Plasma kallikrein inhibitors

Abstract

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

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims the benefit of U.S. Provisional Application No. 63 / 162,477, filed on 17 March 2021, which is incorporated herein by reference in its entirety. [Background technology]

[0002] Plasma kallikrein (PKa) is a serine protease thymogen in the blood that is converted to its catalytically active form by coagulation factor XIIa and contributes to innate inflammatory responses and the endogenous blood coagulation cascade. Mechanisms that trigger activation of this pathway in vivo include interaction with polyphosphate released from activated platelets and deficiency of C1 inhibitors (C1-INH), the major physiological inhibitor of PKa. Cleavage of high molecular weight kininogen via PKa produces bradykinin (BK), a potent vasodilator and pro-inflammatory nonapeptide, which activates the bradykinin 2 receptor. Subsequent cleavage of BK by carboxypeptidase produces 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 B1 and B2 receptors causes vasodilation and increases vascular permeability. pKa is also associated with numerous disorders, including hereditary angioedema (HAE), an autosomal dominant disorder characterized by painful, unpredictable, recurrent inflammatory attacks affecting the hands, feet, face, abdomen, genitourinary tract, and larynx. The prevalence of HAE is uncertain, but is estimated to be about 1 case per 50,000 people, with no known differences between racial groups. HAE is caused by a deficiency (type I) or dysfunction (type II) of C1-INH, which inhibits pKa, bradykinin, and other serine proteases in the blood. Individuals with hereditary angioedema (HAE) lack C1-INH, resulting in excessive bradykinin production, which in turn causes painful, debilitating, and potentially fatal swelling attacks. If left untreated, HAE can result in a high mortality rate of up to 40%, primarily due to upper airway obstruction. [Overview of the project]

[0003] This disclosure is at least in part based on the development of numerous compounds that bind to plasma kallikrein and efficiently inhibit its activity. Accordingly, this specification provides compounds and their uses for treating diseases and disorders that target and / or are mediated by plasma kallikrein.

[0004] In some embodiments, the present invention relates to formula (I): [ka] We provide compounds of or pharmaceutically acceptable salts thereof, in which Cy A Cy B , L, L', R 3 , R 4 , R 5 , R 6 , R 7 , and R 8Each of the embodiments is defined and described herein, both individually and in combination, in the classes and subclasses set forth herein. In certain embodiments, the present invention provides compounds of formula (I) to (VIII-c), which are defined and described in the classes and subclasses herein. In certain embodiments, the present invention provides novel intermediates and processes for preparing the compounds disclosed herein. The present disclosure also extends to pharmaceutical compositions comprising any one of the foregoing, and to the use of the compounds or compositions herein for treating disorders, in particular autoimmune diseases such as HAE or diabetic macular edema.

[0005] In some embodiments, the present invention also provides methods of using the compounds of formula (I) to (VIII-c).

[0006] As an advantage, the compounds of the present disclosure have therapeutic activity and / or appropriate levels of bioavailability and / or appropriate half-life for use as therapeutic agents. MODE FOR CARRYING OUT THE INVENTION

[0007] A. Definitions The compounds of the present invention generally include the compounds described above, as well as compounds further exemplified by the classes, subclasses and species disclosed herein. Unless otherwise stated, the following definitions shall apply as used herein. 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, 75 th Ed. In addition, the general principles of organic chemistry are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March’s Advanced Organic Chemistry", 5 thThis is described in Ed., Ed.: Smith, MB and March, J., John Wiley & Sons, New York: 2001, and its entire contents are incorporated herein by reference.

[0008] Abbreviations used herein have their usual meanings within the fields of chemistry and biology. Chemical structures and formulas described herein are constructed in accordance with the standard rules of chemical valence known in the field of chemistry.

[0009] As used herein, the terms “aliphatic” or “aliphatic group” mean a linear (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 (but not aromatic) that is fully saturated or contains one or more unsaturated units and has a single bond site to the remainder of the molecule (also referred herein as “carbocykryl,” “alicyclic,” or “cycloalkyl”). Unless otherwise specified, an aliphatic group contains 1 to 6 aliphatic carbon atoms. In some embodiments, an aliphatic group contains 1 to 5 aliphatic carbon atoms. In some embodiments, an aliphatic group contains 1 to 4 aliphatic carbon atoms. In some embodiments, an aliphatic group contains 1 to 3 aliphatic carbon atoms, and in further other embodiments, an aliphatic group contains 1 to 2 aliphatic carbon atoms. In some embodiments, "alicyclic" (or "carbocyclyl" or "cycloalkyl") refers to monocyclic C3-C7 hydrocarbons that are fully saturated or contain one or more unsaturated units, but are not aromatic and have a single bond site to the remainder of the molecule. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and their hybrids, e.g., (cycloalkyl)alkyl, (cycloalkenyl)alkyl, or (cycloalkyl)alkenyl.

[0010] The term "heteroatom" refers to one or more oxygen, sulfur, nitrogen, phosphorus, or silicon atoms (any oxidized form of nitrogen, sulfur, phosphorus, or silicon, any quaternated form of basic nitrogen, or a substituteable nitrogen in a heterocycle, e.g., N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR + This means (including, as in N-substituted pyrrolidinyl).

[0011] As used herein, the term “unsaturated” means that a part has one or more unsaturated units.

[0012] The term "alkylene" refers to a divalent alkyl group. An "alkylene chain" is a polymethylene group, i.e., -(CH2) n -, where n is a positive integer, preferably 1-6, 1-4, 1-3, 1-2, or 2-3. The substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are replaced by substituents. Suitable substituents for the substituted aliphatic group are listed below.

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

[0014] The term “aryl” refers to monocyclic and bicyclic ring systems having a total of 5 to 10 ring members, where at least one ring in the system is aromatic, and each ring in the system has 3 to 7 ring members. The term “aryl” may be used interchangeably with the term “aryl ring.” In some embodiments, the 8 to 10-membered bicyclic aryl group is an optionally substituted naphthyl ring. In certain embodiments of the present invention, “aryl” refers to aromatic ring systems that may have one or more substituents, including but not limited to phenyl, biphenyl, naphthyl, and anthracyl. As used herein, the scope of the term “aryl” also includes groups in which the aromatic ring is fused to one or more non-aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenantridinyl, or tetrahydronaphthyl.

[0015] The terms "heteroaryl" and "heteroar-" refer to a group having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms, with 6, 10, or 14 π electrons shared in a cyclic configuration, and having 1 to 5 heteroatoms in addition to carbon atoms. Examples of heteroaryl groups, though not limited to them, include thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridadinyl, pyrimidinyl, pyrazinyl, indolidinyl, prinyl, naphthilidinyl, and pteridinyl. As used herein, the terms “heteroaryl” and “heteroar-” also include groups in which an aromatic heterocycle is fused to one or more aryl, alicyclic, or heterocyclyl rings, and whose radical or bond site lies on the aromatic heterocycle (or, in the case of a divalent condensed heteroarylene ring system, at least one radical or bond site lies on the heteroaromatic ring). Non-limiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzothiazolyl, quinolyl, isoquinolyl, synnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolidinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-1,4-oxazine-3(4H)-one. Heteroaryl groups can be monocyclic or bicyclic. The term "heteroaryl" may be used interchangeably with the terms "heteroaryl ring," "heteroaryl group," or "heterocyclic aromatic," any of which may include rings in which the terms are optionally substituted.

[0016] As used herein, the terms “heterocyclyl,” “heterocyclic radical,” and “heterocyclic” are used interchangeably and refer to stable 5- to 7-membered monocyclic or 7- to 10-membered bicyclic heterocyclic moieties that are either saturated or partially unsaturated and have one or more, preferably 1 to 4, of the above-defined heteroatoms in addition to the carbon atoms. In this context, when used in relation to ring atoms, the term “nitrogen” includes substituted nitrogen. For example, in a saturated or partially unsaturated ring having 0 to 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 + It can be NR (as in N-substituted pyrrolidinyl).

[0017] A heterocyclic ring can be bonded to its pendant group by any heteroatom or carbon atom, resulting in a stable structure, and any of the ring atoms can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl. The terms “heterocyclyl,” “heterocyclyl ring,” “heterocyclic group,” “heterocyclic moiety,” and “heterocyclic radical” are used interchangeably herein and include groups in which a heterocyclyl ring is condensed with one or more aryl, heteroaryl, or alicyclic rings, such as indolinyl, 3H-indolyl, chromanyl, phenantridinyl, or tetrahydroquinolinyl, where the radical or bond site is located on the heterocyclyl ring. The heterocyclyl group may be monocyclic or bicyclic. The term “heterocyclylalkyl” refers to an alkyl group substituted with a heterocyclyl, where the alkyl and heterocyclyl moieties are independently and arbitrarily substituted.

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

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

[0020] As described herein, the compounds of the present invention may contain an "optionally substituted" moiety, where specified. Generally, whether following the term "optionally," the term "substituted" means that one or more hydrogens of a given moiety are replaced with a preferred substituent. "Substitution" applies to one or more hydrogens explicitly or implicitly indicated by the structure (e.g., [ka] At least [ka] It refers to, [ka] At least [ka] (This refers to...). Furthermore, in polycyclic ring systems, unless otherwise indicated, substituents may replace any individual hydrogen on the ring (for example, [ka] At least [ka] (This refers to [a specific group]). Unless otherwise specified, an "optionally substituted" group may have suitable substituents at each of its substituted positions, and if two or more positions in any given structure can be substituted with two or more substituents selected from a specified group, the substituents may be identical or different at all positions. The substituent combinations envisioned by the present invention preferably result in the formation of stable or chemically feasible compounds. The term "stable," as used herein, means a compound that remains substantially unchanged when subjected to conditions that enable their production, detection, and, in certain embodiments, their recovery, purification, and their use for one or more purposes disclosed herein.

[0021] Suitable monovalent substituents on the replaceable carbon atoms of the "arbitrarily substituted" group are, independently, halogens, -(CH2) 0-4 R ○ ,-(CH2) 0-4 Ure ○ -O(CH2) 0-4 R°, -O(CH2) 0-4 C(O)OR°, -O(CH2) 0-4 OR°, -(CH2) 0-4 CH(OR ○ )2, -(CH2) 0-4 SR ○ , may be substituted with R°-(CH2) 0-4 It may be substituted with pH and R° - (CH2) 0-4 O(CH2) 0-1 It may be substituted with Ph, R° - CH=CHPh, R° - (CH2) 0-4 O(CH2)0-1 -ピリジル、-NO2、-CN、-N3、-(CH2) 0-4 N(R ○ )2、-(CH2) 0-4 N(R ○ )C(O)R ○ 、-N(R ○ )C(S)R ○ 、-(CH2) 0-4 N(R ○ )C(O)NR ○ 2、-N(R ○ )C(S)NR ○ 2、-(CH2) 0-4 N(R ○ )C(O)OR ○ 、-N(R ○ )N(R ○ )C(O)R ○ 、-N(R ○ )N(R ○ )C(O)NR ○ 2、-N(R ○ )N(R ○ )C(O)OR ○ 、-(CH2) 0-4 C(O)R ○ 、-C(S)R ○ 、-(CH2) 0-4 C(O)OR ○ 、-(CH2) 0-4 C(O)SR ○ 、-(CH2) 0-4 C(O)OSiR ○ 3、-(CH2) 0-4 OC(O)R ○ 、-OC(O)(CH2) 0-4 SR°、-SC(S)SR°、-(CH2) 0-4 SC(O)R ○ 、-(CH2) 0-4 C(O)NR ○ 2、-C(S) ○ NR2、-C(S)SR°、-SC(S)SR°、-(CH2) 0-4 OC(O)NR ○ 2、-C(O)N(OR ○ )R ○ 、-C(O)C(O)R ○ 、-C(O)CH2C(O)R ○ 、-C(NOR ○)R ○ , -(CH2) 0-4 SSR ○ , -(CH2) 0-4 S(O)2R ○ , -(CH2) 0-4 S(O)2OR ○ , -(CH2) 0-4 OS(O)2R ○ , -S(O)2NR ○ 2, -(CH2) 0-4 S(O)R ○ , -N(R ○ )S(O)2NR ○ 2, -N(R ○ )S(O)2R ○ , -N(OR ○ )R ○ , -C(NH)NR ○ 2, -P(O)2R ○ , -P(O)R ○ 2, -OP(O) ○ R2, -OP(O)(OR ○ )2, SiR ○ 3, -(C 1-4 linear or branched alkylene)O-N(R ○ )2, or -(C 1-4 linear or branched alkylene)C(O)ON(R ○ )2, wherein in the formula, each R ○ may be substituted as defined below, and is independently hydrogen, aliphatic C, -CH2Ph, -O(CH2) 1-6 Ph, -CH2-(5- to 6-membered heteroaryl ring), or a 5- to 6-membered saturated ring, partially unsaturated ring or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur; or, notwithstanding the above definition, two independently occurring R 0-1 , together with the intervening atom(s), form a 3- to 12-membered saturated ring, partially unsaturated ring, aryl monocyclic ring or bicyclic ring, which has 0 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur and may be substituted as defined below. ○

[0022] R ○ ​The above suitable monovalent substituents (or two independently existing R ○ The ring formed together with those intercalating atoms is independently a halogen, -(CH2) 0-2 R ● ,-(HaroR ● ), -(CH2) 0-2 OH, -(CH2) 0-2 Ure ● ,-(CH2) 0-2 CH(OR ● )2;-O(HaroR ● ), -CN, -N3, -(CH2) 0-2 C(O)R ● ,-(CH2) 0-2 C(O)OH, -(CH2) 0-2 C(O)OR ● ,-(CH2) 0-2 SR ● ,-(CH2) 0-2 SH, -(CH2) 0-2 NH2, -(CH2) 0-2 NHR ● ,-(CH2) 0-2 NR ● 2, -NO2, -SiR ● 3. -OSiR ● 3, -C(O)SR ● ,-(C 1-4 (Linear or branched alkylene) C(O)OR ● , or -SSR ● And in the formula, each R ● It is either unsubstituted, or if "halo" precedes it, it is substituted with only one or more halogens, C 1-4 Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph, or independently selected from nitrogen, oxygen, or sulfur, is a 5-6 member saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms. ○ Suitable divalent substituents on the saturated carbon atom include =O and =S.

[0023] Suitable divalent substituents on the saturated carbon atom of the "arbitrarily substituted" group are: =O, =S, =NNR # 2. =NNHC(O)R# ,=NNHC(O)OR # ,=NNHS(O)2R # ,=NR # 、=NOR # , -O(C(R # 2)) 2-3 O-, or -S(C(R # 2)) 2-3 S- is listed, and each R that appears independently in the formula # C may be substituted with hydrogen, -CN, or as defined below. 1-6 Selected from an aliphatic, or unsubstituted 5-6 member saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. A preferred divalent substituent bonded to a substituted carbon adjacent to the "optionally substituted" group is -O(CR # 2) 2-3 O- is mentioned, and each R that appears independently in the formula # C may be substituted with hydrogen as defined below. 1-6 The rings are selected from aliphatic or unsubstituted 5-6 member saturated, partially unsaturated, or aryl rings having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0024] R # Suitable substituents on the aliphatic group include halogens and -R ● ,-(HaroR ● ), -OH, -OR ● ,-O(HaroR ● ), -CN, -C(O)OH, -C(O)OR ● -NH2, -NHR ● , -NR ● 2, or -NO2, and in the formula, each R ● It is either unsubstituted, or if preceded by "halo", it is substituted by only one or more halogens, and independently, C 1-4 Aliphatic, -CH2Ph, -O(CH2) 0-1 It is a 5-6 member saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from pH, nitrogen, oxygen, or sulfur.

[0025] Suitable substitutions on the nitrogen of the "arbitrarily substituted" group include -R † , -NR † 2, -C(O)R † , -C(O)OR † ,-C(O)C(O)R † -C(O)CH2C(O)R † -S(O)2R † -S(O)2NR † 2, -C(S)NR † 2, -C(NH)NR † 2, or -N(R † )S(O)2R † These are listed, and in the formula, each R † C may be substituted independently with hydrogen as defined below. 1-6 An aliphatic, unsubstituted-OPh, or unsubstituted 5-6 member saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the above definition, two independently existing R † However, together with these intervening atoms (multiple atoms are possible), they form an unsubstituted 3-12 member saturated ring, partially unsaturated ring, or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0026] R † Suitable substituents on the aliphatic group are, independently, halogens, -R ● ,-(HaroR ● ), -OH, -OR ● ,-O(HaroR ● ), -CN, -C(O)OH, -C(O)OR ● -NH2, -NHR ● , -NR ● 2, or -NO2, where each R ● It is either unsubstituted, or if preceded by "halo", it is substituted by only one or more halogens, and independently, C 1-4 Aliphatic, -CH2Ph, -O(CH2) 0-1It is a 5-6 member saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from pH, nitrogen, oxygen, or sulfur.

[0027] As used herein, the term “pharmaceutically acceptable salt” means a salt that, within the bounds of sound medical judgment, is suitable for use in contact with human and lower animal tissues without excessive toxicity, irritation, allergic reactions, etc., and that provides a reasonable benefit-risk ratio. pharmaceutically acceptable salts are well known in the art. For example, SMBerge et al., incorporated herein by reference, describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19.

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

[0029] Unless otherwise specified, the structures described herein include all isomers (e.g., enantiomers, diastereomers, and geometric (or conformational)) of the structure; for example, R and S configurations for each chiral center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Thus, single stereochemical isomers of the compounds of the present invention, as well as enantiomer mixtures, diastereomer mixtures, and geometric (or conformational) mixtures, are within the scope of the present invention. Unless otherwise specified, all tautomeric forms of the compounds of the present invention are within the scope of the present invention. In addition, unless otherwise specified, the structures described herein include compounds that differ only in the presence of one or more isotopically enriched atoms; for example, hydrogen substitution with deuterium or tritium, or 13 C concentrated carbon or 14Compounds having the structure of the present invention, including carbon substitution with 13C-enriched carbon, are within the scope of the present invention. Such compounds are useful, for example, as analytical tools in biological assays, as probes, or as therapeutic agents according to the present invention.

[0030] In some embodiments, the compounds of the present disclosure are provided as a single enantiomer or a single diastereoisomer. A single enantiomer refers to an enantiomer excess of 80% or more, for example, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99%. A single diastereoisomer excess refers to an excess of 80% or more, for example, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99%.

[0031] As used herein, the term "oxo" means oxygen that is double-bonded to a carbon atom, thereby forming a carbonyl group.

[0032] symbol [ka] The symbol indicates a bond point of a chemical moiety to the remainder of a molecule or chemical formula, unless used as a bond to indicate an unknown stereochemistry or mixed stereochemistry.

[0033] The articles "a" and "an" are used herein to refer to one or more (i.e., at least one) of the grammatical objects of the article. For example, "an element" means one or more elements.

[0034] A “dosage plan” (or “optimal treatment plan”), as the term is used herein, is a set of unit doses (typically two or more) administered individually to a subject, typically at intervals of a certain period of time. In some embodiments, a given therapeutic agent has a recommended dosage plan requiring one or more doses. In some embodiments, the dosage plan comprises multiple doses, each spaced equally apart from the others, and in some embodiments, the dosage plan comprises multiple doses, with each dose spaced at least two different intervals apart.

[0035] As can be understood from the context, a “reference” compound is a compound that is sufficiently similar to a particular compound of interest to allow for a comparison of its relevance. In some embodiments, information about the reference compound is obtained simultaneously with information about the particular compound. In some embodiments, the information about the reference compound is a medical history. In some embodiments, the information about the reference compound is stored, for example, on a computer-readable medium. In some embodiments, the identity, similarity, or difference of a particular compound of interest to a reference compound is established by comparing the particular compound of interest with the reference compound. As used herein, the term “therapeutic” means that, when administered to a subject, it has a therapeutic effect and / or induces a desired biological and / or pharmacological effect.

[0036] As used herein, the term “therapeutic dose” refers to the amount of a therapeutic agent that produces a therapeutic effect on the subject being treated in a reasonable benefit-risk ratio applicable to any medical treatment. The therapeutic effect may be objective (i.e., measurable by several tests or markers) or subjective (i.e., the subject exhibits signs of or feels an effect). In particular, “therapeutic dose” refers to the amount of a therapeutic agent that is effective in treating, improving, or preventing a desired disease or condition, or that is effective in producing a detectable therapeutic or preventive effect, for example, by improving symptoms associated with the disease, preventing or delaying the onset of the disease, and / or reducing the severity or frequency of the symptoms of the disease. The therapeutic dose is generally administered in a dosing regimen that may include multiple unit doses. For any particular therapeutic agent, the therapeutic dose (and / or appropriate unit dose within an effective dosing regimen) may vary, for example, depending on the route of administration, combination with other pharmaceuticals, etc. Furthermore, the therapeutically effective dose (and / or unit dose) specific to any particular subject may depend on various factors, including the disorder to be treated and its severity, the activity of the particular therapeutic agent used, the specific composition used, the subject's age, weight, health status, sex, and diet, the timing of administration, route of administration, and / or rate of excretion or metabolism of the particular therapeutic agent used, the duration of treatment, and similar factors known in the medical field.

[0037] As used herein, the term “treatment” (similarly “to treat” or “to treat”) refers to any administration of a substance (e.g., a composition provided) that partially or completely reduces, improves, alleviates, inhibits, delays the onset of, reduces the severity of, and / or reduces the incidence of one or more symptoms, features, and / or etiologies of a particular disease, disorder, and / or condition. Such treatment may be for subjects who do not show signs of the disease, disorder, and / or condition in question, and / or for subjects who show only initial signs of the disease, disorder, and / or condition. Alternatively, or further, such treatment may be for subjects who show one or more established signs of the disease, disorder, and / or condition in question. In some embodiments, treatment may be for subjects diagnosed with the disease, disorder, and / or condition in question. In some embodiments, treatment may be for subjects known to have one or more susceptibility factors that statistically correlate with an increased risk of developing the disease, disorder, and / or condition in question.

[0038] B. Compound In some embodiments, the provided compound is of formula (I): [ka] or a pharmaceutically acceptable salt thereof, During the ceremony: Cy A This includes a 4-membered monocyclic carbocylene, a 3-7 member saturated or partially unsaturated monocyclic heterocyclene having 1-3 heteroatoms selected from oxygen, nitrogen, or sulfur, a phenylene, a 5-6 member monocyclic heteroarylene having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, a 7-10 member saturated or partially unsaturated bicyclic heterocyclene having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, or an 8-12 member bicyclic heteroarylene having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, and Cy A This is 0 to 4 R A It is substituted with the base, Each RA These are oxo, halogen, -CN, -C(O)R, -C(O)2R, -C(O)N(R)2, -NO2, -N(R)2, -N(R)C(O)R, -N(R)C(O)2R, -N(R)S(O)2R, -OR, -OC(O)R, -OC(O)N(R)2, -SR, -S(O)R, -S(O)2R, -S(O)N(R)2, -S(O)2N(R)2, or C1-6 aliphatic, phenyl, 3 A group independently selected from any substituted group, which can be selected from a ~7-membered saturated or partially unsaturated monocyclic carbocyclyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur, or a 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from oxygen, nitrogen, or sulfur. Each R is independently hydrogen or optionally substituted with C 1-6 It is an aliphatic group, Cy B This is selected from phenyl, an 8-10 membered bicyclic aryl, a 7-10 membered saturated or partially unsaturated bicyclic carbocyrill, a 5-6 membered heteroaryl having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, a 7-10 membered saturated or partially unsaturated bicyclic heterocycline having 1-3 heteroatoms independently selected from oxygen, nitrogen, or sulfur, or a 7-10 membered heteroaryl having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, and Cy B This is 0 to 5 R B It is substituted with the base, Each R BThese are oxo, halogen, -CN, -C(O)R, -C(O)2R, -C(O)N(R)2, -C(NR)NR2, -C(NR)NROR, -C(NR)NRC(O)OR, -NO2, -N(R)2, -N(R)C(O)R, -N(R)C(O)2R, -N(R)S(O)2R, -OR, -OC(O)R, -OC(O)N(R)2, -SR, -S(O)R, -S(O)2R, -S( A group independently selected from any substituted group, which is either O)N(R)2, -S(O)2N(R)2, or a 3-7 member saturated or partially unsaturated monocyclic heterocycline having 1-2 heteroatoms selected from C1-6 aliphatic, oxygen, nitrogen, or sulfur, or a 5-6 member heteroaryl having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur. L' is covalently bonded or optionally substituted with C 1-4 It is a hydrocarbon chain, in which case 1 to 3 methylene units can be any and independently -O-, -C(O)-, -NR z Substituted with -, -S-, -SO-, SO2-, -S(NH)(O)-, or cyclopropylene, Each R z is hydrogen, -(CH2) 0-3 OR, -(CH2) 0-3 C(O)OR, or any substituted C 1-6 Selected independently from aliphatic groups, L is an arbitrarily substituted C 1-2 It is a hydrocarbon chain, in which case one methylene unit can be any and independently -C(O)-, -O-, -NR z Substituted with -, -S-, -SO-, or -SO2-, or L is an optionally substituted 5-6 member saturated or partially unsaturated heterocyclene having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur. Each R 3 , R 4 , R 5 , R 6 , and R 7 is hydrogen or -L C -R C Selected independently from, in the formula, Each L CC is covalently bonded or optionally substituted. 1-6 Selected independently from the hydrocarbon chain, in which case 1 to 3 methylene units are optionally and independently substituted with -O- or -NR-, Each R C These are halogen, -CN, -C(O)R, -C(O)2R, -C(O)N(R)2, -NO2, -N(R)2, -N(R)C(O)R, -N(R)C(O)2R, -N(R)S(O)2R, -OR, - OC(O)R, -OC(O)N(R)2, -SR, -S(O)R, -S(O)2R, -S(O)N(R)2, -S(O)2N(R)2, Cy C , or independently selected from optionally substituted C1-6 aliphatic elements, Each Cy C This is an optionally substituted ring independently selected from a 3-7 member saturated or partially unsaturated monocyclic carbocyclyl, a 3-7 member saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur, a 5-6 member monocyclic heteroaryl having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, a 6-12 member saturated or partially unsaturated condensed bicyclic heterocyclyl having 1-3 heteroatoms independently selected from phenyl, oxygen, nitrogen, or sulfur, a bridging bicyclic, or a 6-12 member saturated or partially unsaturated bicyclic spiroheterocyclyl having 1-3 heteroatoms independently selected from oxygen, nitrogen, or sulfur.

[0039] In some embodiments, the compound provided is a compound of formula (I), however: Cy B but [ka] If that is the case: L is a -C(O)- or optionally substituted C2 hydrocarbon chain, in which case one methylene unit is optionally and independently -O- or -NR zIt is substituted with -, or is an optionally substituted 5-membered saturated or partially unsaturated heterocyclene having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur.

[0040] In some embodiments, the compound provided is a compound of formula (I), however: Cy A However, it is a 5-membered monocyclic heteroarylene having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, and Cy A However, there are 0 to 4 -R values. A If substituted with: L is a -C(O)- or optionally substituted C2 hydrocarbon chain, in which case one methylene unit is optionally and independently -O- or -NR z It is substituted with -, or is an optionally substituted 5-membered saturated or partially unsaturated heterocyclene having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur.

[0041] In some embodiments, the compound provided is a compound of formula (I), however: i)Cy B but [ka] is, or ii) Cy A However, it is a 5-membered monocyclic heteroarylene having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, and Cy A However, there are 0 to 4 -R values. A If substituted with: L is a -C(O)- or optionally substituted C2 hydrocarbon chain, in which case one methylene unit is optionally and independently -O- or -NR z It is substituted with -, or is an optionally substituted 5-membered saturated or partially unsaturated heterocyclene having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur.

[0042] In some embodiments, the compound provided is a compound of formula (I), except that the compound is not any of the following compounds: [ka] [ka] [ka] [ka] [ka] [ka] [ka] 2-(7-chloroimidazo[1,5-a]pyridine-1-yl)-N-((1-((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)-1H-1,2,3-triazole-4-yl)methyl)acetamide, 1-(7-chloro-8-fluoroimidazo[1,5-a]pyridine-1-yl)-N-((1-((6-cyclopropylimidazo)[1,2-a]pyridine-2-yl)methyl)-1H-1,2,3-triazole-4-yl)methyl)-2,2,2-trifluoroethane-1-amine, 7-chloro-N-( (1-((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)-1H-1,2,3-triazole-4-yl)methyl)-8-fluoroimidazo[1,5-a]pyridine-1-carboxamide, N-((7-chloro-8-fluoroimidazo[1,5-a]pyridine-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)-1H-pyrazole-4-sulfonamide, N-((7-chloro-8-fluoroimidazo[1,5-a]pyridine-1-yl)methyl)-1-( (6-Cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)-1H-1,2,3-triazole-4-sulfonamide, 7-Chloro-N-((1-((6-Cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)-1H-1,2,3-triazole-4-yl)methyl)-8-Fluoroimidazon[1,5-a]pyridine-1-sulfonamide, 7-Chloro-N-(1-(1-((6-Cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)-1H-1,2,3-triazole-4-yl)ethyl N-((7-chloro-8-fluoroimidazo[1,5-a]pyridine-1-sulfonamide, N-((7-chloro-8-fluoroimidazo[1,5-a]pyridine-1-yl)methyl)-5-(6-cyclopropylimidazo[1,2-a]pyridine-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-2-carboxamide, N-((7-chloro-8-fluoroimidazo[1,5-a]pyridine-1-yl)methyl)-5-(6-cyclopropylimidazo[1,2-a]pyridine-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]Imidazole-3-carboxamide, N-((7-cyanoimidazo[1,5-a]pyridine-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)-1H-pyrazole-4-carboxamide, 1-(7-chloro-8-fluoroimidazo[1,5-a]pyridine-1-yl)-N-((1-((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)-1H-1,2,3-triazole-4-yl)methyl)methanamine, N-((7-chloro-8-fluoroimidazo[ 1,5-a]pyridine-1-yl)methyl)-1-(1-((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)-1H-1,2,3-triazole-4-yl)ethane-1-amine, 2-(7-chloroimidazo[1,5-a]pyridine-1-yl)-N-(1-(1-((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)-1H-1,2,3-triazole-4-yl)ethyl)acetamide, 2-((4-((((7-chloro-8-fluoroimidazo[1,5-a]pyridine-1-yl)methyl) Amino)methyl)-1H-1,2,3-triazole-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-carboxylate methyl, 2-((4-((((7-chloro-8-fluoroimidazo)[1,5-a]pyridine-1-yl)methyl)amino)methyl)-1H-1,2,3-triazole-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-carboxylate, N-((7-chloro-8-fluoroimidazo[1,5-a]pyridine-1-yl)methyl)-1-(1-((6-cyclopropylimida Zo[1,2-a]pyridine-2-yl)methyl)-1H-pyrazole-4-yl)-2,2,2-trifluoroethane-1-amine, 3-(2-((4-((((7-chloro-8-fluoroimidazo[1,5-a]pyridine-1-yl)methyl)amino)methyl)-1H-1,2,3-triazole-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-yl)propanoate ethyl, 3-(2-((4-((((7-chloro-8-fluoroimidazo[1,5-a]pyridine-1-yl)methyl)amino)methyl)-1H-1,2,3-triazole-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-yl)propanoic acid, 1-(7-chloro-8-fluoroimidazo[1,5-a]pyridine-1-yl)-N-((1-((6-cyclopropyl-8-(4H-1,2,4-triazole-4-yl)imidazo[1,2-a]pyridine-2-yl)methyl)-1H-1,2,3-triazole-4-yl)methyl)methanamine, 2-(7-chloroimidazo[1,5-a]pyridine-1-yl)-N -(1-(1-((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)-1H-pyrazole-4-yl)-2,2,2-trifluoroethyl)acetamide, N-((7-chloro-8-fluoroimidazo[1,5-a]pyridine-1-yl)methyl)-1-((6-cyclopropyl-8-(4-methylpiperazine-1-yl)imidazo[1,2-a]pyridine-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide, or a pharmaceutically acceptable salt thereof.

[0043] "Oxo" refers to the oxygen substitution of a double bond on a carbon "C=O" atom, and it will be understood that the carbon atom is part of the structure or group that is substituted by the oxo. For example, Cy C ga-L D -R D It is replaced by, in the formula, L D The bond is covalent, and R D If is an oxo, the carbon atom that is substituted by the oxo (i.e., the carbon in C=O) is Cy C It is part of (for example, Cy C The structure is in second place -L D -R D It is substituted with cyclopentyl, in the formula, L D It is a covalent bond, R D teeth [ka] This is the corresponding oxo.

[0044] In some embodiments, Cy AThis is a phenylene, or a 5-6 member monocyclic heteroarylene having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, and Cy A This is 0 to 4 R A It is substituted with a base. In some embodiments, Cy A This is a 5-6 member monocyclic heteroarylene having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, or an 8-12 member bicyclic heteroarylene having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, and Cy A This includes 0 to 4 -R values. A It is substituted with the base.

[0045] In a particular embodiment, Cy A This is a 4-membered monocyclic carbocylene, a 3-7 member saturated or partially unsaturated monocyclic heterocyclene having 1-3 heteroatoms selected from oxygen, nitrogen, or sulfur, a 5-6 member monocyclic heteroarylene having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, a 7-10 member saturated or partially unsaturated bicyclic heterocyclene having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, or a 7-10 member bicyclic heteroarylene having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, and Cy A This is 0 to 4 R A It is substituted with the base.

[0046] In some embodiments, Cy A It is a 4-membered monocyclic carbocyclene, and Cy A This includes 0 to 4 -R values. A It is substituted with a base. In some embodiments, Cy A It is cyclobutenedionediyl, and Cy A This includes 0 to 2 -R values. A It is substituted with a base. In some embodiments, Cy A teeth [ka] That is the case.

[0047] In some embodiments, Cy A It is phenylene, and Cy A This includes 0 to 4 -R values. A It is substituted with a base. In some embodiments, Cy A It is phenylene, and Cy A This includes 0 to 2 -R values. A It is substituted with the base.

[0048] In some embodiments, Cy A This is a 5-6 member monocyclic heteroarylene having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, and Cy A This includes 0 to 4 -R values. A It is substituted with the base.

[0049] In some embodiments, Cy A It is a 6-membered monocyclic heteroarylene having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, and Cy A This includes 0 to 4 -R values. A It is substituted with a base. In some embodiments, Cy A It is a 6-membered monocyclic heteroarylene having 1 to 3 nitrogen heteroatoms, and Cy A This is 0 to 4 R A It is substituted with a base. In some embodiments, Cy A This is 0 to 3 R A It is a pyridinediyl substituted with a group. In some embodiments, Cy A This is 0 to 2 R A It is a pyrimidinediyl substituted with a group. In some embodiments, Cy A This is 0 to 2 R A It is a pyridazinediyl substituted with a group. In some embodiments, Cy A This is 0 to 1 R A It is a pyridinediyl substituted with a group. In some embodiments, Cy A This is 0 to 1 R A It is a pyrimidinediyl substituted with a group. In some embodiments, Cy AThis is 0 to 1 R A It is a pyridandiyl substituted with a group. In some embodiments, Cy A This is 0 to 1 R A It is a triazinediyl substituted with a specific group.

[0050] In some embodiments, Cy A It is a 5-membered monocyclic heteroarylene having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, and Cy A This includes 0 to 2 -R values. A It is substituted with a base. In some embodiments, Cy A is an unsubstituted thiadiazole diyl. In some embodiments, Cy A is an unsubstituted oxadiazole diyl. In some embodiments, Cy A is an unsubstituted triazole diyl. In some embodiments, Cy A This is 0 to 3 R A It is a thiazole diyl substituted with a group.

[0051] In some embodiments, Cy A Cy A This includes 0 to 4 -R values. A It is substituted with the base.

[0052] In some embodiments, Cy A Cy A This includes 0 to 4 -R values. A It is substituted with a base. In some embodiments, Cy A Cy A This includes 0 to 4 -R values. A It is substituted with a base. In some embodiments, Cy ACy A This includes 0 to 4 -R values. A It is substituted with a base. In some embodiments, Cy A Cy A This includes 0 to 4 -R values. A It is substituted with a base. In some embodiments, Cy A It is a 10-membered saturated or partially unsaturated bicyclic heterocyclene having two nitrogen heteroatoms, and Cy A This includes 0 to 4 -R values. A It is substituted with a base. In some embodiments, Cy A This is 0 to 4 R A It is a dihydroindazolone diyl substituted with a group. In some embodiments, Cy A This is 0 to 4 R A This is a kinazolinonjiil that has been substituted with the base.

[0053] In some embodiments, Cy A This is an 8-12 membered bicyclic heteroarylene having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, and Cy A This includes 0 to 4 -R values. A It is substituted with a base. In some embodiments, Cy A It is a 9-membered bicyclic heteroarylene having 3 to 4 heteroatoms independently selected from oxygen and nitrogen, and Cy A This includes 0 to 1 -R A It is substituted with a base. In some embodiments, Cy A It is a 9-membered bicyclic heteroarylene having two nitrogen heteroatoms, and Cy A This includes 0 to 3 -R values. A It is substituted with a base. In some embodiments, Cy A It is a 9-membered bicyclic heteroarylene having two nitrogen heteroatoms, and Cy A This includes 0 to 1 -R AIt is substituted with a base. In some embodiments, Cy A This is 0 to 4 R A It is a benzimidazole diyl substituted with a group. In some embodiments, Cy A It is a 10-membered bicyclic heteroarylene having 3 to 4 heteroatoms independently selected from oxygen and nitrogen, and Cy A This includes 0 to 1 -R A It is substituted with the base.

[0054] In some embodiments, Cy A The group is selected from the following: [ka] [ka] During the ceremony, * This represents the connection point to L.

[0055] In some embodiments, Cy A The group is selected from the following: [ka] During the ceremony, * This represents the connection point to L.

[0056] In some embodiments, Cy A The group is selected from the following: [ka] During the ceremony, * This represents the connection point to L.

[0057] In some embodiments, Cy A The group is selected from the following: [ka] During the ceremony,* This represents the connection point to L.

[0058] In some embodiments, Cy A The group is selected from the following: [ka] During the ceremony, * This represents the connection point to L.

[0059] In some embodiments, Cy A The group is selected from the following: [ka] During the ceremony, * This represents the connection point to L.

[0060] In some embodiments, Cy A The group is selected from the following: [ka] During the ceremony, * This represents the connection point to L.

[0061] In some embodiments, Cy A The group is selected from the following: [ka] During the ceremony, * This represents the connection point to L.

[0062] In some embodiments, Cy A The group is selected from the following: [ka] During the ceremony, * This represents the connection point to L.

[0063] In one embodiment, Cy A is R A It contains 0 units, i.e., Cy A This is a non-substitution.

[0064] In one embodiment, Cy A For example, one R as described herein A It contains groups, especially methyl groups.

[0065] In one embodiment, Cy A For example, two R atoms independently selected from the groups / atoms described herein. A Includes the base.

[0066] Several embodiments, each R A The group is independently selected from oxo, halogen, -CN, -C(O)2R, -N(R)2, -OR, -SR, -S(O)R, -S(O)2R, or C1-6 aliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyryl, or 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur.

[0067] In some embodiments, R is optionally substituted. A The substituents on the group are, independently, halogens, -(CH2) 0-4 Ure ○ , or -(CH2) 0-4 N(R ○ )2, and in the formula, each R ○ These are defined independently above and described in the Classes and Subclasses of this Specified Specification.

[0068] Several embodiments, each R A The group is independently selected from any substituted group, which is selected from oxo, -C(O)R, -C(O)2R, -OR, or a 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from C1-6 aliphatic or oxygen, nitrogen or sulfur.

[0069] In some embodiments, R is optionally substituted. A The substituents on the group are, independently, halogens, -(CH2) 0-4 Ure ○ , or -(CH2) 0-4 C(O)OR ○ And in the formula, each R ○ These are defined independently above and described in the Classes and Subclasses of this Specified Specification.

[0070] It will be understood that references herein to embodiments in which "examples" of substituents are defined are not limited to monosubstituted embodiments. For example, "In some embodiments, R A "One example is oxo" is R A At least one example of is an oxo, and one or more additional R as defined herein. A Embodiments that may include a base are included.

[0071] In some embodiments, R A One example is oxo. In some embodiments, R A One example is halogens. In some embodiments, R A One example is -CN. In some embodiments, R A One example is -C(O)R. In some embodiments, R A One example is -C(O)Me. In some embodiments, R A One example is -C(O)2R. In some embodiments, R A One example is -C(O)2H. In some embodiments, R A One example is -C(O)2Me. In some embodiments, R A One example is -C(O)2Et. In some embodiments, R A One example is -N(R)2. In some embodiments, R A One example is -OR. In some embodiments, R A One example is -OR, where R is any substitute C. 1-6 It is aliphatic. In some embodiments, R AOne example is -OR, where R is -(CH2) 0-4 Ure ○ C arbitrarily replaced by 1-6 It is aliphatic, and each R ○ These are independently defined above and described in the classes and subclasses described herein. In some embodiments, R A One example is -SR. In some embodiments, R A One example is -SR, where R is an arbitrarily substituted C. 1-6 It is aliphatic. In some embodiments, R A One example is -S(O)R. In some embodiments, R A One example is -S(O)R, where R is an arbitrarily substituted C. 1-6 It is aliphatic. In some embodiments, R A One example is -S(O)2R. In some embodiments, R A One example is -S(O)2R, where R is an arbitrarily substituted C. 1-6 It is an aliphatic.

[0072] In some embodiments, R A One example is an arbitrarily substituted C 1-6 It is aliphatic. In some embodiments, R A One example is C substituted with halogen. 1-6 It is aliphatic. In some embodiments, R A One example is -CF3. In some embodiments, R A One example is -(CH2) 0-4 Ure ○ C replaced by 1-6 It is aliphatic, and in the formula, R ○ is hydrogen or C 1-6 Selected from aliphatic materials. In some embodiments, R A One example is -(CH2) 0-4 N(R ○ C replaced with )2 1-6 It is aliphatic, and in the formula, each R ○ is hydrogen or C 1-6 Selected independently of aliphatic elements. In some embodiments, R AOne example is -(CH2) 0-4 C(O)OR ○ C replaced by 1-6 It is aliphatic. In some embodiments, R A An example is selected from the following: [ka]

[0073] In some embodiments, R A An example is an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, R A One example is a cyclopropyl that has been arbitrarily substituted.

[0074] In some embodiments, R A An example is an optionally substituted 3-7 member saturated or partially unsaturated monocyclic heterocycline having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur. In some embodiments, R A An example is an optionally substituted 3-7 member saturated monocyclic heterocycline having 1-2 heteroatoms selected from oxygen and nitrogen. In some embodiments, R A One example is an optionally substituted oxetanyl. In some embodiments, R A One example is halogen or -(CH2) 0-4 Ure ○ It is oxetanyl optionally substituted with R. In some embodiments, R A One example is pyrrolidinil.

[0075] In some embodiments, R A An example is an optionally substituted 5-6 member monocyclic heteroaryl having 1-4 heteroatoms independently selected from oxygen, nitrogen, or sulfur. In some embodiments, R AAn example is an optionally substituted five-membered monocyclic heteroaryl having one to four heteroatoms independently selected from oxygen, nitrogen, or sulfur. In some embodiments, R A An example is an optionally substituted 5-membered monocyclic heteroaryl having 1 to 4 nitrogen heteroatoms. In some embodiments, R A One example is the arbitrarily substituted tetrazolyl.

[0076] In some embodiments, Cy B This is selected from a 5-6 membered heteroaryl having 1-3 heteroatoms independently selected from phenyl, oxygen, nitrogen, and sulfur, or a 7-10 membered heteroaryl having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, and Cy B This includes 0 to 4 -R values. B It is substituted with the base.

[0077] In some embodiments, Cy B This is a 5-6 membered heteroaryl having phenyl and 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, and Cy B This includes 0 to 4 -R values. B It is substituted with the base.

[0078] In some embodiments, Cy B It is selected from phenyl, or a 5-6 membered heteroaryl having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, and Cy B This includes 0 to 4 -R values. B It is substituted with a group, for example, pyrimidinyl has 0 to 4 -R groups. B It is substituted with groups, for example, zero or one group (in particular, one group being methyl).

[0079] In some embodiments, Cy B It is phenyl, and Cy B This includes 0 to 5 -R values. B It is substituted with a base. In some embodiments, Cy B It is phenyl, and CyB This includes 0 to 3 -R values. B It is substituted with a base. In some embodiments, Cy B It is phenyl, and Cy B This includes 0 to 2 -R values. B It is substituted with the base.

[0080] In some embodiments, Cy B It is a 6-membered heteroaryl having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, and Cy B This includes 0 to 4 -R values. B It is substituted with a base. In some embodiments, Cy B It is a 6-membered heteroaryl having 1 to 3 nitrogen atoms, and Cy B This includes 0 to 4 -R values. B It is substituted with a base. In some embodiments, Cy B This includes 0 to 2 -R values. B A pyrimidinyl group substituted with a group. In some embodiments, Cy B This includes 0 to 2 -R values. B A pyridinyl group substituted with a group. In some embodiments, Cy B This includes 0 to 1 -R B It is a pyrazinyl group substituted with a group. In some embodiments, Cy B This includes 0 to 1 -R B A pyridazinyl group substituted with a Cy group. In some embodiments, Cy B This includes 0 to 1 -R B It is a 1,3,5-triazinyl group substituted with a group. In some embodiments, CyB has 0 to 1 additional -R B It is a pyridinonyl group substituted with another group.

[0081] In some embodiments, Cy B It is a 5-membered heteroaryl having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, and Cy B This includes 0 to 4 -R values. B It is substituted with a base. In some embodiments, Cy BIt is a 5-membered heteroaryl having 1-2 heteroatoms independently selected from sulfur and nitrogen, and Cy B This includes 0 to 4 -R values. B It is substituted with a base. In some embodiments, Cy B This includes 0 to 2 -R values. B It is a thienyl group substituted with a group. In some embodiments, Cy B This includes 0 to 1 -R B It is a thiazolyl group substituted with a group. In some embodiments, Cy B This includes 0 to 1 -R B It is a thiadiazolyl group substituted with another group.

[0082] In some embodiments, Cy B The following group is selected: [ka]

[0083] In some embodiments, Cy B The following group is selected: [ka]

[0084] In some embodiments, Cy B The following group is selected: [ka]

[0085] In some embodiments, Cy B teeth: [ka] That is the case.

[0086] In some embodiments, Cy B It is a biring aryl with 8-10 members, and CyB This includes 0 to 4 -R values. B It is substituted with a base. In some embodiments, Cy B It is a 10-membered biring aryl, and Cy B This includes 0 to 4 -R values. B It is substituted with a base. In some embodiments, Cy B It is 1,2,3,4-tetrahydronaphthalenyl, and Cy B This includes 0 to 4 -R values. B It is substituted with a base. In some embodiments, Cy B It is naphthalenyl, and Cy B This includes 0 to 4 -R values. B It is substituted with a base. In some embodiments, Cy B is indolyl, Cy B This includes 0 to 4 -R values. B It is substituted with the base.

[0087] In some embodiments, Cy B Cy is a 7-10 member saturated or partially unsaturated bicyclic carbocyclyl, B This includes 0 to 4 -R values. B It is substituted with a base. In some embodiments, Cy B It is a 9-membered saturated or partially unsaturated bicyclic carbocyclyl, Cy B This includes 0 to 4 -R values. B It is substituted with a base. In some embodiments, Cy B This is 6,7-dihydro-5H-cyclopentapyridinyl, and Cy B This includes 0 to 4 -R values. B It is substituted with the base.

[0088] In some embodiments, Cy B Cy is a 7-10 member saturated or partially unsaturated bicyclic heterocycline having 1-3 heteroatoms selected from oxygen, nitrogen, or sulfur. B This includes 0 to 4 -R values. B It is substituted with a base. In some embodiments, Cy BCy is a 9-membered saturated or partially unsaturated bicyclic heterocycline having 1 to 3 heteroatoms selected from oxygen, nitrogen, or sulfur. B This includes 0 to 4 -R values. B It is substituted with a base. In some embodiments, Cy B Cy is a 9-membered saturated or partially unsaturated bicyclic heterocycline having 1-2 heteroatoms selected from oxygen or nitrogen. B This includes 0 to 4 -R values. B It is substituted with a base. In some embodiments, Cy B It is benzoxazolyl, and Cy B This includes 0 to 4 -R values. B It is substituted with a base. In some embodiments, Cy B It is benzoxazolonyl, and Cy B This is 0 to 3 additional -R B It is further substituted with the base.

[0089] In some embodiments, Cy B This is a 7-10 membered heteroaryl having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, and Cy B This includes 0 to 4 -R values. B It is substituted with a base. In some embodiments, Cy B It is a 9-membered heteroaryl having 1 to 4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, and Cy B This includes 0 to 4 -R values. B It is substituted with a base. In some embodiments, Cy B It is a 9-membered heteroaryl having 1 to 3 nitrogen heteroatoms, and Cy B This includes 0 to 4 -R values. B It is substituted with a base. In some embodiments, Cy B is indoleyl, and Cy B This includes 0 to 4 -R values. B It is substituted with a base. In some embodiments, Cy B It is imidazopyridinyl, and Cy B This includes 0 to 4 -R values. BIt is substituted with a base. In some embodiments, Cy B This is imidazopyridazinyl, and Cy B This includes 0 to 4 -R values. B It is substituted with a base. In some embodiments, Cy B It is benzotriazolyl, Cy B This includes 0 to 4 -R values. B It is substituted with a base. In some embodiments, Cy B It is benzimidazolyl, Cy B This includes 0 to 4 -R values. B It is substituted with a base. In some embodiments, Cy B It is pyrrolopyridinyl, and Cy B This includes 0 to 4 -R values. B It is substituted with the base.

[0090] In some embodiments, Cy B It is a 10-membered heteroaryl having 1 to 4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, and Cy B This includes 0 to 4 -R values. B It is substituted with a base. In some embodiments, Cy B It is a 10-membered heteroaryl having 1-2 nitrogen heteroatoms, and Cy B This includes 0 to 4 -R values. B It is substituted with a base. In some embodiments, Cy B is quinazolinyl, Cy B This includes 0 to 4 -R values. B It is substituted with a base. In some embodiments, Cy B It is phthalazinyl, and Cy B This includes 0 to 4 -R values. B It is substituted with the base.

[0091] In some embodiments, Cy B The following group is selected: [ka] [ka]

[0092] In some embodiments, Cy B The following group is selected: [ka]

[0093] In some embodiments, Cy B teeth [ka] That is the case.

[0094] Several embodiments, each R B The group is independently selected from any substituted group, which is selected from oxo, halogen, -CN, -NO2, -N(R)2, -N(R)C(O)2R, -OR, or a 5-membered heteroaryl having 1 to 4 heteroatoms independently selected from C1-6 aliphatic or oxygen, nitrogen and sulfur.

[0095] In some embodiments, R is optionally substituted. B Substituents on the group include oxo, halogen, and -(CH2) 0-4 Ure ○ Selected independently from, R ○ This is defined above and described in the Classes and Subclasses of this Specified Specification.

[0096] Several embodiments, each R B The group is independently selected from oxy, halogen, -CN, -C(O)N(R)2, -C(NR)NR2, -C(NR)NROR, -C(NR)NRC(O)OR, -N(R)2, -OR, or any optionally substituted group having 1 to 4 heteroatoms independently selected from C1-6 aliphatic or oxygen, nitrogen and sulfur.

[0097] In some embodiments, R is optionally substituted.B Substituents on the group include oxo, halogen, and -(CH2) 0-4 Ure ○ ,-(CH2) 0-4 N(R ○ )2, -(CH2) 0-4 C(O)NR ○ 2, and -(CH2) 0-4 OC(O)R ○ Selected independently from, R ○ This is defined above and described in the Classes and Subclasses of this Specified Specification.

[0098] In some embodiments, R B One example is oxo. In some embodiments, R B One example is halogens. In some embodiments, R B One example is -CN. In some embodiments, R B One example is -NO2. In some embodiments, R B One example is -N(R)2. In some embodiments, R B One example is -NH2. In some embodiments, R B One example is -N(R)C(O)2R. In some embodiments, R B One example is -OR. In some embodiments, R B One example is -OH. In some embodiments, R B One example is -OMe. In some embodiments, R B One example is -C(O)N(R)2. In some embodiments, R B One example is -C(O)NH2.

[0099] In some embodiments, R B One example is -C(NR)NR2. In some embodiments, R B One example is -C(NH)NH2. In some embodiments, R B One example is -C(NH)NHR, where R is an arbitrarily substituted C. 1-6 It is aliphatic. In some embodiments, R BOne example is -C(NR)NRC(O)OR. In some embodiments, R B One example is -C(NH)NHC(O)OR. In some embodiments, R B One example is [ka] In some embodiments, R B One example is [ka] That is the case.

[0100] In some embodiments, R B One example is -C(NR)NROR. In some embodiments, R B One example is -C(NH)NHOH. In some embodiments, R B One example is -C(NH)NHOR, where R is an arbitrarily substituted C. 1-6 It is aliphatic. In some embodiments, R B One example is -C(NH)NHOR, where R is -(CH2) 0-4 OC(O)R ○ C arbitrarily replaced by 1-6 It is aliphatic, R ○ R is defined above and described in the Classes and Subclasses herein. In some embodiments, R B One example is [ka] That is the case.

[0101] In some embodiments, R B One example is an optionally substituted C1-6 aliphatic. In some embodiments, R B One example is C1-6 aliphatic substituted with halogens. In some embodiments, R B One example is [ka] In some embodiments, R B One example is -CH2NH2. In some embodiments, R B One example is -(CH2) 0-4 N(R ○ It is a C1-6 aliphatic substituted with )2. In some embodiments, R B One example is -(CH2) 0-4 C(O)NR ○ It is a C1-6 aliphatic substituted with 2. In some embodiments, R B One example is -CH2C(O)NH2.

[0102] In some embodiments, R B One example is -N(R)C(O)2R, where each R is hydrogen or -(CH2) 0~4 R ○ C arbitrarily replaced by 1-6 They are selected independently of aliphatic cells.

[0103] In some embodiments, R B One example is -OR, where each R is hydrogen, or halogen, -(CH2) 0-4 Ure ○ , or (CH2) 0-4 C(O)OR ○ C arbitrarily replaced by 1-6 They are selected independently of aliphatic cells.

[0104] In some embodiments, R B An example is a five-membered heteroaryl having 1 to 4 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, R B One example is tetrazolyl.

[0105] In some embodiments, L is optionally replaced by C. 1-2 It is a hydrocarbon chain, in which case one methylene unit can be any -C(O)-, -O-, or -NR. zSubstituted with -, or L is an optionally substituted 5-6 member saturated or partially unsaturated heterocyclene having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur.

[0106] In some embodiments, L is -NR z - is

[0107] In some embodiments, R z H and C 1-6 An aliphatic group, such as H or methyl, is selected, particularly methyl.

[0108] In some embodiments, L is a -C(O)- or optionally substituted C2 hydrocarbon chain, in which case one methylene unit is optionally and independently -O- or -NR z It is substituted with -, or is an optionally substituted 5-membered saturated or partially unsaturated heterocyclene having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur.

[0109] In some embodiments, L is optionally replaced by C. 1-2 It is a hydrocarbon chain, and one methylene unit is -C(O)-, -O-, -NR z It can be arbitrarily replaced with -.

[0110] In some embodiments, L is an optionally substituted C1 hydrocarbon chain, where one methylene unit is -C(O)-, -O-, or -NR z It is optionally substituted with -. In some embodiments, L is -C(O)-. In some embodiments, L is halogen or -(CH2) 0-4 Ure ○ A C1 hydrocarbon chain that is arbitrarily substituted with R ○ L is defined above and as described in the Classes and Subclasses herein. In some embodiments, L is -CF2-. In some embodiments, L is -C(OH)H-.

[0111] In some embodiments, L is an optionally substituted C2 hydrocarbon chain, and one methylene unit is -NR z - or -O- is optionally substituted. In some embodiments, L is an optionally substituted C2 hydrocarbon chain, and Cy A The methylene unit connected is -NR z - or -O- is substituted. In some embodiments, L is an optionally substituted C2 hydrocarbon chain, and Cy A The methylene unit connected is -NR z - is substituted. In some embodiments, L is an optionally substituted C2 hydrocarbon chain, and Cy A The methylene unit connected to it is replaced with -O-. In some embodiments, L is optionally replaced. * -NHCH2-, * Cy A Represents the connection point to. In some embodiments, L is optionally substituted * -OCH2-, * Cy A This represents a connection point to [a specific location].

[0112] In some embodiments, L is * -NHCH(Me)-, * Cy A Represents the connection point to. In some embodiments, L is * -NHCH2-, * Cy A Represents the connection point to. In some embodiments, L is * -OCH(Me)- and * Cy A Represents the connection point to. In some embodiments, L is * -OCH2-, * Cy A Represents the connection point to. In some embodiments, L is [ka] And, * Cy ARepresents the connection point to. In some embodiments, L is [ka] And, * Cy A Represents the connection point to. In some embodiments, L is * It is -N(CH3)CH2-, * Cy A Represents the connection point to. In some embodiments, L is [ka] And, * Cy A Represents the connection point to. In some embodiments, L is [ka] And, * Cy A This represents a connection point to [a specific location].

[0113] In some embodiments, L is Cy A and [ka] It includes a two-atom spacer between them.

[0114] In some embodiments, L is an optionally substituted 5-6 member saturated or partially unsaturated heterocyclene having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, L is an optionally substituted 5 member saturated or partially unsaturated heterocyclene having 1 heteroatom independently selected from oxygen, nitrogen, and sulfur. In some embodiments, L is an optionally substituted pyrrolidinediyl group.

[0115] In some embodiments, L is optionally substituted [ka] And, * Cy A Represents the connection point to. In some embodiments, L is optionally substituted [ka] And, * Cy A Represents the connection point to. In some embodiments, L is optionally substituted [ka] And, * Cy A Represents the connection point to. In some embodiments, L is [ka] And, * Cy A Represents the connection point to. In some embodiments, L is [ka] And, * Cy A Represents the connection point to. In some embodiments, L is [ka] And, * Cy A This represents a connection point to [a specific location].

[0116] In some embodiments, any substituent on L is -(CH2) 0-4 R ○ ,-(CH2) 0-4 Ure ○ ,-(CH2) 0-4 OC(O)R ○ , and -(CH2) 0-4 N(R ○ ) Selected independently from 2, each R ○ These are defined independently above and as described in the Classes and Subclasses of this Specified Specified Classes.

[0117] In some embodiments, any substituent on L is independently a halogen, -(CH2) 0-4 R ○ , and -(CH2) 0-4 Ure ○ Selected from, in the formula, each R ○ These are defined independently above and as described in the Classes and Subclasses of this Specified Specified Classes.

[0118] In some embodiments, L' is a covalent bond.

[0119] In some embodiments, L' is optionally replaced by C 1-4 It is a hydrocarbon chain, in which case 1 to 3 methylene units can be any and independently -O-, -C(O)-, -NR z -, -S-, -SO-, SO2-, -S(NH)(O)-, or cyclopropylene are substituted. In some embodiments, L' is optionally substituted with C 1-4 It is a hydrocarbon chain, in which case 1 to 3 methylene units can be any and independently -O-, -C(O)-, -NR z Substituted with -, SO2-, -S(NH)(O)-, or cyclopropylene.

[0120] In some embodiments, L' is an optionally substituted C1 hydrocarbon chain, and one methylene unit is -O-, -C(O)-, or -NR z - is optionally substituted. In some embodiments, L' is an optionally substituted C1 hydrocarbon chain, and one methylene unit is -NR z It is optionally substituted with -. In some embodiments, L' is -NH2-. In some embodiments, L' is an optionally substituted C1 hydrocarbon chain. In some embodiments, L' is -CH2-.

[0121] In some embodiments, L' is an optionally substituted C2 hydrocarbon chain, in which case one or two methylene units are optionally and independently -O-, -C(O)-, or -NR zIt is replaced by -. In some embodiments, L' is -CH2CH2-. In some embodiments, L' is [ka] And, * Cy A Represents the connection point to. In some embodiments, L' is [ka] And, * Cy A This represents a connection point to [a specific location].

[0122] In some embodiments, L' is an optionally substituted C3 hydrocarbon chain, in which case one or two methylene units are optionally and independently -O-, -C(O)-, or -NR z It is replaced by -. In some embodiments, L' is -(CH2) 0-4 R ○ or -(CH2) 0-4 Ure ○ A C3 hydrocarbon chain optionally substituted with -O-, -C(O)-, or -NR. In this case, one or two methylene units are optionally and independently -O-, -C(O)-, or -NR. z - is substituted. In some embodiments, L' is an optionally substituted C3 hydrocarbon chain, in which case one methylene unit is substituted with -C(O)- and another methylene unit is substituted with -NR z - is replaced by: In some embodiments, L' is: [ka] Selected from the group consisting of, During the ceremony, * Cy A This represents a connection point to [a specific location].

[0123] In some embodiments, L' is: [ka] Selected from the group consisting of, During the ceremony,* Cy A This represents a connection point to [a specific location].

[0124] In some embodiments, L' is an optionally substituted C4 hydrocarbon chain, in which case 1 to 3 methylene units are optionally and independently -O-, -C(O)-, or -NR z It is replaced by -. In some embodiments, L' is -(CH2) 0-4 R ○ or =NR # A C4 hydrocarbon chain optionally substituted with -O-, -C(O)-, or -NR. In this case, 1 to 3 methylene units are optionally and independently -O-, -C(O)-, or -NR. z - is substituted. In some embodiments, L' is an optionally substituted C4 hydrocarbon chain, in which case one methylene unit is -NR z Substituted by -, one or two additional methylene units are optionally and independently -O-, -C(O)-, or -NR z - is substituted. In some embodiments, L' is an optionally substituted C4 hydrocarbon chain, in which case one methylene unit is -NR z - is substituted, one methylene unit is substituted with -C(O)-, one methylene unit is -O-, -C(O)-, or -NR z - is optionally replaced by: In some embodiments, L' is: [ka] Selected from the group consisting of, During the ceremony, * Cy A This represents a connection point to [a specific location].

[0125] In some embodiments, L' is optionally replaced by C 1-4 It is a hydrocarbon chain in which one methylene unit is substituted with cyclopropylene, and one or two additional methylene units are optionally and independently -O-, -C(O)-, -NR z It is substituted with -, SO2-, or -S(NH)(O)-. When the single methylene unit of L' is substituted with cyclopropylene, [ka] It is understood that this can occur. In some embodiments, L' is optionally substituted with C 1-4 It is a hydrocarbon chain in which one methylene unit is substituted with cyclopropylene, and one or two additional methylene units are independently -O-, -C(O)-, -NR z It is replaced with -, SO2-, or -S(NH)(O)-. In some embodiments, L' is: [ka] Selected from the group consisting of, During the ceremony, * Cy A This represents a connection point to [a specific location].

[0126] In some embodiments, R 3 、 R 4 , R 5 , R 6 , and R 7 Each of them is hydrogen or L C -R C Selected independently from, in the formula, each L C C is covalently bonded or optionally substituted. 1-6 Selected independently from the hydrocarbon chain, in which case 1 to 3 methylene units are optionally and independently substituted with -O- or -NR-, and each R C Halogen, -CN, -C(O)R, -C(O)2R, -C(O)N(R)2, -N(R)2, -N(R)C(O)R, -N(R)C(O)2R, -N(R)S(O)2R, -S(O)2R, -S(O)2N(R)2, Cy C , or independently selected from any substituted group selected from C1-6 aliphatic groups.

[0127] Several embodiments, each R z is hydrogen. In some embodiments, each R z is hydrogen, -(CH2) 0-3 OR, -(CH2) 0-3C(O)OR, or any substituted C 1-6 Selected independently from aliphatic groups. In some embodiments, each R z is hydrogen or optionally substituted C 1-6 It is aliphatic. In some embodiments, each R z is hydrogen or C 1-6 It is an aliphatic group. In some embodiments, R z It is methyl.

[0128] In some embodiments, R 3 is hydrogen or L C -R C Selected from, in the formula, L C It is a covalent bond, R C is a halogen. In some embodiments, R 3 is hydrogen. In some embodiments, R 3 is L C -R C That is the case.

[0129] In some embodiments, R 4 is hydrogen or L C -R C Selected from, in the formula, L C C is covalently bonded or optionally substituted. 1-6 Selected from hydrocarbon chains, in which case 1 to 3 methylene units are optionally and independently substituted with -O- or -NR-, R C Halogen, -CN, -C(O)R, -C(O)2R, -C(O)N(R)2, -N(R)2, -N(R)C(O)R, -N(R)C(O)2R, -N(R)S(O)2R, -OR, -S(O)2R, -S(O)2N(R)2, Cy C or selected from optionally substituted groups selected from C1-6 aliphatic groups.

[0130] In some embodiments, R 4 is hydrogen or L C -R C Selected from, in the formula, L C It is a covalent bond, R CHalogen, -CN, -C(O)R, -C(O)2R, -C(O)N(R)2, -N(R)2, -N(R)C(O)R, -N(R)C(O)2R, -N(R)S(O)2R, -OR, -S(O)2R, -S(O)2N(R)2, Cy C or selected from optionally substituted groups selected from C1-6 aliphatic groups.

[0131] In some embodiments, L C It is a covalent bond.

[0132] In some embodiments, R 4 is hydrogen. In some embodiments, R 4 is L C -R C In some embodiments, R 4 is L C -R C And L C It is a covalent bond, R C is -CN or Cy C Selected from. In some embodiments, R 4 is L C -R C And L C It is a covalent bond, R C is Cy C And Cy C R is a 3- to 7-membered saturated or partially unsaturated monocyclic heterocycline. In some embodiments, R 4 is L C -R C And L C is an arbitrarily substituted C 1-6 It is a hydrocarbon chain, R C This is either -OR or -OC(O)R.

[0133] In some embodiments, R 4 The following group is selected: [ka]

[0134] In some embodiments, R4 The following group is selected: [ka]

[0135] In some embodiments, R 4 teeth: [ka] That is the case.

[0136] R 4 In some embodiments, C 1-6 Any substituent on the aliphatic group is -(CH2) 0-4 R ○ ,-(CH2) 0-4 Ure ○ -CN, -(CH2) 0-4 N(R ○ )2, and -(CH2) 0-4 C(O)OR ○ Selected from, in the formula, each R ○ These are independently defined above and as described in the Classes and Subclasses of this Specified Specified Classes.

[0137] R 4 In some embodiments, Cy C R is an optionally substituted group selected from a 3-7 member saturated or partially unsaturated monocyclic heterocycline having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur; a 5-6 member monocyclic heteroaryl having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur; a 6-12 member saturated or partially unsaturated condensed bicyclic heterocycline having 1-3 heteroatoms independently selected from oxygen, nitrogen, or sulfur; a bridging bicyclic; or a 6-12 member saturated or partially unsaturated bicyclic spiroheterocycline having 1-3 heteroatoms independently selected from oxygen, nitrogen, or sulfur. 4 In some embodiments, Cy CIt is a five-membered saturated or partially unsaturated monocyclic heterocycline having one or two heteroatoms selected from oxygen, nitrogen, or sulfur.

[0138] R 4 In some embodiments, Cy C is an arbitrarily substituted group selected from the following group: [ka]

[0139] R 4 In some embodiments, Cy C Any substituent above is a halogen, -(CH2) 0-4 R ○ ,-(CH2) 0-4 Ure ○ ,-(CH2) 0-4 N(R ○ )2, -(CH2) 0-4 C(O)OR ○ , and -OP(O)(OR ○ ) Selected from 2, in the formula, each R ○ These are independently defined above and as described in the Classes and Subclasses of this Specified Specified Classes.

[0140] In some embodiments, R 5 It is hydrogen.

[0141] In some embodiments, R 5 is L C -R C And in the formula, L C It is a covalent bond, R C is Cy C That is 。 In some embodiments, Cy C It is a cyclopropyl group.

[0142] In some embodiments, R 6 is hydrogen. In some embodiments, R 6 is hydrogen or L C -R Cis selected from, wherein, L C is a covalent bond, and R C is selected from halogen, -N(R)2, -OR, Cy C , or an optionally substituted C 1-6 aliphatic group. In some embodiments, R 6 is L C -R C , wherein, L C is a covalent bond, and R C is Cy C . In some embodiments of R 6 , Cy C is optionally substituted cyclopropyl. In some embodiments, R 6 is cyclopropyl.

[0143] In some embodiments, R 7 is selected from hydrogen or L C -R C is selected from, wherein, L C is a covalent bond, and R C is Cy C . In some embodiments, R 7 is hydrogen. In some embodiments, R 7 is L C -R C , wherein, L C is a covalent bond, and R C is halogen. In some embodiments, R 7 is fluorine. In some embodiments of R 7 , Cy C is

Chemical Structure

[0144] In some embodiments, the provided compound is a compound of formula (I-a), formula (I-b), or formula (I-c):

Chemical Structure

[0145] Unless otherwise specified or prohibited by the foregoing definitions of Formula (I-a), (I-b), or (I-c), the variable moiety Cy defined above and described in the classes and subclasses herein A , Cy B , L', R 3 , R 4 , R 5 , R 6 , and R 7 embodiments are also understood to apply, both individually and in combination, to the compounds of Formula (I-a), (I-b), or (I-c).

[0146] In some embodiments, the provided compound is a compound of Formula (II), Formula (II-a), Formula (II-b), or Formula (II-c):

Chemical Formula

[0147] Unless otherwise specified or prohibited by the foregoing definitions of Formula (II), (II-a), (II-b), or (II-c), the variable moiety R defined above and described in the classes and subclasses herein A , Cy B , L, L', R3 , R 4 , R 5 , R 6 , and R 7 It is understood that the embodiments of this also apply, both individually and in combination, to compounds of formula (II), (II-a), (II-b), or (II-c).

[0148] In some embodiments, the provided compound is a compound of formula (III), formula (III-a), formula (III-b), or formula (III-c): [ka] or a pharmaceutically acceptable salt thereof, In the formula, R A Cy B , L, L', R 3 , R 4 , R 5 , R 6 , and R 7 Each of these, both individually and in combination, is defined and described in the Classes and Subclasses herein.

[0149] Unless otherwise specified, or prohibited by the aforementioned definitions of formulas (III), (III-a), (III-b), or (III-c), the variable part R as defined above and described in the classes and subclasses herein refers to the variable part R. A Cy B , L, L', R 3 , R 4 , R 5 , R 6 , and R 7 It is understood that the embodiments also apply, both individually and in combination, to compounds of formula (III), (III-a), (III-b), or (III-c).

[0150] In some embodiments, the provided compound is a compound of formula (IV-a), formula (IV-b), formula (IV-c), or formula (IV-d): [ka] or a pharmaceutically acceptable salt thereof, In the formula, Cy A , R B , L, L', R 3 , R 4 , R 5 , R 6 , and R 7 Each of these, both individually and in combination, is defined and described in the Classes and Subclasses herein.

[0151] Unless otherwise specified, or unless prohibited by the aforementioned definitions of formulas (IV), (IV-a), (IV-b), and (IV-c), the variable part Cy as defined above and described in the classes and subclasses herein A , R B , L, L', R 3 , R 4 , R 5 , R 6 , and R 7 It is understood that the embodiments also apply to compounds of formulas (IV), (IV-a), (IV-b), and (IV-c), both individually and in combination.

[0152] In some embodiments, the provided compounds are compounds of formula (V), (Va), formula (Vb), or formula (Vc): [ka] or a pharmaceutically acceptable salt thereof, In the formula, Cy A , R B , L, L', R 3 , R 4 , R 5 , R 6 , and R 7 Each of these, both individually and in combination, is defined and described in the Classes and Subclasses herein.

[0153] Unless otherwise specified, or unless prohibited by the foregoing definitions of formula (V), (V-a), (V-b) and (V-c), the variable moiety Cy defined above and described in the classes and subclasses herein A , R B , L, L', R 3 , R 4 , R 5 , R 6 , and R 7 embodiments are also understood to be applicable, both singly and in combination, to the compounds of formula (V), (V-a), (V-b), and (V-c).

[0154] In some embodiments, the provided compound is a compound of formula (VI), (VI-a), formula (VI-b), or formula (VI-c): Chemical Formula or a pharmaceutically acceptable salt thereof, wherein Cy A , Cy B , L, L', and R 4 each, both singly and in combination, are defined and described in the classes and subclasses herein.

[0155] Unless otherwise specified, or unless prohibited by the foregoing definitions of formula (VI), (VI-a), (VI-b), and (VI-c), the variable moiety Cy defined above and described in the classes and subclasses herein A , Cy B , L, L', and R 4 embodiments are also understood to be applicable, both singly and in combination, to the compounds of formula (VI), (VI-a), (VI-b), and (VI-c).

[0156] In some embodiments, the provided compound is a compound of formula (VII), (VII-a), formula (VII-b), or formula (VII-c): [ka] or a pharmaceutically acceptable salt thereof, In the formula, R A Cy B , L, L', and R 4 Each of these, both individually and in combination, is defined and described in the Classes and Subclasses herein.

[0157] Unless otherwise specified, or prohibited by the aforementioned definitions of formulas (VII), (VII-a), (VII-b), and (VII-c), the variable part R as defined above and described in the classes and subclasses herein refers to the variable part R. A Cy B , L, L', and R 4 It is understood that the embodiments also apply, both individually and in combination, to compounds of formulas (VII), (VII-a), (VII-b), and (VII-c).

[0158] In some embodiments, the provided compound is a compound of formula (VIII), (VIII-a), formula (VIII-b), or formula (VIII-c): [ka] or a pharmaceutically acceptable salt thereof, In the formula, R A Cy B , L, L', and R 4 Each of these, both individually and in combination, is defined and described in the Classes and Subclasses herein.

[0159] Unless otherwise specified, or prohibited by the aforementioned definitions of formulas (VIII), (VIII-a), (VIII-b), and (VIII-c), the variable part R as defined above and described in the classes and subclasses herein refers to the variable part R. A Cy B , L, L', and R 4It is understood that the embodiments also apply to compounds of formulas (VIII), (VIII-a), (VIII-b), and (VIII-c), both individually and in combination.

[0160] In certain embodiments of the provided compounds (i.e., any species not otherwise defined, and any species of formula (I) to (VIII-c)), part L' is a cyclopropyl ring: [ka] And in the formula, the two stereocenters are bonded together. [ka] The relative trans configuration for the coupling shown is * I marked it with: In other words, the part: [ka] In relation to this, "trans" is understood to mean a compound containing the following mixtures: [ka] In some embodiments, such a mixture is a racemic mixture.

[0161] In certain embodiments of the provided compound (i.e., any species not otherwise defined, and any of formulas (I) to (VIII-c)), L' comprises a cyclopropyl ring, part: [ka] The absolute stereochemistry of is as follows: [ka]

[0162] In certain embodiments of the provided compound (i.e., any species not otherwise defined, and any of formulas (I) to (VIII-c)), L' comprises a cyclopropyl ring, part: [ka] The absolute stereochemistry of is as follows: [ka]

[0163] In some embodiments, the present invention provides compounds selected from the following: 2-(7-chloroimidazo[1,5-a]pyridin-1-yl)-N-(6-(((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)amino)pyrimidine-4-yl)acetamide(I-1); 2-(5-chloro-2-cyanophenyl)-N-(6-(((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)amino)pyrimidine-4-yl)acetamide(I-2); 2-(6-cyano-2-fluoro-3-methoxyphenyl)-N-(6-(((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)amino)pyrimidine-4-yl)acetamide(I-3); 2-(7-chloroimidazo[1,5-a]pyridine-1-yl)-N-(6-(((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)amino)pyrimidine-4-yl)propanamide(I-4); 2-(7-chloroimidazo[1,5-a]pyridine-1-yl)-N-(6-(((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)amino)pyrimidine-4-yl)-2-methylpropanamide(I-5); 2-(7-chloroimidazo[1,5-a]pyridine-1-yl)-N-(6-(((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)amino)pyrimidine-4-yl)-2-methoxyacetamide(I-6); 3-(3-chlorophenyl)-N-(6-(((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)amino)pyrimidine-4-yl)-2-methylpropanamide(I-7); 3-(3-chlorophenyl)-N-(6-(((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)amino)pyrimidine-4-yl)propanamide(I-8); 2-((3-chlorophenyl)(methyl)amino)-N-(6-(((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)amino)pyrimidine-4-yl)propanamide(I-9); 2-(5-chloro-2-(1H-tetrazole-5-yl)phenyl)-N-(6-(((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)amino)pyrimidine-4-yl)acetamide(I-10); 4-Chloro-2-(2-((6-(((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)amino)pyrimidine-4-yl)amino)-2-oxoethyl)benzamide(I-11); 2-(7-chloroimidazo[1,5-a]pyridine-1-yl)-N-(6-(((6-cyclopropyl-8-(2-oxopyrrolidine-1-yl)imidazo[1,2-a]pyridine-2-yl)methyl)amino)pyrimidine-4-yl)acetamide(I-12); 2-(7-chloroimidazo[1,5-a]pyridine-1-yl)-N-(6-(((8-cyano-6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)amino)pyrimidine-4-yl)acetamide(I-13); 2-(7-chloroimidazo[1,5-a]pyridine-1-yl)-N-(6-(((6-cyclopropyl-8-(3-hydroxyoxetane-3-yl)imidazo[1,2-a]pyridine-2-yl)methyl)amino)pyrimidine-4-yl)acetamide(I-14); 2-(5-chloro-2-(1H-tetrazole-1-yl)phenyl)-N-(6-(((8-cyano-6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)amino)pyrimidine-4-yl)acetamide(I-15); 2-(7-chloroimidazo[1,5-a]pyridin-1-yl)-N-(2-(((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)amino)pyrimidine-4-yl)acetamide(I-16); 2-(7-chloroimidazo[1,5-a]pyridin-1-yl)-N-(6-(((6-cyclopropyl-8-(4-methylpiperazine-1-yl)imidazo[1,2-a]pyridin-2-yl)methyl)amino)pyrimidine-4-yl)acetamide(I-17); 2-(7-chloroimidazo[1,5-a]pyridine-1-yl)-N-(6-(((6-cyclopropyl-8-(2-oxopyrrolidine-1-yl)imidazo[1,2-a]pyridine-2-yl)methyl)(methyl)amino)pyrimidine-4-yl)acetamide(I-18); 2-(7-chloroimidazo[1,5-a]pyridin-1-yl)-N-(6-(((6-cyclopropyl-8-(3-fluorooxetane-3-yl)imidazo[1,2-a]pyridin-2-yl)methyl)amino)pyrimidine-4-yl)acetamide(I-19); 4-(2-(7-chloroimidazo[1,5-a]pyridine-1-yl)acetamide)-6-(((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)amino)pyrimidine-2-carboxylate ethyl(I-20); 4-(2-(7-chloroimidazo[1,5-a]pyridine-1-yl)acetamide)-6-(((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)amino)pyrimidine-2-carboxylic acid(I-21); 2-(7-chloroimidazo[1,5-a]pyridine-1-yl)-N-(6-((8-cyano-6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methoxy)pyrimidine-4-yl)acetamide(I-22); 2-(7-chloroimidazo[1,5-a]pyridine-1-yl)-N-(4-((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methoxy)pyridine-2-yl)acetamide(I-23); N-(4-(((6-cyclopropyl-8-(2-oxopyrrolidine-1-yl)imidazo[1,2-a]pyridine-2-yl)methyl)amino)pyridine-2-yl)-2-(3-fluoro-4-methoxypyridine-2-yl)acetamidoformate(I-24); N-(4-(((6-cyclopropyl-8-(2-oxopyrrolidine-1-yl)imidazo[1,2-a]pyridine-2-yl)methyl)amino)pyridine-2-yl)-2-(3-fluoro-4-methoxypyridine-2-yl)acetamide; 2-(7-chloroimidazo[1,5-a]pyridine-1-yl)-N-(4-(((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)amino)pyridine-2-yl)acetamidoformate(I-25); 2-(7-chloroimidazo[1,5-a]pyridine-1-yl)-N-(4-((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)amino)pyridine-2-yl)acetamide; 2-(5-chloro-1H-indazole-3-yl)-N-(4-(((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)amino)pyridine-2-yl)acetamide(I-26); 2-(6-chloro-1H-benzo[d][1,2,3]triazole-1-yl)-N-(4-(((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)amino)pyridine-2-yl)acetamide(I-27); 2-(6-chloro-1H-benzo[d]imidazole-1-yl)-N-(4-(((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)amino)pyridine-2-yl)acetamide(I-28); 1-Amino-N-(4-(((6-Cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)amino)pyridine-2-yl)-6,7-dihydro-5H-cyclopenta[c]pyridine-6-carboxamide(I-29); 2-(7-chloroimidazo[1,5-a]pyridine-1-yl)-N-(4-(((8-cyano-6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)amino)pyridine-2-yl)acetamide(I-30); 2-(7-chloroimidazo[1,5-a]pyridine-1-yl)-N-(5-(((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)amino)pyridazine-3-yl)acetamide(I-31); 2-(7-chloroimidazo[1,5-a]pyridin-1-yl)-N-(5-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methoxy)pyridazine-3-yl)acetamide(I-32); 2-(7-chloroimidazo[1,5-a]pyridine-1-yl)-N-(6-((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methoxy)pyrimidine-4-yl)acetamide(I-33); 2-(7-chloroimidazo[1,5-a]pyridine-1-yl)-N-(6-((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methoxy)pyridazine-4-yl)acetamide(I-34); 2-(5-chloro-2-(1H-tetrazole-1-yl)phenyl)-N-(6-(((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)amino)pyrimidine-4-yl)acetamide(I-35); 2-(6-amino-2-fluoro-3-methoxyphenyl)-N-(6-(((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)amino)pyrimidine-4-yl)acetamide(I-36); N-(6-(((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)amino)pyrimidine-4-yl)-2-(2-fluoro-3-methoxy-6-(1H-tetrazole-1-yl)phenyl)acetamidoformate(I-37); N-(6-(((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)amino)pyrimidine-4-yl)-2-(2-fluoro-3-methoxy-6-(1H)-tetrazole-1-yl)phenyl)acetamide; 3-(2-(((6-(2-(7-chloroimidazo[1,5-a]pyridine-1-yl)acetamide)pyrimidine-4-yl)amino)methyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-yl)propanoate ethyl(I-38); 3-(2-(((6-(2-(7-chloroimidazo[1,5-a]pyridine-1-yl)acetamide)pyrimidine-4-yl)amino)methyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-yl)propanoic acid (I-39); 3-(2-(((6-(2-(7-chloroimidazo[1,5-a]pyridine-1-yl)acetamide)pyrimidine-4-yl)amino)methyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-yl)-2,2-dimethylpropanoic acid (I-40); 2-(7-chloroimidazo[1,5-a]pyridin-1-yl)-N-(4-(((6-cyclopropyl-8-(hydroxymethyl)imidazo[1,2-a]pyridin-2-yl)methyl)amino)pyrimidine-5-yl)acetamide(I-41); 2-(7-chloroimidazo[1,5-a]pyridin-1-yl)-N-(4-(((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)amino)pyrimidine-5-yl)acetamide(I-42); 2-(7-chloroimidazo[1,5-a]pyridin-1-yl)-N-(4-(((6-cyclopropyl-5-fluoroimidazo[1,2-a]pyridin-2-yl)methyl)amino)pyrimidine-5-yl)acetamide(I-43); 2-(7-chloroimidazo[1,5-a]pyridine-1-yl)-N-(6-(((6-cyclopropyl-8-(hydroxymethyl)imidazo[1,2-a]pyridine-2-yl)methyl)amino)pyrimidine-4-yl)acetamidoformate(I-44); 2-(7-chloroimidazo[1,5-a]pyridin-1-yl)-N-(6-(((6-cyclopropyl-8-(hydroxymethyl)imidazo[1,2-a]pyridin-2-yl)methyl)amino)pyrimidine-4-yl)acetamide; 2-(7-chloroimidazo[1,5-a]pyridin-1-yl)-N-(6-((1-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)ethyl)amino)pyrimidine-4-yl)acetamide(I-45); 2-(7-chloroimidazo[1,5-a]pyridin-1-yl)-N-(6-(((6-cyclopropyl-5-fluoroimidazo[1,2-a]pyridin-2-yl)methyl)amino)pyrimidine-4-yl)acetamide(I-46); 3-(2-(((6-(2-(7-chloroimidazo[1,5-a]pyridine-1-yl)acetamide)pyrimidine-4-yl)amino)methyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-yl)-2,2-dimethylpropanoate ethyl(I-47); 2-(7-chloroimidazo[1,5-a]pyridin-1-yl)-N-(6-(((6-cyclopropyl-8-(morpholinomethyl)imidazo[1,2-a]pyridin-2-yl)methyl)amino)pyrimidine-4-yl)acetamide(I-48); 2-(3-chlorophenoxy)-N-(6-(((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)amino)pyrimidine-4-yl)propanamide formate (I-49); 2-(3-chlorophenoxy)-N-(6-(((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)amino)pyrimidine-4-yl)propanamide; (E)-3-(3-chlorophenyl)-N-(6-(((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)amino)pyrimidine-4-yl)acrylamide(I-50); 2-(2-bromo-5-chlorophenyl)-N-(6-(((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)amino)pyrimidine-4-yl)acetamide(I-51); 2-(7-chloroimidazo[1,5-a]pyridine-1-yl)-N-(4-(((6-cyclopropyl-8-(hydroxymethyl)imidazo[1,2-a]pyridine-2-yl)methyl)amino)pyridine-2-yl)acetamide(I-52); 2-(7-bromo-8-fluoroimidazo[1,5-a]pyridine-1-yl)-N-(6-(((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)amino)pyrimidine-4-yl)acetamide(I-53); 2-(7-chloroimidazo[1,5-a]pyridine-1-yl)-N-(6-(((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)amino)pyrimidine-4-yl)-2-oxoacetamide(I-54); N 4 -((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)-N 6 -(2-fluoro-3-methoxy-6-(1H-tetrazole-1-yl)benzyl)pyrimidine-4,6-diamine(I-55); N 5 -(6-(((6-Cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)amino)pyrimidine-4-yl)-6,7-dihydro-5H-cyclopenta[c]pyridine-1,5-diamine(I-56); 2-(7-chloroimidazo[1,5-a]pyridine-1-yl)-N-(6-(6-cyclopropylimidazo[1,2-a]pyridine-2-carbonyl)pyrimidine-4-yl)acetamide(I-58); 6-((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)difluoromethyl)-N-(2-fluoro-3-methoxy-6-(1H-tetrazole-1-yl)benzyl)pyrimidine-4-amine(I-62); (6-Cyclopropylimidazo[1,2-a]pyridine-2-yl)(6-((2-fluoro-3-methoxy-6-(1H-tetrazole-1-yl)benzyl)amino)pyrimidine-4-yl)methanol(I-63); (6-(((6-amino-2,4-dimethylpyridine-3-yl)methyl)amino)pyrimidine-4-yl)(6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methanol bisguate (I-64); (6-(((6-amino-2,4-dimethylpyridine-3-yl)methyl)amino)pyrimidine-4-yl)(6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methanol; N-((7-chloroimidazo[1,5-a]pyridine-1-yl)methyl)-6-(((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)amino)pyridazine-4-carboxamide(I-65); N-((7-chloroimidazo[1,5-a]pyridine-1-yl)methyl)-6-((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methoxy)pyridazine-4-carboxamide(I-66); 2-(3-chlorophenyl)-N-(6-(((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)amino)pyrimidine-4-yl)cyclopropane-1-sulfonamide(I-67); 3-(((7-chloroimidazo[1,5-a]pyridine-1-yl)methyl)amino)-4-(((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)amino)cyclobuta-3-en-1,2-dione(I-68); 4-(((6-((6-chloroimidazo[1,2-a]pyridine-2-yl)methoxy)pyrimidine-4-yl)amino)methyl)-3,5-dimethylbenzimidoformate (I-69) 4-(((6-((6-chloroimidazo[1,2-a]pyridin-2-yl)methoxy)pyrimidine-4-yl)amino)methyl)-3,5-dimethylbenzimidoamide; 3-(4-((4-carbamimidol-2,6-dimethylbenzyl)amino)-6-((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methoxy)pyrimidine-2-yl)propanoate ethyl formate (I-70); 3-(4-((4-carbamimidyl-2,6-dimethylbenzyl)amino)-6-((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methoxy)pyrimidine-2-yl)propanoate ethyl; 4-(((6-((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methoxy)pyrimidine-4-yl)amino)methyl)-N-hydroxy-3,5-dimethylbenzimidoamide(I-71); 4-(((6-((6-Cyclopropylimidazo[1,2-a]pyridine-2-yl)methoxy)pyrimidine-4-yl)amino)methyl)-3,5-dimethylbenzimidoformate (I-72); 4-(((6-((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methoxy)pyrimidine-4-yl)amino)methyl)-3,5-dimethylbenzimidoamide; 3-(4-((6-Cyclopropylimidazo[1,2-a]pyridin-2-yl)methoxy)-6-((4-(N-Hydroxycarbamimidoyl)-2,6-dimethylbenzyl)amino)pyrimidine-2-yl)propanoate ethyl(I-73); 3-(4-((4-carbamimidol-2,6-dimethylbenzyl)amino)-6-((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methoxy)pyrimidine-2-yl)propanoate formate (I-74); 3-(4-((4-carbamimidol-2,6-dimethylbenzyl)amino)-6-((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methoxy)pyrimidine-2-yl)propanoic acid; 3-(4-((6-Cyclopropylimidazo[1,2-a]pyridin-2-yl)methoxy)-6-((4-(N-((Hexyloxy)carbonyl)carbamimidoyl)-2,6-dimethylbenzyl)amino)pyrimidine-2-yl)propanoate ethyl(I-75); ((4-(((6-((6-Cyclopropylimidazo[1,2-a]pyridine-2-yl)methoxy)pyrimidine-4-yl)amino)methyl)-3,5-dimethylphenyl)(imino)methyl)carbamate hexyl(I-76); 3-(4-((6-Cyclopropylimidazo[1,2-a]pyridin-2-yl)methoxy)-6-((4-(N-(ethoxycarbonyl)carbamimidoyl)-2,6-dimethylbenzyl)amino)pyrimidine-2-yl)propanoate ethyl(I-77); 3-(4-((6-Cyclopropylimidazo[1,2-a]pyridine-2-yl)methoxy)-6-((4-(N-Hydroxycarbamimidoyl)-2,6-dimethylbenzyl)amino)pyrimidine-2-yl)propanoate formate (I-78); 3-(4-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methoxy)-6-((4-(N-hydroxycarbamimidoyl)-2,6-dimethylbenzyl)amino)pyrimidine-2-yl)propanoic acid; 3-(4-((6-Cyclopropylimidazo[1,2-a]pyridin-2-yl)methoxy)-6-((4-(N-((Hexyloxy)carbonyl)carbamimidoyl)-2,6-dimethylbenzyl)amino)pyrimidine-2-yl)propanoic acid (I-79); 3-(4-((6-Cyclopropylimidazo[1,2-a]pyridin-2-yl)methoxy)-6-((4-(N-(ethoxycarbonyl)carbamimidoyl)-2,6-dimethylbenzyl)amino)pyrimidine-2-yl)propanoic acid (I-80); 4-((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methoxy)-6-((4-(N-hydroxycarbamimidoyl)-2,6-dimethylbenzyl)amino)pyrimidine-2-carboxylate ethyl(I-81); 4-((4-carbamimidol-2,6-dimethylbenzyl)amino)-6-((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methoxy)pyrimidine-2-carboxylate ethyl formate (I-82); 4-((4-carbamimidol-2,6-dimethylbenzyl)amino)-6-((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methoxy)pyrimidine-2-carboxylate ethyl; ((4-(((6-((6-Cyclopropylimidazo[1,2-a]pyridine-2-yl)methoxy)pyrimidine-4-yl)amino)methyl)-3,5-dimethylphenyl)(imino)methyl)carbamate ethyl(I-83); 4-((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methoxy)-6-((4-(N-hydroxycarbamimidoyl)-2,6-dimethylbenzyl)amino)pyrimidine-2-carboxylic acid (I-84); 4-((4-carbamimidol-2,6-dimethylbenzyl)amino)-6-((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methoxy)pyrimidine-2-carboxylate formate (I-85); 4-((4-carbamimidol-2,6-dimethylbenzyl)amino)-6-((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methoxy)pyrimidine-2-carboxylic acid; 4-((6-Cyclopropylimidazo[1,2-a]pyridine-2-yl)methoxy)-6-((4-(N-(ethoxycarbonyl)carbamimidoyl)-2,6-dimethylbenzyl)amino)pyrimidine-2-carboxylate ethyl(I-86); 4-((6-Cyclopropylimidazo[1,2-a]pyridine-2-yl)methoxy)-6-((4-(N-((Hexyloxy)carbonyl)carbamimidoyl)-2,6-dimethylbenzyl)amino)pyrimidine-2-carboxylate ethyl(I-87); 4-((6-Cyclopropylimidazo[1,2-a]pyridine-2-yl)methoxy)-6-((4-(N-(ethoxycarbonyl)carbamimidoyl)-2,6-dimethylbenzyl)amino)pyrimidine-2-carboxylic acid (I-88); 4-((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methoxy)-6-((4-(N-((hexyloxy)carbonyl)carbamimidoyl)-2,6-dimethylbenzyl)amino)pyrimidine-2-carboxylic acid (I-89); ((4-(((6-((6-Cyclopropylimidazo[1,2-a]pyridine-2-yl)methoxy)pyrimidine-4-yl)amino)methyl)3,5-dimethylbenzimidoamide)oxy)methylacetate(I-90); 4-(((6-((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methoxy)-2-(2H-tetrazole-5-yl)pyrimidine-4-yl)amino)methyl)-3,5-dimethylbenzimidoformate (I-91); 4-(((6-((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methoxy)-2-(2H-tetrazole-5-yl)pyrimidine-4-yl)amino)methyl)-3,5-dimethylbenzimidoamide; 3-(4-((4-carbamimidol-2,6-dimethylbenzyl)amino)-6-((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methoxy)pyrimidine-2-yl)-2,2-dimethylpropanoate formate (I-92); 3-(4-((4-carbamimidol-2,6-dimethylbenzyl)amino)-6-((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methoxy)pyrimidine-2-yl)-2,2-dimethylpropanoic acid; 3-(4-((4-carbamimidol-2,6-dimethylbenzyl)amino)-6-((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methoxy)pyrimidine-2-yl)-2,2-dimethylpropanoate ethyl formate (I-93); 3-(4-((4-carbamimidol-2,6-dimethylbenzyl)amino)-6-((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methoxy)pyrimidine-2-yl)-2,2-dimethylpropanoate ethyl; 2-(2-(((6-((4-carbamidoyl-2,6-dimethylbenzyl)amino)pyrimidine-4-yl)oxy)methyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-yl)ethyl acetate formate (I-94); 2-(2-(((6-((4-carbamidoyl-2,6-dimethylbenzyl)amino)pyrimidine-4-yl)oxy)methyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-yl)ethyl acetate; 2-(2-(((6-((4-carbamidoyl-2,6-dimethylbenzyl)amino)pyrimidine-4-yl)oxy)methyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-yl)acetate formate (I-95); 2-(2-(((6-((4-carbamidoyl-2,6-dimethylbenzyl)amino)pyrimidine-4-yl)oxy)methyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-yl)acetic acid; 3-(2-(((6-((4-carbamidoyl-2,6-dimethylbenzyl)amino)pyrimidine-4-yl)oxy)methyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-yl)propanoate ethyl(I-96); 3-(2-(((6-((4-carbamidoyl-2,6-dimethylbenzyl)amino)pyrimidine-4-yl)oxy)methyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-yl)propanoate formate (I-97); 3-(2-(((6-((4-carbamidoyl-2,6-dimethylbenzyl)amino)pyrimidine-4-yl)oxy)methyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-yl)propanoic acid; 4-(((5-(((6-Cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)amino)pyridazine-3-yl)amino)methyl)-3,5-dimethylbenzimidoformate (I-98); 4-(((5-(((6-Cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)amino)pyridazine-3-yl)amino)methyl)-3,5-dimethylbenzimidoamide; 4-(((6-(((6-Cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)amino)pyrimidine-4-yl)amino)methyl)-3,5-dimethylbenzimidoformate (I-99); 4-(((6-(((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)amino)pyrimidine-4-yl)amino)methyl)-3,5-dimethylbenzimidoamide; 2-(7-chloroimidazo[1,5-a]pyridin-1-yl)-N-(6-(((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)amino)-2-(2-methoxyethoxy)pyrimidine-4-yl)acetamide(I-100); 2-(7-chloroimidazo[1,5-a]pyridine-1-yl)-N-(6-(((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)amino)-2-(trifluoromethyl)pyrimidine-4-yl)acetamide(I-101); N-(2-acetyl-6-(((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)amino)pyrimidine-4-yl)-2-(7-chloroimidazo[1,5-a]pyridine-1-yl)acetamide(I-102); 2-(7-chloroimidazo[1,5-a]pyridine-1-yl)-N-(6-(((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)amino)-2-(1-hydroxyethyl)pyrimidine-4-yl)acetamide(I-103); 2-(6-chloroquinazolin-4-yl)-N-(6-(((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)amino)pyrimidine-4-yl)acetamide(I-104); 2-(7-chlorophthalazine-1-yl)-N-(6-(((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)amino)pyrimidine-4-yl)acetamide(I-105); 2-(7-chloro-8-fluoroimidazo[1,5-a]pyridine-1-yl)-N-(6-(((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)amino)pyrimidine-4-yl)-2-hydroxypropanamide(I-106); N-((6-amino-2,4-dimethylpyridine-3-yl)methyl)-6-((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methoxy)pyrimidine-4-amine(I-107); N-(4-(aminomethyl)-2,6-dimethylbenzyl)-6-((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methoxy)pyrimidine-4-amine(I-108); N-((6-amino-2,4-dimethylpyridine-3-yl)methyl)-6-((6-cyclopropyl-8-(3-fluorooxetane-3-yl)imidazo[1,2-a]pyridine-2-yl)methoxy)pyrimidine-4-amine(I-109); 5-(((4-((6-Cyclopropylimidazo[1,2-a]pyridine-2-yl)methoxy)pyridine-2-yl)amino)methyl)-4,6-dimethylpyridine-2-amine(I-110); N 4 -((6-amino-2,4-dimethylpyridine-3-yl)methyl)-N6-((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)pyrimidine-4,6-diamine(I-111); 2-(((6-(((6-amino-2,4-dimethylpyridine-3-yl)methyl)amino)pyrimidine-4-yl)oxy)methyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-carbonitrilate formate (I-112); 2-(((6-(((6-amino-2,4-dimethylpyridine-3-yl)methyl)amino)pyrimidine-4-yl)oxy)methyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-carbonitrile; (2-(((6-(((6-amino-2,4-dimethylpyridine-3-yl)methyl)amino)pyrimidine-4-yl)oxy)methyl)6-cyclopropylimidazo[1,2-a]pyridine-8-yl)methanol formate (I-113); (2-(((6-(((6-amino-2,4-dimethylpyridine-3-yl)methyl)amino)pyrimidine-4-yl)oxy)methyl)6-cyclopropylimidazo[1,2-a]pyridine-8-yl)methanol; (E)-3-(3-chlorophenyl)-N-(4-(((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)amino)pyridine-2-yl)acrylamide(I-114); 2-(6-chloro-1H-indole-1-yl)-N-(4-(((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)amino)pyridine-2-yl)acetamide(I-115); 2-(5-chloro-2-(1H-tetrazole-1-yl)phenoxy)-N-(4-(((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)amino)pyridine-2-yl)acetamide(I-116); 2-((5-chloro-2-(1H-tetrazole-1-yl)phenyl)amino)-N-(4-(((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)amino)pyridine-2-yl)acetamide(I-117); 7-Chloro-N-(4-(((6-Cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)amino)pyridine-2-yl)-2-naphthamide(I-118); 2-(5-chloro-2-oxopyridine-1(2H)-yl)-N-(6-(((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)amino)pyrimidine-4-yl)acetamide(I-119); 7-Chloro-N-(4-(((6-Cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)amino)pyridine-2-yl)-1,2,3,4-tetrahydronaphthalene-2-carboxamide(I-120); N-(6-(((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)amino)pyrimidine-4-yl)-2-(5-methoxy-2-oxopyridine-1(2H)-yl)acetamide(I-121); N-(6-(((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)amino)pyrimidine-4-yl)-2-(5-methoxy-2-oxobenzo[d]oxazole-)3(2H)-yl)acetamide(I-122); 2-(5-chloro-2-oxobenzo[d]oxazole-3(2H)-yl)-N-(6-(((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)amino)pyrimidine-4-yl)acetamide(I-123); 2-(5-chloro-2-oxobenzo[d]oxazole-3(2H)-yl)-N-(4-(((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)amino)pyridine-2-yl)acetamide(I-124); N-(4-(((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)amino)pyridine-2-yl)-2-(5-methoxy-2-oxobenzo[d]oxazole-3(2H)-yl)acetamide(I-125); 2-(1-(3-chlorophenyl)cyclopropyl)-N-(4-(((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)amino)pyridine-2-yl)acetamide(I-126); 2-(3-chloro-1-(4-(((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)amino)pyridine-2-yl)-6-fluoro-1H-indole-5-yl)acetamide(I-127); (E)-1-(3-chlorobenzyl)-2-cyano-3-(4-(((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)amino)pyridine-2-yl)guanidine(I-128); 2-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-(6-(((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)amino)pyrimidine-4-yl)acetamide(I-129) 2-(3-chloro-1H-pyrrolo[2,3-b]pyridine-5-yl)-N-(4-(((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)amino)pyridine-2-yl)acetamide(I-130); 2-(3-chloro-6-fluoro-1H-indole-5-yl)-N-(6-(((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)amino)pyrimidine-4-yl)acetamide(I-131); 2-(3-chloro-6-fluoro-1H-indole-5-yl)-N-(4-(((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)amino)pyridine-2-yl)acetamide(I-132); (2S,3R)-3-(3-chlorophenyl)-N-(6-(((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)amino)pyrimidine-4-yl)-2-methylbutanamide(I-133); (2R,3S)-3-(3-chlorophenyl)-N-(6-(((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)amino)pyrimidine-4-yl)-2-methylbutanamide(I-134); (3S,5R)-1-(6-(((6-amino-2,4-dimethylpyridine-3-yl)methyl)amino)pyrimidine-4-yl)-5-(6-cyclopropylimidazo[1,2-a]pyridine-2-yl)pyrrolidine-3-ol(I-135); N 4-((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)-N6-(2,4-dimethoxybenzyl)pyrimidine-4,6-diamine(I-136); (3S,5R)-1-(6-(((3-chloro-1H-pyrrolo[2,3-b]pyridine-5-yl)methyl)amino)pyrimidine-4-yl)-5-(6-cyclopropylimidazo[1,2-a]pyridine-2-yl)pyrrolidine-3-ol(I-137); N 4 -(((1S,2S)-2-(3-chlorophenyl)cyclopropyl)methyl)-N6-((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)pyrimidine-4,6-diamine(I-138); (3S,5R)-1-(6-(((3-chloro-6-fluoro-1H-indole-5-yl)methyl)amino)pyrimidine-4-yl)-5-(6-cyclopropylimidazo[1,2-a]pyridine-2-yl)pyrrolidine-3-ol(I-139); (3S,5R)-5-(6-cyclopropylimidazo[1,2-a]pyridine-2-yl)-1-(6-(((6-fluoro-1H-indole-5-yl)methyl)amino)pyrimidine-4-yl)pyrrolidine-3-ol(I-140); 2-(3-chloroimidazo[1,5-b]pyridazin-5-yl)-N-(6-(((6-cyclopropyl-8-(3-methyl-2,4-dioxoimidazolidine-1-yl)imidazo)[1,2-a]pyridin-2-yl)methyl)amino)pyrimidine-4-yl)acetamide(I-141); or 2-(3-chlorophenyl)-N-(6-(((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)amino)pyrimidine-4-yl)cyclopropane-1-sulfonimidoamide (I-142), or a pharmaceutically acceptable salt thereof.

[0164] Compounds expressly disclosed herein, including those without reference to stereochemistry, may be claimed as individual compounds.

[0165] In some embodiments, the present invention provides compounds selected from the following: [ka] [ka] [ka] or a pharmaceutically acceptable salt thereof.

[0166] In another embodiment, the present invention provides compounds selected from the following: [ka] or a pharmaceutically acceptable salt thereof.

[0167] In some embodiments, compounds I-1 to I-161 are understood to show improvement compared to a reference compound. In some embodiments, the reference compound is a PKa inhibitor known in the art. In some embodiments, the reference compound is a PKa inhibitor selected from the compounds disclosed in PCT Publication WO2019 / 178129.

[0168] In some embodiments, the present invention also provides methods for using compounds I-1 to I-161.

[0169] C. Pharmaceutical Compositions In another embodiment, the present invention provides a compound of the present disclosure comprising formulas (I) to (VIII-c) or compounds I-57, I-59 to I-61, or I-153, or a combination of a compound of formulas (I) to (VIII-c) or compounds I-57, I-59 to I-61, or I-153 with a pharmaceutically acceptable excipient (e.g., a carrier).

[0170] The pharmaceutical composition comprises optical isomers, diastereomers, or pharmaceutically acceptable salts of the inhibitors disclosed herein. Compounds of formulas (I) to (VIII-c) or compounds I-57, I-59 to I-61, or I-153 contained in the pharmaceutical composition may be covalently bonded to the carrier portion as described above. Alternatively, compounds of formulas (I) to (VIII-c) or compounds I-57, I-59 to I-61, or I-153 contained in the pharmaceutical composition may not be covalently bonded to the carrier portion.

[0171] As used herein, “pharmaceutically acceptable carrier” refers to a pharmaceutically acceptable organic or inorganic carrier substance that does not react adversely with the active agent, for example, a pharmaceutically acceptable organic or inorganic carrier substance suitable for enteral or parenteral administration. Suitable pharmaceutically acceptable carriers include water, salt solutions (e.g., Ringer's solution), alcohol, oil, gelatin, and carbohydrates such as lactose, amylose, or starch, fatty acid esters, hydroxymethylcellulose, and polyvinylpyrrolidine. Such preparations may be sterilized and, if necessary, mixed with adjuvants such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts to affect osmotic pressure, buffers, colorants, and / or fragrances that do not react adversely with the compounds of the present invention.

[0172] The compounds of the present invention can be administered to a subject alone or simultaneously. Simultaneous administration means administering the compounds individually or in combination (two or more compounds) simultaneously or sequentially. The preparations may also be combined with other active agents as needed (for example, to reduce metabolic degradation).

[0173] In some embodiments, compounds such as those described herein may be incorporated into pharmaceutical compositions for administration by methods known to those skilled in the art and by methods described herein for the compounds provided.

[0174] D. Formulation The compounds of the present invention can be prepared and administered in a wide variety of oral, parenteral, and topical dosage forms. Therefore, the compounds of the present invention can be administered by injection (e.g., intravenously, intramuscularly, intradermally, subcutaneously, intraduodenically, or intraperitoneally). In some embodiments, the compounds of the present disclosure are administered orally. Furthermore, the compounds described herein can be administered by inhalation, for example, intranasally. In addition, the compounds of the present invention can be administered percutaneously. It is also conceivable that multiple routes of administration (e.g., intramuscularly, orally, percutaneously) may be used to administer the compounds of the present invention. Accordingly, the present invention also provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier or excipient and one or more compounds of the present invention.

[0175] For preparing pharmaceutical compositions from the compounds of the present invention, pharmaceutically acceptable carriers may be solid or liquid. Examples of solid preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. The solid carrier may be one or more substances that can also function as diluents, flavoring agents, binders, preservatives, tablet disintegrants, or encapsulating materials.

[0176] In the powder form, the carrier is a micronized solid in a mixture with the micronized active ingredient. In the tablet form, the active ingredient is mixed in a suitable ratio with a carrier having the required binding properties and compressed into the desired shape and size.

[0177] Powders and tablets preferably contain 5% to 70% of the active compound. Suitable carriers include magnesium carbonate, magnesium stearate, talc, sugars, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, low-melting-point waxes, and cocoa butter. The term “preparation” is intended to include formulations of the active compound with encapsulating material as a carrier, in which the active ingredient is surrounded by a carrier, either with or without other carriers, thereby providing a capsule in which the carrier associates with the active ingredient. Similarly, cachets and licks are included. Tablets, powders, capsules, pills, cachets, and licks can be used as solid dosage forms suitable for oral administration.

[0178] To prepare the suppositories, a mixture of low-melting-point waxes, such as fatty acid glycerides or cocoa butter, is first melted, and the active ingredients are uniformly dispersed therein by stirring or other means. The melted homogeneous mixture is then poured into a mold of a convenient size and allowed to cool, thereby solidifying.

[0179] Liquid preparations include solutions, suspensions, and emulsions, such as water or water / propylene glycol solutions. In the case of parenteral injections, the liquid preparation may be formulated as a solution of polyethylene glycol aqueous solution.

[0180] When parenteral administration is necessary or desirable, particularly suitable mixtures for the compounds of the present invention include injectable sterile solutions, preferably oily or aqueous solutions, as well as implants comprising suspensions, emulsions, or suppositories. In particular, suitable carriers for parenteral administration include aqueous dextrose, physiological saline, pure water, ethanol, glycerol, propylene glycol, peanut oil, sesame oil, and polyoxyethylene block polymers. Ampoules provide a convenient unit dose. The compounds of the present invention may also be incorporated into liposomes or administered via transdermal pumps or patches. Suitable pharmaceutical mixtures for use in the present invention include, for example, those described in Pharmaceutical Sciences (17th Ed., Mack Pub. Co., Easton, PA) and WO96 / 05309, both of which are incorporated herein by reference.

[0181] Aqueous solutions suitable for oral use can be prepared by dissolving the active ingredient in water and, if desired, adding suitable colorants, flavorings, stabilizers, and thickeners. Aqueous suspensions suitable for oral use can be prepared by dispersing the pulverized active ingredient in water with a viscous material, such as natural or synthetic gum, resin, methylcellulose, sodium carboxymethylcellulose, and other well-known suspending agents.

[0182] This also includes solid formulations intended to be converted into liquid formulations for oral administration immediately before use. Such liquid forms include solutions, suspensions, and emulsions. These preparations may contain, in addition to the active ingredient, colorants, flavorings, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solvents, and the like.

[0183] Pharmaceutical preparations are preferably in unit dosage forms. In such a form, the preparation is subdivided into unit doses containing an appropriate amount of the active ingredient. A unit dosage form may be a packaged preparation, the package containing individual amounts of the preparation, for example, packaged tablets, capsules, and powder in vials or ampoules. Alternatively, a unit dosage form may be a capsule, tablet, cachet, or lozenge itself, or it may be any appropriate number of such in package form.

[0184] The amount of the active ingredient in a unit dose formulation may be changed or adjusted depending on the specific use and potency of the active ingredient. The composition may also contain other suitable therapeutic agents as needed.

[0185] Some compounds may have limited solubility in water and therefore may require a surfactant or other suitable co-solvent in the composition. Examples of such co-solvents include: polysorbates 20, 60, and 80; Pluronic F-68, F-84, and P-103; cyclodextrin; and polyoxyl 35 castor oil. Such co-solvents are typically used at levels ranging from about 0.01% to about 2% by weight.

[0186] To reduce variability during the distribution of a formulation, to decrease the physical separation of components in the suspension or emulsion formulation, and / or to improve the formulation in other ways, a viscosity higher than that of a simple aqueous solution may be desirable. Examples of such viscosity-increasing agents include polyvinyl alcohol, polyvinylpyrrolidone, methylcellulose, hydroxypropyl methylcellulose, hydroxyethylcellulose, carboxymethylcellulose, hydroxypropylcellulose, chondroitin sulfate and its salts, hyaluronic acid and its salts, and combinations thereof. Such agents are typically used at levels between about 0.01% by weight and about 2% by weight.

[0187] The compositions of the present invention may further contain components that provide sustained release and / or comfort. Such components include high molecular weight anionic mucus-mimicking polymers, gelling polysaccharides, and micronized drug carrier substrates. These components are described in more detail in U.S. Patents 4,911,920; 5,403,841; 5,212,162; and 4,861,760. All of the contents of these patents are incorporated herein by reference in their entirety for all purposes.

[0188] E. Effective dose The pharmaceutical compositions provided by the present invention include compositions in which the active ingredient is contained in a therapeutically effective amount, i.e., an amount effective to achieve its intended use. The actual amount effective for a particular use depends particularly on the disease condition to be treated. For example, when administered in a method for treating HAE, such a composition contains an amount of the active ingredient effective to achieve the desired result (e.g., inhibiting pKa in the subject and / or reducing the amount of bradykinin).

[0189] The dose and frequency of administration of the compound (single or multiple doses) may vary depending on various factors, including the route of administration; the recipient's size, age, sex, health status, weight, body mass index, and diet; the nature and severity of the symptoms of the disease to be treated (e.g., a disease that responds to pKa inhibition); the presence of other diseases or other health-related problems; the type of concomitant therapy; and complications from any disease or treatment plan. Other treatment plans or agents may be used in conjunction with the methods and compounds of the present invention.

[0190] For any provided compound or test agent, the therapeutically effective dose can first be determined by a cell culture assay. The target concentration is the concentration of the active compound(s) that can reduce pKa enzyme activity, as measured, for example, using the method described.

[0191] The therapeutically effective dose used in humans can be determined from animal models. For example, the human dose can be formulated to achieve a concentration that has been found to be effective in animals. The human dose can be adjusted, as described above, by monitoring pKa inhibition and adjusting the dose upward or downward.

[0192] The dosage may vary depending on the patient and the requirements of the compound used. In relation to the present invention, the dose administered to the patient must be sufficient to produce a beneficial therapeutic response in the patient over time. The size of the dose is also determined by the presence, nature, and degree of any adverse side effects.

[0193] In one embodiment, the compounds provided herein exhibit one or more improved pharmacokinetic (PK) properties (e.g., C) compared to a reference compound. max t max , C min t 1 / 2It exhibits (AUC, CL, bioavailability, etc.). In some embodiments, the reference compound is a PKa inhibitor known in the art. In some embodiments, the reference compound is a PKa inhibitor selected from the compounds disclosed in PCT Publication WO2019 / 178129.

[0194] In some embodiments, the compounds of the present disclosure or pharmaceutical compositions containing them are provided as unit doses.

[0195] F. Treatment method This disclosure provides compounds and pharmaceutical compositions containing them for use in medicine, i.e., for therapeutic use. This disclosure further provides the use of any of the compounds described herein to inhibit pKa activity, which is beneficial for the treatment of pKa-mediated diseases and conditions. An example of a pKa-mediated disorder is edema, which refers to swelling of the whole body or part thereof in a subject resulting from inflammation or injury when small blood vessels become leaky and release fluid into surrounding tissues. In some embodiments, edema is HAE. In other embodiments, edema occurs in the eye (e.g., diabetic macular edema (DME)). This disclosure provides methods for inhibiting pKa activity. In certain embodiments, this application provides a method for inhibiting pKa activity in vitro by contacting any of the compounds described herein with pKa molecules in a sample, e.g., a biological sample. In certain embodiments, this application provides a method for inhibiting pKa activity in vivo by delivering an effective amount of any of the compounds described herein to a subject in need of treatment via an appropriate route.

[0196] In certain embodiments, the method includes administering one of the compounds described herein or a pharmaceutically acceptable salt thereof to a subject in need (e.g., a human patient with edema). In certain embodiments, the method includes administering a compound of formulas (I) to (VIII-c), or compound I-57, I-59 to I-61, or I-153, or a pharmaceutically acceptable salt or composition thereof, to a subject in need. In some embodiments, the method includes administering a pharmaceutical composition containing a compound of formulas (I) to (VIII-c), or compound I-57, I-59 to I-61, or I-153, or a pharmaceutically acceptable salt thereof, to a subject in need.

[0197] In certain embodiments, the subjects treated by any of the methods described herein are human patients who have, are suspected of having, or are at risk of having edema, such as HAE or diabetic macular edema (DME). Subjects with edema may be identified by routine medical tests, such as clinical tests. Subjects suspected of having edema may exhibit one or more symptoms of the disease / disorder. Subjects at risk of edema may have one or more disease-related risk factors, such as C1-INH deficiency for HAE.

[0198] In certain embodiments, methods for alleviating one or more symptoms of HAE in human patients suffering from HAE attacks are provided herein. Such patients may be identified by routine medical procedures. One or more effective doses of the compounds provided may be administered to the human patient by a preferred route, for example, the routes described herein. The compounds described herein may be used alone or in combination with other anti-HAE agents, such as C1 esterase inhibitors (e.g., Cinryze® or Berinert®), pKa inhibitors (e.g., ecalantide or lanadermab), or bradykinin B2 receptor antagonists (e.g., Firazyr®).

[0199] In other embodiments, this specification provides a method for reducing the risk of HAE attacks in human HAE patients in a sedated state. Such patients may be identified based on various factors, including a history of HAE attacks. One or more effective amounts of the compounds of the present invention can be administered to human patients by a preferred route, for example, the routes described herein. The compounds described herein may be used alone or in combination with other anti-HAE agents, such as C1 esterase inhibitors (e.g., Cinryze® or Berinert®), pKa inhibitors (e.g., ecalantide or lanadermab), or bradykinin B2 receptor antagonists (e.g., Firazyr®).

[0200] In some embodiments, this specification provides prophylactic treatment for HAE in human patients at risk of HAE attacks using one or more of the compounds described herein. In some embodiments, patients suitable for prophylactic treatment for HAE are human subjects who have HAE (e.g., have a history of HAE attacks). In some embodiments, patients suitable for such prophylactic treatment are human subjects for whom a physician determines that a prophylactic approach is justified due to a history of HAE attacks (e.g., human subjects who have experienced more than a certain average number of attacks over a period of time, including one, two, or more attacks per month, but not limited to these). Alternatively, patients suitable for prophylactic treatment may be human subjects who do not have a history of HAE attacks but have one or more risk factors for HAE (e.g., a family history, a genetic defect in the C1-INH gene, etc.). Such prophylactic treatment may require one of the compounds described herein as the sole active agent, or it may require additional anti-HAE agents, e.g., the agents described herein.

[0201] In certain embodiments, this specification provides methods for preventing or reducing edema in the eye of a subject (e.g., a human patient). In some embodiments, the human patient is a diabetic patient who has, is suspected of having, or is at risk of having diabetic macular edema (DME). DME is a proliferative diabetic retinopathy characterized by swelling of the retinal layer, neovascularization, vascular leakage, and retinal thickening, resulting from leakage of fluid from blood vessels in the macula. To carry out the method, an effective amount of one or more of the compounds described herein or a pharmaceutically acceptable salt thereof may be delivered to the eye of a subject requiring treatment. For example, the compounds may be delivered locally by intraocular injection or intravitreal injection. The compounds described herein may be used to treat the subject either as the sole active agent or in combination with another method for treating DME. Non-exclusive examples of treatments for DME include laser photocoagulation, steroids, drugs targeting the VEGF pathway (e.g., Lucentis® (ranibizumab) or Eylea® (aflibercept)), and / or anti-PDGF agents.

[0202] In certain embodiments, the methods disclosed herein involve administering an effective amount of a compound of formulas (I) to (VIII-c), or compounds I-57, I-59 to I-61, or I-153, or a pharmaceutically acceptable salt or composition thereof, to a target. In some embodiments, the effective amount is a therapeutic effective amount. In some embodiments, the effective amount is a prophylactic effective amount.

[0203] In certain embodiments, the subject to be treated is an animal. The animal may be of any sex and at any developmental stage. In certain embodiments, the subject is a mammal. In certain embodiments, the subject to be treated is a human. In certain embodiments, the subject is a 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 other embodiments, the subject is a research animal, such as a rodent (e.g., mouse, rat), dog, pig, or non-human primate. In certain embodiments, the animal is a genetically modified animal. In certain embodiments, the animal is a transgenic animal.

[0204] Certain methods described herein may include administering one or more additional pharmaceuticals in combination with the compounds described herein. The additional pharmaceuticals may be administered simultaneously with the compounds of formulas (I) to (VIII-c) or compounds I-57, I-59 to I-61, or I-153, or at a different time than the compounds of formulas (I) to (VIII-c) or compounds I-57, I-59 to I-61, or I-153. For example, the compounds of formulas (I) to (VIII-c) or compounds I-57, I-59 to I-61, or I-153 and any additional pharmaceuticals may be administered on the same or different schedules. All or part doses of the compounds of formulas (I) to (VIII-c) or compounds I-57, I-59 to I-61, or I-153 may be administered before all or part doses of the additional drug, after all or part doses of the additional drug, within the administration schedule of the additional drug, or in combination thereof. The timing of administration of the compounds of formulas (I) to (VIII-c) or compounds I-57, I-59 to I-61, or I-153 and the additional drug may vary depending on the additional drug.

[0205] Furthermore, this specification also provides the use of the compounds disclosed herein for the manufacture of agents for the conditions / diseases disclosed herein.

[0206] In certain embodiments, additional pharmaceuticals include agents useful for treating edema, such as HAE or DME. Examples of such agents are provided herein.

[0207] In this specification, “comprising” should be interpreted as “including.” Embodiments of the present invention that include certain features / elements are also intended to be extended to alternative embodiments that “consist” or “consisting essentially” of the relevant elements / elements. Where technically appropriate, embodiments of the present invention may be combined.

[0208] Technical references, such as patents and applications, are incorporated herein by reference.

[0209] Any embodiment described specifically and expressly herein may, alone or in combination with one or more further embodiments, form the basis of a disclaimer.

[0210] The background information section of this specification contains relevant technical information that may be used as a basis for modifications. Subject headings in this specification are used to divide the document into sections and are not intended to be used to interpret the meaning of the disclosures provided herein.

[0211] This Specified Use Claims Priority to U.S. Provisional Application No. 63 / 162,477 (filed March 17, 2021), which is incorporated herein by reference. This application may be used as the basis for modifications to this Specified Use, particularly with respect to the chemical structures disclosed herein. [Examples]

[0212] In certain embodiments, the examples describe compounds containing one or more stereocenters, where the particular stereocenter is "S * " or "R * It is indicated by ". In both cases, * The notation " " generally indicates that the exact arrangement is unknown (for example, in the case of a compound with a single stereocenter, R * - or S * The hyphen indicates that either an R-isomer or an S-isomer was isolated, but the stereocenter configuration of the specific isomer was not determined.

[0213] It will be understood that the compounds described in the examples may contain multiple stereocenters. As stated above, single stereoisomers of the compounds of the present invention, as well as enantiomer mixtures, diastereomer mixtures, and geometric (or conformational) mixtures, are within the scope of the present invention. In a specific compound name, multiple "S"s are enclosed in a pair of parentheses. * " or "R * When " is shown (for example, "(1S * ,2S * )」)、 S * and / or R * It is understood that the components are relative to each other. For example, "(1S * ,2S * )-" or "(1R * ,2R * Compounds indicated by "-" specifically refer to either the "(1S,2S)-" or "(1R,2R)-" isomer, but it should be understood that the "(1S,2R)-" or "(1R,2S)-" isomer is not included. Furthermore, "rac-(1S * ,2S * )-" or "rac-(1R * ,2R * Compounds indicated by "-" will be understood to contain a racemic mixture of "(1S,2S)-" and "(1R,2R)-" isomers. Similarly, "(1S * ,2R * )-" or "(1R * ,2S *Compounds indicated by "-" specifically refer to either the "(1R,2S)-" or "(1S,2R)-" isomer, but it should be understood that the "(1S,2S)-" or "(1R,2R)-" isomer is not included. Furthermore, "rac-(1R * ,2S * )-" or "rac-(1S * ,2R * Compounds indicated by "-" will be understood to include a racemic mixture of "(1R,2S)-" and "(1S,2R)-" isomers.

[0214] In certain embodiments, the examples include schemes showing compounds having one or more stereocenters. In some embodiments, a number is indicated adjacent to the stereocenter after the symbol "&". In such cases, it is understood that mixtures (e.g., racemic mixtures) of both stereoisomers (e.g., R- and S-) at that position are included.

[0215] In some embodiments, the term "or" is followed by a number adjacent to the stereocenter. In such cases, it is understood to represent either the "R-" or "S-" isomer, but no specific isomer has been determined.

[0216] Synthesis of intermediates Synthesis of 2-(7-chloroimidazo[1,5-a]pyridine-1-yl)acetic acid [ka] Synthesis of N-((4-chloropyridine-2-yl)methylene)-2-methylpropane-2-sulfinamide. To a stirred suspension of (S)-2-methylpropane-2-sulfinamide (5 g, 41.3 mmol) and CS2CO3 (20.16 g, 61.9 mmol) in DCM (100 mL), a solution of 4-chloropicoline aldehyde (5.84 g, 41.3 mmol) in DCM (20 mL) was added dropwise over 10 minutes at room temperature. The solution was stirred for 2 hours. The reaction mixture was then diluted with water (100 mL) and extracted with DCM (3 × 100 mL). The combined organic layer was dried over MgSO4 and concentrated to obtain the title compound (10.1 g) as a brown oil, which was used in the next step without further purification. ESI-MS (M+H)+: 246.9.

[0217] Synthesis of 3-((tert-butylsulfinyl)amino)-3-(4-chloropyridine-2-yl)propanoate. To a stirred solution of LDA (2M in THF, 43 mL, 86 mmol) in anhydrous THF (100 mL), a solution of butyl acetate (9.4 g, 81 mmol) in THF (20 mL) was added dropwise at -78°C under a nitrogen atmosphere. After stirring for 30 minutes, a solution of N-((4-chloropyridine-2-yl)methylene)-2-methylpropane-2-sulfinamide (10.0 g, 40.98 mmol) in THF (30 mL) was added at the same temperature. After stirring for a further 2 hours at -78°C, the reaction mixture was quenched with saturated ammonium chloride (100 mL) and warmed to room temperature. The organic layer was separated, and the aqueous layer was extracted with RINKAN (3 × 100 mL). The combined organic layers were dried over Na2SO4, concentrated, and purified by column chromatography (PE:siRNA=50:50) to obtain the title compound (9.0 g, 61%) as a white solid. ESI-MS (M+H) + : 361.

[0218] Synthesis of butyl 3-amino-3-(4-chloropyridine-2-yl)propanoate. To a solution of 3-((tert-butylsulfinyl)amino)-3-(4-chloropyridine-2-yl)propanoic acid (3.5 g, 9.7 mmol) in dioxane (30 mL), HCl solution (4 M in dioxane, 10 mL, 40 mmol) was added. The mixture was stirred at room temperature for 4 hours, then concentrated to obtain the title compound as a crude oil (4.3 g), which was used in the next step without purification. ESI-MS (M+H) + : 257.

[0219] Synthesis of butyl 3-(4-chloropyridine-2-yl)-3-formamidepropanoate. A solution of butyl 3-amino-3-(4-chloropyridine-2-yl)propanoate (2.6 g, 10.2 mmol) in formic acid (10 mL) was stirred under reflux for 4 hours. The reaction mixture was then concentrated to obtain the title compound as a dark oily substance (3.0 g), which was used in the next step without purification. ESI-MS (M+H) + : 285.

[0220] Synthesis of 2-(7-chloroimidazo[1,5-a]pyridine-1-yl)butyl acetate. A solution of 3-(4-chloropyridine-2-yl)-3-formamidopropanoate butyl (500 mg, 1.76 mmol) in POCl3 (5 mL) was stirred at 80°C for 1 hour. The mixture was evaporated, the residue was dissolved in  (100 mL), and washed with saturated NaHCO3 solution (50 mL). The organic layer was separated, and the aqueous layer was extracted with  (3 × 50 mL). The combined organic layers were concentrated and purified by silica gel chromatography (PE: = 30:70) to obtain the title compound (290 mg, yield: 62%). ESI-MS (M+H) + : 267.

[0221] Synthesis of 2-(7-chloroimidazo[1,5-a]pyridin-1-yl)acetic acid. To a stirred solution of butyl 2-(7-chloroimidazo[1,5-a]pyridin-1-yl)acetate (310 mg, 1.16 mmol) in THF / H2O (3 / 1, 4 mL), LiOH (139 mg, 5.8 mmol) was added. The mixture was stirred at room temperature for 16 hours, then HCl aqueous solution (1 M) was added to adjust the pH to 6, and the mixture was extracted with DCM / MeOH (10 / 1, 5 × 50 mL). The combined organic layers were dried and concentrated to obtain the title compound (200 mg), which was used without further purification. ESI-MS (M+H) + : 211.

[0222] Synthesis of methyl 2-(7-chloroimidazo[1,5-a]pyridine-1-yl)acetate [ka] To a solution of cooled 2-(7-chloroimidazo[1,5-a]pyridine-1-yl)acetic acid (25 mg, 1.19 mmol) in MeOH (5 mL), acetyl chloride (0.42 mL, 5.93 mmol) was added at 0°C. The mixture was warmed to room temperature and stirred for 18 hours. The residue was treated with NaHCO3 (saturated aqueous solution, 25 mL) and water (25 mL), and extracted with 10% MeOH in DCM (3 × 50 mL). The combined organic phase was dried (MgSO4), filtered, and concentrated under vacuum to obtain the title compound (310 mg, quantitative), which was used without further purification. 1 H NMR (400 MHz, DMSO) δ 8.37 (s, 1H), 8.36 (d, J=0.8 Hz, 1H), 7.82 - 7.80 (m, 1H), 6.71 (dd, J=2.1, 7.5 Hz, 1H), 3.96 (s, 2H), 3.66 (s, 3H).

[0223] Synthesis of 2-(7-chloroimidazo[1,5-a]pyridine-1-yl)propanoic acid [ka] Synthesis of methyl 2-(7-chloroimidazo[1,5-a]pyridine-1-yl)propanoate. To a solution of methyl 2-(7-chloroimidazo[1,5-a]pyridine-1-yl)acetate (2.0 g, 8.9 mmol) in tetrahydrofuran (30 mL), lithium bis(trimethylsilyl)amide (1 M in THF, 9.8 mL, 9.8 mmol) was gradually added. The reaction mixture was stirred at room temperature for 2 hours. Iodomethane (1.39 g, 9.8 mmol) was added, and the mixture was stirred at ambient temperature for 2 hours. This reaction mixture was diluted with water and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with brine, dried on anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate in petroleum ether = 0-100%) to obtain the title compound (0.9 g, yield: 38.5%) as a yellow oil.

[0224] Synthesis of 2-(7-chloroimidazo[1,5-a]pyridine-1-yl)propanoic acid. A solution of methyl 2-(7-chloroimidazo[1,5-a]pyridine-1-yl)propanoate (0.9 g, 3.77 mmol) in tetrahydrofuran (15 mL), methanol (15 mL), and water (15 mL) was mixed with lithium hydroxide hydrate (186 mg, 7.54 mmol). The resulting reaction mixture was stirred at room temperature for 4 hours. After evaporation, the mixture was acidified to pH 4 with 1N HCl. The precipitate was filtered and dried under vacuum to obtain the title compound (560 mg, yield: 66%) as a yellow solid. 1 HNMR (400Hz, DMSO-d6) δ 12.30 (br, 1H), 8.32 (s, 1H), 8.31 (d, J = 6.4 Hz, 1H), 7.72 (t, J = 0.8 Hz, 1H), 6.65(dd, J = 7.2, 2.0 Hz, 1H), 4.10 (q, J = 7.2 Hz, 1H), 1.45 (d, J = 7.2 Hz, 3H).

[0225] Synthesis of 2-(7-chloroimidazo[1,5-a]pyridine-1-yl)-2-methylpropanoic acid [ka] Synthesis of methyl 2-(7-chloroimidazo[1,5-a]pyridine-1-yl)-2-methylpropanoate. Lithium bis(trimethylsilyl)amide (1M in THF, 22 mL, 22 mmol) was gradually added to a solution of methyl 2-(7-chloroimidazo[1,5-a]pyridine-1-yl)acetate (2.0 g, 8.9 mmol) in tetrahydrofuran (30 mL). The reaction mixture was stirred at room temperature for 2 hours. Iodomethane (3.16 g, 22.3 mmol) was added, and the mixture was stirred at ambient temperature for 2 hours. This reaction mixture was diluted with water and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with brine, dried on anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate in petroleum ether = 0-100%) to obtain the title compound (1.3 g, crude) as a yellow oil. ESI-MS (M+H) + : 253.1.

[0226] Synthesis of 2-(7-chloroimidazo[1,5-a]pyridin-1-yl)-2-methylpropanoic acid. A solution of methyl 2-(7-chloroimidazo[1,5-a]pyridin-1-yl)-2-methylpropanoate (1.25 g crude, 4.95 mmol) in tetrahydrofuran (15 mL), methanol (15 mL), and water (15 mL) was mixed with lithium hydroxide hydrate (415 mg, 9.89 mmol). The resulting reaction mixture was stirred at room temperature for 4 hours. After evaporation, the mixture was acidified to pH 4 with 1N HCl. The precipitate was filtered and dried under vacuum to obtain the title compound (300 mg) as a yellow solid. 1 1H NMR (400 Hz, DMSO-d6) δ values: 8.22 (m, 2H), 7.39 (m, 1H), 6.55 (m, 1H), 1.46 (s, 6H). No carboxylic acid protons were observed.

[0227] Synthesis of 2-(7-chloroimidazo[1,5-a]pyridine-1-yl)acetamide [ka] A mixture of 2-(7-chloroimidazo[1,5-a]pyridine-1-yl)acetic acid (2.0 g, 9.5 mmol), EDC (1.8 g, 11 mmol), HOBt (1.5 g, 11 mmol), DIPEA (9.9 mL, 57 mmol), and (NH4)2CO3 (4.6 g, 47 mmol) in THF (20 mL) and DMF (10 mL) was stirred at 60°C for 18 hours. The mixture was cooled and diluted with SiO2. The organic layer was washed with NaHCO3 (saturated aqueous solution) and brine (saturated aqueous solution). The combined aqueous layer was further extracted with a large amount of DCM. The combined organic layer was dried over (MgSO4), filtered, and concentrated under vacuum to obtain the title compound (0.80 g, 40%). ESI-MS (M+H) + : 210, 1 H NMR (400 MHz, DMSO) δ 8.37 - 8.32 (m, 2H), 7.78 (s, 1H), 7.40 (s, 1H), 6.97 (s, 1H), 6.70 - 6.65 (m, 1H), 3.66 (s, 2H).

[0228] The following intermediates were prepared using the same method as described above for 2-(7-chloroimidazo[1,5-a]pyridine-1-yl)acetamide, and the residue was purified by silica gel column chromatography eluting under a concentration gradient of 0-100% ethyl acetate in DCM to obtain the title compound. [Table 1]

[0229] Synthesis of 2-(7-chloroimidazo[1,5-a]pyridine-1-yl)perfluorophenyl acetate [ka] DCC (0.54 g, 2.6 mmol) was added to a stirred suspension of 2-(7-chloroimidazo[1,5-a]pyridine-1-yl)acetic acid (0.50 g, 2.4 mmol) in Depositphotos (25 mL). After 5 minutes, a solution of 2,3,4,5,6-pentafluorophenol (0.48 g, 2.6 mmol) in DMF (2.5 mL) was added, and the mixture was stirred at room temperature for 18 hours. The mixture was filtered and concentrated under vacuum. The residue was dissolved in Depositphotos and a small amount of Et2O was added. The mixture was filtered and concentrated under vacuum. The residue was purified by silica gel column chromatography eluted with 20-80% Depositphotos in isohexane. The residue was pulverized with isohexane and dried to obtain the title compound (0.45 g, 51%). 1 H NMR (400 MHz, DMSO) δ 8.45 (s, 1H), 8.41 (d, J=7.3 Hz, 1H), 7.97 - 7.94 (m, 1H), 6.78 - 6.73 (m, 1H), 4.49 - 4.47 (m, 2H).

[0230] Synthesis of 2-(7-chloroimidazo[1,5-a]pyridine-1-yl)-2-hydroxyacetate methyl [ka] Synthesis of 2-(7-chloroimidazo[1,5-a]pyridine-1-yl)-2-((trimethylsilyl)oxy)acetonitrile. To a solution of 7-chloroimidazo[1,5-a]pyridine-1-carbaldehyde (4.5 g, 25.0 mmol, WO2019178129) in DCM (50 mL), trimethylsilyl cyanide (5 mL, 50.0 mmol) and zinc iodide (1.0 g, 2.5 mmol) were added, and the mixture was stirred overnight at room temperature. The reaction product was quenched with sodium bicarbonate and extracted with DCM (3 × 200 mL). The combined organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated to obtain the title compound (7.0 g, crude) as a brown solid, which was used without further purification. ESI-MS (M+H) + : 280.1.

[0231] Synthesis of 2-(7-chloroimidazo[1,5-a]pyridine-1-yl)-2-hydroxymethyl acetate. A mixture of 2-(7-chloroimidazo[1,5-a]pyridine-1-yl)-2-((trimethylsilyl)oxy)acetonitrile (6.0 g, 21.4 mmol) and hydrogen chloride (15 mL in methanol) was stirred at room temperature for 24 hours. The reaction mixture was quenched with water, the pH was adjusted to 8 with sodium bicarbonate, and extracted with dichloromethane (3 × 80 mL). The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain the crude product, which was purified by silica gel column chromatography using ethyl acetate to obtain the title compound (1.0 g, 60%) as a yellow solid. ESI-MS (M+H) + : 240.9, 1 H NMR (400Hz, DMSO) δ 8.36 (d, J = 7.2 Hz, 1H), 8.32 (s, 1H), 7.81(s, 1H), 6.72 (dd, J = 7.2, 2.0 Hz, 1H), 5.97 (d, J = 5.6 Hz, 1H), 5.50 (d, J = 5.6 Hz, 1H), 3.62 (s, 3H).

[0232] Synthesis of 2-(7-chloroimidazo[1,5-a]pyridine-1-yl)-2-methoxyacetamide [ka] Synthesis of 2-(7-chloroimidazo[1,5-a]pyridine-1-yl)-2-methoxymethyl acetate. MeI (0.019 mL, 0.30 mmol) was added to a stirred mixture of 2-(7-chloroimidazo[1,5-a]pyridine-1-yl)-2-hydroxymethyl acetate (0.048 g, 0.20 mmol) and Ag2O (0.070 g, 0.30 mmol) in DCM (5.0 mL). The mixture was stirred at room temperature for 18 hours, and then MeI (0.019 mL, 0.30 mmol) was added. The mixture was stirred at room temperature for 2 hours, and then MeI (0.019 mL, 0.30 mmol) was added. The mixture was stirred at room temperature for 18 hours, and then MeI (0.13 mL, 2.0 mmol) was added in 6 portions over 8 hours. The mixture was filtered through Celite® and concentrated under vacuum. The residue was purified by silica gel column chromatography eluted with 1-5% MeOH in DCM to obtain the title compound (0.032 g, 62%) as a yellow gum-like substance. 1 H NMR (400 MHz, CDCl3) δ 8.03 (s, 1H), 7.84 (dd, J=1.0, 7.4 Hz, 1H), 7.69 - 7.68 (m, 1H), 6.57 (dd, J=2.0, 7.5 Hz, 1H), 5.20 (s, 1H), 3.77 (s, 3H), 3.44 (s, 3H).

[0233] Synthesis of 2-(7-chloroimidazo[1,5-a]pyridine-1-yl)-2-methoxyacetamide. Ammonia (7N in MeOH, 0.43 mL, 3.0 mmol) was added to a solution of 2-(7-chloroimidazo[1,5-a]pyridine-1-yl)-2-methyl methoxyacetate (76 mg, 0.30 mmol) in MeOH (2 mL), and the mixture was stirred at room temperature for 48 hours. The mixture was concentrated under vacuum, and the residue was ground in diethyl ether to obtain the title compound (22 mg, 31%) as a light brown solid. 1H NMR (400 MHz, DMSO) δ 8.44 - 8.39 (m, 2H), 7.90 - 7.86 (m, 1H), 7.59 (s, 1H), 7.37 (s, 1H), 6.79 - 6.74 (m, 1H), 4.98 (s, 1H), 3.29 (s, 3H).

[0234] Synthesis of 2-(7-chloroimidazo[1,5-a]pyridine-1-yl)-2-hydroxyacetamide [ka] Ammonia (7N in methanol, 1.4 mL) was added to 2-(7-chloroimidazo[1,5-a]pyridine-1-yl)-2-hydroxymethyl acetate (241 mg, 1.0 mmol) in MeOH (1 mL), and the resulting mixture was stirred at room temperature for 18 hours. The formed precipitate was filtered, washed with MeOH, and dried under vacuum at 48°C to obtain the title compound (162 mg, 72%) as an off-white solid. ESI-MS (M+H) + : 226 / 228.

[0235] Synthesis of 2-(7-bromo-8-fluoroimidazo[1,5-a]pyridine-1-yl)acetic acid [ka] Synthesis of 2-(7-bromo-8-fluoroimidazo[1,5-a]pyridine-1-yl)acetonitrile. Potassium tert-butanolate (2.24 g, 20 mmol) was gradually added to a solution of 7-bromo-8-fluoroimidazo[1,5-a]pyridine-1-carbaldehyde (2.43 g, 10 mmol; see WO2019178129) and tosylmethyl isocyanide (2.34 g, 12 mmol) in tetrahydrofuran (50 mL). The reaction mixture was stirred at room temperature for 2 hours. Methanol (50 mL) was added, and the mixture was stirred under reflux for 2 hours. The reaction mixture was concentrated, diluted with water, and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate in petroleum ether = 0-100%) to obtain the title compound (1.1 g, 43%) as a yellow solid. 1 HNMR (400Hz, CDCl3) δ 8.12 (d, J = 2.4 Hz, 1H), 7.64 (d, J = 7.2 Hz, 1H), 6.67 (t, J = 6.8 Hz, 1H), 4.09 (s, 2H).

[0236] Synthesis of methyl 2-(7-bromo-8-fluoroimidazo[1,5-a]pyridine-1-yl)acetate. To a solution of 2-(7-bromo-8-fluoroimidazo[1,5-a]pyridine-1-yl)acetonitrile (1.1 g, 4.35 mmol) in methanol (50 mL), concentrated H2SO4 (10 mL) was added dropwise at 0°C. The reaction mixture was stirred overnight under reflux. The solvent was removed under vacuum, the residue was basicized with saturated sodium bicarbonate solution, and then extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, evaporated, and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:10) to obtain the title compound (1.0 g, yield: 80%) as a yellow solid. 1HNMR (400Hz, DMSO) δ 8.45 (d, J = 2.4 Hz, 1H), 8.14 (d, J = 7.2 Hz, 1H), 6.83 (t, J = 6.8 Hz, 1H), 3.93 (s, 2H), 3.62 (s, 3H).

[0237] Synthesis of 2-(7-bromo-8-fluoroimidazo[1,5-a]pyridine-1-yl)acetic acid. A solution of 2-(7-bromo-8-fluoroimidazo[1,5-a]pyridine-1-yl)acetic acid (1.0 g, 3.48 mmol) in tetrahydrofuran (10 mL), methanol (10 mL), and water (5 mL) was mixed with lithium hydroxide hydrate (439 mg, 10.45 mmol). The resulting reaction mixture was stirred at room temperature for 4 hours. After evaporation, the mixture was acidified to pH 4 with 1N HCl. The precipitate was filtered and dried under vacuum to obtain the title compound (900 mg, yield: 95%) as a white solid. 1 HNMR (400Hz, DMSO) δ 12.43 (br, 1H), 8.44 (d, J = 2.4 Hz, 1H), 8.14 (d, J = 7.2 Hz, 1H), 6.83-6.80 (m, 1H), 3.82 (s, 2H).

[0238] Synthesis of 2-(5-chloro-2-cyanophenyl)acetamide [ka] Synthesis of methyl 2-(5-chloro-2-cyanophenyl)acetate. Pd(PPh3)4 (320 mg, 0.277 mmol) was added to a nitrogen-purged mixture of methyl 2-(2-bromo-5-chlorophenyl)acetate (3.65 g, 13.9 mmol) and zinc cyanide (0.85 g, 7.2 mmol) in DMF (28 mL) and heated at 90°C for 18 hours. The mixture was diluted with water (100 mL), extracted with SiO2 (2 × 100 mL), washed with LiCl (4%, aqueous solution, 40 mL), dried, and concentrated in vacuum. The title compound was obtained by elution using silica gel column chromatography with a concentration gradient of 0 to 60% Et2O in cyclohexane (2.11 g, 72%). 1 H NMR (400 MHz, CDCl3) δ 7.62 - 7.59 (m, 1H), 7.44 (d, J=1.8 Hz, 1H), 7.39 (q, J=3.5 Hz, 1H), 3.87 (s, 2H), 3.76 (s, 3H).

[0239] Synthesis of 2-(5-chloro-2-cyanophenyl)acetic acid. Lithium hydroxide (44 mg, 1.05 mmol) was added to a mixture of methyl 2-(5-chloro-2-cyanophenyl)acetate (200 mg, 0.95 mmol) in THF (10 mL) and water (1 mL). The mixture was stirred at room temperature for 90 minutes. The mixture was acidified to pH 3 using HCl (2N, aqueous solution) and then extracted by DCM. The organic phase was passed through a phase separation cartridge and concentrated under vacuum to obtain the title compound (200 mg, quantitative), which was used without further purification.

[0240] Synthesis of 2-(5-chloro-2-cyanophenyl)acetamide. EDC·HCl (160 mg, 0.84 mmol) was added to a mixture of 2-(5-chloro-2-cyanophenyl)acetic acid (150 mg, 0.77 mmol), HOBt (110 mg, 0.84 mmol), DIPEA (0.6 mL, 3.5 mmol), and (NH4)2CO3 in THF (4.2 mL) and DMF (0.6 mL). The resulting mixture was heated to 50°C for 2.5 hours. The mixture was then diluted with water (30 mL) and DCM (60 mL) and passed through a phase separation cartridge. The organic phase was concentrated under vacuum and purified by silica gel column chromatography eluting with a concentration gradient of 0-10% MeOH in DCM to obtain the title compound (90 mg, 60%). ESI-MS (M+H) + : 195.1, 1 H NMR (400 MHz, CDCl3) δ 7.60 (d, J=8.4 Hz, 1H), 7.55 (d, J=2.0 Hz, 1H), 7.41 - 7.37 (m, 1H), 5.67 (s, 1H), 5.45 (s, 1H), 3.76 (s, 2H).

[0241] Synthesis of 2-((3-chlorophenyl)(methyl)amino)propanamide [ka] Synthesis of N-(3-chlorophenyl)-4-nitrobenzenesulfonamide. A mixture of 3-chloroaniline (0.83 mL, 7.8 mmol), 4-nitrobenzenesulfonyl chloride (1.7 g, 7.8 mmol), and pyridine (0.70 mL, 8.6 mmol) in DCM (40 mL) was stirred at room temperature for 18 hours. Water (100 mL) was added, and the mixture was extracted with DCM (3 × 100 mL). The combined organic layer was dried with (MgSO4), filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography eluted with 0-60% siRNA in cyclohexane to obtain the title compound (2.4 g, 97%) as a yellow solid. ESI-MS (M+H) + : 311.0.

[0242] Synthesis of N-(3-chlorophenyl)-N-methyl-4-nitrobenzenesulfonamide. Methyl iodide (0.57 mL, 9.2 mmol) was added at 0°C under an N2 atmosphere to a stirred mixture of N-(3-chlorophenyl)-4-nitrobenzenesulfonamide (2.4 g, 7.7 mmol) and K2CO3 (1.6 g, 12 mmol) in DMF (20 mL). The mixture was warmed to room temperature and stirred for 3 hours. Water (100 mL) and brine (saturated aqueous solution, 100 mL) were added, and the mixture was extracted with DCM (100 mL). The organic layer was dried over (MgSO4), filtered, and concentrated under vacuum to obtain the title compound (2.6 g, quantitative). 1 H NMR (400 MHz, DMSO) δ 8.45 - 8.40 (m, 2H), 7.84 - 7.81 (m, 2H), 7.43 - 7.41 (m, 2H), 7.30 (d, J=1.6 Hz, 1H), 7.16 - 7.12 (m, 1H), 3.22 (s, 3H).

[0243] Synthesis of 3-chloro-N-methylaniline. A mixture of N-(3-chlorophenyl)-N-methyl-4-nitrobenzenesulfonamide (2.5 g, 7.7 mmol), thiophenol (1.6 mL, 15 mmol), and K2CO3 (2.6 g, 19 mmol) in DMF (20 mL) was stirred at room temperature under an N2 atmosphere for 72 hours. Water (50 mL) and brine (saturated aqueous solution, 50 mL) were added, and the mixture was extracted with HCl (3 × 100 mL). The combined organic layer was dried in (MgSO4), filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography eluted with 0-60% HCl in cyclohexane. The residue was loaded into an SCX cartridge, washed with MeOH in DCM, and further purified by elution with NH3 in MeOH in DCM to obtain the title compound (0.84 g, 78%) as a yellow oil. ESI-MS (M+H) + : 142.1, 1H NMR (400 MHz, DMSO) δ 7.10 - 7.05 (m, 1H), 6.54 - 6.47 (m, 3H), 6.00 - 5.93 (m, 1H), 2.67 (d, J=5.0 Hz, 3H).

[0244] Synthesis of ethyl N-(3-chlorophenyl)-N-methylalaninate. A mixture of 3-chloro-N-methylaniline (0.84 g, 5.9 mmol), ethyl 2-bromopropanoate (0.85 mL, 6.5 mmol), and Na2CO3 (0.94 g, 8.9 mmol) in EtOH (12 mL) was stirred at room temperature for 5 minutes, then sealed and heated in a microwave at 100°C for 15 minutes. The mixture was then opened and heated under reflux for 18 hours. The mixture was again sealed and heated in a microwave at 100°C for 1 hour, then heated in a microwave at 150°C for a further 1 hour. TBAI (1.3 g, 3.5 mmol) was added, and the mixture was stirred in a microwave at 150°C for 4.5 hours. Water (100 mL) was added, and the mixture was extracted with SiO2 (3 × 100 mL). The combined organic layers were dried (MgSO4), filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography eluting with 0-60% ethyl acetate in cyclohexane. The residue was then packed into an SCX cartridge, washed with MeOH in DCM, and further purified by elution with NH3 in MeOH in DCM. The residue was further purified by silica gel column chromatography eluting with 0-40% ethyl acetate in cyclohexane to obtain the title compound (0.40 g, 28%) as a colorless oil. ESI-MS (M+H) + : 242.2, 1 H NMR (400 MHz, DMSO) δ 7.21 - 7.16 (m, 1H), 6.80 - 6.77 (m, 1H), 6.76 - 6.72 (m, 1H), 6.71 - 6.68 (m, 1H), 4.72 (q, J=7.0 Hz, 1H), 4.16 - 4.06 (m, 2H), 2.79 (s, 3H), 1.39 (d, J=7.0 Hz, 3H), 1.17 (t, J=7.1 Hz, 3H).

[0245] Synthesis of 2-((3-chlorophenyl)(methyl)amino)propenamide. Ethyl N-(3-chlorophenyl)-N-methylalaninate (100 mg, 0.41 mmol) was added to a reaction tube containing NH3 (7.0 N, 0.59 mL in MeOH). The reaction tube was sealed and stirred at room temperature for 18 hours. Further addition of NH3 (7.0 N, 0.59 mL in MeOH) was made, and the mixture was heated at 50°C for a further 18 hours. The mixture was concentrated under vacuum and purified by silica gel column chromatography eluting under a concentration gradient of 0-10% MeOH in DCM to obtain the title compound (28 mg, 32%). ESI-MS (M+H)+: 213.1, 1 H NMR (400 MHz, DMSO) δ 7.40 (s, 1H), 7.22 (dd, J=8.1, 8.1 Hz, 1H), 7.12 (s, 1H), 6.81 - 6.70 (m, 3H), 4.40 (q, J=6.9 Hz, 1H), 2.86 (s, 3H), 1.31 (d, J=7.1 Hz, 3H).

[0246] Synthesis of 2-(6-cyano-2-fluoro-3-methoxyphenyl)acetamide [ka] Synthesis of 6-bromo-2-fluoro-3-methoxybenzylmethanesulfonate. Methanesulfonyl chloride (0.43 mL, 5.62 mmol) in DCM (30 mL) was added at 0°C to a chilled mixture of (6-bromo-2-fluoro-3-methoxyphenyl)methanol (1.2 g, 5.11 mmol) and TEA (1.1 mL, 7.66 mmol). The mixture was warmed to room temperature and stirred for 90 minutes. The mixture was then treated with NaHCO3 (30 mL saturated aqueous solution) and extracted with DCM (100 mL). The organic phase was passed through a phase separation cartridge and concentrated under vacuum to obtain the title compound (1.6 g, quantitatively) as a brown oily substance. 1H NMR (400 MHz, CDCl3) δ 7.36 (dd, J=2.0, 8.8 Hz, 1H), 6.96 - 6.91 (m, 1H), 5.41 - 5.40 (m, 2H), 3.90 (s, 3H), 3.07 (s, 3H).

[0247] Synthesis of 2-(6-bromo-2-fluoro-3-methoxyphenyl)acetonitrile. Sodium cyanide (500 mg, 10.20 mmol) was added to a solution of 6-bromo-2-fluoro-3-methoxybenzylmethanesulfonate (1.597 g, 5.10 mmol) in DMF (12 mL) and stirred at room temperature for 18 hours. The mixture was diluted with water (50 mL), extracted with ethyl acetate (300 mL), dried to (MgSO4), filtered, and concentrated under vacuum. The title compound (1.2 g, 95%) was obtained as a white solid by purification by silica gel column chromatography eluting under a concentration gradient of 10-20% ethyl acetate in cyclohexane. 1 H NMR (400 MHz, CDCl3) δ 7.35 (dd, J=2.0, 8.9 Hz, 1H), 6.91 - 6.86 (m, 1H), 3.89 (s, 3H), 3.86 (d, J=2.1 Hz, 2H).

[0248] Synthesis of 2-(6-bromo-2-fluoro-3-methoxyphenyl)acetamide. N,N-diethylhydroxylamine (0.25 mL, 2.46 mmol) was added to a solution of 2-(6-bromo-2-fluoro-3-methoxyphenyl)acetonitrile (150 mg, 0.615 mmol) in DCM (3 mL). The resulting mixture was heated to 40°C for 22 hours. The mixture was then diluted with water (5 mL) and DCM (70 mL), and the phases were separated using a phase separation cartridge. The organic phase was concentrated under vacuum to obtain the title compound (153 mg, 95%). 1 H NMR (400 MHz, CDCl3) δ 7.36 - 7.30 (m, 1H), 6.83 (t, J=8.8 Hz, 1H), 5.40 (s, 2H), 3.88 (s, 3H), 3.80 (d, J=2.5 Hz, 2H).

[0249] Synthesis of 2-(6-cyano-2-fluoro-3-methoxyphenyl)acetamide. Zinc cyanide (69 mg, 0.588 mmol) was added to a nitrogen-purged mixture of 2-(6-bromo-2-fluoro-3-methoxyphenyl)acetamide (140 mg, 0.534 mmol), Pd(dppf)Cl2 (20 mg, 0.027 mmol), and Pd2(dba)3 (24 mg, 0.027 mmol) in DMF (3 mL). The mixture was heated at 80°C for 60 hours, an additional amount of Pd(dppf)Cl2 (20 mg, 0.027 mmol) was added, and the mixture was heated at 100°C for a further 18 hours. The mixture was diluted with water (30 mL), the solid was removed by filtration, and the aqueous phase was extracted with ELISA (120 mL). The organic phases were combined, dried (MgSO4), filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography using a concentration gradient of 0-10% MeOH in DCM to obtain the title compound as a white solid (38 mg, 34%). ESI-MS (M+H) + : 209.1.

[0250] Synthesis of 2-(5-chloro-2-(1H-tetrazole-1-yl)phenyl)acetamide [ka] Synthesis of methyl 2-(2-amino-5-chlorophenyl)acetate. Acetyl chloride (5.5 mL, 77 mmol) was added to ice-cold MeOH solution (55 mL). After 5 minutes, 2-(2-amino-5-chlorophenyl)acetic acid (1.0 g, 5.39 mmol) was added gradually. The mixture was stirred at room temperature for 2 hours and concentrated under vacuum to obtain the title compound, which was used without further purification. 1 H NMR (400 MHz, DMSO) δ 7.44 - 7.37 (m, 2H), 7.34 - 7.29 (m, 1H), 4.51 (br s, 2H), 3.88 (s, 2H), 3.68 (s, 3H).

[0251] Synthesis of methyl 2-(5-chloro-2-(1H-tetrazole-1-yl)phenyl)acetate. Sodium azide (1.05 g, 16.17 mmol) was added to a mixture of methyl 2-(2-amino-5-chlorophenyl)acetate (1.08 g, 5.39 mmol) and triethyl orthoformate (1.8 mL, 16.17 mmol) in AcOH (30 mL), and the mixture was stirred at room temperature for 18 hours. The mixture was diluted with water (60 mL), the precipitate formed was filtered off, and the aqueous layer was extracted by DCM. The organic phase was concentrated under vacuum. The title compound was obtained by purification by silica gel column chromatography eluting under a concentration gradient of 0-50% siRNA in cyclohexane (248 mg, 46%). 1 H NMR (400 MHz, CDCl3) δ 8.92 - 8.90 (m, 1H), 7.51 - 7.48 (m, 2H), 7.35 - 7.32 (m, 1H), 3.64 (s, 3H), 3.57 (s, 2H).

[0252] Synthesis of 2-(5-chloro-2-(1H-tetrazole-1-yl)phenyl)acetic acid. Lithium hydroxide (1N, aqueous solution, 2.4 mL, 2.37 mmol) was added to a solution of methyl 2-(5-chloro-2-(1H-tetrazole-1-yl)phenyl)acetate (300 mg, 1.19 mmol) in THF (10 mL), and the mixture was stirred at room temperature for 3 hours. The mixture was diluted with water and extracted with DCM. The aqueous phase was acidified with HCl (2N, aqueous solution) and extracted with SiO(×3). The organic phases were combined, dried, and concentrated in vacuum to obtain the title compound (252 mg, 89%). 1 H NMR (400 MHz, DMSO) δ 12.54 (s, 1H), 9.86 (s, 1H), 7.79 (s, 1H), 7.71 (s, 2H), 3.73 - 3.70 (m, 2H).

[0253] Synthesis of 2-(5-chloro-2-(1H-tetrazole-1-yl)phenyl)acetamide. EDC·HCl (96 mg, 0.503 mmol) was added to a mixture of HOBt (62 mg, 0.461 mmol), DIPEA (0.33 mL, 1.89 mmol), (NH4)2CO3 (181 mg, 1.89 mmol), and 2-(5-chloro-2-(1H-tetrazole-1-yl)phenyl)acetic acid (100 mg, 0.419 mmol) in THF (3 mL), DMF (0.4 mL). The resulting mixture was heated at 50°C for 3 hours. The mixture was diluted with water (10 mL), extracted with SiO2 (3 × 50 mL), and the combined organic phase was dried and concentrated in (MgSO4) under vacuum. The residue was ground using DCM / DIPE (1:1, 1 mL) to obtain the title compound (70 mg, 70%) as a white solid. ESI-MS (M+H) + : 238.1, 1 H NMR (400 MHz, DMSO) δ 9.77 (s, 1H), 7.70 (d, J=1.4 Hz, 1H), 7.63 - 7.62 (m, 2H), 7.42 - 7.40 (m, 1H), 6.92 - 6.90 (m, 1H), 3.44 (s, 2H).

[0254] Synthesis of 2-(3-fluoro-4-hydroxypyridine-2-yl)acetamide [ka] Synthesis of tert-butyl 2-(3-fluoro-4-methoxypyridine-2-yl)acetate. Pd2(dba)3 (40 mg, 0.433 mmol) was added to a nitrogen-purged mixture of 2-chloro-3-fluoro-4-methoxypyridine (700 mg, 4.33 mol), XPhos (410 mg, 0.87 mmol), and 2-(tert-butoxy)-2-oxoethyl)zinc(II) bromide (1 M, 6.5 mL, 6.5 mmol) in THF (7 mL). The resulting mixture was stirred at room temperature for 18 hours. The mixture was diluted with NH4Cl (5 mL saturated aqueous solution) and NaHCO3 (50 mL saturated aqueous solution) and extracted with ELISA (3 × 50 mL). The organic phases were combined, dried (MgSO4), filtered, and concentrated under vacuum. The title compound (98 mg, 9.4%) was obtained as a yellow oil by purification using silica gel column chromatography eluting under a concentration gradient of 0-100% ethyl acetate in cyclohexane. ESI-MS (M+H) + : 242.2, 1 H NMR (400 MHz, DMSO) δ 8.21 (d, J=5.6 Hz, 1H), 7.20 (dd, J=5.6, 6.7 Hz, 1H), 3.93 (s, 3H), 3.75 (d, J=2.9 Hz, 2H), 1.40 (s, 9H).

[0255] Synthesis of 2-(3-fluoro-4-methoxypyridine-2-yl)acetic acid. Trifluoroacetic acid (0.5 mL, 6.53 mmol) was added to a solution of tert-butyl 2-(3-fluoro-4-methoxypyridine-2-yl)acetate (120 mg, 0.497 mmol) in DCM (3 mL), and the reaction was stirred at room temperature for 18 hours. The mixture was concentrated under vacuum and proceeded to the next step without further purification.

[0256] Synthesis of 2-(3-fluoro-4-methoxypyridine-2-yl)acetamide. Crude 2-(3-fluoro-4-methoxypyridine-2-yl)acetic acid (92 mg, 0.450 mmol) was added to a mixture of THF (4 mL), DMF (1 mL) containing EDC·HCl (110 mg, 0.60 mmol), HOAt (74 mg, 0.55 mmol), DIPEA (0.39 mL, 2.24 mmol), and (NH4)2CO3 (210 mg, 2.24 mmol), and the mixture was heated at 50°C for 4 hours. Additional amounts of DIPEA (0.39 mL, 2.24 mmol) and (NH4)2CO3 (210 mg, 2.24 mmol) were added, and the mixture was stirred at 50°C for 18 hours. The mixture was stirred at 60°C for 18 hours with an additional amount of (NH4)2CO3 (500 mg, 5.20 mmol) and DMAP (catalyst). The mixture was diluted with water (10 mL) and extracted with EtOAC (3 × 20 mL). The organic phases were combined, dried, and concentrated in (MgSO4) under vacuum. The title compound (35 mg, 35%) was purified by silica gel column chromatography eluting a concentration gradient of 0-20% 7N NH3 in MeOH in DCM to obtain a white solid. ESI-MS (M+H) + : 185.1, 1 H NMR (400 MHz, DMSO) δ 8.23 ​​(d, J=5.6 Hz, 1H), 7.55 (s, 1H), 7.20 (q, J=4.0 Hz, 1H), 7.03 (s, 1H), 3.96 (s, 3H), 3.65 (d, J=3.0 Hz, 2H).

[0257] Synthesis of 1-amino-6,7-dihydro-5H-cyclopenta[c]pyridine-6-carboxylate hydrochloride [ka] Synthesis of 5,7-dihydro-6H-cyclopenta[c]pyridine-6,6-dicarboxylate diethyl. Sodium (1.06 g, 46.11 mmol) was gradually added to ethanol (100 mL) and stirred for 1 hour. Diethyl malonate (2.3 mL, 15.37 mmol) was then added dropwise over 5 minutes, followed by the dropwise addition of 3,4-bis(chloromethyl)pyridine (2.71 g, 15.37 mmol) in EtOH (20 mL) at room temperature. The mixture was heated under reflux for 4.5 hours and then concentrated under vacuum. Water was added, and the mixture was extracted with phenylethylamine. The organic phase was dried in (MgSO4), filtered, and concentrated under vacuum. The title compound (2.07 g, 51%) was obtained as an orange oil by purification by silica gel column chromatography eluting under a concentration gradient of 0 to 60% phenylethylamine in cyclohexane. 1 H NMR (400 MHz, CDCl3) δ 8.50 - 8.37 (m, 2H), 7.16 (d, J=4.8 Hz, 1H), 4.25 - 4.19 (m, 4H), 3.63 (s, 2H), 3.60 (s, 2H), 1.29 - 1.24 (m, 6H).

[0258] Synthesis of 6,6-bis(ethoxycarbonyl)-6,7-dihydro-5H-cyclopenta[c]pyridine 2-oxide. A solution of 3-chloroperbenzoic acid (2.58 g, 10.37 mmol) in DCM (20 mL) was passed through a phase separation cartridge, and subsequently added dropwise to a mixture of 5,7-dihydro-6H-cyclopenta[c]pyridine-6,6-dicarboxylate diethyl (1.82 g, 6.91 mmol) in DCM (70 mL), and stirred at room temperature for 18 hours. The mixture was washed with Na2CO3 (10% aqueous solution, 3 times), dried, and concentrated under vacuum to obtain the title compound (1.77 g, 92%) as an orange solid. 1 H NMR (400 MHz, DMSO) δ 8.22 (s, 1H), 8.09 - 8.06 (m, 1H), 7.35 - 7.32 (m, 1H), 4.25 - 4.18 (m, 4H), 3.53 (s, 2H), 3.50 (s, 2H), 1.25 - 1.21 (m, 6H).

[0259] Synthesis of 1-((2,4-dimethoxybenzyl)amino)-5,7-dihydro-6H-cyclopenta[c]pyridine-6,6-dicarboxylate diethyl. PyBroP® (3.84 g, 8.24 mmol) was added to a mixture of 6,6-bis(ethoxycarbonyl)-6,7-dihydro-5H-cyclopenta[c]pyridine 2-oxide (1.77 g, 6.34 mmol), 2,4-dimethoxybenzylamine (1.32 g, 7.92 mmol), and DIPEA (4.1 mL, 23.77 mmol) in DCM (30 mL), and the mixture was stirred at room temperature for 18 hours. The mixture was then poured into NaHCO3 (saturated aqueous solution) and extracted with DCM (×3). The organic phases were combined, dried (MgSO4), and concentrated under vacuum. The title compound (1.05 g, 39%) was obtained as an orange oil by purification using silica gel column chromatography, which eluted the compound under a concentration gradient of 0-40% toluene in cyclohexane. 1 H NMR (400 MHz, CDCl3) δ 8.01 - 7.98 (m, 1H), 7.27 - 7.24 (m, 1H), 6.50 - 6.42 (m, 3H), 4.60 - 4.57 (m, 2H), 4.39 - 4.34 (m, 1H), 4.24 - 4.17 (m, 4H), 3.84 (s, 3H), 3.80 (s, 3H), 3.52 (s, 2H), 3.32 - 3.30 (m, 2H), 1.27 - 1.23 (m, 6H).

[0260] Synthesis of 1-amino-6,7-dihydro-5H-cyclopenta[c]pyridine-6-carboxylate hydrochloride. 1.08 g, 2.52 mmol of 1-((2,4-dimethoxybenzyl)amino)-5,7-dihydro-6H-cyclopenta[c]pyridine-6,6-dicarboxylate diethyl (1.08 g, 2.52 mmol) was heated in HCl (12N, aqueous solution, 5 mL) at 100°C for 6 hours. The mixture was concentrated in vacuum, pulverized with diethyl ether, filtered, and dried in vacuum to obtain the title compound. 1H NMR (400 MHz, DMSO) δ 13.51 (s, 1H), 12.61 (s, 1H), 7.97 (s, 2H), 7.87 (d, J=6.6 Hz, 1H), 6.92 (d, J=6.3 Hz, 1H), 3.81 - 3.05 (m, 5H).

[0261] Synthesis of 2-(6-((diphenylmethylene)amino)-2-fluoro-3-methoxyphenyl)acetamide [ka] Synthesis of (6-bromo-2-fluoro-3-methoxyphenyl)methanol. A solution of 6-bromo-2-fluoro-3-methoxybenzaldehyde (1.4 g, 5.9 mmol) in MeOH (16 mL) was cooled to 0°C. Sodium borohydride (220 mg, 5.9 mmol) was added gradually, and the reaction mixture was stirred at 0°C for 40 minutes. The reaction mixture was warmed to room temperature and concentrated under vacuum. The residue was dissolved in ELISA (130 mL) and washed with water (30 mL) and brine (saturated aqueous solution, 20 mL). The organic matter was dried over MgSO4 and concentrated under vacuum to obtain the title compound (1.3 g, 96%) as a colorless oil, which was used without further purification.

[0262] Synthesis of 6-bromo-2-fluoro-3-methoxybenzylmethanesulfonate. Triethylamine (1.2 mL, 8.5 mmol) was added to a solution of (6-bromo-2-fluoro-3-methoxyphenyl)methanol (1.3 g, 5.7 mmol) in DCM (35 mL), and the reaction mixture was cooled to 0°C. Methanesulfonyl chloride (0.48 mL, 6.2 mmol) was added, and the reaction mixture was warmed to room temperature and stirred for 1 hour. The reaction mixture was diluted with NaHCO3 (saturated aqueous solution, 35 mL) and extracted with DCM (2 × 60 mL). The organic matter was dried on hydrophobic frit and concentrated under vacuum to obtain the title compound (970 mg, 54%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.39 - 7.34 (m, 1H), 6.97 - 6.90 (m, 1H), 5.41 (d, J=2.2 Hz, 2H), 3.90 (s, 3H), 3.07 (s, 3H).

[0263] Synthesis of 2-(6-bromo-2-fluoro-3-methoxyphenyl)acetonitrile. Sodium cyanide (300 mg, 6.2 mmol) was added to a solution of 6-bromo-2-fluoro-3-methoxybenzylmethanesulfonate (970 mg, 3.1 mmol) in DMF (10 mL), and the reaction mixture was stirred at room temperature for 20 hours. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (200 mL). The organic matter was washed with brine (saturated aqueous solution, 100 mL), dried over MgSO4, and concentrated under vacuum. The residue was purified by silica gel column chromatography eluting under a concentration gradient of 0-20% ethyl acetate in isohexane to obtain the title compound (1.1 g, quantitatively) as a white solid. ESI-MS (MH)-: 242.1, 244.0. 1 H NMR (400 MHz, CDCl3) δ 7.35 (dd, J=2.0, 8.9 Hz, 1H), 6.88 (t, J=8.8 Hz, 1H), 3.89 (s, 3H), 3.86 (d, J=2.0 Hz, 2H).

[0264] Synthesis of 2-(6-((diphenylmethylene)amino)-2-fluoro-3-methoxyphenyl)acetonitrile. A mixture of 2-(6-bromo-2-fluoro-3-methoxyphenyl)acetonitrile (930 mg, 3.8 mmol), diphenylmethaneimine (0.96 mL, 5.7 mmol), and Cs2CO3 (3.7 g, 11 mmol) was suspended in anhydrous 1,4-dioxane (15 mL) and degassed for 5 minutes. Xantphos (220 mg, 0.38 mmol) and Pd(OAc)2 (43 mg, 0.19 mmol) were added, and the reaction mixture was degassed for another 5 minutes, then stirred at 90°C for 3.5 hours. The reaction mixture was allowed to cool to room temperature, diluted with Depositphotos (250 mL), and washed with water (100 mL) and brine (50 mL). The organic matter was dried over MgSO4 and concentrated under vacuum. The residue was purified by silica gel column chromatography using a concentration gradient of 0-100% DCM in isohexane to obtain the title compound (550 mg, 42%) as a yellow solid. ESI-MS (M+H) + : 345.1.

[0265] Synthesis of 2-(6-((diphenylmethylene)amino)-2-fluoro-3-methoxyphenyl)acetamide. A mixture of 2-(6-((diphenylmethylene)amino)-2-fluoro-3-methoxyphenyl)acetonitrile (100 mg, 0.29 mmol) and N,N-diethylhydroxylamine (0.18 mL, 1.7 mmol) in DCM (2.0 mL) was placed under an N2 atmosphere, and the reaction mixture was stirred at 40°C for 24 hours. The reaction mixture was allowed to cool to room temperature and partitioned between DCM (50 mL) and water (10 mL). The organic phase was dried over hydrophobic frit and concentrated under vacuum. The residue was purified by silica gel column chromatography eluting under a concentration gradient of 0-25% ethyl ethyl in DCM to obtain the title compound (98 mg, 93%) as a yellow solid. ESI-MS (M+H) + : 363.2, 1H NMR (400 MHz, CDCl3) δ 7.72 (d, J=7.3 Hz, 2H), 7.52 - 7.28 (m, 6H), 7.18 - 7.12 (m, 2H), 6.59 - 6.53 (m, 1H), 6.47 (s, 1H), 6.07 (d, J=8.3 Hz, 1H), 5.25 (s, 1H), 3.78 (s, 3H), 3.71 (s, 2H).

[0266] Synthesis of 2-(7-chloroimidazo[1,5-a]pyridine-1-yl)-N-(6-chloropyrimidine-4-yl)acetamide [ka] LiHMDS (1.0 M, 0.66 mL, 0.66 mmol in THF) was added to a stirred solution of 6-chloropyrimidine-4-amine (0.085 g, 0.66 mmol) in THF (2.4 mL) under an N2 atmosphere at -78°C. After 45 minutes at -78°C, a solution of 2-(7-chloroimidazo[1,5-a]pyridine-1-yl)perfluorophenyl acetate (0.23 g, 0.60 mmol) in THF (4.6 mL) was slowly added. After 30 minutes at -78°C, the mixture was warmed to room temperature and stirred for 4 hours. Then, Na2CO3 (10% aqueous solution, 75 mL) was added, and the mixture was extracted with ELISA (3 × 75 mL). The combined organic layers were dried (MgSO4), filtered, and concentrated under vacuum. The residue was redissolved in DCM, filtered, and concentrated under vacuum. The residue was pulverized with MeOH (×3) to obtain the title compound (0.070 g, 36%) as a yellow solid. ESI-MS (M+H) + : 322.0, 324.0, 1 H NMR (400 MHz, DMSO) δ 11.48 (s, 1H), 8.83 (s, 1H), 8.41 - 8.34 (m, 2H), 8.13 (s, 1H), 7.88 (s, 1H), 6.75 - 6.70 (m, 1H), 4.10 (s, 2H).

[0267] Synthesis of 2-(7-chloroimidazo[1,5-a]pyridine-1-yl)-N-(4-chloropyrimidine-5-yl)acetamide [ka] Trimethylacetyl chloride (0.38 mL, 3.09 mmol) was added dropwise at 0°C to a chilled mixture of 2-(7-chloroimidazo[1,5-a]pyridine-1-yl)acetic acid (500 mg, 2.37 mmol) and TEA (0.66 mL, 4.75 mmol) in THF (25 mL). After 2 hours, 4-chloropyrimidine-5-amine (290 mg, 2.26 mmol) was added. After another hour, the mixture was warmed to room temperature and stirred for 18 hours. The mixture was then diluted with water and brine (saturated aqueous solution) and extracted with ethyl acetate. The organic phase was dried in (MgSO4), filtered, and concentrated under vacuum. The title compound (272 mg, 35%) was obtained as a brown solid by purification by silica gel column chromatography eluting under a concentration gradient of 40-100% ethyl acetate in cyclohexane. 1 H NMR (400 MHz, DMSO) δ 10.25 (s, 1H), 9.19 - 9.18 (m, 1H), 8.82 (s, 1H), 8.41 (s, 1H), 8.35 (dd, J=1.0, 7.5 Hz, 1H), 7.88 - 7.86 (m, 1H), 6.69 (dd, J=2.1, 7.5 Hz, 1H), 4.08 (s, 2H).

[0268] Synthesis of 2-(3-chlorophenoxy)propanoic acid [ka] Synthesis of ethyl 2-(3-chlorophenoxy)propanoate. NaH (65% in mineral oil, 0.28 g, 7.0 mmol) was added at 0°C under an N2 atmosphere to a stirred mixture of 3-chlorophenol (0.62 mL, 5.8 mmol) in THF (11 mL). After 15 minutes, ethyl 2-bromopropanoate (0.83 mL, 6.4 mmol) was added at 0°C. After 30 minutes, the mixture was warmed to room temperature and stirred for 18 hours. Water (50 mL) and brine (saturated aqueous solution, approximately 50 mL) were then added, and the mixture was extracted with DCM (2 × 50 mL) and toluene (50 mL). The combined organic layers were dried in (MgSO4), filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography eluted with 0-40% toluene in cyclohexane to obtain the title compound (1.6 g, quantitative) as a colorless oil. 1 H NMR (400 MHz, DMSO) δ 7.34 - 7.30 (m, 1H), 7.05 - 7.02 (m, 1H), 6.98 (t, J=2.2 Hz, 1H), 6.90 - 6.87 (m, 1H), 5.06 (q, J=6.7 Hz, 1H), 4.19 - 4.13 (m, 2H), 1.52 (d, J=6.8 Hz, 3H), 1.19 (t, J=7.1 Hz, 3H).

[0269] Synthesis of 2-(3-chlorophenoxy)propanoic acid. A mixture of ethyl 2-(3-chlorophenoxy)propanoate (1.3 g, 5.8 mmol) and LiOH (1.0 M aqueous solution, 12 mL, 12 mmol) in THF (12 mL) was stirred at room temperature for 18 hours. Water (50 mL) was added, and the pH was adjusted to 4 with HCl (2.0 M aqueous solution). The mixture was extracted with HCl (3 × 50 mL). The pH of the aqueous layer was adjusted to 1 with HCl (2.0 M aqueous solution), and further extracted with HCl (3 × 50 mL). The combined organic layers were dried (MgSO4), filtered, and concentrated under vacuum to obtain the title compound (1.4 g, quantitatively) as a white solid. 1H NMR (400 MHz, DMSO) δ 13.03 (s, 1H), 7.32 (t, J=8.2 Hz, 1H), 7.03 - 7.00 (m, 1H), 6.95 (t, J=2.2 Hz, 1H), 6.89 - 6.86 (m, 1H), 4.93 (q, J=6.8 Hz, 1H), 1.51 (d, J=6.8 Hz, 3H).

[0270] Synthesis of 2-(3-chlorophenoxy)-N-(6-chloropyrimidine-4-yl)propanamide [ka] Oxalyl chloride (0.91 mL, 10 mmol) was added to a stirred mixture of 2-(3-chlorophenoxy)propanoic acid (0.70 g, 3.5 mmol) and DMF (2 drops) in DCM (14 mL) under an N2 atmosphere at 0°C. The mixture was stirred at 0°C for 3 hours and then concentrated under vacuum. The mixture was redissolved in DCM (35 mL) and 6-chloropyrimidine-4-amine (0.45 g, 3.5 mmol) and pyridine (0.42 mL, 5.2 mmol) were added. The mixture was stirred at room temperature for 18 hours. Water (25 mL) and brine (saturated aqueous solution, 25 mL) were added, and the mixture was extracted with DCM (25 mL, then 2 × 50 mL). The combined organic layers were dried over (MgSO4), filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography using elution with 0-80% siRNA in cyclohexane to obtain the title compound (0.53 g, 49%) as a colorless oil. 1 H NMR (400 MHz, DMSO) δ 11.57 (s, 1H), 8.83 - 8.82 (m, 1H), 8.09 - 8.08 (m, 1H), 7.36 - 7.31 (m, 1H), 7.05 - 7.01 (m, 2H), 6.91 - 6.88 (m, 1H), 5.15 (q, J=6.6 Hz, 1H), 1.57 - 1.54 (m, 3H).

[0271] Synthesis of (E)-3-(3-chlorophenyl)-N-(6-chloropyrimidine-4-yl)acrylamide [ka] Oxalyl chloride (0.26 mL, 3.0 mmol) and DMF (2 drops) were added to a stirred mixture of (E)-3-(3-chlorophenyl)acrylic acid (0.18 g, 1.0 mmol) in DCM (10 mL). The mixture was stirred at room temperature for 2 hours and then concentrated under vacuum. The mixture was redissolved in DCM (10 mL) and cooled to 0°C. A mixture of 6-chloropyrimidine-4-amine (0.13 g, 1.0 mmol) and DIPEA (0.52 mL, 3.0 mmol) in DCM (2.0 mL) was added gradually at 0°C, followed by the addition of DMAP (0.012 mL, 0.10 mmol). The mixture was then warmed to room temperature and stirred for 3 hours. The mixture was then concentrated under vacuum, and the residue was purified by silica gel column chromatography eluted with 1-10% MeOH in DCM to obtain the title compound (0.061 g, 21%) as a cream-green solid. ESI-MS (M+H) + : 293.9.

[0272] Synthesis of 2-(2-bromo-5-chlorophenyl)-N-(6-chloropyrimidine-4-yl)acetamide [ka] Synthesis of 2-(2-bromo-5-chlorophenyl)acetyl chloride. A solution of 2-(2-bromo-5-chlorophenyl)acetic acid (500 mg, 2.0 mmol) in anhydrous DCM (6.0 mL) was placed under an N2 atmosphere, and a few drops of oxalyl chloride (0.52 mL, 6.0 mmol) and DMF (39 μL, 0.50 mmol) were added. The reaction mixture was stirred at room temperature for 20 minutes. The reaction mixture was concentrated under vacuum to obtain the title compound, which was used directly in the next step without further purification.

[0273] Synthesis of 2-(2-bromo-5-chlorophenyl)-N-(6-chloropyrimidine-4-yl)acetamide: A solution of 2-(2-bromo-5-chlorophenyl)acetyl chloride (536 mg, 2.0 mmol) in DCM (10 mL) was added dropwise to an ice-cold mixture of pyridine (0.24 mL, 3.0 mmol) and 6-chloropyrimidine-4-amine (259 mg, 2.0 mmol) in DCM (10 mL). The mixture was warmed to room temperature and stirred for 18 hours. The mixture was diluted with water (10 mL), extracted with DCM (100 mL), and the organic phase was passed through a phase separation cartridge and concentrated under vacuum. The compound was purified by silica gel column chromatography eluting at a concentration gradient of 0-30% ethyl acetate in DCM, followed by grinding with diethyl ether to obtain the title compound (48 mg, 7%). 1 H NMR (400 MHz, CDCl3) δ 8.63 (d, J=1.0 Hz, 1H), 8.23 ​​(d, J=1.0 Hz, 1H), 8.01 (s, 1H), 7.58 - 7.55 (m, 1H), 7.39 (d, J=2.5 Hz, 1H), 7.22 (dd, J=2.6, 8.7 Hz, 1H), 3.89 (s, 2H).

[0274] Synthesis of 2-(5-chloro-2-(1-trityl-1H-tetrazole-5-yl)phenyl)acetamide [ka] Synthesis of methyl 2-(2-bromo-5-chlorophenyl)acetate. A few drops of concentrated sulfuric acid (64 μL, 1.2 mmol) were added to a solution of 2-(2-bromo-5-chlorophenyl)acetic acid (3.0 g, 12 mmol), and the reaction mixture was stirred under reflux for 16 hours. The reaction mixture was allowed to cool to room temperature and concentrated under vacuum. The residue was dissolved in toluene (180 mL) and washed with water (50 mL) and brine (saturated aqueous solution, 50 mL). The organic phase was dried over MgSO4 and concentrated under vacuum to obtain the title compound (3.2 g, quantitatively) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.50 - 7.48 (m, 1H), 7.29 (d, J=2.6 Hz, 1H), 7.13 (dd, J=2.5, 8.5 Hz, 1H), 3.76 (s, 2H), 3.73 (s, 3H).

[0275] Synthesis of methyl 2-(5-chloro-2-cyanophenyl)acetate. A solution of methyl 2-(2-bromo-5-chlorophenyl)acetate (3.7 g, 14 mmol) in DMF (28 mL) was degassed for 10 minutes, and Zn(CN)2 (850 mg, 7.2 mmol) and Pd(PPh3)4 (320 mg, 0.28 mmol) were added. The mixture was degassed for a further 5 minutes. The reaction mixture was then stirred at 90°C for 16 hours. The reaction mixture was allowed to cool to room temperature, diluted with water (100 mL), and extracted with Et2O (3 × 100 mL). The combined organic layers were washed with water (50 mL) and LiCl (4% aqueous solution, 40 mL), dried over MgSO4, and concentrated under vacuum. The residue was purified by silica gel column chromatography eluting under a concentration gradient of 0-40% siRNA in isohexane to obtain the title compound (2.11 g, 72%) as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ 7.62 - 7.59 (m, 1H), 7.44 (d, J=1.8 Hz, 1H), 7.39 (dd, J=2.0, 8.2 Hz, 1H), 3.87 (s, 2H), 3.76 (s, 3H).

[0276] Synthesis of 2-(5-chloro-2-(1H-tetrazole-5-yl)phenyl)methyl acetate. 2-(5-chloro-2-cyanophenyl)methyl acetate (400 mg, 1.9 mmol), NaN3 (190 mg, 2.9 mmol), and Et3N·HCl (390 mg, 2.9 mmol) were stirred in toluene (10 mL) at 100°C for 6 hours. The reaction mixture was allowed to cool to room temperature, diluted with ELISA (20 mL), and extracted with water (40 mL). The aqueous phase was then acidified to pH 3 using HCl (1 M aqueous solution) and extracted with DCM (3 × 40 mL). The combined organic layers were dried on hydrophobic frit and concentrated under vacuum. The residue was purified by silica gel column chromatography eluting with a concentration gradient of 0-10% MeOH in DCM to obtain the title compound (110 mg, 22%) as a colorless oil. 1 ¹H NMR (400 MHz, CDCl3) δ values ​​were 7.96 - 7.92 (m, 1H), 7.48 - 7.46 (m, 2H), 3.84 (s, 3H), and 3.77 (s, 2H). Acidic protons were not observed.

[0277] Synthesis of 2-(5-chloro-2-(1-trityl-1H-tetrazole-5-yl)phenyl)methyl acetate. A mixture of 2-(5-chloro-2-(1H-tetrazole-5-yl)phenyl)methyl acetate (80 mg, 0.32 mmol), trityl chloride (97 mg, 0.35 mmol), and Et3N (66 μL, 0.48 mmol) in DMF (1.0 mL) was stirred at room temperature under an N2 atmosphere for 6 hours. The reaction mixture was diluted with DCM (50 mL) and washed with water (20 mL). The organic phase was dried over hydrophobic frit and concentrated under vacuum. The residue was combined with another batch (starting with 2-(5-chloro-2-(1H-tetrazole-5-yl)phenyl) acetate (20 mg, 0.079 mmol)) to obtain the title compound (220 mg, quantitative), which was used without further purification.

[0278] Synthesis of 2-(5-chloro-2-(1-trityl-1H-tetrazole-5-yl)phenyl)acetic acid. A mixture of methyl 2-(5-chloro-2-(1-trityl-1H-tetrazole-5-yl)phenyl)acetic acid (220 mg, 0.44 mmol) and LiOH·H2O (20 mg, 0.48 mmol) in THF (10 mL) and water (1.0 mL) was stirred at room temperature for 18 hours. The reaction mixture was concentrated under vacuum, the residue was dissolved in water (10 mL), acidified with HCl (2 M aqueous solution, 1 mL), and extracted with DCM (80 mL). The organic layer was dried on hydrophobic frit and concentrated under vacuum to obtain the title compound (230 mg, quantitatively) as a colorless oil. 1 ¹H NMR (400 MHz, CDCl3) δ values ​​were 8.08 - 8.05 (m, 1H), 7.44 - 7.27 (m, 10H), 7.15 - 7.12 (m, 7H), and 3.91 (s, 2H). No exchangeable protons were observed.

[0279] Synthesis of 2-(5-chloro-2-(1-trityl-1H-tetrazole-5-yl)phenyl)acetamide. A mixture of 2-(5-chloro-2-(1-trityl-1H-tetrazole-5-yl)phenyl)acetic acid (230 mg, 0.48 mmol), EDC (100 mg, 0.53 mmol), HOBt (71 mg, 0.53 mmol), and DIPEA (0.38 mL, 2.2 mmol) in THF (5.0 mL) and DMF (0.7 mL) was placed under an N2 atmosphere, (NH4)2CO3 (210 mg, 2.2 mmol) was added, and the reaction mixture was stirred at 50 °C for 6 hours. The reaction mixture was allowed to cool to room temperature, diluted with DCM (50 mL), and washed with water (20 mL). The organic phase was dried on hydrophobic frit and concentrated under vacuum. The residue was purified by silica gel column chromatography eluting under a concentration gradient of 0-10% MeOH in DCM. The residue was further purified by silica gel column chromatography eluting under a concentration gradient of 2-5% MeOH in DCM to obtain the title compound (84 mg, 36%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.08 - 8.05 (m, 1H), 7.58 - 7.57 (m, 1H), 7.43 - 7.28 (m, 10H), 7.17 - 7.13 (m, 6H), 6.29 (s, 1H), 4.83 (s, 1H), 3.69 (s, 2H).

[0280] Synthesis of 2-(6-chloro-1H-benzo[d][1,2,3]triazole-1-yl)acetic acid [ka] Synthesis of 2-(6-chloro-1H-benzo[d][1,2,3]triazole-1-yl)ethyl acetate. Ethyl bromoethyl acetate (0.43 mL, 3.9 mmol) was added dropwise to a stirred mixture of 6-chloro-1H-benzotriazole (0.5 g, 3.3 mmol) and potassium carbonate (0.9 g, 6.5 mmol) in ethanol (15 mL), and the resulting mixture was heated at 70°C for 2 hours. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated under vacuum, and the residue was purified by silica gel column chromatography using a concentration gradient of 2-30% diethyl ether in DCM as the eluent to obtain the title compound (0.2 g, 26%) as a yellow solid and a mixture of positional isomers, which was used without further purification.

[0281] Synthesis of 2-(6-chloro-1H-benzo[d][1,2,3]triazole-1-yl)acetic acid. A mixture of 2-(6-chloro-1H-benzo[d][1,2,3]triazole-1-yl)ethyl acetate (0.19 g, 0.8 mmol), LiOH (0.038 g, 1.6 mmol), and water (0.028 mL, 1.6 mmol) in THF (5 mL) was stirred at room temperature for 24 hours. The reaction mixture was poured into water (25 mL) and brine (25 mL) and washed with RINKAN (3 × 20 mL). The aqueous phase was acidified to pH 3 with 10% citric acid and extracted with RINKAN (6 × 30 mL). The combined organic phase was dried over MgSO4, and the solvent was removed under vacuum to obtain the title compound (0.134 g, 79%) as a white solid and a mixture of positional isomers, which was used without further purification.

[0282] Synthesis of 2-(6-chloro-1H-benzo[d][1,2,3]triazole-1-yl)acetic acid [ka] The title compound was prepared as a mixture of positional isomers using the same method as described for the synthesis of 2-(6-chloro-1H-benzo[d][1,2,3]triazole-1-yl)acetic acid starting from chlorobenzimidazole (0.337 g, 2.2 mmol), and was used without further purification.

[0283] Synthesis of 6-chloro-N-((7-chloroimidazo[1,5-a]pyridine-1-yl)methyl)pyridazine-4-carboxamide [ka] Oxalyl chloride (136 μL, 1.56 mmol) was added to a solution of 6-chloropyridazine-4-carboxylic acid (124 mg, 0.780 mmol) in DCM (10 mL), followed by the addition of DMF (2 drops), and the mixture was stirred at room temperature for 3 hours. The mixture was concentrated under vacuum, dissolved in DCM (5 mL), and added dropwise to a mixture of (7-chloroimidazo[1,5-a]pyridine-1-yl)methaneamine (170 mg, 0.780 mmol, WO2019178129) and DIPEA (543 μL, 3.12 mmol) in DCM (10 mL) at room temperature, and the reaction was stirred for 18 hours. The mixture was concentrated under vacuum, treated with K2CO3 (diluted 5 mL), stirred for 30 minutes, and filtered. The solid was washed with water and dried under vacuum (40°C) to obtain the title compound (175 mg, 70%) as a brown solid. ESI-MS (M+H) + : 323.

[0284] Synthesis of 6-fluoro-N-(2-fluoro-3-methoxy-6-(1H-tetrazole-1-yl)benzyl)pyrimidine-4-amine [ka] 4,6-difluoropyrimidine (0.031 g, 0.27 mmol) was added at 0°C to a stirred solution of (2-fluoro-3-methoxy-6-(1H-tetrazole-1-yl)phenyl)methanamine (0.050 g, 0.22 mmol, WO2017207983) and DIPEA (0.098 mL, 0.56 mmol) in MeCN (0.5 mL). The mixture was stirred at 0°C for 5 minutes and then warmed to room temperature. After 2.5 hours, the mixture was diluted with DCM (50 mL), washed with water, passed through a phase separation cartridge, and concentrated under vacuum. The residue was purified by silica gel column chromatography eluting with 0-100% DCM in ethyl acetate to obtain the title compound (0.040 g, 55%) as a white solid. ESI-MS (M+H) + : 320, 1¹H NMR (400 MHz, CD3OD) δ values ​​were 9.49 (s, 1H), 7.99 (d, J=2.5 Hz, 1H), 7.29 - 7.26 (m, 2H), 5.93 (s, 1H), 5.48 (s, 2H), and 3.98 - 3.97 (m, 3H). No exchangeable protons were observed.

[0285] Synthesis of 2-(4-chlorophenyl)cyclopropane-1-sulfonyl chloride [ka] Synthesis of ethyl 2-(3-chlorophenyl)cyclopropane-1-sulfonate. Ethyl diazomethanesulfonate (240 mg, 1.6 mmol) in 6 mL of DCM was added dropwise to a solution of 1-chloro-3-vinylbenzene (0.3 mL, 2.40 mmol) in 8 mL of DCM at room temperature over 2 hours. The resulting mixture was stirred for 18 hours. The mixture was concentrated under vacuum and used in the next step without further purification.

[0286] Synthesis of potassium 2-(3-chlorophenyl)cyclopropane-1-sulfonate. Ethyl 2-(3-chlorophenyl)cyclopropane-1-sulfonate (417 mg, 1.60 mmol) was added to a mixture of potassium thiocyanate (163 mg, 1.68 mmol) in 1,2-DME (5 mL) and water (5 mL), and the reaction was heated at 80°C for 4 hours. The mixture was diluted with water, washed with ethyl acetate, and the aqueous phase was concentrated under a stream of N2. The residue was dried under vacuum and used in the next step without further purification. 1 H NMR (400 MHz, DMSO) δ 7.34 - 7.10 (m, 4H), 2.35 - 2.30 (m, 1H), 2.26 - 2.20 (m, 1H), 1.34 - 1.26 (m, 1H), 1.10 - 1.05 (m, 1H).

[0287] Synthesis of 2-(3-chlorophenyl)cyclopropane-1-sulfonyl chloride. A mixture of potassium 2-(3-chlorophenyl)cyclopropane-1-sulfonate (100 mg, 0.369 mmol) and thionyl chloride (1.1 mL, 14.77 mmol) in DMF (0.1 mL) was heated at 75°C for 4 hours and concentrated under vacuum. The residue was dissolved in ethyl acetate, washed with water and brine, dried in (MgSO4), and concentrated under vacuum to obtain the title compound, which was used directly in the next step without further purification.

[0288] Synthesis of 2-(3-chlorophenyl)-N-(6-chloropyrimidine-4-yl)cyclopropane-1-sulfonamide [ka] NaH (60% in mineral oil, 0.075 g, 0.19 mmol) was added to a stirred solution of 6-chloropyrimidine-4-amine (0.024 g, 0.19 mmol) in DMF (1.5 mL). After 10 minutes, a solution of 2-(3-chlorophenyl)cyclopropane-1-sulfonyl chloride (0.047 g, 0.19 mmol) in DMF (0.5 mL) was added dropwise. The mixture was stirred at room temperature for 18 hours. The mixture was quenched with water and extracted with SiO(3×). The combined organic layers were dried over (MgSO4), filtered, and concentrated under vacuum to obtain the title compound as a brown gum-like substance, which was used directly without further purification.

[0289] Synthesis of (6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methanamine [ka] Synthesis of 5-Cyclopropylpyridine-2-amine. A mixture of 5-bromopyridine-2-amine (2.0 g, 12 mmol), cyclopropylboronic acid (2.5 g, 29 mmol), and K3PO4 (8.6 g, 40 mmol) in toluene (40 mL) and water (2.0 mL) was degassed with N2 for 10 minutes. Pd(OAc)2 (0.26 g, 1.2 mmol) and PCy3 (0.65 g, 2.3 mmol) were added, and the reaction mixture was degassed for a further 5 minutes. Then, it was heated to 90°C and stirred for 18 hours. The reaction mixture was cooled to room temperature, diluted with water (60 mL), and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were dried over MgSO4 and concentrated under vacuum. The residue was purified by silica gel chromatography eluting under a concentration gradient of 30–100% ethyl acetate in isohexane to obtain the title compound (1.1 g, 71%) as a pale yellow solid. ESI-MS (M+H) + : 135. 1 H NMR (400 MHz, CDCl3) δ 7.91 (d, J=1.8 Hz, 1H), 7.12 (dd, J=2.1, 8.5 Hz, 1H), 6.43 (d, J=8.6 Hz, 1H), 4.34 - 4.19 (m, 2H), 1.82 - 1.72 (m, 1H), 0.91 - 0.84 (m, 2H), 0.60 - 0.54 (m, 2H).

[0290] Synthesis of 6-cyclopropylimidazo[1,2-a]pyridine-2-carboxylate ethyl. A mixture of 5-cyclopropylpyridine-2-amine (1.2 g, 8.6 mmol) and 3-bromo-2-oxopropanoate ethyl (1.7 g, 8.6 mmol) in anhydrous THF (50 mL) was stirred under reflux for 18 hours. The reaction mixture was cooled to room temperature, the precipitate was filtered, washed with Et2O, and dried under vacuum. The residue was purified by silica gel chromatography eluting under a concentration gradient of 30-100% ethyl ethyl phosphate in isohexane to obtain the title compound (0.93 g, 46%) as a colorless solid. ESI-MS (M+H) + : 231, 1H NMR (400 MHz, CDCl3) δ 8.09 (s, 1H), 7.90 (d, J=0.5 Hz, 1H), 7.57 (d, J=9.4 Hz, 1H), 6.99 (dd, J=1.8, 9.4 Hz, 1H), 4.45 (q, J=7.1 Hz, 2H), 1.94 - 1.86 (m, 1H), 1.44 (dd, J=7.2, 7.2 Hz, 3H), 1.02 - 0.97 (m, 2H), 0.73 - 0.68 (m, 2H).

[0291] Synthesis of (6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methanol. A solution of 6-cyclopropylimidazo[1,2-a]pyridine-2-carboxylate ethyl (820 mg, 3.6 mmol) in anhydrous DCM (65 mL) was cooled to -10°C, and a solution of DIBAL-H (1.0 M in THF, 14 mL, 14 mmol) was added dropwise. The reaction mixture was stirred at -10°C to 10°C for 30 minutes. Rochelle salt (saturated aqueous solution, 25 mL) was added dropwise at 0°C to quench the reaction mixture, and it was diluted with water (30 mL). The mixture was separated, and the aqueous phase was further extracted with DCM (60 mL). The combined organic layers were filtered through Celite®, dried on hydrophobic frit, and concentrated under vacuum to obtain the title compound (580 mg, 86%) as an off-white solid. ESI-MS (M+H) + : 189.1, 1 H NMR (400 MHz, DMSO) δ 8.34 (d, J=0.5 Hz, 1H), 7.67 (s, 1H), 7.36 (d, J=9.3 Hz, 1H), 6.95 (dd, J=1.8, 9.3 Hz, 1H), 5.13 (dd, J=5.7, 5.7 Hz, 1H), 4.57 (d, J=5.3 Hz, 2H), 1.98 - 1.90 (m, 1H), 0.96 - 0.90 (m, 2H), 0.71 - 0.66 (m, 2H).

[0292] Synthesis of 2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine. A suspension of (6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methanol (250 mg, 1.3 mmol) in thionyl chloride (0.49 mL, 6.7 mmol) was stirred at room temperature for 30 minutes. The mixture was concentrated under vacuum. The residue was dissolved in DCM (20 mL) and added to warm water (20 mL). The mixture was separated, the organic layer was washed with NaHCO3 (saturated aqueous solution, 30 mL), dried on hydrophobic frit, and concentrated under vacuum to obtain the title compound (200 mg, 73%). 1 H NMR (400 MHz, DMSO) δ 8.35 (s, 1H), 7.88 (s, 1H), 7.43 (d, J=9.4 Hz, 1H), 7.03 (dd, J=1.8, 9.4 Hz, 1H), 4.83 (s, 2H), 1.99 - 1.91 (m, 1H), 0.97 - 0.91 (m, 2H), 0.72 - 0.67 (m, 2H).

[0293] Synthesis of 2-(azidomethyl)-6-cyclopropylimidazo[1,2-a]pyridine. 2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine (200 mg, 0.94 mmol) was dissolved in anhydrous DCM (1.0 mL), and sodium azide (120 mg, 1.9 mmol) was added. The reaction mixture was stirred at 50°C for 1 hour. The reaction mixture was cooled to room temperature, diluted with water (5.0 mL), and extracted with DCM (2 × 10 mL). The combined organic layers were dried on hydrophobic frit and concentrated under vacuum to obtain the title compound (190 mg, 92%) as a brown oil. ESI-MS (M+H) + : 214.1, 1 H NMR (400 MHz, DMSO) δ 8.38 (d, J=0.4 Hz, 1H), 7.86 (s, 1H), 7.45 (d, J=9.4 Hz, 1H), 7.03 (dd, J=1.8, 9.3 Hz, 1H), 4.48 (s, 2H), 2.00 - 1.92 (m, 1H), 0.97 - 0.92 (m, 2H), 0.73 - 0.68 (m, 2H).

[0294] Synthesis of (6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methanamine. To a solution of 2-(azidomethyl)-6-cyclopropylimidazo[1,2-a]pyridine (190 mg, 0.80 mmol) in THF (4.0 mL) and water (0.40 mL), PPh3 (420 mg, 1.6 mmol) was added, and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under vacuum. The residue was loaded into an SCX cartridge, washed with DCM and MeOH, and eluted with 3N NH3 in MeOH. The eluate was concentrated under vacuum. The residue was further purified by loading it into an SCX cartridge, washed with DCM, DCM:MeOH (1:1), and MeOH, and eluted with 3N NH3 in MeOH. The eluate was concentrated under vacuum to obtain the title compound (140 mg, 92%) as a yellow oil. ESI-MS (M+H) + : 188.2, 1 ¹H NMR (400 MHz, DMSO) δ values ​​were 8.32 (s, 1H), 7.65 (s, 1H), 7.35 (d, J=9.3 Hz, 1H), 6.94 (dd, J=1.8, 9.3 Hz, 1H), 3.78 (d, J=0.6 Hz, 2H), 1.97 - 1.89 (m, 1H), 0.95 - 0.90 (m, 2H), and 0.71 - 0.66 (m, 2H). No two interchangeable protons were detected.

[0295] Synthesis of 6-chloro-N-((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)pyrimidine-4-amine [ka] A mixture of (6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methanamine (970 mg, 5.17 mmol), 4,6-dichloropyrimidine (700 mg, 4.70 mmol), and DIPEA (2.5 mL, 14.10 mmol) in iPA (50 mL) was heated at 50°C for 18 hours. Water was added, and the solid was filtered and recovered to obtain the title compound (1.38 g, 98%) as a cream-colored solid.1 H NMR (400 MHz, DMSO) δ 8.35 (s, 2H), 8.25 (d, J=4.5 Hz, 1H), 7.73 (s, 1H), 7.47 - 7.40 (m, 1H), 7.04 - 7.02 (m, 1H), 6.68 (s, 1H), 4.66 - 4.66 (m, 2H), 1.97 (dd, J=4.3, 8.3 Hz, 1H), 1.01 - 0.96 (m, 2H), 0.75 - 0.69 (m, 2H).

[0296] Synthesis of 4-chloro-N-((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)pyrimidine-2-amine [ka] A mixture of (6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methanamine (200 mg, 1.1 mmol), 2,4-dichloropyrimidine (160 mg, 1.1 mmol), and DIPEA (0.56 mL, 3.2 mmol) in iPrOH (10 mL) was stirred at 50°C for 16 hours. The reaction mixture was cooled to room temperature and concentrated under vacuum. The residue was purified by silica gel column chromatography eluting with 0-5% MeOH in DCM to obtain the title compound (170 mg, 53%), which was used without further purification. 1 H NMR (400 MHz, DMSO) δ 8.38 - 8.30 (m, 2H), 7.98 - 7.96 (s, 1H), 7.40 (d, J=9.6 Hz, 1H), 7.01 - 6.97 (m, 1H), 6.56 (d, J=6.0 Hz, 1H), 4.60 - 4.55 (d, J=5.2 Hz, 2H), 1.97 - 1.89 (m, 1H), 0.96 - 0.90 (m, 2H), 0.71 - 0.65 (m, 2H).

[0297] Synthesis of 4-((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methoxy)pyridine-2-amine [ka] NaH (60% in mineral oil, 0.023 g, 0.58 mmol) was added to a solution of (6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methanol (0.10 g, 0.53 mmol) in DMF (5.0 mL) under an N2 atmosphere. The mixture was stirred at 0°C for 5 minutes, then at room temperature for 30 minutes. 4-Fluoropyridine-2-amine (0.060 g, 0.53 mmol) was added at 0°C, and the mixture was stirred at 50°C for 5 hours. The mixture was cooled, diluted with water, and extracted with ethyl acetate. The combined organic layers were dried over (MgSO4), filtered, and concentrated under a stream of air. The residue was purified by silica gel column chromatography eluting with 0-10% NH3 / MeOH in DCM to obtain the title compound (0.065 g, 44%) as a beige solid. 1 H NMR (400 MHz, DMSO) δ 8.39 (s, 1H), 7.89 (s, 1H), 7.77 (d, J=5.8 Hz, 1H), 7.48 (d, J=9.3 Hz, 1H), 7.06 (dd, J=1.8, 9.3 Hz, 1H), 6.26 (dd, J=2.3, 6.1 Hz, 1H), 6.11 (d, J=2.3 Hz, 1H), 5.82 (s, 2H), 5.17 (s, 2H), 2.03 - 1.95 (m, 1H), 1.01 - 0.94 (m, 2H), 0.76 - 0.71 (m, 2H).

[0298] Synthesis of 6-((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methoxy)pyrimidine-4-amine [ka] Sodium hydride (60% in mineral oil, 43 mg, 1.06 mmol) was added to a solution of (6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methanol (100 mg, 0.531 mmol) in THF (10 ml) and stirred at room temperature for 2 hours. A solution of 6-chloropyrimidine-4-amine (83 mg, 0.638 mmol) in THF (2 mL) was added, and the mixture was heated at 65°C for 18 hours. The mixture was diluted with water (10 mL) and extracted with EtOAC (100 mL). The organic phase was dried in (MgSO4) and concentrated under vacuum. The title compound was obtained (77 mg, 52%) by purification by silica gel column chromatography eluting under a concentration gradient of 0-10% MeOH in DCM. ESI-MS (M+H) + : 282, 1 H NMR (400 MHz, CDCl3) δ 8.31 (s, 1H), 7.86 (s, 1H), 7.55 (s, 1H), 7.47 (d, J=9.3 Hz, 1H), 6.96 - 6.91 (m, 1H), 5.85 (s, 1H), 5.53 - 5.51 (m, 2H), 4.73 - 4.68 (m, 2H), 1.92 - 1.83 (m, 1H), 0.99 - 0.92 (m, 2H), 0.70 - 0.64 (m, 2H).

[0299] Synthesis of 6-((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methoxy)pyridazine-4-amine [ka] The title compound (110 mg, 25%) was prepared using the same procedure as that used for 6-((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methoxy)pyrimidine-4-amine, with (6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methanol and 6-chloropyridazine-4-amine as coupling partners. ESI-MS (M+H) + : 282, 1¹H NMR (400 MHz, CD3OD) δ values ​​were 8.28 (d, J=2.3 Hz, 1H), 8.24 - 8.22 (m, 1H), 7.83 (d, J=0.6 Hz, 1H), 7.44 (d, J=9.3 Hz, 1H), 7.13 (dd, J=1.7, 9.3 Hz, 1H), 6.19 (d, J=2.3 Hz, 1H), 5.50 (d, J=0.4 Hz, 2H), 2.02 - 1.94 (m, 1H), 1.04 - 0.98 (m, 2H), and 0.78 - 0.73 (m, 2H). No two interchangeable protons were observed.

[0300] N 4 Synthesis of ((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)pyridine-2,4-diamine [ka] A mixture of (6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methaneamine (0.10 g, 0.53 mmol), 4-chloropyridine-2-amine (0.055 g, 0.43 mmol), and DIPEA (0.14 g, 0.80 mmol) in iPrOH (1.0 mL) was stirred in a microwave at 160°C for 1 hour. The mixture was concentrated under vacuum, and the residue was purified by silica gel column chromatography eluting with 1-20% NH3 in MeOH in DCM to obtain the title compound (0.093 g, 41%) as a yellow gum-like substance. ESI-MS (M+H) + : 280.2, 1H NMR (400 MHz, DMSO) δ 8.23 ​​(s, 1H), 7.54 (s, 1H), 7.37 (d, J=6.1 Hz, 1H), 7.30 (d, J=9.3 Hz, 1H), 6.89 (dd, J=1.8, 9.3 Hz, 1H), 6.68 (t, J=5.7 Hz, 1H), 5.88 (dd, J=2.0, 6.1 Hz, 1H), 5.56 - 5.54 (m, 1H), 5.42 (s, 2H), 4.22 (d, J=5.9 Hz, 2H), 1.87 - 1.79 (m, 1H), 0.86 - 0.80 (m, 2H), 0.61 - 0.56 (m, 2H).

[0301] Synthesis of 2-(3-bromo-2-oxopropyl)isoindoline-1,3-dione [ka] A few drops of bromine (7.6 mL, 150 mmol) solution in AcOH (80 mL) were added at 70°C to a stirred solution of 2-(2-oxopropyl)isoindoline-1,3-dione (20 g, 98 mmol). The reaction mixture was stirred until the solution became colorless. The remaining bromine / AcOH solution was then added dropwise over 2 hours. The reaction mixture was stirred at 70°C for a further 2 hours. The mixture was cooled to room temperature and concentrated under vacuum. The residue was dissolved in DCM (300 mL) and washed with Na2S2O3 solution (1.0 M, 75 mL) and Na2CO3 solution (10% aqueous solution, 2 × 150 mL). The organic phase was dried over MgSO4 and concentrated under vacuum. The residue was pulverized with hot diethyl ether, filtered, and dried to obtain the title compound (22.6 g, 81%) as a white solid. 1 H NMR (400 MHz, CDCl3) δ 7.92 - 7.87 (m, 2H), 7.79 - 7.73 (m, 2H), 4.78 (s, 2H), 4.01 (s, 2H).

[0302] Synthesis of 1-(2-(aminomethyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-yl)pyrrolidine-2-one [ka] Synthesis of 3-chloro-5-cyclopropylpyridine-2-amine. A mixture of toluene (120 mL) and water (12 mL) was degassed for 50 minutes. 5-bromo-3-chloropyridine-2-amine (5.0 g, 24 mmol), cyclopropylboronic acid (2.1 g, 24 mmol), SPhos (0.99 g, 2.4 mmol), and K3PO4 (18 g, 84 mmol) were added to the solvent mixture and heated to 100 °C. Pd(OAc)2 (0.27 g, 1.2 mmol) was added, and the reaction mixture was stirred at this temperature for 3 hours. The mixture was cooled to room temperature, filtered through Celite®, and washed with toluene. The combined organic phase was dried over MgSO4 and concentrated under vacuum. The residue was purified by silica gel column chromatography eluting under a concentration gradient of 5-30% siRNA in cyclohexane to obtain the title compound (3.5 g, 85%) as an orange solid. ESI-MS (M+H) + : 169.0, 1 H NMR (400 MHz, CDCl3) δ 7.45 (s, 1H), 6.99 (d, J=1.5 Hz, 1H), 5.10 (s, 2H), 1.88 - 1.80 (m, 1H), 0.98 - 0.86 (m, 2H), 0.66 - 0.61 (m, 2H).

[0303] Synthesis of 2-((8-chloro-6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)isoindoline-1,3-dione. A solution of 2-(3-bromo-2-oxopropyl)isoindoline-1,3-dione (890 mg, 3.1 mmol) and 3-chloro-5-cyclopropylpyridine-2-amine (530 mg, 3.1 mmol) in 1,4-dioxane (11 mL) was heated at 98°C for 17 hours. The mixture was cooled to room temperature and concentrated under vacuum. The mixture was partitioned between DCM (2 × 50 mL) and NaHCO3 (saturated aqueous solution, 50 mL). The combined organic layer was dried over MgSO4 and concentrated under vacuum. The residue was purified by silica gel column chromatography eluting under a concentration gradient of 10–50% siRNA in isohexane to obtain the title compound (880 mg, 84%). ESI-MS (M+H) + : 352.1, 1 H NMR (400 MHz, CDCl3) δ 7.91 - 7.85 (m, 2H), 7.76 - 7.70 (m, 3H), 7.46 (s, 1H), 6.99 (s, 1H), 5.10 (s, 2H), 1.87 - 1.80 (m, 1H), 0.99 - 0.89 (m, 2H), 0.67 - 0.60 (m, 2H).

[0304] Synthesis of 2-((6-cyclopropyl-8-(2-oxopyrrolidine-1-yl)imidazo[1,2-a]pyridine-2-yl)methyl)isoindoline-1,3-dione. Pyrrolidine-2-one (0.65 mL, 8.5 mmol), 2-((8-chloro-6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)isoindoline-1,3-dione (2000 mg, 5.7 mmol), Xantphos (660 mg, 1.1 mmol), and K2CO3 (1600 mg, 11 mmol) were degassed with N2 for 5 minutes. Pd(OAc)2 (130 mg, 0.57 mmol) was added, and the reaction mixture was heated in a microwave at 160°C for 2 hours. The mixture was cooled to room temperature, filtered through Celite®, and concentrated under vacuum. The residue was purified by silica gel chromatography using a concentration gradient of 20–100% siRNA in cyclohexane to obtain the title compound (1.0 g, 44%). ESI-MS (M+H) + : 401.3, 1 H NMR (400 MHz, CDCl3) δ 7.87 (dd, J=3.0, 5.5 Hz, 2H), 7.72 (dd, J=3.1, 5.5 Hz, 2H), 7.69 - 7.68 (m, 1H), 7.45 (s, 1H), 7.24 (d, J=1.5 Hz, 1H), 5.02 (s, 2H), 4.27 (dd, J=7.1, 7.1 Hz, 2H), 2.58 (t, J=8.2 Hz, 2H), 2.22 - 2.13 (m, 2H), 1.90 - 1.82 (m, 1H), 0.95 - 0.89 (m, 2H), 0.68 - 0.62 (m, 2H).

[0305] Synthesis of 1-(2-(aminomethyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-yl)pyrrolidine-2-one. A mixture of 2-((6-cyclopropyl-8-(2-oxopyrrolidine-1-yl)imidazo[1,2-a]pyridine-2-yl)methyl)isoindoline-1,3-dione (1000 mg, 2.5 mmol) and hydrazine hydrate (0.16 mL, 5.0 mmol) in EtOH (15 mL) was stirred at 75°C for 1 hour. The mixture was cooled to room temperature, loaded into an SCX cartridge, washed with 25% MeOH in DCM, and eluted with 25% 7N NH3 in MeOH in DCM. The eluate was concentrated under vacuum to obtain the title compound (600 mg, 89%). ESI-MS (M+H) + : 271.3, 1 ¹H NMR (400 MHz, CDCl3) δ values ​​were 7.77 (s, 1H), 7.40 (s, 1H), 7.19 (d, J=1.5 Hz, 1H), 4.28 (t, J=7.2 Hz, 2H), 3.99 (d, J=0.6 Hz, 2H), 2.62 (t, J=8.2 Hz, 2H), 2.28 - 2.20 (m, 2H), 1.93 - 1.85 (m, 1H), 0.97 - 0.91 (m, 2H), 0.72 - 0.66 (m, 2H). NH2 was not observed.

[0306] Synthesis of 1-(2-(((6-chloropyrimidine-4-yl)amino)methyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-yl)pyrrolidine-2-one [ka] 4,6-dichloropyrimidine (0.12 g, 0.84 mmol), 1-(2-(aminomethyl)-6-cyclopropylimidazo[1,2-a]pyrrolidine-8-yl)pyrrolidine-2-one (0.25 g, 0.92 mmol), and DIPEA (0.44 mL, 2.52 mmol) were heated at 70°C for 1 hour in 2-propanol (5 mL). The mixture was cooled to room temperature, diluted with water (20 mL), and then extracted with DCM (3 × 10 mL). The combined organic matter was dried over MgSO4 and then concentrated under vacuum. The residue was ground with diethyl ether to obtain the crude product, which was used without further purification (0.27 g, 84%). 1 H NMR (400 MHz, DMSO) δ 8.35 (s, 1H), 8.30 (d, J=1.0 Hz, 1H), 8.25 (s, 1H), 7.77 (s, 1H), 7.18 (s, 1H), 6.69 (s, 1H), 4.67 - 4.66 (m, 2H), 4.19 (dd, J=7.1, 7.1 Hz, 2H), 2.02 - 1.93 (m, 1H), 1.32 (dd, J=7.2, 7.2 Hz, 4H), 0.98 (ddd, J=4.4, 6.4, 8.4 Hz, 2H), 0.72 - 0.67 (m, 2H).

[0307] Synthesis of 1-(2-(((6-chloropyrimidine-4-yl)(methyl)amino)methyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-yl)pyrrolidine-2-one [ka] NaH (60% in mineral oil, 0.0048 g, 0.12 mmol) was added to a stirred solution of 1-(2-(((6-chloropyrimidine-4-yl)amino)methyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-yl)pyrrolidine-2-one (0.031 g, 0.080 mmol) in DMF (1.0 mL). The mixture was stirred at room temperature for 30 minutes, then cooled to 5°C, and a solution of MeI (0.16 M, 0.1 mL, 0.080 mmol in DMF) was added. The mixture was stirred at 0°C for 30 minutes, then warmed to room temperature and stirred for 2 hours. Further addition of MeI (0.16 M, 0.1 mL, 0.080 mmol in DMF) was added, and the mixture was stirred at room temperature for 18 hours. The mixture was diluted with water (10 mL) and extracted with siRNA (3 × 2.0 mL). The combined organic materials were washed with brine (saturated aqueous solution), dried (MgSO4), filtered, and concentrated under vacuum to obtain the title compound (0.026 g, 81%) as a brown, sticky residue. ESI-MS (M+H) + : 397.2, 399.2.

[0308] Synthesis of 1-(2-(((2-bromopyridine-4-yl)amino)methyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-yl)pyrrolidine-2-one [ka] A mixture of 2-bromo-4-fluoropyridine (0.057 mL, 0.56 mmol), 1-(2-(aminomethyl)-6-cyclopropylimidazo[1,2-a]pyrrolidine-8-yl)pyrrolidine-2-one (0.15 g, 0.56 mmol), and DIPEA (0.29 mL, 1.7 mmol) in iPrOH (1.0 mL) was stirred at 70°C for 18 hours. The mixture was cooled and concentrated under vacuum. The residue was purified by silica gel column chromatography eluted with 1-20% NH3MeOH in DCM to obtain the title compound (0.12 g, 52%) as a yellow gum-like substance. 1H NMR (400 MHz, DMSO) δ 8.27 (d, J=1.1 Hz, 1H), 7.79 (d, J=5.8 Hz, 1H), 7.74 (s, 1H), 7.43 (t, J=5.8 Hz, 1H), 7.16 - 7.14 (m, 1H), 6.82 (d, J=2.1 Hz, 1H), 6.62 (dd, J=2.1, 5.8 Hz, 1H), 4.40 (d, J=5.8 Hz, 2H), 4.16 (t, J=7.1 Hz, 2H), 2.51 - 2.46 (m, 2H), 2.18 - 2.09 (m, 2H), 2.01 - 1.90 (m, 1H), 0.99 - 0.91 (m, 2H), 0.69 - 0.64 (m, 2H).

[0309] Synthesis of 2-(aminomethyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-carbonitrile hydrochloride [ka] Synthesis of 2-amino-5-cyclopropylnicotinonitrile. A mixture of 2-amino-5-bromonicotinonitrile (2.0 g, 10 mmol), cyclopropylboronic acid (2.2 g, 25 mmol), SPhos (410 mg, 1.0 mmol), and K3PO4 (7.5 g, 35 mmol) in toluene (48 mL) and water (4.8 mL) was degassed with nitrogen. Pd(OAc)2 (110 mg, 0.5 mmol) was added, and the mixture was refluxed and stirred under a nitrogen atmosphere for 6 hours. The reaction product was cooled and filtered with toluene. The filtrate was washed with water, NaOH (2.0 M aqueous solution × 2) and brine (saturated aqueous solution), dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography eluting under a concentration gradient of 10-70% siRNA in isohexane to obtain the title compound (1.2 g, 75%) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 8.10 (d, J=2.4 Hz, 1H), 7.37 (d, J=2.4 Hz, 1H), 5.02 (s, 2H), 1.83 - 1.76 (m, 1H), 0.97 - 0.92 (m, 2H), 0.62 - 0.57 (m, 2H).

[0310] Synthesis of 2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-carbonitrile. A mixture of 2-amino-5-cyclopropylnicotinonitrile (1.1 g, 6.9 mmol) and 1,3-dichloroacetone (1.1 g, 9.0 mmol) was mixed in DMF (50 mL) and stirred at 95°C for 18 hours. The mixture was cooled, diluted with Et2O (250 mL), and filtered. The mixture was washed with water (3 × 100 mL), dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography eluting under a concentration gradient of 10–90% siRNA in isohexane to obtain the title compound (630 mg, 39%) as a purple solid. 1 H NMR (400 MHz, DMSO) δ 8.69 (d, J=1.1 Hz, 1H), 8.05 (s, 1H), 7.80 (d, J=1.6 Hz, 1H), 4.88 (s, 2H), 2.03 - 1.95 (m, 1H), 0.99 - 0.94 (m, 2H), 0.80 - 0.75 (m, 2H).

[0311] Synthesis of 2-(azidomethyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-carbonitride. 2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-carbonitride (630 mg, 2.70 mmol) and NaN3 (230 mg, 3.5 mmol) were mixed in DMF (5.0 mL) and stirred at room temperature under a nitrogen atmosphere for 18 hours. The mixture was diluted with RINKAN (50 mL), washed with water (2 × 50 mL) and brine (50 mL), then dried over MgSO4, filtered, and concentrated under vacuum to obtain the title compound as a purple oil (580 mg, 89%). ESI-MS (M+H) +: 239.2, 1 H NMR (400 MHz, DMSO) δ 8.72 (dd, J=0.5, 1.7 Hz, 1H), 8.02 (s, 1H), 7.80 (d, J=1.8 Hz, 1H), 4.56 (s, 2H), 2.03 - 1.96 (m, 1H), 0.99 - 0.94 (m, 2H), 0.80 - 0.75 (m, 2H).

[0312] Synthesis of 2-(aminomethyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-carbonitride hydrochloride. 2-(azidomethyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-carbonitride (580 mg, 2.4 mmol) and triphenylphosphine (1.3 g, 4.8 mmol) were mixed in THF (11 mL) and water (1.0 mmol) and stirred at room temperature for 24 hours. The mixture was then concentrated under vacuum, dissolved in DCM, and treated with HCl (4.0 M) in dioxane. The precipitate was collected by filtration and washed with DCM to obtain the title compound (630 mg, quantitatively) as a pale yellow solid. ESI-MS (M+H) + : 213.2, 1 H NMR (400 MHz, DMSO) δ 8.81 (s, 1H), 8.38 (br s, 3H), 8.06 (s, 1H), 7.85 (s, 1H), 4.19 (d, J=5.6 Hz, 2H), 2.04 - 1.97 (m, 1H), 1.02 - 0.95 (m, 2H), 0.82 - 0.76 (m, 2H).

[0313] Synthesis of 2-(((6-chloropyrimidine-4-yl)amino)methyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-carbonitrile [ka] DIPEA (0.38 mL, 2.19 mmol) was added to a stirred mixture of 4,6-dichloropyrimidine (160 mg, 1.05 mmol) and 2-(aminomethyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-carbonitrile hydrochloride (250 mg, 0.877 mmol) in iPrOH (7.0 mL). The reaction mixture was then heated at 80°C for 2.5 hours, cooled to room temperature, and poured into water. The resulting precipitate was collected by vacuum filtration and washed with water to obtain the title compound (210 mg, 75%) as a white solid. ESI-MS (M+H) + : 325.1, 1 H NMR (400 MHz, CDCl3) δ 8.40 (s, 1H), 8.07 - 8.06 (m, 1H), 7.56 (s, 1H), 7.42 (d, J=1.6 Hz, 1H), 6.44 (s, 1H), 5.91 (s, 1H), 4.78 - 4.72 (m, 2H), 1.97 - 1.89 (m, 1H), 1.05 (ddd, J=3.6, 4.8, 9.9 Hz, 2H), 0.73 - 0.68 (m, 2H).

[0314] Synthesis of 6-cyclopropyl-2-(hydroxymethyl)imidazo[1,2-a]pyridine-8-carbonitride [ka] A solution of 2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-carbonitrile (710 mg, 2.4 mmol) in water (6.0 mL) and DMSO (6.0 mL) was heated to 80°C and stirred for 16 hours. The mixture was allowed to cool to room temperature, packed into an SCX cartridge, washed with MeOH and 50% MeOH in DCM, and eluted with 7N NH3 in MeOH. The eluate was concentrated under vacuum. The residue was purified by silica gel column chromatography eluting with a concentration gradient of 0-10% MeOH in DCM to obtain two fractions. The impure fraction was ground with DCM and combined with the previously isolated fraction, and concentrated under vacuum to obtain the title compound (310 mg, 59%). ESI-MS (M+H) +: 214.2

[0315] Synthesis of 2-(((6-chloropyrimidine-4-yl)oxy)methyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-carbonitrile [ka] 6-Cyclopropyl-2-(hydroxymethyl)imidazo[1,2-a]pyridine-8-carbonitrile (0.10 g, 0.47 mmol) was added to a stirred suspension of NaH (60% in mineral oil, 0.021 g, 0.52 mmol) in THF (10 mL), and the mixture was stirred at room temperature for 30 minutes. A solution of 4,6-dichloropyrimidine (0.084 g, 0.57 mmol) in THF (2.0 mL) was added dropwise, and the mixture was stirred at room temperature for 3.5 hours. Water was added, and the mixture was extracted with DCM (×3), passed through a phase separation cartridge, and concentrated under vacuum. The residue was ground with Et2O, filtered, and dried under vacuum to obtain the title compound (0.12 g, 76%) as a beige solid. 1 H NMR (400 MHz, DMSO) δ 8.86 - 8.79 (m, 2H), 8.20 - 8.17 (m, 1H), 7.93 - 7.90 (m, 1H), 7.39 (s, 1H), 5.71 - 5.68 (m, 2H), 2.14 - 2.06 (m, 1H), 1.11 - 1.04 (m, 2H), 0.89 - 0.85 (m, 2H).

[0316] Synthesis of 2-(((2-aminopyridine-4-yl)amino)methyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-carbonitrile [ka] 2-(aminomethyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-carbonitrile hydrochloride (0.075 g, 0.26 mmol), 4-fluoropyridine-2-amine (0.020 mL, 0.26 mmol), and DIPEA (0.18 mL, 1.1 mmol) were degassed with N2 in iPrOH (5.0 mL) and sealed. The mixture was heated in a microwave at 120°C for 30 minutes, then for a further 1 hour. The mixture was heated in a microwave at 140°C for 1 hour, then at 150°C for 6 hours. Water was added, and the mixture was extracted with ELISA. The combined organic layer was passed through hydrophobic frit and concentrated under vacuum. The residue was purified by silica gel column chromatography eluted with 0-20% NH3 / MeOH in DCM to obtain the title compound (0.042 g, 53%). ESI-MS (M+H) + : 305.2.

[0317] Synthesis of 3-(2-(aminomethyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-yl)oxetan-3-ol [ka] Synthesis of 3-(2-amino-5-chloropyridine-3-yl)oxetan-3-ol. n-BuLi (2.4 M in hexane, 9.2 mL, 22 mmol) was added dropwise to a stirred solution of 3-bromo-5-chloropyridine-2-amine (1.1 g, 5.5 mmol) in anhydrous THF (40 mL) under a nitrogen atmosphere at -70°C. The mixture was stirred at -70°C for 1 hour, and then a solution of oxetan-3-one (1.8 mL, 22 mmol) in THF (10 mL) was slowly added over 10 minutes. The resulting mixture was warmed to room temperature and stirred for 1 hour. NH4Cl (saturated aqueous solution, 15 mL) was added, and the mixture was extracted with siRNA (3 × 25 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography using a concentration gradient of 0-10% MeOH in DCM to obtain the title compound as a light brown solid (460 mg, 42%). ESI-MS (M+H) + : 201.1, 1H NMR (400 MHz, CDCl3) δ 8.01 (d, J=2.4 Hz, 1H), 7.45 (d, J=2.4 Hz, 1H), 5.04 - 5.00 (m, 4H), 4.90 - 4.87 (m, 2H), 2.76 (br s, 1H).

[0318] Synthesis of 3-(2-amino-5-cyclopropylpyridine-3-yl)oxetan-3-ol. A mixture of 3-(2-amino-5-chloropyridine-3-yl)oxetan-3-ol (550 mg, 2.8 mmol), cyclopropylboronic acid (350 mg, 4.1 mmol), SPhos (110 mg, 0.28 mmol), Pd(OAc)2 (62 mg, 0.28 mmol), and K3PO4 (2.1 g, 9.6 mmol) in toluene (30 mL) and water (3.0 mL) was degassed with nitrogen and then stirred at 100 °C for 18 hours under a nitrogen atmosphere. The mixture was cooled, filtered through Celite®, and washed with  (75 mL). The combined filtrate was dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography using a concentration gradient of 0-10% MeOH in DCM to obtain the title compound as a pale yellow solid (400 mg, 70%). ESI-MS (M+H) + : 207.1, 1 H NMR (400 MHz, CDCl3) δ 7.85 (d, J=1.9 Hz, 1H), 7.16 (d, J=2.3 Hz, 1H), 5.07 (dd, J=0.8, 7.3 Hz, 2H), 4.89 (dd, J=0.8, 7.3 Hz, 2H), 4.75 (br s, 2H), 2.95 (br s, 1H), 1.85 - 1.78 (m, 1H), 0.94 - 0.88 (m, 2H), 0.62 - 0.57 (m, 2H).

[0319] Synthesis of 2-((6-cyclopropyl-8-(3-hydroxyoxetan-3-yl)imidazo[1,2-a]pyridine-2-yl)methyl)isoindoline-1,3-dione. A mixture of 3-(2-amino-5-cyclopropylpyridine-3-yl)oxetan-3-ol (210 mg, 1.0 mmol) and 2-(3-bromo-2-oxopropyl)isoindoline-1,3-dione (280 mg, 1.0 mmol) in 1,4-dioxane (4.0 mL) was stirred at 80°C for 18 hours. The mixture was cooled to room temperature and diluted with ethyl acetate and K2CO3 (10% aqueous solution). The mixture was separated, and the aqueous layer was further extracted with ethyl acetate. The combined organic layers were washed with brine (saturated aqueous solution), dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography using a concentration gradient of 1-6% MeOH in DCM to obtain the title compound as a pale yellow solid (210 mg, 54%). ESI-MS [M+H] + : 390.2, 1 H NMR (400 MHz, CDCl3) δ 7.88 - 7.85 (m, 2H), 7.76 - 7.75 (m, 1H), 7.74 - 7.71 (m, 2H), 7.47 (s, 1H), 7.36 (s, 1H), 7.24 (d, J=1.6 Hz, 1H), 5.02 - 4.99 (m, 4H), 4.77 (d, J=7.3 Hz, 2H), 2.01 - 1.88 (m, 1H), 1.01 - 0.95 (m, 2H), 0.70 - 0.65 (m, 2H).

[0320] Synthesis of 3-(2-(aminomethyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-yl)oxetan-3-ol. A mixture of 2-((6-cyclopropyl-8-(3-hydroxyoxetan-3-yl)imidazo[1,2-a]pyridine-2-yl)methyl)isoindoline-1,3-dione (120 mg, 0.31 mmol) and hydrazine hydrate (87 μL, 1.8 mmol) in EtOH (3.0 mL) was heated under reflux for 1 hour. The mixture was cooled to room temperature, filtered, and concentrated under vacuum. The residue was redissolved in MeOH, filtered, and concentrated under vacuum. The residue was purified by reverse-phase silica gel column chromatography eluting under a concentration gradient of 30% MeCN (0.1% ((NH4)2CO3) in water to obtain the title compound (0.029 g, 36%) as an off-white solid. 1 ¹H NMR (400 MHz, CD3OD) δ values ​​were 8.19 (s, 1H), 7.84 (s, 1H), 7.21 (s, 1H), 5.37 (d, J=6.8 Hz, 2H), 4.25 (s, 2H), 3.35 (s, 2H), 2.04 - 1.94 (m, 1H), 1.03 - 0.96 (m, 2H), and 0.76 - 0.71 (m, 2H). No exchangeable protons were observed.

[0321] Synthesis of 3-(2-(((6-chloropyrimidine-4-yl)amino)methyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-yl)oxetan-3-ol [ka] A mixture of 3-(2-(aminomethyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-yl)oxetan-3-ol (0.25 g, 1.3 mmol), 4,6-dichloropyrimidine (0.18 g, 1.2 mmol), and DIPEA (0.63 mL, 3.6 mmol) in iPrOH (10 mL) was stirred at 50°C for 3 hours. The mixture was cooled, packed onto silica gel, and purified by silica gel column chromatography eluted with 0-10% MeOH in DCM to obtain the title compound (0.064 g, 35%). 1H NMR (400 MHz, DMSO) δ 8.35 - 8.30 (m, 3H), 7.75 (s, 1H), 7.10 (s, 1H), 6.68 (s, 1H), 6.52 (s, 1H), 5.31 - 5.27 (m, 2H), 4.74 - 4.68 (m, 4H), 2.05 - 1.95 (m, 1H), 1.00 - 0.94 (m, 2H), 0.76 - 0.71 (m, 2H).

[0322] Synthesis of (6-cyclopropyl-8-(3-fluorooxetan-3-yl)imidazo[1,2-a]pyridine-2-yl)methanamine [ka] Synthesis of 2-((6-cyclopropyl-8-(3-fluorooxetan-3-yl)imidazo[1,2-a]pyridine-2-yl)methyl)isoindoline-1,3-dione. Deoxofluor® (50% in THF, 0.6 mL, 1.6 mmol) was added at -70°C to a solution of 2-((6-cyclopropyl-8-(3-hydroxyoxetan-3-yl)imidazo[1,2-a]pyridine-2-yl)methyl)isoindoline-1,3-dione (420 mg, 1.1 mmol) in DCM (20 mL). The mixture was warmed to 0°C and stirred for 3 hours. Further addition of Deoxofluor® (50% in THF, 0.3 mL, 0.82 mmol) was added, and the mixture was stirred at 0°C for a further 2 hours. The mixture was warmed to room temperature and stirred for 18 hours. The mixture was cooled to 0°C, and 15 mL of NaHCO3 (saturated aqueous solution) was added. The mixture was separated, the organic layer was dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography eluting under a concentration gradient of 20–60% siRNA in cyclohexane to obtain the title compound (190 mg, 44%) as a colorless solid. ESI-MS (M+H) + : 392.1, 1H NMR (400 MHz, CDCl3) δ 7.91 - 7.86 (m, 2H), 7.79 (s, 1H), 7.75 - 7.70 (m, 2H), 7.43 (s, 1H), 6.95 (s, 1H), 5.53 - 5.41 (m, 2H), 5.08 (s, 2H), 5.06 - 4.95 (m, 2H), 1.90 - 1.82 (m, 1H), 0.98 - 0.90 (m, 2H), 0.66 - 0.60 (m, 2H).

[0323] Synthesis of (6-cyclopropyl-8-(3-fluorooxetan-3-yl)imidazo[1,2-a]pyridine-2-yl)methaneamine. A mixture of 2-((6-cyclopropyl-8-(3-fluorooxetan-3-yl)imidazo[1,2-a]pyridine-2-yl)methyl)isoindoline-1,3-dione (180 mg, 0.46 mmol) and hydrazine monohydrate (67 μL, 1.4 mmol) in EtOH (5 mL) was stirred under reflux for 1 hour. The mixture was cooled and concentrated under vacuum. The residue was dissolved in a mixture of DCM / MeOH (9:1, 8 mL), filtered, and concentrated under vacuum to obtain the title compound (110 mg, 95%) as a viscous, light brown oil. ESI-MS (M+H) + : 262.0, 1 ¹H NMR (400 MHz, CDCl3) δ 7.88 (s, 1H), 7.44 (s, 1H), 6.97 (s, 1H), 5.56 - 5.46 (m, 2H), 5.14 - 5.04 (m, 2H), 4.02 (s, 2H), 1.01 - 0.93 (m, 2H), 0.70 - 0.64 (m, 2H). No exchangeable protons were observed, and the cyclopropyl CH signal was obscured by the water signal.

[0324] 6-Chloro-N-((6-cyclopropyl-8-(3-fluorooxetan-3-yl)imidazo[1,2-a]pyridine-2-yl)methyl)pyrimidine-4-amine [ka] A mixture of (6-cyclopropyl-8-(3-fluorooxetan-3-yl)imidazo[1,2-a]pyridine-2-yl)methanamine (0.73 g, 0.28 mmol), 4,6-dichloropyrimidine (0.042 g, 0.28 mmol), and DIPEA (0.15 mL, 0.84 mmol) in MeCN (2.0 mL) was stirred under reflux for 6 hours. The mixture was cooled and concentrated under vacuum. The residue was purified by silica gel column chromatography eluted with 1-6% MeOH in DCM to obtain the title compound (0.071 g, 67%) as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ 8.39 (s, 1H), 7.88 (s, 1H), 7.49 - 7.46 (m, 1H), 7.04 - 7.01 (m, 1H), 6.50 - 6.47 (m, 1H), 5.88 (s, 1H), 5.49 (dd, J=8.0, 26.1 Hz, 2H), 5.10 (dd, J=8.0, 23.1 Hz, 2H), 4.68 - 4.68 (m, 2H), 1.95 - 1.86 (m, 1H), 1.02 - 0.96 (m, 2H), 0.71 - 0.65 (m, 2H).

[0325] Synthesis of (6-cyclopropyl-8-(4-methylpiperazin-1-yl)imidazo[1,2-a]pyridine-2-yl)methanamine [ka] Synthesis of 2-((8-bromo-6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)isoindoline-1,3-dione. A solution of 2-(3-bromo-2-oxopropyl)isoindoline-1,3-dione (12 g, 39 mmol), 3-bromo-5-cyclopropylpyridine-2-amine (7.5 g, 35 mmol), and DIPEA (9.2 mL, 53 mmol) in 1,4-dioxane (350 mL) was heated at 100 °C for 16 hours. The mixture was cooled to room temperature and its volume was reduced by half by concentration in a vacuum. The mixture was diluted with DCM (200 mL) and washed with NaHCO3 solution (saturated aqueous solution, 150 mL) and brine (150 mL). The organic matter was dried over MgSO4 and concentrated in a vacuum. The residue was purified by silica gel chromatography using a concentration gradient of 0-100% ethyl acetate in cyclohexane to obtain the title compound (7.2 g, 52%). ESI-MS (M+H) + : 396.1, 398.1, 1 H NMR (400 MHz, DMSO) δ 8.35 (d, J=1.0 Hz, 1H), 7.99 - 7.94 (m, 2H), 7.94 - 7.91 (m, 3H), 7.39 (d, J=1.5 Hz, 1H), 4.94 (s, 2H), 2.02 - 1.94 (m, 1H), 0.96 (m, 2H), 0.76 - 0.71 (m, 2H).

[0326] Synthesis of (8-bromo-6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methaneamine. A mixture of 2-((8-bromo-6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)isoindoline-1,3-dione (1.0 g, 2.5 mmol) and hydrazine monohydrate (0.79 mL, 13 mmol) in EtOH (25 mL) was stirred at 80°C for 1 hour. The mixture was cooled and filtered through Celite®. The residue was dissolved in a 3:1 DCM / MeOH mixture, loaded into an SCX cartridge, washed with the same solvent mixture, and eluted with a 3:1 DCM / 7N NH3 mixture in MeOH. The eluate was concentrated under vacuum to obtain the title compound (700 mg, quantitative). ESI-MS (M+H) + : 266.2, 268.2.

[0327] Synthesis of ((8-bromo-6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)carbamate tert-butyl. A mixture of (8-bromo-6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methaneamine (700 mg, 2.6 mmol), di-tert-butyl dicarbonate (0.73 mL, 3.2 mmol), and Et3N (0.55 mL, 4.0 mmol) in DCM (20 mL) was stirred at room temperature for 2 hours. The reaction mixture was diluted with DCM (50 mL) and washed with NaHCO3 (saturated aqueous solution, 50 mL) and brine (saturated aqueous solution, 100 mL). The organic matter was dried over MgSO4 and concentrated under vacuum. The residue was purified by silica gel chromatography eluting under a concentration gradient of 0-100% ethyl ethyl in isohexane to obtain the title compound (760 mg, 79%). ESI-MS (M+H) + : 366.3, 368.3, 1H NMR (400 MHz, CDCl3) δ 7.83 (s, 1H), 7.52 (s, 1H), 7.20 (d, J=1.5 Hz, 1H), 5.23 (s, 1H), 4.46 (d, J=5.9 Hz, 2H), 1.91 - 1.83 (m, 1H), 1.53 - 1.52 (m, 9H), 1.00 - 0.94 (m, 2H), 0.70 - 0.65 (m, 2H).

[0328] Synthesis of tert-butyl ((6-cyclopropyl-8-(4-methylpiperazine-1-yl)imidazo[1,2-a]pyridine-2-yl)methyl)carbamate. A mixture of 1-methylpiperazine (0.35 mL, 3.1 mmol), tert-butyl ((8-bromo-6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)carbamate (760 mg, 2.1 mmol), Xantphos (240 mg, 0.42 mmol), and Cs2CO3 (1400 mg, 4.2 mmol) in 1,4-dioxane (20 mL) was degassed with N2 for 5 minutes. Pd(OAc)2 (190 mg, 0.21 mmol) was added, and the reaction mixture was stirred at 100°C for 3 hours. The mixture was cooled to room temperature, filtered through Celite®, and concentrated under vacuum. The residue was purified by silica gel column chromatography using a concentration gradient of 0-20% 7N NH3 in MeOH in DCM to obtain the title compound (560 mg, 70%). ESI-MS (M+H) + : 386.5, 1 H NMR (400 MHz, CDCl3) δ 7.49 - 7.48 (m, 1H), 7.32 (s, 1H), 6.20 - 6.19 (m, 1H), 5.19 (s, 1H), 4.43 - 4.39 (m, 2H), 3.52 - 3.49 (m, 4H), 2.72 - 2.66 (m, 4H), 2.39 (s, 3H), 1.87 - 1.79 (m, 1H), 1.45 (s, 9H), 0.94 - 0.87 (m, 2H), 0.67 - 0.61 (m, 2H).

[0329] Synthesis of (6-cyclopropyl-8-(4-methylpiperazin-1-yl)imidazo[1,2-a]pyridine-2-yl)methanamine. A mixture of ((6-cyclopropyl-8-(4-methylpiperazin-1-yl)imidazo[1,2-a]pyridine-2-yl)methyl)carbamate tert-butyl (560 mg, 1.5 mmol) and TFA (2.2 mL, 29 mmol) in DCM (15 mL) was stirred at room temperature for 16 hours. The reaction mixture was concentrated under vacuum and packed into an SCX cartridge. This cartridge was washed with 25% MeOH in DCM and eluted with 25% 7N NH3 in MeOH in DCM. The eluate was concentrated under vacuum to obtain the title compound (400 mg, 96%). ESI-MS (M+H) + : 286.4, 1 ¹H NMR (400 MHz, CDCl3) δ values ​​were 7.51 - 7.49 (m, 1H), 7.29 - 7.28 (m, 1H), 6.19 (d, J=1.4 Hz, 1H), 3.96 (s, 2H), 3.53 (s, 4H), 2.72 - 2.66 (m, 4H), 2.39 - 2.38 (m, 3H), 1.88 - 1.78 (m, 1H), 0.94 - 0.87 (m, 2H), and 0.67 - 0.62 (m, 2H). No two interchangeable protons were observed.

[0330] Synthesis of 6-bromo-N-((6-cyclopropyl-8-(4-methylpiperazin-1-yl)imidazo[1,2-a]pyridine-2-yl)methyl)pyrimidine-4-amine [ka] A mixture of 4,6-dibromopyrimidine (0.18 g, 0.74 mmol), (6-cyclopropyl-8-(4-methylpiperazin-1-yl)imidazo[1,2-a]pyridine-2-yl)methanamine (0.20 g, 0.70 mmol), and DIPEA (0.24 mL, 1.4 mmol) in iPrOH (5.0 mL) was stirred at 80°C for 4 hours. The mixture was cooled and concentrated under vacuum. The residue was purified by silica gel column chromatography eluted with 0-20% NH3 / MeOH in DCM to obtain the title compound (0.095 g, 31%), which was used directly in the next step. ESI-MS (M+H) + : 442.3.

[0331] Synthesis of 4-(2-(7-chloroimidazo[1,5-a]pyridine-1-yl)acetamide)-6-(((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)amino)pyrimidine-2-carboxylate ethyl [ka] Synthesis of ethyl 4,6-dichloropyrimidine-2-carboxylate. A mixture of 4,6-dichloropyrimidine-2-carboxylic acid (0.30 g, 1.6 mmol) and H2SO4 (0.008 mL, 0.16 mmol) in EtOH (8.0 mL) was stirred at 80°C for 18 hours. The mixture was concentrated under vacuum. The residue was redissolved in DCM, washed with NaHCO3 (saturated aqueous solution), and concentrated under vacuum to obtain the title compound (0.27 g, 78%) as a colorless oil, which was used directly in the next step.

[0332] Synthesis of ethyl 4-chloro-6-(((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)amino)pyrimidine-2-carboxylate. A mixture of ethyl 4,6-dichloropyrimidine-2-carboxylate (0.17 g, 0.77 mmol), (6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methanamine (0.12 g, 0.64 mmol), and DIPEA (0.28 mL, 1.6 mmol) in iPrOH (10 mL) was stirred at 70°C for 1 hour. The mixture was diluted with DCM (100 mL), washed with water (30 mL), passed through a phase separation cartridge, and concentrated under vacuum. The residue was purified by silica gel column chromatography eluting with 0-100% DCM in ethyl phosphate to obtain the title compound (0.20 g, 85%) as an off-white solid. ESI-MS (M+H) + : 372, 1 ¹H NMR (400 MHz, CD3OD) δ values ​​were 8.18 (s, 1H), 7.73 (s, 1H), 7.43 - 7.39 (m, 1H), 7.13 - 7.07 (m, 1H), 6.74 - 6.69 (m, 1H), 4.81 (s, 2H), 4.43 (q, J=7.2 Hz, 2H), 2.00 - 1.92 (m, 1H), 1.45 - 1.40 (m, 3H), 1.02 - 0.97 (m, 2H), 0.76 - 0.71 (m, 2H). No exchangeable protons were observed.

[0333] N 5 Synthesis of ((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)pyridazine-3,5-diamine [ka] Synthesis of 6-chloro-N-((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)pyridazin-4-amine. 3,5-dichloropyridazine (240 mg, 1.61 mmol) was added to a suspension of (6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methanamine hydrochloride (300 mg, 1.34 mmol) and TEA (0.56 mL, 4.02 mmol) in iPA (3 mL). The resulting mixture was heated at 85°C for 18 hours. The mixture was diluted with water, filtered, and the solid was dried to obtain the title compound (265 mg, 66%) as a brown solid. ESI-MS(M+H) + : 300.0 / 302.0, 1 H NMR (400 MHz, DMSO) δ 8.67 - 8.61 (m, 1H), 8.36 - 8.32 (m, 1H), 7.90 (s, 1H), 7.76 (s, 1H), 7.45 - 7.38 (m, 1H), 7.04 - 6.97 (m, 1H), 6.85 - 6.81 (m, 1H), 4.46 (d, J=4.9 Hz, 2H), 1.98 - 1.90 (m, 1H), 0.97 - 0.88 (m, 2H), 0.69 - 0.64 (m, 2H).

[0334] Synthesis of N-((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)-6-(methoxyamino)pyridazin-4-amine. O-methylhydroxylamine hydrochloride (1.09 g, 13.0 mmol) was added to a solution of 6-chloro-N-((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)pyridazin-4-amine (260 mg, 0.867 mmol) in EtOH (14 mL) and heated at 80°C for 18 hours. The mixture was concentrated under vacuum, dissolved in DCM, and washed with NaHCO3 (saturated aqueous solution). The organic phase was concentrated under vacuum to obtain the title compound (263 mg, 53%) as a brown solid. ESI-MS (M+H) + : 311.2.

[0335] N 5Synthesis of -((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)pyridazin-3,5-diamine. Iron powder (215 mg, 3.85 mmol) was added to a mixture of N-((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)-6-(methoxyamino)pyridazin-4-amine (240 mg, 0.771 mmol) and AcOH (20% aqueous solution, 1.8 mL) in EtOH (12 mL), and the mixture was heated at 60°C for 18 hours. An additional amount of iron powder (215 mg, 3.85 mmol) was added, and heating was continued for a further 4 hours. The mixture was filtered through Celite® and concentrated under vacuum. The title compound was obtained by purification by silica gel column chromatography eluting under a concentration gradient of 0-10% 7N NH3 / MeOH in DCM (91 mg, 45%). ESI-MS (M+H) + : 281.2, 1 H NMR (400 MHz, DMSO) δ 8.34 - 8.31 (m, 1H), 8.02 (d, J=2.3 Hz, 1H), 7.67 - 7.65 (m, 1H), 7.42 - 7.38 (m, 1H), 7.07 (t, J=5.5 Hz, 1H), 6.99 (q, J=3.6 Hz, 1H), 5.78 (s, 2H), 5.73 (d, J=2.1 Hz, 1H), 4.35 - 4.31 (m, 2H), 1.93 - 1.90 (m, 1H), 0.96 - 0.89 (m, 2H), 0.71 - 0.64 (m, 2H).

[0336] N 4 Synthesis of ((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)pyrimidine-4,6-diamine [ka] N 5The title compound (32 mg, 63%) was prepared using the same procedure as that used for -((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)pyridazine-3,5-diamine, with 4,6-dichloropyrimidine and (6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methanamine hydrochloride as coupling partners. 1 H NMR (400 MHz, DMSO) δ 8.35 - 8.32 (m, 1H), 7.94 - 7.91 (m, 1H), 7.64 - 7.60 (m, 1H), 7.43 - 7.37 (m, 1H), 7.11 - 7.07 (m, 1H), 7.00 (d, J=9.1 Hz, 1H), 6.16 - 6.10 (m, 2H), 5.49 - 5.45 (m, 1H), 4.51 - 4.44 (m, 2H), 1.98 - 1.90 (m, 1H), 0.98 - 0.91 (m, 2H), 0.70 - 0.69 (m, 2H).

[0337] Synthesis of 5-((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methoxy)pyridazine-3-amine [ka] Synthesis of 2-(((6-chloropyridazine-4-yl)oxy)methyl)-6-cyclopropylimidazo[1,2-a]pyridine. Sodium hydride (60% in mineral oil, 145 mg, 3.61 mmol) was added at 0°C to a chilled solution of (6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methanol (400 mg, 2.13 mmol) in DMF (8 ml) and stirred for 2 hours. A solution of 3,5-dichloropyridazine (380 mg, 2.55 mmol) in DMF (1 mL) was added, and the mixture was warmed to room temperature and stirred for 18 hours. The mixture was diluted with water (40 mL), extracted with DCM (200 mL), and the organic phase was passed through a phase separation cartridge and concentrated under vacuum. The title compound was obtained by purification by silica gel column chromatography eluting at a concentration gradient of 0 to 100% siRNA in DCM (290 mg, 45%). 1 H NMR (400 MHz, CDCl3) δ 8.91 (d, J=2.5 Hz, 1H), 7.89 (s, 1H), 7.57 (s, 1H), 7.49 (d, J=9.3 Hz, 1H), 7.18 (d, J=2.5 Hz, 1H), 7.00 (dd, J=1.5, 9.3 Hz, 1H), 5.34 (s, 2H), 1.94 - 1.86 (m, 1H), 1.02 - 0.95 (m, 2H), 0.72 - 0.65 (m, 2H).

[0338] Synthesis of N-(5-((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methoxy)pyridazin-3-yl)-O-methylhydroxylamine. O-methylhydroxylamine hydrochloride (833 mg, 9.98 mmol) was added to a solution of 2-(((6-chloropyridazin-4-yl)oxy)methyl)-6-cyclopropylimidazo[1,2-a]pyridine (200 mg, 0.665 mmol) in EtOH and heated at 85°C for 18 hours. The mixture was diluted with DCM (100 mL), washed with NaHCO3 (50 mL saturated aqueous solution), passed through a phase separation cartridge, and concentrated under vacuum. The title compound was obtained by purification by silica gel column chromatography eluting under a concentration gradient of 0-10% MeOH in DCM (110 mg, 53%). 1H NMR (400 MHz, CDCl3) δ 9.31 (s, 1H), 7.89 - 7.87 (m, 1H), 7.54 (s, 1H), 7.47 (d, J=9.3 Hz, 1H), 7.15 (s, 1H), 6.99 - 6.94 (m, 1H), 5.94 - 5.90 (m, 1H), 5.08 (s, 2H), 3.80 - 3.79 (m, 3H), 1.94 - 1.85 (m, 1H), 1.01 - 0.94 (m, 2H), 0.71 - 0.65 (m, 2H).

[0339] Synthesis of 5-((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methoxy)pyridazin-3-amine. Iron powder (215 mg, 3.85 mmol) was added to a mixture of N-(5-((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methoxy)pyridazin-3-yl)-O-methylhydroxylamine (240 mg, 0.771 mmol) and AcOH (20% aqueous solution, 1.8 mL) in EtOH (12 mL), and the mixture was heated at 60°C for 18 hours. An additional amount of iron powder (215 mg, 3.85 mmol) was added, and heating was continued for a further 4 hours. The mixture was filtered through Celite® and concentrated under vacuum. The title compound was obtained by purification by silica gel column chromatography eluting under a concentration gradient of 0-10% 7N NH3 / MeOH in DCM (91 mg, 45%). 1 ¹H NMR (400 MHz, CD3OD) δ values ​​were 8.24 (s, 1H), 8.22 (d, J=2.6 Hz, 1H), 7.88 - 7.87 (m, 1H), 7.47 - 7.44 (m, 1H), 7.17 - 7.13 (m, 1H), 6.55 - 6.54 (m, 1H), 5.29 - 5.28 (m, 2H), 2.02 - 1.94 (m, 1H), 1.04 - 0.98 (m, 2H), and 0.78 - 0.73 (m, 2H). No two interchangeable protons were observed.

[0340] Synthesis of 3-(2-(aminomethyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-yl)propanoate ethyl [ka] Synthesis of methyl 2-amino-5-cyclopropylnicotinate. A mixture of methyl 2-amino-5-bromonicotinate (10 g, 43 mmol), cyclopropylboronic acid (9.3 g, 110 mmol), PCy3 (1.2 g, 4.3 mmol), and K3PO4 (32 g, 150 mmol) in toluene (220 mL) and water (22 mL) was degassed with nitrogen, and then Pd(OAc)2 (490 mg, 2.2 mmol) was added. The mixture was stirred under a nitrogen atmosphere at 95°C for 18 hours. The reaction product was cooled and then diluted with water (100 mL) and pharmaceutically acceptable ethyl acetate (100 mL). The mixture was separated, brine (saturated aqueous solution, 100 mL) was added to the aqueous layer, and this was further extracted with ethyl acetate (2 × 100 mL). The combined organic layers were filtered through Celite® and concentrated under vacuum. The residue was purified by silica gel column chromatography using a concentration gradient of 0-10% MeOH in DCM to obtain the title compound as a pale green solid (3.4 g, 41%). ESI-MS (M+H) + : 193.2, 1 H NMR (400 MHz, DMSO) δ 8.06 (d, J=2.5 Hz, 1H), 7.70 (d, J=2.5 Hz, 1H), 6.95 (br s, 2H), 3.80 (s, 3H), 1.87 - 1.80 (m, 1H), 0.88 - 0.83 (m, 2H), 0.59 - 0.55 (m, 2H).

[0341] Synthesis of 2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-carboxylate methyl hydrochloride. A mixture of 2-amino-5-cyclopropylnicotinate methyl (2.5 g, 13 mmol) and 1,3-dichloroacetone (2.5 g, 20 mmol) in MeCN (44 mL) was stirred under reflux under a nitrogen atmosphere for 18 hours. The mixture was cooled, the precipitate was collected by filtration, and washed with Et2O to obtain the title compound (3.4 g, 88%) as a cream-colored solid. 1 H NMR (400 MHz, DMSO) δ 8.97 (d, J=1.4 Hz, 1H), 8.37 (s, 1H), 8.24 (s, 1H), 5.08 (s, 2H), 4.02 (s, 3H), 2.24 - 2.15 (m, 1H), 1.12 - 1.06 (m, 2H), 0.88 - 0.82 (m, 2H).

[0342] Synthesis of 2-(azidomethyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-carboxylate methyl. Sodium azide (1.1 g, 17 mmol) was added to a mixture of 2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-carboxylate methyl hydrochloride (3.4 g, 11 mmol) and NEt3 (2.6 g, 26 mmol) in DMF (25 mL). The mixture was stirred at room temperature under a nitrogen atmosphere for 72 hours. The mixture was poured into SiO2 (330 mL), washed with water (330 mL), brine (saturated aqueous solution, 330 mL), and water (330 mL), dried over MgSO4, filtered, and concentrated under vacuum to obtain the title compound (2.7 g, 77%) as a brown oil. ESI-MS (M+H) + : 272.2, 1 H NMR (400 MHz, DMSO) δ 8.62 (dd, J=0.6, 1.8 Hz, 1H), 7.96 (m, 1H), 7.64 (d, J=1.9 Hz, 1H), 4.55 (s, 2H), 3.89 (s, 3H), 2.06 - 1.99 (m, 1H), 0.99 - 0.93 (m, 2H), 0.75 - 0.70 (m, 2H).

[0343] Synthesis of 2-(aminomethyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-carboxylate methyl dihydrochloride. A mixture of 2-(azidomethyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-carboxylate methyl (2.7 g, 10 mmol) and triphenylphosphine (5.3, 20 mmol) in THF (45 mL) and water (5.0 mL) was stirred at room temperature for 18 hours. The mixture was concentrated under vacuum, then dissolved in DCM, and treated with HCl (4.0 M in 1,4-dioxane). The precipitate was recovered by filtration and washed with Et2O to obtain the title compound (2.4 g, 76%) as a cream-colored solid. ESI-MS (M+H) + : 246.2, 1 H NMR (400 MHz, DMSO) δ 8.98 (s, 1H), 8.62 (br s, 3H), 8.25 (s, 1H), 8.12 (s, 1H), 4.36 (s, 2H), 4.00 (s, 3H), 2.18 - 2.14 (m, 1H), 1.10 - 1.04 (m, 2H), 0.86 - 0.82 (m, 2H).

[0344] Synthesis of 2-(((tert-butoxycarbonyl)amino)methyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-carboxylate methyl. Di-tert-butyl dicarbonate (1.7 g, 7.6 mmol) was added at 0°C to a mixture of 2-(aminomethyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-carboxylate methyl dihydrochloride (2.4 g, 7.6 mmol) and NEt3 (5.3 mL, 38 mmol) in MeCN (25 mL). The mixture was warmed to room temperature and stirred under a nitrogen atmosphere for 18 hours. The mixture was diluted with NaHCO3 (saturated aqueous solution, 50 mL) and water (50 mL), and then extracted with DCM (100 mL x 3). The combined organic layers were dried over MgSO4, filtered, and concentrated under vacuum to obtain the title compound as a yellow gum (2.2 g, 82%). ESI-MS (M+H) + : 346.2, 1¹H NMR (400 MHz, DMSO) showed δ values ​​of 8.59 (s, 1H), 7.70 (s, 1H), 7.36 - 7.34 (m, 1H), 4.23 (d, J=5.6 Hz, 2H), 3.88 (s, 3H), 2.04 - 1.95 (m, 1H), 1.40 (s, 9H), 0.98 - 0.91 (m, 2H), and 0.73 - 0.67 (m, 2H). No interchangeable NH was observed.

[0345] Synthesis of tert-butyl ((6-cyclopropyl-8-(hydroxymethyl)imidazo[1,2-a]pyridine-2-yl)methyl)carbamate. LiAlH4 (1.0 M, 6.3 mL, 6.3 mmol in THF) was added dropwise to a solution of 2-(((tert-butoxycarbonyl)amino)methyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-carboxylate methyl (2.2 g, 6.3 mmol) in THF (41 mL) under a nitrogen atmosphere at -40°C. The mixture was stirred at -40°C for 30 minutes, then warmed to 0°C and stirred for 30 minutes, then warmed to room temperature and stirred for 30 minutes. The mixture was cooled to 0°C, and LiAlH4 (1.0 M, 3.2 mL, 3.2 mmol in THF) was added. The mixture was warmed to room temperature and stirred for 45 minutes. The mixture was cooled to 0°C, and water (1.5 mL) and NaOH (20% aqueous solution, 0.35 mL) were added. The mixture was warmed to room temperature and stirred for 15 minutes. Et2O (10 mL) was added, and the mixture was filtered through Celite® using THF and concentrated under vacuum. The residue was redissolved in THF (21 mL) and cooled to -40°C under a nitrogen atmosphere. LiAlH4 (1.0 M, 2.8 mL, 2.8 mmol in THF) was added dropwise, and the mixture was stirred at -40°C for 1.5 hours. Further LiAlH4 (1.0 M, 2.8 mL, 2.8 mmol in THF) was added, and the mixture was stirred for a further 30 minutes at -40°C. The mixture was warmed to room temperature and stirred for 2 hours. The mixture was cooled to 0°C, and water (0.21 mL), NaOH (20% aqueous solution, 0.16 mL), and water (0.66 mL) were slowly added. The mixture was warmed to room temperature and stirred for 15 minutes. MgSO4 was added, and the mixture was filtered through Celite® using THF. The mixture was then concentrated under vacuum to obtain the title compound (1.5 g, 75%) as a yellow, gum-like substance. ESI-MS (M+H) + : 318.2, 1H NMR (400 MHz, DMSO) δ 8.22 (s, 1H), 7.58 (s, 1H), 7.29 - 7.26 (m, 1H), 6.97 - 6.95 (m, 1H), 5.30 (t, J=5.7 Hz, 1H), 4.75 (d, J=5.3 Hz, 2H), 4.19 (d, J=5.9 Hz, 2H), 1.97 - 1.89 (m, 1H), 1.40 (s, 9H), 0.95 - 0.89 (m, 2H), 0.68 - 0.63 (m, 2H).

[0346] Synthesis of tert-butyl ((6-cyclopropyl-8-formylimidazo[1,2-a]pyridine-2-yl)methyl)carbamate. To a solution of tert-butyl ((6-cyclopropyl-8-(hydroxymethyl)imidazo[1,2-a]pyridine-2-yl)methyl)carbamate (400 mg, 1.3 mmol) in 15 mL of DCM, MnO2 (1.1 g, 13 mmol) was added. The mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. The mixture was filtered through Celite®, then washed with DCM, and then with THF (×3). The combined filtrate was concentrated under vacuum to obtain the title compound (210 mg, 32%) as a yellow oil. ESI-MS (M+H) + : 316.2, 1 H NMR (400 MHz, DMSO) δ 10.48 (s, 1H), 8.70 (s, 1H), 7.75 (s, 1H), 7.42 - 7.36 (m, 1H), 6.87 (s, 1H), 4.27 (d, J=5.9 Hz, 2H), 2.08 - 1.99 (m, 1H), 1.41 (s, 9H), 1.01 - 0.94 (m, 2H), 0.77 - 0.71 (m, 2H).

[0347] Synthesis of (E)-3-(2-(((tert-butoxycarbonyl)amino)methyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-yl)acrylate ethyl. DBU (85 μl, 0.57 mmol) was slowly added at 0°C under a nitrogen atmosphere to a solution of ((6-cyclopropyl-8-formylimidazo[1,2-a]pyridine-2-yl)methyl)carbamate tert-butyl (180 mg, 0.57 mmol) and phosphonoacetate triethyl (140 mg, 0.628 mmol) in DCM (10 mL). The mixture was stirred at room temperature for 72 hours. The mixture was diluted with water (20 mL) and brine (saturated aqueous solution, 30 mL) and extracted with DCM (3 × 50 mL). The combined organic layers were passed through a phase separator and concentrated under vacuum. The residue was purified by silica gel column chromatography using elution with 1-5% NH3 in MeOH in DCM, and the title compound (270 mg, quantitative) was obtained as a yellow oily substance. This was used directly in the next step without further purification. ESI-MS (M+H) + : 386.3.

[0348] Synthesis of ethyl 3-(2-(((tert-butoxycarbonyl)amino)methyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-yl)propanoate. NaBH4 (240 mg, 6.2 mmol) was added in three portions under a nitrogen atmosphere at 0°C to a mixture of (E)-3-(2-(((tert-butoxycarbonyl)amino)methyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-yl)acrylate (240 mg, 0.62 mmol) and CuCl (62 mg, 0.62 mmol) in MeOH (10 mL). The mixture was stirred at 0°C for 3 hours. The mixture was diluted with NaHCO3 (saturated aqueous solution, 5.0 mL), water (50 mL), and NaHCO3 (saturated aqueous solution, 45 mL), and extracted with ELISA (3 × 75 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated under vacuum to obtain the title compound (280 mg, quantitatively) as a yellow oil, which was used directly in the next step without further purification. ESI-MS (M+H) + : 388.3.

[0349] Synthesis of ethyl 3-(2-(aminomethyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-yl)propanoate. HCl (4.0 M, 0.9 mL, 3.6 mmol in 1,4-dioxane) was added to a solution of ethyl 3-(2-(((tert-butoxycarbonyl)amino)methyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-yl)propanoate (280 mg, 0.72 mmol) in DCM (2 mL). The mixture was stirred at room temperature for 90 minutes, then concentrated under vacuum to obtain the title compound (250 mg, quantitatively) as a yellow oil, which was used without further purification. ESI-MS (M+H) + : 288.3.

[0350] Synthesis of 3-(2-(aminomethyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-yl)-2,2-dimethylpropanoate ethyl [ka] Synthesis of (2-amino-5-cyclopropylpyridine-3-yl)methanol. 7.6 g, 40 mmol of methyl 2-amino-5-cyclopropylnicotinate in 130 mL of THF cooled to 0°C was mixed with LiAlH4 (2 M in THF, 20 mL, 40 mmol). The reaction mixture was stirred at 0°C for 2 hours. Then, 1.5 mL of water was added, followed by 1.2 mL of NaOH (20% aqueous solution), 4.5 mL of water, 200 mL of Et2O, and 150 mL of siRNA. The mixture was then warmed to room temperature. After 15 minutes, MgSO4 was added, and the mixture was filtered through Celite® and concentrated under vacuum. The residue was purified by silica gel column chromatography eluting under a concentration gradient of 0-15% 7N NH3 in MeOH in DCM to obtain the title compound (3.7 g, 56%) as a yellow solid. ESI-MS (M+H) + : 165.1, 1H NMR (400 MHz, DMSO) δ 7.71 (d, J=2.4 Hz, 1H), 7.08 (d, J=2.4 Hz, 1H), 5.43 (s, 2H), 5.12 (t, J=5.5 Hz, 1H), 4.32 (d, J=5.5 Hz, 2H), 1.82 - 1.74 (m, 1H), 0.86 - 0.81 (m, 2H), 0.56 - 0.51 (m, 2H).

[0351] Synthesis of 2-((6-cyclopropyl-8-(hydroxymethyl)imidazo[1,2-a]pyridine-2-yl)methyl)isoindoline-1,3-dione. A mixture of 2-(3-bromo-2-oxopropyl)isoindoline-1,3-dione (1.6 g, 5.8 mmol), (2-amino-5-cyclopropylpyridine-3-yl)methanol (0.95 g, 5.8 mmol), and DIPEA (1.0 mL, 5.8 mmol) in 1,4-dioxane (20 mL) was heated at 100 °C for 16 hours. The mixture was cooled to room temperature and concentrated under vacuum. The residue was purified by silica gel column chromatography eluting under a concentration gradient of 0-10% MeOH in DCM to obtain the title compound (2.0 g, 99%). ESI-MS (M+H) + : 348.2, 1 H NMR (400 MHz, DMSO) δ 8.16 - 8.14 (m, 1H), 7.95 - 7.87 (m, 4H), 7.73 (s, 1H), 6.99 - 6.97 (m, 1H), 5.29 (t, J=5.7 Hz, 1H), 4.87 (s, 2H), 4.73 (d, J=5.6 Hz, 2H), 1.98 - 1.90 (m, 1H), 0.95 - 0.90 (m, 2H), 0.67 - 0.62 (m, 2H).

[0352] Synthesis of 2-((8-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)isoindoline-1,3-dione. SOCl2 (0.15 mL, 2.0 mmol) was added to a solution of 2-((6-cyclopropyl-8-(hydroxymethyl)imidazo[1,2-a]pyridine-2-yl)methyl)isoindoline-1,3-dione (0.20 g, 0.58 mmol) in DCM (5.0 mL). The reaction mixture was stirred at room temperature for 2 hours and then concentrated under vacuum. The residue was washed with NaHCO3 (saturated aqueous solution, 25 mL) and extracted with DCM (3 × 25 mL). The combined organic matter was dried over MgSO4 and concentrated under vacuum to obtain the title compound (190 mg, 92%) as a yellow solid. 1 H NMR (400 MHz, DMSO) δ 8.28 - 8.26 (m, 1H), 7.95 - 7.87 (m, 4H), 7.79 (s, 1H), 7.17 - 7.16 (m, 1H), 4.94 (s, 2H), 4.91 (s, 2H), 1.98 - 1.90 (m, 1H), 0.96 - 0.90 (m, 2H), 0.69 - 0.64 (m, 2H).

[0353] Synthesis of 3-(6-cyclopropyl-2-((1,3-dioxoisoindolin-2-yl)methyl)imidazo[1,2-a]pyridine-8-yl)-2,2-dimethylpropanoate ethyl. n-BuLi (2.5 M, 1.7 mL, 4.3 mmol in hexane) was added to a solution of diisopropylamine (0.69 mL, 4.9 mmol) in THF (18 mL) under an N2 atmosphere at -78°C. The solution was stirred at -78°C for 30 minutes, then ethyl isobutyrate (0.57 mL, 4.3 mmol) was slowly added, and the reaction mixture was stirred at -78°C for 4 hours. Next, a solution of 2-((8-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)isoindoline-1,3-dione (1.2 g, 3.3 mmol) in THF (6.0 mL) and DMPU (6.0 mL) was slowly added over 45 minutes, and the reaction mixture was stirred at -78°C for 90 minutes. The reaction mixture was then warmed to 0°C, NH4Cl (saturated aqueous solution, 10 mL) was added, and the reaction mixture was then warmed to room temperature. The mixture was diluted with water (100 mL) and extracted with ethyl acetate (3 × 100 mL). The combined organic matter was dried over MgSO4 and concentrated under vacuum. The residue was purified by silica gel chromatography eluting under a concentration gradient of 0-80% ethyl acetate in cyclohexane to obtain the title compound as a yellow oil (0.18 g, 12%). ESI-MS (M+H) + : 446.3, 1 H NMR (400 MHz, DMSO) δ 8.19 - 8.16 (m, 1H), 7.99 - 7.89 (m, 4H), 7.72 (s, 1H), 6.67 (s, 1H), 4.91 (s, 2H), 4.07 - 4.00 (m, 2H), 3.10 (s, 2H), 1.98 - 1.87 (m, 1H), 1.16 - 1.11 (m, 9H), 1.00 - 0.91 (m, 2H), 0.67 - 0.60 (m, 2H).

[0354] Synthesis of 3-(2-(aminomethyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-yl)-2,2-dimethylpropanoate ethyl. A mixture of 3-(6-cyclopropyl-2-((1,3-dioxoisoindolin-2-yl)methyl)imidazo[1,2-a]pyridine-8-yl)-2,2-dimethylpropanoate ethyl (180 mg, 0.39 mmol) and hydrazine monohydrate (49 μL, 0.79 mmol) in EtOH (4.0 mL) was stirred at 70°C for 24 hours. The mixture was cooled, packed into an SCX cartridge, washed with 50% MeOH in DCM, and eluted with 50% 7N NH3 in MeOH in DCM. The eluate was concentrated under vacuum to obtain the title compound (110 mg, 89%) as a yellow oil. ESI-MS (M+H) + : 316.3, 1 H NMR (400 MHz, DMSO) δ 8.24 (s, 1H), 7.66 (s, 1H), 6.64 (s, 1H), 4.08 (q, J=7.1 Hz, 2H), 3.83 (s, 2H), 3.22 (s, 2H), 3.17 (s, 2H), 1.97 - 1.88 (m, 1H), 1.22 - 1.17 (m, 9H), 1.00 - 0.92 (m, 2H), 0.68 - 0.63 (m, 2H).

[0355] Synthesis of 3-(2-(aminomethyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-yl)-2,2-dimethylpropanoate tert-butyl [ka] Synthesis of 3-(6-cyclopropyl-2-((1,3-dioxoisoindolin-2-yl)methyl)imidazo[1,2-a]pyridine-8-yl)-2,2-dimethylpropanoate tert-butyl. A solution of diisopropylamine (0.41 mL, 4.1 mmol) in anhydrous THF (10 mL) was placed under an N2 atmosphere and cooled to -78°C. Then n-BuLi (2.5 M in hexane, 1.3 mL, 3.2 mmol) was slowly added, and the reaction mixture was stirred at -78°C for 30 minutes. Then 2-methylpropanoate tert-butyl (0.59 mL, 3.6 mmol) was added, and the resulting mixture was stirred at -78°C for 1 hour. Next, a solution of 2-((8-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)isoindoline-1,3-dione (1.0 g, 2.7 mmol) in anhydrous THF (5.0 mL) and DMPU (5.0 mL) was added dropwise, and the reaction mixture was stirred at -78°C for 2 hours. The reaction mixture was then warmed to room temperature, and NH4Cl (saturated aqueous solution, 10 mL) was added. The mixture was diluted with water (100 mL) and extracted with ethyl acetate (3 × 100 mL). The combined organic matter was dried over MgSO4 and concentrated under vacuum. The residue was purified by silica gel column chromatography eluting under a concentration gradient of 20–80% ethyl acetate in cyclohexane to obtain the title compound. This compound was further purified by crystallization from EtOH to obtain the title compound (0.085 g, 7%) as a white solid. ESI-MS (M+H) + : 474.4.

[0356] Synthesis of tert-butyl 3-(2-(aminomethyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-yl)-2,2-dimethylpropanoate. A mixture of tert-butyl 3-(6-cyclopropyl-2-((1,3-dioxoisoindorin-2-yl)methyl)imidazo[1,2-a]pyridine-8-yl)-2,2-dimethylpropanoate (0.08 g, 0.17 mmol) and hydrazine hydrate (0.021 mL, 0.34 mmol) in ethanol (2 mL) was stirred at 70°C for 24 hours. Further hydrazine hydrate (0.042 mL, 0.68 mmol) was added, and the mixture was stirred at 70°C for a further 3 hours. The reaction mixture was cooled to room temperature and then packed into an SCX cartridge. The cartridge was washed with 50% MeOH in DCM, and eluted with 50% 7N NH3 in MeOH in DCM. The eluate was concentrated under vacuum to obtain the title compound (110 mg, 89%) as a yellow oil. ESI-MS (M+H) + : 344.3.

[0357] Synthesis of (2-(aminomethyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-yl)methanol. A mixture of 2-((6-cyclopropyl-8-(hydroxymethyl)imidazo[1,2-a]pyridine-2-yl)methyl)isoindoline-1,3-dione (0.50 g, 1.4 mmol) and hydrazine monohydrate (0.18 mL, 2.9 mmol) in EtOH (14 mL) was stirred at 70°C for 18 hours. The mixture was cooled to room temperature, loaded into an SCX cartridge, and washed with MeOH. The product was eluted with 7N NH3 in MeOH to obtain the title compound (0.25 g, 80%) as an orange gum-like substance. ESI-MS (M+H) + : 218.2, 11H NMR (400 MHz, DMSO) δ values ​​were 8.21 (s, 1H), 7.65 (s, 1H), 6.95 (d, J=1.4 Hz, 1H), 4.77 (s, 2H), 3.79 (s, 2H), 3.18 (s, 1H), 1.99 - 1.90 (m, 1H), 0.93 (ddd, J=4.3, 6.3, 8.3 Hz, 2H), 0.69 - 0.64 (m, 2H). NH2 was not observed.

[0358] Synthesis of (6-cyclopropyl-5-fluoroimidazo[1,2-a]pyridine-2-yl)methanamine [ka] Synthesis of 5-cyclopropyl-6-fluoropyridine-2-amine. 5-bromo-6-fluoropyridine-2-amine (2.2 g, 12 mmol), cyclopropylboronic acid (2.5 g, 29 mmol), PCy3 (350 mg, 2.3 mmol), Pd(OAc)2 (260 mg, 1.2 mmol), and K3PO4 (8.6 g, 40 mmol) were degassed for 10 minutes in toluene (60 mL) and water (3 mL) and stirred at 95°C for 18 hours. The reaction mixture was cooled and concentrated in vacuum to half its original volume. The mixture was diluted with water (50 mL) and ethyl acetate (150 mL) and stirred at room temperature for 15 minutes. The mixture was then filtered through Celite® and separated. The organic matter was dried over MgSO4 and concentrated in vacuum. The residue was purified by silica gel chromatography using a concentration gradient of 10-30% ELISA in isohexane to obtain the title compound as a pale yellow oil (1.5 g, 86%). ESI-MS (M+H) + : 153.0, 1 H NMR (400 MHz, CDCl3) δ 7.16 - 7.09 (m, 1H), 6.27 - 6.23 (m, 1H), 4.36 (s, 2H), 1.91 - 1.81 (m, 1H), 0.91 - 0.84 (m, 2H), 0.62 - 0.55 (m, 2H).

[0359] Synthesis of 6-cyclopropyl-5-fluoroimidazo[1,2-a]pyridine-2-carboxylate ethyl. A mixture of 5-cyclopropyl-6-fluoropyridine-2-amine (1.5 g, 9.9 mmol) and 3-bromo-2-oxopropanoate ethyl (1.3 mL, 10 mmol) in THF (45 mL) was stirred under reflux for 24 hours. The mixture was cooled and concentrated under vacuum. The residue was partitioned between DCM (200 mL) and K2CO3 (100 mL saturated aqueous solution). The organic layer was dried over MgSO4 and concentrated under vacuum. The residue was purified by silica gel column chromatography eluting with a concentration gradient of 1-5% MeOH in DCM. The residue was further purified by silica gel column chromatography eluting with a concentration gradient of 25-100% ethyl + : 249.1, 1 H NMR (400 MHz, CDCl3) δ 8.20 (s, 1H), 7.44 (d, J=9.3 Hz, 1H), 6.92 (t, J=8.6 Hz, 1H), 4.46 (q, J=7.2 Hz, 2H), 2.11 - 2.01 (m, 1H), 1.47 - 1.42 (m, 3H), 1.10 - 1.02 (m, 2H), 0.81 - 0.74 (m, 2H).

[0360] Synthesis of (6-cyclopropyl-5-fluoroimidazo[1,2-a]pyridine-2-yl)methanol. DIBAL-H (1.0 M, 4.4 mL, 4.4 mmol in THF) was added dropwise to a solution of 6-cyclopropyl-5-fluoroimidazo[1,2-a]pyridine-2-carboxylate ethyl (550 mg, 2.2 mmol) in THF (15 mL) under a nitrogen atmosphere at 0°C. Additional DIBAL-H (1.0 M, 0.5 mL, 0.5 mmol in THF) was added dropwise, and the reaction mixture was stirred at room temperature for 1 hour. The mixture was treated dropwise with Rochelle salt solution (10% aqueous solution, 3 mL), stirred at room temperature for 30 minutes, and extracted with ELISA (20 mL). The organic matter was dried over MgSO4 and concentrated under vacuum. The residue was purified by silica gel column chromatography using a concentration gradient of 1-10% MeOH in DCM to obtain the title compound as a green, gum-like substance (330 mg, 71%). ESI-MS (M+H) + : 207.1, 1 ¹H NMR (400 MHz, CDCl3) δ values ​​were 7.57 - 7.56 (m, 1H), 7.31 (d, J=9.2 Hz, 1H), 6.89 - 6.84 (m, 1H), 4.85 - 4.84 (m, 2H), 2.07 - 2.00 (m, 1H), 1.05 - 0.99 (m, 2H), and 0.76 - 0.71 (m, 2H). No exchangeable protons were observed.

[0361] Synthesis of 2-(chloromethyl)-6-cyclopropyl-5-fluoroimidazo[1,2-a]pyridine. A solution of (6-cyclopropyl-5-fluoroimidazo[1,2-a]pyridine-2-yl)methanol (150 mg, 0.73 mmol) in SOCl2 (0.32 mL, 4.4 mmol) was stirred at room temperature for 6 hours. The reaction mixture was then azeotropically mixed with toluene (×2). The residue was washed with K2CO3 (diluted aqueous solution, 2 mL) and extracted with DCM (10 mL). The organic layer was dried over MgSO4 and concentrated under vacuum to obtain the title compound (170 mg, quantitatively) as a dark brown oil, which was used without further purification.

[0362] Synthesis of 2-(azidomethyl)-6-cyclopropyl-5-fluoroimidazo[1,2-a]pyridine. A mixture of 2-(chloromethyl)-6-cyclopropyl-5-fluoroimidazo[1,2-a]pyridine (160 mg, 0.73 mmol) and NaN3 (62 mg, 0.95 mmol) in DMF (1.0 mL) was stirred at room temperature for 18 hours. The mixture was diluted with water (10 mL) and extracted with EtOAC (15 mL). The organic matter was washed with water (2 × 10 mL) and brine (20 mL), dried over MgSO4, and concentrated under vacuum to obtain the title compound (130 mg, 76%) as a viscous brown oil. ESI-MS (M+H) + : 232.1, 1 H NMR (400 MHz, CDCl3) δ 7.60 (s, 1H), 7.36 - 7.31 (m, 1H), 6.89 (t, J=8.6 Hz, 1H), 4.53 (s, 2H), 2.07 - 2.01 (m, 1H), 1.06 - 0.99 (m, 2H), 0.79 - 0.71 (m, 2H).

[0363] Synthesis of (6-cyclopropyl-5-fluoroimidazo[1,2-a]pyridine-2-yl)methaneamine. A mixture of 2-(azidomethyl)-6-cyclopropyl-5-fluoroimidazo[1,2-a]pyridine (130 mg, 0.55 mmol) and triphenylphosphine (290 mg, 1.1 mmol) in THF (5.0 mL) and water (0.5 mL) was stirred at room temperature for 6 hours. The reaction mixture was concentrated under vacuum, and the residue was then dissolved in DCM (10 mL), dried over MgSO4, and concentrated under vacuum. The residue was purified by silica gel column chromatography eluting under a concentration gradient from 5% MeOH in DCM to 2% 7N NH3 in MeOH in DCM, yielding the title compound (87 mg, 77%) as a greenish-brown solid. ESI-MS (M+H) + : 206.1, 1¹H NMR (400 MHz, CDCl3) δ values ​​were 7.50 - 7.49 (m, 1H), 7.28 (d, J=9.3 Hz, 1H), 6.87 - 6.82 (m, 1H), 4.03 - 4.03 (m, 2H), 2.06 - 1.99 (m, 1H), 1.04 - 0.98 (m, 2H), and 0.76 - 0.71 (m, 2H). No two interchangeable protons were observed.

[0364] N 4 Synthesis of -((8-(((tert-butyldiphenylsilyl)oxy)methyl)-6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)pyridine-2,4-diamine [ka] Synthesis of (2-(((2-aminopyridine-4-yl)amino)methyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-yl)methanol. 4-fluoropyridine-2-amine (0.10 g, 0.92 mmol), (2-(aminomethyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-yl)methanol (0.20 g, 0.92 mmol), and DIPEA (0.24 mL, 1.4 mmol) in iPrOH (2.0 mL) were stirred in microwave at 130°C for 2 hours. The mixture was concentrated under vacuum, and the residue was purified by silica gel column chromatography eluting with 10-50% NH3 in MeOH in DCM to obtain the title compound (0.14 g, 51%) as an orange gum-like substance. ESI-MS (M+H) + : 310.2, 1H NMR (400 MHz, DMSO) δ 8.22 - 8.20 (m, 1H), 7.61 (s, 1H), 7.47 - 7.45 (m, 1H), 6.99 (d, J=1.5 Hz, 1H), 6.59 (t, J=5.8 Hz, 1H), 5.92 (dd, 0.95 - 0.89 (m, 2H), 0.68 - 0.63 (m, 2H).

[0365] N 4 Synthesis of -((8-(((tert-butyldiphenylsilyl)oxy)methyl)-6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)pyridine-2,4-diamine. TBDPSCl (0.14 mL, 0.54 mmol) was added to a mixture of (2-(((2-aminopyridine-4-yl)amino)methyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-yl)methanol (0.15 g, 0.47 mmol) and imidazole (0.064 g, 0.94 mmol) in DMF (3.0 mL). The mixture was stirred at room temperature for 18 hours. Further addition of TBDPSCl (0.14 mL, 0.54 mmol) and imidazole (0.064 g, 0.94 mmol) was added, and the mixture was stirred at room temperature for 24 hours. Water (15 mL) and brine (saturated aqueous solution, 25 mL) were added, and the mixture was extracted with toluene (3 × 50 mL). The combined organic layer was dried (MgSO4), filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography eluting with 1-20% NH3 in MeOH in DCM to obtain the title compound (0.15 g, 57%) as a yellow solid. 1H NMR (400 MHz, DMSO) δ 8.27 (s, 1H), 7.69 (dd, J=1.7, 7.8 Hz, 4H), 7.62 - 7.61 (m, 1H), 7.51 - 7.42 (m, 7H), 7.14 - 7.09 (m, 1H), 6.51 (t, J=5.7 Hz, 1H), 5.87 (dd, J=2.0, 5.8 Hz, 1H), 5.56 (d, J=2.0 Hz, 1H), 5.25 (s, 2H), 5.03 (s, 2H), 4.24 - 4.21 (m, 2H), 2.01 - 1.93 (m, 1H), 1.10 (s, 9H), 0.99 - 0.93 (m, 2H), 0.66 - 0.61 (m, 2H).

[0366] Synthesis of 6-((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)pyrimidine-4-amine [ka] Synthesis of N-(6-chloropyrimidine-4-yl)acetamide. 6-chloropyrimidine-4-amine (5.0 g, 39 mmol) was stirred in Ac2O (35 mL) at 110°C for 6 hours. The mixture was cooled and diluted with HCl (150 mL). The mixture was washed with NaHCO3 (saturated aqueous solution, 100 mL) and brine (saturated aqueous solution, 100 mL), dried, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography eluted with 30-80% HCl in cyclohexane to obtain the title compound (4.3 g, 80%) as a white powder. 1 H NMR (400 MHz, DMSO) δ 11.21 (s, 1H), 8.74 (s, 1H), 8.09 (s, 1H), 2.15 (s, 3H).

[0367] Synthesis of N-(6-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)pyrimidine-4-yl)acetamide. A mixture of N-(6-chloropyrimidine-4-yl)acetamide (0.40 g, 2.3 mmol) and hexamethyldisin (0.48 mL, 2.3 mmol) in toluene (12 mL) was degassed with N2, and Pd(PPh3)4 (0.27 g, 0.23 mmol) was added. The mixture was stirred at 100°C for 18 hours under an N2 atmosphere. The mixture was cooled and added to a stirred mixture of 2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine (0.48 g, 2.3 mmol) in toluene (11 mL). The mixture was degassed with N2, and stirred at 105°C for 18 hours under an N2 atmosphere. The mixture was concentrated under vacuum, and the residue was purified by silica gel column chromatography eluting with 1-10% NH3 in MeOH in DCM to obtain the title compound (0.043 g, 6%) as a yellow, gum-like substance. ESI-MS (M+H) + : 308.2, 1 H NMR (400 MHz, DMSO) δ 10.82 (s, 1H), 8.76 (d, J=1.3 Hz, 1H), 8.32 - 8.31 (m, 1H), 7.97 (d, J=1.1 Hz, 1H), 7.68 - 7.66 (m, 1H), 7.38 - 7.35 (m, 1H), 6.99 - 6.95 (m, 1H), 4.11 (s, 2H), 2.10 - 2.10 (m, 3H), 1.97 - 1.86 (m, 1H), 0.96 - 0.90 (m, 2H), 0.71 - 0.66 (m, 2H).

[0368] Synthesis of 6-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)pyrimidine-4-amine. A mixture of N-(6-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)pyrimidine-4-yl)acetamide (0.28 g, 0.91 mmol) and K2CO3 (0.255 g, 1.8 mmol) in MeOH (15 mL) was stirred at room temperature for 18 hours. The mixture was concentrated under vacuum. Water (50 mL) was added, and the mixture was extracted with MeOH (1:9, 4 × 50 mL) in DCM. The combined organic layers were dried (MgSO4), filtered, and concentrated under vacuum to obtain the title compound (0.17 g, 69%) as an orange gum-like substance, which was used without further purification. ESI-MS (M+H) + : 266.2.

[0369] Synthesis of (6-chloropyrimidine-4-yl)(6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methanone [ka] Synthesis of 6-cyclopropylimidazo[1,2-a]pyridine-2-carbaldehyde. A suspension of (6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methanol (2.0 g, 11 mmol) and manganese(IV) oxide (9.2 g, 110 mmol) in chloroform (25 mL) and MeCN (25 mL) was stirred at 50°C for 1 hour. The mixture was cooled to room temperature, filtered through Celite®, and concentrated under vacuum to obtain the title compound (1.3 g, 66%), which was used without further purification. ESI-MS (M+H) + : 187.2, 1 H NMR (400 MHz, CDCl3) δ 10.13 (s, 1H), 8.06 (s, 1H), 7.93 (s, 1H), 7.57 (d, J=9.6 Hz, 1H), 7.03 (dd, J=1.8, 9.3 Hz, 1H), 1.95 - 1.87 (m, 1H), 1.05 - 0.99 (m, 2H), 0.75 - 0.69 (m, 2H).

[0370] Synthesis of (6-chloropyrimidine-4-yl)(6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methanone. 6-cyclopropylimidazo[1,2-a]pyridine-2-carbaldehyde (3.1 g, 16.7 mmol), 4,6-dichloropyrimidine (1.9 g, 13 mmol), and 1-butyl-3-methylimidazolium tetrafluoroborate (1.0 mL, 5.5 mmol) were dissolved in DCM (200 mL) under N2 conditions. Sodium hydride (60% in mineral oil, 0.67 g, 17 mmol) was added gradually, and the resulting reaction mixture was heated at 40°C for 3 hours. The reaction mixture was allowed to cool to room temperature and poured into ice-cold water (100 mL) and saturated brine solution (100 mL). The solutions were extracted with DCM (100 mL), and the organic layer was dried over MgSO4. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (eluting with a concentration gradient of cyclohexane -> 100% siRNA). The crude title compound was further purified by silica gel column chromatography eluting with an isocratic concentration gradient of 10% MeOH / NH3 in DCM to obtain the title compound (900 mg, 23%), which was used without further purification. 1 H NMR (400 MHz, CDCl3): δ ppm 9.20 (1H, d, J = 1.0 Hz), 8.87 (1H, d, J = 0.9 Hz), 8.24 (1H, d, J = 1.0 Hz), 7.95 (1H, ddd, J = 0.9, 0.9, 1.6 Hz), 7.61 (1H, dd, J = 0.9, 1.0, 9.5 Hz), 7.04 (1H, dd, J = 1.6, 9.5 Hz), 1.96 - 1.88 (1H, m), 1.06 - 1.00 (2H, m), 0.76 - 0.71 (2H, m).

[0371] Synthesis of 1-(6-cyclopropylimidazo[1,2-a]pyridine-2-yl)ethanol [ka] To a solution of 6-cyclopropylimidazo[1,2-a]pyridine-2-carbaldehyde (6) (1.2 g, 6.45 mmol) in anhydrous tetrahydrofuran (30 mL), MeMgBr (3 M, 3.2 mL, 9.68 mmol) was added dropwise at 0°C. The reaction mixture was stirred at 0°C for 3 hours, then quenched with saturated NH4Cl solution (10 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated to obtain the crude product, which was purified by silica gel column chromatography using 10% MeOH in DCM to obtain the title compound as a pale yellow solid (836 mg, yield: 64%). ESI-MS (M+H) + : 203.0. 1 HNMR (400Hz, DMSO) δ 8.31 (t, J = 1.2 Hz, 1H), 7.62 (s, 1H), 7.35 (d, J = 9.2 Hz, 1H), 6.93 (dd, J = 10.0, 2.0 Hz, 1H), 5.14 (d, J = 4.8 Hz, 1H), 4.84 - 4.75 (m, 1H), 1.96- 1.86 (m, 1H), 1.40 (d, J = 6.4 Hz, 3H), 0.96 - 0.88 (m, 2H), 0.70- 0.64 (m, 2H).

[0372] Synthesis of 1-(6-cyclopropylimidazo[1,2-a]pyridine-2-yl)ethane-1-amine [ka] Synthesis of 2-(1-(6-cyclopropylimidazo[1,2-a]pyridine-2-yl)ethyl)isoindoline-1,3-dione. A mixture of 1-(6-cyclopropylimidazo[1,2-a]pyridine-2-yl)ethane-1-ol (140 mg, 0.71 mmol), phthalimide (120 mg, 0.78 mmol), and PPh3 (280 mg, 1.1 mmol) in THF (20 mL) was cooled to 0°C, and DIAD (0.21 mL, 1.1 mmol) was added. The reaction mixture was then stirred at 0°C for 30 minutes, and then at room temperature for 20 hours. The mixture was diluted with ELISA (20 mL) and washed with water (20 mL) and brine (50 mL saturated aqueous solution). The organic matter was dried over MgSO4 and concentrated under vacuum. The residue was purified by silica gel column chromatography using a concentration gradient of 1-10% MeOH in DCM to obtain the title compound as a yellow, gum-like substance (290 mg, quantitative). ESI-MS (M+H) + : 332.1.

[0373] Synthesis of 1-(6-cyclopropylimidazo[1,2-a]pyridine-2-yl)ethane-1-amine. A mixture of 2-(1-(6-cyclopropylimidazo[1,2-a]pyridine-2-yl)ethyl)isoindoline-1,3-dione (240 mg, 0.71 mmol) and hydrazine monohydrate (44 μL, 1.4 mmol) in MeOH (5.0 mL) was stirred under reflux for 6 hours. The mixture was cooled to room temperature and concentrated under vacuum. The residue was purified by silica gel column chromatography eluting with a concentration gradient of 1-10% MeOH in DCM, followed by 1-10% 7N NH3 in MeOH in DCM, to obtain the title compound as a brown gum-like substance (25 g, 17%). ESI-MS (M+H) + : 202.2, 1¹H NMR (400 MHz, CDCl3) δ values ​​were 7.85 (s, 1H), 7.44 (d, J=9.3 Hz, 1H), 7.37 (s, 1H), 6.93 - 6.88 (m, 1H), 4.27 (q, J=6.6 Hz, 1H), 1.92 - 1.83 (m, 1H), 1.52 (d, J=6.5 Hz, 3H), 0.99 - 0.91 (m, 2H), and 0.70 - 0.62 (m, 2H). No two interchangeable protons were observed.

[0374] Synthesis of 2-((6-chloropyrimidine-4-yl)difluoromethyl)-6-cyclopropylimidazo[1,2-a]pyridine [ka] A solution of (6-chloropyrimidine-4-yl)(6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methanone (0.18 g, 0.60 mmol) in DCM (2.0 mL) was degassed with N2. DAST (0.20 mL, 1.5 mmol) was added dropwise to the stirred solution under an N2 atmosphere at room temperature. The mixture was stirred at room temperature for 4 hours. Another DAST (0.20 mL, 1.5 mmol) was added, and the mixture was stirred at room temperature for 18 hours. The mixture was added dropwise to ice water (20 mL) and extracted with DCM (3 × 30 mL). The combined organic layer was concentrated under vacuum. The residue was purified by silica gel column chromatography eluted with 5-95% ethyl acetate in cyclohexane to obtain the title compound (0.10 g, 52%). 1 H NMR (400 MHz, CDCl3) δ 9.03 (s, 1H), 7.94 - 7.89 (m, 3H), 7.49 - 7.46 (m, 1H), 7.02 - 6.98 (m, 1H), 1.95 - 1.86 (m, 1H), 1.02 - 0.97 (m, 2H), 0.71 - 0.66 (m, 2H).

[0375] Synthesis of (6-chloropyrimidine-4-yl)(6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methanol [ka] NaBH4 (32 mL) was gradually added over 10 minutes under an N2 atmosphere to a solution of (6-chloropyrimidine-4-yl)(6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methanone (0.10 g, 0.34 mmol) in THF (10 mL). The mixture was stirred at 50°C for 30 minutes. The mixture was cooled and water (5.0 mL) was added. The mixture was extracted with DCM (3 × 10 mL), and the combined organic layers were passed through a phase separator and concentrated under vacuum. The residue was purified by silica gel column chromatography eluted with 0-30% ethyl acetate in cyclohexane to obtain the title compound (0.033 g, 32%). ESI-MS (M+H) + : 301.0.

[0376] Synthesis of tert-butyl (5-(aminomethyl)-4,6-dimethylpyridine-2-yl)(tert-butoxycarbonyl)carbamate [ka] Synthesis of 5-bromo-4,6-dimethylpyridine-2-amine. To a solution of 4,6-dimethylpyridine-2-amine (5.0 g, 41 mmol) in CH3CN (100 mL), a solution of NBS (7.3 g, 41 mmol) in CH3CN (50 mL) was added at room temperature. The reaction mixture was stirred at room temperature for 3 hours. Water (200 mL) was added, and the mixture was extracted with  (100 mL x 3). The combined organic layer was washed with brine (100 mL), dried over anhydrous Na2SO4, and concentrated to obtain the crude product. This was purified by column chromatography (eluent: PE /  = 5 / 1) to obtain 5-bromo-4,6-dimethylpyridine-2-amine (7.0 g, yield: 85%) as a yellow solid. ESI-MS [M +H]+: 201.2.

[0377] Synthesis of 6-amino-2,4-dimethylnicotinonitrile. A mixture of 5-bromo-4,6-dimethylpyridine-2-amine (2.0 g, 10 mmol), CuCN (1.8 g, 20 mmol), and Pd2(dba)3 (458 mg, 0.5 mmol) in DMF (20 mL) was stirred in a sealed tube. After degassing with N2 for 1 minute, the reaction mixture was microwaved at 160 °C for 4 hours. After cooling the reaction mixture to room temperature, the reaction mixture was filtered through celite®, and the filtrate cake was washed with DCM / MeOH (10 / 1, 50 mL). The filtrate was concentrated to obtain the crude product, which was purified by column chromatography (eluate: PE / siRNA = 5 / 1) to obtain 6-amino-2,4-dimethylnicotinonitrile (1.1 g, yield: 75%) as a yellow solid. ESI-MS [M +H]+: 148.2.

[0378] Synthesis of tert-butyl (tert-butoxycarbonyl)(5-cyano-4,6-dimethylpyridine-2-yl)carbamate. A mixture of 6-amino-2,4-dimethylnicotinonitrile (1.1 g, 7.5 mmol), Boc2O (4.9 g, 22.5 mmol), DMAP (92 mg, 0.75 mmol), and Et3N (3.0 g, 30 mmol) in THF (30 mL) was stirred at room temperature for 16 hours. The mixture was concentrated to obtain the crude product, which was purified by column chromatography (eluent: PE / siRNA = 10 / 1) to obtain tert-butyl (tert-butoxycarbonyl)(5-cyano-4,6-dimethylpyridine-2-yl)carbamate (2.2 g, yield: 85%) as a white solid. ESI-MS [M +H]+: 348.2.

[0379] Synthesis of tert-butyl (5-(aminomethyl)-4,6-dimethylpyridine-2-yl)(tert-butoxycarbonyl)carbamate. Raney nickel was added to a solution of (tert-butoxycarbonyl)(5-cyano-4,6-dimethylpyridine-2-yl)carbamate tert-butyl (2.2 g mg, 6.3 mmol) in MeOH (20 mL). The reaction mixture was stirred under H2 at room temperature for 1 hour, then filtered through Celite®, and the filtrate cake was washed with DCM / MeOH (10 / 1, 100 mL). The filtrate was concentrated to obtain the crude product, which was purified by column chromatography (eluent: DCM / MeOH = 30 / 1) to obtain (5-(aminomethyl)-4,6-dimethylpyridine-2-yl)(tert-butoxycarbonyl)carbamate tert-butyl (1.7 g, yield: 77%) as a yellow solid. ESI-MS [M +H]+: 352.2.

[0380] Synthesis of 4-(aminomethyl)-3,5-dimethylbenzonitrile. [ka] Synthesis of 4-bromo-2,6-dimethylbenzonitrile. To a suspension of 4-bromo-2,6-dimethylphenylamine (4.92 g, 24.6 mmol) in HCl (2 M aqueous solution, 50 ml), sodium nitrite solution (1.7 g, 25 mmol) in water (10 mL) was added at 0°C, and the reaction mixture was stirred at 0°C for 45 minutes. After neutralizing the reaction mixture with solid Na2CO3 at 0°C, the resulting solution was gradually added to a solution of sodium cyanide (3.8 g, 78 mmol) and copper cyanide (2.7 g, 30 mmol) in toluene / water (50 mL / 10 mL). The resulting mixture was stirred at 0°C for 1 hour, then slowly heated to 60°C, and stirred for a further 2.5 hours. The reaction mixture was then cooled to room temperature, concentrated, and the aqueous phase was extracted with siRNA (100 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under vacuum to obtain the crude product. This was purified by silica gel column chromatography (eluent: siRNA / PE: 1 / 1) to obtain 4-bromo-2,6-dimethylbenzonitrile (4.1 g, yield: 79%) as a yellow oil. ESI-MS [M +H]+: 210.2.

[0381] Synthesis of (4-bromo-2,6-dimethylphenyl)methaneamine. To a solution of 4-bromo-2,6-dimethylbenzonitrile (1.0 g, 4.76 mmol) in THF (30 mL), BH3-THF (1 M, 10 mL, 10 mmol) was slowly added at 0°C, and the mixture was stirred at room temperature for 16 hours. MeOH (20 mL) was added, and the mixture was stirred for 1 hour. The reaction mixture was concentrated under vacuum to obtain the crude product, which was purified by silica gel column chromatography (eluent: DCM / MeOH = 10 / 1) to obtain (4-bromo-2,6-dimethylphenyl)methaneamine (500 mg, 49%) as an orange oil. ESI-MS [M +H]+: 214.2.

[0382] Synthesis of (4-bromo-2,6-dimethylbenzyl)carbamate tert-butyl. To a solution of (4-bromo-2,6-dimethylphenyl)methaneamine (500 mg, 2.35 mmol) in DCM (20 mL), Boc2O (770 mg, 3.52 mmol) and Et3N (715 mg, 7.05 mmol) were added. The mixture was stirred at room temperature for 16 hours, then water (40 mL) was added and extracted with DCM (30 mL x 3). The combined organic layer was washed with brine, dried over Na2SO4, and concentrated under vacuum to obtain the crude product. This was purified by silica gel column chromatography (eluate: DCM / MeOH = 20 / 1) to obtain (4-bromo-2,6-dimethylbenzyl)carbamate tert-butyl (700 mg, yield 95%) as a yellow solid. ESI-MS [M +H]+: 314.2.

[0383] Synthesis of tert-butyl (4-cyano-2,6-dimethylbenzyl)carbamate. To a solution of tert-butyl (4-bromo-2,6-dimethylbenzyl)carbamate (700 mg, 2.2 mmol) in DMF (20 mL), Zn(CN)2 (516 mg, 4.4 mmol), Pd2(dba)3 (200 mg, 0.22 mmol) and dppf (244 mg, 0.44 mmol) were added. The mixture was stirred under N2 at 100°C for 8 hours. Then, it was cooled to room temperature, water (50 mL) was added, and it was extracted with ELISA (50 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under vacuum to obtain the crude product, which was purified by silica gel chromatography (eluate: PE / siRNA = 3 / 1) to obtain tert-butyl (4-cyano-2,6-dimethylbenzyl)carbamate (350 mg, yield: 61%) as a yellow solid. ESI-MS [M +H]+: 261.2.

[0384] Synthesis of 4-(aminomethyl)-3,5-dimethylbenzonitrile. To a solution of tert-butyl (4-cyano-2,6-dimethylbenzyl)carbamate (350 mg, 1.35 mmol) in 1,4-dioxane (10 mL), HCl (2 mL, 4 M in dioxane) was added, and the mixture was stirred at room temperature for 2 hours. The reaction product was concentrated under vacuum, and the residue was neutralized with NaHCO3 (saturated aqueous solution, 20 mL) and extracted with DCM / MeOH (10 / 1, 20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, and concentrated to obtain the crude product, which was purified by preparative TLC using DCM / MeOH (10 / 1) to obtain the product 4-(aminomethyl)-3,5-dimethylbenzonitrile as a white solid (150 mg, yield: 69%). ESI-MS [M +H]+: 161.2.

[0385] Synthesis of 2-(5-methoxy-2-oxobenzo[d]oxazole-3(2H)-yl)acetic acid. [ka] Synthesis of 5-methoxybenzo[d]oxazole-2(3H)-one. N,N-carbonyldiimidazole (1.61 g, 9.88 mmol) was added at room temperature to a suspension of 4-methoxy-2-aminophenol (1.25 g, 8.98 mmol) in anhydrous dichloromethane (45 mL). The resulting solution was stirred overnight and quenched with water (20 mL) and hydrochloric acid (2 M, 20 mL). The layers were separated, and the organic layer was washed again with hydrochloric acid (2 M, 20 mL). The combined aqueous layer was extracted with dichloromethane. The combined organic layer was dried over (MgSO4), filtered, silica gel was added to the filtrate, and the solvent was evaporated. The residue was purified by column chromatography (50 g silica gel) using a concentration gradient of heptane:ethyl acetate = 9:1 to 1:1 to obtain 5-methoxybenzo[d]oxazole-2(3H)-one (1.18 g, 80%) as a pale orange solid. LCMS [System 2, 4.5 min buffering] RT = 2.13 min; [M + H] + 166. 1H NMR (400 MHz, CD3SOCD3, ppm) δ 11.55 (s, 1H), 7.18 (d, J 9 Hz, 1H), 6.65 (d, J 2 Hz, 1H), 6.61 (dd, J 2, 9 Hz, 1H), 3.74 (s, 3H).

[0386] Synthesis of tert-butyl 2-(5-methoxy-2-oxobenzo[d]oxazole-3(2H)-yl)acetate. Tert-butyl bromoacetate (1.27 mL, 8.57 mmol) was added to a suspension of 5-methoxybenzo[d]oxazole-2(3H)-one (1.18 g, 7.15 mmol) and potassium carbonate (1.19 g, 17.2 mmol) in acetone (18 mL). The mixture was heated under reflux for 2.5 hours. Further addition of tert-butyl bromoacetate (1.27 mL, 8.57 mmol) was added, and the mixture was heated for a further 2 hours. Further addition of potassium carbonate (1.19 g, 17.2 mmol) was added, and the mixture was heated for a further 1 hour. The mixture was cooled to room temperature, and the solvent was removed under reduced pressure. The residue was partitioned between ethyl acetate (50 mL) and water (100 mL), and the aqueous layer was extracted once with ethyl acetate (20 mL). The organic solutions were combined, washed with brine, dried, filtered, and evaporated to obtain an orange oily substance. The crude product was purified on silica gel (50 g) eluting with a heptane:ethyl acetate concentration gradient of 8:2 to 7:3 to obtain 2-(5-methoxy-2-oxobenzo[d]oxazole)-3(2H)-yl) tert-butyl acetate (1.87 g, 94%) as a pale pink solid. LC-MS [System 2, 4.5 min buffering] RT = 2.80 min; [M - Bu t + H] + 224. 1 H NMR (400 MHz, CDCl3, ppm) δ 7.11 (d, J 9 Hz, 1H), 6.63 (dd, J 9, 2 Hz, 1H), 6.44 (d, J 2 Hz, 1H), 4.42 (s, 2H), 3.80 (s, 3H), 1.47 (s, 9H).

[0387] Synthesis of 2-(5-methoxy-2-oxobenzo[d]oxazole-3(2H)-yl)acetic acid. Trifluoroacetic acid (10 mL) was added to a solution of tert-butyl 2-(5-methoxy-2-oxobenzo[d]oxazole-3(2H)-yl)acetic acid (1.87 g, 11.3 mmol) in dichloromethane (10 mL). The resulting mixture was stirred at 22°C for 2 hours. Volatile substances were removed under reduced pressure, and the residue was subjected to reverse-phase chromatography (Biotage SNAP ULTRA C) using a concentration gradient of A:B = 8:2 to 1:9 (A is 0.1% v / v formic acid in water, and B is 0.1% v / v formic acid in acetonitrile) over 10 column volumes. 18 The solution was purified using a 60g cartridge at 50mL / min. The fraction containing the pure product was pooled and concentrated to obtain 2-(5-methoxy-2-oxobenzo[d]oxazole-3(2H)-yl)acetic acid (1.10g, 73%) as a colorless solid. UP-LC [Method A1] RT = 2.42 min; [M + H] + = 224. 1 H NMR (400 MHz, CD3SOCD3, ppm) δ 13.32 (s, 1H), 7.26 (d, J 9 Hz, 1H), 7.04 (d, J 2 Hz, 1H), 6.67 (dd, J 9, 2 Hz, 1H), 4.63 (s, 2H), 3.75 (s, 3H).

[0388] Synthesis of (2R,3S)-3-(3-chlorophenyl)-2-methylbutanoic acid and (2S,3R)-3-(3-chlorophenyl)-2-methylbutanoic acid. [ka] Synthesis of 2-(3-chlorophenyl)-1,1-bis(phenylsulfonyl)ethane. A mixture of 3-chlorobenzaldehyde (3.86 mL, 30.7 mmol), bis(phenylsulfonyl)methane (10.0 g, 33.7 mmol), diethylammonium chloride (6.39 g, 58.3 mmol) and potassium fluoride (270 mg, 4.60 mmol) in anhydrous toluene was prepared by Dean The mixture was heated under nitrogen and refluxed in a flask connected to a Stark water separator. After 26 hours, the mixture was cooled to room temperature and the solvent was evaporated. The residue was partitioned into water (50 mL) and dichloromethane (160 mL). The aqueous layer was extracted with dichloromethane (2 × 50 mL). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain a yellow solid. A mixture of diethyl ether and dichloromethane (4:1, 40 mL) was added to this solid. The resulting suspension was filtered, and the solid was washed with tert-butyl ether methyl (30 mL) to obtain (2-(3-chlorophenyl)-1,1-bis(phenylsulfonyl)ethene (5.86 g, 41%) as a colorless solid. The yellow mother liquor was concentrated under reduced pressure and purified by silica gel (250 g) flash chromatography eluting with a concentration gradient of heptane:ethyl acetate = 85:15 to 70:30 to obtain a second batch of the product as a yellow solid (880 mg, 6%). LC-MS [System 2, 4.5 min buffering] RT = 3.49 min; [M + H] + 419. 1 H NMR (400 MHz, CDCl3, ppm) δ 8.58 (s, 1H), 8.09-8.04 (m, 2H), 7.74-7.68 (m, 1H), 7.65-7.57 (m, 4H), 7.55-7.51 (m, 1H), 7.40-7.29 (m, 6H).

[0389] Synthesis of (2R,3S)-3-(3-chlorophenyl)-2-methyl-4,4-bis(phenylsulfonyl)butan-1-ol. A suspension of (2-(3-chlorophenyl)-1,1-bis(phenylsulfonyl)ethene (1.09 g, 2.29 mmol) and (R)-α,α-bis[3,5-bis(trifluoromethyl)phenyl]-2-pyrrolidinemethanoltrimethylsilyl ether (137 mg, 0.23 mmol) in anhydrous chloroform (2.5 mL) was cooled to 0°C. Propionaldehyde (1.7 mL, 22.9 mmol) was added, and the reaction mixture was stirred overnight at 0°C. After 16 hours, the crude mixture was combined with two other batches (starting from 2.29 mmol) and concentrated under reduced pressure. The residue was diluted with methanol (400 mL), and the resulting mixture was cooled in an ice bath. Sodium borohydride (2.60 g, 68 mmol) was added. 7 mmol) was added gradually over 15 minutes (the temperature rose to 10°C), and the mixture was stirred at 5-10°C for 45 minutes. The reaction was quenched with hydrochloric acid (0.5 M, 320 mL), and ethyl acetate (500 mL) and brine (150 mL) were added. The layers were separated, and the aqueous layer was extracted with ethyl acetate (2 × 250 mL). The combined organic extract was washed with water (200 mL) and brine (200 mL), dried over anhydrous Na₂SO₄, and concentrated to obtain a viscous yellow solid (4.8 g). The crude product was dissolved in dimethyl sulfoxide and eluted by reverse-phase chromatography (Biotage Ultra C) using water:acetonitrile = 70:30 over 2 column volumes, and then water:acetonitrile in a ratio of 70:30 to 25:75 over 12 column volumes. 18 The sample was purified using a 120g cartridge (in three separate steps). The fractions from these three purifications, containing a mixture of isomers, were combined and concentrated under reduced pressure. The mixture was then eluted using reverse-phase chromatography (Biotage Ultra C) with water:acetonitrile = 65:35 over two column volumes, followed by water:acetonitrile in a ratio of 65:35 to 30:70 over twelve column volumes. 18The solution was re-purified using a 400g cartridge. All fractions with purity >99% by LC were combined and concentrated under vacuum to obtain (2R,3S)-3-(3-chlorophenyl)-2-methyl-4,4-bis(phenylsulfonyl)butan-1-ol (2.20g, 67%) as a colorless solid. LC-MS [System 2, 4.5 min buffered]: RT = 3.35 min, [MH] - = 477. 1 H NMR (400 MHz, CDCl3, ppm): δ 7.75-7.73 (m, 2H), 7.69-7.67 (m, 2H), 7.59-7.53 (m, 2H), 7.46-7.37 (m, 5H), 7.28 (s, 1H), 7.22 (d, J 4.8 Hz, 2H), 5.81 (d, J 1.8 Hz, 1H), 4.17-4.12 (m, 1H), 3.80 (dd, J 10.6, 1.8 Hz, 1H), 3.65-3.56 (m, 1H), 3.16-3.07 (m, 1H), 2.20 (dd, J 7.0, 4.5 Hz, 1H), 0.74 (d, J 6.7 Hz, 3H).

[0390] Synthesis of (2R,3S)-3-(3-chlorophenyl)-2-methylbutan-1-ol. In a nitrogen-filled dry flask, shavings of magnesium (2.78 g, 24.31 mmol) and a catalytic amount of iodine (7 mg, 0.03 mmol) were stirred for 10 minutes. The flask was gently heated until sublimation of iodine was observed. The flask was then placed in a 20°C water bath and a solution of (2R,3S)-3-(3-chlorophenyl)-2-methyl-4,4-bis(phenylsulfonyl)butan-1-ol (2.23 g, 4.65 mmol) in methanol (220 mL) was added. After 3 hours, the reaction mixture was filtered through a short pad of Dicalite and rinsed with methanol (50 mL) and methyl tert-butyl ether (100 mL). A saturated ammonium chloride aqueous solution (200 mL) and hydrochloric acid (2 M, 50 mL) were added to the filtrate and extracted with methyl tert-butyl ether (2 × 300 mL). The combined organic solution was washed with sodium thiosulfate aqueous solution (150 mL) and brine (200 mL), dried, and concentrated under reduced pressure to obtain (2R,3S)-3-(3-chlorophenyl)-2-methylbutan-1-ol (856 mg, 92%) as a yellow oil. LC-MS [System 2, 4.5 min buffered]: RT = 3.05 min, no ionization. 1 H NMR (400 MHz, CDCl3, ppm): δ 7.23-7.16 (m, 3H), 7.06 (dt, J 7.3, 1.5 Hz, 1H), 3.62-3.52 (m, 2H), 2.82-2.75 (m, 1H), 1.87-1.77 (m, 1H), 1.28 (d, J 6.7 Hz, 3H), 0.79 (d, J 6.7 Hz, 3H).

[0391] Synthesis of (2R,3S)-3-(3-chlorophenyl)-2-methylbutanoic acid. A saturated sodium bicarbonate aqueous solution (13 mL) was added to a solution of (2R,3S)-3-(3-chlorophenyl)-2-methylbutan-1-ol (840 mg, 4.23 mmol) in acetone (40 mL). The resulting mixture was cooled to 0°C. Potassium bromide (101 mg, 0.85 mmol) and TEMPO (13.2 mg, 0.08 mmol) were added. Trichloroisocyanuric acid (TCCA, 1.97 g, 8.46 mmol) was added in six portions over 20 minutes. The yellow mixture was stirred at 0°C for 30 minutes, then stirred overnight at 22°C. After 24 hours, 2-propanol (3 mL) was added. After a few minutes, a white solid precipitated. The solid was filtered off, and the filtrate was concentrated under reduced pressure to remove the acetone. The residue was treated with an aqueous sodium carbonate solution (10% w / v, 15 mL) and ethyl acetate (5 mL), filtered again to remove the insoluble white solid, and rinsed with ethyl acetate (5 mL) and water (5 mL). The filtrate layer was separated. The aqueous layer was washed with ethyl acetate (10 mL), treated with hydrochloric acid (2 M, 15 mL) to pH 1, and extracted with ethyl acetate (2 × 20 mL). The organic layers were combined, dried (Na₂SO₄), filtered, and concentrated under vacuum to obtain (2R,3S)-3-(3-chlorophenyl)-2-methylbutanoic acid (722 mg, 80%) as a colorless oil, which crystallized upon standing. UP-LC [Method A1]: RT = 3.13 min, [M - H] - = 211. 1 H NMR (400 MHz, CD3SOCD3, ppm) δ 12.28 (s, 1H), 7.35-7.25 (m, 3H), 7.22-7.19 (m, 1H), 2.90-2.82 (m, 1H), 2.55-2.49 (m, 1H), 1.19 (d, J 7.3 Hz, 3H), 0.81 (d, J 7.3 Hz, 3H).

[0392] Synthesis of (2S,3R)-3-(3-chlorophenyl)-2-methylbutanoic acid. (2S,3R)-3-(3-chlorophenyl)-2-methylbutanoic acid (590 mg, 83%) was synthesized from (2-(3-chlorophenyl)-1,1-bis(phenylsulfonyl)ethene) and (S)-α,α-bis[3,5-bis(trifluoromethyl)phenyl]-2-pyrrolidinemethanoltrimethylsilyl ether using the same method as for (2R,3S)-3-(3-chlorophenyl)-2-methylbutanoic acid. UP-LC [Method A1]: RT = 3.16 min, [M - H] - = 211. 1 H NMR (400 MHz, CD3SOCD3, ppm) δ 12.28 (s, 1H), 7.35-7.26 (m, 3H), 7.22-7.19 (m, 1H), 2.90-2.82 (m, 1H), 2.55-2.49 (m, 1H), 1.19 (d, J 7.3 Hz, 3H), 0.81 (d, J 7.3 Hz, 3H).

[0393] Synthesis of 2-(3-chloro-6-fluoro-1H-indole-5-yl)acetic acid. [ka] Synthesis of 6-fluoro-1-(triisopropylsilyl)-1H-indole. 6-fluoroindole (4.54 g, 33.6 mmol) was dissolved in anhydrous tetrahydrofuran (75 mL) and cooled to -78°C under nitrogen. n-butyllithium (2.5 M in hexane, 23.0 mL, 57.5 mmol) was added dropwise over 15 minutes, and the mixture was stirred for 5 minutes. A solution of triisopropylsilyl chloride (8.20 mL, 38.2 mmol) in anhydrous tetrahydrofuran (15 mL) was added over 5 minutes. The mixture was stirred at -78°C for 10 minutes, then stirred at room temperature for a further 1.5 hours. The mixture was poured into water (100 mL) and extracted with dichloromethane (1 × 100 mL, 2 × 50 mL). The extract was dried (MgSO4), filtered, and concentrated to obtain a brown oily substance. Reverse-phase column chromatography (Biotage Ultra C) is used to elute oily substances using a concentration gradient: 70% acetonitrile in water across 2 column volumes, 70-95% acetonitrile in water across 5 column volumes, and finally 95% acetonitrile in water across 5 column volumes. 18 The product was purified using a cartridge (120 g, 25 μm). The fraction containing the product was pooled and concentrated under reduced pressure to obtain 6-fluoro-1-(triisopropylsilyl)-1H-indole (4.173 g, 43%) as a pale yellow oil. LC-MS (System 2, 8 min buffering); RT = 4.53 min, [M - H] - 291. 1 H NMR (400 MHz, CDCl3, ppm) δ 7.52 (dd, J 9.1, 5.8 Hz, 1H), 7.22 (d, J 3.0 Hz, 1H), 7.19 (dd, J 11.2, 2.1 Hz, 1H), 6.88 (td, J 9.1, 2.1 Hz, 1H), 6.59 (d, J 3.0 Hz, 1H), 1.68 (septet, J 7.3 Hz, 3H), 1.14 (d, J 7.3 Hz, 18H). 19 F NMR (373 MHz, CDCl3, ppm) δ -121.65 (dt, J 9.1, 5.8 Hz).

[0394] Synthesis of 6-fluoro-5-iodo-1-(triisopropylsilyl)-1H-indole. 6-fluoro-1-(triisopropylsilyl)-1H-indole (4.173 g, 14.3 mmol) and N,N,N',N”,N”-pentamethyldiethylenetriamine (3.80 mL, 18.2 mmol) in anhydrous tetrahydrofuran (25 mL) were cooled to -78°C under nitrogen. A solution of sec-butyllithium (1.27 M, 18.0 mL, 22.9 mmol) in cyclohexane was added, and the mixture was stirred at -78°C for 6 hours. A solution of iodine (5.74 g, 22.6 mmol) in anhydrous tetrahydrofuran (12 mL) was added, and the mixture was stirred at -78°C for 30 minutes. The mixture was poured into water (100 mL) and extracted with dichloromethane (1 × 100 mL, 2 × 50 mL). The combined extracts were washed with a 10% sodium thiosulfate aqueous solution (80 mL), dried (MgSO4), filtered, and concentrated to obtain a brown oily substance. The oily substance was eluted using reversed-phase column chromatography (Biotage Ultra C) with a concentration gradient of 70% acetonitrile in water over 2 column volumes, 70-95% acetonitrile in water over 10 column volumes, and finally 95% acetonitrile in water over 5 column volumes. 18 The product was purified using a cartridge (120 g, 25 μm). The fraction containing the product was pooled and concentrated under reduced pressure to obtain 6-fluoro-5-iodo-1-(triisopropylsilyl)-1H-indole (4.68 g, 78%) as a light brown oil. LC-MS (System 2, 8 min buffered); RT = 4.88 min, [M - Si[CH(CH3)2]3] - 260. 1 H NMR (400 MHz, CDCl3, ppm) δ 7.94 (d, J 6.1 Hz, 1H), 7.24 (d, J 10.3 Hz, 1H), 7.21 (d, J 2.8 Hz, 1H), 6.53 (d, J 2.8 Hz, 1H), 1.66 (sept, J 7.3 Hz, 3H), 1.13 (d, J 7.3 Hz, 18H). 19 F NMR (373 MHz, CDCl3, ppm) δ -102.90 (dd, J 10.3, 6.1 Hz).

[0395] Synthesis of 2-(6-fluoro-1-(triisopropylsilyl)-1H-indole-5-yl) tert-butyl acetate. Zinc powder (2.97 g, 45.4 mmol) was suspended in anhydrous tetrahydrofuran (80 mL) under nitrogen, and chlorotrimethylsilane (0.45 mL, 3.6 mmol) was added. The mixture was heated at 65°C for 15 minutes, then cooled to 50°C over 20 minutes. Tert-butyl bromoacetate (4.1 mL, 27.8 mmol) was added dropwise over 5 minutes, and the mixture was stirred at 50°C for 40 minutes to produce (2-(tert-butoxy)-2-oxoethyl)zinc(II) bromide. The mixture was then allowed to cool, and the solid was allowed to settle over 20 minutes. Separately, a mixture of 6-fluoro-5-iodo-1-(triisopropylsilyl)-1H-indole (4.43 g, 10.6 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (1.147 g, 2.4 mmol), and tris(dibenzylideneacetone)dipalladium(0) (1.134 g, 1.20 mmol) in anhydrous tetrahydrofuran (10 mL) was stirred under nitrogen at room temperature for 10 minutes. The supernatant of the solution containing (2-(tert-butoxy)-2-oxoethyl)zinc(II) bromide was taken with a syringe and added to the mixture of indole and palladium catalyst. The mixture was then heated under reflux for 4.5 hours, cooled to room temperature, and poured into saturated ammonium chloride aqueous solution (200 mL). The mixture was extracted with ethyl acetate (200 mL), washed with brine (200 mL), dried (MgSO4), filtered, and concentrated under reduced pressure to obtain a dark orange oily substance (10.22 g). The oily substance was adsorbed onto silica gel (30 g) using dichloromethane (80 mL) and purified by flash column chromatography (SiliCycle SiliaSep cartridge, 220 g) with elution using 0% ethyl acetate in heptane over 2 column volumes and 0-50% ethyl acetate in heptane over 15 column volumes. The fraction containing the product was pooled and concentrated under reduced pressure, and the residue was eluted by reverse-phase column chromatography (Biotage Ultra C) with elution using a concentration gradient of 70% acetonitrile in water over 2 column volumes, 70-95% acetonitrile in water over 10 column volumes, and finally 95% acetonitrile in water over 2 column volumes.18 The product was re-purified using a cartridge (120 g, 25 μm). The fraction containing the product was pooled and concentrated under reduced pressure to obtain tert-butyl 2-(6-fluoro-1-(triisopropylsilyl)-1H-indole-5-yl)acetate (3.418 g, 79%) as a pale yellow oil. LC-MS (System 2, 8 min buffering); RT = 4.71 min, [M + H] + 406. 1 H NMR (400 MHz, CDCl3, ppm) δ 7.42 (d, J 8.0 Hz, 1H), 7.18 (d, J 3.2 Hz, 1H), 7.18 (d, J 11.6 Hz, 1H), 6.54 (d, J 3.2 Hz, 1H), 3.64 (s, 2H), 1.72-1.61 (m, 3H), 1.46 (s, 9H), ...

Claims

1. Compound of formula I: 【Chemistry 1】 (I) or a pharmaceutically acceptable salt thereof During the ceremony: Cy Ａ However, it is a four-membered monocyclic carbocyclene, or a six-membered monocyclic heteroarylene having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, and Cy Ａ However, there are 0 to 4 R Ａ It is substituted with the base, each R Ａ is independently selected from oxo, halogen, -CN, -C(O)R, -C(O)OR, -C(O)N(R) ２ , -NO ２ , -N(R) ２ , -N(R)C(O)R, -N(R)C(O)OR, -N(R)S(O) ２ R, -OR, -OC(O)R, -OC(O)N(R) ２ , -SR, -S(O)R, -S(O) ２ R, -S(O)N(R) ２ , -S(O) ２ N(R) ２ , and optionally substituted groups independently selected from C １ - ６ aliphatic, phenyl, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 2 heteroatoms selected from oxygen, nitrogen and sulfur, and 5- or 6-membered monocyclic heteroaryl having 1 to 4 heteroatoms independently selected from oxygen, nitrogen and sulfur, Each R is independently replaced by hydrogen or optionally substituted with C. １－６ It is an aliphatic group, Cy Ｂ However, selected from phenyl, 8-10 membered bicyclic aryls, 7-10 membered saturated or partially unsaturated bicyclic carbocyclyls, 5 or 6 membered heteroaryls having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, 7-10 membered saturated or partially unsaturated bicyclic heterocyclyls having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, and 7-10 membered heteroaryls having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, Cy Ｂ However, there are 0 to 5 R Ｂ It is substituted with the base, Each R Ｂ However, oxo, halogen, -CN, -C(O)R, -C(O)OR, -C(O)N(R) ２ , -C(NR)NR ２ , -C(NR)NROR, -C(NR)NRC(O)OR, -NO ２ , -N(R) ２ , -N(R)C(O)R, -N(R)C(O)OR, -N(R)S(O) ２ R, -OR, -OC(O)R, -OC(O)N(R) ２ , -SR, -S(O)R, -S(O) ２ R, -S(O)N(R) ２ , -S(O) ２ N(R) ２ , and C １ - ６ A group independently selected from substituted groups, which include 3-7 member saturated or partially unsaturated monocyclic heterocyclines having 1-2 heteroatoms selected from aliphatic, oxygen, nitrogen, and sulfur, and 5-6 member heteroaryls having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, L' is arbitrarily substituted into C １－４ It is a hydrocarbon chain, in which case 1 to 3 methylene units are independently -C(O)-, -NR ｚ -, -S-, -SO-, SO ２ Substituted with -, -S(NH)(O)-, or cyclopropylene, Each R ｚ However, hydrogen, -(CH ２ ) ０－３ OR, -(CH ２ ) ０－３ C(O)OR, and any substituted C １－６ Selected independently from aliphatic groups, L is arbitrarily replaced by C １－２ It is a hydrocarbon chain, in which case each methylene unit is independently -C(O)-, -O-, -NR ｚ -, -S-, -SO-, or -SO ２ A substituted or optionally substituted 5 or 6-membered saturated or partially unsaturated heterocyclene having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, Each R ３ , R ４ , R ５ , R ６ , and R ７ However, hydrogen and -L Ｃ -R Ｃ Selected independently from, in the formula, Each L Ｃ However, covalent bonds and optionally substituted C １－６ Selected independently from the hydrocarbon chain, in which case one to three methylene units are arbitrarily and independently substituted with -O- or -NR-, Each R Ｃ However, halogen, -CN, -C(O)R, -C(O)OR, -C(O)N(R) ２ , -NO ２ , -N(R) ２ , -N(R)C(O)R, -N(R)C(O)OR, -N(R)S(O) ２ R, -OR, -OC(O)R, -OC(O)N(R) ２ , -SR, -S(O)R, -S(O) ２ R, -S(O)N(R) ２ , -S(O) ２ N(R) ２ Cy Ｃ , and optionally substituted C １ - ６ Selected independently from aliphatic species, Each Cy Ｃ The compound, or a pharmaceutically acceptable salt thereof, is an optionally substituted ring independently selected from a 3-7 member saturated or partially unsaturated monocyclic carbocyclyl, a 3-7 member saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, and sulfur, a 5-6 member monocyclic heteroaryl having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, a 6-12 member saturated or partially unsaturated condensed bicyclic heterocyclyl having 1-3 heteroatoms independently selected from phenyl, oxygen, nitrogen, and sulfur, a bridging bicyclic, and a 6-12 member saturated or partially unsaturated bicyclic spiroheterocyclyl having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur.

2. Cy Ａ but: 【Chemistry 2】 Selected from the group consisting of, During the ceremony, ＊ The compound according to claim 1, wherein the bond site to L is represented.

3. Each R Ａ However, oxo, -C(O)R, -C(O)OR, -OR, and C １ - ６ The compound according to claim 1 or 2, independently selected from an optionally substituted group selected from an aliphatic or a 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from oxygen, nitrogen or sulfur.

4. Cy Ｂ but: 【Transformation 3】 【change】 A compound according to any one of claims 1 to 3, selected from the group consisting of the following.

5. Each R Ｂ However, oxo, halogen, -CN, -C(O)N(R) ２ , -C(NR)NR ２ , -C(NR)NROR, -C(NR)NRC(O)OR, -N(R) ２ , -OR, and C １ - ６ The compound according to any one of claims 1 to 4, independently selected from aliphatic groups and optionally substituted groups selected from five or six-membered heteroaryl groups having one to four heteroatoms independently selected from oxygen, nitrogen, and sulfur.

6. L is arbitrarily replaced by C １－２ It is a hydrocarbon chain, in which case one methylene unit is -C(O)-, -O-, -NR ｚ The compound according to any one of claims 1 to 5, wherein L is substituted with -, or is an optionally substituted 5-6 member saturated or partially unsaturated heterocyclene having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur.

7. L is -C(O)- or *-NHCH(Me)-, ＊ -NHCH ２ -, ＊ -OCH ２ -, or ＊ -N(CH ３ )CH ２ -, wherein, ＊ represents the point of attachment to Cy, Ａ The compound according to any one of claims 1 to 6.

8. L' is arbitrarily substituted into C １－４ It is a hydrocarbon chain, in which case 1 to 3 methylene units are independently -C(O)-, -NR ｚ -, SO ２ The compound according to any one of claims 1 to 7, which is substituted with -, -S(NH)(O)-, or cyclopropylene.

9. L' is: -NH ２ -、 【Chemistry 4】 Selected from the group consisting of, During the ceremony, ＊ However, Cy Ａ A compound according to any one of claims 1 to 8, representing a bonding site to a compound.

10. R ３ The compound according to any one of claims 1 to 9, wherein R is hydrogen.

11. R ４ but: Hydrogen, -CN, 【Transformation 5】 A compound according to any one of claims 1 to 10, selected from the group consisting of the following.

12. R ５ The compound according to any one of claims 1 to 11, wherein the compound is hydrogen or cyclopropyl.

13. R ６ The compound according to any one of claims 1 to 12, wherein the compound is hydrogen or cyclopropyl.

14. R ７ The compound according to any one of claims 1 to 13, wherein is hydrogen.

15. The compound is a compound of formula (I-a), formula (I-b), or formula (I-c): 【Chemistry 6-1】 【Chemistry 6-2】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

16. The compound is a compound of formula (II), formula (II-a), formula (II-b), or formula (II-c): 【Transformation 7】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

17. The compound is a compound of formula (III), formula (III-a), formula (III-b), or formula (III-c): 【Transformation 8】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

18. The compound is a compound of formula (IV-a), formula (IV-b), formula (IV-c), or formula (IV-d): 【Chemistry 9】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

19. The compound is a compound of formula (V), formula (V-a), formula (V-b), or formula (V-c): 【Chemistry 10】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

20. The compound is a compound of formula (VI), formula (VI-a), formula (VI-b), or formula (VI-c): 【Chemistry 11】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

21. The compound is a compound of formula (VII), formula (VII-a), formula (VII-b), or formula (VII-c): 【Chemistry 12】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

22. The compound is a compound of formula (VIII), formula (VIII-a), formula (VIII-b), or formula (VIII-c): 【Chemistry 13】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

23. The aforementioned compound, 【Chemistry 14】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 The compound according to claim 1, or selected from a pharmaceutically acceptable salt thereof.

24. A pharmaceutical composition comprising the compound described in any one of claims 1 to 23.

25. A compound according to any one of claims 1 to 23 for use in the treatment of diseases or disorders mediated by plasma kallikrein.

26. The compound according to claim 25, wherein the disease or disorder is hereditary angioedema or diabetic macular edema.

27. The composition according to claim 24 for use in the treatment of diseases or disorders mediated by plasma kallikrein.

28. The composition according to claim 27, wherein the disease or disorder is hereditary angioedema or diabetic macular edema.

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