 hours. After the reaction was completed, the reaction mixture was cooled to room temperature and carefully poured into a saturated aqueous sodium bicarbonate solution (200 mL). The resulting mixture was stirred at room temperature for 2 hours and extracted with ethyl acetate (3 x 200 mL). The combined organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. 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.

[0336] Synthesis of (Z)-N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methylene)-2-methylpropane-2-sulfinamide. 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) was added tetraethoxytitanium (15.0 g, 65.50 mol). The reaction mixture was stirred at reflux overnight. After completion of the reaction, the reaction mixture was concentrated and the residue was purified by column chromatography (ethyl acetate) to give (E)-N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methylene)-2-methylpropane-2-sulfinamide (7.77 g, 98%) as a white solid. ESI-MS [M+H] + :302.1.

[0337] 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 hours. After the reaction was completed, the reactant was quenched with H2O (50 mL). The resulting mixture was extracted with ethyl acetate (200 mL x 3), and the combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to afford N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-2-methylpropane-2-sulfenamide (7.77 g, 99%) as a white solid. ESI-MS [M+H] + :304.1.

[0338] Synthesis of (7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride. A mixture of N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-2-methylpropane-2-sulfinamide (7.77 g, 25.5 mmol) and hydrochloric acid in ethyl acetate (3 M, 100 mL) was stirred at room temperature for 2 hours, and the reaction mixture was then filtered to give the crude product, which was washed with ethyl acetate and dried in vacuo to give (7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride (6.03 g, quantitative) as a white solid. ESI-MS [M-NH2] + :182.9. 1 H NMR (400MHz, DMSO): δ8.64 (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).

[0339] Synthesis of ethyl 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate

[0340] Synthesis of 5-cyclopropylpyridine-2-amine. A solution of 5-bromopyridine-2-amine (5g, 29.1mmol), cyclopropylboronic acid (3.75g, 43.6mmol), Pd(OAc)2(651mg, 2.91mmol), SPhos (1.19g, 2.91mmol) and K3PO4(18.5g, 87.3mmol) in toluene / HO (100mL / 10mL) was stirred at 95°C under nitrogen for 12 hours. The reaction mixture was then quenched with HO (50mL) and extracted with DCM (200mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo to give a crude residue, which was purified by silica gel chromatography (PE / EtOAc=1 / 1) to give 5-cyclopropylpyridine-2-amine (3.8g, 97.4% yield) as a yellow solid. ESI-MS[M+H] + :135.2.

[0341] Synthesis of 2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine. To a solution of 5-cyclopropyl-4-methylpyridin-2-amine (500mg, 3.70mmol) in DMF (10mL) was added 1,3-dichloropropane-2-one (1409mg, 11.1mmol) at room temperature. The resulting reactant was stirred at 85 ° C for 2 hours. The solution was quenched with H2O (60mL), adjusted to pH 8 by adding saturated NaHCO3, and extracted with EtOAc (50mL x 3). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo to give a crude product, which was purified by preparative TLC (PE / EtOAc=1 / 1) to give 2-(chloromethyl)-6-cyclopropyl-7-methylimidazo[1,2-a]pyridine (300mg, yield: 39%) as a light yellow oil. ESI-MS[M+H] + :207.2.

[0342] Synthesis of ethyl 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate. To a solution of 2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine (2 g, 9.70 mmol) in DMF (20 mL) was added ethyl 1H-pyrazole-4-carboxylate (906 mg, 6.46 mmol) and CsCO (6.32 g, 19.38 mmol) at room temperature. The resulting reactant was stirred at room temperature for 12 hours. HO (150 mL) was added to the reactant, and the mixture was then extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo to give 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.

[0343] tert-1-((8-bromo-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid Synthesis of Butyl Ester

[0344] Synthesis of 3-bromo-5-cyclopropylpyridin-2-amine. At 0 ° C, NBS (11.72 g, 66 mmol) was added to a solution of 5-cyclopropylpyridin-2-amine (8.08 g, 60 mmol) in MeCN (200 mL) in batches over 30 minutes. The mixture was stirred at 0 ° C for another 30 minutes and then concentrated to give a crude product, which was purified by silica gel chromatography (PE / EA = 5 / 1 to 4 / 1) to give 3-bromo-5-cyclopropylpyridin-2-amine (8.23 g, yield: 64%) as a white solid. ESI-MS [M + H] + :212.8,

[0345] Synthesis of 8-bromo-2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine. A solution of 3-bromo-5-cyclopropylpyridine-2-amine (8.23 g, 38.6 mmol) and 1,3-dichloropropane-2-one (7.46 g, 57.9 mmol) in EtOAc (80 mL) was stirred at 70 ° C for 48 ° C. The reaction mixture was diluted with EtOAc (300 mL) and washed with saturated NaHCO3 aqueous solution (100 mL). The organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo to give a crude product, which was purified with silica gel (EtOAc / PE=1 / 2) to give (8 g, yield: 72.3%) as a yellow solid. ESI-MS[M+H] + :284.8

[0346] 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 (1g, 3.5mmol) in DMF (15mL) was added NaN3 (230mg, 3.5mmol). The resulting mixture was stirred at 50°C under nitrogen for 24 hours. H2O (50mL) was added to the reactant and extracted with EtOAc (50mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo to give 2-(azidomethyl)-8-bromo-6-cyclopropylimidazo[1,2-a]pyridine (1.1g, crude product), which was used in the next step without further purification. ESI-MS[M+H] + :292.0.

[0347] Synthesis of tert-butyl 1-((8-bromo-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate. To a solution of 2-(azidomethyl)-8-bromo-6-cyclopropylimidazo[1,2-a]pyridine (1.1 g, crude from the previous step) and tert-butyl propiolate (860 mg, 6.8 mmol) in t-BuOH / H2O (15 mL / 15 mL) was 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 hours. The mixture was concentrated in vacuo to give the crude product, which was purified by silica gel chromatography (PE / EtOAc=1 / 2) to give tert-butyl 1-((8-bromo-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate (500 mg, 34% over 2 steps) as a brown oil. ESI-MS [M+H] + :417.7.

[0348] Example 1

[0349] 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)

[0350] Solution 1

[0351]

[0352] Synthesis of (1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methanol

[0353]

[0354] To a solution of ethyl 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate (10.0 g, 33.7 mmol) in THF (100 mL) was added DIBAL-H (67.3 mL, 67.3 mmol) at -60 ° C. The mixture was stirred at room temperature for 3 hours, then quenched with saturated aqueous NaHCO solution (300 mL) and extracted with EtOAc (150 mL x 3). The combined organic layers were washed with brine (200 mL), dried over Na SO, and concentrated in vacuo. The residue was purified by flash column chromatography (PE / EtOAc 0% to 80%) to give (1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methanol (7.5 g, yield: 82%) as an off-white solid. ESI-MS [M+H] + :270.1

[0355] Synthesis of 2-((4-(azidomethyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridine

[0356]

[0357] To a solution of (1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methanol (5 g, 18.6 mmol) and DPPA (10.2 g, 37.2 mmol) in DCM (80 mL) was added DBU (11.3 g, 74.4 mmol) dropwise at 0° C. After stirring at room temperature for 18 hours, the reaction was quenched with saturated aqueous NH4Cl (100 mL) and extracted with DCM (100 mL x 3). The combined organic layers were washed with brine (70 mL), dried over Na2SO4 and concentrated in vacuo to give the crude product, which was purified by silica gel chromatography (PE / EtOAc 0% to 50%) to give 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

[0358] Synthesis of (1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methanamine

[0359]

[0360] A mixture of 2-((4-(azidomethyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridine (2 g, 6.8 mmol) and Pd / C (200 mg) in THF (80 mL) was stirred at room temperature under an H2 atmosphere for 18 hours. The reaction mixture was filtered and washed with MeOH (100 mL). The filtrate was concentrated in vacuo to give (1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methanamine (1 g, yield: 54.9%) as a yellow solid. [M+H]+: 269.2

[0361] 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)

[0362]

[0363] A mixture of 2-(7-chloro-1,8a-dihydroimidazo[1,5-a]pyridin-1-yl)acetic acid (40 mg, 0.19 mmol), HATU (110 mg, 0.29 mmol), DIPEA (74 mg, 0.57 mmol) and (1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methanamine (51 mg, 0.19 mmol) in DMF (3 mL) was stirred at room temperature for 18 hours. Water (30 mL) was added and the mixture was extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (40 mL x 2), dried over Na2SO4, and concentrated in vacuo to give a crude product, which was purified by preparative TLC (DCM / MeOH=20 / 1) to afford 2-(7-chloroimidazo[1,5-a]pyridin-1-yl)-N-((1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methyl)acetamide (50 mg, yield: 57%) as a white solid. ESI-MS: [M+H] + 461.2.

[0364] 1H NMR (400MHz, DMSO) δ8.45–8.42(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=9.4Hz,1H),6.63–6.61(m,1H),5.63(s,2H),4.27(d,J=5.6Hz,2H), 3.66(s,2H),1.97–1.90(m,1H),0.95–0.90(m,2H),0.70–0.66(m,2H).

[0365] Example 2

[0366] 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)

[0367] Option 2

[0368]

[0369] Synthesis of 1-(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)-2,2,2-trifluoroethan-1-ol

[0370]

[0371] To a solution of 7-chloro-8-fluoroimidazo[1,5-a]pyridine (510 mg, 3 mmol) in DMF (15 mL) was added TFAA (1.58 g, 7.5 mmol) dropwise at 0 ° C. The reaction mixture was stirred at 0 ° C for 3 hours, then H2O (50 mL) was added and the mixture was extracted with EtOAc (50 mL x 3). The combined organic layers were washed with (50 mL) brine, dried over Na2SO4, and concentrated in vacuo to give a crude product, which was purified by silica gel column (PE / EtOAc=1 / 1) to provide 1-(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)-2,2,2-trifluoroethane-1-one (400 mg, yield: 50%) as a yellow solid. ESI-MS[M+H]+: 267.0.

[0372] Synthesis of 1-(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)-2,2,2-trifluoroethan-1-ol

[0373]

[0374] To a solution of 1-(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)-2,2,2-trifluoroethan-1-one (50 mg, 0.19 mmol) in MeOH (10 mL) was added NaBH4 (29 mg, 0.77 mmol) at 0 ° C. The reaction mixture was stirred at room temperature for 2 hours, and then H2O (20 mL) was added. The aqueous phase was extracted with EtOAc (30 mL x 3). The combined organic layers were washed with (30 mL x 2) brine, dried over Na2SO4, and concentrated in vacuo to give a crude product, which was purified by preparative TLC (DCM / MeOH=10 / 1) to give 1-(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)-2,2,2-trifluoroethan-1-ol (46 mg, 90.2%) as a white solid. ESI-MS[M+H]+: 269.0.

[0375] Synthesis of 7-chloro-1-(1-chloro-2,2,2-trifluoroethyl)-8-fluoroimidazo[1,5-a]pyridine

[0376]

[0377] To a solution of 1-(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)-2,2,2-trifluoroethan-1-ol (46 mg, 0.17 mmol) in DCM (10 mL) was added SOCl2 (0.5 mL). The resulting mixture was heated to 50 ° C and stirred for 12 hours. The reaction mixture was concentrated in vacuo to give 7-chloro-1-(1-chloro-2,2,2-trifluoroethyl)-8-fluoroimidazo[1,5-a]pyridine (49 mg crude product), which was used in the next step without further purification (49 mg crude product). ESI-MS [M+H] +: 288.1

[0378] 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

[0379]

[0380] To a solution of (1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methanamine (46 mg, 0.17 mmol) and triethylamine (174 mg, 1.72 mmol) in DCM (5 mL) was added 7-chloro-1-(1-chloro-2,2,2-trifluoroethyl)-8-fluoroimidazo[1,5-a]pyridine (46 mg, 0.16 mmol) at 0 ° C. The reaction mixture was stirred at room temperature for 1 hour. The resulting mixture was poured into HO (20 mL) and extracted with DCM (25 mL x 3). The combined organic layers were washed with brine (30 mL x 2), dried over Na2SO4, and concentrated in vacuo to give the crude product, which was purified by preparative HPLC to afford 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 (6 mg, 7%) as a white solid. ESI-MS [M+H]+: 519.1.

[0381] 1H NMR (400MHz, DMSO) δ8.39(d,J=7.5Hz,1H),8.35(s,1H),7.86(s,1H),7.78(s,1H),7.60(s,1H),7.40(d,J=9.3Hz,1H),7.01(d,J=9.4Hz, 1H), 6.89 (t, J = 7.0Hz, 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).

[0382] Example 3

[0383] 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)

[0384] Option 3

[0385]

[0386] Synthesis of 7-chloro-8-fluoroimidazo[1,5-a]pyridine-1-carboxylic acid

[0387]

[0388] To a solution of 7-chloro-8-fluoroimidazo[1,5-a]pyridine-1-carboxaldehyde (0.3 g, 1.5 mmol) in H2O (5 mL) and t-BuOH (10 mL) was added NaH2PO4 (0.4 g, 3.0 mmol) and NaClO2 (0.3 g, 3.0 mmol). The mixture was stirred at room temperature for 48 hours. Water (30 mL) was added and the mixture was extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, concentrated and purified by silica gel chromatography (DCM / MeOH=10 / 1) to give 7-chloro-8-fluoroimidazo[1,5-a]pyridine-1-carboxylic acid (0.15 g, yield: 46.6%) as a white solid. ESI-MS[M+H] + :215.0.

[0389] 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

[0390]

[0391] To a solution of 7-chloro-8-fluoroimidazo[1,5-a]pyridine-1-carboxylic acid (60 mg, 0.28 mmol) in DMF (5 mL) was added (1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methanamine (75 mg, 0.28 mmol), HOBt (56.7 mg, 0.42 mmol), EDCI (80.6 mg, 0.42 mmol) and DIPEA (108.4 mg, 0.84 mmol). The mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated in vacuo to give the 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-carboxamide (30 mg, yield: 23.1%) as a white solid. ESI-MS [M+H]+: 465.1.

[0392] 1H NMR (400MHz, DMSO) δ8.63(t,J=6.0Hz,1H),8.58(d,J=1.5Hz,1H),8.40–8.31(m,2H),8.19(s,1H),7.92(s,1H),7.81(s,1H),7.40 (d,J=9.3Hz,1H),6.94–7.06(m,2H),5.63(s,2H),4.50(d,J=6.0Hz,2H),1.84–1.98(m,1H),0.97–0.86(m,2H),0.73–0.62(m,2H).

[0393] Example 4

[0394] 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)

[0395] Option 4

[0396]

[0397] Synthesis of N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-sulfonamide

[0398]

[0399] To a solution of (7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride (1.06 g, 5.3 mmol) and DIPEA (1.33 mL, 7.5 mmol) in THF (15 mL) was added a solution of 1H-pyrazole-4-sulfonyl chloride (250 mg, 1.5 mmol) in DMSO (5 mL) at 0° C. The reaction mixture was stirred at 0° C. for 1 hour. Water (30 mL) was added and the mixture was extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo to give a crude product, which was purified by silica gel chromatography (eluent: DCM / MeOH=10 / 1) to give N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-sulfonamide (70 mg, yield: 14.2%) as a yellow solid, ESI-MS [M+H]+: 330.2

[0400] 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

[0401]

[0402] A mixture of N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-sulfonamide (70 mg, 0.21 mmol), 2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine (43 mg, 0.21 mmol) and CsCO (205 mg, 0.63 mmol) in DMF (10 mL) was stirred at room temperature for 12 hours. Water (25 mL) was added and the mixture was extracted with EtOAc (40 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo 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-pyrazole-4-sulfonamide (7 mg, 6.7%) as a white solid. ESI-MS [M+H]+: 500.1, purity: 99.75% (214 nm), 99.89% (254 nm).

[0403] 1H NMR (400MHz, DMSO) δ8.41(d,J=2.3Hz,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=9.3Hz,1H),7.01(d d,J=9.4,1.7Hz,1H),6.75(t,J=8.0Hz,1H),5.42(s,2H),4.23(d,J=5.5Hz,2H),1.97–1.87(m,1H),0.95–0.90(m,2H),0.70–0.66(m,2H).

[0404] Example 5

[0405] 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)

[0406] Option 5

[0407]

[0408] Synthesis of ((Benzylthio)ethynyl)trimethylsilane

[0409]

[0410] To a solution of ethynyltrimethylsilane (9.8 g, 100 mmol) in anhydrous Et2O (150 mL) was slowly added n-BuLi (42 mL, 2.4 M solution in hexane, 100.8 mmol) at -78 ° C. The reactant was stirred at -78 ° C for 15 minutes. S (3.2 g, 100 mmol) was then added and the reaction mixture was stirred at -78 ° C for another 15 minutes. The reactant was warmed to room temperature and stirred for 1 hour until S was consumed, and then cooled to 0 ° C. BnBr (17.1 g, 100 mmol) was added and the resulting mixture was stirred at room temperature for 14 hours. The reactant was concentrated in vacuo to give a crude product, which was purified by silica gel chromatography (eluent: PE) to give ((benzylthio)ethynyl)trimethylsilane (20 g, 91%) as a yellow oil. 1H NMR (400MHz, CDCl3) δ7.25–7.13 (m, 5H), 3.80 (s, 2H), 0.00 (s, 9H).

[0411] Synthesis of benzyl(ethynyl)sulfane

[0412]

[0413] To a solution of ((benzylthio)ethynyl)trimethylsilane (20 g, 90.9 mmol) in THF (50 mL) was added TBAF (75 mL, 1 M solution in THF, 75 mmol). The resulting solution was stirred at room temperature for 12 hours. The reaction was quenched with saturated aqueous NH4Cl (100 mL) and extracted with Et2O (100 mL x 2). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo to give benzyl(ethynyl)sulfane, which was used in the next step without further purification. (12 g, crude yield: 91%)

[0414] 1H NMR (400MHz, CDCl3) δ7.35–7.26(m,5H),3.96(s,2H),2.82(s,1H).

[0415] Synthesis of benzyl(ethynyl)sulfane

[0416]

[0417] To a solution of benzyl(ethynyl)sulfane (4 g, 27 mmol) and 2-(azidomethyl)-6-cyclopropylimidazo[1,2-a]pyridine (6.9 g, 32.4 mmol) in tBuOH / H2O (40 mL / 40 mL) was added CuSO4 (2.1 g, 13.2 mmol) and sodium ascorbate (2.61 g, 13.2 mmol). The reaction was stirred at room temperature for 12 hours. H2O (150 mL) was added and the mixture was extracted with DCM (150 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo to give a crude product, which was purified by silica gel chromatography (DCM / MeOH=15 / 1) to give 2-((4-(benzylthio)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridine (3.5 g, 36%) as a black solid. ESI-MS [M+H]+: 362.2

[0418] Synthesis of 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-sulfonyl chloride

[0419]

[0420] To a solution of 2-((4-(benzylthio)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridine (500 mg.1.39 mmol) in AcOH / H2O (15 mL / 5 mL) was added NCS (197 mg, 1.39 mmol). The reactants were stirred at room temperature for 2 hours. Additional NCS (197 mg, 1.39 mmol) was added to the reactants. The resulting reaction mixture was stirred for an additional 3 hours. The mixture was concentrated in vacuo to give a crude product, which was used in the next step without further purification (650 mg, crude product). ESI-MS[M+H]+: 338.0

[0421] 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

[0422]

[0423] To a mixture of (7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride (100 mg, 0.42 mmol) and DIPEA (774 mg, 6 mmol) in anhydrous THF (15 mL) was added 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-sulfonyl chloride (650 mg crude product from the previous step) in 5 mL of THF at 0 ° C. The reaction was stirred at room temperature for 1 hour. Water (50 mL) was added and the mixture was extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo to give a crude product, which was purified by preparative HPLC to afford 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)

[0424] 1H NMR (400MHz, DMSO) δ8.70(s,1H),8.58(s,1H),8.37(s,1H),7.88(s,1H),7.39(d,J=9.3Hz,1H),7.20–7.10(m,2H),7.03–7.00(m,2H) ,6.85(d,J=3.6Hz,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).

[0425] Example 6

[0426] 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)

[0427] Option 6

[0428]

[0429] Synthesis of 7-chloro-8-fluoro-1-iodoimidazo[1,5-a]pyridine

[0430]

[0431] A mixture of 7-chloro-8-fluoroimidazo[1,5-a]pyridine (1.7 g, 10 mmol), NIS (2.5 g, 11 mmol) and TFA (342 mg, 3.0 mmol) in MeCN (15 mL) was stirred at 60 ° C for 4 hours. The reactant was cooled to 0 ° C, quenched with saturated NaHCO3 aqueous solution (50 mL), and extracted with DCM (50 mL x 3). The combined organic layer was washed with brine (30 mL), dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography (MeOH / DCM=1 / 20) to give 7-chloro-8-fluoro-1-iodoimidazo[1,5-a]pyridine (1.5 g, yield: 50%) as a yellow oil. ESI-MS[M+H]+: 297.0.

[0432] Synthesis of 7-chloro-8-fluoro-1-((4-methoxybenzyl)thio)imidazo[1,5-a]pyridine

[0433]

[0434] A mixture of 7-chloro-8-fluoro-1-iodoimidazo[1,5-a]pyridine (1.18 g, 4.0 mmol), (4-methoxyphenyl)methanethiol (0.74 g, 4.8 mmol), Xantphos (116 mg, 0.2 mmol), Pd2(dba)3 (183 mg, 0.2 mmol) and DIPEA (1.03 g, 8.0 mmol) in dioxane (15 mL) was stirred at 100° C. for 18 hours. The reaction was cooled to room temperature, diluted with water (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over NaSO, and concentrated in vacuo to give a crude product, which was purified by silica gel chromatography (eluent: MeOH / DCM = 1 / 20) to give 7-chloro-8-fluoro-1-((4-methoxybenzyl)thio)imidazo[1,5-a]pyridine (1.2 g, yield: 93%) as a yellow oil. ESI-MS [M+H]+: 323.0.

[0435] Synthesis of 7-chloro-8-fluoroimidazo[1,5-a]pyridine-1-sulfonyl chloride

[0436]

[0437] 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 another 2 hours. The reactant was then quenched with saturated NaHCO3 aqueous solution (50 mL) and extracted with DCM (50 mL x 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 product) as a brown oil, which was used directly in the next step without further purification. ESI-MS[M+H] + :269.0.

[0438] 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

[0439]

[0440] A mixture of 7-chloro-8-fluoroimidazo[1,5-a]pyridine-1-sulfonyl chloride (150 mg, 0.56 mmol), (1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methanamine (150 mg, 0.56 mmol) and DIPEA (217 mg, 1.68 mmol) in DMF (100 mL) was stirred at room temperature for 18 hours. The reaction was quenched with saturated aqueous NaHCO3 (30 mL) and extracted with EtOAc (30 mL x 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 light yellow solid. ESI-MS [M+H] + :501.1.

[0441] 1H NMR (400MHz, DMSO) δ8.60(s,1H),8.43–8.34(m,2H),8.22(s,1H),7.82(d,J=7.9Hz,2H),7.43(d,J=9.2Hz, 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).

[0442] Example 7

[0443] 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)

[0444]

[0445] Synthesis of 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

[0446] To a solution of 1-(1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)ethyl-1-amine (70 mg, 0.248 mmol) and triethylamine (75 mg, 0.743 mmol) in DMF (3 mL) was added a solution of 7-chloro-8-fluoroimidazo[1,5-a]pyridine-1-sulfonyl chloride (100 mg, 0.373 mmol) in 3 mL of DMF at 0 ° C. The reaction mixture was stirred at room temperature for 8 hours. Water (30 mL) was added and the mixture was extracted with EtOAc (50 mL x 3). The combined organic layer was washed with brine (30 mL), dried over Na2SO4, and concentrated to give a crude product. It was purified by preparative HPLC to give 7-chloro-N-(1-(1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)ethyl)-8-fluoroimidazo[1,5-a]pyridine-1-sulfonamide[1,5-a]pyridine-1-sulfonamide (5.4 mg, yield: 4.3%) as a white solid. ESI-MS: [M+H] + , 515.1, purity: 97.25% (214nm); 98.25% (254nm).

[0447] 1H NMR (400MHz, DMSO) δ8.52(d,J=2.1Hz,1H),8.37-8.35(m,2H),8.19(d,J=8.5Hz,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=7.0Hz,3H),0.94-0.91(m,2H),0.71-0.67(m,2H).

[0448]

[0449] Synthesis of 1-(1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)ethan-1-ol

[0450]

[0451] To a mixture of 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carbaldehyde (2.0 g, 7.5 mmol) in THF (30 mL) was added MeMgBr (30.0 mL, 30.0 mmol) at 0 ° C. The mixture was stirred at 0 ° C for 1 hour. The reaction mixture was then quenched with saturated NH4Cl aqueous solution (50 mL) and extracted with EtOAc (30 mL x 5). The combined organic layer was washed with brine (30 mL), dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography (MeOH / DCM 0% to 5%) to give 1-(1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)ethan-1-ol (1.5 g, yield: 71%) as a yellow oil. ESI-MS [M+H] + :284.1

[0452] Synthesis of 2-((4-(1-chloroethyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridine

[0453]

[0454] To a mixture of 1-(1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)ethan-1-ol (500 mg, 1.77 mmol) in DCM (10 mL) was added SOCl2 (1.0 mL) at 0°C and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated to give crude 2-((4-(1-chloroethyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridine (600 mg, crude) as a yellow oil, which was used directly in the next step without further purification. ESI-MS [M+H] + :302.1

[0455] Synthesis of 2-((4-(1-azidoethyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridine

[0456]

[0457] A mixture of 2-((4-(1-chloroethyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridine (600mg, crude product) and NaN3(344mg, 5.30mmol) in DMF (10mL) was stirred at room temperature for 16 hours. The reaction mixture was diluted with water (100mL) and extracted with EtOAc (50mL x 3). The combined organic layers were washed with brine (30mL), dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography (MeOH / DCM 0% to 3%) to give 2-((4-(1-azidoethyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridine (250mg, yield: 46% over 2 steps) as a yellow oil. ESI-MS[M+H] + :309.2.

[0458] Synthesis of 1-(1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)ethan-1-amine

[0459]

[0460] 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 under a hydrogen atmosphere for 18 hours. After completion, the reaction mixture was filtered and the filtrate was concentrated to give crude 1-(1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)ethan-1-amine (150 mg, yield: 66%) as a yellow oil, which was used directly in the next step without further purification. ESI-MS [M+H] + :283.2

[0461] Example 8

[0462] 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)

[0463] Option 8

[0464]

[0465] Synthesis of 1-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)prop-2-en-1-ol

[0466]

[0467] To a mixture of 6-cyclopropylimidazo[1,2-a]pyridine-2-carboxaldehyde (1.86 g, 10.0 mmol) in THF (30 mL) was added vinylmagnesium bromide (15 mL, 15.0 mmol) and the temperature was maintained at -60 ° C. The reaction mixture was stirred at -60 ° C for 2 hours, then quenched with saturated NH4Cl aqueous solution (100 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4 and concentrated to give 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-ene-1-ol (1.6 g, yield: 75%) as a light yellow solid. ESI-MS [M+H] +: 215.2.

[0468] Synthesis of methyl 2-(3-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)-3-oxopropyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylate

[0469]

[0470] A mixture of 1-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)prop-2-en-1-ol (1.2 g, 5.6 mmol), 2-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylic acid methyl ester (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) was degassed with N2 and stirred at 120 ° C for 18 hours. The reaction mixture was cooled to room temperature and water (100 mL) was added. The mixture was extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL) and concentrated in vacuo 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 (900 mg, yield: 34%) as an off-white solid. ESI-MS [M+H]+: 468.2.

[0471] Synthesis of methyl 2-(3-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)-3-oxopropyl)-1H-imidazole-4-carboxylate

[0472]

[0473] A mixture of methyl 2-(3-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)-3-oxopropyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylate (500 mg, 1.07 mmol) in TFA / DCM (3.5 mL / 10 mL) was stirred at 50 ° C for 5 hours. The reaction mixture was cooled to room temperature and concentrated to give a residue, which was diluted with saturated aqueous NaHCO (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, and concentrated in vacuo to give a crude product, which was purified by flash column chromatography (eluent: DCM / MeOH = 15 / 1) to give methyl 2-(3-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)-3-oxopropyl)-1H-imidazole-4-carboxylate (300 mg, yield: 83%) as a yellow solid. ESI-MS [M+H]+: 338.1.

[0474] Synthesis of 2-(3-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)-3-hydroxypropyl)-1H-imidazole-4-carboxylic acid methyl ester

[0475]

[0476] To a solution of methyl 2-(3-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)-3-oxopropyl)-1H-imidazole-4-carboxylate (0.3 g, 0.89 mmol) in MeOH (15 mL) was slowly added NaBH4 (67 mg, 1.78 mmol) at 0 ° C. The reaction mixture was stirred at room temperature for 2 hours. Water (50 mL) was added and the mixture was extracted with DCM / MeOH (10 / 1, 30 mL x 3). The combined organic layers were washed with brine (20 mL) and concentrated in vacuo to give a crude product, which was purified by flash column chromatography (eluent: DCM / MeOH=8 / 1) to give methyl 2-(3-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)-3-hydroxypropyl)-1H-imidazole-4-carboxylate (220 mg, yield: 73%) as a white solid. ESI-MS [M+H]+: 341.1.

[0477] Synthesis of 5-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-2-carboxylic acid methyl ester

[0478]

[0479] To a mixture of methyl 2-(3-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)-3-hydroxypropyl)-1H-imidazole-4-carboxylate (100 mg, 0.29 mmol) and PPh (152 mg, 0.58 mmol) in THF (5 mL) was added DIAD (118 mg, 0.58 mmol) at 0 ° C. The mixture was warmed to room temperature and stirred for 3 hours. The reactant was diluted with water (30 mL) and extracted with DCM / MeOH (10 / 1, 30 mL x 3). The combined organic layers were washed with brine (30 mL) and concentrated to give a crude product, which was purified by flash column chromatography (eluent: DCM / MeOH = 10 / 1) to give methyl 5-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-2-carboxylate (25 mg, yield: 26%) as a colorless oil. ESI-MS [M+H] +: 323.1.

[0480] Synthesis of 5-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-2-carboxylic acid

[0481]

[0482] A mixture of methyl 5-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-2-carboxylate (25 mg, 0.078 mmol) and LiOH.HO (16 mg, 0.390 mmol) in EtOH / THF / HO (1.5 mL / 1.5 mL / 0.5 mL) was stirred at 35 ° C. for 18 hours. The reaction mixture was adjusted to pH 5 by adding HCl (1 N) and concentrated to give 5-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-2-carboxylic acid (40 mg, crude) as a white solid, which was used in the next step without further purification. ESI-MS [M+H] +: 309.2.

[0483] 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

[0484]

[0485] A mixture of 5-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-2-carboxylic acid (40 mg, 0.13 mmol crude), (7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride (30 mg, 0.13 mmol), HOBT (17.5 mg, 0.13 mmol), EDCI (25 mg, 0.13 mmol) and DIPEA (50 mg, 0.39 mmol) in DMF (1 mL) was stirred at room temperature for 18 hours. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (10 mL×3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, and concentrated in vacuo to give a crude product, which was purified by preparative HPLC to afford 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 (10 mg, yield: 15.7%) as a white solid. ESI-MS [M+H]+: 490.2.

[0486] 1H NMR (400MHz, DMSO) δ8.45(d,J=2.4Hz,1H),8.32(s,1H),8.21(d,J=7.4Hz,1H),7. 96(t,J=5.4Hz,1H),7.73(s,1H),7.45(s,1H),7.41(d,J=9.3Hz,1H),7.02-6.99( m,1H),6.76–6.74(m,1H),5.58-5.54(m,1H),4.66(d,J=5.4Hz,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).

[0487] Synthesis of methyl 2-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylate (Compound 3)

[0488]

[0489] Synthesis of methyl 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylate

[0490] To a stirred solution of 1H-imidazole-4-formyl ester (4 g, 31.75 mmol) in anhydrous DMF (75 mL) was added NaH (1.46 g, 60% suspension in paraffin oil, 36.5 mmol) at 0 ° C. The reaction mixture was stirred at 0 ° C for 30 minutes and then treated dropwise with (2- (chloromethoxy) ethyl) trimethylsilane (6.32 g, 38.1 mmol). The reaction was allowed to warm to room temperature and stirred for 18 hours. The reaction was quenched with ice water (80 mL) and extracted with EtOAc (80 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, and concentrated in vacuo to give the crude product, which was purified by silica gel chromatography (eluent: MeOH / DCM = 1 / 20) to provide methyl 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylate (6.8 g, yield: 84%) as a white solid. ESI-MS [M+H]+: 257.2.

[0491] Synthesis of methyl 2-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylate

[0492]

[0493] To a stirred solution of 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylic acid methyl ester (5.0 g, 19.5 mmol) in carbon tetrachloride (50 mL) was added NBS (3.47 g, 19.5 mmol) and AIBN (160 mg, 5 mol%) at room temperature. The reaction mixture was stirred at 60 ° C for 3 hours, then cooled to room temperature and filtered through a small celite pad. The filtrate was concentrated in vacuo to give a light yellow residue, which was dissolved in EtOAc (100 mL) and washed with 10% NaHCO (100 mL) aqueous solution. The organic layer was washed with brine (70 mL), dried over Na SO and concentrated to give the crude compound. The crude material was purified by silica gel chromatography (eluent: PE / EtOAc=2 / 1) to provide methyl 2-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylate (4 g, yield: 61.5%). ESI-MS [M+H]+: 355.2.

[0494] Example 9

[0495] 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)

[0496] Option 9

[0497]

[0498] Synthesis of methyl 2-(3-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)-3-((methylsulfonyl)oxy)propyl)-1H-imidazole-4-carboxylate

[0499]

[0500] To a solution of methyl 2-(3-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)-3-hydroxypropyl)-1H-imidazole-4-carboxylate (200 mg, 0.59 mmol) in DCM (4 mL) was added triethylamine (119.3 mg, 1.18 mmol) and MsCl (101.2 g, 0.88 mmol) at 0°C. After stirring at 0°C for 2 hours, the reaction was concentrated in vacuo to give methyl 2-(3-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)-3-((methylsulfonyl)oxy)propyl)-1H-imidazole-4-carboxylate (240 mg, yield: 98%) as a black solid, which was used in the subsequent step without further purification. ESI-MS [M+H] + :419.1.

[0501] Synthesis of 5-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-3-carboxylic acid methyl ester

[0502]

[0503] A mixture of methyl 2-(3-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)-3-((methylsulfonyl)oxy)propyl)-1H-imidazole-4-carboxylate (240 mg, 0.57 mmol) and CsCO(557 mg, 1.71 mmol) in DMF (15 mL) was stirred at room temperature for 12 hours. Water (30 mL) was added and the mixture was extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine, dried over NaSO, and concentrated in vacuo to give a crude product, which was purified by silica gel chromatography (EtOAc / PE=1 / 1) to give methyl 5-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-3-carboxylate (102 mg, yield: 55.7%) as a yellow solid. ESI-MS[M+H] + :323.1.

[0504] Synthesis of 5-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-3-carboxylic acid

[0505]

[0506] To a solution of 5- (6- cyclopropylimidazo [1,2-a] pyridin-2-yl) -6,7- dihydro -5H- pyrrolo [1,2-a] imidazole -3- carboxylic acid methyl ester (102 mg, 0.32 mmol) in MeOH (1 mL) and THF (1 mL) was added LiOH (31.6 mg, 1.32 mmol) and H o (0.5 mL). The reaction mixture was stirred at room temperature for 12 hours. The mixture was adjusted to pH 5 with 1N HCl and then extracted with EtOAc (30 mL x 3). The combined organic layers were concentrated to give 5- (6- cyclopropylimidazo [1,2-a] pyridin-2-yl) -6,7- dihydro -5H- pyrrolo [1,2-a] imidazole -3- carboxylic acid (65 mg, yield: 67%) as a white solid, which was used in subsequent steps without further purification. ESI-MS [M+H]+: 309.1.

[0507] 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

[0508]

[0509] To a solution of 5-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-3-carboxylic acid (65 mg, 0.21 mmol) in DMF (2 mL) was added (7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride (64.7 mg, 0.27 mmol), HATU (102.6 mg, 0.27 mmol) and DIPEA (387 mg, 3.0 mmol). The reaction mixture was stirred at room temperature for 4 hours. Water (20 mL) was added and the mixture was extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over NaSO, filtered, and concentrated to give a crude product, which was purified by preparative HPLC to afford N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-5-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-2-carboxamide (32 mg, 50% yield) as a white solid. ESI-MS [M+H]: 490.2. Purity: 98.98% (214 nm), 99.54% (254 nm).

[0510] 1H NMR (400MHz, DMSO) δ8.48(t,J=5.3Hz,1H),8.43(d,J=2.4Hz,1H),8.26(s,1H),8.19(d,J=7 .4Hz,1H),7.58(s,1H),7.41(s,1H),7.34(d,J=9.3Hz,1H),6.98-6.95(m,1H),6.78–6.71( m,1H),5.86(d,J=7.6Hz,1H),4.68-4.65(m,1H),4.51-4.46(m,1H),3.02-2.88(m,2H),2.8 1–2.71(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).

[0511] Example 10

[0512] 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)

[0513]

[0514] To a solution of 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylic acid (60 mg, 0.21 mmol), 1-(aminomethyl)imidazo[1,5-a]pyridine-7-carbonitrile (55 mg, 0.32 mmol) and HATU (120 mg, 0.31 mmol) in DMF (2 mL) was added DIPEA (81 mg, 0.63 mmol). The resulting reaction was stirred at room temperature for 12 hours. H O (25 mL) was added and the mixture was extracted with EtOAc (15 mL x 3). The combined organic layers were washed with brine (15 mL), dried over Na2SO4, and concentrated in vacuo to give a crude product, which was purified by preparative TLC (DMC / MeOH=10 / 1) to give N-((7-cyanoimidazolo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (22 mg, yield: 24%) as a white solid. ESI-MS [M+H]+: 437.2.

[0515] 1H NMR(400MHz,DMSO)δ8.65(t,J=5.7Hz,1H),8.50(s,1H),8.44(s,1H),8.4 0-8.37(m,1H),8.32(s,1H),8.21(s,1H),7.86(s,1H),7.72(s,1H),7.39( d,J=9.3Hz,1H),7.01-6.97(m,1H),6.85-6.81(m,1H),5.39(s,2H),4.63( d,J=5.7Hz,2H),1.94–1.88(m,1H),0.93–0.88(m,2H),0.68–0.64(m,2H).

[0516] Example 11

[0517] 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)

[0518] Plan 11

[0519]

[0520] Synthesis of (1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methanol

[0521]

[0522] To a solution of ethyl 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate (10.0 g, 33.7 mmol) in THF (100 mL) was added DIBAL-H (67.3 mL, 67.3 mmol) at -60 ° C. The mixture was stirred at room temperature for 3 hours, then quenched with saturated aqueous NaHCO solution (300 mL) and extracted with EtOAc (150 mL x 3). The combined organic layers were washed with brine (200 mL), dried over Na SO, and concentrated in vacuo. The residue was purified by flash column chromatography (PE / EtOAc 0% to 20%) to give (1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methanol (7.5 g, yield: 82%) as an off-white solid. ESI-MS [M+H] + :270.1

[0523] Synthesis of 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carbaldehyde

[0524]

[0525] A mixture of (1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methanol (300 mg, 1.12 mmol) and MnO2 (963 mg, 11.2 mmol) in DCM (10 mL) was stirred at room temperature for 18 hours. The reaction mixture was then filtered and concentrated in vacuo to give 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carbaldehyde (220 mg, yield: 74%) as a yellow solid, which was used in the next step without purification. ESI-MS [M+H] + :268.1

[0526] 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

[0527]

[0528] A mixture of 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carbaldehyde (100mg, 0.37mmol), (7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methylamine hydrochloride (88mg, 0.37mmol) and triethylamine (37mg, 0.37mmol) in MeOH (5mL) was stirred at room temperature for 16 hours. NaBH(OAc) was added (157mg, 0.74mmol) and the mixture was stirred at room temperature for another 2 hours. The reactant was quenched with water (50mL) and extracted with ethyl acetate (30mL x 3). The combined organic layer was washed with brine (30mL), dried over NaSO, and concentrated in vacuo. The residue was purified by preparative TLC (MeOH / DCM=1 / 15) to give 1-(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)-N-((1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methyl)methanamine (5.5 mg, yield: 3.3%) as a white solid. ESI-MS [M+H]+: 451.1.

[0529] 1H NMR (400MHz, DMSO) δ8.44(d,J=2.1Hz,1H),8.34(s,1H),8.19(d,J=7.4Hz,1H),7.92(s,1H),7.79(s,1H),7.41(d,J=9.3Hz,1H),7.00(d ,J=9.4Hz,1H),6.73(t,J=6.9Hz,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).

[0530] Example 12

[0531] 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)

[0532] Plan 12

[0533]

[0534] Synthesis of 1-(1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)ethan-1-ol

[0535]

[0536] To a mixture of 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carbaldehyde (2.0 g, 7.5 mmol) in THF (30 mL) was added MeMgBr (30.0 mL, 30.0 mmol) at 0 ° C. The mixture was stirred at 0 ° C for 1 hour. The reaction mixture was then quenched with saturated NH4Cl aqueous solution (50 mL) and extracted with EtOAc (30 mL x 5). The combined organic layer was washed with brine (30 mL), dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography (MeOH / DCM 0% to 5%) to give 1-(1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)ethan-1-ol (1.5 g, yield: 71%) as a yellow oil. ESI-MS [M+H] + :284.1

[0537] Synthesis of 2-((4-(1-chloroethyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridine

[0538]

[0539] To a mixture of 1-(1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)ethan-1-ol (500 mg, 1.77 mmol) in DCM (10 mL) was added SOCl2 (1.0 mL) at 0°C and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated to give crude 2-((4-(1-chloroethyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridine (600 mg, crude) as a yellow oil, which was used directly in the next step without further purification. ESI-MS [M+H] + :302.1

[0540] Synthesis of 2-((4-(1-azidoethyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridine

[0541]

[0542] A mixture of 2-((4-(1-chloroethyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridine (600mg, crude product) and NaN3(344mg, 5.30mmol) in DMF (10mL) was stirred at room temperature for 16 hours. The reaction mixture was diluted with water (100mL) and extracted with EtOAc (50mL x 3). The combined organic layers were washed with brine (30mL), dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography (MeOH / DCM 0% to 3%) to give 2-((4-(1-azidoethyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridine (250mg, yield: 46% over 2 steps) as a yellow oil. ESI-MS[M+H] + :309.2

[0543] Synthesis of 1-(1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)ethan-1-amine

[0544]

[0545] 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 under a hydrogen atmosphere for 18 hours. After completion, the reaction mixture was filtered and the filtrate was concentrated to give crude 1-(1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)ethan-1-amine (150 mg, yield: 66%) as a yellow oil, which was used directly in the next step without further purification. ESI-MS [M+H] + :283.2

[0546] Synthesis of N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-(1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)ethan-1-amine.

[0547]

[0548] To a solution of 1-(1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)ethyl-1-amine (80 mg, 0.284 mmol) in MeOH (4 mL) was added 7-chloro-8-fluoroimidazo[1,5-a]pyridine-1-carbaldehyde (51 mg, 0.256 mmol) and triethylamine (57.5 mg, 0.568 mmol). The mixture was stirred at room temperature for 4 hours. NaBH4 (11 mg, 0.291 mmol) was added and the reaction mixture was stirred at room temperature for another 3 hours. Water (40 mL) was added and the mixture was extracted with EA (30 ml x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4 and concentrated. The crude product was purified by preparative TLC (DCM:MeOH=10:1) to give N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-(1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)ethan-1-amine (18 mg, yield: 13.6%) as a yellow solid. ESI-MS [M+H]+: 465.2

[0549] 1H NMR (400MHz, DMSO) δ8.42(d,J=2.4Hz,1H),8.35(s,1H),8.17(d,J=7.4Hz,1H),7.90(s,1H),7.79(s,1H),7.42(d,J=9.3Hz,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=6.6Hz,3H),0.95–0.89(m,2H),0.70–0.64(m,2H).

[0550] Example 13

[0551] 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)

[0552] 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

[0553]

[0554] A mixture of 1-(1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)ethan-1-amine (37.1 mg, 0.131 mmol), 2-(7-chloroimidazo[1,5-a]pyridin-1-yl)acetic acid (60 mg, 0.285 mmol), HATU (100.07 mg, 0.263 mmol), DIPEA (114.2 mg, 0.885 mmol) in DMF (4 mL) was stirred at room temperature for 16 hours. Water (50 mL) was added and the mixture was extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (30 mL) and concentrated. The residue was purified by preparative HPLC to give 2-(7-chloroimidazo[1,5-a]pyridin-1-yl)-N-(1-(1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)ethyl)acetamide as a white solid (40 mg, yield: 47.7%). ESI-MS [M+H]+: 475.2.

[0555] 1H NMR(400MHz,DMSO)δ8.45(d,J=8.2Hz,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=9.3Hz,1H),7.05-6.9 8(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=7.0Hz,3H),0.95-0.89(m,2H),0.71-0.65(m,2H).

[0556] Example 14

[0557] 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)

[0558] Plan 14

[0559]

[0560] Synthesis of 1-((8-bromo-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid methyl ester

[0561]

[0562] To a stirred solution of tert-butyl 1-((8-bromo-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate (2.7 g, 6.45 mmol) in MeOH (50 mL) was added concentrated H2SO4 (1 mL) dropwise at room temperature. The mixture was heated at reflux for 16 hours, then cooled to room temperature, diluted with water (50 mL), and concentrated in vacuo to remove MeOH, and the residue was adjusted to pH = 9 to 10 by adding saturated aqueous NaHCO3. The resulting precipitate was collected by filtration and dried in vacuo to give methyl 1-((8-bromo-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate (2.0 g, yield: 82%) as a light brown solid. ESI-MS [M+H] + :376.0.

[0563] Synthesis of (1-((8-bromo-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methanol

[0564]

[0565] To a stirred solution of 1-((8-bromo-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid methyl ester (600mg, 1.59mmol) in MeOH (10mL) and THF (10mL) was added NaBH4 (693mg, 18.32mmol) in batches at 0°C. The mixture was stirred at room temperature for 8 hours, then quenched with saturated NH4Cl aqueous solution (30mL) and concentrated in vacuo to remove MeOH and THF. The residue was extracted with DCM (40mL x 3). The combined organics were washed with brine (80 mL), dried over NaSO, and concentrated to afford (1-((8-bromo-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methanol (500 mg, 91% yield) as a light brown solid, which was used directly in the next step without further purification. ESI-MS [M+H]: 348.0.

[0566] Synthesis of methyl 6-cyclopropyl-2-((4-(hydroxymethyl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridine-8-carboxylate

[0567]

[0568] A mixture of (1-((8-bromo-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methanol (500 mg, 1.44 mmol), Pd(dppf)Cl2 (105 mg, 0.143 mmol) and triethylamine (729 mg, 7.218 mmol) in MeOH (20 mL) was refluxed for 16 hours, then cooled to room temperature and filtered. The filtrate was concentrated and purified by silica gel chromatography (DCM / MeOH=20 / 1) to give methyl 6-cyclopropyl-2-((4-(hydroxymethyl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridine-8-carboxylate (400 mg, yield: 85%) as a yellow solid. ESI-MS [M+H] + :328.1.

[0569] Synthesis of methyl 6-cyclopropyl-2-((4-formyl-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridine-8-carboxylate

[0570]

[0571] A mixture of 6-cyclopropyl-2-((4-(hydroxymethyl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridine-8-carboxylic acid methyl ester (400 mg, 1.22 mmol) and MnO2 (2.12 g, 24.4 mmol) in DCM (15 mL) was stirred at room temperature for 16 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography (DCM / MeOH=20 / 1) to give 6-cyclopropyl-2-((4-formyl-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridine-8-carboxylic acid methyl ester (180 mg, yield: 45%) as a yellow solid. ESI-MS[M+H] + :326.1.

[0572] 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

[0573]

[0574] By 6- cyclopropyl -2- ((4- formyl -1H- 1,2,3- triazol -1- bases) methyl) imidazo [1,2- a] pyridine -8- methyl formate (180mg, 0.553mmol) and (7- chloro- 8- fluoroimidazo [1,5- a] pyridin-1- bases) methylamine (144mg, 0.721mmol) in MeOH (10mL) mixture is stirred at room temperature for 1 hour.NaBH is addedCN (174mg, 2.77mmol) and the reaction mixture is stirred at room temperature for another 3 hours.The reaction mixture is concentrated in a vacuum, then diluted with water (40mL) and extracted with DCM / MeOH (50mL x 3, v / v 10 / 1).The organic matter merged is washed with brine (50mL), through NaSODry and concentrate. The residue was purified by silica gel chromatography (DCM / MeOH=20 / 1) to give methyl 2-((4-((((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)amino)methyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-carboxylate (130 mg, yield: 46%) as a pale solid. ESI-MS [M+H] + :509.2.

[0575] 1 H NMR (400MHz, DMSO) δ8.58(s,1H),8.47(s,1H),8.20(d,J=7.4Hz,1H),8.00(s,1H),7.86(s,1H),7.61(d,J=1.6Hz,1H),6.76(t , J=6.9Hz,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).

[0576] Example 15

[0577] 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)

[0578]

[0579] To a solution of methyl 2-((4-((((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)amino)methyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-carboxylate (110 mg, 0.216 mmol) in THF (4 mL) and water (2 mL) was added lithium hydroxide monohydrate (18 mg, 0.429 mmol). The mixture was stirred at 40 ° C for 1 hour. The reaction mixture was diluted with water (20 mL), acidified to pH = 5 to 6 by adding HCl (2M), and concentrated in vacuo. The residue was purified by preparative HPLC to give 2-((4-((((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)amino)methyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-carboxylic acid (50 mg, yield: 47%) as a white solid. ESI-MS [M+H] + :495.1.

[0580] 1 H NMR (400MHz, DMSO) δ8.59(s,1H),8.48(s,1H),8.21(d,J=7.4Hz,1H),8.16(s,1H),8.08(s,1H),7.92(s,1H),7.66(s,1H) ,6.76(t,J=6.8Hz,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).

[0581] Example 16

[0582] 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)

[0583] Plan 16

[0584]

[0585] Synthesis of (1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazol-4-yl)methanol

[0586]

[0587] To a solution of ethyl 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate (600 mg, 1.94 mmol) in THF (20 mL) was slowly added LiAlH4 (221 mg, 5.81 mmol) at 0 ° C under N2. The mixture was stirred at 0 ° C for 5 hours. The mixture was quenched with Na2SO4-10H2O and diluted with EtOAc (50 mL). The resulting suspension was filtered and the filtrate was concentrated in vacuo to give (1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazol-4-yl)methanol (588 mg, crude product) as a yellow solid, which was used directly in the next step without further purification. ESI-MS [M+H] + :269.2.

[0588] Synthesis of 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carbaldehyde

[0589]

[0590] A mixture of (1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazol-4-yl)methanol (588 mg, 2.19 mmol) and MnO2 (1.7 g, 19.54 mmol) in DCM (20 mL) was stirred at room temperature for 72 hours. The mixture was filtered, and the filtrate was concentrated to give a crude product. The residue was purified by preparative TLC (DCM:MeOH=20:1) to give 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carbaldehyde (365 mg, yield: 63%) as a yellow oil. ESI-MS [M+H] + :267.1.

[0591] Synthesis of 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carbaldehyde

[0592]

[0593] To a solution of 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carbaldehyde (365 mg, 1.37 mmol) and CsF (584 mg, 3.845 mmol) in THF (10 mL) was added trimethyl(trifluoromethyl)silane (312 mg, 2.19 mmol) at room temperature. The mixture was stirred at 60 ° C under nitrogen for 16 hours. The mixture was then diluted with EtOAc (50 mL) and washed with water (30 mL x 3). The organic layer was dried over Na2SO4 and concentrated to give 1-(1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-yl)-2,2,2-trifluoroethane-1-ol (430 mg, yield: 93.5%) as a yellow solid, which was used directly in the next step without further purification. ESI-MS[M+H] + :337.2.

[0594] Synthesis of 2-((4-(1-chloro-2,2,2-trifluoroethyl)-1H-pyrazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridine

[0595]

[0596] To a mixture of 1-(1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazol-4-yl)-2,2,2-trifluoroethane-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) as a yellow solid, which was used directly in the next step without further purification. ESI-MS [M+H] + :355.1.

[0597] Synthesis of 2-((4-(1-azido-2,2,2-trifluoroethyl)-1H-pyrazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridine

[0598]

[0599] A mixture of 2-((4-(1-chloro-2,2,2-trifluoroethyl)-1H-pyrazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridine (450 mg, 1.27 mmol) and NaN3(165 mg, 2.54 mmol) in DMSO (5 mL) was stirred at 80 ° C under N2 for 16 hours. The reaction mixture was then diluted with EtOAc (50 mL) and washed with water (30 mL x 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 (450 mg, crude product) as a yellow solid, which was used directly in the next step without further purification. ESI-MS[M+H] + :362.2.

[0600] Synthesis of 1-(1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazol-4-yl)-2,2,2-trifluoroethan-1-amine

[0601]

[0602] A mixture of 2-((4-(1-azido-2,2,2-trifluoroethyl)-1H-pyrazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridine (450 mg, 1.25 mmol) and Pd / C (50 mg) in anhydrous THF (10.0 mL) was stirred at room temperature under H for 16 hours. Upon completion, the reaction mixture was filtered and the filtrate was concentrated in vacuo to afford (1-(1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazol-4-yl)-2,2,2-trifluoroethan-1-amine (400 mg, crude) as a light yellow oil, which was used directly in the next step without further purification. ESI-MS [M+H]: 336.1.

[0603] 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

[0604]

[0605] A mixture of 1-(1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazol-4-yl)-2,2,2-trifluoroethan-1-amine (50 mg, 0.15 mmol) and 7-chloro-8-fluoroimidazo[1,5-a]pyridine-1-carbaldehyde (29.5 mg, 0.15 mmol) in MeOH / AcOH (5.0 mL / 0.1 mL) was stirred at room temperature for 4 hours. The reaction mixture was then cooled to 0° C. and NaBH 4 (8.6 mg, 0.227 mmol) was added. The reaction mixture was stirred at room temperature for an additional hour, then concentrated in vacuo and purified by preparative HPLC to afford N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-(1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazol-4-yl)-2,2,2-trifluoroethan-1-amine (19.8 mg, yield: 25.49%) as a light yellow solid. ESI-MS [M+H]+: 518.1.

[0606] 1H NMR(400MHz,DMSO)δ8.44(d,J=2.4Hz,1H),8.34(s,1H),8.18(d,J=7.4Hz,1H), 7.81(s,1H),7.69(s,1H),7.48(s,1H),7.41(d,J=9.3Hz,1H),7.00(dd,J=9.4, 1.8Hz,1H),6.78–6.68(m,1H),5.37(s,2H),4.48-4.40(m,1H),3.97-3.87(m,2 H),2.73–2.64(m,1H),1.98–1.86(m,1H),0.99–0.86(m,2H),0.75–0.60(m,2H).

[0607] Example 17

[0608] 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)

[0609] 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)

[0610] Plan 17

[0611]

[0612] 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

[0613]

[0614] A mixture of (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), Pd(dba) (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) was stirred at 90 ° C for 8 hours. The reaction mixture was cooled to room temperature, diluted with water (100 mL) and extracted with EtOAc (50 mL x 4). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, and concentrated in vacuo. The crude product was purified by flash column chromatography (PE / EtOAc 0% to 30%) to give (E)-ethyl 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.

[0615] 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

[0616]

[0617] To a solution of (E)-3-(6-cyclopropyl-2-((4-(hydroxymethyl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-8-yl)ethyl acrylate (400 mg, 1.09 mmol) in MeOH (10 mL) was added CuCl (162 mg, 1.63 mmol) and NaBH4 (245 mg, 6.48 mmol) at 0 ° C. The mixture was stirred at 0 ° C for 1 hour, then quenched with water (50 mL) and extracted with EtOAc (40 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, and concentrated in vacuo. The crude product was dissolved in DCM (10 mL). MnO2 (1.9 g, 21.8 mmol) was added and the mixture was stirred at room temperature for 18 hours, then filtered and concentrated in vacuo. The residue was purified by flash column chromatography (PE / EtOAc 0% to 20%) to give ethyl 3-(6-cyclopropyl-2-((4-formyl-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-8-yl)propanoate (160 mg, yield: 40%) as a colorless oil.

[0618] Synthesis of ethyl 3-(2-((4-((((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)amino)methyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)propanoate

[0619]

[0620] To a mixture of ethyl 3-(6-cyclopropyl-2-((4-formyl-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-8-yl)propanoate (160 mg, 0.44 mmol) and (7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methylamine hydrochloride (87 mg, 0.44 mmol) in EtOH (10 mL) was added a drop of AcOH. The reaction mixture was stirred at room temperature for 18 hours. NaBH (50 mg, 1.32 mmol) was added and the mixture was stirred at room temperature for another 2 hours. The reactant was quenched with saturated NH4Cl aqueous solution (50 mL) and extracted with EtOAc (30 mL x 3). The combined organic layer was washed with brine (30 mL), dried over Na2SO4 and concentrated. The residue was purified by preparative HPLC to give ethyl 3-(2-((4-((((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)amino)methyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)propanoate (120 mg, 50% yield) as a white solid. ESI-MS [M+H]+: 551.2.

[0621] 1H NMR (400MHz, DMSO) δ8.44(d,J=2.4Hz,1H),8.21(d,J=1.3Hz,1H),8.18(d,J=7.4Hz, 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=7.1Hz,2H),3.92(s,2H),3.74(s,2H),3.07(t,J=7.6Hz,2H),2.77(t,J=7.7Hz,2 H),1.92-1.84(m,1H),1.13(t,J=7.1Hz,3H),0.93–0.87(m,2H),0.68–0.62(m,2H).

[0622] 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

[0623]

[0624] A mixture of ethyl 3-(2-((4-((((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)amino)methyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)propanoate (90 mg, 0.16 mmol) and LiOH.HO (21 mg, 0.50 mmol) in EtOH / THF / HO (3 mL / 3 mL / 2 mL) was stirred at room temperature for 2 hours. The reaction mixture was adjusted to pH approximately 5 by the addition of HCl (2 M) and concentrated in vacuo. The residue was purified by preparative HPLC to give 3-(2-((4-((((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)amino)methyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)propanoic acid (60 mg, 71.5% yield) as a white solid. ESI-MS [M+H]+: 523.2. Purity: 95.01 (214 nm), 95.35 (254 nm).

[0625] 1H NMR (400MHz, DMSO) δ8.44(d,J=2.3Hz,1H),8.18(d,J=7.4Hz,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=7.7Hz,2H),2.36(t,J=7.7Hz,2H),1.90-1.81(m,1H),0.91–0.85(m,2H),0.67–0.61(m,2H).

[0626] Example 18

[0627] 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)

[0628] Plan 18

[0629]

[0630] Synthesis of tert-butyl (6-cyclopropyl-2-((4-(hydroxymethyl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-8-yl)carbamate

[0631]

[0632] To a solution of (1-((8-bromo-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methanol (450 mg, 1.3 mmol) in dioxane (10 mL) was added NH2Boc (227.6 mg, 1.95 mmol), Pd(OAc)2 (29.1 mg, 0.13 mmol), Xantphos (75.1 mg, 0.13 mmol) and Cs2CO3 (1.27 g, 3.9 mmol) at room temperature. The mixture was stirred at 95°C under N2 for 16 hours. The mixture was concentrated and purified by silica gel chromatography (DCM / MeOH=30 / 1) to give the product tert-butyl (6-cyclopropyl-2-((4-(hydroxymethyl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-8-yl)carbamate (90 mg, yield: 18%) as a white solid. ESI-MS [M+H] + :385.2.

[0633] Synthesis of (1-((8-amino-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methanol

[0634]

[0635] A solution of tert-butyl (6-cyclopropyl-2-((4-(hydroxymethyl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-8-yl)carbamate (90 mg, 0.23 mmol) in HCl (4 M in dioxane) (5.0 mL) was stirred at room temperature for 1 hour. The mixture was concentrated in vacuo to afford (1-((8-amino-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methanol (90 mg, crude) as a yellow solid, which was used directly in the next step without further purification. ESI-MS [M+H]: 285.1.

[0636] 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

[0637]

[0638] To a solution of (1-((8-amino-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methanol (300 mg, 1.06 mmol) in pyridine (15 mL) was added N'-formylformic acid hydrazide (280 mg, 3.18 mmol) and Et3N (749 mg, 7.42 mmol) at room temperature. TMSCl (1.72 g, 15.9 mmol) was then added at 0°C under N2. The resulting solution was stirred at 100°C for 18 hours and then cooled to room temperature. The mixture was concentrated in vacuo and the residue was purified by silica gel chromatography (DCM / MeOH=20 / 1 to 10 / 1) to give (1-((6-cyclopropyl-8-(4H-1,2,4-triazol-4-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methanol (150 mg, 42%) as a white solid. ESI-MS [M+H]+: 337.1.

[0639] 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

[0640]

[0641] To a solution of (1-((6-cyclopropyl-8-(4H-1,2,4-triazol-4-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methanol (60 mg, 0.18 mmol) in DCM (5.0 mL) was added MnO (157 mg, 1.8 mmol) at room temperature. The reaction mixture was stirred at room temperature for 18 hours. Additional MnO (78 mg.0.9 mmol) was added, and the reaction mixture was stirred for another 3 hours. Upon completion, the mixture was filtered and the filtrate was concentrated to give 1-((6-cyclopropyl-8-(4H-1,2,4-triazol-4-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carbaldehyde (40 mg, crude product) as a yellow solid, which was used directly in the next step without further purification. ESI-MS [M+H]+: 335.1.

[0642] 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

[0643]

[0644] To a mixture of 1-((6-cyclopropyl-8-(4H-1,2,4-triazol-4-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carbaldehyde (40 mg, 0.12 mmol) and (7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine (30 mg, 0.15 mmol) in MeOH (5.0 mL) was added AcOH (0.1 mL) at room temperature. The reaction mixture was stirred at room temperature for 18 hours. NaBH4 (8.5 mg, 0.22 mmol) was then added, and the mixture was stirred at room temperature for another 4 hours. The mixture was then concentrated and the residue was purified by preparative TLC (DCM / MeOH=15:1) to give 1-(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)-N-((1-((6-cyclopropyl-8-(4H-1,2,4-triazol-4-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methyl)methanamine (5 mg, 8%) as a light yellow solid. ESI-MS [M+H]+: 518.2.

[0645] 1H NMR (400MHz, DMSO) δ9.41(s,2H),8.48(s,1H),8.44(s,1H),8.26(s,1H),8.18(d,J=7.4Hz,1H),8.03(s,1H),7.98(s,1H),7.45(d,J=0.9Hz,1 H),6.73(t,J=6.9Hz,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).

[0646] Example 19

[0647] 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)

[0648]

[0649] A mixture of 1-(1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazol-4-yl)-2,2,2-trifluoroethane-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 hours. The mixture was diluted with EtOAc (50 mL) and washed with brine (30 mL x 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 light yellow solid. ESI-MS [M+H]+: 528.1.

[0650] 1H NMR (400MHz, DMSO) δ9.11 (d, J = 9.4Hz, 1H), 8.35 (s, 1H), 8.32–8.25 (m, 2H), 7.9 2(s,1H),7.74(s,1H),7.73–7.72(m,1H),7.58(s,1H),7.41(d,J=9.4Hz,1H),7 .00(dd,J=9.4,1.7Hz,1H),6.63(dd,J=7.5,2.1Hz,1H),5.80–5.64(m,1H),5.3 9(s,2H),3.78(s,2H),2.01–1.87(m,1H),1.00–0.85(m,2H),0.79–0.53(m,2H).

[0651] Example 20

[0652] 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)

[0653] Plan 20

[0654]

[0655] Synthesis of 2-(Chloromethyl)-6-cyclopropyl-8-(4-methylpiperazin-1-yl)imidazo[1,2-a]pyridine

[0656]

[0657] To a mixture of 5-cyclopropyl-3-(4-methylpiperazin-1-yl)pyridin-2-amine (460 mg, 1.98 mmol) in DME (25 mL) was added 1,3-dichloropropane-2-one (620 mg, 5 mmol). The reactants were stirred at 90 ° C for 16 hours. The reaction mixture was concentrated in vacuo to give 2-(chloromethyl)-6-cyclopropyl-8-(4-methylpiperazin-1-yl)imidazo[1,2-a]pyridine (400 mg, yield: 32%, crude product) as a yellow solid, which was used directly in the next step without further purification. ESI-MS [M + H] +: 305.1.

[0658] Synthesis of 2-(Azidomethyl)-6-cyclopropyl-8-(4-methylpiperazin-1-yl)imidazo[1,2-a]pyridine

[0659]

[0660] To a mixture of 2-(chloromethyl)-6-cyclopropyl-8-(4-methylpiperazine-1-yl)imidazo[1,2-a]pyridine (400 mg, 1.3 mmol) in DMF (5 mL) was added NaN (250 mg, 3.9 mmol). The reaction mixture was stirred at room temperature for 16 hours. Water (50 mL) was added and the mixture was extracted with EtOAc (30 ml x 3). The combined organic layers were washed with brine (30 ml), dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography (MeOH / DCM 0% to 10%) to give 2-(azidomethyl)-6-cyclopropyl-8-(4-methylpiperazine-1-yl)imidazo[1,2-a]pyridine (100 mg, yield: 25%) as a yellow solid. ESI-MS[M+H] + :312.1.

[0661] 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

[0662]

[0663] To a mixture of 2-(azidomethyl)-6-cyclopropyl-8-(4-methylpiperazine-1-yl)imidazo[1,2-a]pyridine (100 mg, 0.32 mmol) in t-BuOH (5 mL) and H o (5 mL) was added tert-butyl propiolate (52 mg, 0.42 mmol), CuSO (25 mg, 0.16 mmol) and sodium ascorbate (31 mg, 0.16 mmol). The reaction mixture was stirred at room temperature for 2 hours. Water (30 mL) was added and the mixture was extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na SO and concentrated in vacuo. The residue was purified by flash column chromatography (MeOH / DCM 0% to 10%) to give tert-butyl 1-((6-cyclopropyl-8-(4-methylpiperazin-1-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate (20 mg, yield: 14%) as a yellow solid. ESI-MS [M+H] + :438.2.

[0664] 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

[0665]

[0666] A mixture of tert-butyl 1-((6-cyclopropyl-8-(4-methylpiperazin-1-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate (15 mg, 0.034 mmol) in anhydrous DCM (3 mL) and TFA (0.6 mL) was stirred at room temperature for 4 hours. The reaction mixture was concentrated in vacuo to give 1-((6-cyclopropyl-8-(4-methylpiperazin-1-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid (3 mg, yield: 23% crude) as a yellow solid, which was used directly in the next step without further purification. ESI-MS [M+H] +: 382.1.

[0667] 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

[0668]

[0669] A mixture of 1-((6-cyclopropyl-8-(4-methylpiperazin-1-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid (20 mg, 0.05 mmol), (7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride (20 mg, 0.1 mmol), HOBT (10 mg, 0.074 mmol), EDCI (14 mg, 0.075 mmol) and DIPEA (32 mg, 0.25 mmol) in anhydrous DMF (5 ml) was stirred at room temperature for 16 hours. Water (50 mL) was added and the mixture was extracted with EtOAc (20 mL x 3). The organic layer was washed with brine (20 mL), dried over NaSO, and concentrated in vacuo. The residue was purified by preparative TLC (MeOH / DCM=10%) to give N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(4-methylpiperazin-1-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide as a yellow solid (1 mg, yield: 14%). ESI-MS [M+H]+: 563.1.

[0670] 1H NMR (400MHz, DMSO) δ8.66(t,J=5.4Hz,1H),8.47(s,1H),8.40(d,J=2.4Hz,1H),8.16(d,J=7.4Hz,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=5.5Hz,2H),3.46(s,4H),2.56(s,4 H),2.27(s,3H),1.84–1.80(m,1H),0.84–0.79(m,2H),0.64–0.50(m,2H).

[0671] Example 21

[0672] Inhibitory activity of exemplary compounds against plasma kallikrein. The inhibitory effects of exemplary compounds on human activated kallikrein were evaluated in two assay formats employing a fluorogenic 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 activated kallikrein, 300 uM Pro-Phe-Arg-7-amino-4-methylcoumarin substrate. Prior to initiation of the reaction with substrate, the enzyme and inhibitor were preincubated at room temperature for 30 minutes. Following initiation with substrate, the reaction was incubated at room temperature for 10 minutes, and fluorescence emission at 460 nm under 380 nm excitation was measured using a microplate reader. In another assay format, the reagent concentrations are as follows: 20 mM Tris pH 7.5, 1 mM EDTA, 150 mM sodium chloride, 0.1% PEG-400, 0.1% Triton X-100, 5 pM activated kallikrein, and 300 μM Pro-Phe-Arg-7-amino-4-methylcoumarin substrate. The enzyme and inhibitor are preincubated at room temperature for 30 minutes before initiation of the reaction with substrate. Following initiation with substrate, the reaction is incubated at room temperature for 18 hours, and fluorescence emission at 460 nm under 380 nm excitation is measured using a microplate reader.

[0673] Table 1 provides the results of the assay using 500 pM activated kallikrein. For the compounds listed in Table 1, EC values ​​are reported according to the following ranges: 50 Value: A≤50nM; 50nM <B≤200nM;200nM<C≤1000nM;1000nM<D。

[0674] Table 1

[0675]

[0676] Although many embodiments of the present invention have been described, it is apparent that the basic examples can be modified to provide other embodiments utilizing the compounds and methods of the present invention. Therefore, it should be understood that the scope of the present invention is defined by the appended claims rather than by the specific embodiments represented by the examples.

Claims

1. A compound of formula (I): or a pharmaceutically acceptable salt thereof, in: Het A is selected from 5- to 6-membered monocyclic heteroarylene groups having 1-4 heteroatoms selected from oxygen, nitrogen and sulfur, and 7- to 10-membered bicyclic heteroarylene groups having 1-5 heteroatoms selected from oxygen, nitrogen and sulfur, wherein Het A 0-4 R A group substitution; Each R A An optionally substituted group independently selected from the following: C 1-6 aliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic group, and 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic group having 1-2 heteroatoms selected from oxygen, nitrogen and sulfur, wherein the optionally substituted R A The substituents on the group are independently selected from halogen, (CH2) 0-4 R°, -(CH2) 0-4 OR° and -(CH2) 0-4 C(O)OR°, wherein each R° is independently hydrogen, C 1-6 an aliphatic group or a 5-6 membered saturated, partially unsaturated or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; L is selected from -C(R)2NRC(O)-#, -C(R)2C(O)NRC(R)2-#, -C(R)2NRC(O)C(R)2-#, -C(R)2NRC(R)2-#, -C(R)2C(R)2NRC(R)2-#, -C(O)NRC(R)2-#, -C(R)2C(R)2NRC(R)2-#, -C(O)NRC(R)2-#, -C(R)2C(O)NR-#, -NRC(O)C(R)2-#, -CR2C(O)NRC(R)2-#, -SO2NRC(R)2-# and -C(R)2NRSO2-#, wherein # represents the same A and wherein each R is independently hydrogen or C optionally substituted by halogen 1-3 aliphatic groups; R' and R" are independently selected from hydrogen, halogen, -OR, -NR2, -SR and -(CH2) 0-4 C(O)OR° substituted C 1-6 Aliphatic groups, wherein R° is hydrogen or C 1-6 aliphatic, and each R is independently selected from hydrogen and C 1-6 Aliphatic group; wherein R' can be combined with a monocyclic Het A together forming a fused 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclylene having 1-4 heteroatoms selected from oxygen, nitrogen and sulfur; R 1 、R 2 、R 3 and R 4 independently selected from hydrogen, halogen, -CN, -C(O)2R, and optionally substituted groups selected from: C 1-6 aliphatic, 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen and sulfur, and 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic group having 1-2 heteroatoms selected from oxygen, nitrogen and sulfur, wherein the optionally substituted R 1 、R 2 、R 3 and R 4 The substituents on the 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°, wherein each R° is independently hydrogen, C 1-6 an aliphatic group, or a 3- to 5-membered saturated, partially unsaturated, or aromatic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein each R is independently hydrogen or C 1-6 aliphatic groups; R 5 、R 6 、R 7 、R 8 and R 9 independently selected from hydrogen, halogen, -CN, -N(R)2, and -OR, wherein each R is independently hydrogen or C 1-6 aliphatic groups; n is 0 or 1, and wherein when L is -C(R)2NRC(O)-# or -C(R)2C(O)NR-#, one of the following (a), (b) or (c) applies: (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 1 is an optionally substituted saturated monocyclic heterocycle containing 1-2 nitrogen atoms, with the proviso 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-morpholinoimidazolo[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, -1-yl)methyl)-1H-1,2,3-triazole-4-carboxamide, N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(2-oxooxazolidin-3-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide, 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.

2. The compound according to claim 1, wherein 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-#, wherein # represents the same A connection point.

3. The compound according to claim 1, wherein L is selected from the group consisting of: -C(R)2C(O)NRC(R)2-#, -C(R)2NRC(R)2-#, -C(R)2C(R)2NRC(R)2-#, -C(O)NRC(R)2-#, -C(R)2C(O)NRC(R)2-#, -SO2NRC(R)2-# and -C(R)2NRSO2-#, wherein # represents the same A connection point.

4. The compound of claim 1, wherein L is not -C(R)2NRC(O)-# or -C(R)2C(O)NR-#.

5. The compound of claim 1, wherein L is not -CH2NRC(O)-# or -CH2C(O)NR-#.

6. The compound of claim 1, wherein when L is -C(R)2NRC(O)-# or -C(R)2C(O)NR-#, n is 0.

7. The compound according to claim 1, wherein when L is -C(R)2NRC(O)-# or -C(R)2C(O)NR-#, R' is the same as the monocyclic Het A Together they form a fused 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclylene group having 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur.

8. The compound according to claim 1, wherein when L is -CH2NRC(O)-# or -CH2C(O)NR-#, R' is the same as the monocyclic Het A Together they form a fused 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclylene group having 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur.

9. The compound according to claim 1, wherein L is -C(R)2NRC(O)-#, then n is 0.

10. A compound according to any one of claims 1 to 5, wherein L is -C(R)2C(O)NRC(R)2-#, wherein each R is independently hydrogen or C(O) optionally substituted by halogen. 1-3 Aliphatic group.

11. The compound of claim 10, wherein L is -CH2C(O)NHCH(CF3)-#.

12. The compound of claim 10, wherein L is -CH2C(O)NHCH(CH3)-#.

13. The compound of claim 10, wherein L is -CH2C(O)NHCH2-#.

14. A compound according to any one of claims 1 to 5, wherein L is -C(R)2NRC(R)2-#, wherein each R is independently hydrogen or C optionally substituted by halogen. 1-3 Aliphatic group.

15. The compound of claim 14, wherein L is -CH2NHCH(CF3)-#.

16. The compound of claim 14, wherein L is -CH2NHCH2-#.

17. The compound of claim 14, wherein L is -CH2NHCH(CH3)-#.

18. The compound of claim 14, wherein L is -CH(CF3)NHCH2-#.

19. A compound according to any one of claims 1 to 5, wherein L is -C(R)2NRSO2-#, wherein each R is independently hydrogen or C optionally substituted by halogen. 1-3 Aliphatic group.

20. The compound of claim 19, wherein L is -CH2NHSO2-#.

21. A compound according to any one of claims 1 to 5, wherein L is -SO2NRC(R)2-#, wherein each R is independently hydrogen or C optionally substituted by halogen. 1-3 Aliphatic group.

22. The compound of claim 21, wherein L is -SO2NHCH2-#.

23. The compound of claim 21, wherein L is -SO2NHCH(CH3)-#.

24. according to the compound of any one of claims 1-5, wherein L is -C(O)NRC(R)2-#, wherein each R is independently hydrogen or C optionally substituted by halogen. 1-3 Aliphatic group.

25. The compound of claim 24, wherein L is -C(O)NHCH2-#.

26. The compound according to claim 1, wherein the compound has a structure of Formula (Ia), Formula (Ib), Formula (Ic), or Formula (Id), or a pharmaceutically acceptable salt thereof.

27. The compound of claim 1, wherein the compound has the structure of Formula (II): or a pharmaceutically acceptable salt thereof.

28. The compound according to claim 1, wherein the compound has a structure of Formula (II-a) or Formula (II-b): or a pharmaceutically acceptable salt thereof.

29. The compound according to claim 1, wherein R' is a monocyclic Het A Together they form a fused ring, and the compound has the structure of formula (III): where R fus With Het A fused to form a fused 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclylene having 1-4 heteroatoms selected from oxygen, nitrogen and sulfur, or a pharmaceutically acceptable salt thereof.

30. The compound according to claim 1, wherein the compound has a structure of Formula (III-a) or Formula (III-b): or a pharmaceutically acceptable salt thereof.

31. A compound according to any one of claims 1-9, 27 or 29, wherein Het A is a 5-membered monocyclic heteroarylene group having 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur, wherein Het A 0-2 R A Group substitution.

32. The compound according to claim 31, wherein Het A is a 5-membered monocyclic heteroarylene group having 2-3 heteroatoms selected from nitrogen, wherein Het A 0-2 R A Group substitution.

33. The compound according to claim 32, wherein Het A Is 0-2 R A A pyrazole diyl group substituted with a group.

34. The compound of claim 32, wherein Het A Is 0-1 R A A triazolediyl group substituted with a group.

35. The compound of claim 32, wherein Het A It is an unsubstituted pyrazolediyl.

36. The compound according to claim 32, wherein Het A It is an unsubstituted 1,2,3-triazolediyl.

37. A compound according to any one of claims 1-9 or 27, wherein Het A Selected from: Where * indicates the connection point with L.

38. A compound according to any one of claims 1-9 or 27-29, wherein R A A single example is a C substituted by a halogen 1-6 Aliphatic group.

39. A compound according to any one of claims 1-9 or 26-28, wherein R' and R" are each hydrogen.

40. The compound according to claim 1, wherein R" is hydrogen and R' is a monocyclic Het A Together they form a fused 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclylene group having 1-4 heteroatoms selected from oxygen, nitrogen or sulfur.

41. The compound of claim 26, wherein n is 1, R" is hydrogen, and R' is a monocyclic Het A Together they form a fused 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclylene group having 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur.

42. The compound of claim 26, wherein n is 1, R" is hydrogen, and R' is the same as the monocyclic Het A Together they form a fused 8-membered saturated or partially unsaturated bicyclic heterocyclylene group having 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur.

43. according to the compound described in any one of claim 1-6, wherein when n is 0, Het A is a 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclylene group having 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur.

44. The compound of any one of claims 1-6, wherein n is 0.

45. The compound of any one of claims 1-6, wherein n is 1.

46. ​​A compound according to any one of claims 1-9, 26-30 or 40-42, wherein R 2 、R 3 、R 4 、R 5 、R 7 、R 8 and R 9 Each is hydrogen.

47. A compound according to any one of claims 1-9, 26-30 or 40-42, wherein R 1 、R 2 、R 3 、R 4 、R 7 、R 8 and R 9 Each is hydrogen.

48. A compound according to any one of claims 1-9, 26-30 or 40-42, wherein R 1 、R 2 、R 3 、R 4 、R 5 、R 7 、R 8 and R 9 Each is hydrogen.

49. A compound according to any one of claims 1-9, 26-30 or 40-42, wherein R 1 is an optionally substituted group selected from the group consisting of 5- to 6-membered heteroaryl groups having 1-4 heteroatoms selected from oxygen, nitrogen and sulfur, and 3- to 7-membered saturated and partially unsaturated monocyclic heterocyclic groups having 1-2 heteroatoms selected from oxygen, nitrogen or sulfur, wherein the optionally substituted R 1 The substituents on the alkyl group are -F, -CN, -R°, -OR°, -N(R°)2, -COOR° or -OC(R°)2C(R°)2N(R°)2, wherein each R° is independently hydrogen, C 1-6 an aliphatic group, or a 4-membered saturated ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur.

50. A compound according to any one of claims 1-9, 26-30 or 40-42, wherein R 1 is an optionally substituted 5-membered heteroaryl group having 2 to 4 heteroatoms selected from oxygen or nitrogen, wherein the optionally substituted R 1 The substituents on are -F, -CN, -R°, -OR°, -N(R°)2, -COOR° or -OC(R°)2C(R°)2N(R°)2, wherein each R° is independently hydrogen, C 1-6 an aliphatic group, or a 4-membered saturated ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur.

51. A compound according to any one of claims 1-9, 26-30 or 40-42, wherein R 1 is optionally substituted piperazinyl or optionally substituted triazolyl, wherein the optionally substituted R 1 The substituents on the alkyl group are -F, -CN, -R°, -OR°, -N(R°)2, -COOR° or -OC(R°)2C(R°)2N(R°)2, wherein each R° is independently hydrogen, C 1-6 an aliphatic group, or a 4-membered saturated ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur.

52. A compound according to any one of claims 1-9, 26-30 or 40-42, wherein R 1 is an optionally substituted C 1-6 an aliphatic group, wherein the optionally substituted R 1 The substituents on the alkyl group are -F, -CN, -R°, -OR°, -N(R°)2, -COOR° or -OC(R°)2C(R°)2N(R°)2, wherein each R° is independently hydrogen, C 1-6 an aliphatic group, or a 4-membered saturated ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur.

53. A compound according to any one of claims 1-9, 26-30 or 40-42, wherein R 5 and R 6 are each independently halogen.

54. A compound according to any one of claims 1-9, 26-30 or 40-42, wherein R 5 is F and R 6 It's Cl.

55. A compound according to any one of claims 1-9, 26-30 or 40-42, wherein R 6 It is Cl or CN.

56. The compound of claim 1, wherein the compound is selected from:

57. A pharmaceutical composition comprising a compound according to any one of claims 1-9, 26-30, 40-42 or 56.

58. A pharmaceutical composition comprising a compound according to any one of claims 1-9, 26-30, 40-42 or 56 and a pharmaceutically acceptable excipient.

59. The pharmaceutical composition of claim 57, wherein the composition is suitable for oral administration.

60. The pharmaceutical composition of claim 58, wherein the composition is suitable for oral administration.

61. Use of a compound according to any one of claims 1-9, 26-30, 40-42 or 56 for the preparation of a medicament for the treatment of a plasma kallikrein-mediated disease or condition.

62. The use according to claim 61, wherein the disease or condition is hereditary angioedema or diabetic macular edema.

63. Use of a compound according to any one of claims 1-9, 26-30, 40-42 or 56 for the preparation of a medicament for the treatment of hereditary angioedema or diabetic macular edema.

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