Plasma kallikrein inhibitors and uses thereof

Abstract

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

Description

[0001] I. Cross-reference to Related Applications

[0002] This application claims priority to and the benefit of U.S. Provisional Patent Application Serial No. 62 / 902,353, filed September 18, 2019, entitled “PLASMA KALLIKREIN INHIBITORS AND USES THEREOF,” the disclosure of which is incorporated herein by reference in its entirety.

[0003] II. Background Technology

[0004] 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 intrinsic cascade of innate inflammatory responses and blood coagulation. Mechanisms leading to the activation of this pathway in vivo include interaction with polyphosphates released by activated platelets and the deficiency of C1 inhibitor (C1-INH), the main physiological inhibitor of pKal. pKal-mediated cleavage of high molecular weight kininogen produces the potent vasodilator and proinflammatory nonapeptide bradykinin (BK), which activates bradykinin 2 receptors. BK is subsequently cleaved by carboxypeptidases to produce 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.

[0005] pKal is also associated with many 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 throat. The prevalence of HAE is uncertain, but it is estimated to be approximately 1 case per 50,000 people, with no known differences between ethnic groups. HAE is caused by insufficient levels (type I) or dysfunctional (type II) of C1-INH, an enzyme that inhibits pKal, bradykinin, and other serine proteases in the blood. Individuals with hereditary angioedema (HAE) lack C1-INH and therefore produce too much bradykinin, which in turn causes painful, debilitating, and potentially fatal episodes of swelling. If left untreated, HAE can lead to a mortality rate of up to 40%, primarily due to upper airway obstruction.

[0006] III. Summary of the Invention

[0007] 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.

[0008] In some embodiments, the present invention provides compounds of formula (I):

[0009]

[0010] or a pharmaceutically acceptable salt thereof, wherein Cy A 、Cy B , L, R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 Each of and n is defined and described in classes and subclasses herein. In certain embodiments, the invention provides compounds of Formula (I)-(IV) as defined and described in classes and subclasses herein.

[0011] In some embodiments, the present invention also provides methods of using the compounds of Formula (I)-(IV).

[0012] IV. Specific Implementation Methods

[0013] A. Definition

[0014] 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, the following definitions apply unless otherwise indicated. 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, eds. Smith, MB and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference.

[0015] Abbreviations used herein have their conventional meanings in the fields of chemistry and biology.The chemical structures and formulae listed herein are constructed according to standard rules of chemical valence known in the chemical arts.

[0016] 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 hetero groups thereof, such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl, or (cycloalkyl)alkenyl.

[0017] 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)).

[0018] The term "unsaturated" as used herein means a moiety having one or more units of unsaturation.

[0019] 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.

[0020] The term "halogen" means F, Cl, Br or I.

[0021] The term "aryl" refers to monocyclic and bicyclic ring systems having a total of five to ten 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 bear one or more substituents, including but not limited to phenyl, biphenyl, naphthyl, anthracenyl, and the like. Also included within the scope of the term "aryl" as used herein are groups in which an aromatic ring is fused to one or more non-aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl.

[0022] The terms "heteroaryl" and "heteroar-" refer to groups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms; sharing a total of 6, 10, or 14 π electrons in the ring array; and having one to five heteroatoms in addition to carbon atoms. Heteroaryl groups include, but are not limited to, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridinyl, 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. 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.

[0023] 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 that is saturated or partially unsaturated and has, in addition to carbon atoms, one or more, preferably one to four, heteroatoms as defined above. The term "nitrogen," when used in this context with respect to ring atoms, 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).

[0024] The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure, and any ring atom may be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic groups include, but are not limited to, tetrahydrofuranyl, tetrahydrophenylthiopyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolane, diazepine, oxazolidinyl ... Oxazolin thiazolinone The terms "heterocyclyl", "heterocycle (heterocyclyl ring)", "heterocyclic group (heterocyclic group)", "heterocyclic moiety" and "heterocyclic radical (heterocyclic radical)" are used interchangeably herein and also include groups in which the heterocyclyl ring is fused to one or more aryl, heteroaryl or alicyclic rings, such as indolinyl, 3H-indolyl, chromanyl, phenanthridinyl or tetrahydroquinolinyl. The heterocyclyl group can be monocyclic or bicyclic. The term "heterocyclylalkyl" refers to an alkyl group substituted by a heterocyclyl, wherein the alkyl and heterocyclyl moieties are independently optionally substituted.

[0025] 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.

[0026] As used herein, and unless otherwise indicated, the suffix "sub" is used to describe a divalent group. Thus, any of the above terms can be modified with the suffix "sub" to describe the divalent form of the moiety. For example, a divalent carbocyclic ring is "carbocyclylene," a divalent aryl ring is "arylene," a divalent benzene ring is "phenylene," a divalent heterocyclic ring is "heterocyclylene," a divalent heteroaryl ring is "heteroarylene," a divalent alkyl chain is "alkylene," a divalent alkenyl chain is "alkenylene," a divalent alkynyl chain is "alkynylene," and so on.

[0027] As described herein, the compounds of the present invention may contain "optionally substituted" moieties where indicated. In general, the term "substituted," whether or not preceded by the term "optionally," means that one or more hydrogens of the designated moiety are replaced by a suitable substituent. 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 designated group, the substituents may be the same or different at each position. The combinations of substituents contemplated by the present invention are preferably those that result in 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 the compound to be prepared, detected, and in certain embodiments, recovered, purified, and used for one or more purposes disclosed herein.

[0028] Suitable monovalent substituents on substitutable carbon atoms of an "optionally substituted" group are independently halogen; -(CH2) 0-4 R o ; -(CH2) 0-4 OR o ;-O(CH2) 0-4 R o ;-O(CH2) 0-4 C(O)OR o ;-O(CH2) 0-4 OR o ; -(CH2) 0-4 CH(OR o )2;-(CH2) 0-4 SR o ; can be R o Substituted -(CH2) 0-4 Ph; can be R o Substituted -(CH2) 0-4 O(CH2) 0-1 Ph; can be R o -CH=CHPh substituted; can be R o Substituted -(CH2) 0-4 O(CH2) 0-1 -pyridyl; -NO2; -CN; -N3; ​​-(CH2) 0-4 N(R o )2;-(CH2) 0-4 N(R o )C(O)R o ;-N(R o )C(S)R o ; -(CH2) 0-4 N(R o )C(O)NR o 2;-N(Ro )C(S)NR o 2;-(CH2) 0-4 N(R o )C(O)OR o ;-N(R o )N(R o )C(O)R o ;-N(R o )N(R o )C(O)NR o 2;-N(R o )N(R o )C(O)OR o ;-(CH2) 0-4 C(O)R o ;-C(S)R o ;-(CH2) 0-4 C(O)OR o ;-(CH2) 0-4 C(O)SR o ;-(CH2) 0-4 C(O)OSiR o 3;-(CH2) 0-4 OC(O)R o ;-OC(O)(CH2) 0-4 SR o ;-SC(S)SR o ;-(CH2) 0-4 SC(O)R o ;-(CH2) 0-4 C(O)NR o 2;-C(S)NR o 2;-C(S)SR o ;-SC(S)SR o ;-(CH2) 0-4 OC(O)NR o 2;-C(O)N(OR o )R o ;-C(O)C(O)R o ;-C(O)CH2C(O)R o ;-C(NOR o )R o ;-(CH2) 0-4 SSR o ;-(CH2) 0-4 S(O)2R o ;-(CH2) 0-4 S(O)2OR o ;-(CH2) 0-4 OS(O)2R o;-S(O)2NR o 2; -(CH2) 0-4 S(O)R o ;-N(R o )S(O)2NR o 2;-N(R o )S(O)2R o ;-N(OR o )R o ;-C(NH)NR o 2;-P(O)2R o ;-P(O)R o 2;-OP(O)R o 2;-OP(O)(OR o )2;SiR o 3;-(C 1-4 linear or branched alkylene)ON(R o )2; or -(C 1-4 linear or branched alkylene) C(O)ON(R o )2, where each R o may be substituted as defined below and are independently hydrogen, C 1-6 Aliphatic groups, -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 definitions, two independent occurrences of R o Together with their intervening atoms they form a 3-12 membered saturated, partially unsaturated or aromatic monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, which may be substituted as defined below.

[0029] R o (or two independent occurrences of R o Suitable monovalent substituents on the ring formed by taking together with their intervening atoms 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) 0-2C(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, when preceded by "halo", substituted only by one or more halogens, and is independently selected from C 1-4 Aliphatic groups, -CH2Ph, -O(CH2) 0-1 Ph or a 5-6 membered saturated ring, partially unsaturated ring or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur. o Suitable divalent substituents on a saturated carbon atom of include =0 and =S.

[0030] 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 an aliphatic group 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 bonded to the ortho-substitutable carbon of the "optionally substituted" group include: -O(C(R * )2) 2-3 O-, where each independent occurrence of R * is selected from hydrogen, C which may be substituted as defined below 1-6an aliphatic group or an unsubstituted 5-6 membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0031] 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 · 、-N(R · )2 or -NO2, where each R · is unsubstituted or, when preceded by "halo", substituted only by one or more halogens, and is independently C 1-4 Aliphatic groups, -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.

[0032] Suitable substituents on a substitutable nitrogen of an "optionally substituted" group include Each of these is independently hydrogen, C which may be substituted as defined below 1-6 aliphatic, unsubstituted -OPh, or an unsubstituted 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the above definitions, two independent occurrences of Together with their intervening atoms they form an unsubstituted 3- to 12-membered saturated, partially unsaturated or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0033] 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 by one or more halogens, and is independently C 1-4 Aliphatic groups, -CH2Ph, -O(CH2)0-1 Ph or a 5- to 6-membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0034] 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., and are commensurate with a reasonable benefit / risk ratio, within the scope of sound medical judgment. 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.

[0035] 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 a 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.

[0036] Unless otherwise stated, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, 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 present compounds are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the present compounds are within the scope of the invention. In addition, unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, structures having structures including replacement of hydrogen by deuterium or tritium, or replacement of carbon by isotopically enriched atoms, are also meant to include isotopically enriched atoms. 13 C or 14 Compounds of the present structures having C-enriched carbon substitutions are within the scope of the present invention. Such compounds are useful, for example, as analytical tools, probes in biological assays, or therapeutic agents according to the present invention.

[0037] The term "oxo" as used herein refers to an oxygen double-bonded to a carbon atom, thereby forming a carbonyl group.

[0038] Except when used to describe a bond of unknown or mixed stereochemistry, the symbol Indicates the point of attachment of a chemical moiety to the rest of a molecule or chemical formula.

[0039] The articles "a" and "an" are used herein to refer to one or more than one (ie, to at least one) of the grammatical object of the article. For example, "an" means one element or more than one element.

[0040] As used herein, the term "dosing regimen" (or "treatment regimen") is a group of unit doses (usually more than one) that are administered individually to a subject, typically at intervals of time. In some embodiments, a given therapeutic agent has a recommended dosing regimen that may involve one or more doses. In some embodiments, the dosing regimen comprises multiple doses, each of which is separated from another 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.

[0041] As will be understood from the context, "reference" sample or subject is a sample or subject that is sufficiently similar to the particular sample or subject being paid close attention to so as to allow for relevant comparison. In some embodiments, the information about the reference sample is obtained simultaneously with the information about the particular sample. In some embodiments, the information about the reference sample is past. In some embodiments, the information about the reference sample is stored in, for example, a computer-readable medium. In some embodiments, the particular sample being paid close attention to is compared with the reference sample to establish the identity, similarity or difference of the particular sample being paid close attention to relative to the reference.

[0042] 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 fluid; feces; lymph; gynecological fluids; skin swabs; vaginal swabs; oral swabs; nasal swabs; washings or lavages, such as duct lavage or bronchoalveolar lavage; aspirates; scrapings; bone marrow samples; tissue biopsy samples; surgical samples; feces, other body fluids, secretions and / or excretions; and / or cells produced 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 apparent from the context, the term "sample" refers to a preparation obtained by processing (e.g., by removing one or more components of the raw sample and / or by adding one or more reagents to the raw sample). For example, filtration using a semipermeable membrane. Such a "processed sample" may include, for example, nucleic acids or proteins extracted from the sample or obtained by subjecting the raw sample to techniques such as amplification or reverse transcription of mRNA, separation and / or purification of certain components, etc.

[0043] 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.

[0044] As used herein, the term "therapeutically effective amount" refers to the amount of the therapeutic agent that gives the therapeutic effect to the treated subject in a reasonable benefit / risk ratio applicable to any medical treatment. The therapeutic effect can be objective (that is, it can be measured by some tests or markers) or subjective (that is, the subject gives an indication of the effect). In particular, "therapeutically effective amount" refers to an amount of the therapeutic agent that effectively treats, improves or prevents the disease or illness expected by improving the symptoms associated with the disease, preventing or delaying the onset of the disease and / or also alleviating the severity or frequency of the disease symptoms, or showing a detectable therapeutic or preventive effect. Typically, a therapeutically effective amount is administered in a dosage regimen that can include multiple unit doses. For any specific therapeutic agent, a therapeutically effective amount (and / or the appropriate unit dose in an effective dosage regimen) may be different, for example, depending on route of administration, with a combination of other agents. In addition, the specific therapeutically effective amount (and / or unit dose) for any particular subject may depend on a variety of factors, including the condition being treated and the severity of the condition; the activity of the specific therapeutic agent used; the specific composition used; 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 specific therapeutic agent used; the duration of the treatment; and like factors well known in the medical arts.

[0045] As used herein, the term "treatment" (treatment / treat / treating) refers to any partial or complete alleviation, improvement, relief, suppression of one or more symptoms, characteristics and / or causes of a specific disease, disorder and / or illness, delaying its onset, reducing its severity and / or reducing its incidence of a substance (e.g., a provided composition). This treatment can be for a subject who does not show signs of the relevant disease, disorder and / or illness and / or for a subject who only shows early signs of a disease, disorder and / or illness. Alternatively or in addition, this treatment can be for a subject who shows one or more confirmed signs of the relevant disease, disorder and / or illness. In some embodiments, treatment can be for a subject who has been diagnosed with a relevant disease, disorder and / or illness. In some embodiments, treatment can be for a subject who is known to have one or more susceptibility factors that are statistically associated with an increased risk of developing the relevant disease, disorder and / or illness.

[0046] B. Compounds

[0047] In some embodiments, provided compounds have Formula (I):

[0048]

[0049] or a pharmaceutically acceptable salt thereof,

[0050] in:

[0051] Cy A is selected from 5-membered monocyclic heteroarylene groups having 1-4 heteroatoms independently selected from oxygen, nitrogen and sulfur and 7- to 10-membered partially unsaturated bicyclic heterocyclylene groups having 1-4 heteroatoms independently selected from oxygen, nitrogen and sulfur, wherein Cy A 0-4 R A group substitution;

[0052] 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 an aliphatic group, a phenyl group, a 5- to 6-membered heteroaryl group having 1 to 4 heteroatoms selected from oxygen, nitrogen or sulfur, a 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 to 2 heteroatoms selected from oxygen, nitrogen or sulfur;

[0053] Cy B is selected from phenyl, a 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen and sulfur, a 7- to 10-membered partially unsaturated bicyclic carbocyclic group, a 10-membered bicyclic aryl, a 7- to 10-membered bicyclic heterocyclic group having 1-4 heteroatoms selected from oxygen, nitrogen and sulfur, a 7- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen and sulfur, and a 12-membered tricyclic heterocyclic group having 1-4 heteroatoms selected from oxygen, nitrogen and sulfur, wherein Cy B 0-5 R B group substitution;

[0054] Each R B independently selected from halogen, -CN, oxo, -C(R)=N(R), -C(O)R, -C(O)2R, -C(O)N(R), -C(=N(R))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 1-6aliphatic, 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, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic group having 1-2 heteroatoms selected from oxygen, nitrogen or sulfur, 7- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen and sulfur, and 8- to 10-membered spirocyclic heterocyclic group having 1-3 heteroatoms selected from oxygen, nitrogen or sulfur;

[0055] L is an optionally substituted C 1-6 a hydrocarbon chain in which 1 to 3 methylene units are independently replaced by –Cy-, –O–, –NR–, –C(O)–, –C(O)NR–, –NRC(O)–, –S(O)2NR–, –NRS(O)2–, or –S(O)2–;

[0056] -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;

[0057] R 1 and R 2 independently selected from hydrogen, halogen, -OR, -SR, -N(R)2 and optionally substituted C 1-6 aliphatic group; wherein R 1 Can be used with monocyclic Cy A taken together to 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;

[0058] R 3 、R 4 、R 5 and R 7 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 an aliphatic group, a phenyl group, a 5- to 6-membered heteroaryl group having 1 to 4 heteroatoms selected from oxygen, nitrogen or sulfur, a 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 to 2 heteroatoms selected from oxygen, nitrogen or sulfur;

[0059] R6 an optionally substituted group selected from 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 a group selected from: C 1-6 an aliphatic group, a phenyl group, a 5- to 6-membered heteroaryl group having 1 to 4 heteroatoms selected from oxygen, nitrogen or sulfur, a 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 to 2 heteroatoms selected from oxygen, nitrogen or sulfur;

[0060] Each R is independently hydrogen or an optionally substituted group selected from: C 1-6 an aliphatic group, a phenyl group, a 5- to 6-membered heteroaryl group having 1 to 4 heteroatoms selected from oxygen, nitrogen or sulfur, a 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 to 2 heteroatoms selected from oxygen, nitrogen or sulfur;

[0061] 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; and

[0062] n is 0 or 1;

[0063] The conditions are:

[0064] (a)R 3 、R 4 、R 5 、R 6 and R 7 At least one of them is C 1-6 an aliphatic group or a halogen; and

[0065] (b) the compound is not N-[1-[(6-fluoroimidazo[1,2-a]pyridin-2-yl)methyl]-5-methyl-1H-pyrazol-3-yl]-3-pyridinecarboxamide, N-[1-[(6-chloroimidazo[1,2-a]pyridin-2-yl)methyl]-5-methyl-1H-pyrazol-3-yl]-3-pyridinecarboxamide, 3-chloro-4-[[5-[8-chloro-6-(trifluoromethyl)imidazo[1 ,2-a]pyridin-2-yl]-1,3,4-oxadiazol-2-yl]amino]-phenylpropionic acid, 2-[(6,8-dichloroimidazo[1,2-a]pyridin-2-yl)methyl]-4-methyl-N-phenyl-5-thiazolecarboxamide and N-(furan-2-ylmethyl)-N,3,5-trimethyl-1-((6-methylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-sulfonamide.

[0066] In some embodiments, provided compounds or pharmaceutically acceptable salts thereof have the structure of Formula (I), with the proviso that Cy B For not The group, R 3 、R 4 、R 5 、R 6 and R 7 At least one of them is C 1-6 aliphatic or halogen, and the compound is not N-[1-[(6-fluoroimidazo[1,2-a]pyridin-2-yl)methyl]-5-methyl-1H-pyrazol-3-yl]-3-pyridinecarboxamide, N-[1-[(6-chloroimidazo[1,2-a]pyridin-2-yl)methyl]-5-methyl-1H-pyrazol-3-yl]-3-pyridinecarboxamide, 3-chloro-4-[[5-[8-chloro-6-(trifluoromethyl)imidazole imidazo[1,2-a]pyridin-2-yl]methyl]-1,3,4-oxadiazol-2-yl]amino]-phenylpropionic acid, 2-[(6,8-dichloroimidazo[1,2-a]pyridin-2-yl)methyl]-4-methyl-N-phenyl-5-thiazolecarboxamide, and N-(furan-2-ylmethyl)-N,3,5-trimethyl-1-((6-methylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-sulfonamide.

[0067] In some embodiments, Cy A is selected from 5-membered monocyclic heteroarylene groups having 1-4 heteroatoms independently selected from oxygen, nitrogen and sulfur and 7- to 10-membered partially unsaturated bicyclic heterocyclylene groups having 1-4 heteroatoms independently selected from oxygen, nitrogen and sulfur, wherein Cy A 0-4 R A Group substitution.

[0068] In some embodiments, Cy Ais selected from 5-membered monocyclic heteroarylene groups having 1-4 heteroatoms independently selected from oxygen, nitrogen and sulfur, wherein Cy A 0-3 R A In some embodiments, Cy A is selected from 5-membered monocyclic heteroarylene groups having 1-4 heteroatoms independently selected from oxygen, nitrogen and sulfur, wherein Cy A 0-2 R A In some embodiments, Cy A is selected from 5-membered monocyclic heteroarylene groups having 1-4 heteroatoms independently selected from oxygen, nitrogen and sulfur, wherein Cy A Is unsubstituted.

[0069] In some embodiments, Cy A is a 5-membered heteroarylene group having 1 to 4 heteroatoms independently selected from oxygen and nitrogen, wherein Cy A 0-3 R A In some embodiments, Cy A is a 5-membered heteroarylene group having 1 to 4 nitrogen atoms, wherein Cy A 0-3 R A In some embodiments, Cy A is a 5-membered heteroarylene group having 2-3 nitrogen atoms, wherein Cy A 0-2 R A In some embodiments, Cy A is a 5-membered heteroarylene group having one nitrogen atom, wherein Cy A 0-3 R A In some embodiments, Cy A is a 5-membered heteroarylene group having 2 nitrogen atoms, wherein Cy A 0-2 R A In some embodiments, Cy A is a 5-membered heteroarylene group having 3 nitrogen atoms, wherein Cy A 0-1 R A In some embodiments, Cy A is an unsubstituted 5-membered heteroarylene group having 2 nitrogen atoms and 1 oxygen atom. A is unsubstituted pyrrolediyl. In some embodiments, Cy A Is 0-2 R A In some embodiments, Cy A Is an unsubstituted imidazole diyl. In some embodiments, Cy A is an unsubstituted triazole diyl. In some embodiments, CyA is unsubstituted tetrazolyl. In some embodiments, Cy A It is an unsubstituted oxadiazole diyl group.

[0070] In some embodiments, when n is 0, Cy 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.

[0071] In some embodiments, Cy A is a 7- to 10-membered partially unsaturated bicyclic heterocyclylene radical having 1-4 heteroatoms selected from oxygen, nitrogen, and sulfur. A is an 8-membered partially unsaturated bicyclic heterocyclylene radical having 1-4 heteroatoms selected from oxygen, nitrogen and sulfur. A is an 8-membered partially unsaturated bicyclic heterocyclylene radical having 2-3 heteroatoms selected from oxygen, nitrogen and sulfur. A is an 8-membered partially unsaturated bicyclic heterocyclylene radical having 2-3 heteroatoms selected from oxygen and nitrogen. A is an 8-membered partially unsaturated bicyclic heterocyclylene group having 2 nitrogen atoms. A is an 8-membered partially unsaturated bicyclic heterocyclylene group having 3 nitrogen atoms. A is an 8-membered partially unsaturated bicyclic heterocyclylene group having 2 nitrogen atoms and 1 oxygen atom. A is unsubstituted pyrrolopyrazolediyl. In some embodiments, Cy A is an unsubstituted pyrroloimidazole diyl. In some embodiments, Cy A is unsubstituted pyrrolotriazolediyl. In some embodiments, Cy A It is an unsubstituted dihydroimidazooxazolediyl group.

[0072] In some embodiments, Cy A Selected from the group consisting of:

[0073]

[0074] Where * represents the connection point with L.

[0075] In some embodiments, each R A Independently selected from optionally substituted groups, the optionally substituted groups are selected from C 1-6 an aliphatic group, a 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.

[0076] In some embodiments, optionally substituted R A The substituents on the group are independently halogen, (CH2) 0-4 R o 、-(CH2) 0-4 OR o ; and -(CH2) 0-4 C(O)OR o , where each R o are independently hydrogen, C 1-6 an aliphatic group or a 5- to 6-membered saturated, partially unsaturated, or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0077] In some embodiments, R A A single example is a C substituted by a halogen 1-6 Aliphatic group.

[0078] In some embodiments, R A A single instance of -(CH2) 0-4 OR o Substituted C 1-6 aliphatic group, where R o is hydrogen or C 1-6 Aliphatic group.

[0079] In some embodiments, R A A single instance of -(CH2) 0-4 C(O)OR o Substituted C 1-6 aliphatic group, where R o is hydrogen or C 1-6 Aliphatic group.

[0080] In some embodiments, R A A single example of is C substituted with a 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. 1-6 Aliphatic group.

[0081] 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 instance of -(CH2) 0-4 C(O)OR o Substituted cyclopropyl, and R o is hydrogen or C 1-6 Aliphatic group.

[0082] In some embodiments, each R A Independently selected from unsubstituted C 1-6 In some embodiments, each R A is independently selected from methyl, ethyl, n-propyl, isopropyl, cyclopropyl, butyl and cyclopentyl. A Independently selected from methyl and ethyl.

[0083] In some embodiments, Cy B is selected from phenyl, a 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen and sulfur, a 7- to 10-membered partially unsaturated bicyclic carbocyclic group, a 10-membered bicyclic aryl, a 7- to 10-membered bicyclic heterocyclic group having 1-4 heteroatoms selected from oxygen, nitrogen and sulfur, a 7- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen and sulfur, and a 12-membered tricyclic heterocyclic group having 1-4 heteroatoms selected from oxygen, nitrogen and sulfur, wherein Cy B 0-5 R B Group substitution.

[0084] In some embodiments, Cy B Is phenyl, where Cy B 0-3 R B In some embodiments, Cy B Is phenyl, where Cy B By 3 R B In some embodiments, Cy B Is phenyl, where Cy B By 2 R B In some embodiments, Cy B Is phenyl, where Cy B By 1 R B In some embodiments, Cy B It is an unsubstituted phenyl group.

[0085] In some embodiments, Cy B is a 5- to 6-membered monocyclic heteroaryl group having 1-4 heteroatoms selected from oxygen, nitrogen and sulfur, wherein Cy B 0-3 R B Group substitution.

[0086] In some embodiments, Cy B is a 5-membered monocyclic heteroaryl group having 1 to 4 heteroatoms independently selected from oxygen, nitrogen and sulfur, wherein Cy B 0-3 R B In some embodiments, Cy Bis a 5-membered monocyclic heteroaryl group having 2-3 heteroatoms independently selected from oxygen, nitrogen and sulfur, wherein Cy B 0-2 R B In some embodiments, Cy B is a 5-membered monocyclic heteroaryl group having 2-3 heteroatoms independently selected from oxygen and nitrogen, wherein Cy B 0-2 R B In some embodiments, Cy B is a 5-membered monocyclic heteroaryl group having 2-3 heteroatoms independently selected from nitrogen and sulfur, wherein Cy B 0-2 R B In some embodiments, Cy B is a 5-membered monocyclic heteroaryl group having 2-3 nitrogen atoms, wherein Cy B 0-2 R B In some embodiments, Cy B Is 1 R B In some embodiments, Cy B Is 1 R B In some embodiments, Cy B Is 1 R B In some embodiments, Cy B Is 1 R B In some embodiments, Cy B Is 1 R B A thiadiazole diyl group substituted with a group.

[0087] In some embodiments, Cy B is a 6-membered monocyclic heteroaryl group having 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur, wherein Cy B 0-3 R B In some embodiments, Cy B is a 6-membered monocyclic heteroaryl group having 1 to 4 nitrogen atoms, wherein Cy B 0-3 R B In some embodiments, Cy B is a 6-membered monocyclic heteroaryl group having 1-2 nitrogen atoms, wherein Cy B 0-3 R B In some embodiments, Cy B It is 2-3 R B In some embodiments, Cy B It is 2 R BIn some embodiments, Cy B It is the 3 R B A pyridinediyl group substituted with a group.

[0088] In some embodiments, Cy B is a 7- to 10-membered partially unsaturated bicyclic carbocyclic group, wherein Cy B 0-1 R B In some embodiments, Cy B Is 0-1 R B Indenediyl substituted with a group.

[0089] In some embodiments, Cy B Is a 10-membered bicyclic aromatic group, wherein Cy B 0-1 R B In some embodiments, Cy B Is 1 R B A naphthalene diyl group substituted with a group.

[0090] In some embodiments, Cy B is a 7- to 10-membered bicyclic heterocyclic group having 1-4 heteroatoms selected from oxygen, nitrogen and sulfur, wherein Cy B 0-2 R B Group substitution.

[0091] In some embodiments, Cy B is a 7- to 10-membered bicyclic heteroaryl group having 1-4 heteroatoms selected from oxygen, nitrogen and sulfur, wherein Cy B 0-3 R B In some embodiments, Cy B is a 9- to 10-membered bicyclic heteroaryl group having 1-4 heteroatoms selected from oxygen, nitrogen and sulfur, wherein Cy B 0-3 R B In some embodiments, Cy B is a 9- to 10-membered bicyclic heteroaryl group having 1-3 heteroatoms selected from oxygen, nitrogen and sulfur, wherein Cy B 0-3 R B In some embodiments, Cy B is a 9-membered bicyclic heteroaryl group having 1 to 3 heteroatoms selected from oxygen, nitrogen and sulfur, wherein Cy B 0-3 R B In some embodiments, Cy B is a 10-membered bicyclic heteroaryl group having 1-2 heteroatoms selected from oxygen, nitrogen and sulfur, wherein Cy B 0-3 R B Group substitution.

[0092] In some embodiments, Cy B is a 9-membered bicyclic heteroaryl group having 1 to 3 heteroatoms selected from oxygen, nitrogen and sulfur, wherein Cy B 0-3 R B In some embodiments, Cy B Is 1-3 R B In some embodiments, Cy B Is 1-2 R B In some embodiments, Cy B Is 0-1 R B In some embodiments, Cy B Is 0-2 R B In some embodiments, Cy B Is 1-2 R B In some embodiments, Cy B It is the 3 R B In some embodiments, Cy B Is 1 R B In some embodiments, Cy B Is 1 R B In some embodiments, Cy B Is 1 R B A triazolopyridinediyl group substituted with a group.

[0093] In some embodiments, Cy B is a 10-membered bicyclic heteroaryl group having 1-2 heteroatoms selected from oxygen, nitrogen and sulfur, wherein Cy B 0-3 R B In some embodiments, Cy B Is 1 R B In some embodiments, Cy B It is the 3 R B In some embodiments, Cy B Is 0-1 R B A quinolinone diyl substituted with a group.

[0094] In some embodiments, Cy B is a 12-membered tricyclic heterocyclic group having 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur, wherein Cy B 0-1 RB In some embodiments, Cy B Is 1 R B A dihydroimidazoquinolinediyl substituted with a group.

[0095] In some embodiments, Cy B Selected from the group consisting of:

[0096]

[0097]

[0098] In some embodiments, each R B independently selected from halogen, -CN, -OR, -N(R)2, -N(R)CN, -C(=N(R))N(R)2, -S(O)R, -S(O)2R, -S(O)2N(R)2 or 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 radical, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic radical having 1-2 heteroatoms selected from oxygen, nitrogen or sulfur, 7- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen and sulfur, and 8- to 10-membered spirocyclic heterocyclic radical having 1-3 heteroatoms selected from oxygen, nitrogen or sulfur, wherein each R is independently hydrogen or an optionally substituted C 1-6 Aliphatic group.

[0099] In some embodiments, optionally substituted R B The substituents on the group are independently selected from halogen, C 1-6 Aliphatic group, -(CH2) 0-4 C(O)OR o and -(CH2) 0-4 N(R o )2, where each R o are independently hydrogen, C 1-6 an aliphatic group, or two independent occurrences of R o Together with their intervening atoms they form an optionally substituted 3 to 12 membered saturated, partially unsaturated or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, which may be further substituted.

[0100] In some embodiments, R B A single example of is halogen. In some embodiments, R B A single example of is -F. In some embodiments, R B A single example of is -Cl. In some embodiments, R BA single example of is -Br. In some embodiments, R B A single example of is -CN. In some embodiments, R B A single example is -N(R)2, where R is hydrogen or C 1-6 In some embodiments, R B A single example is -OR, wherein R is hydrogen or C optionally substituted by halogen. 1-6 In some embodiments, R B A single example is -N(R)CN, where R is hydrogen or C 1-6 In some embodiments, R B A single example is -C(=N(R))N(R)2, where each R is independently hydrogen or C 1-6 In some embodiments, R B A single example of is -C(=N(R))N(R)2, where R is hydrogen. In some embodiments, R B A single example is -S(O)R, where R is hydrogen or C 1-6 In some embodiments, R B A single instance of -S(O)R, where R is C 1-6 In some embodiments, R B A single example of is -S(O)R, wherein R is methyl. In some embodiments, R B A single example is -S(O)2R, where R is hydrogen or C 1-6 In some embodiments, R B A single instance of -S(O)2R, where R is C 1-6 In some embodiments, R B A single example of is -S(O)2R, wherein R is methyl. In some embodiments, R B A single example is -S(O)2N(R)2, where R is hydrogen or C 1-6 In some embodiments, R B A single example is -S(O)2N(R)2, where R is C 1-6 In some embodiments, R B A single example of is -S(O)2N(R)2, where R is methyl. In some embodiments, R B A single example of is -S(O)2N(R)2, wherein two independent occurrences of R are taken together with their intervening atoms to form an optionally substituted 3- to 12-membered saturated ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R BA single example of is -S(O)2N(R)2, wherein two independent occurrences of R are taken together with their intervening atoms to form an optionally substituted 5- to 6-membered saturated ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0101] In some embodiments, R B A single example is a C substituted by a halogen 1-6 Aliphatic group.

[0102] In some embodiments, R B A single instance of -(CH2) 0-4 N(R o )2 substituted C 1-6 aliphatic group, where R o is hydrogen or C 1-6 In some embodiments, R B A single instance of -(CH2) 0-4 N(R o )2 substituted C1 aliphatic group, wherein R o is hydrogen or C 1-6 In some embodiments, R B A single instance of -N(R o )2 substituted C1 aliphatic group, wherein R o is hydrogen or C 1-6 In some embodiments, R B A single example of is –CH2NH2.

[0103] In some embodiments, R B A single example of is C substituted with a 7- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen and sulfur. 1-6 aliphatic, which may be further substituted. B A single example of is C substituted with a 9-membered bicyclic heteroaryl having 1-2 heteroatoms selected from oxygen, nitrogen and sulfur 1-6 aliphatic, which may be further substituted. B A single example is C substituted with an imidazopyridinediyl group. 1-6 aliphatic, which may be further substituted. B A single example is C substituted with an imidazopyridinediyl group. 1-6 aliphatic groups, which may be C 1-6 In some embodiments, R B A single example is C substituted with an imidazopyridinediyl group. 1-6 An aliphatic group, which may be further substituted with a cyclopropyl group.

[0104] In some embodiments, R B A single example of is optionally substituted phenyl. In some embodiments, R B A single instance of -(CH2) 0-4 C(O)OR o Substituted phenyl, and R o is hydrogen or C 1-6 Aliphatic group.

[0105] In some embodiments, R B A single example of is an optionally substituted 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen or sulfur.

[0106] In some embodiments, R B A single example of is an optionally substituted 5-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, and sulfur. B A single example of is an optionally substituted 5-membered heteroaryl having 1-4 heteroatoms selected from oxygen and nitrogen. B A single example of is an optionally substituted 5-membered heteroaryl group having 1-4 nitrogen atoms. In some embodiments, R B A single example of is optionally substituted pyrazolediyl. In some embodiments, R B A single example is C optionally substituted by halogen 1-6 In some embodiments, R B A single instance of C 1-6 In some embodiments, R B A single example is unsubstituted pyrazolediyl. In some embodiments, R B A single example of is optionally substituted imidazole. In some embodiments, R B A single example is unsubstituted imidazole. In some embodiments, R B A single example of is optionally substituted triazolediyl. In some embodiments, R B A single example of is triazolediyl substituted with halogen. In some embodiments, R B A single example is C optionally substituted by halogen 1-6 In some embodiments, R B A single example of is unsubstituted triazolediyl. In some embodiments, R B A single example of is optionally substituted tetrazolyl. In some embodiments, R B A single example of is unsubstituted tetrazolyl. In some embodiments, R BA single example of is optionally substituted oxadiazolediyl. In some embodiments, R B A single example of is unsubstituted oxadiazolediyl.

[0107] In some embodiments, R B A single example of is an optionally substituted 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur. In some embodiments, R B A single example of is an optionally substituted 6-membered heteroaryl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur. In some embodiments, R B A single example of is an optionally substituted 6-membered heteroaryl group having 1-2 nitrogen atoms. In some embodiments, R B A single example of is optionally substituted pyridinediyl. In some embodiments, R B A single example of is pyridinediyl substituted with halogen. In some embodiments, R B A single example of is unsubstituted pyridinediyl. In some embodiments, R B A single example of is optionally substituted pyridazinediyl. In some embodiments, R B A single example of is unsubstituted pyridazinediyl. In some embodiments, R B A single example of is optionally substituted pyrimidinediyl. In some embodiments, R B A single instance of -(CH2) 0-4 C(O)OR o Substituted pyrimidinediyl, and R o is hydrogen or C 1-6 Aliphatic group.

[0108] In some embodiments, R B A single example of is an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, R B A single example of is optionally substituted cyclopropyl. In some embodiments, R B A single example of is unsubstituted cyclopropyl.

[0109] In some embodiments, R B A single example of is an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen or sulfur.

[0110] In some embodiments, R B A single example of is an optionally substituted 7- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, and sulfur. B A single example of is an optionally substituted 9-membered bicyclic heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, and sulfur.B A single example of is an optionally substituted 9-membered bicyclic heteroaryl having 1-2 nitrogen atoms. B A single example of is optionally substituted pyrazolopyridinediyl. In some embodiments, R B A single example of is unsubstituted pyrazolopyridinediyl. In some embodiments, R B A single example of is optionally substituted imidazopyridinediyl. In some embodiments, R B A single example of is unsubstituted imidazopyridinediyl.

[0111] In some embodiments, R B A single example of is an optionally substituted 8- to 10-membered spirocyclic heterocyclyl having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur. B A single example of is unsubstituted oxazaspiroheptyl.

[0112] In some embodiments, L is optionally substituted C 1-6 A hydrocarbon chain in which 1 to 3 methylene units are independently replaced by -O-, -NR-, -C(O)-, -C(O)NR-, -NRC(O)-, -S(O)2NR-, -NRS(O)2- or -S(O)2-, wherein each R is independently hydrogen or C optionally substituted by halogen. 1-6 In some embodiments, L is selected from -(C(R)2) m NR(C(R)2) m -#、-(C(R)2) m NRC(O)(C(R)2) m -#、-(C(R)2) m C(O)NR(C(R)2) m -#、-NRC(O)NR-#、-(C(R)2) m OC(O)NR(C(R)2) m -#, -O(C(R)2) m NRC(O)-#、-O(C(R)2) m NRS(O)2-#、-(C(R)2) m S(O)2NR(C(R)2) m -# and -(C(R)2) m NRS(O)2(C(R)2) m -#, wherein each R is independently hydrogen or C 1-6 Aliphatic group, each m is independently 0, 1 or 2, and # represents Cy AIn some embodiments, L is selected from -NR-#, -C(R)2NR-#, -C(R)2NRC(R)2-#, -NRC(O)-#, -C(R)2NRC(O)-#, -C(R)2C(R)2NRC(O)-#, -C(O)NRC(R)2-#, -C(R)2C(O)NR-#, -C(R)2C(O)NRC(R)2- #, -NRC(O)NR-#, -C(R)2OC(O)NR-#, -OC(R)2C(R)2NRC(O)-#, -OC(R)2C(R)2NRS(O)2-#, -S(O)2NRC(R)2-#, -C(R)2NRS(O)2-# and -C(R)2C(R)2NRS(O)2-#, wherein each R is independently hydrogen or C 1-6 Aliphatic group, and # represents Cy A In some embodiments, L is selected from -NR-#, -C(R)2NR-#, -C(R)2NRC(R)2-#, -NRC(O)-#, -C(R)2NRC(O)-#, -C(R)2C(R)2NRC(O)-#, -C(O)NRC(R)2-#, -C(R)2C(O)NR-#, -C(R)2C(O)NRC(R)2-#, -N RC(O)NR-#, -C(R)2OC(O)NR-#, -OC(R)2C(R)2NRC(O)-#, -OC(R)2C(R)2NRS(O)2-#, -S(O)2NRC(R)2-#, -C(R)2NRS(O)2-# and -C(R)2C(R)2NRS(O)2-#, wherein each R is independently hydrogen or methyl, and # represents a cyclic ... A connection point.

[0113] In some embodiments, L is selected from the group consisting of: -NH-#, -CH2NH-#, -CH2NHCH2-#, -C(CF3)HNHCH2-#, -NHC(O)-#, -CH2NHC(O)-#, -CH(CH3)NHC(O)-#, -CH2N(CH3)C(O)-#, CH2CH2NHC(O)-#, -CH2C(O)NH-#, -C(CH3)HC(O)NH-#, -C(O)NHCH2-#, -CH2C(O)NHCH2-#, -NHC(O)NH-#, -CH2OC(O)NH-#, -C(CH3)HOC(O)NH-#, -S(O)2NHCH2-#, S(O)2NHC(CH3)H-#, -CH2NHS(O)2-#, -C(CH3)HNHS(O)2-#, -CH2CH2NHS(O)2-#, -OCH2CH2NHC(O)-# and -OCH2CH2NHS(O)2-#, where # represents the point of attachment to Cy A the point of attachment.

[0114] In some embodiments, L is selected from –NRC(O)-#, –C(R)2NRC(O)-#, -C(R)2NRC(R)2-# and –C(R)2NRSO2-#, where each R is independently selected from hydrogen and C 1-6 aliphatic group, and # represents the point of attachment to Cy A the point of attachment. In some embodiments, L is selected from –NRC(O)-#, –C(R)2NRC(O)-#, -C(R)2NRC(R)2-# and –C(R)2NRSO2-#, where each R is independently selected from hydrogen and methyl, and # represents the point of attachment to Cy A the point of attachment. In some embodiments, L is selected from –NRC(O)-# and –C(R)2NRC(O)-#, where each R is independently selected from hydrogen and C 1-6 aliphatic group, and # represents the point of attachment to Cy A the point of attachment. In some embodiments, L is selected from –NRC(O)-# and –C(R)2NRC(O)-#, where each R is independently selected from hydrogen and methyl, and # represents the point of attachment to Cy A the point of attachment.

[0115] In some embodiments, R 1 and R 2 are each hydrogen. In some embodiments, R 2 is hydrogen, and R 1 together with monocyclic Cy A forms a fused 7- to 10-membered saturated or partially unsaturated bicyclic heteroazacyclic group having 1-4 heteroatoms selected from oxygen, nitrogen or sulfur. In some embodiments, n is 1, R 2is hydrogen, and R 1 With monocyclic Cy 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 2 is hydrogen, and R 1 With monocyclic Cy 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.

[0116] In some embodiments, R 1 and R 2 independently selected from hydrogen, halogen, -OR, -SR, -N(R)2 and optionally substituted C 1-6 an aliphatic group wherein each R is independently selected from hydrogen and C 1-6 In some embodiments, R 1 and R 2 are independently selected from hydrogen, fluorine, -OH, -SH, -NH2 and -(CH2) 0-4 C(O)OR o Substituted C 1-6 aliphatic group, where R o is hydrogen or C 1-6 In some embodiments, R 1 and R 2 are independently selected from hydrogen, fluorine, -OH and -(CH2) 0-4 C(O)OR o Substituted C 1-6 aliphatic group, where R o is hydrogen, methyl or ethyl.

[0117] In some embodiments, R 3 、R 4 、R 5 and R 7 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 1-6aliphatic, 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 3 、R 4 、R 5 and R 7 independently selected from hydrogen, halogen, -CN, -C(O)2R or an optionally substituted group selected from: C 1-6 aliphatic groups, 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 heterocyclic groups having 1-2 heteroatoms selected from oxygen, nitrogen or sulfur.

[0118] In some embodiments, optionally substituted R 3 、R 4 、R 5 and R 7 The substituents on each of the above groups are independently halogen, -CN, (CH2) 0-4 R o 、-(CH2) 0-4 OR o 、-(CH2) 0-4 N(R o )2、-(CH2) 0-4 O(CH2) 1-4 N(R o )2 and -(CH2) 0-4 C(O)OR o , where each R o are independently hydrogen, C 1-6 an aliphatic group or a 3- to 5-membered saturated, partially unsaturated, or aromatic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0119] In some embodiments, optionally substituted R 3 、R 4 、R 5 and R 7 The substituents on each independently are -F, -CN, -R o 、-OR o 、-N(R o )2. -COOR o or -OC(R o )2C(R o )2N(R o )2, where each R o are independently hydrogen, C 1-6 aliphatic or a 4-membered saturated ring having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur.3 、R 4 、R 5 and R 7 The substituents on the alkylene oxide are each independently selected from -F, -CN, -CH3, -OH, -NH2, -COOH, -COOCH2CH2, -OCH2CH2NH2, -OCH2CH2N(CH3)2 and

[0120] In some embodiments, R 4 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 4 is selected from hydrogen, halogen, -CN, -C(O)2R or an optionally substituted group selected from: C 1-6 aliphatic groups, 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 heterocyclic groups having 1-2 heteroatoms selected from oxygen, nitrogen or sulfur.

[0121] In some embodiments, optionally substituted R 4 The substituents on the o 、-OR o 、-N(R o )2. -COOR o or -OC(R o )2C(R o )2N(R o )2, where each R o are independently hydrogen, C 1-6 aliphatic or a 4-membered saturated ring having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur. 4 The substituents on the amine group are selected from -F, -CN, -CH3, -OH, -NH2, -COOH, -COOCH2CH2, -OCH2CH2NH2, -OCH2CH2N(CH3)2 and

[0122] In some embodiments, each R is independently hydrogen or optionally substituted C 1-6an aliphatic group, or two R groups on the same carbon or nitrogen together with their intervening atoms form a ring selected from the group consisting of 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.

[0123] In some embodiments, n is 0. In some embodiments, n is 1.

[0124] In some embodiments, provided compounds have formula (II):

[0125]

[0126] or a pharmaceutically acceptable salt thereof, wherein Cy A 、Cy B 、R 1 、R 2 、R 4 、R 6 Each of R, R, and n is defined and described in classes and subclasses herein;

[0127] Q is selected from -C(R)2-, -C(O)-, and -S(O)2-; and

[0128] p is 0, 1, or 2;

[0129] with the proviso that the compound is not N-(furan-2-ylmethyl)-N,3,5-trimethyl-1-((6-methylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-sulfonamide and 2-[(6,8-dichloroimidazo[1,2-a]pyridin-2-yl)methyl]-4-methyl-N-phenyl-5-thiazolecarboxamide.

[0130] It will be understood that, unless otherwise specified or prohibited by the definition of formula (II) above, the variables Cy as defined above and described in classes and subclasses herein are A 、Cy B 、R 1 、R 2 、R 4 、R 6 The embodiments of R, R and n also apply to the compounds of formula (II), whether alone or in combination.

[0131] In some embodiments, Q is -C(R) 2- , and p is 1. In some embodiments, Q is -C(O)-, and p is 1. In some embodiments, -C(O)-, and p is 0. In some embodiments, Q is -S(O)2-, and p is 1.

[0132] In some embodiments, provided compounds have formula (III):

[0133]

[0134] in represents a single bond or a double bond;

[0135] X is selected from C and N;

[0136] Each W is independently selected from CR A , CH, N and O; and

[0137] R A 、Cy B , L, R 1 、R 2 、R 4 and R 6 Each of these is defined and described in classes and subclasses herein;

[0138] with the proviso that the compound is not N-(furan-2-ylmethyl)-N,3,5-trimethyl-1-((6-methylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-sulfonamide.

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

[0140]

[0141] where R A 、Cy B , L, R 4 and R 6 Each of these is defined and described in classes and subclasses herein;

[0142] with the proviso that the compound is not N-(furan-2-ylmethyl)-N,3,5-trimethyl-1-((6-methylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-sulfonamide.

[0143] In some embodiments, provided compounds or pharmaceutically acceptable salts thereof have the structure of Formula (III-ai), Formula (III-bi), Formula (III-ci), Formula (III-di), Formula (III-ei), Formula (III-fi), or Formula (III-gi),

[0144]

[0145]

[0146] wherein Q is selected from –C(R)2-, –C(O)-, and –S(O)2-;

[0147] p is 0, 1, or 2; and

[0148] R A 、Cy B , L, R 4 、R 6 Each of and R is defined and described in classes and subclasses herein;

[0149] with the proviso that the compound is not N-(furan-2-ylmethyl)-N,3,5-trimethyl-1-((6-methylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-sulfonamide.

[0150] In some embodiments, Q is -C(R)2-, and p is 1. In some embodiments, Q is -C(O)-, and p is 1. In some embodiments, -C(O)-, and p is 0. In some embodiments, Q is -S(O)2-, and p is 1.

[0151] It will be understood that, unless otherwise specified or prohibited by the definition of formula (III) above, the variables R as defined above and described in classes and subclasses herein are A 、Cy B 、R 1 、R 2 、R 6 and R 7 The embodiments also apply to compounds of formula (III-a), formula (III-b), formula (III-c), formula (III-d), formula (III-e), formula (III-f) and formula (III-g), as well as formula (III-ai), formula (III-bi), formula (III-ci), formula (III-di), formula (III-ei), formula (III-fi) and formula (III-gi), whether alone or in combination.

[0152] In which R 1 With monocyclic Cy A In some embodiments, taken together to form an optionally substituted fused ring, the compound has Formula (IV):

[0153]

[0154] in represents a single bond or a double bond;

[0155] Each X is independently N or C;

[0156] Each Y is independently CR A , CH or N;

[0157] Z is CH2 or O; and

[0158] R A 、Cy B , L, R 4 and R 6 Each of these is defined and described in classes and subclasses herein.

[0159] In some embodiments, provided compounds or pharmaceutically acceptable salts thereof have the structures of Formula (IV-a), Formula (IV-b), Formula (IV-c), and Formula (IV-d),

[0160]

[0161] Among them, Cy B , L, R 4 and R 6 Each of these is defined and described in classes and subclasses herein.

[0162] In some embodiments, provided compounds or pharmaceutically acceptable salts thereof have the structures of Formula (IV-ai), Formula (IV-bi), Formula (IV-ci), and Formula (IV-di),

[0163]

[0164] wherein Q is selected from –C(R)2-, –C(O)-, and –S(O)2-;

[0165] p is 0, 1, or 2; and

[0166] Cy B 、R 4 、R 6 Each of and R is defined and described in classes and subclasses herein.

[0167] In some embodiments, Q is -C(R) 2- , and p is 1. In some embodiments, Q is -C(O)-, and p is 1. In some embodiments, -C(O)-, and p is 0. In some embodiments, Q is -S(O)2-, and p is 1.

[0168] It will be understood that, unless otherwise specified or prohibited by the definition of formula (IV) above, the variables R as defined above and described in classes and subclasses herein are A ,L,Cy B ,R 4 ,R 6The embodiments of R and R also apply to compounds of formula (IV-a), formula (IV-b), formula (IV-c) and formula (IV-d), as well as formula (IV-ai), formula (IV-bi), formula (IV-ci) and formula (IV-di), whether alone or in combination.

[0169] In some embodiments, the compound provided is any one of compounds I-1 to I-155 as shown in Table 1:

[0170] Table I

[0171]

[0172]

[0173]

[0174]

[0175]

[0176]

[0177]

[0178] or a pharmaceutically acceptable salt thereof.

[0179] C. Pharmaceutical Compositions

[0180] In another aspect, the present invention provides pharmaceutical compositions comprising a compound of Formula (I)-(IV) or a compound of Formula (I)-(IV) in combination with a pharmaceutically acceptable excipient (eg, a carrier).

[0181] The pharmaceutical composition includes an optical isomer, diastereomer, or pharmaceutically acceptable salt of the inhibitor disclosed herein. As described above, the compound of Formula (I)-(IV) included in the pharmaceutical composition can be covalently linked to a carrier moiety. Alternatively, the compound of Formula (I)-(IV) included in the pharmaceutical composition is not covalently linked to a carrier moiety.

[0182] As used herein, "pharmaceutically acceptable carrier" refers to a pharmaceutical excipient, such as a pharmaceutically, physiologically acceptable organic or inorganic carrier substance suitable for enteral or parenteral administration, which does not react adversely 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 that do not react adversely with the compounds of the present invention.

[0183] The compounds of the present invention can be administered alone or in combination to a subject. Co-administration is intended to include administering the compounds alone or in combination (more than one compound) simultaneously or sequentially. When desired, the preparation can also be combined with other active substances (e.g., to reduce metabolic degradation).

[0184] In some embodiments, test agents as described herein can be incorporated into pharmaceutical compositions for administration by methods known to those skilled in the art and described herein for the provided compounds.

[0185] D. Preparation

[0186] The compounds of the present invention can be prepared and administered in a wide variety of oral, parenteral and topical dosage forms. Thus, the compounds of the present invention can be administered by injection (e.g., intravenously, intramuscularly, intradermally, subcutaneously, intraduodenally or intraperitoneally). Additionally, the compounds described herein can be administered by inhalation, such as intranasally. Additionally, the compounds of the present invention can be administered transdermally. It is also contemplated that a variety of routes of administration (e.g., intramuscularly, orally, transdermally) 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.

[0187] 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 can also serve as a diluent, flavoring agent, binder, preservative, tablet disintegrant, or encapsulant.

[0188] In powders, the carrier is a finely divided solid which is mixed with the finely divided active ingredient. In tablets, the active ingredient is mixed with a carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.

[0189] 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 wax, cocoa butter, and the like. The term "preparation" is intended to encompass the formulation of the active compound with an encapsulating material such as a carrier providing a capsule in which the active ingredient, with or without other carriers, is surrounded by the 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.

[0190] 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 by stirring. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool, and thereby solidify.

[0191] 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.

[0192] When parenteral application is needed or desired, a particularly suitable mixture of the compound of the present invention is an injectable sterile solution, preferably an oily or aqueous solution, and a suspension, emulsion or implant, including a suppository. Specifically, carriers for parenteral administration include aqueous solutions of glucose, saline, purified water, ethanol, glycerol, propylene glycol, peanut oil, sesame oil, polyoxyethylene-block polymers, etc. Ampoules are suitable unit doses. The compound of the present invention can also be incorporated into liposomes or administered by transdermal pumps or patches. Suitable pharmaceutical mixtures for the present invention include, for example, those described in Pharmaceutical Sciences (17th edition, Mack Pub. Co., Easton, PA) and WO 96 / 05309, the teachings of which are hereby incorporated by reference.

[0193] 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 desired. 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.

[0194] Also included are solid form preparations that are intended to be converted into liquid form preparations for oral administration just 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, solubilizing agents, and the like.

[0195] 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.

[0196] The amount of active ingredient in a unit dose preparation may be varied or adjusted between 0.1 mg and 10,000 mg, more typically 1.0 mg to 1,000 mg, and 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.

[0197] Some compounds may have limited solubility in water, so a surfactant or other suitable co-solvent may be required in the composition. Such co-solvents include: polysorbates 20, 60, and 80; Pluronic F-68, F-84, and P-103; cyclodextrins; and polyoxyl 35 castor oil. Such co-solvents are typically used at levels between about 0.01% and about 2% by weight.

[0198] A viscosity greater than that of a simple aqueous solution may be desirable to reduce variability in dispensing the formulation, to reduce physical separation of components of a suspension or emulsion of the formulation, 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 its salts, hyaluronic acid and its salts, and combinations of the foregoing. Such agents are typically used at a level between about 0.01% and about 2% by weight.

[0199] The compositions of the present invention may further include components to provide sustained release and / or comfort. Such components include high molecular weight anionic high permeability polymers, curdlan, and finely dispersed drug carrier matrices. These components are discussed in more detail in U.S. Patents 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.

[0200] E. Effective dose

[0201] The pharmaceutical compositions provided herein include compositions containing 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 compositions 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).

[0202] The dose 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 any complications of the disease or treatment regimen. Other treatment regimens or agents may be used in conjunction with the methods and compounds of the present invention.

[0203] For any provided compound or test agent, a therapeutically effective amount can be initially determined from cell culture assays.The target concentration will be that concentration of active compound that is capable of reducing pKal enzyme activity, for example, as measured using the described methods.

[0204] The therapeutically effective amount for use in humans can be determined from animal models. For example, a dose for use in humans can be formulated to achieve a concentration that has been found to be effective in animals. As described above, the dose in humans can be adjusted by monitoring pKal inhibition and adjusting the dose upward or downward.

[0205] 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 for the circumstances is achieved. In some embodiments, the dosage range is 0.001% to 10% (w / v). In some embodiments, the dosage range is 0.1% to 5% (w / v).

[0206] Dosage amount and interval may be adjusted individually to provide a level of administered compound effective for the particular clinical indication being treated. This will provide a treatment regimen commensurate with the severity of the individual disease state.

[0207] F. Treatment

[0208] The present disclosure provides compounds for medicine. The present disclosure further provides any compound described herein for use in suppressing the activity of pKal, which will be beneficial for treating diseases and illnesses mediated by pKal. Exemplary pKal-mediated conditions include edema, which refers to swelling of the entire body or a part thereof caused by inflammation or damage when small blood vessels become leaky and release fluid into nearby tissues. In some instances, edema is HAE. In other instances, edema occurs in the eye, such as diabetic macular edema (DME). The present disclosure provides methods for suppressing the activity of pKal. In certain embodiments, the application provides methods for suppressing the activity of pKal in vitro by contacting any compound described herein with a pKal molecule in a sample (such as a biological sample). In certain embodiments, the application provides methods for suppressing the activity of pKal in vivo by delivering an effective amount of any compound described herein to a subject in need of treatment through an appropriate route.

[0209] In certain embodiments, the method comprises administering any compound 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)-(IV), 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)-(IV), or a pharmaceutically acceptable salt thereof, to a subject in need thereof.

[0210] In certain embodiments, the subject to be treated by any of the methods described herein is a human patient having, suspected of having, or at risk of developing edema (e.g., HAE or diabetic macular edema (DME)). A subject with edema can be identified by routine medical examination (e.g., laboratory tests). A subject suspected of having edema may display one or more symptoms of the disease / disorder. A subject at risk of developing edema can be a subject with one or more risk factors associated with the disease, such as, for HAE, a lack of C1-INH.

[0211] 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 routine medical procedures. An effective amount of one or more provided compounds can be administered to a human patient via a suitable route (e.g., those described herein). The compounds described herein can be used alone or in combination with other anti-HAE agents, such as C1 esterase inhibitors (e.g., or ), pKal inhibitors (e.g., ecallantide or lanadelumab), or bradykinin B2 receptor antagonists (e.g., ).

[0212] 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 of the compounds can be administered to a human patient via a suitable route, such as those described herein. The compounds described herein can be used alone or in combination with other anti-HAE agents, such as C1 esterase inhibitors (e.g., or ), pKal inhibitors (e.g., ecallantide or lanadelumab), or bradykinin B2 receptor antagonists (e.g., ).

[0213] In yet other embodiments, provided herein is the prophylactic treatment of HAE in human patients at risk of HAE attacks using one or more compounds 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 have one or more HAE risk factors (e.g., family history, genetic defects in the C1-INH gene, etc.). Such prophylactic treatment may involve a compound as described herein as the only active agent, or may involve additional anti-HAE agents, such as those described herein.

[0214] In certain embodiments, provided herein are methods for preventing or reducing edema in the eyes of a subject (e.g., a human patient). In some instances, the human patient is a diabetic patient suffering from, suspected of suffering from, or at risk of developing 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 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 DME treatment. Non-limiting examples of DME treatments include laser photocoagulation, steroids, VEGF pathway targeting agents (e.g., (ranibizumab) or (aflibercept)) and / or anti-PDGF agents.

[0215] In certain embodiments, the methods disclosed herein comprise administering to a subject an effective amount of a compound of Formula (I)-(IV) 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.

[0216] 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, cow, pig, horse, sheep, or goat. In certain embodiments, the subject is a companion animal, such as a dog or cat. In certain embodiments, the subject is a livestock animal, such as a cow, pig, horse, sheep, or goat. In certain embodiments, the subject is a zoo animal. In 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.

[0217] Certain methods described herein may include administering one or more additional agents in combination with the compounds described herein. (Multiple) additional agents may be administered simultaneously with the compound of formula (I)-(IV), or at a different time than the compound of formula (I)-(IV). For example, the compound of formula (I)-(IV) and any additional agent may be administered on the same schedule or on different schedules. Administration of all or some doses of the compound of formula (I)-(IV) may be before all or some doses of the additional agent, after all or some doses of the additional agent, within the administration schedule of the additional agent, or a combination thereof. For different additional agents, the timing of administration of the compound of formula (I)-(IV) and the additional agent may be different.

[0218] In certain embodiments, the additional agent includes an agent useful in treating edema, such as HAE or DME. Examples of such agents are provided herein.

[0219] V. Exemplary Embodiments

[0220] The present disclosure contemplates, inter alia, the following numbered embodiments:

[0221] 1. A compound of formula (I):

[0222]

[0223] or a pharmaceutically acceptable salt thereof,

[0224] in:

[0225] Cy A is selected from 5-membered monocyclic heteroarylene groups having 1-4 heteroatoms independently selected from oxygen, nitrogen and sulfur and 7- to 10-membered partially unsaturated bicyclic heterocyclylene groups having 1-4 heteroatoms independently selected from oxygen, nitrogen and sulfur, wherein Cy A 0-4 R A group substitution;

[0226] 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 an aliphatic group, a phenyl group, a 5- to 6-membered heteroaryl group having 1 to 4 heteroatoms selected from oxygen, nitrogen or sulfur, a 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 to 2 heteroatoms selected from oxygen, nitrogen or sulfur;

[0227] Cy B is selected from phenyl, a 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen and sulfur, a 7- to 10-membered partially unsaturated bicyclic carbocyclic group, a 10-membered bicyclic aryl, a 7- to 10-membered bicyclic heterocyclic group having 1-4 heteroatoms selected from oxygen, nitrogen and sulfur, a 7- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen and sulfur, and a 12-membered tricyclic heterocyclic group having 1-4 heteroatoms selected from oxygen, nitrogen and sulfur, wherein Cy B 0-5 R B group substitution;

[0228] Each R B independently selected from halogen, -CN, oxo, -C(R)=N(R), -C(O)R, -C(O)2R, -C(O)N(R), -C(=N(R))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 1-6aliphatic, 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, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic group having 1-2 heteroatoms selected from oxygen, nitrogen or sulfur, 7- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen and sulfur, and 8- to 10-membered spirocyclic heterocyclic group having 1-3 heteroatoms selected from oxygen, nitrogen or sulfur;

[0229] L is an optionally substituted C 1-6 a hydrocarbon chain in which 1 to 3 methylene units are independently replaced by –Cy-, –O–, –NR–, –C(O)–, –C(O)NR–, –NRC(O)–, –S(O)2NR–, –NRS(O)2–, or –S(O)2–;

[0230] -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;

[0231] R 1 and R 2 independently selected from hydrogen, halogen, -OR, -SR, -N(R)2 and optionally substituted C 1-6 aliphatic group; wherein R 1 Can be used with monocyclic Cy A taken together to 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;

[0232] R 3 、R 4 、R 5 and R 7 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 an aliphatic group, a phenyl group, a 5- to 6-membered heteroaryl group having 1 to 4 heteroatoms selected from oxygen, nitrogen or sulfur, a 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 to 2 heteroatoms selected from oxygen, nitrogen or sulfur;

[0233] R6 an optionally substituted group selected from 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 a group selected from: C 1-6 an aliphatic group, a phenyl group, a 5- to 6-membered heteroaryl group having 1 to 4 heteroatoms selected from oxygen, nitrogen or sulfur, a 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 to 2 heteroatoms selected from oxygen, nitrogen or sulfur;

[0234] Each R is independently hydrogen or an optionally substituted group selected from: C 1-6 an aliphatic group, a phenyl group, a 5- to 6-membered heteroaryl group having 1 to 4 heteroatoms selected from oxygen, nitrogen or sulfur, a 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 to 2 heteroatoms selected from oxygen, nitrogen or sulfur;

[0235] 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; and

[0236] n is 0 or 1;

[0237] The conditions are:

[0238] (a)R 3 、R 4 、R 5 、R 6 and R 7 At least one of them is C 1-6 an aliphatic group or a halogen; and

[0239] (b) the compound is not N-[1-[(6-fluoroimidazo[1,2-a]pyridin-2-yl)methyl]-5-methyl-1H-pyrazol-3-yl]-3-pyridinecarboxamide, N-[1-[(6-chloroimidazo[1,2-a]pyridin-2-yl)methyl]-5-methyl-1H-pyrazol-3-yl]-3-pyridinecarboxamide, 3-chloro-4-[[5-[8-chloro-6-(trifluoromethyl)imidazo[1 ,2-a]pyridin-2-yl]-1,3,4-oxadiazol-2-yl]amino]-phenylpropionic acid, 2-[(6,8-dichloroimidazo[1,2-a]pyridin-2-yl)methyl]-4-methyl-N-phenyl-5-thiazolecarboxamide and N-(furan-2-ylmethyl)-N,3,5-trimethyl-1-((6-methylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-sulfonamide.

[0240] 2. The compound of embodiment 1, wherein Cy A is selected from 5-membered heteroarylene groups having 1 to 4 heteroatoms independently selected from oxygen and nitrogen and 8-membered partially unsaturated bicyclic heterocyclylene groups having 2 to 3 heteroatoms selected from oxygen and nitrogen, wherein Cy A 0-3 R A Group substitution.

[0241] 3. The compound of embodiment 1, wherein Cy A is a 5-membered heteroarylene group having 1 to 4 heteroatoms independently selected from oxygen and nitrogen, wherein Cy A 0-3 R A Group substitution.

[0242] 4. The compound of embodiment 1, wherein Cy A is an 8-membered partially unsaturated bicyclic heterocyclylene group having 2-3 heteroatoms selected from oxygen and nitrogen, wherein Cy A 0-3 R A Group substitution.

[0243] 5. The compound of embodiment 1, wherein Cy A Selected from the group consisting of:

[0244]

[0245] Where * represents the connection point with L.

[0246] 6. The compound according to any one of the preceding embodiments, wherein R 3 、R 5 and R 7 It's hydrogen.

[0247] 7. The compound of embodiment 1, wherein the compound has formula (III):

[0248]

[0249] or a pharmaceutically acceptable salt thereof,

[0250] in:

[0251] represents a single bond or a double bond;

[0252] X is selected from C and N;

[0253] Each W is independently selected from CR A , CH, N and O;

[0254] R 4 is selected from hydrogen, halogen, -CN, -C(O)OR or an optionally substituted group selected from: C 1-6 aliphatic groups, 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 heterocyclic groups having 1-2 heteroatoms selected from oxygen, nitrogen or sulfur;

[0255] R 6 Selected from C 1-6 an aliphatic group or a halogen; and

[0256] Each R is independently hydrogen or selected from C 1-6 an optionally substituted group of an aliphatic group;

[0257] or two R groups on the same carbon or nitrogen together with their intervening atoms form a ring selected from the group consisting of 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;

[0258] with the proviso that the compound is not N-(furan-2-ylmethyl)-N,3,5-trimethyl-1-((6-methylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-sulfonamide.

[0259] 8. The compound of embodiment 1, wherein R 1 With monocyclic Cy 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.

[0260] 9. The compound of embodiment 1 or 8, wherein the compound has formula (IV):

[0261]

[0262] in represents a single bond or a double bond;

[0263] Each X is independently N or C;

[0264] Each Y is independently CR A , CH or N;

[0265] Z is CH2 or O;

[0266] R A is selected from an optionally substituted group, the optionally substituted group is selected from C 1-6 an aliphatic group, a 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;

[0267] R 4 is selected from hydrogen, halogen, -CN, -C(O)OR 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; and

[0268] R 6 Selected from C 1-6 an aliphatic group or a halogen.

[0269] 10. The compound of embodiment 1 or 7, wherein the compound has Formula (III-a), Formula (III-b), Formula (III-c), Formula (III-d), Formula (III-e), Formula (III-f), or Formula (III-g):

[0270]

[0271]

[0272] or a pharmaceutically acceptable salt thereof,

[0273] in:

[0274] R A is selected from an optionally substituted group, the optionally substituted group is selected from C 1-6 an aliphatic group, a 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;

[0275] R 4 is selected from hydrogen, halogen, -CN, -C(O)OR or an optionally substituted group selected from: C 1-6aliphatic, 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; and

[0276] R 6 Selected from C 1-6 an aliphatic group or a halogen;

[0277] with the proviso that the compound is not N-(furan-2-ylmethyl)-N,3,5-trimethyl-1-((6-methylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-sulfonamide.

[0278] 11. The compound of embodiment 1 or 9, wherein the compound has formula (IV-a), formula (IV-b), formula (IV-c) or formula (IV-d):

[0279]

[0280]

[0281] or a pharmaceutically acceptable salt thereof,

[0282] in:

[0283] R 4 is selected from hydrogen, halogen, -CN, -C(O)OR 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; and

[0284] R 6 Selected from C 1-6 an aliphatic group or a halogen.

[0285] 12. The compound according to any one of the preceding embodiments, wherein L is selected from -(C(R)2) m NR(C(R)2) m -#、-(C(R)2) m NRC(O)(C(R)2) m -#、-(C(R)2) m C(O)NR(C(R)2) m -#、-NRC(O)NR-#、-(C(R)2) m OC(O)NR(C(R)2) m -#, -O(C(R)2) m NRC(O)-#、-O(C(R)2) mNRS(O)2-#、-(C(R)2) m S(O)2NR(C(R)2) m -# and -(C(R)2) m NRS(O)2(C(R)2) m -#, wherein each R is independently hydrogen or optionally substituted C 1-6 Aliphatic group, each m is independently 0, 1 or 2, and # represents Cy A connection point.

[0286] 13. The compound of any one of the preceding embodiments, wherein L is selected from -NR-#, -C(R)2NR-#, -C(R)2NRC(R)2-#, -NRC(O)-#, -C(R)2NRC(O)-#, -C(R)2C(R)2NRC(O)-#, -C(O)NRC(R)2-#, -C(R)2C(O)NR-#, -C(R)2C(O)NRC( R)2-#, -NRC(O)NR-#, -C(R)2OC(O)NR-#, -OC(R)2C(R)2NRC(O)-#, -OC(R)2C(R)2NRS(O)2-#, -S(O)2NRC(R)2-#, -C(R)2NRS(O)2-# and -C(R)2C(R)2NRS(O)2-#, each R is independently hydrogen or optionally substituted C 1-6 Aliphatic group, and # represents Cy A connection point.

[0287] 14. The compound of any one of the preceding embodiments, wherein L is selected from -NRC(O)-#, -C(R)2NRC(O)-#, -C(R)2NRC(R)2-#, and -C(R)2NRSO2-#, wherein each R is independently selected from hydrogen and optionally substituted C 1-6 Aliphatic group, and # represents Cy A connection point.

[0288] 15. The compound of any one of the preceding embodiments, wherein L is selected from -NRC(O)-# and -C(R)2NRC(O)-#, wherein each R is independently selected from hydrogen and optionally substituted C 1-6 Aliphatic group, and # represents Cy A connection point.

[0289] 16. The compound of embodiment 1, wherein the compound has formula (II):

[0290]

[0291] or a pharmaceutically acceptable salt thereof,

[0292] in:

[0293] Cy A is selected from 5-membered monocyclic heteroarylene groups having 1-4 heteroatoms independently selected from oxygen, nitrogen and sulfur and 7- to 10-membered partially unsaturated bicyclic heterocyclylene groups having 1-4 heteroatoms independently selected from oxygen, nitrogen and sulfur, wherein Cy A 0-4 R A group substitution;

[0294] R A is selected from an optionally substituted group, the optionally substituted group is selected from C 1-6 an aliphatic group, a 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;

[0295] Q is selected from -C(R)2-, -C(O)- and -S(O)2-;

[0296] Cy B is selected from phenyl, a 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen and sulfur, a 7- to 10-membered partially unsaturated bicyclic carbocyclic group, a 10-membered bicyclic aryl, a 7- to 10-membered bicyclic heterocyclic group having 1-4 heteroatoms selected from oxygen, nitrogen and sulfur, a 7- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen and sulfur, and a 12-membered tricyclic heterocyclic group having 1-4 heteroatoms selected from oxygen, nitrogen and sulfur, wherein Cy B 0-5 R B group substitution;

[0297] R B an optionally substituted group selected from halogen, -CN, -OR, -N(R)2, -N(R)CN, -C(=N(R))N(R)2, -S(O)R, -S(O)2R, -S(O)2N(R)2 or a 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 radical, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic radical having 1-2 heteroatoms selected from oxygen, nitrogen or sulfur, 7- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen and sulfur, and 8- to 10-membered spirocyclic heterocyclic radical having 1-3 heteroatoms selected from oxygen, nitrogen or sulfur, wherein each R is independently hydrogen or an optionally substituted C 1-6 aliphatic groups;

[0298] R 1 and R 2 independently selected from hydrogen, halogen, -OR, -SR, -N(R)2 and optionally substituted C 1-6 aliphatic group; wherein R 1 Can be used with monocyclic CyA taken together to 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;

[0299] R 4 is selected from hydrogen, halogen, -CN, -C(O)OR or an optionally substituted group selected from: C 1-6 aliphatic groups, 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 heterocyclic groups having 1-2 heteroatoms selected from oxygen, nitrogen or sulfur;

[0300] R 6 Selected from C 1-6 an aliphatic group or a halogen;

[0301] Each R is independently hydrogen or selected from C 1-6 an optionally substituted group of an aliphatic group;

[0302] or two R groups on the same carbon or nitrogen together with their intervening atoms form a ring selected from the group consisting of 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;

[0303] n is 0 or 1; and

[0304] p is 0, 1, or 2;

[0305] with the proviso that the compound is not N-(furan-2-ylmethyl)-N,3,5-trimethyl-1-((6-methylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-sulfonamide and 2-[(6,8-dichloroimidazo[1,2-a]pyridin-2-yl)methyl]-4-methyl-N-phenyl-5-thiazolecarboxamide.

[0306] 17. The compound of embodiment 16, wherein Cy A is selected from 5-membered heteroarylene groups having 1 to 4 heteroatoms independently selected from oxygen and nitrogen and 8-membered partially unsaturated bicyclic heterocyclylene groups having 2 to 3 heteroatoms selected from oxygen and nitrogen, wherein Cy A 0-3 R A Group substitution.

[0307] 18. The compound of embodiment 16, wherein Cy A is a 5-membered heteroarylene group having 1 to 4 heteroatoms independently selected from oxygen and nitrogen, wherein Cy A 0-3 R A Group substitution.

[0308] 19. The compound of embodiment 16, wherein Cy A is an 8-membered partially unsaturated bicyclic heterocyclylene group having 2-3 heteroatoms selected from oxygen and nitrogen, wherein Cy A 0-3 R A Group substitution.

[0309] 20. The compound of embodiment 16, wherein Cy A Selected from the group consisting of:

[0310]

[0311] Where * represents the connection point with L.

[0312] 21. The compound of embodiment 1, wherein the compound has Formula (III-ai), Formula (III-bi), Formula (III-ci), Formula (III-di), Formula (III-ei), Formula (III-fi), or Formula (III-gi):

[0313]

[0314] or a pharmaceutically acceptable salt thereof,

[0315] in:

[0316] Q is selected from -C(R)2-, -C(O)- and -S(O)2-;

[0317] R A is selected from an optionally substituted group, the optionally substituted group is selected from C 1-6 an aliphatic group, a 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;

[0318] R 4 is selected from hydrogen, halogen, -CN, -C(O)OR or an optionally substituted group selected from: C 1-6 aliphatic groups, 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 heterocyclic groups having 1-2 heteroatoms selected from oxygen, nitrogen or sulfur;

[0319] R 6 Selected from C 1-6 an aliphatic group or a halogen; and

[0320] p is 0, 1, or 2;

[0321] with the proviso that the compound is not N-(furan-2-ylmethyl)-N,3,5-trimethyl-1-((6-methylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-sulfonamide.

[0322] 22. The compound of embodiment 8, wherein the compound has Formula (IV-ai), Formula (IV-bi), Formula (IV-ci), Formula (IV-di), Formula (IV-ei), Formula (IV-fi), Formula (IV-gi):

[0323]

[0324] or a pharmaceutically acceptable salt thereof,

[0325] in:

[0326] Q is selected from -C(R)2-, -C(O)- and -S(O)2-;

[0327] p is 0, 1, or 2;

[0328] R 4 is selected from hydrogen, halogen, -CN, -C(O)OR 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; and

[0329] R 6 Selected from C 1-6 an aliphatic group or a halogen.

[0330] 23. The compound of any one of embodiments 16 to 22, wherein Q is -C(R)2-, and p is 1.

[0331] 24. The compound of any one of embodiments 16 to 22, wherein Q is -C(O)-, and p is 1.

[0332] 25. The compound of any one of embodiments 16 to 22, wherein -C(O)-, and p is 0.

[0333] 26. The compound of any one of embodiments 16 to 22, wherein Q is -S(O)2-, and p is 1.

[0334] 27. The compound of any one of the preceding embodiments, wherein Cy Bis selected from phenyl, a 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen and sulfur, a 7- to 10-membered partially unsaturated bicyclic carbocyclic group, a 10-membered bicyclic aryl, a 7- to 10-membered bicyclic heterocyclic group having 1-4 heteroatoms selected from oxygen, nitrogen and sulfur, a 7- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen and sulfur, and a 12-membered tricyclic heterocyclic group having 1-4 heteroatoms selected from oxygen, nitrogen and sulfur, wherein Cy B 0-5 R B Group substitution.

[0335] 28. The compound of embodiment 27, wherein Cy B Is 0-5 R B substituted phenyl groups.

[0336] 29. The compound of embodiment 27, wherein Cy B is a 5-membered monocyclic heteroaryl group having 2-3 heteroatoms independently selected from oxygen, nitrogen and sulfur, wherein Cy B 0-2 R B Group substitution.

[0337] 30. The compound of embodiment 27, wherein Cy B is a 6-membered monocyclic heteroaryl group having 1-2 nitrogen atoms, wherein Cy B 0-3 R B Group substitution.

[0338] 31. The compound of embodiment 27, wherein Cy B is a 9- to 10-membered bicyclic heteroaryl group having 1-4 heteroatoms selected from oxygen, nitrogen and sulfur, wherein Cy B 0-3 R B replace.

[0339] 32. The compound of embodiment 27, wherein Cy B Selected from the group consisting of:

[0340]

[0341]

[0342] 33. A compound according to any one of the preceding embodiments, wherein Cy B For not: group.

[0343] 34. A compound according to any one of the preceding embodiments, wherein R 6 It is C 1-6 Aliphatic group.

[0344] 35. The compound of any one of the preceding embodiments, wherein R6 It is C 1-6 Cycloalkyl.

[0345] 36. A compound according to any one of the preceding embodiments, wherein R 6 It is cyclopropyl.

[0346] 37. The compound according to any one of the preceding embodiments, wherein the compound is any one of compounds I-1 to I-137 as shown in Table I, or a pharmaceutically acceptable salt thereof.

[0347] 38. The compound according to any one of the preceding embodiments, wherein the compound is any one of compounds I-1 to I-125 and I-128 to I-137 as shown in Table I, or a pharmaceutically acceptable salt thereof.

[0348] 39. A pharmaceutical composition comprising a compound according to any one of the preceding embodiments, further comprising a pharmaceutically acceptable excipient.

[0349] 40. A method of treating a plasma kallikrein-mediated disease or condition using a compound or composition according to any one of the preceding embodiments.

[0350] 41. A method of treating hereditary angioedema or diabetic macular edema comprising administering to a patient in need thereof a compound according to any one of the preceding embodiments.

[0351] VI. Examples

[0352] Example 1

[0353] General Procedure A for Amide Synthesis:

[0354] Solution 1

[0355]

[0356] Synthesis of 5-cyclopropylpyridin-2-amine. A solution of 5-bromopyridin-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 / H2O (100mL / 10mL) was stirred at 95°C under nitrogen for 12h. The reaction mixture was then quenched with H2O (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-cyclopropylpyridin-2-amine as a yellow solid (3.8g, 97.4% yield). ESI-MS[M+H] + :135.2.

[0357] Synthesis of 2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine. To a solution of 5-cyclopropyl-4-methylpyridin-2-amine (500 mg, 3.70 mmol) in DMF (10 mL) was added 1,3-dichloropropane-2-one (1409 mg, 11.1 mmol) at room temperature. The resulting reactant was stirred at 85 ° C for 2 h. The solution was quenched with H2O (60 mL), adjusted to pH 8 by adding saturated NaHCO3 solution, and extracted with EtOAc (50 mL x3). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo to give a crude material, which was purified by preparative TLC (PE / EtOAc=1 / 1) to give 2-(chloromethyl)-6-cyclopropyl-7-methylimidazo[1,2-a]pyridine (300 mg, yield: 39%) as a light yellow oil. ESI-MS[M+H] + :207.2.

[0358] 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 Cs2CO3 (6.32 g, 19.38 mmol) at room temperature. The resulting reaction was stirred at room temperature for 12 h. H2O (150 mL) was added to the reaction, and the mixture was 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 material, 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.

[0359] Synthesis of 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylic acid. To a solution of ethyl 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate (1.2 g, 3.87 mmol) in THF (20 mL) and H2O (10 mL) was added LiOH (464 mg, 19.35 mmol). The mixture was stirred at room temperature for 16 h. Most of the THF was removed, and the pH was adjusted to 4-5 by adding HCl (1 M). The resulting precipitate was collected and dried to give 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylic acid as a white solid (1.0 g, yield: 91%). ESI-MS [M+H] + :283.2.

[0360] General Procedure A for Amide Coupling. To a solution of 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylic acid (60 mg, 0.21 mmol), amine (0.32 mmol) and HATU (120 mg, 0.31 mmol) in DMF (8 mL) was added DIPEA (81 mg, 0.63 mmol). The reaction mixture was stirred at room temperature for 12 h. Water (25 mL) was added and the mixture was extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to give the crude product, which was purified by preparative TLC, preparative HPLC or silica gel chromatography to give the desired product.

[0361] The following compounds were synthesized according to General Procedure A starting from 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide and the indicated amines: N-((3-amino-5,7-dimethylbenzo[d]isoxazol-6-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (I-134), N-((7-bromonaphthalen-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (I-133), N-(3-bromophenethyl)-1-((6-cyclopropylimidazo[1,2-a] -1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (I-132), N-((7-chloroisoquinolin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (I-131), N-(2-(3-chlorophenoxy)ethyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (I-129), N-((5-chlorobenzo[b]thiophen-3-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (I-128), N-((5- 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (I-127), N-((6-chloro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (I-126), N-(5-chloro-2-(1H-tetrazol-1-yl)benzyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (I-125), 1-((6-cyclopropylimidazo[1,2 -a]pyridin-2-yl)methyl)-N-((4,6-dimethyl-1H-indol-5-yl)methyl)-1H-pyrazole-4-carboxamide (I-124), N-((3-chloro-4,6-dimethyl-1H-indol-5-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (I-123), N-((6-bromo-2-oxo-1,2-dihydroquinolin-4-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (I-122), N-(3-chlorobenzyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (I-121), N-((6-chloro-8-fluoroimidazo[1,5-a]pyridin-3-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (I-137), 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-((2-oxo-1,2-dihydroquinolin-4-yl)methyl yl)-1H-pyrazole-4-carboxamide (I-120), N-(6-cyano-2-fluoro-3-methoxybenzyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (I-119) and N-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)benzyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (I-116).

[0362] Example 2

[0363] N-((3-amino-5,7-dimethylbenzo[d]isoxazol-6-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (I-134)

[0364] Option 2

[0365]

[0366] Synthesis of N-((3-amino-5,7-dimethylbenzo[d]isoxazol-6-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide. N-((3-amino-5,7-dimethylbenzo[d]isoxazol-6-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide was synthesized according to General Procedure A starting from 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide and 6-(aminomethyl)-5,7-dimethylbenzo[d]isoxazol-3-amine hydrochloride. The crude product was purified by preparative TLC (DCM / MeOH=10 / 1) to give the product (17 mg, yield: 26.7%) as a white solid. ESI-MS [M+H] + :456.2. 1H NMR (400MHz, DMSO) δ8.49(t,J=5.3Hz,1H),8.34(s,1H),8.23(s,1H),7.88(s,1H),7.75(s,1H),7.40(d,J=9.3Hz,1H),7.00(d,J=9.3Hz,1H),6.87( s,1H),5.85(s,2H),5.40(s,2H),4.43(d,J=5.4Hz,2H),2.50(s,3H),2.3 2(s,3H),1.95-1.89(m,1H),0.92(d,J=6.7Hz,2H),0.67(d,J=4.6Hz,2H).

[0367] Example 3

[0368] N-((7-bromonaphthalen-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (I-133)

[0369] Option 3

[0370]

[0371] Synthesis of N-((7-bromonaphthalen-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide. N-((7-bromonaphthalen-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide was synthesized starting from 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide and 6-(7-bromonaphthalen-1-yl)methanamine according to General Procedure A. The crude product was purified by preparative TLC (DCM / MeOH = 10 / 1) to give the product (6 mg, yield: 20%) as a white solid. ESI-MS [M+H]+: 500.1. 1 H NMR (400MHz, MeOD) δ8.32(s,1H),8.16(d,J=6.4Hz,2H),7.95(s,1H),7.81(d,J=8.6Hz,2H),7.70(s,1H),7.62–7.51(m,2H),7.50–7.4 3(m,1H),7.37(d,J=9.3Hz,1H),7.12–7.06(m,1H),5.44(s,2H),4.92(s,2H),1.98–1.88(m,1H),1.00–0.94(m,2H),0.73–0.67(m,2H).

[0372] Example 4

[0373] N-(3-bromophenethyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (I-132)

[0374] Option 4

[0375]

[0376] Synthesis of N-(3-bromophenethyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide. N-(3-bromophenethyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide was synthesized according to General Procedure A starting from 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide and 2-(3-bromophenyl)ethan-1-amine. The crude product was purified by preparative TLC (DCM / MeOH = 10 / 1) to give the product (35 mg, yield: 42.7%) as a pink solid. ESI-MS [M+H]+: 464.1. 1 H NMR (400MHz, DMSO) δ8.34(s,1H),8.15(s,2H),7.81(s,1H),7.74(s,1H),7.47–7.35(m,3H),7.27–7.17(m,2H),7.02-6.9 7(m,1H),5.39(s,2H),3.43-3.31(m,2H),2.78(t,J=7.2Hz,2H),1.95-1.87(m,1H),0.95–0.88(m,2H),0.70–0.64(m,2H).

[0377] Example 5

[0378] N-((7-chloroisoquinolin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (I-131)

[0379] Option 5

[0380]

[0381] Synthesis of N-((7-chloroisoquinolin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide. N-((7-chloroisoquinolin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide was synthesized starting from 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide and (7-chloroisoquinolin-1-yl)methanamine according to General Procedure A. The crude product was purified by preparative TLC (DCM / MeOH = 10 / 1) to give the product (12 mg, yield: 12.5%) as a white solid. ESI-MS [M+H] + :457.2. 1 HNMR(400MHz, DMSO)δ8.71(t,J=5.7Hz,1H),8.47–8.46(m,2H),8.33(s,1H),8.26(s,1H),8.05(d,J=8.8Hz,1H),7.90(s,1H),7.82–7.79(m,2H),7 .74(s,1H),7.40(d,J=9.3Hz,1H),7.02-6.97(m,1H),5.40(s,2H),5.01( d,J=5.7Hz,2H),1.93–1.59(m,1H),0.94–0.90(m,2H),0.68–0.64(m,2H).

[0382] Example 6

[0383] N-(2-(3-chlorophenoxy)ethyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (I-129)

[0384] Option 6

[0385]

[0386] Synthesis of N-(2-(3-chlorophenoxy)ethyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide. N-(2-(3-chlorophenoxy)ethyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide was synthesized according to General Procedure A starting from 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide and 2-(3-chlorophenoxy)ethan-1-amine. The crude product was purified by preparative HPLC to give the product (38 mg, yield: 25%) as a light yellow solid. ESI-MS [M+H]+: 436.2. 1 H NMR (400MHz, DMSO) δ8.34(s,1H),8.30(t,J=5.5Hz,1H),8.20(s,1H),7.85(s,1H),7.74(s,1H),7.40(d,J=9.3Hz,1H),7.29(t,J=8.2Hz, 1H),7.05–6.90(m,4H),5.40(s,2H),4.07(t,J=5.8Hz,2H),3.57-3.49(m,2H),1.98–1.85(m,1H),0.97–0.87(m,2H),0.71–0.62(m,2H).

[0387] Example 7

[0388] N-((5-chlorobenzo[b]thien-3-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (I-128)

[0389] Option 7

[0390]

[0391] Synthesis of N-((5-chlorobenzo[b]thiophen-3-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide. N-((5-chlorobenzo[b]thiophen-3-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide was synthesized starting from 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide and (5-chlorobenzo[b]thiophen-3-yl)methanamine according to General Procedure A. The crude product was purified by preparative TLC (DCM:MeOH = 20:1) to give the product (18.8 mg, yield: 27%) as a white solid. ESI-MS[M+H]+:462.2. 1 H NMR (400MHz, DMSO) δ8.63(t,J=5.7Hz,1H),8.32(s,1H),8.23(s,1H),8.03–7.99(m,2H),7.88(s,1H),7.73(s,1H),7.65(s,1H),7 .41-7.37(m,2H),7.01-6.96(m,1H),5.40(s,2H),4.60(d,J=5.7Hz,2H),1.94-1.88(m,1H),0.94-0.86(m,2H),0.70-0.62(m,2H).

[0392] Example 8

[0393] N-((7-chloronaphth-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (I-130)

[0394] Option 8

[0395]

[0396] Synthesis of N-((7-chloronaphthalen-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide. To a solution of methyl 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (100 mg, 0.354 mmol) in anhydrous DMF (5 mL) was added DIPEA (200 mg, 1.55 mmol). The mixture was stirred at room temperature for 1 h. (7-chloronaphthalen-1-yl)methylamine (1100 mg, 0.522 mmol) was then added. The final mixture was stirred at room temperature for 16 h. The mixture was quenched with water (50 mL) and extracted with EA (30 mL*3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4 and concentrated. The residue was purified by preparative TLC (DCM / MeOH = 10 / 1) to provide N-((7-chloronaphthalen-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (40 mg, yield: 24.8%) as a brown solid. ESI-MS [M+H]+: 456.2. Purity: 96.2 (214 nm), 97.0 (254 nm). 1 H NMR (400MHz, DMSO) δ8.65(t,J=5.8Hz,1H),8.33(s,1H),8.28–8.20(m,2H),8.00(d,J=8.8Hz,1H),7.93–7.83(m,2H),7.75(s,1H),7.60–7.45(m,3H) ),7.40(d,J=9.3Hz,1H),7.02-6.95(m,1H),5.41(d,J=4.8Hz,2H),4.82( d,J=5.8Hz,2H),1.95-1.85(m,1H),0.97–0.86(m,2H),0.72–0.60(m,2H).

[0397] Example 9

[0398] N-((5-chlorobenzo[d]isothiazol-3-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (I-127)

[0399] Option 9

[0400]

[0401] Synthesis of N-((5-chlorobenzo[d]isothiazol-3-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide. N-((5-chlorobenzo[d]isothiazol-3-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide was synthesized starting from 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide and (5-chlorobenzo[d]isothiazol-3-yl)methanamine according to General Procedure A. The crude product was purified by preparative TLC (DCM / MeOH = 10 / 1) to give the product (10 mg, yield: 18%) as a white solid. ESI-MS[M+H]+:463.1. 1 H NMR (400MHz, DMSO) δ8.82(t,J=5.9Hz,1H),8.38–8.30(m,2H),8.26-8.22(m,2H),7.89(s,1H),7.74(s,1H),7.66-7.62(m,1H),7.4 0(d,J=9.3Hz,1H),7.01-6.98(m,1H),5.41(s,2H),4.85(d,J=5.9Hz,2H),1.95–1.87(m,1H),0.96–0.87(m,2H),0.69–0.62(m,2H).

[0402] Example 10

[0403] N-((6-chloro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (I-126)

[0404] Plan 10

[0405]

[0406] Synthesis of N-((6-chloro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide. N-((6-chloro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide was synthesized according to General Procedure A starting from 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide and (6-chloro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methanamine hydrobromide. The crude product was purified by preparative TLC (DCM / MeOH=10 / 1) to give the product (15 mg, yield: 16%) as a white solid. ESI-MS [M+H] + :447.1. 1 H NMR (400MHz, DMSO) δ8.90(t,J=5.8Hz,1H),8.86-8.84(m,1H),8.34(s,1H),8.24(s,1H),7.88(s,1H),7.84-7.81(m,1H),7.74(s,1H) ,7.44-7.39(m,2H),7.03-6.98(m,1H),5.41(s,2H),4.91(d,J=5.8Hz,2H),1.96–1.88(m,1H),0.95–0.86(m,2H),0.71–0.62(m,2H).

[0407] Example 11

[0408] 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide

[0409] Plan 11

[0410]

[0411] Synthesis of 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide. To a mixture of 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylic acid (100 mg, 0.35 mmol), NH4Cl (187 mg, 3.5 mmol), HOBT (94.5 mg, 0.7 mmol) and EDCI (134.4 mg, 0.7 mmol) in DMF (5 mL) was added DIPEA (225.8 mg, 1.76 mmol). The reaction mixture was stirred at room temperature for 18 h, then diluted with water (50 mL) and extracted with EtOAc (30 mL x 5). The combined organic layers were washed with brine (50 mL), dried over Na2SO4 and concentrated in vacuo. The residue was purified by preparative HPLC to give 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (15 mg, 15.2%) as a white solid. ESI-MS [M+H] + :282.2. 1 H NMR (400MHz, DMSO) δ8.34(s,1H),8.16(S,1H),7.82(s,1H),7.74(s,1H),7.54(s,1H),7.40(d,J=9. 3Hz,1H),7.03–6.95(m,2H),5.39(s,2H),1.96–1.89(m,1H),0.94–0.91(m,2H),0.73–0.66(m,2H).

[0412] Example 12

[0413] N-(5-chloro-2-(1H-tetrazol-1-yl)benzyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (I-125)

[0414] Plan 12

[0415]

[0416] Synthesis of N-(5-chloro-2-(1H-tetrazol-1-yl)benzyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide. N-(5-chloro-2-(1H-tetrazol-1-yl)benzyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide was synthesized according to General Procedure A starting from 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide and (5-chloro-2-(1H-tetrazol-1-yl)phenyl)methanamine. The crude product was purified by preparative TLC (DCM / MeOH = 10 / 1) to give the product (10 mg, yield: 21%) as a yellow solid. ESI-MS[M+H]+:474.2. 1 H NMR (400MHz, DMSO) δ9.87(s,1H),8.59(t,J=5.7Hz,1H),8.34(s,1H),8.19(s,1H),7.82(s,1H),7.76(s,1H),7.63(d,J=1.3Hz,2H),7.58(s,1 H), 7.40 (d, J = 9.4Hz, 1H), 7.00 (d, J = 9.4Hz, 1H), 5.41 (s, 2H), 4.22 (d, J = 5.7Hz, 2H), 1.96-1.89 (m, 1H), 0.93-0.89 (m, 2H), 0.69-0.65 (m, 2H).

[0417] Example 13

[0418] 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-((4,6-dimethyl-1H-indol-5-yl)methyl)-1H-pyrazole-4-carboxamide (I-124)

[0419] Plan 13

[0420]

[0421] Synthesis of 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-((4,6-dimethyl-1H-indol-5-yl)methyl)-1H-pyrazole-4-carboxamide. 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide was synthesized starting from 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide and (4,6-dimethyl-1H-indol-5-yl)methanamine according to General Procedure A. The crude product was purified by preparative HPLC to give the product (25 mg, yield: 25%) as a white solid. ESI-MS [M+H]+: 439.2. 1 HNMR(400MHz,DMSO)δ10.84(s,1H),8.31(s,1H),8.24(s,1H),7.90-7.84(m ,2H),7.71(s,1H),7.38(d,J=9.3Hz,1H),7.24–7.16(m,1H),7.05(s,1H),7 .00-6.95(m,1H),6.40(s,1H),5.36(s,2H),4.49(d,J=4.4Hz,2H),2.47(s, 3H),2.37(s,3H),1.95-1.86(m,1H),0.96–0.84(m,2H),0.71–0.61(m,2H).

[0422] Example 14

[0423] N-((3-chloro-4,6-dimethyl-1H-indol-5-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (I-123)

[0424] Plan 14

[0425]

[0426] Synthesis of N-((3-chloro-4,6-dimethyl-1H-indol-5-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide. N-((3-chloro-4,6-dimethyl-1H-indol-5-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide was synthesized starting from 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide and (3-chloro-4,6-dimethyl-1H-indol-5-yl)methanamine according to General Procedure A. The crude product was purified by preparative HPLC to give the product (15 mg, yield: 8.6%) as a white solid. ESI-MS[M+H]+:473.2. 1 H NMR (400MHz, DMSO) δ11.14(s,1H),8.32(s,1H),8.24(s,1H),7.91-7.84(m,2H),7.72(s,1H),7.41-7.32(m,2H),7.06(s,1H),6.98(d, J=9.1Hz,1H),5.37(s,2H),4.47(d,J=4.0Hz,2H),2.71(s,3H),2.37(s,3H),1.92-01.87(m,1H),0.94-0.86(m,2H),0.69-0.62(m,2H).

[0427] Example 15

[0428] N-((6-bromo-2-oxo-1,2-dihydroquinolin-4-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (I-122)

[0429] Plan 15

[0430]

[0431] Synthesis of N-((6-bromo-2-oxo-1,2-dihydroquinolin-4-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide. N-((6-bromo-2-oxo-1,2-dihydroquinolin-4-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide was synthesized according to General Procedure A starting from 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide and 4-(aminomethyl)-6-bromoquinolin-2(1H)-one. The crude product was purified by preparative TLC (MeOH / DCM=1 / 10) to give the product (17.6 mg, yield: 16%) as a white solid. ESI-MS [M+H] + : 517.1. 1 H NMR(400MHz,DMSO)δ11.82(s,1H),8.66(t,J=5.7Hz,1H),8.34(s,1H),8.27(s,1 H),8.01(d,J=1.8Hz,1H),7.91(s,1H),7.76(s,1H),7.69-7.65(m,1H),7.41(d,J =9.3Hz,1H),7.27(d,J=8.8Hz,1H),7.02-6.97(m,1H),6.36(s,1H),5.42(s,2H) ,4.59(d,J=5.6Hz,2H),1.95-1.89(m,1H),0.94-0.88(m,2H),0.71-0.63(m,2H).

[0432] Example 16

[0433] N-(3-chlorobenzyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (I-121)

[0434] Plan 16

[0435]

[0436] Synthesis of N-(3-chlorobenzyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide. N-(3-chlorobenzyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide was synthesized according to General Procedure A starting from 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide and (3-chlorophenyl)methanamine. The crude product was purified by preparative HPLC to give the product (55 mg, 27%) as a white solid. ESI-MS [M+H]+: 406.1. 1 H NMR (400MHz, DMSO) δ8.66(t,J=6.0Hz,1H),8.34(s,1H),8.23(s,1H),7.88(s,1H),7.75(s,1H),7.49–7.13(m,5H),7.0 0(dd,J=9.4,1.8Hz,1H),5.41(s,2H),4.39(d,J=6.0Hz,2H),2.05–1.78(m,1H),1.05–0.80(m,2H),0.82–0.37(m,2H).

[0437] Example 17

[0438] N-((6-chloro-8-fluoroimidazo[1,5-a]pyridin-3-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (I-137)

[0439] Plan 17

[0440]

[0441] Synthesis of N-((6-chloro-8-fluoroimidazo[1,5-a]pyridin-3-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide. N-((6-chloro-8-fluoroimidazo[1,5-a]pyridin-3-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide was synthesized according to General Procedure A starting from 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide and (6-chloro-8-fluoroimidazo[1,5-a]pyridin-3-yl)methanamine hydrochloride. The crude product was purified by preparative TLC (DCM / MeOH=10 / 1) to give the product (20 mg, yield: 21%) as a white solid. ESI-MS [M+H] + : 464.1.1 H NMR (400MHz, DMSO) δ8.81(t,J=5.7Hz,1H),8.55(s,1H),8.33(s,1H),8.23(s,1H),7.87(s,1H),7.73(s,1H),7.57(s,1H),7.39(d,J=9.3H z,1H),7.01-6.98(m,1H),6.94-6.90(m,1H),5.39(s,2H),4.80(d,J=5.7Hz,2H),1.95–1.87(m,1H),0.95–0.86(m,2H),0.71–0.62(m,2H).

[0442] Example 18

[0443] 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-((2-oxo-1,2-dihydroquinolin-4-yl)methyl)-1H-pyrazole-4-carboxamide (I-120)

[0444] Plan 18

[0445]

[0446] Synthesis of 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-((2-oxo-1,2-dihydroquinolin-4-yl)methyl)-1H-pyrazole-4-carboxamide. 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-((2-oxo-1,2-dihydroquinolin-4-yl)methyl)-1H-pyrazole-4-carboxamide was synthesized starting from 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide and 4-(aminomethyl)quinolin-2(1H)-one according to General Procedure A. The crude product was purified by preparative HPLC to give the product (10 mg, yield: 10%) as a white solid. ESI-MS [M+H]+: 439.2. 1H NMR (400MHz, DMSO) δ11.68(s,1H),8.65(t,J=5.8Hz,1H),8.35(s,1H),8.28(s,1H),7. 92(s,1H),7.82(d,J=7.9Hz,1H),7.76(s,1H),7.55–7.48(m,1H),7.41(d,J=9.3Hz,1H ),7.33(d,J=7.6Hz,1H),7.19(t,J=7.6Hz,1H),7.03-6.98(m,1H),6.33(s,1H),5.43( s,2H),4.63(d,J=5.6Hz,2H),1.97-1.88(m,1H),0.95-0.88(m,2H),0.74–0.63(m,2H).

[0447] Example 19

[0448] N-(6-cyano-2-fluoro-3-methoxybenzyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (I-119)

[0449] Plan 19

[0450]

[0451] Synthesis of N-(6-cyano-2-fluoro-3-methoxybenzyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide. N-(6-cyano-2-fluoro-3-methoxybenzyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide was synthesized according to General Procedure A starting from 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide and 2-(aminomethyl)-3-fluoro-4-methoxybenzonitrile. The crude product was purified by silica gel column chromatography (DCM / MeOH=10 / 1) to give the product (3.2 mg, yield: 0.5%) as a white solid. ESI-MS [M+H] + :445.2. 1H NMR (400MHz, DMSO) δ8.56(s,1H),8.33(s,1H),8.19(s,1H),7.83(s,1H),7.73(s,1H),7.66(d,J=8.6Hz,1H),7.40(d,J=9.3Hz,1H),7.27(t,J=8. 4Hz,1H),6.99(d,J=9.2Hz,1H),5.39(s,2H),4.50(d,J=4.3Hz,2H),3.91 (s,3H),1.93–1.83(m,1H),0.91(d,J=7.1Hz,2H),0.66(d,J=4.6Hz,2H).

[0452] Example 20

[0453] N-(5-chloro-2-(2H-tetrazol-5-yl)benzyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (I-117)

[0454] Plan 20

[0455]

[0456] Synthesis of N-(5-chloro-2-(2H-tetrazol-5-yl)benzyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide. A mixture of 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylic acid (209 mg, 0.740 mmol), (5-chloro-2-(1H-tetrazol-5-yl)phenyl)methanamine (222 mg, 1.06 mmol), EDCI (203 mg, 1.06 mmol), HOBT (143 mg, 1.06 mmol) and Et3N (226 mg, 2.23 mmol) in DMF (6 mL) was stirred at room temperature for 16 h. The reaction mixture was concentrated and purified by preparative HPLC to give N-(5-chloro-2-(2H-tetrazol-5-yl)benzyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (38 mg, yield: 11%) as a white solid. ESI-MS [M+H] + :474.2. 1H NMR (400MHz, DMSO) δ8.74(t,J=5.8Hz,1H),8.35(s,1H),8.24(s,1H),7.90–7.82(m,2H),7.76(s,1H),7.51(dd,J=8.3,1.9Hz,1H) ,7.47–7.37(m,2H),7.01(d,J=9.4Hz,1H),5.43(s,2H),4.70(d,J=5.8Hz,2H),1.96–1.89(m,1H),0.92(m,2H),0.72–0.63(m,2H).

[0457] Example 21

[0458] N-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)benzyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (I-116)

[0459] Plan 21

[0460]

[0461] Synthesis of N-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)benzyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide. N-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)benzyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide was synthesized according to General Procedure A starting from 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide and (3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)methanamine. The crude product was purified by flash chromatography (DCM / MeOH=10 / 1) to give the product (14.5 mg, yield: 13.4%) as a white solid. ESI-MS [M+H] + : 491.9. 1H NMR (400MHz, HDMSO) δ9.84 (s, 1H), 8.47-8.45 (t, J = 5.0Hz, 1H), 8.33 (s, 1H), 8.10 (s,1H),7.86-7.82(t,J=8.2Hz,1H),7.72(s,2H),7.50(dd,J=8.7,1.1Hz,1H),7. 39(d,J=9.3Hz,1H),6.99(dd,J=9.4,1.7Hz,1H),5.37(s,2H),4.26(d,J=4.8Hz,2 H),1.94-1.88(m,J=13.5,8.4,5.1Hz,2H),0.94–0.89(m,2H),0.68–0.64(m,2H).

[0462] Example 22

[0463] N-(3-chloro-2-fluoro-6-(2-oxa-6-azaspiro[3.3]hept-6-yl)benzyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (I-114)

[0464] Plan 22

[0465]

[0466] Synthesis of N-(6-bromo-3-chloro-2-fluorobenzyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide. To a solution of (6-bromo-3-chloro-2-fluorophenyl)methanamine hydrochloride (600 mg, 2.2 mmol) in DMF (5 mL) was added 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylic acid (568 mg, 2.0 mmol), HOBT (335 mg, 2.50 mmol), EDCI (483 mg, 2.52 mmol), and DIPEA (1.1 g, 8.4 mmol). The reaction mixture was stirred at room temperature for 3 h. Water (30 mL) was added, and the mixture was extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine, dried over NaSO, and concentrated in vacuo to afford the crude material, which was purified by flash chromatography to afford N-(6-bromo-3-chloro-2-fluorobenzyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (362 mg, yield: 43%) as a white solid. ESI-MS [M+H]: 502.2.

[0467] Synthesis of N-(3-chloro-2-fluoro-6-(2-oxa-6-azaspiro[3.3]hept-6-yl)benzyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide. To a mixture of N-(6-bromo-3-chloro-2-fluorobenzyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide (50 mg, 0.099 mmol) in 1,4-dioxane (15 mL) was added 2-oxa-6-azaspiro[3.3]heptane (15 mg, 0.149 mmol), Pd2(dba)3 (20 mg, 0.022 mmol), Xantphos (20 mg, 0.035 mmol) and Cs2CO3 (0.5 mmol, 163 mmol). The reaction mixture was stirred at 100 ° C. under N2 for 3 h. The mixture was concentrated in vacuo, and the residue was purified by preparative HPLC to afford N-(3-chloro-2-fluoro-6-(2-oxa-6-azaspiro[3.3]hept-6-yl)benzyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide (22.9 mg, 44% yield) as a yellow solid. ESI-MS [M+H]+: 520.9. Purity: 98.0 (214 nm), 98.1 (254 nm). 1 H NMR (400MHz, DMSO) δ8.33 (s, 1H), 8.26 (s, 1H), 8.12 (t, J = 4.1Hz, 1H), 7.88 (s ,1H),7.75(s,1H),7.40(d,J=9.3Hz,1H),7.31(t,J=8.7Hz,1H),6.99(dd,J=9 .4,1.8Hz,1H),6.33–6.27(m,1H),5.39(s,2H),4.66(s,4H),4.30(d,J=1.8H z,2H),4.12(s,4H),1.96–1.86(m,1H),0.93-0.85(m,2H),0.71–0.62(m,2H).

[0468] Example 23

[0469] N-(4-Carbamoyl-2,6-dimethylbenzyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (I-103)

[0470] Plan 23

[0471]

[0472] Synthesis of N-(4-cyano-2,6-dimethylbenzyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide. To a solution of 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (150.0 mg crude), 4-(aminomethyl)-3,5-dimethylbenzonitrile (82 mg, 0.51 mmol), 1-hydroxybenzotriazole (71 mg, 0.44 mmol), and EDCI (101 mg, 0.53 mmol) in DMF (10 mL) was added triethylamine (214 mg, 2.12 mmol). After stirring at room temperature for 2 hours, the reaction was quenched with saturated aqueous ammonium chloride (20 mL) and extracted with ethyl acetate (20 x 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude material, which was purified by silica gel column chromatography (DCM / MeOH=20 / 1) to give N-(4-cyano-2,6-dimethylbenzyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (50 mg, 22%). ESI-MS [M+H]+: 425.1.

[0473] Synthesis of N-(4-carbamoyl-2,6-dimethylbenzyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide. HCl (gas) was bubbled into a solution of N-(4-cyano-2,6-dimethylbenzyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (50 mg, 0.11 mmol) in anhydrous MeOH (8 mL) at 0 ° C for 1 h. The reaction mixture was then stirred at room temperature for 3 h. The reaction was concentrated in vacuo, redissolved in MeOH (6 mL), and NH4HCO3 (220 mg, 2.78 mmol) was slowly added. The resulting mixture was stirred at room temperature for 16 h and then concentrated in vacuo to afford the crude material, which was purified by reverse phase flash chromatography (Biotage SNAPC18, 12 g) using a gradient of acetonitrile in water containing 0.1% formic acid (0-25% over 10 column volumes) to afford N-(4-carbamoyl-2,6-dimethylbenzyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (20 mg, 41%). ESI-MS [M+H]+: 442.1. 1H NMR(400MHz,DMSO,ppm)δ11.49(bs,1H),8.89(bs,0.7H),8.44(s,1.62H),8.33(s,1H ),8.22(s,1H),8.18(t,J=4.8Hz,1H),7.83(d,J=15.3Hz,1H),7.74(s,1H),7.49(s,2H ),7.38(d,J=9.3Hz,1H),6.99(dd,J=9.4,1.7Hz,1H),5.40(d,J=14.0Hz,2H),4.45(d ,J=4.8Hz,2H),2.41(s,6H),1.99-1.84(m,1H),0.97-0.87(m,2H),0.71-0.62(m,2H).

[0474] Example 24

[0475] N-(6-cyano-2-fluoro-3-methoxybenzyl)-1-((8-cyano-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (I-118)

[0476] Plan 24

[0477]

[0478] Synthesis of 2-amino-5-cyclopropylnicotinonitrile. To a mixture of 2-amino-5-bromonicotinonitrile (1 g, 5.1 mmol), cyclopropylboronic acid (647 mg, 7.6 mmol), and K3PO4 (3.78 g, 17.85 mmol) in toluene / H2O (20 mL / 2 mL) were added Pd(OAc)2 (114 mg, 0.51 mmol) and S-Phos (209 mg, 0.51 mmol). The mixture was stirred at 95°C for 16 h. The reaction was cooled to room temperature, and the mixture was filtered. The filtrate was concentrated to give the crude product, which was purified by silica gel chromatography (EtOAc / PE = 4 / 1) to give 2-amino-5-cyclopropylnicotinonitrile (570 mg, yield: 71%) as a yellow solid. ESI-MS [M+H] + :160.1

[0479] Synthesis of 2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-carbonitrile. To a solution of 2-amino-5-cyclopropylnicotinonitrile (570 mg, 3.58 mmol) in EtOH (20 mL) was added 1,3-dichloropropane-2-one (1.37 g, 10.75 mmol). The reaction mixture was stirred at 85 ° C for 16 h. The reactants were concentrated, and the residue was diluted with NaHCO3 (aqueous solution, 20 mL) and extracted with EtOAc (50 mL x3). The combined organic layers were concentrated to give a crude material, which was purified by silica gel chromatography (EtOAc / PE=2 / 1) to give 2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-carbonitrile (500 mg, yield: 58%) as a yellow solid. ESI-MS[M+H] + :232.1.

[0480] Synthesis of ethyl 1-((8-cyano-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate. To a solution of 2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-carbonitrile (500 mg, 2.15 mmol) in DMF (10 mL) were added ethyl 1H-pyrazole-4-carboxylate (331 mg, 2.36 mmol) and Cs2CO3 (1.4 g, 4.3 mmol). The reaction mixture was stirred at room temperature for 12 h. Water (50 mL) was added, and the mixture was extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine, dried over NaSO, and concentrated in vacuo to afford a crude product, which was purified by silica gel chromatography (DCM / MeOH = 20 / 1) to afford ethyl 1-((8-cyano-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate (433 mg, yield: 60%) as a white solid. ESI-MS [M+H]: 336.2.

[0481] Synthesis of 1-((8-cyano-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylic acid. To a solution of 1-((8-cyano-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate (400 mg, 1.19 mmol) in THF (15 mL) and H2O (5 mL) was added LiOH (464 mg, 146 mmol). The mixture was stirred at room temperature for 16 h. Most of the THF was removed in vacuo, and the mixture was adjusted to pH 4-5 by adding HCl (1 M). The resulting precipitate was collected and dried to give 1-((8-cyano-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylic acid as a white solid (300 mg, 82%). ESI-MS[M+H] + :308.2.

[0482] Synthesis of N-(6-cyano-2-fluoro-3-methoxybenzyl)-1-((8-cyano-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide. A solution of 1-((8-cyano-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (100 mg, 0.326 mmol) in SOCl2 (0.5 mL) was stirred at room temperature for 1 h. After vacuum concentration, a solution of 2-(aminomethyl)-3-fluoro-4-methoxybenzonitrile (70 mg, 0.39 mmol) in THF (2 mL) was added, followed by LiHMDS (1 M in THF, 1.3 mL). The reaction mixture was stirred at room temperature for 2 h. The reaction was quenched with saturated aqueous ammonium chloride solution (10 mL) and extracted with ethyl acetate (3x30 mL). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated to give a residue, which was purified by preparative TLC (MeOH / DCM = 1 / 10) to give N-(6-cyano-2-fluoro-3-methoxybenzyl)-1-((8-cyano-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (8 mg, yield: 5%) as a white solid. ESI-MS [M+H]: 470.1. 1HNMR (400MHz, DMSO) δ8.68(d,J=1.4Hz,1H),8.59(t,J=5.0Hz,1H),8.24(s,1H),7.87(s,2H),7.78(d,J=1.6Hz,1H),7.67(dd,J=8.6,1.3Hz,1H), 7.28(t,J=8.4Hz,1H),5.48(s,2H),4.51(d,J=4.7Hz,2H),3.92(s,3H),1 .97(ddd,J=13.5,8.5,5.1Hz,1H),0.99–0.90(m,2H),0.79–0.71(m,2H).

[0483] Example 25

[0484] General procedure B-1 for amide synthesis:

[0485] Plan 25

[0486]

[0487] 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 h. The reaction was concentrated in vacuo to give a crude material, 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.

[0488] Synthesis of 2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine. A mixture of 5-cyclopropylpyridin-2-amine (61 g, 455 mmol) and 1,3-dichloropropane-2-one (172 g, 1365 mmol) in EtOH (1 L) was stirred at 95 ° C for 13 h. 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 (1 Lx3). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo to give a crude material, which was purified by silica gel chromatography (EA) to give 2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine (40 g, yield: 42%) as a yellow solid. ESI-MS [M+H] + :207.1.

[0489] Synthesis of 2-(azidomethyl)-6-cyclopropylimidazo[1,2-a]pyridine. To a solution of 2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine (40 g, 193 mmol) in DMF (600 mL) was added NaN3 (18.8 g, 290 mmol). The resulting reaction was stirred at room temperature for 2 h. 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 material, 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.

[0490] Synthesis of ethyl 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate. A mixture of 2-(azidomethyl)-6-cyclopropylimidazo[1,2-a]pyridine (35 g, 163.5 mmol), ethyl propiolate (17.6 g, 180 mmol), CuSO4 (2.6 g, 16.35 mmol), and sodium ascorbate (3.3 g, 16.35 mmol) in H2O / t-BuOH (150 mL / 150 mL) was stirred at room temperature for 3 h. A yellow solid precipitated after 3 h, 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.

[0491] Synthesis of 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid. A mixture of ethyl 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate (29 g, 93.2 mmol) and LiOH (6.7 g, 279.6 mmol, in 50 mL of H2O) in THF / EtOH (150 mL / 150 mL) was stirred at 50 ° C for 2 h. The reaction was concentrated to remove most of the solvent. The pH of the residue was adjusted to 4 by 2N HCl, and a pink solid precipitated. The mixture was filtered and the filter cake was dried to give 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid (20 g, 77%) as a pink solid. ESI-MS [M+H] + :284.1.

[0492] General Synthesis of Amide Compounds (Procedure B-1). To a solution of 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid (60 mg, 0.21 mmol), amine (0.32 mmol) and HATU (120 mg, 0.31 mmol) in DMF (8 mL) was added DIPEA (81 mg, 0.63 mmol). The reaction mixture was stirred at room temperature for 12 h. Water (25 mL) was added, and the mixture was extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by preparative TLC, preparative HPLC or silica gel chromatography to give the desired product.

[0493] The following compounds were synthesized according to General Procedure B-1 starting from 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide and the indicated amines: N-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)benzyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide (I-106), 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(1H-tetrazol-1-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide (I-105), 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide 1-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-6-(1H-tetrazol-1-yl)-3-(trifluoromethoxy)benzyl)-1H-1,2,3-triazole-4-carboxamide (I-98), 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-6-(1H-tetrazol-1-yl)-3-(trifluoromethoxy)benzyl)-1H-1,2,3-triazole-4-carboxamide (I-100), N-(6-chloro-8,9-dihydro-7H-imidazo[4,5,1-ij]quinolin-9-yl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide (I-135), 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-6-(1H-tetrazol-1-yl)-3-(trifluoromethoxy)benzyl)-1H-1,2,3-triazole-4-carboxamide (I-98), 1- ((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(4H-1,2,4-triazol-4-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide (I-96), 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(1H-pyrazol-1-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide (I-95), N-(3-bromo-2-fluoro-6-(1H-tetrazol-1-yl)benzyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide Amine (IX), 2'-((1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamido)methyl)-3'-fluoro-4'-methoxy-[1,1'-biphenyl]-4-carboxylic acid methyl ester (I-87), 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(pyridazin-4-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide (I-86), 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-ethyl-2-fluoro-6-(1H-tetrazol-1-yl)benzyl)-1H-1,2,3-Triazole-4-carboxamide (I-83), N-(3-chloro-6-(difluoromethyl)-2-fluorobenzyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide (I-79), N-(3-cyclopropyl-2-fluoro-6-(1H-tetrazol-1-yl)benzyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide (I-78), 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(imidazo[1,2-a]pyridin-6-ylmethyl)-1H-1,2,3-triazole- 4-carboxamide (I-136), 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(1H-1,2,3-triazol-1-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide (I-76), 5-(2-((1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamido)methyl)-3-fluoro-4-methoxyphenyl)pyrimidine-2-carboxylic acid methyl ester (I-75), 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(6-(3,4-dimethyl-1H-pyrazol-1-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide -1,2,3-triazole-4-carboxamide (I-70), 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(1H-pyrazol-4-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide (I-67), 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(1H-pyrazol-4-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide )-N-(2-fluoro-3-methoxy-6-(1H-tetrazol-1-yl)benzyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide (I-66), N-((3-chloro-1H-indol-5-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide (I-65), 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(pyrazolo[1,5-a]pyridin-2-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide (I-63), 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide (I-52), 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(1H-1,2,3-triazol-4-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide ( I-49), 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(1-(2-fluoro-3-methoxy-6-(1H-tetrazol-1-yl)phenyl)ethyl)-1H-1,2,3-triazole-4-carboxamide (I-31), N-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide Amide (I-26), N-((5-amino-1,3,4-thiadiazol-2-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide (I-20), N-((5-amino-1,3,4-oxadiazol-2-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide (I-1 9), N-((2-aminothiazol-5-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide (I-18) and N-(6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluoro-3-methoxybenzyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide (I-1).

[0494] Example 26

[0495] General procedure B-2 for amide synthesis:

[0496] Plan 26

[0497]

[0498] General synthesis of amide compounds (Procedure B-2). To a solution of 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid (150 mg, 0.53 mmol), amine (1.01 mmol), HOBT (130 mg, 0.96 mmol) and EDCI (184 mg, 0.96 mmol) in DMF (10 mL) was added DIPEA (413 mg, 3.2 mmol). The reaction mixture was stirred at room temperature for 12 h. Water (20 mL) was added, and the mixture was extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to give the crude product, which was purified by preparative TLC, preparative HPLC or silica gel chromatography to give the desired product.

[0499] The following compounds were synthesized according to General Procedure B-2 starting from 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid and the indicated amines: 4-((4-carbamoylaminoacyl-2,6-dimethylbenzyl)amino)-6-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methoxy)pyrimidine-2-carboxylic acid (I-115), N-(6-bromo-2-fluoro-3-methoxybenzyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide (I-102), 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide (I-103), 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide (I-104), 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide (I-105), 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide (I-106), 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid and the indicated amines. pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(pyridin-4-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide (I-101), N-(benzo[b]thien-5-ylmethyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide (I-84), 7-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)-N-(2-fluoro-3-methoxy-6-(1H-tetrazol-1-yl)benzyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide (I-82), N-(3-chloro- -2-methyl-6-(1H-tetrazol-1-yl)benzyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide (I-80), N-((6-chlorobenzo[b]thiophen-2-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide (I-77), N-((5-cyano-3-fluoro-2-methoxypyridin-4-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide (I-72), 1 -((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2,6-difluoro-3-methoxybenzyl)-1H-1,2,3-triazole-4-carboxamide (I-64), 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide (I-62), N-benzyl-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide (I-60), 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(methylsulfinyl)benzyl)-1H-1,2,3-triazole-4-carboxamide (I-58), 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(6-(N,N-dimethylsulfamoyl)-2-fluoro-3-methoxybenzyl)-1H-1,2,3-triazole-4-carboxamide (I-57), 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-(methylsulfonyl)benzyl)-1H-1 ,2,3-triazole-4-carboxamide (I-51), 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(morpholinosulfonyl)benzyl)-1H-1,2,3-triazole-4-carboxamide (I-48), N-(1-amino-6,7-dihydro-5H-cyclopenta[c]pyridin-5-yl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide (I-23), N-(5-amino-4H-1,2 ,4-triazol-3-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide (I-21), N-(1-amino-3-methyl-6,7-dihydro-5H-cyclopenta[c]pyridin-5-yl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide (I-16), N-((4-chlorothieno[3,2-c]pyridin-2-yl)methyl)-1-((6-cyclopropylimidazo[1, -1,2,3-triazole-4-carboxamide (I-3).

[0500] Example 27

[0501] 4-((4-Carbamoylimidoyl-2,6-dimethylbenzyl)amino)-6-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methoxy)pyrimidine-2-carboxylic acid (I-115)

[0502] Plan 27

[0503]

[0504] Synthesis of N-(4-cyano-2,6-dimethylbenzyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide. N-(4-cyano-2,6-dimethylbenzyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide was synthesized starting from 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide and 4-(aminomethyl)-3,5-dimethylbenzonitrile hydrochloride according to General Procedure B-2. The crude product was purified by preparative TLC (DCM / MeOH = 15 / 1) to give the product (100 mg, yield: 44.3%) as a yellow solid. ESI-MS[M+H] + :426.1

[0505] Synthesis of N-(4-carbamoyl-2,6-dimethylbenzyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide. To a solution of N-(4-cyano-2,6-dimethylbenzyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide (100 mg, 0.24 mmol) in MeOH (10 mL) was bubbled with HCl (g) for 4 h. The reaction mixture was concentrated in vacuo, and MeOH (15 mL) and NH4HCO3 (182 mg, 2.3 mmol) were added. The resulting mixture was stirred at room temperature for 13 h. The reaction was concentrated in vacuo to give a crude material which was purified by preparative HPLC to give N-(4-carbamoylimidoyl-2,6-dimethylbenzyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide as a white solid. ESI-MS [M+H] + :443.0 1H NMR (400MHz, DMSO) δ11.07 (s, 1H), 8.88 (s, 1H), 8.71 (t, J = 5.3Hz, 1H), 8. 55(s,1H),8.43(s,1H),8.35(s,1H),7.84(s,1H),7.46(s,2H),7.40(d,J= 9.3Hz,1H),7.01(dd,J=9.4,1.7Hz,1H),5.72(s,2H),4.51(d,J=5.3Hz,2 H),2.44(s,6H),1.98–1.89(m,1H),0.94–0.90(m,2H),0.69–0.65(m,2H).

[0506] Example 28

[0507] N-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)benzyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide (I-106)

[0508] Plan 28

[0509]

[0510] Synthesis of N-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)benzyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide. N-(4-cyano-2,6-dimethylbenzyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide was synthesized according to General Procedure B-1 starting from 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide and (3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)methanamine. The crude product was purified by flash chromatography (DCM / MeOH=10 / 1) to give the product (40 mg 45%) as a white solid. ESI-MS [M+H]+: 493.1. Purity: 99.32 (214 nm), 100.00 (254 nm). 1H NMR (400MHz, DMSO) δ9.85 (s, 1H), 8.90 (t, J = 5.4Hz, 1H), 8.49 (s, 1H), 8.34 (s, 1H), 7.86-7.82 (m, 2H), 7.50 (dd, J = 8.7Hz, 1.3Hz, 1H), 7.40 (d ,J=9.3Hz,1H),7.00(dd,J=9.4Hz,1.7Hz,1H),5.70(s,2H),4.37(d,J=5.1Hz,2H),1.94–1.90(m,1H),0.93–0.90(m,2H),0.69–0.65(m,2H).

[0511] Example 29

[0512] 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(1H-tetrazol-1-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide (I-105)

[0513] Plan 29

[0514]

[0515] Synthesis of 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(1H-tetrazol-1-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide. 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(1H-tetrazol-1-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide was synthesized starting from 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide and (2-fluoro-3-methoxy-6-(1H-tetrazol-1-yl)phenyl)methanamine according to General Procedure B-1. The crude product was purified by preparative TLC (DCM / MeOH=13 / 1) to give the product (14.3 mg, yield: 21%) as a white solid. ESI-MS [M+H] + : 489.2. 1H NMR (400MHz, DMSO) δ9.74 (s, 1H), 8.76 (t, J = 5.4Hz, 1H), 8.49 (s, 1H), 8.36 (s, 1H), 7.84 (s, 1H), 7.44-7.32 (m, 3H), 7.06 -7.03(m,1H),5.72(s,2H),4.29(d,J=5.2Hz,2H),3.92(s,3H),1.93-1.90(m,1H),0.93-0.90(m,2H),0.70-0.67(m,2H).

[0516] Example 30

[0517] N-(6-bromo-2-fluoro-3-methoxybenzyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide (I-102)

[0518] Plan 30

[0519]

[0520] Synthesis of N-(6-bromo-2-fluoro-3-methoxybenzyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide. 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide was synthesized according to General Procedure B-2 starting from 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide and (6-bromo-2-fluoro-3-methoxyphenyl)methanamine. The crude product was purified by preparative TLC (DCM / MeOH=20 / 1) to give the product (390 mg, yield: 84%) as a white solid. ESI-MS [M+H] + :499.1. 1 H NMR (400MHz, DMSO) δ8.68–8.61(m,1H),8.55(s,1H),8.35(s,1H),7.83(s,1H),7.42–7.39(m,2H),7.09(t,J=8.7Hz,1H),7.0 1(d,J=9.3Hz,1H),5.72(s,2H),4.55(d,J=2.8Hz,2H),3.83(s,3H),1.95–1.89(m,1H),0.93–0.91(m,2H),0.68–0.67(m,2H).

[0521] Example 31

[0522] 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-6-(1H-imidazol-1-yl)-3-methoxybenzyl)-1H-1,2,3-triazole-4-carboxamide (I-104)

[0523] Plan 31

[0524]

[0525] Synthesis of 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-6-(1H-imidazol-1-yl)-3-methoxybenzyl)-1H-1,2,3-triazole-4-carboxamide. A mixture of N-(6-bromo-2-fluoro-3-methoxybenzyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide (75 mg, 0.15 mmol), 1H-imidazole (81 mg, 1.19 mmol), K2CO3 (245 mg, 1.78 mmol) and CuI (33 mg, 0.17 mmol) in DMF (2 mL) was stirred in a microwave at 150°C for 1 h. The reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (30 mL x 3). The organic layer was concentrated to give a crude material, which was purified by preparative TLC (DCM:MeOH = 20:1) to give 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-6-(1H-imidazol-1-yl)-3-methoxybenzyl)-1H-1,2,3-triazole-4-carboxamide (26.1 mg, yield: 36%) as a white solid. ESI-MS [M+H] + :487.1. Purity: 99.51% (214nm), 100.00% (254nm). 1 H NMR (400MHz, DMSO) δ8.72(t,J=4.9Hz,1H),8.52(s,1H),8.35(s,1H),7.82(d,J=5.0Hz,2H),7.42–7.39(m,2H),7.24(t,J=8.8Hz,1H),7.16(d ,J=9.0Hz,1H),7.04–7.00(m,2H),5.72(s,2H),4.23(d,J=4.7Hz,2H), 3.88(s,3H),1.96–1.89(m,1H),0.92–0.89(m,2H),0.69–0.65(m,2H).

[0526] Example 32

[0527] 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide (I-97)

[0528] Plan 32

[0529]

[0530] Synthesis of methyl 2-((1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamido)methyl)-3-fluoro-4-methoxybenzoate. A solution of N-(6-bromo-2-fluoro-3-methoxybenzyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide (100 mg, 0.20 mmol), Pd(dppf)Cl2 (33 mg, 0.045 mmol), and Et3N (76 mg, 0.75 mmol) in MeOH (10 mL) was stirred at 90°C under CO2 for 72 h. The solution was filtered, and the filtrate was extracted with EtOAc (50 mL x 2). The combined organic layers were concentrated and purified by preparative TLC (DCM / MeOH = 15:1) to give methyl 2-((1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamido)methyl)-3-fluoro-4-methoxybenzoate as a white solid (35 mg, yield: 36.6%). ESI-MS [M+H] + :479.1.

[0531] Synthesis of 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-6-(hydrazinecarbonyl)-3-methoxybenzyl)-1H-1,2,3-triazole-4-carboxamide. A solution of methyl 2-((1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamido)methyl)-3-fluoro-4-methoxybenzoate (35 mg, 0.073 mmol) and hydrazine hydrate (purity: 80%) (0.25 mL) in EtOH (1 mL) was stirred at 90° C. for 16 h. The mixture was concentrated in vacuo and purified by preparative TLC (DCM / MeOH = 12:1) to give 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-6-(hydrazinecarbonyl)-3-methoxybenzyl)-1H-1,2,3-triazole-4-carboxamide (15 mg, yield: 43%) as a white solid. ESI-MS [M+H] + :479.2.

[0532] Synthesis of 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide. A solution of 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-6-(hydrazinecarbonyl)-3-methoxybenzyl)-1H-1,2,3-triazole-4-carboxamide (15 mg, 0.03 mmol), triethoxymethane (0.25 mL), and NHCl (10 mg, 0.15 mmol) in EtOH (1 mL) was stirred at 80° C. for 16 h. The reaction mixture was concentrated in vacuo and purified by preparative TLC (DCM / MeOH = 10:1) to give 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide as a white solid (2.9 mg, yield: 20%). ESI-MS [M+H]+: 489.2. 1HNMR (400MHz, DMSO) δ9.37(s,1H),8.75(t,J=5.7Hz,1H),53(s,1H),8.33(s,1H),7.79(s,1H),7.74(d,J=8.8Hz,1H),7.38–7.31(m,2 H),7.00(d,J=9.2Hz,1H),5.70(s,2H),4.88(d,J=5.1Hz,2H),3.92(s,3H),1.94–1.88(m,1H),0.94–0.90(m,2H),0.68–0.66(m,2H).

[0533] Example 33

[0534] 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(pyridin-4-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide (I-101)

[0535] Plan 33

[0536]

[0537] Synthesis of 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(pyridin-4-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide. 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(pyridin-4-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide was synthesized starting from 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide and (2-fluoro-3-methoxy-6-(pyridin-4-yl)phenyl)methanamine according to General Procedure B-2. The crude product was purified by preparative TLC (DCM / MeOH=10 / 1) to give the product (7 mg, yield: 18%) as a white solid. ESI-MS [M+H] + : 498.2. 1H NMR(400MHz,DMSO)δ8.65(t,J=4.9Hz,1H),8.58–8.57(m,2H),8.51(s,1H), 8.35(s,1H),7.83(s,1H),7.43–7.40(m,3H),7.23(t,J=8.6Hz,1H),7.08(d ,J=8.6Hz,1H),7.01(dd,J=9.4,1.7Hz,1H),5.71(s,2H),4.40(d,J=4.5Hz, 2H),3.87(s,3H),1.96–1.89(m,1H),0.93–0.90(m,2H),0.65–0.69(m,2H).

[0538] Example 34

[0539] 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxybenzyl)-1H-1,2,3-triazole-4-carboxamide (I-100)

[0540] Plan 34

[0541]

[0542] Synthesis of 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxybenzyl)-1H-1,2,3-triazole-4-carboxamide. 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide was synthesized starting from 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide and (2-fluoro-3-methoxyphenyl)methanamine according to General Procedure B-1. The crude product was purified by preparative HPLC to give the product (2 mg, yield: 7%) as a white solid. ESI-MS [M+H] + :421.2. 1 H NMR (400MHz, DMSO) δ8.98(t,J=6.1Hz,1H),8.52(s,1H),8.32–8.30(m,1H),7.79(s,1H),7.35(d,J=9.3Hz,1H),7.00–6.94(m,3H ),6.82–6.79(m,1H),5.68(s,2H),4.41(d,J=6.1Hz,2H),3.76(s,3H),1.89–1.84(m,1H),0.89–0.84(m,2H),0.64–0.60(m,2H).

[0543] Example 35

[0544] N-(6-chloro-8,9-dihydro-7H-imidazo[4,5,1-ij]quinolin-9-yl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide (I-135)

[0545] Plan 35

[0546]

[0547] Synthesis of N-(6-chloro-8,9-dihydro-7H-imidazo[4,5,1-ij]quinolin-9-yl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide. N-(6-Chloro-8,9-dihydro-7H-imidazo[4,5,1-ij]quinolin-9-yl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide was synthesized starting from 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide and 6-chloro-8,9-dihydro-7H-imidazo[4,5,1-ij]quinolin-9-amine hydrochloride according to General Procedure B-1. The crude product was purified by preparative HPLC to give the product (18.3 mg, yield: 19.4%) as a white solid. ESI-MS [M+H] + :473.1. 1 HNMR(400MHz,DMSO)δ8.59(s,1H),8.56(d,J=8.4Hz,1H),8.35(s,1H),8.27(s,1 H),8.17(d,J=7.4Hz,1H),7.83(s,1H),7.41(d,J=9.3Hz,1H),7.01(dd,J=9.3,1 .6Hz,1H),6.65(d,J=7.4Hz,1H),5.73(s,2H),5.50–5.35(m,1H),2.93-2.89(m, 2H),2.18-2.08(m,2H),1.96–1.89(m,1H),1.00–0.85(m,2H),0.76–0.61(m,2H).

[0548] Example 36

[0549] 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-6-(1H-tetrazol-1-yl)-3-(trifluoromethoxy)benzyl)-1H-1,2,3-triazole-4-carboxamide (I-98)

[0550] Plan 36

[0551]

[0552] Synthesis of 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-6-(1H-tetrazol-1-yl)-3-(trifluoromethoxy)benzyl)-1H-1,2,3-triazole-4-carboxamide. 1-((6-Cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide was synthesized starting from 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid and (2-fluoro-6-(1H-tetrazol-1-yl)-3-(trifluoromethoxy)phenyl)methanamine according to General Procedure B-1. The crude product was purified by preparative TLC (DCM / MeOH = 10:1) to give the product (70 mg, yield: 33%) as a white solid. ESI-MS [M+H] + :543.20. 1 H NMR(400MHz, DMSO-d6)δ9.86(s,1H),8.91(t,J=5.3Hz,1H),8.49(s,1H),8.34(s,1H),7.88–7.80(m,2H),7.60(m,1H),7.40 (d,J=9.3Hz,1H),7.01(m,1H),5.71(s,2H),4.40(d,J=5.2Hz,2H),1.97–1.87(m,1H),0.96–0.87(m,2H),0.70–0.63(m,2H).

[0553] Example 37

[0554] 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(4H-1,2,4-triazol-4-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide (I-96)

[0555] Plan 37

[0556]

[0557] Synthesis of 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(4H-1,2,4-triazol-4-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide. 1-((6-Cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide was synthesized from 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid and (2-fluoro-3-methoxy-6-(4H-1,2,4-triazol-4-yl)phenyl)methanamine according to General Procedure B-1. The crude product was purified by preparative TLC (DCM / MeOH = 10:1) to give the product (46 mg, yield: 28.6%) as a yellow solid. ESI-MS [M+H]+: 488.1. 1 H NMR (400MHz, DMSO) δ8.83(t,J=5.2Hz,1H),8.74(s,1H),8.52(s,1H),8.35(d,J=0.7Hz,1H),7.82(s,1H),7.41(d,J=9.3Hz,1H),7.26(dt,J=18.9, 9.3Hz,2H),7.01(dd,J=9.4,1.8Hz,1H),5.72(s,2H),4.21(d,J=5.0Hz,2 H),3.89(s,3H),1.99–1.83(m,1H),0.98–0.83(m,2H),0.75–0.55(m,2H).

[0558] Example 38

[0559] 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(1H-pyrazol-1-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide (I-95)

[0560] Plan 38

[0561]

[0562] Synthesis of 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(1H-pyrazol-1-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide. 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(1H-pyrazol-1-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide was synthesized starting from 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide and (2-fluoro-3-methoxy-6-(1H-pyrazol-1-yl)phenyl)methanamine according to General Procedure B-1. The crude product was purified by preparative TLC (DCM / MeOH=10:1) to give the product (33 mg, yield: 39.8%) as a white solid. ESI-MS [M+H] + :487.2. 1 H NMR(400MHz,DMSO)δ8.55(s,1H),8.47(t,J=5.6Hz,1H),8.34(s,1H),8.09(d,J =2.2Hz,1H),7.81(s,1H),7.77(d,J=1.6Hz,1H),7.41(d,J=9.2Hz,1H),7.28–7. 22(m,2H),7.02–6.99(m,1H),6.51(t,J=2.1Hz,1H),5.71(s,2H),4.38(d,J=4. 7Hz,2H),3.88(s,3H),1.96–1.89(m,1H),0.93–0.89(m,2H),0.69–0.65(m,2H).

[0563] Example 39

[0564] N-(3-bromo-2-fluoro-6-(1H-tetrazol-1-yl)benzyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide (I-90)

[0565] Plan 39

[0566]

[0567] Synthesis of N-(3-bromo-2-fluoro-6-(1H-tetrazol-1-yl)benzyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide. N-(3-bromo-2-fluoro-6-(1H-tetrazol-1-yl)benzyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide was synthesized according to General Procedure B-1 starting from 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide and (3-bromo-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)methanamine. The crude product was purified by preparative TLC (DCM / MeOH=10:1) to give the product as a white solid (72 mg, yield: 24.4%). ESI-MS [M+H] + : 538.2. 1 H NMR (400MHz, DMSO) δ9.85(s,1H),8.89(t,J=5.4Hz,1H),8.49(s,1H),8.36(s,1H),7.95(dd,J=8.5,7.3Hz,1H),7.83(s,1H),7.44–7. 40(m,2H),7.03(dd,J=9.4,1.7Hz,1H),5.71(s,2H),4.37(d,J=5.1Hz,2H),1.96–1.90(m,1H),0.95–0.90(m,2H),0.69–0.65(m,2H).

[0568] Example 40

[0569] 2'-((1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamido)methyl)-3'-fluoro-4'-methoxy-[1,1'-biphenyl]-4-carboxylic acid methyl ester (I-87)

[0570] Plan 40

[0571]

[0572] Synthesis of methyl 2'-((1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamido)methyl)-3'-fluoro-4'-methoxy-[1,1'-biphenyl]-4-carboxylate. Methyl 2'-((1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate) was synthesized according to General Procedure B-1 starting from 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid and methyl 2'-(aminomethyl)-3'-fluoro-4'-methoxy-[1,1'-biphenyl]-4-carboxylate. The crude product was purified by preparative HPLC to give the product (27.7 mg, yield: 35.7%) as a white solid. ESI-MS [M+H] + :555.2. 1 HNMR(400MHz,DMSO)δ8.58(t,J=4.8Hz,1H),8.51(s,1H),8.35(s,1H),7.97(d,J=8 .1Hz,2H),7.82(s,1H),7.53(d,J=8.1Hz,2H),7.41(d,J=9.4Hz,1H),7.21(t,J=8. 5Hz,1H),7.07(d,J=8.5Hz,1H),7.01(d,J=9.0Hz,1H),5.71(s,2H),4.38(d,J=4.4 Hz,2H),3.87(d,J=4.2Hz,6H),1.92-1.91(m,1H),0.96-0.88(m,2H),0.67(m,,2H).

[0573] Example 41

[0574] 2'-((1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamido)methyl)-3'-fluoro-4'-methoxy-[1,1'-biphenyl]-4-carboxylic acid (I-88)

[0575] Plan 41

[0576]

[0577] Synthesis of 2'-((1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamido)methyl)-3'-fluoro-4'-methoxy-[1,1'-biphenyl]-4-carboxylic acid. A solution of methyl 2'-((1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamido)methyl)-3'-fluoro-4'-methoxy-[1,1'-biphenyl]-4-carboxylate (20 mg, 0.036 mmol) and LiOH-H2O (7.6 mg, 0.18 mmol) in THF / MeOH / water (1 mL / 1 mL / 1 mL) was stirred at room temperature for 2 h. The reaction mixture was concentrated in vacuo and purified by preparative HPLC to give 2'-((1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamido)methyl)-3'-fluoro-4'-methoxy-[1,1'-biphenyl]-4-carboxylic acid (7.6 mg, yield: 40%) as a white solid. ESI-MS [M+H] + :541.2. 1 H NMR(400MHz,DMSO)δ8.55(t,J=4.7Hz,1H),8.52(s,1H),8.35(s,1H),8.31(s, 1H),7.94(d,J=7.8Hz,2H),7.82(s,1H),7.46-7.40(m,,3H),7.20(t,J=8.6Hz, 1H),7.06(d,J=8.4Hz,1H),7.01(d,J=8.0Hz,1H),5.71(s,2H),4.39(d,J=4.1 Hz,2H),3.87(s,3H),1.94–1.89(m,1H),0.94–0.89(m,2H),0.71–0.65(m,2H).

[0578] Example 42

[0579] 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(pyridazin-4-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide (I-86)

[0580] Plan 42

[0581]

[0582] Synthesis of 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(pyridazin-4-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide. 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(pyridazin-4-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide was synthesized according to General Procedure B-1 starting from 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide and (2-fluoro-3-methoxy-6-(pyridazin-4-yl)phenyl)methanamine. The crude product was purified by preparative HPLC to give the product (21 mg, yield: 32.4%) as a white solid. ESI-MS [M+H] + :499.2. 1 H NMR (400MHz, DMSO) δ9.31–9.23(m,1H),9.20(dd,J=5.3,0.9Hz,1H),8.73(t,J=5.1Hz,1H) ,8.45(s,1H),8.32(s,1H),7.79(s,1H),7.72(dd,J=5.3,2.4Hz,1H),7.38(d,J=9.4Hz,1H) ,7.24(t,J=8.5Hz,1H),7.13(d,J=8.6Hz,1H),6.98(dd,J=9.4,1.7Hz,1H),5.68(s,2H),4. 38(d,J=4.9Hz,2H),3.86(s,3H),1.94–1.84(m,1H),0.96–0.87(m,2H),0.70–0.62(m,2H).

[0583] Example 43

[0584] N-(Benzo[b]thiophen-5-ylmethyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide (I-84)

[0585] Plan 43

[0586]

[0587] Synthesis of N-(Benzo[b]thiophen-5-ylmethyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide. N-(Benzo[b]thiophen-5-ylmethyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide was synthesized according to General Procedure B-2 starting from 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide and benzo[b]thiophen-5-ylmethylamine hydrochloride. The crude product was purified by preparative TLC (MeOH / DCM = 1 / 10) to give the product (40 mg, 52% yield) as a white solid. ESI-MS[M+H]+:429.1. 1 H NMR(400MHz,DMSO)δ9.16(t,J=6.2Hz,1H),8.58(s,1H),8.36(s,1H),7.93(d, J=8.3Hz,2H),7.85(s,1H),7.78(s,1H),7.73(d,J=5.4Hz,1H),7.46–7.38(m, 2H),7.33(dd,J=8.3,1.2Hz,1H),7.02(dd,J=9.4,1.6Hz,1H),5.74(s,2H),4. 55(d,J=6.3Hz,2H),1.95–1.91(m,1H),0.98–0.87(m,2H),0.75–0.65(m,2H).

[0588] Example 44

[0589] 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-ethyl-2-fluoro-6-(1H-tetrazol-1-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide (I-83)

[0590] Plan 44

[0591]

[0592] Synthesis of 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-ethyl-2-fluoro-6-(1H-tetrazol-1-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide. 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-ethyl-2-fluoro-6-(1H-tetrazol-1-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide was synthesized starting from 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide and (3-ethyl-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)methanamine according to General Procedure B-1. The crude product was purified by preparative TLC (MeOH / DCM=1 / 10) to give the product (114 mg, yield: 65.1%) as a white solid. ESI-MS [M+H] + : 487.1. 1 H NMR (400MHz, DMSO) δ9.80 (s, 1H), 8.76 (t, J = 5.5Hz, 1H), 8.49 (s, 1H), 8.34 (s, 1 H),7.82(s,1H),7.51(t,J=8.0Hz,1H),7.37(dd,J=20.4,8.8Hz,2H),7.01(dd, J=9.4,1.8Hz,1H),5.70(s,2H),4.32(d,J=5.3Hz,2H),2.72(q,J=7.5Hz,2H),1 .92-1.89(m,1H),1.21(t,J=7.6Hz,3H),0.94-0.89(m,2H),0.69-0.65(m,2H).

[0593] Example 45

[0594] 7-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)-N-(2-fluoro-3-methoxy-6-(1H-tetrazol-1-yl)benzyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide (I-82)

[0595] Plan 45

[0596]

[0597] Synthesis of 7-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)-N-(2-fluoro-3-methoxy-6-(1H-tetrazol-1-yl)benzyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide. N-(Benzo[b]thiophen-6-ylmethyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide was synthesized according to General Procedure B-2 starting from 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide and benzo[b]thiophen-6-ylmethanamine. The crude product was purified by preparative TLC (7% MeOH / DCM) to give the product (20 mg, 26% yield) as a white solid. ESI-MS [M+H] + : 429.1. 1 H NMR(400MHz,DMSO)δ9.20(t,J=6.3Hz,1H),8.63(s,1H),8.54(s,1H),8.05 (s,1H),7.88(s,1H),7.81(d,J=8.2Hz,1H),7.71(d,J=5.4Hz,1H),7.61(d, J=9.4Hz,1H),7.41(d,J=5.4Hz,1H),7.37–7.34(m,2H),5.88(s,2H),4.56 (d,J=6.2Hz,2H),2.05-1.95(m,1H),1.03-0.93(m,2H),0.75-0.69(m,2H).

[0598] Example 46

[0599] N-(3-chloro-2-methyl-6-(1H-tetrazol-1-yl)benzyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide (I-80)

[0600] Plan 46

[0601]

[0602] Synthesis of N-(3-chloro-2-methyl-6-(1H-tetrazol-1-yl)benzyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide. N-(3-chloro-2-methyl-6-(1H-tetrazol-1-yl)benzyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide was synthesized according to General Procedure B-2 starting from 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide and (3-chloro-2-methyl-6-(1H-tetrazol-1-yl)phenyl)methanamine. The crude product was purified by preparative TLC (MeOH / DCM=1 / 10) to give the product (35 mg, yield: 20%). ESI-MS [M+H] + :489.2. 1 H NMR (400MHz, DMSO) δ9.76(s,1H),8.78(t,J=6.0Hz,1H),8.52(s,1H),8.34(s,1H),7.82(s,1H),7.68(d,J=8.0Hz,1H),7.44-7.39(m ,2H),7.02-6.99(m,1H),5.71(s,2H),4.22(d,J=8.0Hz,2H),2.47(s,3H),1.96-1.89(m,1H),0.94-0.89(m,2H),0.69-0.65(m,2H).

[0603] Example 47

[0604] N-(3-chloro-6-(difluoromethyl)-2-fluorobenzyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide (I-79)

[0605] Plan 47

[0606]

[0607] Synthesis of N-(3-chloro-6-(difluoromethyl)-2-fluorobenzyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide. N-(3-chloro-6-(difluoromethyl)-2-fluorobenzyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide was synthesized according to General Procedure B-1 starting from 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide and (3-chloro-6-(difluoromethyl)-2-fluorophenyl)methanamine. The crude product was purified by preparative TLC (MeOH / DCM=1 / 10) to give the product (80 mg, 42%) as a white solid. ESI-MS [M+H]+: 475.1. 1 H NMR (400MHz, DMSO) δ9.10(t,J=5.5Hz,1H),8.56(s,1H),8.35(s,1H),7.83(s,1H),7.71–7.68(m,1H),7.60–7.32(m,3H), 7.01(dd,J=9.4,1.7Hz,1H),5.72(s,2H),4.58(d,J=5.2Hz,2H),1.96–1.89(m,1H),0.93–0.89(m,2H),0.69–0.65(m,2H).

[0608] Example 48

[0609] N-(3-cyclopropyl-2-fluoro-6-(1H-tetrazol-1-yl)benzyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide (I-78)

[0610] Plan 48

[0611]

[0612] Synthesis of N-(3-cyclopropyl-2-fluoro-6-(1H-tetrazol-1-yl)benzyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide. N-(3-cyclopropyl-2-fluoro-6-(1H-tetrazol-1-yl)benzyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide was synthesized according to General Procedure B-1 starting from 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide and (3-cyclopropyl-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)methanamine. The crude product was purified by preparative TLC (MeOH / DCM=1 / 10) to give the product (23.4 mg, yield: 13.69%) as a white solid. ESI-MS [M+H] + : 499.2. 1 H NMR(400MHz,DMSO)d 9.78(s,1H),8.77(t,J=5.5Hz,1H),8.49(s,1H),8.34(s,1H),7.82(s,1H),7.40 (d,J=9.3Hz,1H),7.30(d,J=8.4Hz,1H),7.16(t,J=8.1Hz,1H),7.01(dd,J=9.4,1 .7Hz,1H),5.70(s,2H),4.32(d,J=5.1Hz,2H),2.18-2.10(m,1H),1.96-1.88(m, 1H),1.09–1.01(m,2H),0.95–0.88(m,2H),0.85–0.78(m,2H),0.70–0.64(m,2H).

[0613] Example 49

[0614] 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(imidazo[1,2-a]pyridin-6-ylmethyl)-1H-1,2,3-triazole-4-carboxamide (I-136)

[0615] Plan 49

[0616]

[0617] Synthesis of 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(imidazo[1,2-a]pyridin-6-ylmethyl)-1H-1,2,3-triazole-4-carboxamide. 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(imidazo[1,2-a]pyridin-6-ylmethyl)-1H-1,2,3-triazole-4-carboxamide was synthesized starting from 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide and imidazo[1,2-a]pyridin-6-ylmethanamine hydrochloride according to General Procedure B-1. The crude product was purified by preparative TLC (MeOH / DCM=1 / 15) to give the product (6 mg, yield: 8%) as a white solid. ESI-MS [M+H] + : 413.2. 1 H NMR (400MHz, DMSO) δ9.16(t,J=6.0Hz,1H),8.58(s,1H),8.45(s,1H),8.36(s,1H),7.97(s,1H),7.85(s,1H),7.51( s,2H),7.41(d,J=9.3Hz,1H),7.23(s,1H),7.01(d,J=9.1Hz,1H),5.74(s,2H),4.42(d,J=6.0Hz,2H),1.98-1.87(m Hz,1H),0.96-0.88(m,2H),0.71-0.63(m,2H).

[0618] Example 50

[0619] N-((6-chlorobenzo[b]thien-2-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide (I-77)

[0620] Plan 50

[0621]

[0622] Synthesis of N-((6-chlorobenzo[b]thiophen-2-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide. N-((6-chlorobenzo[b]thiophen-2-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide was synthesized starting from 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide according to General Procedure B-2 and (6-chlorobenzo[b]thiophen-2-yl)methanamine. The crude product was purified by preparative HPLC (MeOH / DCM=1 / 15) to give the product (15 mg, yield: 12%) as a white solid. ESI-MS [M+H] + : 462.7. 1 H NMR (400MHz, DMSO) δ9.31(t,J=5.6Hz,1H),8.61(s,1H),8.36(s,1H),8.03(s,1H),7.85(s,1H),7.78(d,J=8.6Hz,1H),7.41(d,J=9.4Hz,1H),7.36 (d,J=8.5Hz,1H),7.29(s,1H),7.01(d,J=9.5Hz,1H),5.75(s,2H),4.67( d,J=5.6Hz,2H),1.96-1.90(m,1H),0.93-0.91(m,2H),0.68-0.67(m,2H).

[0623] Example 51

[0624] 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(1H-1,2,3-triazol-1-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide (I-76)

[0625] Plan 51

[0626]

[0627] Synthesis of 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(1H-1,2,3-triazol-1-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide. 1-((6-Cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide was synthesized starting from 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid and (2-fluoro-3-methoxy-6-(1H-1,2,3-triazol-1-yl)phenyl)methanamine according to General Procedure B-1. The crude product was purified by preparative HPLC (MeOH / DCM = 1 / 15) to give the product (25 mg, 14%) as a pink solid. ESI-MS [M+H]: 488.2. 1 H NMR (400MHz, DMSO) δ8.63–8.60(m,3H),8.50(d,J=0.9Hz,1H),8.14(s,1H),7.93(d,J=0.9Hz,1H),7.71(d,J=9.3Hz,1H),7.55(d,J=9. 5Hz,1H),7.35–7.29(m,2H),5.92(s,2H),4.31(d,J=5.1Hz,2H),3.91(s,3H),2.09–2.03(m,1H),1.05–1.01(m,2H),0.78–0.74(m,2H).

[0628] Example 52

[0629] Methyl 5-(2-((1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamido)methyl)-3-fluoro-4-methoxyphenyl)pyrimidine-2-carboxylate (I-75)

[0630] Plan 52

[0631]

[0632] Synthesis of methyl 5-(2-((1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamido)methyl)-3-fluoro-4-methoxyphenyl)pyrimidine-2-carboxylate. Methyl 5-(2-((1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamido)methyl)-3-fluoro-4-methoxyphenyl)pyrimidine-2-carboxylate was synthesized according to General Procedure B-1 starting from methyl 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate and methyl 5-(2-(aminomethyl)-3-fluoro-4-methoxyphenyl)pyrimidine-2-carboxylate. The crude product was purified by preparative HPLC (MeOH / DCM=1 / 10) to give the product (80 mg, yield: 48%) as a yellow solid. ESI-MS [M+H] + :557.2. 1 H NMR (400MHz, DMSO) δ9.00 (s, 2H), 8.79 (t, J = 5.2Hz, 1H), 8.48 (s, 1H), 8.34 (s, 1H),7.81(s,1H),7.40(d,J=9.3Hz,1H),7.28(t,J=8.5Hz,1H),7.18(d,J=8.5 Hz,1H),7.01(dd,J=9.4,1.7Hz,1H),5.70(s,2H),4.39(d,J=4.8Hz,2H),3.92 (s,3H),3.89(s,3H),1.92–1.88(m,1H),1.01–0.85(m,2H),0.73–0.65(m,2H).

[0633] Example 53

[0634] 5-(2-((1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamido)methyl)-3-fluoro-4-methoxyphenyl)pyrimidine-2-carboxylic acid (I-74)

[0635] Plan 53

[0636]

[0637] Synthesis of 5-(2-((1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamido)methyl)-3-fluoro-4-methoxyphenyl)pyrimidine-2-carboxylic acid. A solution of methyl 5-(2-((1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamido)methyl)-3-fluoro-4-methoxyphenyl)pyrimidine-2-carboxylate (56 mg, 0.1 mmol) and LiOH-H2O (21 mg, 0.5 mmol) in THF / MeOH / water (1 mL / 1 mL / 1 mL) was stirred at room temperature for 2 h. The reaction mixture was concentrated in vacuo and purified by preparative HPLC to give 5-(2-((1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamido)methyl)-3-fluoro-4-methoxyphenyl)pyrimidine-2-carboxylic acid (12 mg, yield: 22%) as a light yellow solid. ESI-MS [M+H] + :543.2. 1 H NMR (400MHz, DMSO) δ13.57 (s, 1H), 8.96 (s, 2H), 8.80 (t, J = 5.1Hz, 1H), 8.49 (s ,1H),8.34(s,1H),7.80(s,1H),7.40(d,J=9.3Hz,1H),7.27(t,J=8.5Hz,1H),7 .17(d,J=8.6Hz,1H),7.01(dd,J=9.3,1.6Hz,1H),5.70(s,2H),4.39(d,J=4.7 Hz,2H),3.89(s,3H),1.95–1.91(m,1H),0.95–0.81(m,2H),0.75–0.65(m,2H).

[0638] Example 54

[0639] 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(6-(3,4-dimethyl-1H-pyrazol-1-yl)-2-fluoro-3-methoxybenzyl)-1H-1,2,3-triazole-4-carboxamide (I-73)

[0640] Plan 54

[0641]

[0642] Synthesis of 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(6-(3,4-dimethyl-1H-pyrazol-1-yl)-2-fluoro-3-methoxybenzyl)-1H-1,2,3-triazole-4-carboxamide. 1-((6-Cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide was synthesized starting from 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid and (6-(3,4-dimethyl-1H-pyrazol-1-yl)-2-fluoro-3-methoxyphenyl)methanamine according to General Procedure B-1. The crude product was purified by preparative HPLC (MeOH / DCM = 1 / 10) to give the product (37.6 mg, yield: 37% over two steps) as a yellow solid. ESI-MS [M+H] + :515.2. 1 H NMR (400MHz, DMSO) δ8.80(t,J=5.8Hz,1H),8.58(s,1H),8.43(s,1H),7.92(s,1H),7.78(s,1H),7.50(d,J=9.4Hz,1H),7.21–7.16(m,3H ),5.79(s,2H),4.42(d,J=4.9Hz,2H),3.86(s,3H),2.19(s,3H),2.00(s,3H),1.95-1.91(m,1H),1.02–0.88(m,2H),0.78–0.64(m,2H).

[0643] Example 55

[0644] N-((5-cyano-3-fluoro-2-methoxypyridin-4-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide (I-72)

[0645] Plan 55

[0646]

[0647] Synthesis of N-((5-bromo-3-fluoro-2-methoxypyridin-4-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide. N-((5-bromo-3-fluoro-2-methoxypyridin-4-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide was synthesized according to General Procedure B-2 starting from 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide and (5-bromo-3-fluoro-2-methoxypyridin-4-yl)methanamine. The crude product was purified by recrystallization from MeOH to give the product (160 mg, yield: 76%) as a white solid. ESI-MS [M+H] + : 500.1.

[0648] Synthesis of N-((5-cyano-3-fluoro-2-methoxypyridin-4-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide. A solution of N-((5-bromo-3-fluoro-2-methoxypyridin-4-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide (110 mg, 0.22 mmol), Zn(CN)2 (52 mg, 0.44 mmol), Pd(dppf)Cl2 (19.7 mg, 0.027 mmol) and Pd2(dba)3 (25 mg, 0.027 mmol) in DMF (4 mL) was stirred in a microwave at 110°C for 50 minutes. The reaction mixture was washed with water (30 mL) and extracted with EtOAc (50 mL x 2). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, concentrated, and purified by preparative TLC (DCM / MeOH = 15:1) to give N-((5-cyano-3-fluoro-2-methoxypyridin-4-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide (55.4 mg, yield: 56%) as a white solid. ESI-MS [M+H] +: 447.1. 1H NMR (400MHz, DMSO) δ9.18(t,J=5.3Hz,1H),8.56(s,1H),8.48(s,1H),8.34(s,1H),7.83(s,1H),7.40(d,J=9.3Hz,1H),7.00(dd ,J=9.4,1.4Hz,1H),5.73(s,2H),4.56(d,J=5.2Hz,2H),4.00(s,3H),1.95–1.88(m,1H),0.91–0.88(m,2H),0.68–0.64(m,2H).

[0649] Example 56

[0650] 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-6-(imidazo[1,2-a]pyridin-2-yl)-3-methoxybenzyl)-1H-1,2,3-triazole-4-carboxamide (I-70)

[0651] Plan 56

[0652]

[0653] Synthesis of 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(pyrazolo[1,5-a]pyridin-2-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide. 1-((6-Cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide was synthesized starting from 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide and (2-fluoro-6-(imidazo[1,2-a]pyridin-2-yl)-3-methoxyphenyl)methanamine according to General Procedure B-1. The crude product was purified by preparative HPLC to give the product (80 mg, 42% over two steps) as a white solid. ESI-MS [M+H]: 537.2. 1HNMR (400MHz, DMSO) δ9.37 (s, 1H), 8.67 (d, J = 6.7Hz, 1H), 8.52 (s, 1H), 8.4 1(s,1H),8.32(s,1H),7.89(s,1H),7.67(d,J=8.9Hz,1H),7.52–7.42(m,3H ),7.22(t,J=8.6Hz,1H),7.16-7.11(m,2H),5.75(s,2H),4.67(d,J=5.5Hz, 2H),3.86(s,3H),1.97–1.91(m,1H),0.94–0.90(m,2H),0.69–0.66(m,2H).

[0654] Example 57

[0655] 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(1H-pyrazol-4-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide (I-67)

[0656] Plan 57

[0657]

[0658] Synthesis of 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(1H-pyrazol-4-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide. 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(1H-pyrazol-4-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide was synthesized starting from 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide and (2-fluoro-3-methoxy-6-(1H-pyrazol-4-yl)phenyl)methanamine according to General Procedure B-1. The crude product was purified by preparative HPLC to give the product (2.5 mg, yield: 2%) as a yellow solid. ESI-MS [M+H] + :487.2. 1H NMR (400MHz, DMSO) δ8.72–8.63(m,2H),8.60-8.57(m,1H),8.19-8.14(m,1H),7.77-7.73(m,3H),7.64–7.58(m,1H),7. 17–7.12(m,2H),5.96(s,2H),4.51–4.50(m,2H),3.84(s,3H),2.11-2.03(m,1H),1.09–0.95(m,2H),0.82–0.69(m,2H).

[0659] Example 58

[0660] 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(1H-tetrazol-1-yl)benzyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide (I-66)

[0661] Plan 58

[0662]

[0663] Synthesis of 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(1H-tetrazol-1-yl)benzyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide. 1-((6-Cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(1H-tetrazol-1-yl)benzyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide was synthesized starting from 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid and 1-(2-fluoro-3-methoxy-6-(1H-tetrazol-1-yl)phenyl)-N-methylmethanamine according to General Procedure B-1. The crude product was purified by preparative TLC (DCM / MeOH = 10:1) to give the product (30 mg, 15%) as a white solid. ESI-MS [M+H]: 503.2. 1H NMR (400MHz, DMSO) δ9.72 (s, 1H), 8.45–8.35 (m, 2H), 7.84 (d, J = 11.1Hz, 1H), 7.42–7.35 (m, 3H), 7.02 (d, J = 9.4Hz, 1H), 5.71 (d, J = 10. 4Hz,2H),5.20(s,1H),4.54(s,1H),3.94(s,3H),3.17(s,2H),2.68(s,1H),1.96–1.89(m,1H),0.94–0.86(m,2H),0.69–0.66(m,2H).

[0664] Example 59

[0665] N-((3-chloro-1H-indol-5-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide (I-65)

[0666] Plan 59

[0667]

[0668] Synthesis of N-((3-chloro-1H-indol-5-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide. N-((3-chloro-1H-indol-5-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide was synthesized starting from 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide according to General Procedure B-1 and (3-chloro-1H-indol-5-yl)methanamine hydrochloride. The crude product was purified by preparative HPLC to give the product (20 mg, yield: 25%) as a light yellow solid. ESI-MS[M+H] + :445.8. 1 H NMR (400MHz, MeOD) δ8.51(d,J=4.0Hz,2H),8.14(s,1H),7.69(d,J=3.0Hz,2H),7.51(s,1H),7.33(d,J=5.0Hz,1H),7 .24(s,1H),7.21(d,J=4.0Hz,1H)5.97(s,2H),4.68(s,2H),2.14-2.05(m,1H),1.15-1.06(m,2H),0.86-0.79(m,2H).

[0669] Example 60

[0670] 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2,6-difluoro-3-methoxybenzyl)-1H-1,2,3-triazole-4-carboxamide (I-64)

[0671] Plan 60

[0672]

[0673]

[0266] Synthesis of 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2,6-difluoro-3-methoxybenzyl)-1H-1,2,3-triazole-4-carboxamide. 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide was synthesized starting from 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide and (2,6-difluoro-3-methoxyphenyl)methanamine according to General Procedure B-2. The crude product was purified by flash column chromatography (0-4% MeOH in DCM) to give the product (90 mg, 62%) as a white solid. ESI-MS[M+H] + :439.1. 1 H NMR (400MHz, DMSO) δ8.82(t,J=5.4Hz,1H),8.54(s,1H),8.34(s,1H),7.82(s,1H),7.40(d,J=9.3Hz,1H),7.15-7.05(m,1H), 7.04-6.94(m,2H),5.72(s,2H),4.49(d,J=5.3Hz,2H),3.80(s,3H),1.97-1.86(m,1H),0.97-0.86(m,2H),0.71-0.61(m,2H).

[0674] Example 61

[0675] 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(pyrazolo[1,5-a]pyridin-2-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide (I-63)

[0676] Plan 61

[0677]

[0678] Synthesis of 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(pyrazolo[1,5-a]pyridin-2-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide. 1-((6-Cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide was synthesized starting from 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide and (2-fluoro-3-methoxy-6-(pyrazolo[1,5-a]pyridin-2-yl)phenyl)methanamine according to General Procedure B-1. The crude product was purified by preparative HPLC to give the product (2.0 mg, 12.9%) as a white solid. ESI-MS [M+H]: 537.2. 1 HNMR(400MHz,DMSO)δ8.97(t,J=5.9Hz,1H),8.64(d,J=6.9Hz,1H),8.56(s,1H),8.33(s,1 H),7.80(s,1H),7.71(d,J=8.9Hz,1H),7.53(d,J=8.7Hz,1H),7.39(d,J=9.3Hz,1H),7.24 (d,J=8.8Hz,2H),7.01-6.98(m,1H),6.94(d,J=6.9Hz,1H),6.91(s,1H),5.71(s,2H),4.7 3(d,J=4.9Hz,2H),3.87(s,3H),2.00–1.96(m,1H),0.91-0.89(m,2H),0.67–0.64(m,2H).

[0679] Example 62

[0680] 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide (I-62)

[0681] Plan 62

[0682]

[0683] Synthesis of 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide. 1-((6-Cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide was synthesized starting from 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid and (2-fluoro-3-methoxy-6-(3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)methanamine according to General Procedure B-2. The crude product was purified by preparative TLC (DCM / MeOH = 10 / 1) to give the product (29.1 mg, yield: 66%) as a white solid. ESI-MS [M+H]+: 555.1. 1 H NMR (400MHz, DMSO) δ8.55(t,J=5.5Hz,1H),8.51(s,1H),8.34(s,1H),8.31(dd,J =2.3Hz,J=0.9Hz,1H),7.81(s,1H),7.40(d,J=9.3Hz,1H),7.33–7.25(m,2H),7. 01(dd,J=9.4Hz,J=1.8Hz,1H),6.96(d,J=2.3Hz,1H),5.70(s,2H),4.34(d,J=5. 2Hz,2H),3.90(s,3H),1.96–1.89(m,1H),0.92–0.89(m,2H),0.69–0.65(m,2H).

[0684] Example 63

[0685] 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(1H-1,2,4-triazol-1-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide (I-61)

[0686] Plan 63

[0687]

[0688] Synthesis of tert-butyl (6-(2-(diphenylmethylene)hydrazinyl)-2-fluoro-3-methoxybenzyl)carbamate. A mixture of tert-butyl (6-bromo-2-fluoro-3-methoxybenzyl)carbamate (333 mg, 1.0 mmol), (diphenylmethylene)hydrazine (245 mg, 1.25 mmol), Pd-PEPPSI-IPENT-Cl-(o-methylpyridine) (42 mg, 0.05 mmol) and Cs2CO3 (652 mg, 2.0 mmol) in DME (15 mL) was stirred at 90°C under N2 for 16 h. The reaction mixture was concentrated in vacuo and purified by silica gel chromatography with DCM / MeOH=10 / 1 to give tert-butyl (6-(2-(diphenylmethylene)hydrazinyl)-2-fluoro-3-methoxybenzyl)carbamate (210 mg, 47%) as a yellow oil. ESI-MS [M+H] + :450.1.

[0689] Synthesis of (6-(2-(diphenylmethylene)hydrazinyl)-2-fluoro-3-methoxyphenyl)methanamine hydrochloride. A mixture of tert-butyl (6-(2-(diphenylmethylene)hydrazinyl)-2-fluoro-3-methoxybenzyl)carbamate (200 mg, 0.445 mmol) in HCl (4 M in dioxane, 5.0 mL) was stirred at room temperature for 1 h. The reaction mixture was concentrated in vacuo to give (6-(2-(diphenylmethylene)hydrazinyl)-2-fluoro-3-methoxyphenyl)methanamine hydrochloride (160 mg, crude) as a yellow solid, which was used in the next step without further purification. ESI-MS [M+H] + :350.1.

[0690] Synthesis of 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(6-(2-(diphenylmethylene)hydrazino)-2-fluoro-3-methoxybenzyl)-1H-1,2,3-triazole-4-carboxamide. 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(6-(2-(diphenylmethylene)hydrazino)-2-fluoro-3-methoxybenzyl)-1H-1,2,3-triazole-4-carboxamide was synthesized according to General Procedure B-1 starting from 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide and (6-(2-(diphenylmethylene)hydrazino)-2-fluoro-3-methoxyphenyl)methanamine hydrochloride. The crude product was purified by preparative TLC (DCM / MeOH=20 / 1) to give the product (120 mg, yield: 44%, two steps) as a yellow solid. ESI-MS [M+H] + :615.2.

[0691] Synthesis of 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-6-hydrazino-3-methoxybenzyl)-1H-1,2,3-triazole-4-carboxamide. A mixture of 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(6-(2-(diphenylmethylene)hydrazino)-2-fluoro-3-methoxybenzyl)-1H-1,2,3-triazole-4-carboxamide (122.8 mg, 0.2 mmol) in concentrated HCl / EtOH (2.0 mL / 4.0 mL) was stirred at 75 ° C for 1 h. The reaction mixture was concentrated in vacuo to give the desired product (90 mg, crude material) as a yellow solid, which was used in the next step without further purification. ESI-MS [M+H] + :451.1.

[0692] Synthesis of 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(1H-1,2,4-triazol-1-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide. A mixture of 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-6-hydrazino-3-methoxybenzyl)-1H-1,2,3-triazole-4-carboxamide (90 mg, crude) in formamide (3 mL) was stirred at 120° C. for 16 h. The reaction mixture was diluted with EtOAc (50 mL) and washed with water (50 mL). The organic layer was separated, dried over Na2SO4, and concentrated in vacuo to give the crude product, which was purified by preparative HPLC to give 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(1H-1,2,4-triazol-1-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide (7.3 mg, yield: 7.5% over two steps) as a white solid. ESI-MS [M+H] + :488.1. Purity: 95.8% (214nm), 95.5% (254nm). 1H NMR (400MHz, DMSO) δ8.84(s,1H),8.56(t,J=5.4Hz,1H),8.51(s,1H),8.34(s,1H),8.22(s,1H),7.81(s,1H),7.40(d,J=9.3Hz,1H),7.34–7.24 (m,2H),7.01(dd,J=9.4,1.7Hz,1H),5.71(s,2H),4.36(d,J=4.9Hz,2H) ,3.90(s,3H),1.93–1.86(m,1H),0.98–0.89(m,2H),0.73–0.65(m,2H).

[0693] Example 64

[0694] N-Benzyl-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide (I-60)

[0695] Plan 64

[0696]

[0697] Synthesis of N-benzyl-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide. N-benzyl-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide was synthesized starting from 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide and benzylamine according to General Procedure B-2. The crude product was purified by preparative TLC (DCM / MeOH = 10 / 1) to give the product (120 mg, yield: 45%) as a white solid. ESI-MS [M+H]+: 373.2. 1 H NMR (400MHz, DMSO) δ9.08(t,J=6.3Hz,1H),8.57(s,1H),8.36(s,1H),7.85(s,1H),7.41(d,J=9.3Hz,1H),7.34–7.27(m,4H),7.25–7. 17(m,1H),7.04-7.00(m,1H),5.75(d,J=7.0Hz,2H),4.43(d,J=6.3Hz,2H),1.97–1.87(m,1H),0.96–0.87(m,2H),0.72–0.63(m,2H).

[0698] Example 65

[0699] 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(methylsulfinyl)benzyl)-1H-1,2,3-triazole-4-carboxamide (I-58)

[0700] Plan 65

[0701]

[0702] Synthesis of 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(methylthio)benzyl)-1H-1,2,3-triazole-4-carboxamide. 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(methylthio)benzyl)-1H-1,2,3-triazole-4-carboxamide was synthesized starting from 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide and (2-fluoro-3-methoxy-6-(methylthio)phenyl)methanamine according to General Procedure B-2. The crude product was purified by preparative TLC (DCM / MeOH=10 / 1) to give the product (300 mg, 49.5%) as a yellow solid. ESI-MS [M+H] + :467.1.

[0703] Synthesis of 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(methylsulfinyl)benzyl)-1H-1,2,3-triazole-4-carboxamide. To a solution of 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(methylthio)benzyl)-1H-1,2,3-triazole-4-carboxamide (100 mg, 0.21 mmol) in DCM (5 mL) was added 3-chloroperoxybenzoic acid (36 mg, 0.21 mmol) at 0°C. The reaction mixture was stirred at 0°C for 1 h. The mixture was diluted with DCM (15 mL), washed with brine (30 mL), 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-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(methylsulfinyl)benzyl)-1H-1,2,3-triazole-4-carboxamide (20 mg, yield: 19.4%) as a white solid. ESI-MS [M+H] + :483.1. Purity: 91.77 (214nm), 91.39 (254nm).1 H NMR (400MHz, CDCl3) δ = 8.27 (t, J = 6.4Hz, 1H), 8.23 ​​(s, 1H), 7.85 (s, 1H), 7.53 (d, J = 8.0Hz ,1H),7.46(s,1H),7.14(t,J=8.8Hz,1H),7.01(dd,J=9.2,1.6Hz,1H),6.82(dd,J=9.2,4. 0Hz,1H),5.75(s,2H),5.12(dd,J=14.4,6.4Hz1H),4.91(dd,J=14.4,6.4Hz,1H),3.85(s, 3H), 3.03 (s, 3H), 1.92–1.85 (m, 1H), 0.98 (dd, J=14.0, 5.6Hz, 2H), 0.67 (q, J=5.6Hz, 2H).

[0704] Example 66

[0705] 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(methylsulfonyl)benzyl)-1H-1,2,3-triazole-4-carboxamide (I-53)

[0706] Plan 66

[0707]

[0708] Synthesis of 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(methylsulfonyl)benzyl)-1H-1,2,3-triazole-4-carboxamide. To a solution of 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(methylthio)benzyl)-1H-1,2,3-triazole-4-carboxamide (100 mg, 0.21 mmol) in DCM (5 mL) was added 3-chloroperoxybenzoic acid (72 mg, 0.42 mmol) at 0°C. The reaction mixture was stirred at room temperature for 1 h. The mixture was diluted with DCM (15 mL), washed with brine (30 mL), dried over Na2SO4 and concentrated to give the crude product, which was purified by preparative HPLC to give 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(methylsulfonyl)benzyl)-1H-1,2,3-triazole-4-carboxamide (20 mg, yield: 19%) as a white solid. ESI-MS [M+H] + :498.8. Purity: 99.79 (214nm), 99.16 (254nm).1 H NMR (400MHz, CDCl3) δ = 8.37 (s, 1H), 8.12 (s, 1H), 8.04 (t, J = 6.4Hz, 1H), 7.92 (d,J=9.2Hz,1H),7.77(s,1H),7.44(d,J=9.2Hz,1H),7.32(t,J=9.2Hz,1H), 7.02(dd,J=9.2,4.0Hz,1H),5.96(s,2H),5.04(d,J=6.0Hz,2H),3.96(s,3H) ,3.34(s,3H),2.02-1.95(m,1H),1.1(q,J=6.4Hz,2H),0.77(q,J=5.6Hz,2H).

[0709] Example 67

[0710] 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(6-(N,N-dimethylsulfamoyl)-2-fluoro-3-methoxybenzyl)-1H-1,2,3-triazole-4-carboxamide (I-57)

[0711] Plan 67

[0712]

[0713] Synthesis of 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(6-(N,N-dimethylsulfamoyl)-2-fluoro-3-methoxybenzyl)-1H-1,2,3-triazole-4-carboxamide. 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(6-(N,N-dimethylsulfamoyl)-2-fluoro-3-methoxybenzyl)-1H-1,2,3-triazole-4-carboxamide was synthesized starting from 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide and 2-(aminomethyl)-3-fluoro-4-methoxy-N,N-dimethylbenzenesulfonamide according to General Procedure B-2. The crude product was purified by preparative TLC (DCM / MeOH=10 / 1) to give the product (30 mg, yield: 20%) as a white solid.ESI-MS [M+H] + : 528.2. 1HNMR (400MHz, DMSO) δ8.58(s,1H),8.34(s,1H),8.30(t,J=5.3Hz,1H),7.82(s,1H),7.67(d,J=8.9Hz,1H),7.40(d,J=9.3Hz,1H),7.33(t,J=8.5H z,1H),7.02-6.99(m,1H),5.72(s,2H),4.81(d,J=4.3Hz,2H),3.93(s,3H ),2.71(s,6H),1.96-1.90(m,1H),0.96–0.85(m,2H),0.73–0.64(m,2H).

[0714] Example 68

[0715] 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide (I-52)

[0716] Plan 68

[0717]

[0718] Synthesis of 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide. 1-((6-Cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide was synthesized starting from 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid and (2-fluoro-3-methoxy-6-(3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl)phenyl)methanamine hydrochloride according to General Procedure B-1. The crude product was purified by preparative HPLC to give the product (27.8 mg, 33% yield) as a yellow solid. ESI-MS [M+H]: 556.2. 1H NMR (400MHz, DMSO) δ9.13(s,1H),8.71(s,1H),8.48(s,1H),8.34(s,1H),7.81(s,1H),7.40(d,J=9.2Hz,2H),7.31(t,J=8.7Hz,1H) ,7.01(d,J=9.2Hz,1H),5.70(s,2H),4.37(d,J=5.1Hz,2H),3.91(s,3H),2.00–1.82(m,1H),1.02–0.83(m,2H),0.76–0.58(m,2H).

[0719] Example 69

[0720] 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-(methylsulfonyl)benzyl)-1H-1,2,3-triazole-4-carboxamide (I-51)

[0721] Plan 69

[0722]

[0723] Synthesis of 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-(methylsulfonyl)benzyl)-1H-1,2,3-triazole-4-carboxamide. 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide was synthesized starting from 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide and (2-(methylsulfonyl)phenyl)methanamine according to General Procedure B-2. The crude product was purified by preparative TLC (DCM / MeOH = 10 / 1) to give the product (30 mg, yield: 8%) as a white solid. ESI-MS[M+H]+:451.2. 1H NMR(400MHz,DMSO)δ9.22(t,J=6.1Hz,1H),8.61(s,1H),8.36(s,1H),8.27(s, 1H),7.92(d,J=7.8Hz,1H),7.86(s,1H),7.68(t,J=7.5Hz,1H),7.61–7.47(m, 2H),7.41(d,J=9.3Hz,1H),7.01(d,J=9.4Hz,1H),5.75(s,2H),4.83(d,J=6.1 Hz,2H),3.37(s,3H),1.96-1.91(m,1H),0.98-0.92(m,2H),0.74-0.66(m,2H).

[0724] Example 70

[0725] 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(1H-1,2,3-triazol-4-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide (I-49)

[0726] Plan 70

[0727]

[0728] Synthesis of 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(1H-1,2,3-triazol-4-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide. 1-((6-Cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(1H-1,2,3-triazol-4-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide was synthesized starting from 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid and (2-fluoro-3-methoxy-6-(1H-1,2,3-triazol-4-yl)phenyl)methanamine hydrochloride according to General Procedure B-1. The crude product was purified by preparative HPLC to give the product (3.1 mg, yield: 3.2% over two steps) as a yellow solid. ESI-MS [M+H]+: 488.2. 1H NMR(400MHz,DMSO)δ8.81(s,1H),8.55(s,1H),8.43(s,2H),8.33(s,1H),8.16(s,1H),7.79(s,1H),7.52–7.31(m,2H),7.20-7.1 8(m,1H),7.00(d,J=9.2Hz,1H),5.72(s,2H),4.65(s,2H),3.86(s,3H),1.98–1.84(m,1H),1.00–0.82(m,2H),0.68-0.66(m,2H).

[0729] Example 71

[0730] 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(morpholinosulfonyl)benzyl)-1H-1,2,3-triazole-4-carboxamide (I-48)

[0731] Plan 71

[0732]

[0733] Synthesis of 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(morpholinosulfonyl)benzyl)-1H-1,2,3-triazole-4-carboxamide. 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(morpholinosulfonyl)benzyl)-1H-1,2,3-triazole-4-carboxamide was synthesized starting from 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide and (2-fluoro-3-methoxy-6-(morpholinosulfonyl)phenyl)methanamine according to General Procedure B-2. The crude product was purified by preparative TLC (DCM / MeOH=10 / 1) to give the product (30 mg, yield: 14%) as a white solid.ESI-MS [M+H] + : 570.2. 1H NMR (400MHz, DMSO) δ8.59(s,1H),8.38-8.33(m,2H),7.82(s,1H),7.70(d,J=8.9Hz,1H),7.42–7.31(m,2H),7.04-6.95(m,1H),5.73(s ,2H),4.83-4.79(m,2H),3.95(s,3H),3.62–3.55(m,4H),3.04-2.95(m,4H),1.93-1.88(m,1H),0.95–0.85(m,2H),0.71–0.60(m,2H).

[0734] Example 72

[0735] 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(1-(2-fluoro-3-methoxy-6-(1H-tetrazol-1-yl)phenyl)ethyl)-1H-1,2,3-triazole-4-carboxamide (I-31)

[0736] Plan 72

[0737]

[0738] Synthesis of 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(1-(2-fluoro-3-methoxy-6-(1H-tetrazol-1-yl)phenyl)ethyl)-1H-1,2,3-triazole-4-carboxamide. 1-((6-Cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide was synthesized starting from 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid and 1-(2-fluoro-3-methoxy-6-(1H-tetrazol-1-yl)phenyl)ethan-1-amine according to General Procedure B-1. The crude product was purified by preparative TLC (DCM / MeOH = 18 / 1) to give the product (17.4 mg, 41%) as an off-white solid. ESI-MS [M+H] + :503.2. 1H NMR (400MHz, DMSO) δ9.78(s,1H),8.77(d,J=6.4Hz,1H),8.51(s,1H),8.34(s,1H),7.81(s,1H),7.41–7.30(m,3H),7.01(d,J=9.3Hz ,1H),5.71(s,2H),4.47–4.43(m,1H),3.90(s,3H),1.95–1.89(m,1H),1.56(d,J=7.0Hz,3H),0.92–0.91(m,2H),0.67–0.66(m,2H).

[0739] Example 73

[0740] N-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide (I-26)

[0741] Plan 73

[0742]

[0743] Synthesis of N-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide. N-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide was synthesized according to General Procedure B-1 starting from 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide and 5-(aminomethyl)-4,6-dimethylpyridin-2-amine hydrochloride. The crude product was purified by preparative TLC (DCM / MeOH=10 / 1) to give the product (50 mg, yield: 35%) as an off-white solid.ESI-MS [M+H] + : 417.2. 1H NMR (400MHz, DMSO) δ8.55(s,1H),8.35(s,1H),8.31(t,J=5.1Hz,1H),7.83(s,1H),7.40(d,J=9.3Hz,1H),7.02-7.00(m,1H),6.09(s,1H ),5.71(s,2H),5.65(s,2H),4.32(d,J=5.2Hz,2H),2.30(s,3H),2.17(s,3H),1.97-1.88(m,1H),0.96–0.88(m,2H),0.70–0.65(m,2H).

[0744] Example 74

[0745] N-(1-amino-6,7-dihydro-5H-cyclopenta[c]pyridin-5-yl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide (I-23)

[0746] Plan 74

[0747]

[0748] Synthesis of N-(1-amino-6,7-dihydro-5H-cyclopenta[c]pyridin-5-yl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide. N-(1-amino-6,7-dihydro-5H-cyclopenta[c]pyridin-5-yl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide was synthesized according to General Procedure B-2 starting from 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide and 6,7-dihydro-5H-cyclopenta[c]pyridin-1,5-diamine hydrochloride. The crude product was purified by preparative TLC (DCM / MeOH=10 / 1) to give the product (30 mg, 42%) as a white solid. ESI-MS [M+H] + :415.2. 1H NMR (400MHz, DMSO) δ8.74(d,J=8.6Hz,1H),8.59(d,J=6.2Hz,1H),8.36(s,1H),7.85(s, 1H),7.72(d,J=5.1Hz,1H),7.41(d,J=9.3Hz,1H),7.02(dd,J=9.4,1.3Hz,1H),6.39(d,J =5.1Hz,1H),5.77(s,2H),5.74(s,2H),5.42(q,J=8.2Hz,1H),2.79–2.73(m,1H),2.58–2 .50(m,1H),2.41–2.34(m,1H),2.05–1.90(m,2H),0.95–0.90(m,2H),0.69–0.66(m,2H).

[0749] Example 75

[0750] N-((5-amino-4H-1,2,4-triazol-3-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide (I-21)

[0751] Plan 75

[0752]

[0753] Synthesis of N-((5-amino-4H-1,2,4-triazol-3-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide. N-((5-amino-4H-1,2,4-triazol-3-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide was synthesized according to General Procedure B-2 starting from 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide and 5-(aminomethyl)-4H-1,2,4-triazol-3-amine hydrochloride. The crude product was purified by trituration with DCM / MeOH (200 / 100 mL) to afford the product (100 mg, 31%). ESI-MS [M+H] + :379.2. 1H NMR (400MHz, DMSO) δ11.71(s,1H),8.56(s,1H),8.45(s,1H),8.34(s,1H),7.83(s,1H),7.40(d,J=9.4Hz,1H),7.00(dd,J=9 .4Hz,1.6Hz,1H),5.86(s,2H),5.72(s,2H),4.25(d,J=4.9Hz,2H),1.94–1.90(m,1H),0.92–0.90(m,2H),0.68–0.64(m,2H).

[0754] Example 76

[0755] N-((5-amino-1,3,4-thiadiazol-2-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide (I-20)

[0756] Plan 76

[0757]

[0758] Synthesis of N-((5-amino-1,3,4-thiadiazol-2-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide. N-((5-amino-1,3,4-thiadiazol-2-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide was synthesized according to General Procedure B-1 starting from 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide and 5-(aminomethyl)-1,3,4-thiadiazol-2-amine hydrochloride. The crude product was purified by preparative TLC (MeOH / DCM=1 / 10) to give the product (40 mg, yield: 21%) as a white solid. ESI-MS [M+H] + : 396.1. 1 H NMR (400MHz, DMSO) δ9.26(t,J=5.9Hz,1H),8.61(s,1H),8.35(s,1H),7.84(s,1H),7.42(d,J=9.3Hz,1H),7.1 0–6.97(m,3H),5.74(s,2H),4.53(d,J=5.9Hz,2H),1.93–1.90(m,1H),0.93–0.90(m,2H),0.68–0.65(m,2H).

[0759] Example 77

[0760] N-((5-amino-1,3,4-oxadiazol-2-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide (I-19)

[0761] Plan 77

[0762]

[0763] Synthesis of N-((5-amino-1,3,4-oxadiazol-2-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide. N-((5-amino-1,3,4-oxadiazol-2-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide was synthesized according to General Procedure B-1 starting from 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide and 5-(aminomethyl)-1,3,4-oxadiazol-2-amine. The crude product was purified by preparative HPLC to give the product (29 mg, yield: 36.2%) as a white solid. ESI-MS [M+H] + : 380.2. 1 H NMR (400MHz, DMSO) δ = 9.11 (s, 1H), 8.61 (s, 1H), 8.37 (s, 1H), 7.85 (s, 1H), 7.42-7.40 (m, 1H), 7.03 –6.95(m,3H),5.75(s,2H),4.46(s,2H),1.95–1.90(m,1H),0.95–0.91(m,2H),0.69-0.65(m,2H).

[0764] Example 78

[0765] N-((2-aminothiazol-5-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide (I-18)

[0766] Plan 78

[0767]

[0768] Synthesis of N-((2-aminothiazol-5-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide. N-((2-aminothiazol-5-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide was synthesized starting from 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide and 5-(aminomethyl)thiazol-2-amine according to General Procedure B-1. The crude product was purified by preparative HPLC to give the product (6.0 mg, yield: 7.5%) as a white solid. ESI-MS [M+H]+: 395.1. 1 H NMR (400MHz, DMSO) δ8.94(t,J=6.0,1H),8.56(s,1H),8.35(s,1H),8.18(s,1H),7.83(s,1H),7.41(d,J=9.4,1H),7.01-6. 96(m,1H),6.75(d,J=4.9,2H),5.73(s,2H),4.34(d,J=6.0,2H),1.93-1.90(m,1H),0.97–0.87(m,2H),0.73–0.62(m,2H).

[0769] Example 79

[0770] N-(1-amino-3-methyl-6,7-dihydro-5H-cyclopenta[c]pyridin-5-yl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide (I-16)

[0771] Plan 79

[0772]

[0773] Synthesis of N-(1-amino-3-methyl-6,7-dihydro-5H-cyclopenta[c]pyridin-5-yl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide. N-(1-Amino-3-methyl-6,7-dihydro-5H-cyclopenta[c]pyridin-5-yl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide was synthesized starting from 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide and 3-methyl-6,7-dihydro-5H-cyclopenta[c]pyridin-1,5-diamine according to General Procedure B-2. The crude product was purified by preparative HPLC to give the product (8 mg, yield: 21%) as a white solid. ESI-MS [M+H]+: 429.2. 1 H NMR(400MHz,DMSO)δ8.70(d,J=8.7Hz,1H),8.58(s,1H),8.36(s,1H),7.85(s ,1H),7.42(d,J=9.3Hz,1H),7.02(d,J=9.4Hz,1H),6.25(s,1H),5.74(s,2H), 5.77(s,2H),5.38(m,1H),2.65-2.75(m,1H),2.46-2.50(m,1H),2.42–2.30( m,1H),2.18(s,3H),1.90–2.03(m,2H),0.96-0.88(m,2H),0.71-0.68(m,2H).

[0774] Example 80

[0775] N-((4-chlorothieno[3,2-c]pyridin-2-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide (I-11)

[0776] Plan 80

[0777]

[0778] Synthesis of N-((4-chlorothieno[3,2-c]pyridin-2-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide. N-((4-chlorothieno[3,2-c]pyridin-2-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide was synthesized according to General Procedure B-2 starting from 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide and (4-chlorothieno[3,2-c]pyridin-2-yl)methanamine. The crude product was purified by preparative TLC (10% MeOH / DCM) to afford the product (9.2 mg, 2.6% yield) as an off-white solid. ESI-MS [M+H] + : 464.1. 1 H NMR (400MHz, DMSO) δ9.40(t,J=6.1Hz,1H).,8.62(s,1H),8.35(s,1H),8.19(d,J=5.5Hz,1H),8.01(d,J=5.5Hz,1H),7.85(s,1H),7 .44-7.38(m,2H),7.05-6.98(m,1H),5.75(s,2H),4.75(d,J=6.0Hz,2H),1.98-1.87(m,1H),0.97-0.87(m,2H),0.72-0.62(m,2H).

[0779] Example 81

[0780] 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-((3-fluoro-4-methoxypyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide (I-7)

[0781] Plan 81

[0782]

[0783] Synthesis of 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-((3-fluoro-4-methoxypyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide. 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-((3-fluoro-4-methoxypyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide was synthesized starting from 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide and (3-fluoro-4-methoxypyridin-2-yl)methanamine according to General Procedure B-2. The crude product was purified by preparative TLC (MeOH / DCM=1 / 10) to give the product (55 mg, 58.5%) as a white solid.ESI-MS: [M+H]+, 422.2. 1 H NMR (400MHz, DMSO) δ8.80–8.76(m,1H),8.58(s,1H),8.38–8.33(m,1H),8.22(d,J=5.5Hz,1H),7.84(s,1H),7.41(d,J=9.3Hz,1H),7.21 –7.14(m,1H),7.05–6.98(m,1H),5.74(s,2H),4.61–4.55(m,2H),3.92(s,3H),1.98–1.87(m,1H),0.95–0.88(m,2H),0.70–0.63(m,2H).

[0784] Example 82

[0785] N-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)benzyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide (I-3)

[0786] Plan 82

[0787]

[0788] Synthesis of N-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)benzyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide. N-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)benzyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide was synthesized starting from 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide and (5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)methanamine according to General Procedure B-2. The crude product was purified by preparative TLC (DCM / MeOH = 15 / 1) to give the product (50 mg, yield: 46%) as a white solid. ESI-MS [M+H] + :508.1. 1 H NMR (400MHz, MeOD) δ8.45(s,1H),8.37(s,1H),8.21–8.19(m,1H),7.80(s,1H),7.62(d,J=2.2Hz,1H),7.50(dd,J=8.5,2.3Hz,1H),7.46(d,J=8. 5Hz,1H),7.39(d,J=9.4Hz,1H),7.11(dd,J=9.4,1.7Hz,1H),5.75(s,2H ),4.45(s,2H),1.98–1.90(m,1H),1.00–0.95(m,2H),0.74–0.69(m,2H).

[0789] Example 83

[0790] N-(6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluoro-3-methoxybenzyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide (I-1)

[0791] Plan 83

[0792]

[0793] Synthesis of N-(6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluoro-3-methoxybenzyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide. N-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)benzyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide was synthesized starting from 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid and (6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluoro-3-methoxyphenyl)methanamine according to General Procedure B-1. The crude product was purified by flash chromatography (PE / EtOAc = 1 / 1) to give the product (30 mg, yield: 29.7%) as a white solid. ESI-MS [M+H]+: 522.2. 1 H NMR (400MHz, DMSO) δ8.76(s,1H),8.69-8.61(m,1H),8.50(s,1H),8.34(s,1H),7.82(s,1H),7.40(d,J=9.3Hz,1H),7.45–7.28(m, 2H),7.05-6.97(m,1H),5.71(s,2H),4.35(d,J=5.2Hz,2H),3.91(s,3H),1.98-1.85(m,1H),0.95–0.85(m,2H),0.71–0.60(m,2H).

[0794] Example 84

[0795] Ethyl 3-(2-((4-((3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)benzyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)propanoate (I-113)

[0796] Plan 84

[0797]

[0798] Synthesis of 3-bromo-5-cyclopropylpyridin-2-amine. To a solution of 5-cyclopropylpyridin-2-amine (10.00 g, 74.5 mmol) in MeCN (130 mL) was added 1-bromo-2,5-pyrrolidinedione (16 g, 89.4 mmol) at room temperature. The reaction mixture was stirred for 3 h and then concentrated in vacuo to give 3-bromo-5-cyclopropylpyridin-2-amine (15.0 g, crude material) as a yellow solid, which was used in the next reaction without further purification. ESI-MS [M+H] + :213.0

[0799] Synthesis of ethyl 3-(2-amino-5-cyclopropylpyridin-3-yl)acrylate. To a solution of 3-bromo-5-cyclopropylpyridin-2-amine (7.00 g, 32.85 mmol) in DMF (60 mL) was added Et3N (15 mL), PPh3 (1.74 g, 16.43 mmol), Pd(OAc)2 (0.75 g 3.3 mmol) and ethyl acrylate (6 mL, 65.7 mmol) at room temperature. The reaction mixture was heated to 95°C. ℃ The mixture was stirred for 16 h. The mixture was concentrated in vacuo and washed with EtOAc to give ethyl 3-(2-amino-5-cyclopropylpyridin-3-yl)acrylate (4 g, yield: 52.42%) as a yellow solid. ESI-MS [M+H] + :233.1.

[0800] The synthesis of 3-(2-amino-5-cyclopropylpyridine-3-yl)ethyl propionate.To the solution of 3-(2-amino-5-cyclopropylpyridine-3-yl)ethyl acrylate (5g, 21.53mmol) in EtOH (50mL) / EtOAc (10mL), Pd / C (500mg) is added.The mixture is stirred for 16h at room temperature and under a hydrogen atmosphere.The mixture is filtered and concentrated in vacuo to obtain 3-(2-amino-5-cyclopropylpyridine-3-yl)ethyl propionate (5.4g, thick material), which is a yellow oil that is used for the next step without further purification.ESI-MS[M+H]+: 235.1.

[0801] Synthesis of ethyl 3-(2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)propanoate. To a solution of ethyl 3-(2-amino-5-cyclopropylpyridin-3-yl)propanoate (5.4 g, crude material) in DMF (60 mL) was added 1,3-dichloropropan-2-one (11.7 g, 92.16 mmol) at room temperature. The reaction mixture was heated to 95 ℃The mixture was stirred for 16 h. The mixture was concentrated in vacuo and purified by flash chromatography (0-60% EtOAc in PE) to afford ethyl 3-(2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)propanoate (2.2 g, 31.1% yield) as a red oil. ESI-MS [M+H]+: 307.1.

[0802] Synthesis of ethyl 3-(2-(azidomethyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)propanoate. To a solution of ethyl 3-(2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)propanoate (2.2 g, 7.17 mmol) in DMF (30 mL) was added NaN3 (416 mg, 6.40 mmol). The reaction mixture was stirred at room temperature for 2 h. The reactant was diluted with H2O (30 mL) and extracted with EtOAc (50 mL×3). The combined organic phases were washed with brine (50 mL) and concentrated in vacuo to give ethyl 3-(2-(azidomethyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)propanoate (1.6 g, crude material) as a red oil, which was used in the next step without further purification. ESI-MS[M+H]+:314.1.

[0803] Synthesis of benzyl 1-((6-cyclopropyl-8-(3-ethoxy-3-oxopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate. To a solution of ethyl 3-(2-(azidomethyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)propanoate (1.6 g, 5.11 mmol) in t-BuOH / H₂O (20 mL / 20 mL) was added benzyl propiolate (0.98 g, 6.13 mmol), sodium ascorbate (0.202 g, 1.02 mmol), and CuSO₄ (0.163 g, 1.02 mmol) at room temperature. The mixture was stirred for 2 h. The reaction was diluted with water (30 mL) and extracted with EtOAc (50 mL x 3). The combined organic phases were washed with brine (50 mL) and concentrated in vacuo to afford benzyl 1-((6-cyclopropyl-8-(3-ethoxy-3-oxopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate (1.4 g, crude) as a red oil, which was used in the next step without further purification. ESI-MS [M+H]: 474.2.

[0804] Synthesis of 1-((6-cyclopropyl-8-(3-ethoxy-3-oxopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid. A mixture of benzyl 1-((6-cyclopropyl-8-(3-ethoxy-3-oxopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate (1.4 g, 2.97 mmol) and Pd / C (2 g) in EtOH / EtOAc (20 mL / 20 mL) was stirred at room temperature under a hydrogen atmosphere for 1 hour. The mixture was filtered and washed with MeOH (100 mL). The filtrate was concentrated in vacuo to give 1-((6-cyclopropyl-8-(3-ethoxy-3-oxopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid (600 mg, crude) as a white solid. ESI-MS [M+H]+: 384.1.

[0805] Synthesis of ethyl 3-(2-((4-((3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)benzyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)propanoate. To a solution of 1-((6-cyclopropyl-8-(3-ethoxy-3-oxopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid (100 mg, 0.261 mmol) in DMF (3 mL) was added HATU (119.01 mg, 0.313 mmol), DIPEA (134.84 mg, 1.04 mmol) and (3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)methanamine (59.9 mg, 0.261 mmol) at room temperature. After stirring for 16 h, the reaction mixture was quenched with water (20 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine, dried over NaSO, concentrated, and purified by preparative HPLC to give ethyl 3-(2-((4-((3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)benzyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)propanoate (95.4 mg, yield: 61.68%) as a white solid. ESI-MS [M+H]: 593.2. 1H NMR(400MHz,DMSO)9.84(s,1H),8.93(t,J=5.3Hz,1H),8.53(s,1H),8.36(s,1H ),7.95(s,1H),7.88–7.82(m,1H),7.53-7.48(m,1H),5.81(s,2H),4.38(d,J=5 .1Hz,2H),4.04(q,J=7.1Hz,2H),3.08(t,J=7.6Hz,2H),2.77(t,J=7.7Hz,2H), 2.00-1.90(m,1H),1.14(t,J=7.1Hz,3H),1.00-0.90(m,2H),0.75-0.65(m,2H).

[0806] Example 85

[0807] 3-(2-((4-((3-chloro-6-cyanamido-2-fluorobenzyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)propanoic acid (I-110) and 3-(2-((4-((3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)benzyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)propanoic acid (I-109)

[0808] Plan 85

[0809]

[0810] Synthesis of 3-(2-((4-((3-chloro-6-cyanamido-2-fluorobenzyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)propanoic acid and 3-(2-((4-((3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)benzyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)propanoic acid. To a solution of ethyl 3-(2-((4-((3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)benzyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)propanoate (80 mg, 0.135 mmol) in EtOH / HO (10 mL / 10 mL) was added LiOH HO (10.8 mg, 0.27 mmol) at room temperature. The reaction mixture was stirred at room temperature for 0.5 h. The mixture was adjusted to pH 3 by adding HCl (1 M, aqueous solution) and the mixture was extracted with EtOAc (20 mL x 3). The combined organic layers were concentrated in vacuo and purified by preparative HPLC to give: 3-(2-((4-((3-chloro-6-cyanamido-2-fluorobenzyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)propanoic acid (I-110, 32.4 mg, yield: 44.7%) as a white solid, and 3-(2-((4-((3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)benzyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)propanoic acid (I-109, 5.4 mg, yield: 7.1%) as a white solid. I-110: ESI-MS [M+H]+: 537.1. 1 H NMR(400MHz,DMSO)d 12.16(s,1H),10.20(s,1H),9.22(s,1H),8.62(s,1H),8.20(s,1H),7.78(s,1H),7.53(t,J=8.4Hz,1H),6.96(d,J=8.8Hz,1H),6.85(s,1H) ,5.75(s,2H),4.44(d,J=4.7Hz,2H),3.03(t,J=7.6Hz,2H),2.69(t,J=7.6Hz,2H),1.93-1.84(m,1H),0.96–0.86(m,2H),0.70–0.62(m,2H). I-109: ESI-MS [M+H]+: 565.1. 1H NMR(400MHz,DMSO)d 12.18(s,1H),9.85(s,1H),8.91(d,J=5.4Hz,1H),8.49(s,1H),8.20(d,J =1.2Hz,1H),7.87–7.82(m,1H),7.76(s,1H),7.50(dd,J=8.7,1.4Hz,1H), 6.84(s,1H),5.71(s,2H),4.37(d,J=4.9Hz,2H),3.03(t,J=7.6Hz,2H),2. 70–2.66(m,2H),1.91–1.85(m,1H),0.94-0.86(m,2H),0.68-0.60(m,2H).

[0811] Example 86

[0812] Ethyl 3-(2-((4-((6-cyano-2-fluoro-3-methoxybenzyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)propanoate (I-108)

[0813] Plan 86

[0814]

[0815] Synthesis of ethyl 3-(2-((4-((6-cyano-2-fluoro-3-methoxybenzyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)propanoate. A mixture of 1-((6-cyclopropyl-8-(3-ethoxy-3-oxopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid (192 mg, 0.5 mmol) in SOCl2 (2 mL) was stirred at room temperature for 2 h and then concentrated in vacuo. The residue was redissolved in THF (3 mL) at 0 ° C and added to a solution of 2-(aminomethyl)-3-fluoro-4-methoxybenzonitrile (90 mg, 0.5 mmol) and LiHMDS (1 M in THF, 2 mL) in THF (5 mL). The resulting mixture was stirred at room temperature for 2 h. The reaction was quenched with saturated NH4Cl aqueous solution (10 mL) and extracted with EtOAc (20x3 mL). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated in vacuo to give a crude material, which was purified by preparative HPLC to give ethyl 3-(2-((4-((6-cyano-2-fluoro-3-methoxybenzyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)propanoate (20 mg, yield: 7%) as a pale white solid. ESI-MS[M+H]+:546.2. 1 H NMR (400MHz, DMSO) δ9.04 (t, J = 5.3Hz, 1H), 8.55 (s, 1H), 8.22 (s, 1H), 7.78 (s, 1H), 7.6 5(dd,J=8.6,1.3Hz,1H),7.27(t,J=8.4Hz,1H),6.84(s,1H),5.74(s,2H),4.58(d,J=5 .1Hz,2H),4.03(q,J=7.1Hz,2H),3.91(s,3H),3.07(t,J=7.6Hz,2H),2.76(t,J=7.6Hz ,2H),1.91-1.85(m,1H),1.14(t,J=7.1Hz,3H),0.97–0.82(m,2H),0.74–0.56(m,2H).

[0816] Example 87

[0817] 3-(2-((4-((6-cyano-2-fluoro-3-methoxybenzyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)propanoic acid (I-107)

[0818] Plan 87

[0819]

[0820] Synthesis of 3-(2-((4-((6-cyano-2-fluoro-3-methoxybenzyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)propanoic acid. A mixture of ethyl 3-(2-((4-((6-cyano-2-fluoro-3-methoxybenzyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)propanoate (55 mg, 0.1 mol) in TFA (2 mL) and Et3SiH (1 mL) was stirred at 80°C for 36 h. The reaction mixture was concentrated in vacuo to give a crude material, which was purified by preparative HPLC to afford 3-(2-((4-((6-cyano-2-fluoro-3-methoxybenzyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)propanoic acid (5 mg, yield: 10%) as a white solid. ESI-MS [M+H]: 518.2. 1 H NMR (400MHz, DMSO) δ12.17 (s, 1H), 9.04 (t, J = 5.4Hz, 1H), 8.56 (s, 1H), 8.21 (s ,1H),7.77(s,1H),7.65(dd,J=8.6,1.3Hz,1H),7.27(t,J=8.4Hz,1H),6.84(s, 1H),5.74(s,2H),4.58(d,J=5.2Hz,2H),3.91(s,3H),3.04(t,J=7.6Hz,2H),2 .68(t,J=7.6Hz,2H),1.92-1.85(m,1H),0.94–0.85(m,2H),0.70–0.59(m,2H).

[0821] Example 88

[0822] Ethyl 3-(6-cyclopropyl-2-((4-((2-fluoro-3-methoxy-6-(1H-tetrazol-1-yl)benzyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-8-yl)propanoate (I-89) and 3-(6-cyclopropyl-2-((4-((2-fluoro-3-methoxy-6-(1H-tetrazol-1-yl)benzyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-8-yl)propanoate (I-92)

[0823] Plan 88

[0824]

[0825] Synthesis of ethyl 3-(6-cyclopropyl-2-((4-((2-fluoro-3-methoxy-6-(1H-tetrazol-1-yl)benzyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-8-yl)propanoate. To a solution of 1-((6-cyclopropyl-8-(3-ethoxy-3-oxopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid (200 mg, 0.52 mmol), (2-fluoro-3-methoxy-6-(1H-tetrazol-1-yl)phenyl)methanamine (116 mg, 0.52 mmol), and HATU (257 mg, 0.678 mmol) in DMF (5 mL) was added DIPEA (335 mg, 2.6 mmol). The reaction mixture was stirred at room temperature for 14 h. Water (20 mL) was added, and the mixture was extracted with EtOAc (20 mL × 3). The combined organic layers were concentrated in vacuo and purified by preparative TLC (DCM / MeOH=10 / 1) to give ethyl 3-(6-cyclopropyl-2-((4-((2-fluoro-3-methoxy-6-(1H-tetrazol-1-yl)benzyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-8-yl)propanoate as a white solid (150 mg, yield: 49%). ESI-MS[M+H]+: 589.3. 1 HNMR(400MHz,DMSO)9.74(s,1H),8.77(t,J=5.4Hz,1H),8.50(s,1H),8.27(s,1H),7 .84(s,1H),7.39–7.32(m,2H),6.95(s,1H),5.75(s,2H),4.29(d,J=5.2Hz,2H),4.0 3(q,J=7.1Hz,2H),3.92(s,3H),3.07(t,J=7.6Hz,2H),2.76(t,J=7.6Hz,2H),1.90( d,J=4.6Hz,1H), 1.14(t,J=7.1Hz,3H), 0.93(d,J=6.7Hz,2H), 0.67(d,J=5.3Hz,2H).

[0826] Synthesis of 3-(6-cyclopropyl-2-((4-((2-fluoro-3-methoxy-6-(1H-tetrazol-1-yl)benzyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-8-yl)propanoic acid. To a solution of ethyl 3-(6-cyclopropyl-2-((4-((2-fluoro-3-methoxy-6-(1H-tetrazol-1-yl)benzyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-8-yl)propanoate (80 mg, 0.136 mmol) in THF / H2O (5 mL / 1 mL) was added LiOH·H2O (17 mg, 0.408 mmol). The reaction mixture was stirred at room temperature for 2 h. The mixture was adjusted to pH 5 by adding HCl (1M, aqueous solution), and the mixture was extracted with EtOAc (20mL x3). The combined organic layers were concentrated in vacuo and purified by preparative TLC (DCM / MeOH=10 / 1) to give 3-(6-cyclopropyl-2-((4-((2-fluoro-3-methoxy-6-(1H-tetrazol-1-yl)benzyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-8-yl)propanoic acid as a white solid (28 mg, yield: 36.8%). ESI-MS[M+H]+: 561.2. 1 H NMR (400MHz, DMSO) δ12.17(s,1H),9.74(s,1H),8.77(t,J=5.4Hz,1H),8. 50(s,1H),8.23(s,1H),7.79(s,1H),7.47–7.21(m,2H),6.89(s,1H),5.73 (s,2H),4.29(d,J=5.2Hz,2H),3.92(s,3H),3.03(t,J=7.6Hz,2H),2.68( t,J=7.6Hz,2H),1.97–1.83(m,1H),0.94-0.89(m,2H),0.68-0.65(m,2H).

[0827] Example 89

[0828] Ethyl 2-((4-((4-carbamoyl-2,6-dimethylbenzyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-carboxylate (I-112) and 2-((4-((4-carbamoyl-2,6-dimethylbenzyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-carboxylate (I-111)

[0829] Plan 89

[0830]

[0831] Synthesis of ethyl 2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-carboxylate. A mixture of ethyl 2-amino-5-cyclopropylnicotinate (3g, 14.55mmol) and 1,3-dichloropropane-2-one (5.5g, 43.32mmol) in EtOH (100mL) was stirred at 95 ° C for 1h. The reaction mixture was concentrated in vacuo to remove EtOH. The residue was adjusted to pH 9 using saturated NaHCO3 aqueous solution and then extracted with EtOAc (100mL x3). The combined organic layers were washed with brine (150mL), dried over Na2SO4 and concentrated in vacuo to give a crude material, which was purified by flash chromatography (PE / EtOAc=1 / 1) to give ethyl 2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-carboxylate (2.5g, yield: 61.7%). ESI-MS[M+H] + :279.2.

[0832] Synthesis of ethyl 2-(azidomethyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-carboxylate. To a solution of ethyl 2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-carboxylate (2.5 g, 9 mmol) in DMF (50 mL) was added NaN3 (0.88 g, 13.5 mmol). The reaction mixture was stirred at room temperature for 3 h. H2O (100 mL) was added, and the mixture was extracted with EtOAc (150 mL×2). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo to give crude ethyl 2-(azidomethyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-carboxylate as a brown solid, which was used in the next step without further purification (2.6 g of crude material). ESI-MS [M+H] + :286.2.

[0833] Synthesis of ethyl 2-((4-((benzyloxy)carbonyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-carboxylate. To a solution of ethyl 2-(azidomethyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-carboxylate (2.6 g crude material from the previous step) and benzyl propiolate (1.58 g, 9.9 mmol) in t-BuOH / H2O (20 mL / 20 mL) were added CuSO4 (288 mg, 1.8 mmol) and sodium ascorbate (356 mg, 1.8 mmol). The reaction mixture was stirred at room temperature for 3 h. H2O (50 mL) was added, and the mixture was extracted with DCM (100 mL×3). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo to give a crude material, which was purified by column chromatography (DCM / MeOH=20 / 1) to give ethyl 2-((4-((benzyloxy)carbonyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-carboxylate (1.5 g, 38% over 2 steps). ESI-MS [M+H] + :446.2.

[0834] Synthesis of ethyl 2-((4-((benzyloxy)carbonyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-carboxylate. A mixture of ethyl 2-((4-((benzyloxy)carbonyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-carboxylate (700 mg, 1.57 mmol) and Pd / C (300 mg) in MeOH (20 mL) was stirred under H2 atmosphere at room temperature for 4 h. The reaction mixture was filtered to give 1-((6-cyclopropyl-8-(ethoxycarbonyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid (300 mg, yield: 53.8%), which was used in the next step without further purification. ESI-MS [M+H] + :356.2.

[0835] Synthesis of ethyl 2-((4-((4-cyano-2,6-dimethylbenzyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-carboxylate. To a solution of 1-((6-cyclopropyl-8-(ethoxycarbonyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid (300 mg, 0.84 mmol), 4-(aminomethyl)-3,5-dimethylbenzonitrile hydrochloride (215 mg, 1.34 mmol), HOBT (176 mg, 1.3 mmol), and EDCI (250 mg, 1.3 mmol) in DMF (20 mL) was added DIPEA (549 mg, 4.25 mmol). The reaction mixture was stirred at room temperature for 14 h. H2O (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 material, which was purified by column chromatography (DCM / MeOH = 20 / 1) to give ethyl 2-((4-((4-cyano-2,6-dimethylbenzyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-carboxylate (250 mg, 59.8%) as a brown solid. ESI-MS [M+H] + :498.2

[0836] Synthesis of ethyl 2-((4-((4-carbamoyl-2,6-dimethylbenzyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-carboxylate. To a solution of ethyl 2-((4-((4-cyano-2,6-dimethylbenzyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-carboxylate (280 mg, 0.56 mmol) in MeOH (20 mL) was bubbled with HCl (g) for 3 h. The reaction mixture was concentrated in vacuo. MeOH (20 mL) and NH4HCO3 (442 mg, 5.6 mmol) were added. The reaction mixture was stirred at room temperature for 14 h. The mixture was concentrated in vacuo to give a crude material which was purified by preparative HPLC to give ethyl 2-((4-((4-carbamoyl-2,6-dimethylbenzyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-carboxylate (140 mg, 48.6%) as a white solid. ESI-MS [M+H] + :515.2. 1HNMR (400MHz, DMSO) δ10.20 (s, 2H), 9.02 (s, 1H), 8.74 (t, J = 5.4Hz, 1H), 8.5 9–8.57(m,2H),8.38(s,1H),7.91(s,1H),7.62(d,J=1.8Hz,1H),7.46(s,2H) ,5.78(s,2H),4.52(d,J=5.3Hz,2H),4.33(q,J=7.1Hz,2H),2.45(s,6H),2.0 1–1.98(m,1H),1.31(t,J=7.1Hz,2H),1.02–0.89(m,2H),0.79–0.65(m,2H).

[0837] Synthesis of 2-((4-((4-carbamoyl-2,6-dimethylbenzyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-carboxylic acid. To a solution of ethyl 2-((4-((4-carbamoyl-2,6-dimethylbenzyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-carboxylate (90 mg, 0.17 mmol) in THF / H2O (15 mL / 15 mL) was added LiOH (22 mg, 0.52 mmol). The reaction mixture was stirred at room temperature for 3 h. The mixture was concentrated in vacuo to give a crude material which was purified by preparative HPLC to give 2-((4-((4-carbamoyl-2,6-dimethylbenzyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-carboxylic acid (20 mg, 24%) as a white solid. ESI-MS [M+H] + :487.2. 1 H NMR (400MHz, DMSO) δ9.20 (s, 2H), 8.92 (s, 2H), 8.80 (t, J = 5.4Hz, 1H), 8.74 (s, 1H), 8.61 (s, 1H), 8.12 (s, 1H), 7.92 (s, 1H) ,7.47(s,2H),5.88(s,2H),4.52(d,J=5.4Hz,2H),2.45(s,6H),2.19–2.04(m,1H),1.05–1.00(m,2H),0.79–0.75(m,2H).

[0838] Example 90

[0839] 1-((6-cyclopropyl-8-fluoroimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(1H-tetrazol-1-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide (I-99)

[0840] Plan 90

[0841]

[0842] Synthesis of 5-cyclopropyl-3-fluoropyridin-2-amine. A mixture of 5-chloro-3-fluoropyridin-2-amine (2 g, 13.65 mmol), cyclopropylboronic acid (1.76 g, 20.47 mmol), Pd(OAc)2 (306 mg, 1.365 mmol), SPhos (1.12 g, 2.73 mmol) and K3PO4 (10.14 g, 47.78 mmol) in toluene (40 mL) and H2O (10 mL) was stirred at 90°C under N2 for 16 h. The reaction mixture was filtered and washed with EtOAc. The combined filtrate was washed with H2O (100 mL) and brine (100 mL), dried over Na2SO4, concentrated and purified by silica gel chromatography (EA / PE=1 / 2) to give 5-cyclopropyl-3-fluoropyridin-2-amine (2.2 g, yield: 100%) as a yellow syrup. ESI-MS [M+H] + :153.2.

[0843] Synthesis of 2-(chloromethyl)-6-cyclopropyl-8-fluoroimidazo[1,2-a]pyridine. A mixture of 5-cyclopropyl-3-fluoropyridin-2-amine (2.2 g, 13.65 mmol) and 1,3-dichloropropane-2-one (5.5 g, 43.38 mmol) in EtOH (40 mL) was stirred at 85 ° C for 16 h. The reaction mixture was concentrated. The residue was washed with a NaHCO3 aqueous solution and extracted with EtOAc (100 mL×3). The organic layer was washed with brine (100 mL), dried over Na2SO4, concentrated and purified by silica gel chromatography (EA / PE=1 / 2) to give 2-(chloromethyl)-6-cyclopropyl-8-fluoroimidazo[1,2-a]pyridine (1.8 g, 58%) as a yellow solid. ESI-MS[M+H] + :225.1.

[0844] Synthesis of 2-(azidomethyl)-6-cyclopropyl-8-fluoroimidazo[1,2-a]pyridine. A mixture of 2-(chloromethyl)-6-cyclopropyl-8-fluoroimidazo[1,2-a]pyridine (1.8 g, 8.01 mmol) and NaN3 (625 mg, 9.61 mmol) in DMF (20 mL) was stirred at room temperature for 3 h. The reaction mixture was poured into H2O (100 mL) and extracted with EtOAc (80 mL×2). The combined organics were washed with brine (160 mL), concentrated and dried in vacuo to give 2-(azidomethyl)-6-cyclopropyl-8-fluoroimidazo[1,2-a]pyridine (1.75 g, yield: 95%) as a white solid. ESI-MS [M+H] + :232.1.

[0845] Synthesis of ethyl 1-((6-cyclopropyl-8-fluoroimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate. A mixture of 2-(azidomethyl)-6-cyclopropyl-8-fluoroimidazo[1,2-a]pyridine (1.75 g, 7.57 mmol), ethyl propiolate (891 mg, 9.08 mmol), CuSO₄ (362 mg, 2.27 mmol), and sodium ascorbate (750 mg, 3.79 mmol) in t-BuOH (20 mL) and H₂O (20 mL) was stirred at room temperature for 3 h. H₂O (50 mL) was added to the reaction, and the mixture was extracted with EtOAc (100 mL x 3). The combined organics were washed with brine (100 mL), dried over Na2SO4, and concentrated to give a crude product, which was purified by silica gel chromatography (EA / PE = 1 / 2) to give ethyl 1-((6-cyclopropyl-8-fluoroimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate (1.0 g, yield: 40%) as a white solid. ESI-MS [M+H] + :330.1.

[0846] Synthesis of 1-((6-cyclopropyl-8-fluoroimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid. To a solution of ethyl 1-((6-cyclopropyl-8-fluoroimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate (270 mg, 0.82 mmol) in methanol (4 mL), THF (4 mL), and H₂O (2 mL) was added lithium hydroxide monohydrate (138 mg, 3.28 mmol). The mixture was stirred at 40°C for 2 h. The MeOH and THF were removed. The residue was diluted in H₂O (20 mL) and the pH was acidified to 5-6 with HCl (1 N), resulting in the precipitation of a yellow solid. The mixture was filtered and dried in vacuo to give 1-((6-cyclopropyl-8-fluoroimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid (220 mg, 89%) as a yellow solid. ESI-MS [M+H] + :302.1.

[0847] Synthesis of 1-((6-cyclopropyl-8-fluoroimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(1H-tetrazol-1-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide. A mixture of 1-((6-cyclopropyl-8-fluoroimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid (60 mg, 0.2 mmol), (2-fluoro-3-methoxy-6-(1H-tetrazol-1-yl)phenyl)methanamine (45 mg, 0.2 mmol), HATU (114 mg, 0.3 mmol), and DIPEA (155 mg, 1.2 mmol) in DMF (3 mL) was stirred at room temperature for 16 h. The reaction mixture was poured into water (40 mL), and a white solid precipitated. The mixture was filtered, washed with water (30 mL), dried in vacuo, and purified by silica gel chromatography (DCM / MeOH=20 / 1) to give 1-((6-cyclopropyl-8-fluoroimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(1H-tetrazol-1-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide (40 mg, yield: 40%) as a white solid. ESI-MS [M+H] + :507.2. 1HNMR(400MHz,DMSO)δ9.75(s,1H),8.77(t,J=5.5Hz,1H),8.51(s,1H),8.26(d,J=0.8Hz,1H),7.94(d,J=3.0Hz,1H),7.40–7.31(m,2H), 6.95(dd,J=12.4,1.2Hz,1H),5.73(s,2H),4.29(d,J=5.1Hz,2H),3.92(s,3H),1.97–1.91(m,1H),0.96–0.89(m,2H),0.72–0.67(m,2H).

[0848] Example 91

[0849] 1-((6-cyclopropyl-8-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(1H-tetrazol-1-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide (I-93)

[0850] Plan 91

[0851]

[0852] Synthesis of 2-(chloromethyl)-6-cyclopropyl-8-(trifluoromethyl)imidazo[1,2-a]pyridine. A mixture of 5-cyclopropyl-3-(trifluoromethyl)pyridin-2-amine (600 mg, 2.97 mmol) and 1,3-dichloropropane-2-one (1.14 g, 8.98 mmol) in EtOH (5 mL) was stirred at 85 ° C overnight. The reaction mixture was concentrated in vacuo, diluted with saturated NaHCO3 aqueous solution (50 mL), and extracted with EtOAc (50 mL x3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, concentrated and purified by silica gel chromatography (PE / EtOAc=2 / 1) to give 2-(chloromethyl)-6-cyclopropyl-8-(trifluoromethyl)imidazo[1,2-a]pyridine (350 mg, yield: 43%) as a brown solid. ESI-MS[M+H] + :275.1.

[0853] Synthesis of 2-(azidomethyl)-6-cyclopropyl-8-(trifluoromethyl)imidazo[1,2-a]pyridine. A mixture of 2-(chloromethyl)-6-cyclopropyl-8-(trifluoromethyl)imidazo[1,2-a]pyridine (350 mg, 1.27 mmol) and NaN3 (413 mg, 6.4 mmol) in DMF (10 mL) was stirred at room temperature for 3 h. Water (20 mL) was added, and the mixture was extracted with EtOAc (20 mL×3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, and concentrated to give 2-(azidomethyl)-6-cyclopropyl-8-(trifluoromethyl)imidazo[1,2-a]pyridine (400 mg crude material) as a yellow solid. ESI-MS[M+H] + :282.1.

[0854] Synthesis of ethyl 1-((6-cyclopropyl-8-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate. A mixture of 2-(azidomethyl)-6-cyclopropyl-8-(trifluoromethyl)imidazo[1,2-a]pyridine (400 mg, 1.4 mmol), ethyl propiolate (420 mg, 4.25 mmol), CuSO4 (115 mg, 0.7 mmol), and sodium ascorbate (125 mg, 0.7 mmol) in H2O / t-BuOH (10 mL / 10 mL) was stirred at room temperature for 3 h. The reaction mixture was concentrated, diluted with water (45 mL), and extracted with EtOAc (30 mL x 5). The combined organic layers were washed with brine (40 mL), dried over NaSO, and concentrated in vacuo to give a crude material, which was purified by silica gel chromatography (DCM / MeOH = 15 / 1) to give ethyl 1-((6-cyclopropyl-8-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate (350 mg, yield: 66%) as a yellow solid. ESI-MS [M+H]: 380.1.

[0855] Synthesis of 1-((6-cyclopropyl-8-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid. 1-((6-cyclopropyl-8-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid ethyl ester (350 mg, 0.9 mmol) and LiOH were reacted with 1% paraformaldehyde to obtain ... -A mixture of H₂O (76 mg, 1.8 mmol) in THF / EtOH / H₂O (4 mL / 4 mL / 2 mL) was stirred at 50°C for 3 h. The reaction mixture was concentrated in vacuo to a residue, which was diluted with water (10 mL) and acidified to pH 2-3 with HCl (3 M). The resulting precipitate was collected by filtration and dried to afford 1-((6-cyclopropyl-8-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid (300 mg, yield: 95%) as a white solid. ESI-MS [M+H]+: 352.1.

[0856] Synthesis of 1-((6-cyclopropyl-8-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(1H-tetrazol-1-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide. A mixture of 1-((6-cyclopropyl-8-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide (35 mg, 0.1 mmol), (2-fluoro-3-methoxy-6-(1H-tetrazol-1-yl)phenyl)methanamine (25 mg, 0.11 mmol), HOBT (27 mg, 0.2 mmol), EDCI (38 mg, 0.2 mmol), and DIPEA (65 mg, 0.5 mmol) in DMF (2 mL) was stirred at room temperature for 16 h. Water (20 mL) was added, and the mixture was extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (30 mL), dried over NaSO, concentrated, and purified by silica gel chromatography (DCM / MeOH = 10 / 1) to afford 1-((6-cyclopropyl-8-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(1H-tetrazol-1-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide (24.8 mg, yield: 45%) as a white solid. ESI-MS [M+H]+: 557.2. 1 HNMR (400MHz, DMSO) δ9.74 (s, 1H), 8.78 (t, J = 5.4Hz, 1H), 8.60 (s, 1H), 8.51 (s, 1H), 7.92 (s, 1H), 7.50 (s, 1H), 7.50–7. 32(m,2H),5.78(s,2H),4.29(d,J=5.2Hz,2H),3.92(s,3H),2.07–1.99(m,1H),0.98–0.93(m,2H),0.77–0.0.73(m,2H).

[0857] Example 92

[0858] 1-((6-cyclopropyl-8-(3-fluorooxetan-3-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(1H-tetrazol-1-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide (I-91)

[0859] Plan 92

[0860]

[0861] Synthesis of 3-(2-amino-5-chloropyridin-3-yl)oxetane-3-ol. At -78 ° C, n-BuLi (35 mL, 2.4 M solution in hexane, 84 mmol) was added dropwise to a solution of 3-bromo-5-chloropyridin-2-amine (5 g, 24 mmol) in THF (100 mL). After 5 minutes, oxetane-3-one (17 g, 240 mmol) in THF (50 mL) was added thereto and stirred for 2 h at -78 ° C. The reaction was quenched with saturated NH4Cl aqueous solution (100 mL) and extracted with ethyl acetate (100 mL x3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, and concentrated to give a crude material, which was purified by silica gel column chromatography (DCM / MeOH=15 / 1) to give 3-(2-amino-5-chloropyridin-3-yl)oxetan-3-ol (2.8 g, 58% yield) as a yellow solid. ESI-MS [M+H] + :201.1. 1 H NMR (400MHz, DMSO-d6) δ7.93 (d, J = 2.5 Hz, 1H), 7.61 (d, J = 2.5 Hz, 1H), 6.49 (s, 1H), 5.81 (s, 2H), 4.84 (d, J = 7.4 Hz, 2H), 4.72 (d, J = 7.4 Hz, 2H).

[0862] Synthesis of 3-(2-amino-5-cyclopropylpyridin-3-yl)oxetan-3-ol. A mixture of 3-(2-amino-5-chloropyridin-3-yl)oxetan-3-ol (2.8 g, 14 mmol), cyclopropylboronic acid (2.4 g, 28 mmol), K 3 PO 4 (8.9 g, 42 mmol), SPhos (1.1 g, 2.7 mmol), and Pd(OAc) 2 (0.3 g, 1.3 mmol) in toluene / H 2 O (50 mL / 5 mL) was stirred at 90° C. for 16 h. The reaction mixture was filtered through celite and washed with EtOAc (100 mL). The filtrate was concentrated to give a crude material, which was purified by silica gel column chromatography (DCM / MeOH=8 / 1) to give 3-(2-amino-5-cyclopropylpyridin-3-yl)oxetan-3-ol (2.1 g, 73% yield) as a yellow solid. ESI-MS [M+H] + :207.2. 1 H NMR (400MHz, DMSO-d6) δ7.75(d,J=1.8Hz,1H),7.17(d,J=2.1Hz,1H),6.34(s,1H),5.34(s,2H),4.85(d,J =7.1Hz,2H),4.70(d,J=7.2Hz,2H),3.61(s,1H),1.85-1.78(m,1H),0.86-0.80(m,2H),0.64-0.59(m,2H).

[0863] Synthesis of 3-(2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)oxetan-3-ol: A mixture of 3-(2-amino-5-cyclopropylpyridin-3-yl)oxetan-3-ol (2 g, 9.7 mmol) and 1,3-dichloropropan-2-one (3.85 g, 31 mmol) in EtOH (50 mL) was stirred at 80°C for 16 h. The reaction was concentrated, and the residue was diluted with ethyl acetate (50 mL), washed with saturated aqueous NaHCO3 (30 mL), H2O (30 mL), and brine (30 mL), dried over Na2SO4, and concentrated to give a crude material, which was purified by silica gel column chromatography (DCM / MeOH=8 / 1) to give 3-(2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)oxetan-3-ol (1.2 g, 44% yield) as a yellow solid. ESI-MS [M+H] + :279.1. 1H NMR (400MHz, DMSO-d6) δ8.54(s,1H),8.15(s,1H),7.54(s,1H),5.10(d,J=6.5Hz,2H),4.96(s ,2H),4.80(d,J=6.4Hz,2H),2.07(d,J=4.7Hz,1H),1.06-0.98(m,2H),0.80(d,J=5.1Hz,2H).

[0864] Synthesis of ethyl 1-((6-cyclopropyl-8-(3-hydroxyoxetan-3-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate. A mixture of 3-(2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)oxetan-3-ol (500 mg, 1.8 mmol) and NaN (176 mg, 2.7 mmol) in DMF (15 mL) was stirred at room temperature for 3 h. HO (30 mL) was added to the reaction, 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 (EA / PE = 1 / 1) to give 3-(2-(azidomethyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)oxetan-3-ol (420 mg, yield: 82%) as a yellow solid. ESI-MS [M+H] + :286.1

[0865] Synthesis of ethyl 1-((8-(3-hydroxyoxetan-3-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate. To a solution of 3-(2-(azidomethyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)oxetan-3-ol (420 mg, 1.47 mmol) in t-BuOH / H₂O (10 mL / 10 mL) was added ethyl propiolate (158 mg, 1.6 mmol), CuSO₄ (70 mg, 0.44 mmol), and sodium ascorbate (87 mg, 0.44 mmol). The reaction was stirred at room temperature for 3 h. The reaction was concentrated in vacuo to give a residue, which was purified by silica gel chromatography (EA / PE = 1 / 1) to give ethyl 1-((8-(3-hydroxyoxetan-3-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate (400 mg, yield: 71%) as a yellow solid. ESI-MS [M+H] + :383.2

[0866] Synthesis of 1-((8-(3-hydroxyoxetan-3-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid. A mixture of ethyl 1-((8-(3-hydroxyoxetan-3-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate (400 mg, 1.05 mmol) and LiOH (140 mg, 5.8 mmol) in THF / H2O (15 mL / 5 mL) was stirred at 50°C for 3 h. The reaction was concentrated in vacuo to give a crude product, which was purified by preparative HPLC to give 1-((8-(3-hydroxyoxetan-3-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid (220 mg, yield: 58%) as a yellow solid. ESI-MS [M+H] + :356.2

[0867] Synthesis of 1-((6-cyclopropyl-8-(3-hydroxyoxetan-3-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(1H-tetrazol-1-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide. To a solution of 1-((6-cyclopropyl-8-(3-hydroxyoxetan-3-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid (125 mg, 0.35 mmol), (2-fluoro-3-methoxy-6-(1H-tetrazol-1-yl)phenyl)methanamine hydrochloride (178 mg, 0.70 mmol), EDCI (102 mg, 0.53 mmol), and HOBT (72 mg, 0.53 mmol) in DMF (10 mL) was added DIPEA (135 mg, 1.05 mmol). The reaction mixture was stirred at room temperature for 12 h. HO (30 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 NaSO, and concentrated in vacuo to give a crude material, which was purified by preparative TLC (DCM / MeOH = 10 / 1) to give 1-((6-cyclopropyl-8-(3-hydroxyoxetan-3-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(1H-tetrazol-1-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide (20 mg, yield: 10%) as a white solid. ESI-MS [M+H]: 561.2.

[0868] Synthesis of 1-((6-cyclopropyl-8-(3-fluorooxetan-3-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(1H-tetrazol-1-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide. To a solution of 1-((6-cyclopropyl-8-(3-hydroxyoxetan-3-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(1H-tetrazol-1-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide (20 mg, 0.036 mmol) in DCM (5 ml) was added DAST (11 mg, 0.072 mmol) at -78°C under nitrogen. The mixture was stirred at -20°C for 3 h. The reaction was quenched with saturated aqueous NaHCO3 (15 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4 and concentrated in vacuo to give a crude material, which was purified by silica gel chromatography (DCM / MeOH=10 / 1) to give 1-((6-cyclopropyl-8-(3-fluorooxetane-3-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(1H-tetrazol-1-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide (10 mg, yield: 49%) as a white solid. ESI-MS[M+H] + :563.2. 1 H NMR (400MHz, DMSO) δ9.74(d,J=2.6Hz,1H),8.778-8.74(m,1H),8.48(d,J=2.6Hz,1H),8.42(s,1H),7.81(s,1H),7.39-7.35(m,2H),7.17(s ,1H),5.75(s,2H),5.33-5.25(m,2H),4.99-4.91(m,2H),4.29(s,2H) ,3.93(s,3H),1.98-1.95(m,1H),0.95-0.92(m,2H),0.74-071(m,2H).

[0869] Example 93

[0870] Ethyl 3-(6-cyclopropyl-2-((4-((2-fluoro-3-methoxy-6-(1H-tetrazol-1-yl)benzyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-8-yl)-2,2-dimethylpropanoate (I-85)

[0871] Plan 93

[0872]

[0873] Synthesis of tert-butyl 1-((6-cyclopropyl-8-(hydroxymethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate. A mixture of (2-(azidomethyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)methanol (20 g, 82.38 mmol), tert-butyl propiolate (10.4 g, 82.38 mmol), CuSO4 (657 mg, 4.12 mmol), and sodium ascorbate (1.63 g, 8.24 mmol) in t-BuOH (100 mL) and H2O (100 mL) was stirred at 25°C for 16 h. The t-BuOH was removed to give a residue, which was diluted in H2O (100 mL) and extracted with DCM (150 mL x 3). The combined organics were washed with brine (300 mL), dried over Na2SO4, and concentrated to give a crude material, which was triturated with EtOAc and dried to give tert-butyl 1-((6-cyclopropyl-8-(hydroxymethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate (18 g, yield: 59%) as a light brown solid. ESI-MS [M+H] + :370.1.

[0874] Synthesis of tert-butyl 1-((8-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate. To a stirred solution of tert-butyl 1-((6-cyclopropyl-8-(hydroxymethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate (2 g, 5.41 mmol) in DCM (30 mL) was added SOCl2 (1.29 g, 10.82 mmol) dropwise at 0°C. The mixture was stirred at 25°C for 1 h. The reaction mixture was concentrated, and the residue was dissolved in DCM (80 mL), washed with saturated aqueous NaHCO3 (80 mL) and brine, dried over Na2SO4, and concentrated to give a crude material, which was purified by silica gel chromatography (EtOAc / PE=1 / 1) to give tert-butyl 1-((8-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate (1.8 g, yield: 86%) as a light brown solid. ESI-MS [M+H] + :388.1.

[0875] Synthesis of tert-butyl 1-((6-cyclopropyl-8-(3-ethoxy-2,2-dimethyl-3-oxopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate. To a stirred solution of ethyl isobutyrate (808 mg, 6.96 mmol) in THF (20 mL) was added dropwise LDA (3.7 mL, 2 M, 7.4 mmol) at -40°C under N2. After 1 hour, a solution of tert-butyl 1-((8-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate (1.8 g, 4.64 mmol) in THF (15 mL) was added to the reaction at -78°C over 30 minutes. The resulting mixture was stirred at -78 ° C for another 1.5 h. The reaction mixture was quenched with NH4Cl aqueous solution (100 mL) and extracted with EtOAc (100 mL x3). The combined organics were washed with brine (140 mL), dried over Na2SO4, and concentrated to give a crude material, which was purified by silica gel chromatography (EtOAc / PE=1 / 2) to give tert-butyl 1-((6-cyclopropyl-8-(3-ethoxy-2,2-dimethyl-3-oxopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate (1.24 g, yield: 57%) as a colorless syrup. ESI-MS[M+H] + :468.2.

[0876] Synthesis of 1-((6-cyclopropyl-8-(3-ethoxy-2,2-dimethyl-3-oxopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid. A mixture of tert-butyl 1-((6-cyclopropyl-8-(3-ethoxy-2,2-dimethyl-3-oxopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate (1.24 g, 2.65 mmol) and HCl in dioxane (10 mL, 4N) was stirred at 25° C. for 18 h. The reaction mixture was concentrated and dried in vacuo to give 1-((6-cyclopropyl-8-(3-ethoxy-2,2-dimethyl-3-oxopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid (1.3 g, yield: 100%) as a colorless syrup. ESI-MS [M+H] + :412.2.

[0877] Synthesis of ethyl 3-(6-cyclopropyl-2-((4-((2-fluoro-3-methoxy-6-(1H-tetrazol-1-yl)benzyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-8-yl)-2,2-dimethylpropanoate. A mixture of 1-((6-cyclopropyl-8-(3-ethoxy-2,2-dimethyl-3-oxopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid (167 mg, 0.406 mmol), (2-fluoro-3-methoxy-6-(1H-tetrazol-1-yl)phenyl)methanamine (91 mg, 0.406 mmol), EDCI (156 mg, 0.812 mmol), HOBT (110 mg, 0.812 mmol) and DIPEA (525 mg, 4.06 mmol) in DMF (5 mL) was stirred at room temperature for 16 h. The reaction mixture was poured into water (50 mL) and extracted with EtOAc / THF (50 mL x 2, 5 / 1). The combined organic layers were washed sequentially with water (100 mL x 3) and brine (100 mL x 1), dried over Na2SO4, concentrated in vacuo, and purified by preparative TLC (DCM / MeOH=10 / 1) to give ethyl 3-(6-cyclopropyl-2-((4-((2-fluoro-3-methoxy-6-(1H-tetrazol-1-yl)benzyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-8-yl)-2,2-dimethylpropanoate as a pale white solid (100 mg, yield: 40%). ESI-MS [M+H] + :617.2. 1 H NMR (400MHz, DMSO) δ9.71(s,1H),8.72(t,J=5.4Hz,1H),8.41(s,1H),8.19(s,1H),7.73(s,1H),7.36–7.29(m,2H),6.63(s,1H),5.65(s, 2H), 4.26 (d, J = 5.4Hz, 2H), 3.94–3.88 (m, 5H), 3.05 (s, 2H), 1.87–1.82 (m, 1H), 1.08–1.03 (m, 9H), 0.90–0.85 (m, 2H), 0.60–0.55 (m, 2H).

[0878] Example 94

[0879] 3-(6-cyclopropyl-2-((4-((2-fluoro-3-methoxy-6-(1H-tetrazol-1-yl)benzyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-8-yl)-2,2-dimethylpropanoic acid (I-81)

[0880] Plan 94

[0881]

[0882] Synthesis of 3-(6-cyclopropyl-2-((4-((2-fluoro-3-methoxy-6-(1H-tetrazol-1-yl)benzyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-8-yl)-2,2-dimethylpropanoic acid. To a solution of ethyl 3-(6-cyclopropyl-2-((4-((2-fluoro-3-methoxy-6-(1H-tetrazol-1-yl)benzyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-8-yl)-2,2-dimethylpropanoate (75 mg, 0.122 mmol) in dioxane (3 mL) and H2O (1 mL) was added concentrated H2SO4 (1 mL). The reaction mixture was stirred at 75 ° C for 16 h and then poured into water (30 mL). The mixture was adjusted to pH 4-5 using saturated NaHCO3 aqueous solution and then extracted with EtOAc / THF (40 mL x2, 5 / 1). The combined organic layers were washed with brine (80 mL), dried over Na2SO4, concentrated and purified by preparative HPLC to give 3-(6-cyclopropyl-2-((4-((2-fluoro-3-methoxy-6-(1H-tetrazol-1-yl)benzyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-8-yl)-2,2-dimethylpropanoic acid as a white solid (30 mg, yield: 42%). ESI-MS [M+H] + :589.2. 1 H NMR (400MHz, DMSO) δ12.34(s,1H),9.74(s,1H),8.76(s,1H),8.45(s,1H),8.21(d,J=1.4Hz,1H),7.74(s,1H),7.39–7.32(m,2H),6.72(d,J=1. 3Hz,1H),5.70(s,2H),4.29(d,J=5.2Hz,2H),3.92(s,3H),3.09(s,2H) ,1.90–1.83(m,1H),1.06(s,6H),0.93–0.87(m,2H),0.65–0.59(m,2H).

[0883] Example 95

[0884] 1-((8-(2-cyano-2-methylpropyl)-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2,6-difluoro-3-methoxybenzyl)-1H-1,2,3-triazole-4-carboxamide (I-12)

[0885] Plan 95

[0886]

[0887] Synthesis of ethyl 3-(6-cyclopropyl-2-((4-((2,6-difluoro-3-methoxybenzyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-8-yl)-2,2-dimethylpropanoate. A mixture of 1-((6-cyclopropyl-8-(3-ethoxy-2,2-dimethyl-3-oxopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid (352 mg, crude), (2,6-difluoro-3-methoxyphenyl)methanamine hydrochloride (179 mg, 0.855 mmol), EDCI (328 mg, 1.71 mmol), HOBT (231 mg, 1.71 mmol) and DIPEA (662 mg, 5.13 mmol) in DMF (15 mL) was stirred at room temperature for 16 h. The reaction mixture was poured into water (80 mL) and extracted with EtOAc / THF (60 mL x 2, 5 / 1). The combined organics were washed with water (120 mL x 3) and brine (120 mL), dried over Na2SO4, concentrated, and purified by silica gel chromatography (EtOAc / PE = 1 / 1) to give ethyl 3-(6-cyclopropyl-2-((4-((2,6-difluoro-3-methoxybenzyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-8-yl)-2,2-dimethylpropanoate (320 mg, yield: 66% over two steps) as a pale white solid. ESI-MS [M+H] + :567.2.

[0888] Synthesis of 3-(6-cyclopropyl-2-((4-((2,6-difluoro-3-methoxybenzyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-8-yl)-2,2-dimethylpropanoic acid. To a solution of ethyl 3-(6-cyclopropyl-2-((4-((2,6-difluoro-3-methoxybenzyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-8-yl)-2,2-dimethylpropanoate (320 mg, 0.565 mmol) in methanol (6 mL), THF (6 mL), and water (4 mL) was added lithium hydroxide monohydrate (95 mg, 2.26 mmol). The reaction mixture was stirred at 40°C for 2 h. MeOH and THF were removed in vacuo, and the mixture was diluted in water (40 mL) and extracted with EtOAc (40 mL). The organic layer was discarded. The aqueous layer was acidified to pH 5-6 using HCl (2M, aqueous solution) and extracted with EtOAc (40 mL x2). The combined organics were washed with brine (80 mL), dried over Na2SO4, concentrated and dried in vacuo to give 3-(6-cyclopropyl-2-((4-((2,6-difluoro-3-methoxybenzyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-8-yl)-2,2-dimethylpropanoic acid (270 mg, 88%) as a white solid. ESI-MS [M+H] + :539.2.

[0889] Synthesis of 1-((8-(3-amino-2,2-dimethyl-3-oxopropyl)-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2,6-difluoro-3-methoxybenzyl)-1H-1,2,3-triazole-4-carboxamide. A mixture of 3-(6-cyclopropyl-2-((4-((2,6-difluoro-3-methoxybenzyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-8-yl)-2,2-dimethylpropanoic acid (270 mg, 0.501 mmol), NHCl (266 mg, 5.01 mmol), EDCI (192 mg, 1.0 mmol), HOBT (135 mg, 1.0 mmol) and DIPEA (324 mg, 2.51 mmol) in DMF (8 mL) was stirred at room temperature for 16 h. The reaction mixture was poured into water (60 mL) and extracted with EtOAc (60 mL x 2). The combined organics were washed with water (120 mL x 3) and brine (120 mL x 1), dried over Na2SO4, concentrated, and purified by silica gel chromatography (EtOAc / MeOH = 10 / 1) to give 1-((8-(3-amino-2,2-dimethyl-3-oxopropyl)-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2,6-difluoro-3-methoxybenzyl)-1H-1,2,3-triazole-4-carboxamide (240 mg, yield: 89%) as a pale white solid. ESI-MS [M+H] + :538.2.

[0890] Synthesis of 1-((8-(2-cyano-2-methylpropyl)-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2,6-difluoro-3-methoxybenzyl)-1H-1,2,3-triazole-4-carboxamide. A mixture of 1-((8-(3-amino-2,2-dimethyl-3-oxopropyl)-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2,6-difluoro-3-methoxybenzyl)-1H-1,2,3-triazole-4-carboxamide (120 mg, 0.223 mmol) in POCl₃ (4 mL) was stirred at 60°C for 3 h. The reaction mixture was poured into water (30 mL). The mixture was adjusted to pH 9-10 with saturated aqueous NaHCO₃ and extracted with EtOAc (30 mL x 2). The combined organics were washed with brine (60 mL), dried over Na2SO4, concentrated, and purified by silica gel chromatography (EtOAc / PE=1 / 2) to give 1-((8-(2-cyano-2-methylpropyl)-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2,6-difluoro-3-methoxybenzyl)-1H-1,2,3-triazole-4-carboxamide (50 mg, 43%) as a white solid. ESI-MS [M+H]+: 520.2. 1 H NMR (400MHz, DMSO) δ8.79(t,J=5.5Hz,1H),8.49(s,1H),8.31(s,1H),7.81(s,1H),7.15–7.06(m,1H),7.02–6.94(m,2H),5.72( s,2H),4.48(d,J=5.4Hz,2H),3.80(s,3H),3.12(s,2H),1.92–1.89(m,1H),1.29(s,6H),0.97–0.90(m,2H),0.69–0.64(m,2H).

[0891] Example 96

[0892] 1-((6-cyclopropyl-8-(4H-1,2,4-triazol-4-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(1H-tetrazol-1-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide (I-71)

[0893] Plan 96

[0894]

[0895] Synthesis of 2-(azidomethyl)-8-bromo-6-cyclopropylimidazo[1,2-a]pyridine. To a solution of 8-bromo-2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine (1 g, 3.5 mmol) in DMF (15 mL) was added NaN3 (230 mg, 3.5 mmol). The resulting mixture was stirred at 50 ° C under nitrogen for 24 h. H2O (50 mL) was added to the reactants and extracted with EtOAc (50 mL×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 (1.1 g, crude material), which was used in the next step without further purification. ESI-MS [M+H] + :292.0.

[0896] 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 material 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 h. 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.

[0897] Synthesis of tert-butyl 1-((8-((tert-butoxycarbonyl)amino)-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate. To a solution of tert-butyl 1-((8-bromo-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate (1 g, 2 mmol) and tert-butyl carbamate (0.56 g, 4 mmol) in dioxane (10 mL) were added Pd(dba) (0.18 g, 0.2 mmol), XantPhos (0.23 g, 0.4 mmol), and CsCO (1.95 g, 6 mmol). The reaction mixture was stirred at 100° C. under N for 16 h. The reaction mixture was cooled to room temperature and H0 (50 mL) was added. The aqueous phase was extracted with ethyl acetate (100 mL x 3), the combined organic layers were dried over sodium sulfate, evaporated, and the residue was purified by silica gel chromatography (DCM:MeOH=15:1) to give tert-butyl 1-((8-((tert-butoxycarbonyl)amino)-6-cyclopropylimidazo[1,2-a]167pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate (900 mg, 99%) as a yellow solid. ESI-MS [M+H] + :455.2.

[0898] Synthesis of methyl 1-((8-amino-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate. A solution of tert-butyl 1-((8-((tert-butoxycarbonyl)amino)-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate (300 mg, 0.66 mmol) in MeOH (5 mL) and HCl / dioxane (4 M, 5 mL) was stirred at room temperature for 16 h. LCMS showed that the reaction was complete. The solvent of the reaction mixture was evaporated to give a crude product, which was used in the next step without further purification. (230 mg, yield 100%) as a yellow solid. ESI-MS [M+H] + :313.3.

[0899] Synthesis of 1-((6-cyclopropyl-8-(4H-1,2,4-triazol-4-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(1H-tetrazol-1-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide. To a solution of 1-((6-cyclopropyl-8-(4H-1,2,4-triazol-4-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid (120 mg, 0.34 mmol) in anhydrous DMF (3 mL) was added (2-fluoro-3-methoxy-6-(1H-tetrazol-1-yl)phenyl)methanamine (152 mg, 0.68 mmol), HATU (155.8 mg, 0.41 mmol) and DIPEA (175 mg, 1.36 mmol). The reaction mixture was stirred at room temperature for 2 hours, then diluted with water (20 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (20 mL x 2), dried over sodium sulfate and concentrated in vacuo. The residue was purified by preparative TLC (DCM / MeOH = 10:1) to give 1-((6-cyclopropyl-8-(4H-1,2,4-triazol-4-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(1H-tetrazol-1-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide (80 mg, yield: 43%) as a white solid. ESI-MS [M+H] + :556.2. 1 H NMR(400MHz,HDMSO-d6)δ9.74(s,1H),9.39(s,2H),8.77(t,J=5.4Hz,1H),8.57(s,1H),8.47(s,1H),8.00(s,1H),7.45(d,J=1.1Hz,1H) ,7.42–7.32(m,2H),5.77(d,J=6.9Hz,2H),4.29(d,J=5.1Hz,2H),3.90(s,3H),2.01–1.93(m,1H),1.03–0.93(m,2H),0.86–0.77(m,2H).

[0900] Example 97

[0901] 1-((6-cyclopropyl-8-(oxetan-3-ylmethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(1H-tetrazol-1-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide (I-68)

[0902] Plan 97

[0903]

[0904] Synthesis of ethyl 1-((6-cyclopropyl-8-(hydroxymethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate. To a solution of 1-((6-cyclopropyl-8-(hydroxymethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid (800 mg, 2.56 mmol) in EtOH (50 mL) was added SOCl2 (10 mL). The resulting reaction was stirred at 70 °C for 14 h. The reaction was concentrated in vacuo to give ethyl 1-((6-cyclopropyl-8-(hydroxymethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate as a yellow solid (850 mg, 97.5%). ESI-MS [M+H] + :342.2

[0905] Synthesis of ethyl 1-((8-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate. To a solution of ethyl 1-((6-cyclopropyl-8-(hydroxymethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate (850 mg, 2.49 mmol) in DCM (25 mL) was added SOCl2 (3 mL) at 0°C. The resulting reaction was stirred at room temperature for 4 h. The reaction was concentrated in vacuo to give ethyl 1-((8-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate as a yellow solid (900 mg crude). ESI-MS [M+H] + :360.3.

[0906] Synthesis of ethyl 1-((6-cyclopropyl-8-((triphenyl-14-phosphonyl)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate. A mixture of ethyl 1-((8-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate (900 mg crude material from the previous step) and PPh3 (720 mg, 2.74 mmol) in toluene (40 mL) was stirred at 110°C for 12 h. The reaction was concentrated in vacuo to give ethyl 1-((6-cyclopropyl-8-((triphenyl-14-phosphonyl)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate as a yellow solid which was used in the next step without further purification (1.62 g crude material). ESI-MS [M+H] + :586.1.

[0907] Synthesis of ethyl 1-((6-cyclopropyl-8-(oxetan-3-ylidenemethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate. A mixture of ethyl 1-((6-cyclopropyl-8-((triphenyl-14-phosphonyl)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate (1 g of crude material from the previous step), oxetan-3-one (369 mg, 5.1 mmol), and NaH (340 mg, 8.5 mmol, 60 wt% in oil) in THF (30 mL) was stirred at 65 ° C. under N2 for 14 h. The reaction was quenched with aqueous NH4Cl (50 mL) and 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 on silica gel (eluent: DCM / MeOH = 30 / 1) to give ethyl 1-((6-cyclopropyl-8-(oxetan-3-ylidenemethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate as a yellow solid (450 mg, 47.7% over 3 steps). ESI-MS [M+H] + :380.2.

[0908] Synthesis of ethyl 1-((6-cyclopropyl-8-(oxetan-3-ylmethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate. A mixture of ethyl 1-((6-cyclopropyl-8-(oxetan-3-ylidenemethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate (450 mg, 1.19 mmol) and Pd / C (100 mg) in THF (25 mL) was stirred under H2 atmosphere for 2 h. The reaction was filtered and concentrated in vacuo to afford ethyl 1-((6-cyclopropyl-8-(oxetan-3-ylmethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate as a yellow solid (180 mg, 40%). ESI-MS [M+H] + :382.2

[0909] Synthesis of 1-((6-cyclopropyl-8-(oxetan-3-ylmethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid. To a solution of ethyl 1-((6-cyclopropyl-8-(oxetan-3-ylmethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate (180 mg, 0.47 mmol) in THF / H2O (8 mL / 8 mL) was added LiOH·H2O (79 mg, 1.88 mmol). The resulting mixture was stirred at room temperature for 4 h. The reaction was concentrated in vacuo to give a crude product, which was purified by preparative HPLC to give 1-((6-cyclopropyl-8-(oxetan-3-ylmethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid as a white solid (90 mg, 54%). ESI-MS [M+H] + :354.2.

[0910] Synthesis of 1-((6-cyclopropyl-8-(oxetan-3-ylmethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(1H-tetrazol-1-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide. To a mixture of 1-((6-cyclopropyl-8-(oxetan-3-ylmethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide (50 mg, 0.14 mmol), HATU (80 mg, 0.21 mmol), and DIPEA (90 mg, 0.70 mmol) in DMF (10 mL) was added (2-fluoro-3-methoxy-6-(1H-tetrazol-1-yl)phenyl)methanamine (47 mg, 0.21 mmol). The reaction mixture was stirred at room temperature for 14 h, then quenched with H o (20 mL). The aqueous phase was extracted with EtOAc (20 mL x3). The combined organic layer was washed with brine (30 mL x2), dried over Na sO and concentrated in vacuo to give a crude material which was purified by preparative HPLC to give 1- ((6- cyclopropyl -8- (oxetanes -3- ylmethyl) imidazo [1,2-a] pyridin-2-yl) methyl) -N- (2- fluoro-3-methoxy -6- (1H- tetrazol-1-yl) benzyl) -1H-1,2,3- triazole -4- carboxamide (10 mg, 12.8%) as a white solid. ESI-MS [M+H] +: 559.2. 1 H NMR (400MHz, DMSO) δ9.74 (s, 1H), 8.76 (t, J = 5.4Hz, 1H), 8.47 (s, 1H), 8.19 (d, J = 1.3 Hz,1H),7.76(s,1H),7.39–7.32(m,2H),6.80(s,1H),5.70(s,2H),4.61(dd,J=7.7,5 .9Hz,2H),4.36(t,J=6.0Hz,2H),4.29(d,J=5.1Hz,2H),3.92(s,3H),3.42–3.37(m, 1H), 3.15 (d, J = 7.7Hz, 2H), 1.91–1.84 (m, 1H), 0.92–0.88 (m, 2H), 0.68–0.64 (m, 2H).

[0911] Example 98

[0912] 1-((6-cyclopropyl-8-(hydroxy(oxetan-3-yl)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(1H-tetrazol-1-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide (I-27)

[0913] Plan 98

[0914]

[0915] The synthesis of (2-amino-5-cyclopropylpyridine-3-yl) (oxetane-3-yl) methanol. At -60 ° C, to a solution of 3-bromo-5-cyclopropylpyridine-2-amine (500 mg, 2.35 mmol) in dry THF (25 mL), n-BuLi (3.5 mL, 2.4 M solution in hexane, 8.4 mmol) was added. The resulting mixture was stirred at -60 ° C for 30 minutes. A solution of oxetane-3-carboxaldehyde (714 mg, 8.3 mmol) in 3 mL THF was then slowly added at -60 ° C and stirred for another 30 minutes. The reaction was quenched with water (10 mL) and concentrated in vacuo to give a crude residue, which was purified by preparative TLC (DCM / MeOH=6 / 1) to give (2-amino-5-cyclopropylpyridine-3-yl) (oxetane-3-yl) methanol as a yellow oil (310 mg, 60%). ESI-MS[M+H] + :221.2.

[0916] Synthesis of (2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)(oxetane-3-yl)methanol. A mixture of (2-amino-5-cyclopropylpyridin-3-yl)(oxetane-3-yl)methanol (310 mg, 1.41 mmol) and 1,3-dichloropropane-2-one (533 mg, 4.23 mmol) in EtOH (25 mL) was stirred at 80 ° C for 14 h. The reaction mixture was adjusted to pH 8 using saturated aqueous NaHCO3 solution and concentrated in vacuo to give a crude residue, which was purified by preparative TLC (DCM / MeOH=10 / 1) to give (2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)(oxetane-3-yl)methanol as a yellow oil (210 mg, 51%). ESI-MS[M+H] + :293.2.

[0917] Synthesis of (2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)(oxetane-3-yl)methanol. To a solution of (2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)(oxetane-3-yl)methanol (210 mg, 0.72 mmol) in DMF (5 mL) was added NaN3 (70 mg, 1.08 mmol). The resulting mixture was stirred at room temperature for 3 h. The reactants were concentrated in vacuo to give a crude residue (280 mg, crude material) which was used in the next step without further purification. ESI-MS [M+H]+ :300.2.

[0918] Synthesis of ethyl 1-((6-cyclopropyl-8-(hydroxy(oxetan-3-yl)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate. To a solution of (2-(azidomethyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)(oxetan-3-yl)methanol (210 mg, 0.7 mmol) in t-BuOH / H2O (15 mL / 15 mL) were added ethyl propiolate (89 mg, 0.91 mmol), CuSO4 (45 mg, 0.28 mmol), and sodium ascorbate (54 mg, 0.28 mmol). The reaction was stirred at room temperature for 3 h. Water (15 mL) was added to the reaction, and the mixture was extracted with DCM / MeOH (15 / 1, 30 mL x 3). The combined organic layers were dried over Na2SO4 and concentrated in vacuo to give a crude residue, which was purified by preparative TLC (DCM / MeOH = 10 / 1) to give ethyl 1-((6-cyclopropyl-8-(hydroxy(oxetan-3-yl)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate as a yellow solid (210 mg, 75%). ESI-MS [M+H] + :398.2.

[0919] Synthesis of 1-((6-cyclopropyl-8-(hydroxy(oxetan-3-yl)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid. To a solution of ethyl 1-((6-cyclopropyl-8-(hydroxy(oxetan-3-yl)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate (210 mg, 0.53 mmol) in THF / H2O (8 mL / 8 mL) was added LiOH·H2O (65 mg, 1.58 mmol). The reaction was stirred at room temperature for 2 h. The reaction mixture was then adjusted to pH 5 using 1N HCl and freeze-dried to give 1-((6-cyclopropyl-8-(hydroxy(oxetan-3-yl)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid (300 mg crude material), which was used in the next step without further purification. ESI-MS [M+H] + :370.1.

[0920] Synthesis of 1-((6-cyclopropyl-8-(hydroxy(oxetan-3-yl)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(1H-tetrazol-1-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide. To a solution of 1-((6-cyclopropyl-8-(hydroxy(oxetan-3-yl)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid (100 mg) in DMF (10 mL) was added (2-fluoro-3-methoxy-6-(1H-tetrazol-1-yl)phenyl)methanamine (52 mg, 0.23 mmol), HOBT (36.5 mg, 0.27 mmol), EDCI (52 mg, 0.27 mmol) and DIPEA (110 mg, 0.85 mmol). The reaction mixture was stirred at room temperature for 12 h. The reaction was concentrated in vacuo to give the crude product, which was purified by preparative HPLC to give 1-((6-cyclopropyl-8-(hydroxy(oxetan-3-yl)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(1H-tetrazol-1-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide (8 mg, 6%) as a white solid.

[0921] ESI-MS[M+H] + :575.2. Purity: 98.39% (214nm), 100% (254nm). 1 H NMR (400MHz, DMSO) δ9.75 (s, 1H), 8.90 (t, J = 4.6Hz, 1H), 8.66–8.60 (m, 2H), 8.49 (s, 2H), 8.31 (d, J = 5. 6Hz,1H),7.65(d,J=9.4Hz,1H),6.14(d,J=12.3Hz,2H),5.32(t,J=4.7Hz,1H),5.02(d,J=2.0Hz,0.5H) ,4.88(d,J=9.1Hz,0.5H),4.56–4.48(m,1H),4.30(d,J=5.1Hz,2H),4.10–4.05(m,0.5H),3.92(s,3H), 3.87(d,J=11.8Hz,0.5H),3.80–3.63(m,3H),2.02–1.95(m,1H),1.09–1.05(m,2H),0.85–0.74(m,2H).

[0922] Example 99

[0923] 1-((8-(Aminomethyl)-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(1H-tetrazol-1-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide (I-25)

[0924] Plan 99

[0925]

[0926] Synthesis of (2-amino-5-cyclopropylpyridin-3-yl)methanol. To a mixture of 2-amino-5-cyclopropylnicotinate (7.4 g, 36 mmol) in THF (70 mL) was added LAH (2.3 g, 61 mmol) and stirred at 0 ° C. The mixture was stirred at 0 ° C under an N2 atmosphere for 3 h. The reaction was monitored by LCMS until the starting material was exhausted. The reaction was quenched with H2O (5 mL), NaOH (15% aqueous solution, 5 mL), H2O (15 mL), and after the mixture was stirred for 10 minutes, the mixture was filtered through diatomaceous earth and concentrated to obtain a residue. It was diluted with H2O (100 mL) and extracted with EtOAc (100 mL x 5). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo to give a crude product, which was purified on silica gel (eluent: EtOAc / PE: 1 / 2 to 1 / 0) to give (2-amino-5-cyclopropylpyridin-3-yl)methanol (5 g, yield: 84%) as a white solid. ESI-MS [M+H] + :165.2.

[0927] Synthesis of (2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)methanol. To a solution of (2-amino-5-cyclopropylpyridin-3-yl)methanol (5g, 30mmol) in DMF (30mL) was added 1,3-dichloropropane-2-one (14.8g, 117mmol). The mixture was stirred at 95 °C for 3h. The reaction was monitored by LCMS until the starting material was exhausted. The reaction was quenched with saturated NaHCO3 aqueous solution until pH = 8 and extracted with EtOAc (100mL x3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo to give the crude product, which was purified on silica gel (eluent: DCM / MeOH: 50 / 1 to 10 / 1) to give (2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)methanol (4.7 g, yield: 66%) as a yellow solid. ESI-MS [M+H] + :237.1.

[0928] Synthesis of (2-(azidomethyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)methanol. To a solution of (2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)methanol (4.7 g, 20 mmol) in ...

Claims

1. A compound of formula (I): or a pharmaceutically acceptable salt thereof, in: Cy A is selected from 5-membered monocyclic heteroarylene groups having 1-4 heteroatoms independently selected from oxygen, nitrogen and sulfur and 7- to 10-membered partially unsaturated bicyclic heterocyclylene groups having 1-4 heteroatoms independently selected from oxygen, nitrogen and sulfur, wherein Cy 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 or sulfur, wherein the optionally substituted R A The substituents on the group are independently halogen, (CH2) 0-4 R°, -(CH2) 0-4 OR°; and -(CH2) 0- 4C(O)OR°, wherein each R° is independently hydrogen, C 1-6 an aliphatic group or a 5- to 6-membered saturated, partially unsaturated, or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Cy B Selected from: R B independently selected from halogen, -CN, -OR, -N(R)2, -N(R)CN, -C(=N(R))N(R)2, -S(O)R, -S(O)2R, -S(O)2N(R)2, and an optionally substituted group selected from the group consisting of: C 1-6 aliphatic, phenyl, 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen and sulfur, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic radical, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic radical having 1-2 heteroatoms selected from oxygen, nitrogen and sulfur, 7- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen and sulfur, and 8- to 10-membered spirocyclic heterocyclic radical having 1-3 heteroatoms selected from oxygen, nitrogen and sulfur, wherein each R is independently hydrogen or an optionally substituted C 1-6 aliphatic, and wherein the optionally substituted R B The substituents on the group are independently selected from halogen, C 1-6 Aliphatic group, -(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° taken together with their intervening atoms form a 3- to 12-membered saturated, partially unsaturated or aromatic monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; L is selected from –(C(R)2) m NR(C(R)2) m -#、-(C(R)2) m NRC(O)(C(R)2) m -#、-(C(R)2) m C(O)NR(C(R)2) m -#、-NRC(O)NR-#、-(C(R)2) m OC(O)NR(C(R)2) m -#, -O(C(R)2) m NRC(O)-#、-O(C(R)2) m NRS(O)2-#、-(C(R)2) m S(O)2NR(C(R)2) m -# and -(C(R)2) m NRS(O)2(C(R)2) m -#, wherein each R is independently hydrogen or C 1-6 Aliphatic group, each m is independently 0, 1 or 2, and # represents Cy A connection points; R 1 and R 2 are independently selected from hydrogen, halogen, -OR, -SR, -N(R)2 and -(CH2) 0-4 C(O)OR° substituted C 1-6 Aliphatic groups, wherein R° is hydrogen or C 1-6 aliphatic group; wherein R 1 Can be used with monocyclic Cy 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 and sulfur, wherein each R is independently hydrogen or C 1-6 an aliphatic group, or two R groups on the same carbon or nitrogen group taken together with their intervening atoms form a ring selected from the group consisting of 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 and sulfur; R 3 、R 4 、R 5 and R 7 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 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 3 、R 4 、R 5 and R 7 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 an aliphatic group, or two R groups on the same carbon or nitrogen group taken together with their intervening atoms form a ring selected from the group consisting of 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 and sulfur; R 6 Selected from C 3-7 cycloalkyl; and n is 0 or 1.

2. The compound of claim 1, wherein Cy A is selected from 5-membered heteroarylene groups having 1 to 4 heteroatoms independently selected from oxygen and nitrogen and 8-membered partially unsaturated bicyclic heterocyclylene groups having 2 to 3 heteroatoms selected from oxygen and nitrogen, wherein Cy A 0-3 R A Group substitution.

3. The compound of claim 1, wherein Cy A is a 5-membered heteroarylene group having 1 to 4 heteroatoms independently selected from oxygen and nitrogen, wherein Cy A 0-3 R A Group substitution.

4. The compound of claim 1, wherein Cy A is an 8-membered partially unsaturated bicyclic heterocyclylene group having 2-3 heteroatoms selected from oxygen and nitrogen, wherein Cy A 0-3 R A Group substitution.

5. The compound of claim 1, wherein Cy A Selected from the group consisting of: Where * represents the connection point with L.

6. The compound of claim 1, wherein R 3 、R 5 and R 7 It's hydrogen.

7. The compound of claim 1, wherein the compound has formula (III): or a pharmaceutically acceptable salt thereof, in: represents a single bond or a double bond; X is selected from C and N; and Each W is independently selected from CR A , CH, N and O.

8. The compound of claim 1, wherein R 1 With monocyclic Cy 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.

9. The compound of claim 1, wherein the compound has formula (IV): in represents a single bond or a double bond; Each X is independently N or C; Each Y is independently CR A , CH or N; and Z is CH2 or O.

10. The compound of claim 1, wherein the compound has Formula (III-a), Formula (III-b), Formula (III-c), Formula (III-d), Formula (III-e), Formula (III-f), or Formula (III-g): or a pharmaceutically acceptable salt thereof.

11. The compound of claim 1, wherein the compound has Formula (IV-a), Formula (IV-b), Formula (IV-c), or Formula (IV-d): or a pharmaceutically acceptable salt thereof.

12. The compound of claim 1, wherein L is selected from -NR-#, -C(R)2NR-#, -C(R)2NRC(R)2-#, -NRC(O)-#, -C(R)2NRC(O)-#, -C(R)2C(R)2NRC(O)-#, -C(O)NRC(R)2-#, -C(R)2C(O)NR-#, -C(R)2C(O)NR C(R)2-#, -NRC(O)NR-#, -C(R)2OC(O)NR-#, -OC(R)2C(R)2NRC(O)-#, -OC(R)2C(R)2NRS(O)2-#, -S(O)2NRC(R)2-#, -C(R)2NRS(O)2-# and -C(R)2C(R)2NRS(O)2-#, each R is independently hydrogen or C 1-6 Aliphatic group, and # represents Cy A connection point.

13. The compound of claim 1, wherein L is selected from -NRC(O)-#, -C(R)2NRC(O)-#, -C(R)2NRC(R)2-#, and -C(R)2NRSO2-#, wherein each R is independently selected from hydrogen and C 1-6 Aliphatic group, and # represents Cy A connection point.

14. The compound of claim 1, wherein L is selected from -NRC(O)-# and -C(R)2NRC(O)-#, wherein each R is independently selected from hydrogen and C 1-6 Aliphatic group, and # represents Cy A connection point.

15. The compound of claim 1, wherein the compound has formula (II): or a pharmaceutically acceptable salt thereof, in: Cy A is selected from 5-membered monocyclic heteroarylene groups having 1-4 heteroatoms independently selected from oxygen, nitrogen and sulfur and 7- to 10-membered partially unsaturated bicyclic heterocyclylene groups having 1-4 heteroatoms independently selected from oxygen, nitrogen and sulfur, wherein Cy A 0-4 R A group substitution; R A is selected from an optionally substituted group, the optionally substituted group is selected from C 1-6 an aliphatic group, a 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 and sulfur, wherein the optionally substituted R A The substituents on the group are independently halogen, (CH2) 0-4 R°, -(CH2) 0-4 OR°; and -(CH2) 0- 4C(O)OR°, wherein each R° is independently hydrogen, C 1-6 an aliphatic group or a 5- to 6-membered saturated, partially unsaturated, or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Q is selected from -C(R)2-, -C(O)-, and -S(O)2-, wherein each R is independently hydrogen or C 1-6 an aliphatic group, or two R groups on the same carbon, taken together with their intervening atoms, form a ring selected from the group consisting of a 3- to 7-membered saturated or partially unsaturated monocyclic ring having 0-2 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur, and a 5- to 6-membered heteroaryl group having 1-4 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur; In formula (II) The R of the group is hydrogen or C 1-6 aliphatic groups; Cy B Selected from: R B independently selected from halogen, -CN, -OR, -N(R)2, -N(R)CN, -C(=N(R))N(R)2, -S(O)R, -S(O)2R, -S(O)2N(R)2, and an optionally substituted group selected from the group consisting of: C 1-6 aliphatic, phenyl, 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen and sulfur, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic radical, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic radical having 1-2 heteroatoms selected from oxygen, nitrogen and sulfur, 7- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen and sulfur, and 8- to 10-membered spirocyclic heterocyclic radical having 1-3 heteroatoms selected from oxygen, nitrogen and sulfur, wherein each R is independently hydrogen or an optionally substituted C 1-6 aliphatic, and wherein the optionally substituted R B The substituents on the group are independently selected from halogen, C 1-6 Aliphatic group, -(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° taken together with their intervening atoms form a 3- to 12-membered saturated, partially unsaturated or aromatic monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; R 1 and R 2 are independently selected from hydrogen, halogen, -OR, -SR, -N(R)2 and -(CH2) 0-4 C(O)OR° substituted C 1-6 Aliphatic groups, wherein R° is hydrogen or C 1-6 aliphatic group; wherein R 1 Can be used with monocyclic Cy 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 and sulfur, wherein each R is independently hydrogen or C 1-6 an aliphatic group, or two R groups on the same carbon or nitrogen group taken together with their intervening atoms form a ring selected from the group consisting of 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 and sulfur; R 4 is selected from hydrogen, halogen, -CN, -C(O)OR 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 heterocyclic group having 1-2 heteroatoms selected from oxygen, nitrogen or sulfur, wherein the optionally substituted 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 aliphatic 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 an aliphatic group, or two R groups on the same carbon or nitrogen group taken together with their intervening atoms form a ring selected from the group consisting of 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 and sulfur; R 6 Selected from C 3-7 Cycloalkyl; n is 0 or 1; and p is 0, 1, or 2; with the proviso that the compound is not N-(furan-2-ylmethyl)-N,3,5-trimethyl-1-((6-methylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-sulfonamide and 2-[(6,8-dichloroimidazo[1,2-a]pyridin-2-yl)methyl]-4-methyl-N-phenyl-5-thiazolecarboxamide.

16. The compound of claim 15, wherein Cy A is selected from 5-membered heteroarylene groups having 1 to 4 heteroatoms independently selected from oxygen and nitrogen and 8-membered partially unsaturated bicyclic heterocyclylene groups having 2 to 3 heteroatoms selected from oxygen and nitrogen, wherein Cy A 0-3 R A Group substitution.

17. The compound of claim 15, wherein Cy A is a 5-membered heteroarylene group having 1 to 4 heteroatoms independently selected from oxygen and nitrogen, wherein Cy A 0-3 R A Group substitution.

18. The compound of claim 15, wherein Cy A is an 8-membered partially unsaturated bicyclic heterocyclylene group having 2-3 heteroatoms selected from oxygen and nitrogen, wherein Cy A 0-3 R A Group substitution.

19. The compound of claim 15, wherein Cy A Selected from the group consisting of: Where * represents the connection point with L.

20. The compound of claim 15, wherein the compound has Formula (III-ai), Formula (III-bi), Formula (III-ci), Formula (III-di), Formula (III-ei), Formula (III-fi), or Formula (III-gi): or a pharmaceutically acceptable salt thereof.

21. The compound of claim 15, wherein the compound has Formula (IV-ai), Formula (IV-bi), Formula (IV-ci), or Formula (IV-di): or a pharmaceutically acceptable salt thereof.

22. The compound of any one of claims 15-21, wherein Q is -C(R)2-, and p is 1.

23. The compound of any one of claims 15-21, wherein Q is -C(O)-, and p is 1.

24. The compound of any one of claims 15-21, wherein -C(O)-, and p is 0.

25. The compound of any one of claims 15-21, wherein Q is -S(O)2-, and p is 1.

26. A compound as described in any one of claims 1 to 21, wherein R 6 It is cyclopropyl.

27. The compound of claim 1, wherein the compound is selected from: or a pharmaceutically acceptable salt thereof.

28. A pharmaceutical composition comprising the compound of any one of claims 1-27, further comprising a pharmaceutically acceptable excipient.

29. Use of the composition according to claim 28 for the preparation of a medicament for treating a disease or condition mediated by plasma kallikrein.

30. The use of claim 29, wherein the disease or condition is hereditary angioedema or diabetic macular edema.

31. Use of a compound according to any one of claims 1 to 27 for the preparation of a medicament for treating hereditary angioedema or diabetic macular edema.

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