Polycyclic inhibitor of plasma kallikrein

Abstract

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

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims the interests of U.S. Provisional Patent Application No. 63 / 162,483, filed on 17 March 2021, which is incorporated herein by reference in its entirety. [Background technology]

[0002] I. Background technology 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 inhibitor (C1-INH), the major physiological inhibitor of PKa. Cleavage of high molecular weight kininogen mediated by PKa generates bradykinin (BK), a potent vasodilatory and pro-inflammatory nonapeptide, which activates the bradykinin 2 receptor. Subsequent cleavage of BK by carboxypeptidase generates des-Arg9-BK, which activates the B1 receptor. Both B1 and B2 receptors are expressed in vascular, glial, and neuronal cell types, with the highest levels of retinal expression detected in the ganglion cell layer as well as the inner and outer granular layers. Activation of B1 and B2 receptors causes vasodilation and increases vascular permeability.

[0003] 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 levels, 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]

[0004] II. Outline of the Invention 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, compounds and their uses for targeting plasma kallikrein and / or treating plasma kallikrein-mediated diseases and disorders, novel intermediates, and processes for preparing the compounds disclosed herein are provided herein. This disclosure also extends to pharmaceutical compositions comprising any one of them, and the use of the compounds or compositions herein for treatment (particularly for the treatment of autoimmune diseases such as HAE).

[0005] In some embodiments, the present invention relates to formula (I): [ka] We provide compounds of or pharmaceutically acceptable salts thereof, in the formula Cy A ,X,Cy B Cy C , L, R x , R x’ , R Y , and R Y’Each of the above is, both alone and in combination, defined and described in the classes and subclasses herein. In certain embodiments, the present invention provides a compound of formula (I) to (VI-c), as defined and described in the classes and subclasses herein.

[0006] In some embodiments, the present invention also provides a method of using the compound of formula (I) to (VI-c).

[0007] Advantageously, the compounds of the present disclosure have therapeutic activity, as well as a suitable level of bioavailability and / or a suitable half-life for use as a therapeutic agent. Mode for Carrying Out the Invention

[0008] III. Mode for Carrying Out the Invention A. Definitions Compounds of the present invention include those generally described above, as well as those further exemplified by the classes, subclasses, and specific chemical species disclosed herein. As used herein, the following definitions shall apply unless otherwise indicated. For the purposes of the present invention, chemical elements are identified in accordance with 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 th Ed., Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are incorporated herein by reference.

[0009] 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.

[0010] 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 that is fully saturated or contains one or more unsaturated units, but is not aromatic (also referred herein as “carbocyclyl,” “alicyclic,” or “cycloalkyl”), and has a single bond site to the remainder of the molecule. 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 either 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.

[0011] The term "heteroatom" refers to one or more oxygen, sulfur, nitrogen, phosphorus, or silicon (any oxidation form of nitrogen, sulfur, phosphorus, or silicon; any quaternation form of basic nitrogen; or a substituteable nitrogen in a heterocyclic ring, e.g., N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR+ This means (including, as in N-substituted pyrrolidinyl).

[0012] As used herein, the term “unsaturated” means that a part has one or more unsaturated units.

[0013] 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.

[0014] The term "halogen" refers to F, Cl, Br, or I.

[0015] The term “aryl” refers to monocyclic and bicyclic ring systems having a total of 5 to 10 ring members, wherein at least one ring in the system is aromatic and each ring in the system contains 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, anthrasyl, etc. 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, etc.

[0016] 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 the carbon atom. 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 “hetero-” also include groups in which an aromatic heterocycle is fused to one or more aryl rings, alicyclic rings, or heterocyclyl rings, and in which the radical or bond site is located on the aromatic heterocycle (or, in the case of a divalent condensed heteroarylene ring system, at least one radical or bond site is located on the aromatic heterocycle). 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 optionally substituted rings.

[0017] As used herein, the terms “heterocyclyl,” “heterocyclic radical,” and “heterocyclic ring” are used interchangeably and refer to stable 5-7 membered monocyclic or 7-10 membered bicyclic heterocyclic moieties that are either saturated or partially unsaturated and have one or more, preferably 1-4, of the above-defined heteroatoms in addition to 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 0-3 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).

[0018] Heterocyclic rings can be bonded to their 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 fused to 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.

[0019] 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.

[0020] As used herein, and unless otherwise specified, the suffix "-ene" is used to describe a divalent group. Thus, any of the above terms can be modified with the suffix "-ene" to describe 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.

[0021] As described herein, the compounds of the present invention may contain, where specified, “optionally substituted” moieties. Generally, whether following the term “optionally,” the term “substituted” means that one or more hydrogens of a given moiety are replaced with preferred substituents. “Substituted” applies to one or more hydrogens that are evident or implicitly indicated by the structure (e.g., [ka] At least [ka] It refers to, [ka] At least [ka] (This refers to...). In addition, in polycyclic ring systems, unless otherwise specified, substituents can replace any hydrogen on any individual 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 the 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.

[0022] A suitable monovalent substituent on the replaceable carbon atom of the "optionally substituted" group is, independently, a halogen;-(CH2) 0~4 R°;-(CH2) 0~4 OR°;-O(CH2) 0~4 R°, -O(CH2) 0~4 C(O)OR°;-O(CH2) 0~4 OR °;-(CH2) 0~4 CH(OR°)2;-(CH2) 0~4 SR°;R° may be substituted -(CH2) 0~4 It may be substituted with Ph;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 -Pyridyl;-NO2;-CN;-N3;-(CH2) 0~4 N(R°)2;-(CH2) 0~4N(R°)C(O)R°;-N(R°)C(S)R°;-(CH2) 0~4 N(R°)C(O)NR°2;-N(R°)C(S)NR°2;-(CH2) 0~4 N(R°)C(O)OR°;-N(R°)N(R°)C(O)R°;-N(R°)N(R°)C(O)NR°2;-N(R°)N(R°)C(O)OR°;-(CH2) 0~4 C(O)R°;-C(S)R°;-(CH2) 0~4 C(O)OR°;-(CH2) 0~4 C(O)SR°;-(CH2) 0~4 C(O)OSiR°3;-(CH2) 0~4 OC(O)R°;-OC(O)(CH2) 0~4 SR°, -SC(S)SR°;-(CH2) 0~4 SC(O)R°;-(CH2) 0~4 C(O)NR°2;-C(S)NR°2;-C(S)SR°;-SC(S)SR°, -(CH2) 0~4 OC(O)NR°2;-C(O)N(OR°)R°;-C(O)C(O)R°;-C(O)CH2C(O)R°;-C(NOR°)R°;-(CH2) 0~4 SSR°;-(CH2) 0~4 S(O)2R°;-(CH2) 0~4 S(O)2OR°;-(CH2) 0~4 OS(O)2R°;-S(O)2NR°2;-(CH2) 0~4 S(O)R°;-N(R°)S(O)2NR°2;-N(R°)S(O)2R°;-N(OR°)R°;-C(NH)NR°2;-P(O)2R°;-P(O)R°2;-OP(O)R°2;-OP(O)(OR°)2;SiR°3;-(C 1~4 Linear or branched alkylene)ON(R°)2; or -(C 1~4 The linear or branched alkylene is C(O)ON(R°)2, where each R° may be substituted as defined below, independently of hydrogen and C. 1~6 Aliphatic, -CH2Ph, -O(CH2) 0~1Ph, -CH2- (a 5-6 member heteroaryl ring), or a 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 independent appearances of R°, together with the intervening atom(s), form a 3-12 member saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below.

[0023] A suitable monovalent substituent on R° (or a ring formed by the independent appearance of two R° atoms together with the intervening 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 preceded by "halo", it is substituted by only one or more halogens, C 1~4aliphatic, -CH2Ph, -O(CH2) 0~1 Ph, or is independently selected from 5- to 6-membered saturated rings, partially unsaturated rings or aryl rings having 0 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur. Preferred divalent substituents on a saturated carbon atom of R° include =O and =S.

[0024] Preferred divalent substituents on a saturated carbon atom of an "optionally substituted" group include the following: =O, =S, =NNR # 2, =NNHC(O)R # , =NNHC(O)OR # , =NNHS(O)2R # , =NR # , =NOR # , -O(C(R # 2)) 2~3 O-, or -S(C(R # 2)) 2~3 S-, wherein each independently occurring R # is selected from hydrogen, C which may be substituted as defined below 1~6 aliphatic, or an unsubstituted 5- to 6-membered saturated ring, partially unsaturated ring or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur. Preferred divalent substituents bonded to adjacent substitutable carbons of an "optionally substituted" group include -O(CR # 2) 2-3 O-, wherein each independently occurring R # is selected from hydrogen, C which may be substituted as defined below 1~6 aliphatic, or an unsubstituted 5- to 6-membered saturated ring, partially unsaturated ring or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0025] R # Preferred substituents on the aliphatic group of include halogen, -R ● , -(halo R ● ), -OH, -OR ● , -O(halo R ● ), -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, 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.

[0026] A suitable substituent on the substituted nitrogen of the "arbitrarily substituted" group is -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 R † The independent occurrences of these atoms, along with the intervening atoms (maybe multiple atoms), form unsubstituted 3-12 member saturated, partially unsaturated, or aryl monocyclic or bicyclic rings having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0027] 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, 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.

[0028] 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 is commensurate with a reasonable benefit-risk ratio. Pharmacologically acceptable salts are well known in the art. For example, SMBerge et al., in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference, describe pharmaceutically acceptable salts in detail.

[0029] 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.

[0030] Unless otherwise specified, the structures shown herein include all isomers (e.g., enantiomers, diastereomers, and geometric (or conformational) forms) 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. Therefore, 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 shown 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 14 Compounds having the structure of the present invention, including carbon substitution with 1C-enriched carbon, are within the scope of the present invention. Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents according to the present invention. In some embodiments, the compounds of the present disclosure are provided as a single enantiomer or a single diastereoisomer. A single enantiomer means that the enantiomer excess is 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 means that the excess is 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] In this specification, the articles "a" and "an" are used to refer to one or more (i.e., at least one) grammatical objects of the article. For example, "an element" means one element or two or more elements.

[0034] A “dosage plan” (or “treatment plan”), as the term is used herein, is a set of unit doses (usually two or more) administered individually to a subject, usually at intervals of time. In some embodiments, a given therapeutic agent has a recommended dosage plan that may require one or more doses. In some embodiments, the dosage plan consists of multiple doses, each separated from the others by periods of equal length, and in some embodiments, the dosage plan consists of multiple doses, with each dose separated by at least two different periods.

[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 enable a related comparison. 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 historical. In some embodiments, the information about the reference compound is stored, for example, on a computer-readable medium. In some embodiments, a comparison of the particular compound of interest with the reference compound establishes the identity, similarity, or difference between the particular compound of interest and the reference compound.

[0036] As used herein, the term “therapeutic agent” means any agent that has a therapeutic effect and / or, when administered to a subject, induces a desired biological and / or pharmacological effect.

[0037] 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-to-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. A therapeutic dose is generally administered in a dosing regimen that may consist of 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, a specific therapeutically effective dose (and / or unit dose) for any particular subject may depend on various factors, including the disorder being treated and its severity; the activity of the specific therapeutic agent used; the specific composition used; the subject's age, weight, health status, sex, and diet; the timing, route of administration, and / or rate of elimination or metabolism of the specific therapeutic agent used; the duration of treatment; and similar factors well known in the medical field.

[0038] As used herein, the term “treatment” (as in “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, characteristics, and / or causes of a particular disease, disorder, and / or condition. Such treatment may be treatment of a subject that does not show signs of the disease, disorder, and / or condition in question, and / or treatment of a subject that shows only initial signs of the disease, disorder, and / or condition. Alternatively or additionally, such treatment may be treatment of a subject that shows one or more established signs of the disease, disorder, and / or condition in question. In some embodiments, treatment may be treatment of a subject that has been diagnosed with the disease, disorder, and / or condition in question. In some embodiments, treatment may be treatment of a subject that is known to have one or more susceptibility factors that are statistically correlated with an increased risk of developing the disease, disorder, and / or condition in question.

[0039] B. Compound In some embodiments, the provided compound is of formula (I): [ka] A compound of or a pharmaceutically acceptable salt thereof, During the ceremony: Cy A This is an 8-10 member bicyclic heteroarylene having 1-5 heteroatoms independently selected from oxygen, nitrogen, and sulfur; a 10-14 member tricyclic heteroarylene having 1-6 heteroatoms independently selected from oxygen, nitrogen, and sulfur; an 8-14 member saturated or partially unsaturated bicyclic heterocycline having 1-6 heteroatoms independently selected from oxygen, nitrogen, or sulfur; or a 10-15 member saturated or partially unsaturated tricyclic heterocycline having 1-6 heteroatoms independently selected from oxygen, nitrogen, or sulfur, where Cy A This includes 0 to 6 -R values. A It is substituted with the base; Each R AThis is independently selected from 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, oxygen, nitrogen, and sulfur. A group independently selected from a 5-6 membered heteroaryl having ~4 heteroatoms, a 3-7 membered saturated or partially unsaturated monocyclic carbocyryl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur, or an optionally substituted group selected from a 6-12 membered spirocyclic ring system having 0-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur; Each R is independently either hydrogen or C 1~6 An optionally substituted group selected from aliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyls, or 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyls having 1 to 2 heteroatoms selected from oxygen, nitrogen, or sulfur; X is -N= or -NR-, where X is a Cy bonded to a cyclopropyl ring. A It is adjacent to the ring atom; Each R Y and R Y’ C is hydrogen, halogen, and optionally substituted C 1~6 Selected independently from aliphatic groups; Each R x and R x ' is independently selected from hydrogen, halogen, or CN; Cy B This is selected from phenyl, an 8-10 membered bicyclic aryl, a 5-6 membered heteroaryl having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, or a 7-10 membered heteroaryl having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur (where Cy B This includes 0 to 5 -R values. B Substituted with the base); or Cy B and R x These, along with the intervening atoms, form a 6-12 member spirocyclic ring system having 0-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, where Cy B and R x The ring(s) formed by this process contain 0 to 4 -R B It may also be substituted with the base; Each R B The group is independently selected from 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 a 3-7 member saturated or partially unsaturated monocyclic heterocycline having 1-2 heteroatoms selected from C1-6 aliphatic, oxygen, nitrogen, or sulfur, or an optionally substituted group having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur; L is an arbitrarily substituted C 1~3 Hydrocarbon chain (1 to 3 methylene units are arbitrarily and independently -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 z is hydrogen, -(CH2) 0~3 OR, -(CH2) 0~3 C(O)OR, or any substituted C 1~6 Selected independently from aliphatic groups; Cy CThis is a 7-10 membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, or a 6-12 membered saturated or partially unsaturated bicyclic heterocycline having 1-4 heteroatoms independently selected from oxygen, nitrogen, or sulfur, where Cy C This includes 0 to 6 -L C -R C It is substituted with the base; Each L C is a covalent bond, or optionally substituted C 1~6 A hydrocarbon chain (in which 1 to 3 methylene units are arbitrarily and independently replaced with -O- or -NR-) is independently selected; Each R C is 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 D Independently selected from, or any substituted group selected from C1-6 aliphatic groups; Each Cy D This is 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 bicyclic heterocyclyl having 1-3 heteroatoms independently selected from phenyl, oxygen, nitrogen, or sulfur, a bridged bicycle, or a 6-12 member saturated or partially unsaturated bicyclic spiroheterocyclyl having 1-3 heteroatoms independently selected from oxygen, nitrogen, or sulfur, where Cy D There are 0 to 4 L D -R D It is substituted with the base; Each L D is a covalent bond, or optionally substituted C1~6 A hydrocarbon chain (in which 1 to 3 methylene units are arbitrarily and independently replaced with -O- or -NR-) is independently selected; Each R D The group is independently selected from 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 any optionally substituted group selected from C1-6 aliphatic, phenyl, 3-7 membered saturated or partially unsaturated monocyclic carbocyryl, or 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur.

[0040] "Oxo" refers to the substitution of oxygen in a double bond on a carbon atom ("C=O"), and it should be understood that this carbon atom is part of a structure or group that has been substituted by an oxo. For example, Cy C ga-L D -R D Replaced with L D The bond is covalent and R D If is an oxo, then the carbon atom substituted with the oxo (i.e., the carbon in C=O) is Cy C Part of (for example, cyclopentyl is in 2nd place -L) D -R D Cy is replaced with C (components of L) D It is a covalent bond, R D teeth, [ka] This is the equivalent oxo.

[0041] Regarding formula I, "Cy bonded to the cyclopropyl ring" A The reference to "ring atoms" should be understood as referring to the ring atoms marked with an asterisk (*) below. [ka]

[0042] In some embodiments, Cy A This is an 8-10 membered bicyclic heteroarylene having 1-5 heteroatoms independently selected from oxygen, nitrogen, and sulfur, where Cy A 0 to 4 -R A It is substituted with the base. In certain embodiments, Cy A This includes 0 to 4 -R values. A It is a quinolinylene substituted with a group.

[0043] In some embodiments, Cy A This is a 10-14 member tricyclic heteroarylene having 1-6 heteroatoms independently selected from oxygen, nitrogen, and sulfur, where Cy A 0 to 5 -R A It is substituted with the base.

[0044] In some embodiments, Cy A teeth, [ka] Selected from the group consisting of: Each Y is selected independently of =C(H)- or =N-; W is selected from -C(O)- or -S(O)2-; V is selected from =CH- or =N-; * indicates a bond site to the cyclopropyl ring.

[0045] In some embodiments, Cy A teeth, [ka] Selected from the group consisting of: * indicates a bond site to the cyclopropyl ring.

[0046] In some embodiments, CyA teeth, [ka] Selected from the group consisting of the following, where * represents a bond site to the cyclopropyl ring.

[0047] In some embodiments, Cy A teeth, [ka] Selected from the group consisting of the following, where * represents a bond site to the cyclopropyl ring.

[0048] In some embodiments, Cy A teeth, [ka] Selected from the group consisting of the following, where * represents a bond site to the cyclopropyl ring.

[0049] In some embodiments, Cy A teeth, [ka] Selected from the group consisting of the following, where * represents a bond site to the cyclopropyl ring.

[0050] Several embodiments, each R A The group is independently selected from oxo, halogen, -CN, -N(R)2, -N(R)S(O)2R, -OR, or 5-6 membered heteroaryls having 1-4 heteroatoms independently selected from C1-6 aliphatic, oxygen, nitrogen, and sulfur, 3-7 membered saturated or partially unsaturated monocyclic heterocyclils having 1-2 heteroatoms independently selected from oxygen, nitrogen, or sulfur, or optionally substituted groups selected from 6-12 membered spirocyclic ring systems having 0-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur.

[0051] 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 -N(R)2. In some embodiments, R A One example is -N(R)2, where each R is independently hydrogen or optionally substituted with C. 1~6 It is an aliphatic group. In some embodiments, R A One example is -N(R)S(O)2R. In some embodiments, R A One example is -N(R)S(O)2R, where each R is an arbitrarily substituted C. 1~6 It is an aliphatic group. It will be understood that references herein to embodiments in which “one example” of a substituent is defined are not limited to monosubstituted embodiments. For example, “In some embodiments, R A One example is oxo. 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.

[0052] In some embodiments, R A One example of this is -OR. In some embodiments, R A One example is -OR, where R is hydrogen or C 1~6 The group is selected from aliphatic or optionally substituted groups, which are selected from 3-7 member saturated or partially unsaturated monocyclic heterocyclines having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur. In some embodiments, R A One example is -OR, where R is oxetanyl. In some embodiments, R A One example is -OR, where R is piperidinyl.

[0053] In some embodiments, R A One example is the arbitrarily substituted C 1~6 It is an aliphatic group.

[0054] In some embodiments, R A One example is an optionally substituted 5-6 member heteroaryl having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, R A One example is imidazolyl. In some embodiments, R A One example is pyrazolyl. In some embodiments, R A One example of this is triazolyl.

[0055] In some embodiments, R A One 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 One example is azetidinil. In some embodiments, R A One example is piperazinil. In some embodiments, R A One example is morpholinil. In some embodiments, R A One example of this is thiomorpholinyl.

[0056] In some embodiments, R A One example is an optionally substituted 6-12 membered spirocyclic ring system having 0-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, R A One example is, [ka] That is the case.

[0057] In some embodiments, R is optionally substituted. A The substituents on the group are independently -(CH2) 0~4 R°, -(CH2)0~4 OR°, or -CN, where each R° is independently defined as defined above and described in the Classes and Subclasses herein.

[0058] In some embodiments, X is -N=. In some embodiments, X is -NR-. In some embodiments, X is -NH-.

[0059] 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, where Cy B This includes 0 to 4 -R values. B It is substituted with the base.

[0060] In some embodiments, Cy B is selected from phenyl, or a 5-6 membered heteroaryl having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, where Cy B This includes 0 to 4 -R values. B It is substituted with a base. In some embodiments, Cy B is selected from phenyl, or a 6-membered heteroaryl having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, where Cy B This includes 0 to 4 -R values. B It is substituted with the base.

[0061] In some embodiments, Cy B is phenyl, and here, Cy B This includes 0 to 4 -R values. B It is substituted with a base. In some embodiments, Cy B is phenyl, and here, Cy B This includes 0 to 3 -R values. B It is substituted with the base.

[0062] In some embodiments, Cy B This is a 6-membered heteroaryl having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, where Cy B This includes 0 to 4 -R values. B It is substituted with a base. In some embodiments, Cy B This is a 6-membered heteroaryl having 1 to 3 nitrogen atoms, where 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 triazine group.

[0063] In some embodiments, Cy B This is a 5-membered heteroaryl having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, where Cy B This includes 0 to 4 -R values. B It is substituted with a base. In some embodiments, Cy B This is a 5-membered heteroaryl having 1-2 heteroatoms independently selected from sulfur and nitrogen, where 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 BIt 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.

[0064] In some embodiments, Cy B teeth, [ka] It is selected from the group consisting of the following.

[0065] In some embodiments, Cy B teeth, [ka] It is selected from the group consisting of the following.

[0066] In some embodiments, Cy B teeth, [ka] It is selected from the group consisting of the following.

[0067] In some embodiments, Cy B and R x These, along with the intervening atoms, form a 6-12 member spirocyclic ring system having 0-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, where Cy B and R x The ring(s) formed by this process contain 0 to 4 -R B It may be substituted with a group. References to the number of atoms in spirocyclic ring systems (e.g., 6- to 12 members) in this specification will be understood to include the cyclopropyl ring shown.

[0068] In some embodiments, Cy B and Rx These, together with the intervening atoms, form a 6-12 member spirocyclic ring system having 0-1 nitrogen heteroatoms, where Cy B and R x The ring(s) formed by this process contain 1 to 3 -R B It may be substituted with the base.

[0069] In some embodiments, Cy B and R x Along with the atoms interposed therein, [ka] It forms a spirocyclic ring system of 6 to 12 members selected from the available options.

[0070] Several embodiments, each R B The group is independently selected from oxo, halogen, -CN, -NO2, -N(R)2, -N(R)C(O)2R, -OR, or C1-6 aliphatic, or any substituted group selected from 5-membered heteroaryls having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur.

[0071] In some embodiments, R is optionally substituted. B Substituents on the group include oxo, halogen, and -(CH2) 0~4 OR° is selected independently, where each R° is independently as defined above and described in the Classes and Subclasses herein.

[0072] 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 chloroform. In some embodiments, R B One example is -CN. In some embodiments, R B One example is -NO2. In some embodiments, R BOne example is -N(R)2. In some embodiments, R B One example is -N(R)C(O)2R. In some embodiments, R B One example of this is -OR.

[0073] In some embodiments, R B One example is the optionally substituted C1-6 aliphatic. In some embodiments, R B One example is C1-6 aliphatic ions substituted with halogens. In some embodiments, R B One example of this is methyl.

[0074] In some embodiments, R B One example is -N(R)C(O)2R, where each R is hydrogen, or -(CH2) 0~4 C arbitrarily substituted with R° 1~6 Selected independently of aliphatic elements, where each R° is independently as defined above and described in the classes and subclasses herein.

[0075] In some embodiments, R B One example is -OR, where each R is hydrogen, or halogen, -(CH2) 0~4 OR°, or (CH2) 0~4 C(O)OR° is arbitrarily substituted. 1~6 Selected independently of aliphatic elements, where each R° is independently as defined above and described in the classes and subclasses herein.

[0076] In some embodiments, R B One 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 of this is tetrazolyl.

[0077] In some embodiments, R x and R x’Each of these is independently selected from hydrogen and halogen. In some embodiments, R x and R x’ Each of them is hydrogen. In some embodiments, R x and R x’ One of them is hydrogen, and the other is a halogen.

[0078] In some embodiments, R Y and R Y’ Each of these is selected independently from hydrogen and halogens.

[0079] In some embodiments, R Y and R Y’ Each of them is hydrogen.

[0080] In some embodiments, R Y is an arbitrarily substituted C 1~6 It is an aliphatic group, R Y’ is hydrogen. In some embodiments, R Y is, -(CH2) 0~4 OR° is substituted, where R° is as defined above and as described in the Classes and Subclasses herein.

[0081] In some embodiments, L is optionally replaced by C. 1~3 It is a hydrocarbon chain, where 1 to 3 methylene units are -O-, -NR z -, -S-, or -SO2- are optionally replaced. In some embodiments, L is optionally replaced with C 1~3 It is a hydrocarbon chain, where one methylene unit is -O-, -NR z It is optionally replaced with -, -S-, or -SO2-.

[0082] In some embodiments, L is an optionally substituted C1 hydrocarbon chain.

[0083] In some embodiments, L is an optionally substituted C1 hydrocarbon chain, where one methylene unit is -(CH2)0~4 It is replaced by a 5-membered saturated or partially unsaturated heterocyclene having one nitrogen heteroatom, which is optionally substituted with OR°, where R° is as defined above and described in the classes and subclasses herein.

[0084] In some embodiments, L is -CH2-. In some embodiments, L is optionally substituted. [ka] And in the formula, * is Cy A Represents the connection point to. In some embodiments, L is optionally substituted [ka] And in the formula, * is Cy A Represents the connection point to. In some embodiments, L is optionally substituted [ka] And in the formula, * is Cy A Represents the connection point to. In some embodiments, L is [ka] And in the formula, * is Cy A Represents the connection point to. In some embodiments, L is [ka] And in the formula, * is Cy A Represents the connection point to. In some embodiments, L is [ka] And in the formula, * is Cy A This represents a connection point to [a specific location].

[0085] In some embodiments, L is an optionally substituted C2 hydrocarbon chain, where one methylene unit is -NR z - or -O- is optionally replaced. In some embodiments, L is an optionally substituted C2 hydrocarbon chain, where Cy A The methylene unit connected to -NR z - or -O- is replaced. In some embodiments, L is an optionally substituted C2 hydrocarbon chain, where Cy A The methylene unit connected to -NR z - is replaced by. In some embodiments, L is an optionally substituted C2 hydrocarbon chain, where Cy A The methylene unit connected to -NR z It is replaced with -, R z is hydrogen, -(CH2) 0~3 C(O)OR, or any substituted C 1~6 Selected from aliphatic groups.

[0086] In some embodiments, L is an optionally substituted C2 hydrocarbon chain, where Cy A The methylene unit connected to it is replaced with -O-.

[0087] In some embodiments, L is *-NHCH(Me)-, where * is Cy A Represents the connection point to. In some embodiments, L is [ka] And in the formula, * is Cy A Represents the connection point to. In some embodiments, L is [ka] And in the formula, * is Cy A Represents the junction point to . In some embodiments, L is *-NHCH2-, where * is Cy AThis represents the bonding point to . In some embodiments, L is *-N(CH3)CH2-, where * is Cy A Represents the connection point to. In some embodiments, L is [ka] And in the formula, * is Cy A Represents the connection point to. In some embodiments, L is [ka] And in the formula, * is Cy A Represents the junction point to . In some embodiments, L is *-OCH(Me)-, where * is Cy A Represents the connection point to . In some embodiments, L is *-OCH2-, where * is Cy A This represents a connection point to [a specific location].

[0088] In some embodiments, L is Cy A and Cy C Includes a two-atom spacer between them.

[0089] 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. In some embodiments, L is optionally substituted [ka] And in the formula, * is Cy A This represents a connection point to [a specific location].

[0090] In some embodiments, any substituent on L is -(CH2) 0~4 R°, -(CH2) 0~4 OR°, -(CH2)0~4 OC(O)R°, and -(CH2) 0~4 N(R°) is independently selected from 2, where each R° is independently as defined above and as described in the classes and subclasses herein.

[0091] In some embodiments, Cy C This is a biring aryl with 8-10 members, where Cy C This includes 0 to 6 -L C -R C It is substituted with a base. In some embodiments, Cy C This includes 0 to 6 -L C -R C It is a quinolinyl molecule substituted with a specific group.

[0092] In some embodiments, Cy C This is an 8-10 membered heteroaryl having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, where Cy C This includes 0 to 6 -L C -R C It is substituted with a base. In some embodiments, Cy C This is a 9-10 membered heteroaryl having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, where Cy C This includes 0 to 6 -L C -R C It is substituted with a base. In some embodiments, Cy C This is a 9-membered heteroaryl having 1 to 4 nitrogen heteroatoms, where Cy C This includes 0 to 6 -L C -R C It is substituted with a base. In some embodiments, Cy C This is a 9-membered heteroaryl having one nitrogen heteroatom and one sulfur heteroatom, where Cy C This includes 0 to 6 -L C -R C It is substituted with a base. In some embodiments, Cy CThis is a 10-membered heteroaryl having 1 to 4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, where Cy C This includes 0 to 6 -L C -R C It is substituted with a base. In some embodiments, Cy C This is a 10-membered heteroaryl having one nitrogen heteroatom, where Cy C This includes 0 to 6 -L C -R C It is substituted with a base. In some embodiments, Cy C This is a 9-membered heteroaryl having two nitrogen heteroatoms, where Cy C This includes 0 to 6 -L C -R C It is substituted with the base.

[0093] In some embodiments, Cy C This is triazolopyridinyl, and here, Cy C This includes 0 to 4 -L C -R C It is substituted with a base. In some embodiments, Cy C This is pyrazolopyridinyl, and here, Cy C This includes 0 to 5 -L C -R C It is substituted with a base. In some embodiments, Cy C This is pyrazolopyrimidinyl, and here, Cy C This includes 0 to 4 -L C -R C It is substituted with a base. In some embodiments, Cy C This is triazolopyridazinyl, and here, Cy C This includes 0 to 3 -L C -R C It is substituted with a base. In some embodiments, Cy C This is imidazopyridazinyl, and here, Cy C This includes 0 to 4 -L C -R C It is substituted with a base. In some embodiments, Cy C This is imidazopyrimidinyl, and here, CyC This includes 0 to 4 -L C -R C It is substituted with a base. In some embodiments, Cy C This is imidazopyrimidinone, and here, Cy C This includes 0 to 4 -L C -R C It is substituted with a base. In some embodiments, Cy C This is imidazopyrazinyl, and here, Cy C This includes 0 to 4 -L C -R C It is substituted with a base. In some embodiments, Cy C This is benzimidazolyl, and here, Cy C This includes 0 to 4 -L C -R C It is substituted with a base. In some embodiments, Cy C This is triazolopyrimidinyl, and here, Cy C This includes 0 to 3 -L C -R C It is substituted with a base. In some embodiments, Cy C This is thienopyridinyl, and here, Cy C This includes 0 to 6 -L C -R C It is substituted with a base. In some embodiments, Cy C This is quinolinyl, and here, Cy C This includes 0 to 6 -L C -R C It is substituted with the base.

[0094] In some embodiments, Cy C teeth, [ka] It is selected from the group consisting of the following.

[0095] In some embodiments, Cy C teeth, [ka] It is selected from the group consisting of the following.

[0096] In some embodiments, Cy C teeth, [ka] It is selected from the group consisting of the following.

[0097] In some embodiments, the provided compound is of formula II: [ka] A compound of or a pharmaceutically acceptable salt thereof, where Cy A Cy B L, X, R x , R x’ , R Y , and R Y’ Each of these, both individually and in combination, is defined and described in the Classes and Subclasses herein, and each R 3 , R 4 , R 5 , R 6 , and R 7 is hydrogen or -L C -R C It is selected independently of others.

[0098] Unless otherwise specified or prohibited by the definition of Formula II above, the variable part Cy defined above and described in the Classes and subclasses herein A Cy B L, X, R x , R x’ , R Y , R Y’ , R 3 , R 4 , R 5 , R 6 , and R 7 It will also be understood that the embodiments are applicable to the compounds of formula II, both individually and in combination.

[0099] 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, where each L C C is covalently bonded or optionally substituted. 1~6 A hydrocarbon chain (in which 1 to 3 methylene units are arbitrarily and independently replaced with -O- or -NR-) is independently selected; 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 D Independently selected from, or any substituted group selected from C1-6 aliphatic groups.

[0100] In some embodiments, R 3 is hydrogen or L C -R C Selected from, here, L C It is a covalent bond, R C is a halogen. In some embodiments, R 3 It is hydrogen.

[0101] In some embodiments, R 4 is hydrogen or -L C -R C Selected from, here, L C C is covalently bonded or optionally substituted. 1~6 Selected from hydrocarbon chains (where 1 to 3 methylene units are arbitrarily and independently replaced 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 D , or any substituted group selected from C1-6 aliphatic groups.

[0102] In some embodiments, R 4 is hydrogen or -L C -R C Selected from, here, L C It is a covalent bond, 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 D , or any substituted group selected from C1-6 aliphatic groups.

[0103] In some embodiments, R 4 teeth, [ka] It is selected from the group consisting of the following.

[0104] R 4 In some embodiments, C 1~6 Any substituent on the aliphatic group is -(CH2) 0~4 R°, -(CH2) 0~4 OR°, -CN, -(CH2) 0~4 N(R°)2 and -(CH2) 0~4 Selected from C(O)OR°, where each R° is independently defined as described above and in the classes and subclasses herein.

[0105] R 4 In some embodiments, Cy DThis is 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 bisculus; or a 6-12 member saturated or partially unsaturated bicyclic spiroheterocycline having 1-3 heteroatoms independently selected from oxygen, nitrogen, or sulfur, where Cy D There are 0 to 4 L D -R D It is substituted with R. 4 In some embodiments, Cy D It is a five-membered saturated or partially unsaturated monocyclic heterocycline having one or two heteroatoms selected from oxygen, nitrogen, or sulfur.

[0106] R 4 In some embodiments, Cy D teeth, [ka] It is selected from the group consisting of the following.

[0107] R 4 In some embodiments, R D The group is selected from oxo, halogen, -C(O)2R, -N(R)2, -OR, or C1-6 aliphatic, phenyl, 3-7 member saturated or partially unsaturated monocyclic carbocyryl, or optionally substituted groups selected from 3-7 member saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur.

[0108] R 4 R D In some embodiments of the base, R D Any substituent above is a halogen, -(CH2)0~4 R°, -(CH2) 0~4 OR°, -(CH2) 0~4 N(R°)2, -(CH2) 0~4 Selected from C(O)OR° and -OP(O)(OR°)2, where each R° is independently defined as described above and in the classes and subclasses herein.

[0109] R 4 In some embodiments, L D This is a covalent bond.

[0110] In some embodiments, R 5 It is hydrogen.

[0111] In some embodiments, R 5 L C -R C And here, L C It is a covalent bond, R C is Cy D In some embodiments, Cy D This is a cyclopropyl group.

[0112] In some embodiments, R 6 is hydrogen or L C -R C Selected from, here, L C It is a covalent bond, R C Halogen, -N(R)2, -OR, Cy D , or optionally replaced C 1~6 Selected from aliphatic groups.

[0113] R 6 In some embodiments, Cy D This is 0 to 4 L D -R D It is a cyclopropyl group substituted with a group. In some embodiments, L D It is a covalent bond, R D This includes halogens and optionally substituted C 1~6 Selected from aliphatic species.

[0114] In some embodiments, R 7 is hydrogen or L C -R C Selected from, here, L C It is a covalent bond, R C is Cy D That is the case.

[0115] In some embodiments, R 7 It is hydrogen.

[0116] R 7 In some embodiments, Cy D teeth, [ka] That is the case.

[0117] In some embodiments, the provided compound is of formula III: [ka] A compound of or a pharmaceutically acceptable salt thereof, In the formula, Cy A Cy B L, X, R x , R x’ , R Y , and R Y’ Each of these, both individually and in combination, is defined and described in the Classes and Subclasses herein, and in formulas, X 1 is N, CH, or CL C -R C and; each X 2 is N, CH, or CL C -R C Selected independently of; X 3 and X 4 is independently N or C, where X 3 or X 4 At least one of them is C; X 5 , X6 , X 7 , and X 8 Each of these is N, CH, or CL. C -R C Selected independently of; n is either 1 or 2.

[0118] In some embodiments, X 1 In some embodiments, X 1 is CH. In some embodiments, X 1 CL C -R C And here, L C and R C This is defined both individually and in combination as defined above and described in the Classes and Subclasses herein.

[0119] In some embodiments, X 3 is N or C, and X 4 In some embodiments, X 3 C is X 4 is N or C. In some embodiments, X 3 is N, and X 4 In some embodiments, X 3 C is X 4 In some embodiments, X 3 C is X 4 It is N.

[0120] In some embodiments, X 5 In some embodiments, X 5 is CH. In some embodiments, X 5 CL C -R C And here, L C and R C X is defined above and described herein in terms of classes and subclasses, both individually and in combination. In some embodiments, X 6 In some embodiments, X6 is CH. In some embodiments, X 6 CL C -R C And here, L C and R C X is defined above and described herein in terms of classes and subclasses, both individually and in combination. In some embodiments, X 7 In some embodiments, X 7 is CH. In some embodiments, X 7 CL C -R C And here, L C and R C X is defined above and described herein in terms of classes and subclasses, both individually and in combination. In some embodiments, X 8 In some embodiments, X 8 is CH. In some embodiments, X 8 CL C -R C And here, L C and R C This is defined both individually and in combination as defined above and described in the Classes and Subclasses herein.

[0121] In some embodiments, n is 1. In some embodiments, n is 2.

[0122] In some embodiments, n is 1, and X 8 is N. In some embodiments, n is 1 and X 8 is CH. In some embodiments, n is 1 and X 8 CL C -R C And here, L C and R C This is defined both individually and in combination as defined above and described in the Classes and Subclasses herein.

[0123] In some embodiments, n is 2, and each X 2 is N, CH, or CL C -R C Selected independently from, where L C and R C These are, both individually and in combination, as defined above and described in the classes and subclasses herein. In some embodiments, n is 2, and one X 2 One is N, and the other is CH. In some embodiments, n is 2 and X 2 Both occurrences are CH.

[0124] In some embodiments, the provided compound is of formula IV-a, IV-b, or IV-c: [ka] A compound of or a pharmaceutically acceptable salt thereof, where Cy A , R B L, X, R x , R x’ , R Y , R Y’ , 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.

[0125] Unless otherwise specified or prohibited by the aforementioned definitions of formulas IV-a, IV-b, or IV-c, the variable part Cy defined above and described in the classes and subclasses herein refers to the variable part Cy A , R B L, X, R x , R x’ , R Y , R Y’ , R 3 , R 4 , R 5 , R 6 , and R 7It will also be understood that the embodiments are applicable, both individually and in combination, to compounds of formula IV-a, IV-b, or IV-c.

[0126] In some embodiments, the provided compounds are of the formula Va, Vb, or Vc: [ka] A compound of or a pharmaceutically acceptable salt thereof, where Cy A Cy B X, R°, R x , R x’ , R Y , R Y’ , 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. In some embodiments of formulas Va and Vb, R° is hydrogen or methyl. In some embodiments of formula Vc, R° is hydrogen or -OH.

[0127] Unless otherwise specified or prohibited by the above definitions of formulas Va, Vb, or Vc, the variable part Cy defined above and described in the classes and subclasses herein refers to the variable part Cy A Cy B X, R°, R x , R x’ , R Y , R Y’ , R 3 , R 4 , R 5 , R 6 , and R 7 It will also be understood that the embodiments can be applied, both individually and in combination, to compounds of formulas Va, Vb, or Vc.

[0128] In some embodiments, the provided compound is of formula VI-a, VI-b, or VI-c: [ka] A compound of or a pharmaceutically acceptable salt thereof, where Cy A , R B Each of L and X, both individually and in combination, is defined and described in the Classes and Subclasses herein; R 4 is hydrogen or L C -R C And here, L C It is a covalent bond, R C is halogen or Cy D And Cy D Cy is a 5-membered saturated or partially unsaturated monocyclic heterocycline having 1-2 heteroatoms selected from nitrogen. D This includes 0 to 4 -L D -R D It is substituted with the base.

[0129] Unless otherwise specified or prohibited by the above definitions of formulas VI-a, VI-b, or VI-c, the variable part Cy defined above and described herein in the classes and subclasses refers to the variable part Cy A , R B , L, R 4 It will be understood that the embodiments of X, as well as those of formula VI-a, VI-b, or VI-c, are applicable both individually and in combination.

[0130] In some embodiments of formulas VI-a, VI-b, or VI-c, Cy D teeth, [ka] It is a ring selected from.

[0131] In certain embodiments of the provided compounds (i.e., any compound of any kind not otherwise defined, and any compound of formulas (I) to (VI-c)), part: [ka] (R x , R x’ , R Y , or R Y’ (Including cases where one or more of them are hydrogen) Cy bonded to the two stereocenters marked with * B and Cy A It is in a transformer configuration relative to the base. In other words, part: [ka] In this context, "trans" means [ka] It will be understood that this refers to a compound containing a mixture of these elements. In some embodiments, such a mixture is a racemic mixture.

[0132] In certain embodiments of the provided compounds (i.e., any compound of any kind not otherwise defined, and any compound of formulas (I) to (VI-c)), part: [ka] The absolute stereochemistry of is as follows: [ka] That is correct.

[0133] In certain embodiments of the provided compounds (i.e., any compound of any kind not otherwise defined, and any compound of formulas (I) to (VI-c)), part: [ka] The absolute stereochemistry of is as follows: [ka] That is correct.

[0134] In some embodiments, the provided compounds are selected from Table A. Table A. rac-N 7 -((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)-N 4 ,N 4 -Dimethyl-2-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline-4,7-diamine(I-1); 2-((1S,2S)-2-(3-chlorophenyl)cyclopropyl)-7-(((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)amino)pyrido[4,3-d]pyrimidine-4(3H)-one(I-2); rac-2-((1S*,2S*)-2-(3-chlorophenyl)cyclopropyl)-7-(((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)amino)pyrido[4,3-d]pyrimidine-4(3H)-one(I-3); rac-1-(2-(((2-((1S*,2S*)-2-(3-chlorophenyl)cyclopropyl)-4-methoxyquinoline-7-yl)amino)methyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-yl)pyrrolidine-2-one(I-4); rac-1-(2-(((2-((1S*,2S*)-2-(3-chlorophenyl)cyclopropyl)-4-oxo-1,4-dihydroquinoline-7-yl)amino)methyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-yl)-3-methylimidazolidin-2,4-dione(I-5); 1-(2-(((2-((1S,2S)-2-(3-chlorophenyl)cyclopropyl)-4-oxo-3,4-dihydroquinazoline-7-yl)amino)methyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-yl)-3-methylimidazolidin-2,4-dione(I-6); rac-1-(6-cyclopropyl-2-(((2-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)-4-oxo-3,4-dihydropyrido[4,3-d]pyrimidine-7-yl)amino)methyl)imidazo[1,2-a]pyridin-8-yl)-3-methylimidazolidin-2,4-dione(I-7); rac-1-(6-cyclopropyl-2-(((2-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)-4-oxo-1,4-dihydroquinazoline-7-yl)amino)methyl)imidazo[1,2-a]pyridine-8-yl)-3-methylimidazolidin-2,4-dione(I-8); rac-1-(6-cyclopropyl-2-(((2-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)-4-oxo-3,4-dihydropyrido[3,2-d]pyrimidine-7-yl)amino)methyl)imidazo[1,2-a]pyridine-8-yl)-3-methylimidazolidined-2,4-dione(I-9); rac-1-(6-cyclopropyl-2-(((2-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)-4-oxo-1,4-dihydro-1,6-naphthyridine-7-yl)amino)methyl)imidazo[1,2-a]pyridine-8-yl)-3-methylimidazolidined-2,4-dione(I-10); rac-1-(6-cyclopropyl-2-(((2-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)-4-oxo-1,4-dihydroquinoline-7-yl)amino)methyl)imidazo[1,2-a]pyridine-8-yl)-3-methylimidazolidin-2,4-dione(I-11); 1-(6-cyclopropyl-2-(((2-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)-4-oxo-1,4-dihydroquinoline-7-yl)amino)methyl)imidazo[1,2-a]pyridine-8-yl)-3-methylimidazolidined-2,4-dione, the first isomer to elute (I-12); 1-(6-cyclopropyl-2-(((2-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)-4-oxo-1,4-dihydroquinoline-7-yl)amino)methyl)imidazo[1,2-a]pyridine-8-yl)-3-methylimidazolidined-2,4-dione, second isomer to elute (I-13); 1-(6-cyclopropyl-2-(((2-((1S,2S)-2-(4-methylpyrimidine-2-yl)cyclopropyl)-4-oxo-1,4-dihydroquinoline-7-yl)amino)methyl)imidazo[1,2-a]pyridine-8-yl)-3-methylimidazolidin-2,4-dione; 1-(6-cyclopropyl-2-(((2-((1R,2R)-2-(4-methylpyrimidine-2-yl)cyclopropyl)-4-oxo-1,4-dihydroquinoline-7-yl)amino)methyl)imidazo[1,2-a]pyridine-8-yl)-3-methylimidazolidin-2,4-dione; 1-(6-cyclopropyl-2-(((2-((1S,2S)-2-(4-methylpyrimidine-2-yl)cyclopropyl)-4-oxo-1,4-dihydroquinoline-7-yl)amino)methyl)imidazo[1,2-a]pyridine-8-yl)-3-methylimidazolidin-2,4-dione; 1-(6-cyclopropyl-2-(((2-((1R,2R)-2-(4-methylpyrimidine-2-yl)cyclopropyl)-4-oxo-1,4-dihydroquinoline-7-yl)amino)methyl)imidazo[1,2-a]pyridine-8-yl)-3-methylimidazolidin-2,4-dione; rac-1-(6-cyclopropyl-2-(((6-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)-1,5-naphthyridine-3-yl)amino)methyl)imidazo[1,2-a]pyridine-8-yl)-3-methylimidazolidin-2,4-dione(I-14); rac-1-(6-cyclopropyl-2-(((2-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)-1,6-naphthyridine-7-yl)amino)methyl)imidazo[1,2-a]pyridine-8-yl)-3-methylimidazolidinedion-2,4-diongate (I-15); rac-1-(6-cyclopropyl-2-(((6-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline-3-yl)amino)methyl)imidazo[1,2-a]pyridine-8-yl)-3-methylimidazolidin-2,4-dione(I-16); rac-1-(6-cyclopropyl-2-((methyl(6-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline-3-yl)amino)methyl)imidazo[1,2-a]pyridine-8-yl)-3-methylimidazolidin-2,4-dione(I-17); 1-(2-(((2-((1S,2S)-2-(3-chlorophenyl)cyclopropyl)-4-methoxy-1,6-naphthyridine-7-yl)amino)methyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-yl)-3-methylimidazolidin-2,4-dione(I-18); rac-N-((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)-2-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline-7-amine(I-19); rac-N-((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)-4-methoxy-2-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline-7-amineformate(I-20); rac-1-(6-cyclopropyl-2-(((4-methoxy-2-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline-7-yl)amino)methyl)imidazo[1,2-a]pyridine-8-yl)-3-methylimidazolidin-2,4-dione(I-21); rac-1-(6-cyclopropyl-2-(((4-methoxy-2-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline-7-yl)amino)methyl)imidazo[1,2-a]pyridine-8-yl)-3-methylimidazolidin-2,4-dione (I-22), the first isomer to elute; rac-1-(6-cyclopropyl-2-(((4-methoxy-2-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline-7-yl)amino)methyl)imidazo[1,2-a]pyridine-8-yl)-3-methylimidazolidin-2,4-dione (I-23), the second isomer to elute; 1-(6-cyclopropyl-2-(((4-methoxy-2-((1S,2S)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline-7-yl)amino)methyl)imidazo[1,2-a]pyridine-8-yl)-3-methylimidazolidin-2,4-dione; 1-(6-cyclopropyl-2-(((4-methoxy-2-((1R,2R)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline-7-yl)amino)methyl)imidazo[1,2-a]pyridine-8-yl)-3-methylimidazolidin-2,4-dione; rac-1-(6-cyclopropyl-2-(((3-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline-6-yl)amino)methyl)imidazo[1,2-a]pyridine-8-yl)-3-methylimidazolidin-2,4-dione(I-24); rac-1-(2-(((4-(1H-imidazole-1-yl)-2-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline-7-yl)amino)methyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-yl)-3-methylimidazolidin-2,4-dione(I-25); rac-1-(6-cyclopropyl-2-(((2-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)-4-(1H-1,2,4-triazole-1-yl)quinoline-7-yl)amino)methyl)imidazo[1,2-a]pyridine-8-yl)-3-methylimidazolidin-2,4-dione(I-26); 1-(6-cyclopropyl-2-(((4-(1-methyl-1H-pyrazole-4-yl)-2-((1S,2S)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline-7-yl)amino)methyl)imidazo[1,2-a]pyridine-8-yl)-3-methylimidazolidin-2,4-dione(I-27); 1-(6-cyclopropyl-2-(((5-methoxy-2-((1S,2S)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline-7-yl)amino)methyl)imidazo[1,2-a]pyridine-8-yl)-3-methylimidazolidin-2,4-dione(I-28); rac-1-(6-cyclopropyl-2-(((4-(dimethylamino)-2-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline-7-yl)amino)methyl)imidazo[1,2-a]pyridine-8-yl)-3-methylimidazolidin-2,4-dione(I-29); 1-(2-(((4-(azetidine-1-yl)-2-((1S,2S)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline-7-yl)amino)methyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-yl)-3-methylimidazolidinedion-2,4-dione, formate (I-30); 1-(2-(((4-(azetidine-1-yl)-2-((1S,2S)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline-7-yl)amino)methyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-yl)-3-methylimidazolidin-2,4-dione; 1-(6-cyclopropyl-2-(((4-(3-hydroxyazetidine-1-yl)-2-((1S,2S)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline-7-yl)amino)methyl)imidazo[1,2-a]pyridine-8-yl)-3-methylimidazolidin-2,4-dione(I-31); rac-1-(6-cyclopropyl-2-(((4-(methylamino)-2-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline-7-yl)amino)methyl)imidazo[1,2-a]pyridine-8-yl)-3-methylimidazolidinedion-2,4-dione, formate (I-32); rac-1-(6-cyclopropyl-2-(((2-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)-4-(oxetane-3-yloxy)quinoline-7-yl)amino)methyl)imidazo[1,2-a]pyridine-8-yl)-3-methylimidazolidin-2,4-dione(I-33); rac-N-(7-(((6-cyclopropyl-8-(3-methyl-2,4-dioxoimidazolidine-1-yl)imidazo[1,2-a]pyridine-2-yl)methyl)amino)-2-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline-4-yl)-N-methylmethanesulfonamide, formate (I-34); rac-N-(7-(((6-cyclopropyl-8-(3-methyl-2,4-dioxoimidazolidine-1-yl)imidazo[1,2-a]pyridine-2-yl)methyl)amino)-2-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline-4-yl)-N-methylmethanesulfonamide; rac-1-(6-cyclopropyl-2-(((4-((1-methylpiperidine-4-yl)oxy)-2-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline-7-yl)amino)methyl)imidazo[1,2-a]pyridine-8-yl)-3-methylimidazolidin-2,4-dione(I-35); 1-(6-cyclopropyl-2-(((2-((1S,2S)-2-(4-methylpyrimidine-2-yl)cyclopropyl)-4-(2-oxa-6-azaspiro[3,3]heptan-6-yl)quinoline-7-yl)amino)methyl)imidazo[1,2-a]pyridine-8-yl)-3-methylimidazolidinedion-2,4-dione, formate (I-36); 1-(6-cyclopropyl-2-(((2-((1S,2S)-2-(4-methylpyrimidine-2-yl)cyclopropyl)-4-(2-oxa-6-azaspiro[3,3]heptan-6-yl)quinoline-7-yl)amino)methyl)imidazo[1,2-a]pyridin-8-yl)-3-methylimidazolidin-2,4-dione; 1-(6-cyclopropyl-2-(((4-(1,1-dioxidethiomorpholino)-2-((1S,2S)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline-7-yl)amino)methyl)imidazo[1,2-a]pyridine-8-yl)-3-methylimidazolidinedion-2,4-dione, formate (I-37); 1-(6-cyclopropyl-2-(((4-(1,1-dioxidethiomorpholino)-2-((1S,2S)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline-7-yl)amino)methyl)imidazo[1,2-a]pyridine-8-yl)-3-methylimidazolidin-2,4-dione; 1-(6-cyclopropyl-2-(((4-((2-hydroxy-2-methylpropyl)amino)-2-((1S,2S)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline-7-yl)amino)methyl)imidazo[1,2-a]pyridine-8-yl)-3-methylimidazolidin-2,4-dione(I-38); 1-(6-cyclopropyl-2-(((4-(4-methylpiperazine-1-yl)-2-((1S,2S)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline-7-yl)amino)methyl)imidazo[1,2-a]pyridine-8-yl)-3-methylimidazolidinedion-2,4-dione, formate (I-39); 1-(6-cyclopropyl-2-(((4-(4-methylpiperazine-1-yl)-2-((1S,2S)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline-7-yl)amino)methyl)imidazo[1,2-a]pyridine-8-yl)-3-methylimidazolidin-2,4-dione; rac-1-(6-cyclopropyl-2-(((2-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)-4-morpholinoquinoline-7-yl)amino)methyl)imidazo[1,2-a]pyridine-8-yl)-3-methylimidazolidin-2,4-dione(I-40); rac-1-(6-cyclopropyl-2-(((2-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)-4-morpholinoquinoline-7-yl)amino)methyl)imidazo[1,2-a]pyridine-8-yl)-3-methylimidazolidined-2,4-dione, the first isomer to elute (I-41); rac-1-(6-cyclopropyl-2-(((2-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)-4-morpholinoquinoline-7-yl)amino)methyl)imidazo[1,2-a]pyridine-8-yl)-3-methylimidazolidin-2,4-dione (I-42), second eluting isomer (I-42); 1-(6-cyclopropyl-2-(((2-((1S,2S)-2-(4-methylpyrimidine-2-yl)cyclopropyl)-4-morpholinoquinoline-7-yl)amino)methyl)imidazo[1,2-a]pyridine-8-yl)-3-methylimidazolidin-2,4-dione; 1-(6-cyclopropyl-2-(((2-((1R,2R)-2-(4-methylpyrimidine-2-yl)cyclopropyl)-4-morpholinoquinoline-7-yl)amino)methyl)imidazo[1,2-a]pyridine-8-yl)-3-methylimidazolidin-2,4-dione; 1-[6-cyclopropyl-2-[[2-[(1S,2S)-2-(4-methylpyrimidine-2-yl)cyclopropyl]-4-(2-oxa-6-azaspiro[3,3]heptan-6-yl)-7-quinolyl]oxymethyl]imidazo[1,2-a]pyridine-8-yl]-3-methylimidazolidin-2,4-dione(I-43); 8-((1S,2S)-2-(3-chlorophenyl)cyclopropyl)-7-((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)-7H-purine(I-44); 2-((1S,2S)-2-(3-chlorophenyl)cyclopropyl)-N-((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)-1H-benzo[d]imidazole-6-amine(I-45); 2-((1S,2S)-2-(3-chlorophenyl)cyclopropyl)-N-((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)-1H-benzo[d]imidazole-7-amine(I-46); rac-tert-butyl(2-((1S*,2S*)-2-(3-chlorophenyl)cyclopropyl)-4-methoxyquinoline-7-yl)((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)carbamate(I-47); rac-2-((1S*,2S*)-2-(3-chlorophenyl)cyclopropyl)-N-((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)-4-methoxyquinoline-7-amine(I-48); rac-2-((1S*,2S*)-2-(3-chlorophenyl)cyclopropyl)-7-(((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)amino)quinoline-4(1H)-one(I-49); 2-((1S,2S)-2-(3-chlorophenyl)cyclopropyl)-7-(((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)amino)quinazoline-4(1H)-one(I-50); 2-((1S,2S)-2-(3-chlorophenyl)cyclopropyl)-7-(((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)amino)quinoline-4-ol(I-51); 7-((2R,4S)-4-((tert-butyldimethylsilyl)oxy)-2-(6-cyclopropylimidazo[1,2-a]pyridine-2-yl)pyrrolidine-1-yl)-4-methoxy-2-((1RS,2RS)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline(I-52); (3S,5R)-5-(6-cyclopropylimidazo[1,2-a]pyridine-2-yl)-1-(4-methoxy-2-(rac(1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline-7-yl)pyrrolidine-3-ol(I-53); rac-7-((2R,4S)-2-(6-cyclopropylimidazo[1,2-a]pyridine-2-yl)-4-hydroxypyrrolidine-1-yl)-2-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline-4-ol(I-54); rac-6-(((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)amino)-3-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)-4H-benzo[b][1,4]thiazine 1,1-dioxide(I-55); rac-(3S,5R)-1-(2-((1S*,2S*)-2-(3-chlorophenyl)cyclopropyl)-3-fluoro-1H-pyrrolo[3,2-c]pyridine-6-yl)-5-(6-cyclopropylimidazo[1,2-a]pyridine-2-yl)pyrrolidine-3-ol(I-56); rac-1-(6-cyclopropyl-2-(((2-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline-7-yl)amino)methyl)imidazo[1,2-a]pyridine-8-yl)-3-methylimidazolidin-2,4-dione(I-57); 1-(6-cyclopropyl-2-(((2-((1R,2R)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline-7-yl)amino)methyl)imidazo[1,2-a]pyridine-8-yl)-3-methylimidazolidined-2,4-dione, the first isomer to elute (I-58); 1-(6-cyclopropyl-2-(((2-((1S,2S)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline-7-yl)amino)methyl)imidazo[1,2-a]pyridine-8-yl)-3-methylimidazolidin-2,4-dione, second isomer to elute (I-59); rac-1-(6-cyclopropyl-2-(((2-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinazoline-7-yl)amino)methyl)imidazo[1,2-a]pyridine-8-yl)-3-methylimidazolidin-2,4-dione(I-60); rac-1-(6-cyclopropyl-2-(((3-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)-1,1-dioxide-4H-benzo[b][1,4]thiadin-6-yl)amino)methyl)imidazo[1,2-a]pyridine-8-yl)-3-methylimidazolidined-2,4-dione(I-61); rac-1-(6-cyclopropyl-2-(((3-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoxaline-6-yl)amino)methyl)imidazo[1,2-a]pyridine-8-yl)-3-methylimidazolidin-2,4-dione(I-62); rac-1-(6-cyclopropyl-2-(((2-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)pyrido[4,3-d]pyrimidine-7-yl)amino)methyl)imidazo[1,2-a]pyridine-8-yl)-3-methylimidazolidin-2,4-dione(I-63); rac-6-(((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)amino)-3-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide(I-64); rac-6-(((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)amino)-3-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide, the first isomer to elute (I-65); rac-6-(((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)amino)-3-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide, second eluting isomer (I-66); 6-(((6-Cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)amino)-3-((1S,2S)-2-(4-methylpyrimidine-2-yl)cyclopropyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 6-(((6-Cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)amino)-3-((1R,2R)-2-(4-methylpyrimidine-2-yl)cyclopropyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; rac-1-(6-cyclopropyl-2-((2R,4S)-4-hydroxy-1-(4-methoxy-2-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline-7-yl)pyrrolidine-2-yl)imidazo[1,2-a]pyridine-8-yl)-3-methylimidazolidin-2,4-dione(I-67); rac-1-(6-cyclopropyl-2-((2R,4S)-4-hydroxy-1-(2-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline-7-yl)pyrrolidine-2-yl)imidazo[1,2-a]pyridine-8-yl)-3-methylimidazolidin-2,4-dione(I-68); rac-1-(6-cyclopropyl-2-(((4-(2-hydroxyethoxy)-2-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline-7-yl)amino)methyl)imidazo[1,2-a]pyridine-8-yl)-3-methylimidazolidin-2,4-dione(I-69); rac-1-(6-cyclopropyl-2-(((2-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline-8-yl)amino)methyl)imidazo[1,2-a]pyridine-8-yl)-3-methylimidazolidin-2,4-dione(I-70); rac-1-(6-cyclopropyl-2-((5-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)-3H-imidazo[4,5-b]pyridine-3-yl)methyl)imidazo[1,2-a]pyridine-8-yl)-3-methylimidazolidined-2,4-dione(I-71); rac-1-(6-cyclopropyl-2-((5-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)-1H-imidazo[4,5-b]pyridine-1-yl)methyl)imidazo[1,2-a]pyridine-8-yl)-3-methylimidazolidined-2,4-dione(I-72); 1-(6-cyclopropyl-2-((5-((1S,2S)-2-(4-methylpyrimidine-2-yl)cyclopropyl)-1H-imidazo[4,5-b]pyridine-1-yl)methyl)imidazo[1,2-a]pyridine-8-yl)-3-methylimidazolidined-2,4-dione; 1-(6-cyclopropyl-2-((5-((1R,2R)-2-(4-methylpyrimidine-2-yl)cyclopropyl)-1H-imidazo[4,5-b]pyridine-1-yl)methyl)imidazo[1,2-a]pyridine-8-yl)-3-methylimidazolidined-2,4-dione; rac-7-(((6-cyclopropyl-8-(3-methyl-2,4-dioxoimidazolidine-1-yl)imidazo[1,2-a]pyridine-2-yl)methyl)amino)-2-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline-4-carbonitrile(I-73); rac-N-((6-cyclopropyl-8-(4-ethylpiperazine-1-yl)imidazo[1,2-a]pyridine-2-yl)methyl)-2-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline-7-amine(I-74); rac-1-(6-cyclopropyl-2-(((5-(methoxymethyl)-2-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline-7-yl)amino)methyl)imidazo[1,2-a]pyridine-8-yl)-3-methylimidazolidin-2,4-dione(I-75); rac-1-(6-cyclopropyl-2-(((4-(methoxymethyl)-2-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline-7-yl)amino)methyl)imidazo[1,2-a]pyridine-8-yl)-3-methylimidazolidin-2,4-dione(I-76); rac-1-(6-cyclopropyl-2-(((4-(hydroxymethyl)-2-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline-7-yl)amino)methyl)imidazo[1,2-a]pyridine-8-yl)-3-methylimidazolidin-2,4-dione(I-77); rac-1-(6-cyclopropyl-2-(((2-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline-7-yl)amino)methyl)imidazo[1,2-a]pyridine-8-yl)-3-(oxetane-3-yl)imidazolidin-2,4-dione(I-78); rac-1-(6-cyclopropyl-2-(((2-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)-4,4-dioxide-1H-pyrido[3,4-b][1,4]thiadin-7-yl)amino)methyl)imidazo[1,2-a]pyridine-8-yl)-3-methylimidazolidined-2,4-dione(I-79); rac-6-(((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)(methyl)amino)-3-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide(I-80); rac-1-(6-cyclopropyl-2-(((2-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline-7-yl)amino)methyl)imidazo[1,2-a]pyridine-8-yl)imidazolidin-2,4-dione(I-81); rac-7-(((6-cyclopropyl-8-(3-methyl-2,4-dioxoimidazolidine-1-yl)imidazo[1,2-a]pyridine-2-yl)methyl)amino)-2-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline-5-carbonitrile(I-82); rac-4-chloro-2-((1S*,2S*)-2-(7-(((6-cyclopropyl-8-(3-methyl-2,4-dioxoimidazolidine-1-yl)imidazo[1,2-a]pyridine-2-yl)methyl)amino)quinoline-2-yl)cyclopropyl)benzonitrile(I-83); rac-1-(6-cyclopropyl-2-(((6-methoxy-2-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline-7-yl)amino)methyl)imidazo[1,2-a]pyridine-8-yl)-3-methylimidazolidin-2,4-dione(I-84); rac-2-(7-(((6-cyclopropyl-8-(3-methyl-2,4-dioxoimidazolidine-1-yl)imidazo[1,2-a]pyridine-2-yl)methyl)amino)-2-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline-4-yl)acetonitrile(I-85); rac-1-(6-cyclopropyl-2-(((5-hydroxy-7-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)pyrido[2,3-d]pyrimidine-2-yl)amino)methyl)imidazo[1,2-a]pyridin-8-yl)-3-methylimidazolidin-2,4-dione(I-86); 6-((1-(6-cyclopropylimidazo[1,2-a]pyridine-2-yl)ethyl)amino)-3-((1S,2S)-2-(4-methylpyrimidine-2-yl)cyclopropyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide(I-87); rac-1-(6-cyclopropyl-2-(((5-(dimethylamino)-2-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline-7-yl)amino)methyl)imidazo[1,2-a]pyridine-8-yl)-3-methylimidazolidin-2,4-dione(I-88); rac-7-chloro-6-(((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)amino)-3-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide(I-89); rac-1-(6-cyclopropyl-2-(((2-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline-7-yl)amino)methyl)imidazo[1,2-a]pyridine-8-yl)-5-(3-hydroxyoxetane-3-yl)-3-methylimidazolidin-2,4-dione(I-90); 6-((6-Cyclopropylimidazo[1,2-a]pyridine-2-yl)methoxy)-3-((1S,2S)-2-(4-methylpyrimidine-2-yl)cyclopropyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide(I-91); rac-6-((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methoxy)-3-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide(I-92); 4-Chloro-2-((1S,2S)-2-(7-(((6-Cyclopropyl-8-(3-Methyl-2,4-Dioxoimidazolidine-1-yl)imidazo[1,2-a]pyridine-2-yl)methyl)amino)quinoline-2-yl)cyclopropyl)benzonitrile(I-93); 6-(((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)amino)-4-methyl-3-((1S,2S)-2-(4-methylpyrimidine-2-yl)cyclopropyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide(I-94); rac-1-(6-cyclopropyl-2-(((4-(2-hydroxypropan-2-yl)-2-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline-7-yl)amino)methyl)imidazo[1,2-a]pyridine-8-yl)-3-methylimidazolidin-2,4-dione(I-95); 3-methyl-1-(6-methyl-2-(((2-((1S,2S)-2-(4-methylpyrimidine-2-yl)cyclopropyl)-4-(2-oxa-6-azaspiro[3,3]heptan-6-yl)quinoline-7-yl)oxy)methyl)imidazo[1,2-a]pyridine-8-yl)imidazolidin-2,4-dione(I-96); 1-(6-cyclopropyl-2-(((4-((2-hydroxy-2-methylpropyl)amino)-2-((1S,2S)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline-7-yl)oxy)methyl)imidazo[1,2-a]pyridine-8-yl)-3-methylimidazolidin-2,4-dione(I-97); 1-(6-cyclopropyl-2-((methyl(2-((1S,2S)-2-(4-methylpyrimidine-2-yl)cyclopropyl)-4-(2-oxa-6-azaspiro[3,3]heptan-6-yl)quinoline-7-yl)amino)methyl)imidazo[1,2-a]pyridine-8-yl)-3-methylimidazolidin-2,4-dione(I-98); 1-(6-cyclopropyl-2-(1-((2-((1S,2S)-2-(4-methylpyrimidine-2-yl)cyclopropyl)-4-(2-oxa-6-azaspiro[3,3]heptan-6-yl)quinoline-7-yl)amino)ethyl)imidazo[1,2-a]pyridine-8-yl)-3-methylimidazolidin-2,4-dione(I-99); 1-(6-cyclopropyl-2-(((4-((2-hydroxy-2-methylpropyl)(methyl)amino)-2-((1S,2S)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline-7-yl)amino)methyl)imidazo[1,2-a]pyridine-8-yl)-3-methylimidazolidin-2,4-dione(I-100); 1-(6-cyclopropyl-2-((R)-1-((2-((1S,2S)-2-(4-methylpyrimidine-2-yl)cyclopropyl)-4-(2-oxa-6-azaspiro[3,3]heptan-6-yl)quinoline-7-yl)amino)ethyl)imidazo[1,2-a]pyridine-8-yl)-3-methylimidazolidin-2,4-dione(I-101); rac-1-(6-cyclopropyl-2-(((5-methoxy-2-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline-7-yl)oxy)methyl)imidazo[1,2-a]pyridine-8-yl)-3-methylimidazolidin-2,4-dione(I-102); 1-(6-cyclopropyl-2-(((2-((1S,2S)-2-(4-methylpyrimidine-2-yl)cyclopropyl)-4-(2-oxa-6-azaspiro[3,3]heptan-6-yl)-1,6-naphthyridine-7-yl)oxy)methyl)imidazo[1,2-a]pyridine-8-yl)-3-methylimidazolidined-2,4-dione(I-103); rac-1-(2-(((5-Methoxy-2-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline-7-yl)amino)methyl)-6-methylimidazo[1,2-a]pyridine-8-yl)-3-methylimidazolidin-2,4-dione(I-104); 6-(((6-cyclopropyl-8-fluoroimidazo[1,2-a]pyridine-2-yl)methyl)amino)-3-((1S,2S)-2-(4-methylpyrimidine-2-yl)cyclopropyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide(I-105); rac-1-(6-cyclopropyl-2-(((2-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline-7-yl)amino)methyl)imidazo[1,2-a]pyrazine-8-yl)-3-methylimidazolidin-2,4-dione(I-106); 1-(5-cyclopropyl-2-(((2-((1S,2S)-2-(4-methylpyrimidine-2-yl)cyclopropyl)-4-(2-oxa-6-azaspiro[3,3]heptan-6-yl)quinoline-7-yl)amino)methyl)pyrazolo[1,5-a]pyridin-7-yl)-3-methylimidazolidin-2,4-dione(I-107); 1-(5-cyclopropyl-2-(((2-((1S,2S)-2-(4-methylpyrimidine-2-yl)cyclopropyl)-4-(2-oxa-6-azaspiro[3,3]heptan-6-yl)quinoline-7-yl)oxy)methyl)pyrazolo[1,5-a]pyridin-7-yl)-3-methylimidazolidin-2,4-dione(I-108); or their pharmaceutical salts.

[0135] Compounds expressly disclosed herein may be claimed as individual compounds, including those without reference to stereochemistry.

[0136] C. Pharmaceutical Compositions In another aspect, the present invention provides compounds according to the present disclosure, for example, compounds of formula (I) to (VI-c), or pharmaceutical compositions comprising compounds of formula (I) to (VI-c) or compounds named in combination with, for example, pharmaceutically acceptable excipients (e.g., carriers).

[0137] The pharmaceutical composition comprises optical isomers, diastereomers, or pharmaceutically acceptable salts of the inhibitors disclosed herein. The compounds of formulas (I) to (VI-c) contained in the pharmaceutical composition may be covalently bonded to the support portion as described above. Alternatively, the compounds of formulas (I) to (VI-c) contained in the pharmaceutical composition may not be covalently bonded to the support portion.

[0138] As used herein, “pharmaceutically acceptable carrier” refers to a pharmaceutically and physiologically acceptable organic or inorganic carrier substance that does not react adversely with pharmaceutical excipients, e.g., activators, and is 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, e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts to affect osmotic pressure, buffers, colorants, and / or fragrances, etc., that do not react adversely with the compounds of the present invention.

[0139] The compounds of the present invention can be administered to a subject alone or in combination. Co-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).

[0140] In some embodiments, a test agent as described herein may be incorporated into a pharmaceutical composition for administration by methods known to those skilled in the art and by methods described herein for the provided compound.

[0141] D. Pharmaceuticals The compounds of the present invention can be prepared in a wide variety of oral, parenteral, and topical dosage forms and can be administered in a wide variety of oral, parenteral, and topical dosage forms. Accordingly, the compounds of the present invention can be administered by injection (e.g., intravenously, intramuscularly, intradermally, subcutaneously, intraduodenally, or intraperitoneally). In some embodiments, the compounds of the present disclosure are administered orally. The compounds described herein can also 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.

[0142] 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.

[0143] 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.

[0144] 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.

[0145] 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.

[0146] Liquid preparations include solutions, suspensions, and emulsions, such as water or water / propylene glycol solutions. For parenteral injections, the liquid preparation may be formulated as a solution of polyethylene glycol aqueous solution.

[0147] Where parenteral administration is required or desired, particularly suitable mixtures for the compounds of the present invention are injectable sterile solutions, preferably oily or aqueous solutions, and suspensions, emulsions, or inserts (including suppositories). 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.

[0148] 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.

[0149] This also includes solid preparations intended to be converted into liquid preparations for oral administration immediately before use. Such liquid preparations 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.

[0150] 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, and the package contains individual amounts of the preparation, such as packaged tablets, capsules, and powder in vials or ampoules. Alternatively, a unit dosage form may be the capsule, tablet, cachet, or lollipop itself, or it may be any appropriate number of such in the packaged form.

[0151] The amount of the active ingredient in a unit dose preparation 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.

[0152] Some compounds may have limited water solubility 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 between about 0.01% by weight and about 2% by weight.

[0153] 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 otherwise improve the formulation, 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.

[0154] 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. The entirety of these patents is incorporated herein by reference for all purposes.

[0155] E. Effective dosage The pharmaceutical compositions provided by the present invention include compositions containing an active ingredient in a therapeutically effective amount, i.e., an amount effective to achieve its intended use. The actual amount effective for a particular use depends, in particular, on the condition being treated. For example, when administered in a method of 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).

[0156] The dosage and frequency (single or multiple doses) of the compound administered 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 being treated (e.g., a disease responding to PKa inhibition); the presence of other diseases or other health-related problems; the type of concomitant treatment; 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.

[0157] 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, for example, when measured using the method described.

[0158] The therapeutically effective dose for use 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.

[0159] The dosage may be modified depending on the patient and the requirements of the compound used. In the context of the present invention, the dose administered to a patient must be sufficient to produce a beneficial therapeutic response over time in the patient. The size of the dose is also determined by the presence, nature, and degree of any adverse side effects. In some embodiments, the compounds of this disclosure or pharmaceutical compositions containing them are provided as unit doses.

[0160] In one embodiment, the compounds provided herein exhibit one or more pharmacokinetic (PK) properties (e.g., C) compared to a reference compound. max t max , C min t 1 / 2It shows improvements in 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 those disclosed in PCT Publication WO2019 / 178129.

[0161] F. Treatment Method This disclosure provides compounds and pharmaceutical compositions containing them for use in pharmaceuticals, i.e., for use in treatment. This disclosure further provides the use of any of the compounds described herein to inhibit the activity of PKa, 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 of a subject resulting from inflammation or damage when small vessels become leaky and release fluid into surrounding tissue. In some examples, edema is HAE. In other examples, edema occurs in the eye (e.g., diabetic macular edema (DME)). This disclosure provides methods for inhibiting the activity of PKa. In certain embodiments, this application provides a method for inhibiting the activity of PKa 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 the activity of PKa in vivo by delivering an effective amount of any of the compounds described herein to a subject requiring treatment through a preferred route.

[0162] In certain embodiments, the method involves administering one of the compounds described herein or a pharmaceutically acceptable salt thereof to a subject that needs administration (e.g., a human patient (e.g., one with edema)). In certain embodiments, the method involves administering a compound of formula (I) to (VI-c) or a pharmaceutically acceptable salt or composition thereof to a subject that needs them. In some embodiments, the method involves administering a pharmaceutical composition containing a compound of formula (I) to (VI-c) or a pharmaceutically acceptable salt thereof to a subject that needs them.

[0163] 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 a C1-INH deficiency for HAE.

[0164] 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 standard medical procedures. One or more effective doses of the compounds provided may be administered to the human patient via 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®).

[0165] In other embodiments, methods for reducing the risk of HAE attacks in human HAE patients in a sedated state are provided herein. Such patients may be identified based on various factors, including a history of HAE attacks. One or more effective doses of the compounds may be administered to the human patient via 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®).

[0166] In further embodiments, prophylactic treatment for HAE in human patients at risk of HAE attacks using one or more of the compounds described herein is provided 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 whom a physician determines to be worthy of a prophylactic approach based on their history of HAE attacks (e.g., human subjects who have experienced a certain average number of attacks over a period of time (including, in non-limiting examples, one, two, or more attacks per month)). 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). 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., those described herein.

[0167] In certain embodiments, methods for preventing or reducing edema in the eye of a subject (e.g., a human patient) are provided herein. In some examples, the human patient is a diabetic patient who has, is suspected of having, or is at risk of having diabetic macular edema (DME). DME is a proliferative diabetic retinopathy characterized by swelling of the retinal layer, neovascularization, vascular leakage, and retinal thickening, resulting from leakage of fluid from blood vessels in the macula. To carry out this method, an effective amount of one or more of the compounds described herein or a pharmaceutically acceptable salt thereof can be delivered to the eye of a subject requiring treatment. For example, the compounds can be delivered topically by intraocular or intravitreal injection. The subject may be treated with the compounds described herein either as the sole active agent or in combination with another treatment method for DME. Non-exclusive examples of treatments for DME include laser photocoagulation, steroids, VEGF pathway-targeting agents (e.g., Lucentis® (ranibizumab) or Eylea® (aflibercept)), and / or anti-PDGF agents.

[0168] In certain embodiments, the methods disclosed herein involve administering an effective amount of a compound of formula (I) to (VI-c) or a pharmaceutically acceptable salt or composition thereof to a target. In some embodiments, the effective amount is a therapeutically effective amount. In some embodiments, the effective amount is a prophylactically effective amount.

[0169] In certain embodiments, the subject being 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 being treated is a human. In certain embodiments, the subject is a domesticated animal, such as a dog, cat, cow, pig, horse, sheep, or goat. In certain embodiments, the subject is a companion animal, such as a dog or cat. In certain embodiments, the subject is a domesticated 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.

[0170] 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 (VI-c) or at different times. For example, the compounds of formulas (I) to (VI-c) and any additional pharmaceuticals may be administered on the same or different schedules. All or some doses of the compounds of formulas (I) to (VI-c) may be administered before all or some doses of the additional pharmaceuticals, after all or some doses of the additional pharmaceuticals, within the administration schedule of the additional pharmaceuticals, or in combination thereof. The timing of administration of the compounds of formulas (I) to (VI-c) and the additional pharmaceuticals may vary depending on the additional pharmaceuticals.

[0171] In certain embodiments, additional pharmaceuticals include agents useful in the treatment of edema, such as HAE or DME. Examples of such agents are provided herein.

[0172] Furthermore, the use of the compounds of this disclosure for the manufacture of pharmaceuticals for the conditions / diseases disclosed herein is also provided.

[0173] In the context of this specification, “comprising” should be interpreted as “including.” Embodiments of the present invention that include a particular characteristic / element are also intended to extend to alternative embodiments that “consist of” or “essentially consist of” the relevant element / characteristic. Where technically appropriate, embodiments of the present invention can be combined.

[0174] Technical references, such as patents and applications, are incorporated herein by reference.

[0175] Any embodiment specifically and expressly enumerated herein may, alone or in combination with one or more further embodiments, form the basis of a disclaimer.

[0176] The background technical sections of this specification contain relevant technical information that may be used as a basis for modifications. Subject headings are used to divide the document into sections and are not intended to be used to interpret the meaning of the disclosure provided herein.

[0177] This specification claims priority to U.S. Provisional Patent Application No. 63 / 162,483, filed on 17 March 2021 and incorporated herein by reference. This application may be used as the basis for amendments to this specification, particularly with respect to the chemical structures disclosed herein. [Examples]

[0178] IV. Examples In certain embodiments, the examples describe compounds containing one or more stereocenters, where a particular stereocenter is designated as "S*" or "R*". In either case, the "*" notation generally indicates that the exact configuration is unknown (for example, in the case of a compound with a single stereocenter, the notation R*- or S*- indicates that either an R-isomer or an S-isomer was isolated, but the configuration of the stereocenter of the particular isomer that was isolated was not determined).

[0179] It will be understood that the compounds described in the examples may contain two or more 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. When two or more "S*" or "R*" appear in a pair of parentheses within a particular compound name (e.g., "(1S*,2S*)"), it will be understood that the S* configuration and / or R* configuration are relative to each other. For example, it will be understood that a compound indicated as "(1S*,2S*)-" or "(1R*,2R*)-" clearly refers to either the "(1S,2S)-" isomer or the "(1R,2R)-" isomer, but not the "(1S,2R)-" or "(1R,2S)-" isomer. Furthermore, compounds denoted as "rac-(1S*,2S*)-" or "rac-(1R*,2R*)-" will be understood to include racemic mixtures of the "(1S,2S)-" and "(1R,2R)-" isomers. Similarly, compounds denoted as "(1S*,2R*)-" or "(1R*,2S*)-" will be understood to clearly refer to either the "(1R,2S)-" isomer or the "(1S,2R)-" isomer, but not to the "(1S,2S)-" or "(1R,2R)-" isomer. In addition, compounds denoted as "rac-(1R*,2S*)-" or "rac-(1S*,2R*)-" will be understood to include racemic mixtures of the "(1R,2S)-" and "(1S,2R)-" isomers. In certain embodiments, the examples include schemes showing compounds having one or more stereocenters. In some embodiments, a number is displayed adjacent to the stereocenter after the symbol "&". In such cases, it is understood that the position includes a mixture of both configurations (e.g., R- and S-).

[0180] In some embodiments, a number appears adjacent to the stereocenter after the term "or". In such cases, it is understood that either the "R-" or "S-" isomer is indicated, and a specific isomer has not been determined.

[0181] In some embodiments, the numbering following the symbol "&" or the term "or" refers to the relationship between one stereocenter and another in the compound. For example, if two stereocenters in a compound are each numbered the same (e.g., two instances of "&1"), the arrangements are understood to be relative to each other (e.g., if the structure is described as (S,S) and both stereocenters are indicated by "&1", it is understood that a mixture of (S,S) and (R,R) isomers is included, but no (S,R) or (R,S) isomers are included). However, if each stereocenter is numbered differently (e.g., one instance of "&1" and one instance of "&2"), the arrangements can be independent of each other (e.g., if the structure is described as (S,S) and one stereocenter is indicated by "&1" and the other by "&2", it is understood that a mixture of (S,S), (S,R), (R,S), and (R,R) isomers is included).

[0182] Synthesis of intermediates Synthesis of (1S,2S)-2-(4-methylpyrimidine-2-yl)cyclopropane-1-carboxamide [ka] A mixture of 2-chloro-4-methylpyrimidine (6.4 g, 50 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (10 g, 65 mmol), Pd(dppf)Cl2-DCM (2 g, 2.5 mmol), and K2CO3 (17.25 g, 125 mmol) in dioxane (100 mL) and H2O (5 mL) was stirred at 90°C for 12 hours. The reaction mixture was treated with H2O (50 mL) and extracted with EA (50 mL x 3). The combined organic layer was washed with brine (50 mL), dried over Na2SO4, and concentrated under vacuum (30°C). The crude product was purified by silica column chromatography (PE / siRNA=5 / 1) to obtain 4-methyl-2-vinylpyrimidine (4.8 g, 80%) as a yellow oil. ESI-MS [M +H] + : 121.2.

[0183] Synthesis of rac-ethyl(1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropane-1-carboxylate [ka] A solution of 4-methyl-2-vinylpyrimidine (4.8 g, 40 mmol) and 2-ethyl diazoethyl acetate (9.12 g, 80 mmol) in toluene (70 mL) was refluxed at 110 °C for 8 hours. The reaction mixture was concentrated under vacuum, and the crude product was purified by silica gel column (PE / EA = 5 / 1) to obtain rac-ethyl(1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropane-1-carboxylate (3.6 g, 43.7%) as a yellow oily substance. ESI-MS [M +H] + : 207.2.

[0184] Synthesis of rac-(1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropane-1-carboxylic acid [ka] A mixture of rac-ethyl(1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropane-1-carboxylate (3.6 g, 17.5 mmol) and LiOH-OH (1.4 g, 35 mmol) in THF / H2O (20 mL / 10 mL) was stirred at room temperature for 12 hours. The reaction mixture was concentrated under vacuum to remove THF, and the pH of the residue was adjusted to 3 with HCl (2N). The white solid was precipitated, the mixture was filtered, and dried to obtain rac-(1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropane-1-carboxylic acid (2.4 g, 77%) as a white solid. ESI-MS [M + H] + : 179.2.

[0185] Synthesis of (1S,2S)-2-(4-methylpyrimidine-2-yl)cyclopropane-1-carboxylic acid [ka] A racemic mixture of rac-(1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropane-1-carboxylic acid (2.4 g) was chiral-separated by SFC to obtain (1S,2S)-2-(4-methylpyrimidine-2-yl)cyclopropane-1-carboxylic acid (1.1 g, 45.8%) as a white solid. ESI-MS [M +H]+: 179.1.

[0186] Synthesis of (1S,2S)-2-(4-methylpyrimidine-2-yl)cyclopropane-1-carboxamide [ka] To a solution of (1S,2S)-2-(4-methylpyrimidine-2-yl)cyclopropane-1-carboxylic acid (1.1 g, 6.1 mmol) in dry DCM (20 mL), (COCl)2 (1.56 g, 12.3 mmol) was slowly added at 0°C, and the mixture was stirred at 0°C for a further 1 hour. The reaction mixture was concentrated under vacuum, and the resulting acid chloride was dissolved in dry THF (20 mL), cooled to 0°C, and then NH3 (20 mL, 2 M solution in iPrOH) was added. The resulting solution was stirred at room temperature for a further 1 hour, concentrated under vacuum, and the crude product was obtained. This was purified by silica gel chromatography (eluent: DCM / MeOH = 20 / 1) to obtain (1S,2S)-2-(4-methylpyrimidine-2-yl)cyclopropane-1-carboxamide (900 mg, 81.2%) as a yellow solid. ESI-MS [M +H]+: 178.1.

[0187] Synthesis of (1S,2S)-2-(3-chlorophenyl)cyclopropane-1-carboxylic acid (the first isomer to elute) [ka] rac-(1S*,2S*)-2-(3-chlorophenyl)cyclopropane-1-carboxylic acid (10 g) was separated using SFC (SFC80, Daicel CHIRALPAK AD-H 250 mm × inner diameter 20 mm, 5 μm, CO2 / EtOH = 86 / 14, 50 g / min, 35 °C) to obtain (1S,2S)-2-(3-chlorophenyl)cyclopropane-1-carboxylic acid (4.5 g, first isomer to elute, Rt = 3.0 min, 99.9% ee) and (1R,2R)-2-(3-chlorophenyl)cyclopropane-1-carboxylic acid (4.3 g, second isomer to elute, Rt = 4.0 min, 99.9% ee).

[0188] Synthesis of 6-cyclopropylimidazo[1,2-a]pyridine-2-carbaldehyde [ka] Synthesis of 5-cyclopropylpyridine-2-amine 5-Bromopyridine-2-amine (10 g, 58 mmol), cyclopropylboronic acid (12 g, 120 mmol), SPhos (2.4 g, 5.8 mmol), and K3PO4 (43 g, 200 mmol) were placed under an N2 atmosphere and suspended in toluene (220 mL) and water (22 mL). The resulting suspension was degassed for 10 minutes and Pd(OAc)2 (0.65 g, 2.9 mmol) was added. The reaction mixture was stirred under an N2 atmosphere at 95°C for 16 hours. The mixture was cooled to room temperature, diluted with water (30 mL), and extracted with ethyl acetate (3 × 30 mL). The organic phase was washed with brine (150 mL), dried on hydrophobic frit, and concentrated under vacuum. The residue was purified by silica gel chromatography eluting under a 10–95% siRNA gradient in hexane to obtain the title compound (5.3 g, 68%) as a red solid. ESI-MS (M+H)+: 135.0, 1 H NMR (400 MHz, DMSO) δ 7.78 (d, J=2.5 Hz, 1H), 7.07 (dd, J=2.5, 8.6 Hz, 1H), 6.39 (d, J=8.4 Hz, 1H), 5.66 (s, 2H), 1.80 - 1.72 (m, 1H), 0.86 - 0.81 (m, 2H), 0.56 - 0.52 (m, 2H).

[0189] Synthesis of ethyl 6-cyclopropylimidazo[1,2-a]pyridine-2-carboxylate A solution of 5-cyclopropylpyridine-2-amine (5.3 g, 40 mmol) and ethyl 3-bromo-2-oxopropanoate (5.9 mL, 47 mmol) in ethanol (110 mL) was stirred under reflux for 1 hour. The mixture was cooled to room temperature and concentrated under vacuum. The residue was dissolved in DCM (100 mL), washed with Na2CO3 (saturated aqueous solution, 60 mL), dried on hydrophobic frit, and concentrated under vacuum. The residue was purified by silica gel chromatography eluting under a 20-80% siRNA gradient in hexane to obtain the title compound (5 g, 54%) as an orange solid. ESI-MS (M+H)+: 231.2, 1H NMR (400 MHz, CDCl3) δ 8.10 - 8.09 (m, 1H), 7.91 - 7.89 (m, 1H), 7.57 (d, J=9.5 Hz, 1H), 6.99 (dd, J=1.6, 9.5 Hz, 1H), 4.45 (q, J=7.1 Hz, 2H), 1.94 - 1.86 (m, 1H), 1.44 (t, J=7.2 Hz, 3H), 1.03 - 0.97 (m, 2H), 0.73 - 0.68 (m, 2H).

[0190] Synthesis of (6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methanol LiAlH4 (1M, 42.99 mmol, 42.99 mL in THF) was added to a solution of ethyl 6-cyclopropylimidazo[1,2-a]pyridine-2-carboxylate (21.50 mmol, 4.95 g) in THF (25 mL) and cooled to 0°C under N2. The mixture was stirred for 1 hour, and then siRNA (5 mL) was added dropwise. The mixture was stirred at room temperature for 1 hour, and then washed with water (30 mL) and brine (30 mL). The organic matter was dried over MgSO4 and then concentrated under vacuum to obtain the title compound, which was used without further purification. 1 H NMR (400 MHz, CDCl3) δ 7.86 (s, 1H), 7.46 - 7.42 (m, 2H), 6.92 (dd, J=1.8, 9.4 Hz, 1H), 4.82 (s, 2H), 3.88 - 3.84 (m, 1H), 1.87 (s, 1H), 0.99 - 0.93 (m, 2H), 0.69 - 0.64 (m, 2H).

[0191] Synthesis of 6-cyclopropylimidazo[1,2-a]pyridine-2-carbaldehyde (6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methanol (2.0 g, 11 mmol) and manganese(IV) oxide (9.2 g, 110 mmol) were suspended in chloroform (25 mL) and MeCN (25 mL) and 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%). 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).

[0192] Synthesis of 2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine [ka] To a solution of (6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methanol (0.13 g, 0.69 mmol) in DCM (3.0 mL), SOCl2 (1.0 mL) was slowly added at 0°C. The reaction mixture was stirred at room temperature for 2 hours. The resulting mixture was concentrated under vacuum to obtain 2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine (0.14 g, 98%) as a yellow solid, which was used without further purification.

[0193] Synthesis of 2-((8-bromo-6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)isoindoline-1,3-dione [ka] Synthesis of 2-(3-bromo-2-oxopropyl)isoindoline-1,3-dione A few drops of bromine (7.6 mL, 150 mmol) 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 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 combined organic matter was dried over MgSO4 and concentrated under vacuum. The residue was tritulated 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).

[0194] 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 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 vacuum. The residue was purified by column chromatography on silica gel eluted in cyclohexane with a gradient of 0 to 100% siRNA to obtain the title compound (7.2 g, 52%). ESI-MS (M+H)+: 396.1, 398.1 1H 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).

[0195] Synthesis of 2-((8-chloro-6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)isoindoline-1,3-dione [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 matter was dried over MgSO4 and concentrated under vacuum. The residue was purified by column chromatography using silica gel eluted with a 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).

[0196] 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 organic matter was dried over MgSO4 and concentrated under vacuum. The residue was purified by column chromatography on silica gel eluted with a 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).

[0197] Synthesis of tert-butyl((8-bromo-6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)carbamate [ka] Synthesis of 8-bromo-2-(bromomethyl)-6-cyclopropylimidazo[1,2-a]pyridine [ka] A mixture of 3-bromo-5-cyclopropylpyridine-2-amine (1.06 g, 5.0 mmol) and 1,3-dibromopropan-2-one (1.62 g, 7.5 mmol) in DME (20.0 mL) was stirred at 90°C for 16 hours under N2. The reaction mixture was warmed to room temperature, quenched with saturated NaHCO3 solution (50 mL), and extracted with ethyl acetate (3 × 50 mL). The combined organic compounds were washed with brine (50 mL), dried over Na2SO4, and concentrated under vacuum. The crude residue was purified by column chromatography (eluent: DCM / MeOH = 50 / 1 to 30 / 1) to obtain the product 8-bromo-2-(bromomethyl)-6-cyclopropylimidazo[1,2-a]pyridine (1.2 g, 73%) as a yellow solid. ESI-MS [M + H] + : 330.2.

[0198] Synthesis of 2-(azidomethyl)-8-bromo-6-cyclopropylimidazo[1,2-a]pyridine [ka] A mixture of 8-bromo-2-(bromomethyl)-6-cyclopropylimidazo[1,2-a]pyridine (1.0 g, 3.0 mmol) and NaN3 (244 mg, 3.75 mmol) in DMF (10.0 mL) was stirred at room temperature under N2 for 16 hours. The mixture was diluted with ELISA (100 mL) and washed with brine (3 × 50 mL). The organic layer was dried over Na2SO4 and concentrated under vacuum to obtain 2-(azidomethyl)-8-bromo-6-cyclopropylimidazo[1,2-a]pyridine (900 mg, crude) as a yellow solid, which was used in the next step without purification. ESI-MS [M + H] + : 292.2.

[0199] Synthesis of (8-bromo-6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methanamine [ka] A mixture of 2-(azidomethyl)-8-bromo-6-cyclopropylimidazo[1,2-a]pyridine (870 mg, 3.0 mmol) and PPh3 (983 mg, 3.75 mmol) in MeOH (25 mL) was stirred under reflux for 2 hours. The mixture was concentrated under vacuum and purified by preparative TLC (eluent: DCM / MeOH = 10 / 1) to obtain (8-bromo-6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methaneamine (550 mg, 69%) as a yellow oil. ESI-MS [M + H] + : 266.2.

[0200] Synthesis of tert-butyl((8-bromo-6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)carbamate [ka] A mixture of (8-bromo-6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methaneamine (550 mg, 2.08 mmol), (Boc)2O (679 mg, 3.11 mmol), and Et3N (630 mg, 6.24 mmol) in DCM (20 mL) was stirred at room temperature for 16 hours. The mixture was quenched with water (50 mL) and extracted with DCM (3 × 50 mL). The combined organic matter was washed with brine (50 mL), dried over Na2SO4, and concentrated under vacuum. The residue was purified by preparative TLC (eluent: DCM / MeOH = 20 / 1) to obtain tert-butyl((8-bromo-6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)carbamate (520 mg, 69%) as a yellow solid. ESI-MS [M + H] + : 366.2.

[0201] Synthesis of 1-(2-(aminomethyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-yl)-3-methylimidazolidin-2,4-dione [ka] 1,1-dimethoxy-N,N-dimethylethane-1-amine (4g, 30 mmol) was added to a reaction mixture of imidazolidine-2,4-dione (1g, 10 mmol) in dry toluene (25 mL). The reaction mixture was stirred under N2 at 110°C for 3 hours. The reaction mixture was cooled to 0°C for 15 minutes and filtered. The organic layer was concentrated and purified by silica gel chromatography (eluent: DCM / MeOH = 10 / 1) to obtain 3-methylimidazolidine-2,4-dione (400 mg, 34%) as a white solid. ESI-MS [M +H] + : 115.1.

[0202] Synthesis of tert-butyl((6-cyclopropyl-8-(3-methyl-2,4-dioxoimidazolidine-1-yl)imidazo[1,2-a]pyridine-2-yl)methyl)carbamate [ka] 3-methylimidazolidine-2,4-dione (224 mg, 2 mmol), tert-butyl((8-bromo-6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)carbamate (365 mg, 1 mmol), and Cs2CO3 (975 mg, 3 mmol) were mixed in 10 mL of dry dioxane. Pd2(dba)3 (183 mg, 0.2 mmol) and XantPhos (116 mg, 0.2 mmol) were added to the mixture. The reaction was stirred under N2 at 100°C for 16 hours. The reaction was quenched with water (50 mL) and extracted with ELISA (30 mL x 3). The organic layer was washed with brine (30 mL), dried over Na2SO4, concentrated under vacuum, and purified by silica gel chromatography (eluent: DCM / MeOH = 10 / 1) to obtain tert-butyl((6-cyclopropyl-8-(3-methyl-2,4-dioxoimidazolidine-1-yl)imidazo[1,2-a]pyridine-2-yl)methyl)carbamate (150 mg, 37%) as a yellow solid. ESI-MS [M +H] + : 400.0.

[0203] Synthesis of 1-(2-(aminomethyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-yl)-3-methylimidazolidin-2,4-dione [ka] To a reaction mixture of tert-butyl((6-cyclopropyl-8-(3-methyl-2,4-dioxoimidazolidine-1-yl)imidazo[1,2-a]pyridin-2-yl)methyl)carbamate (500 mg, 1.25 mmol) in dry DCM (10 mL), TFA (2 mL) was added. The reaction mixture was stirred under N2 at room temperature for 16 hours. The reaction mixture was neutralized with NH3 in MeOH, then concentrated under vacuum, and purified by silica gel chromatography (eluent: DCM / MeOH = 10 / 1) to obtain 1-(2-(aminomethyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)-3-methylimidazolidin-2,4-dione (150 mg, 40%) as a white solid. ESI-MS [M +H] + : 300.1.

[0204] Synthesis of 6-cyclopropyl-8-(3-methyl-2,4-dioxoimidazolidine-1-yl)imidazo[1,2-a]pyridine-2-carbaldehyde [ka] Synthesis of 8-bromo-6-cyclopropyl-imidazo[1,2-a]pyridine-2-carboxylate A mixture of 3-bromo-5-cyclopropylpyridine-2-amine (5.0 g, 24 mmol), ethyl bromopyruvate (4.9 mL, 35 mmol), and DIPEA (8.2 mL, 47 mmol) in 1,4-dioxane (200 mL) was stirred at 90°C for 3 hours. The mixture was allowed to cool and concentrated under vacuum. The residue was dissolved in DCM, washed with water, dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography eluted with 10-60% ethyl ethyl cyclohexane to obtain the title compound (4.9 g, 67%) as a brown solid. ESI-MS (M+H)+: 309, 1 H NMR (400 MHz, DMSO) δ 8.58 (s, 1H), 8.47 (s, 1H), 7.54 (d, J=1.3 Hz, 1H), 4.37 (q, J=7.1 Hz, 2H), 2.07 - 1.98 (m, 1H), 1.38 (t, J=7.0 Hz, 3H), 1.04 - 0.97 (m, 3H), 0.83 - 0.76 (m, 2H).

[0205] Synthesis of (8-bromo-6-cyclopropyl-imidazo[1,2-a]pyridine-2-yl)methanol DIBAL-H (1.0 M in THF, 54 mL, 53.8 mmol) was added dropwise to a stirred solution of ethyl 8-bromo-6-cyclopropyl-imidazo[1,2-a]pyridine-2-carboxylate (4.8 g, 15 mmol) in DCM (95 mL) under an N2 atmosphere at -10°C. The mixture was warmed to room temperature over 2 hours. Rochelle salt (saturated aqueous solution) was added, and the mixture was stirred for 18 hours. The mixture was extracted with DCM (3 times), the combined organic matter was dried over MgSO4, filtered through Celite®, concentrated under vacuum, and the title compound (3.0 g, 73%) was obtained as a grayish-white solid, which was used without further purification. ESI-MS (M+H)+: 267, 269, 1 H NMR (400 MHz, DMSO) δ 8.40 (s, 1H), 7.81 (s, 1H), 7.33 (s, 1H), 5.25 (dd, J=5.7, 5.7 Hz, 1H), 4.59 (d, J=5.8 Hz, 2H), 2.00 - 1.91 (m, 1H), 0.97 - 0.90 (m, 2H), 0.76 - 0.70 (m, 2H).

[0206] Synthesis of 1-(6-cyclopropyl-2-(hydroxymethyl)imidazo[1,2-a]pyridine-8-yl)-3-methylimidazolidin-2,4-dione A mixture of (8-bromo-6-cyclopropyl-imidazo[1,2-a]pyridine-2-yl)methanol (2.44 g, 9.13 mmol), 3-methylimidazolidined-2,4-dione (1.20 g, 10 mmol), Pd2(dba)3 (420 mg, 0.46 mmol), Xantphos (530 mg, 0.91 mmol), and Cs2CO3 (8.9 g, 27 mmol) in 1,4-dioxane (110 mL) was degassed with N2 and heated at 100°C for 18 hours. Water (200 mL) was added, and the mixture was extracted in ELISA (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 eluting with 0-10% MeOH in DCM to obtain the title compound (1.40 g, 51%) as a yellow / brown solid. ESI-MS (M+H)+: 301, 1 H NMR (400 MHz, DMSO) δ 8.40 (s, 1H), 7.81 (s, 1H), 7.33 (s, 1H), 5.25 (dd, J=5.7, 5.7 Hz, 1H), 4.59 (d, J=5.8 Hz, 2H), 2.00 - 1.91 (m, 1H), 0.97 - 0.90 (m, 2H), 0.76 - 0.70 (m, 2H).

[0207] Synthesis of 6-cyclopropyl-8-(3-methyl-2,4-dioxoimidazolidine-1-yl)imidazo[1,2-a]pyridine-2-carbaldehyde To a stirred solution of 1-(6-cyclopropyl-2-(hydroxymethyl)imidazo[1,2-a]pyridine-8-yl)-3-methylimidazolidined-2,4-dione (1.2 g, 4.0 mmol) in DCM (40 mL), MnO2 (3.5 g, 40 mmol) was added, and the mixture was stirred at room temperature for 18 hours. Another 3.5 g, 40 mmol of MnO2 was added, and the mixture was stirred at room temperature for 5 hours. A further 690 mg, 7.8 mmol of MnO2 was added, and the mixture was stirred at room temperature for 18 hours. The mixture was filtered through Celite® and concentrated under vacuum to obtain the title compound (800 mg, 67%) as a grayish-white solid. ESI-MS (M+H)+: 299.2, 1 H NMR (400 MHz, DMSO) δ 10.03 (s, 1H), 8.60 - 8.59 (m, 1H), 8.38 - 8.37 (m, 1H), 7.53 (d, J=1.5 Hz, 1H), 4.93 (s, 2H), 3.00 (s, 3H), 2.06 - 1.98 (m, 1H), 1.04 - 0.98 (m, 2H), 0.74 - 0.69 (m, 2H).

[0208] Synthesis of 1-(2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-yl)-3-methylimidazolidin-2,4-dione [ka] To a solution of 1-(6-cyclopropyl-2-(hydroxymethyl)imidazo[1,2-a]pyridine-8-yl)-3-methylimidazolidin-2,4-dione (0.40 g, 1.3 mmol) in DCM (10 mL), SOCl2 (3.0 mL) was added. The resulting mixture was stirred under N2 at 25°C for 2 hours. The reaction mixture was concentrated under vacuum to obtain 1-(2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-yl)-3-methylimidazolidin-2,4-dione (0.42 g, quantitatively) as a yellow solid, which was used in the next step without further purification. ESI-MS [M +H]+: 319.1.

[0209] Synthesis of 1-(6-cyclopropyl-2-(1-hydroxyethyl)imidazo[1,2-a]pyridine-8-yl)-3-methylimidazolidined-2,4-dione [ka] Synthesis of 8-bromo-6-cyclopropylimidazo[1,2-a]pyridine-2-carbaldehyde A mixture of (8-bromo-6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methanol (10 g, 37.45 mmol) and MnO2 (9.8 g, 112 mmol) was stirred at room temperature for 12 hours. A second batch of MnO2 (9.8 g, 112 mmol) was added, and the mixture was stirred at room temperature for another 12 hours. The reaction mixture was filtered through a short silica pad and washed with ELISA (500 mL). The filtrate was concentrated under vacuum to obtain 8-bromo-6-cyclopropylimidazo[1,2-a]pyridine-2-carbaldehyde (8 g, 80.8%) as a yellow solid. ESI-MS [M + H] + : 266.2.

[0210] Synthesis of 1-(8-bromo-6-cyclopropylimidazo[1,2-a]pyridine-2-yl)ethane-1-ol To a solution of 8-bromo-6-cyclopropylimidazo[1,2-a]pyridine-2-carbaldehyde (8 g, 30 mmol) in dry THF (100 mL), MeMgBr (30 mL, 3 M solution in Et2O, 90 mmol) was slowly added at -65°C, and the resulting solution was stirred at -65°C for 2 hours. The reaction mixture was quenched at -65°C with saturated NH4Cl aqueous solution (70 mL), stirred, warmed to room temperature, and then extracted with siRNA (4 × 75 mL). The combined organic layers were washed with brine (75 mL), dried over Na2SO4, and then concentrated under vacuum to obtain the crude product. This crude product was purified by silica gel chromatography (eluent: DCM / MeOH = 15 / 1) to obtain 1-(8-bromo-6-cyclopropylimidazo[1,2-a]pyridine-2-yl)ethane-1-ol (7.3 g, 86.9%) as a yellow solid. ESI-MS [M +H] + : 281.2.

[0211] Synthesis of 1-(6-cyclopropyl-2-(1-hydroxyethyl)imidazo[1,2-a]pyridine-8-yl)-3-methylimidazolidined-2,4-dione A mixture of 1-(8-bromo-6-cyclopropylimidazo[1,2-a]pyridine-2-yl)ethane-1-ol (7.3 g, 25.98 mmol), 3-methylimidazolidine-2,4-dione (8.9 g, 77.9 mmol), Pd2(dba)3 (2.38 g, 2.6 mmol), Xantphos (3 g, 5.2 mmol), and Cs2CO3 (25 g, 77 mmol) in dioxane (75 mL) was stirred at 95°C for 18 hours. The reaction mixture was cooled to room temperature, filtered through Celite®, and washed with EtoAc (3 × 75 mL). The combined filtrate was washed with brine (80 mL), dried over Na2SO4, and then concentrated under vacuum to obtain the crude product. This was purified by silica gel chromatography (eluent: DCM / MeOH = 15 / 1) to obtain 1-(6-cyclopropyl-2-(1-hydroxyethyl)imidazo[1,2-a]pyridine-8-yl)-3-methylimidazolidin-2,4-dione (6.1 g, 75%) as a yellow solid. ESI-MS [M +H] + : 315.2.

[0212] Synthesis of 1-(6-cyclopropyl-2-(hydroxymethyl)imidazo[1,2-a]pyrazine-8-yl)-3-methylimidazolidin-2,4-dione [ka] Synthesis of 5-cyclopropylpyrazine-2-amine To a mixture of 5-bromopyrazine-2-amine (10 g, 57 mmol) in toluene / H2O (V / V=1 / 1, 400 mL), cyclopropylboronic acid (15 g, 0.17 mol), S-phos (2.4 g, 5.8 mmol), K3PO4 (36 g, 0.17 mol), and Pd(OAc)2 (1.3 g, 5.8 mmol) were added. The mixture was stirred at 100 °C for 16 hours under N2 and then cooled to room temperature. The reaction mixture was filtered through Celite® and the filtrate was washed with DCM / MeOH (10 / 1, 100 mL). The filtrate was concentrated under vacuum to obtain a crude product, which was purified by silica gel chromatography (eluent: PE / siRNA=10 / 1~5 / 1) to obtain 5-cyclopropylpyrazine-2-amine (5.6 g, 72%) as a yellow solid. ESI-MS [M +H] + : 136.1.

[0213] Synthesis of 3-bromo-5-cyclopropylpyrazine-2-amine 5-Cyclopropylpyrazine-2-amine (5.6 g, 41 mmol) was mixed with CH3CN (40 mL) and NBS (7.4 g, 42 mmol) was added at 0°C. The mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic material was washed with saturated brine (100 mL) and dried over Na2SO4. The organic layer was concentrated and purified by silica gel column chromatography (eluent: PE / ethyl acetate = 10 / 1) to obtain 3-bromo-5-cyclopropylpyrazine-2-amine (2.0 g, yield 23%). ESI-MS [M + H]+: 214.0

[0214] Synthesis of ethyl 8-bromo-6-cyclopropylimidazo[1,2-a]pyrazine-2-carboxylate To a mixture of 3-bromo-5-cyclopropylpyrazine-2-amine (2.0 g, 9.3 mmol) in DME (30 mL), ethyl 3-bromo-2-oxopropanoate (2.0 g, 10 mmol) was added. The mixture was stirred at 90°C for 16 hours and then cooled to room temperature. The mixture was then poured into water (50 mL) and extracted with ethyl HCl (3 × 50 mL). The combined organic matter was washed with saturated brine solution (100 mL), dried over Na₂SO₄, and concentrated under vacuum. The residue was purified by silica gel column chromatography (eluent: PE / HCl = 2 / 1) to obtain ethyl 8-bromo-6-cyclopropylimidazo[1,2-a]pyrazine-2-carboxylate (1.0 g, 35%). ESI-MS [M +H]+: 310.0

[0215] Synthesis of (8-bromo-6-cyclopropylimidazo[1,2-a]pyrazine-2-yl)methanol A mixture of 8-bromo-6-cyclopropylimidazo[1,2-a]pyrazine-2-carboxylate (1.0 g, 3.2 mmol) in THF (20 mL) was mixed with DIBAL-H (11 mL, 11 mmol) at -65°C. The mixture was stirred at -65°C for 1 hour, then warmed to 25°C and stirred for another hour. The reaction mixture was poured into ice water (20 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic matter was washed with saturated brine solution (50 mL), dried over Na₂SO₄, concentrated under vacuum to obtain a residue, which was purified by silica gel column chromatography (eluent: PE / ethyl acetate = 5 / 1) to obtain (8-bromo-6-cyclopropylimidazo[1,2-a]pyrazine-2-yl)methanol (0.49 g, yield 57%). ESI-MS [M +H]+: 268.0

[0216] Synthesis of 1-(6-cyclopropyl-2-(hydroxymethyl)imidazo[1,2-a]pyrazine-8-yl)-3-methylimidazolidin-2,4-dione To a mixture of (8-bromo-6-cyclopropylimidazo[1,2-a]pyrazine-2-yl)methanol (0.49 g, 1.8 mmol) in dioxane (15 mL), 3-methylimidazolidinedione-2,4-dione (0.83 g, 7.3 mmol), Pd2(dba)3 (0.34 g, 0.37 mmol), Xant-Phos (0.38 g, 0.66 mmol), and Cs2CO3 (1.8 g, 5.5 mmol) were added. After stirring at 90°C for 16 hours under N2, the reaction mixture was filtered, and the filter cake was washed with DCM / MeOH (10 / 1, 50 mL). The filtrate was concentrated under vacuum to obtain the crude product, which was purified by silica gel column chromatography (eluent: DCM / MeOH = 30 / 1 to 10 / 1) to obtain 1-(6-cyclopropyl-2-(hydroxymethyl)imidazo[1,2-a]pyrazine-8-yl)-3-methylimidazolidin-2,4-dione (0.40 g, 74%). ESI-MS [M +H]+: 302.1

[0217] Synthesis of 7-bromo-4-chloro-2-((1S,2S)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline [ka] Synthesis of (1S,2S)-N-(2-acetyl-5-bromophenyl)-2-(4-methylpyrimidine-2-yl)cyclopropane-1-carboxamide Oxalyl chloride (0.98 mL, 11 mmol) was added dropwise at 0°C to a stirred solution of (1S,2S)-2-(4-methylpyrimidine-2-yl)cyclopropane-1-carboxylic acid (1.00 g, 5.6 mmol) and DMF (0.050 mL) in THF (10 mL), and the mixture was stirred at 0°C for 30 minutes. The reaction mixture was then concentrated under vacuum. The residue was suspended in THF (20 mL), and 1-(2-amino-4-bromophenyl)ethanone (1300 mg, 5.9 mmol) and pyridine (4.5 mL, 56 mmol) were added. The mixture was heated at 70°C for 18 hours. The mixture was cooled to room temperature, quenched with water (50 mL), the precipitate formed was filtered, washed with water, dried over MgSO4, and concentrated under vacuum to obtain the title compound (1.7 g, 85%) as a dark brown solid. ESI-MS (M+H)+: 374.0, 376.0, 1 H NMR (400 MHz, DMSO) δ 11.55 (s, 1H), 8.60 (d, J=5.1 Hz, 1H), 8.53 (d, J=2.0 Hz, 1H), 7.95 (d, J=8.6 Hz, 1H), 7.48 (dd, J=2.0, 8.3 Hz, 1H), 7.28 (d, J=5.1 Hz, 1H), 2.68 - 2.61 (m, 4H), 2.41 - 2.35 (m, 1H), 1.65 - 1.59 (m, 2H).

[0218] Synthesis of 7-bromo-2-((1S,2S)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline-4(1H)-one NaOH (440 mg, 11 mmol) was azeotropically mixed with toluene (three times), and then added to a stirred suspension of (1S,2S)-N-(2-acetyl-5-bromophenyl)-2-(4-methylpyrimidine-2-yl)cyclopropane-1-carboxamide (1.70 g, 4.5 mmol) in 1,4-dioxane (20 mL). The reaction mixture was heated at 100 °C for 1 hour. The reaction mixture was cooled to room temperature and poured into NH4Cl (saturated aqueous solution, 50 mL). The resulting precipitate was filtered and dried under high vacuum to obtain the title compound (1.3 g, 77%) as a dark brown solid. 1H NMR (400 MHz, DMSO) δ 11.71 - 11.71 (m, 1H), 8.58 (d, J=5.1 Hz, 1H), 7.96 (d, J=8.7 Hz, 1H), 7.75 (s, 1H), 7.44 (dd, J=1.7, 8.6 Hz, 1H), 5.94 (s, 1H), 2.71 - 2.64 (m, 1H), 2.59 - 2.54 (m, 1H), 2.45 (s, 3H), 1.83 - 1.71 (m, 2H).

[0219] Synthesis of 7-bromo-4-chloro-2-((1S,2S)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline 7-Bromo-2-((1S,2S)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline-4(1H)-one (1.30 g, 3.65 mmol) was stirred in POCl3 (8.5 mL, 91.2 mmol) at 100°C for 90 minutes, cooled to room temperature for 30 minutes, and then stirred at 100°C for 30 minutes. The mixture was cooled and concentrated under vacuum. The residue was dissolved in DCM (500 mL), washed with NaHCO3 (saturated aqueous solution, 150 mL), water (100 mL), brine (saturated aqueous solution, 150 mL), and water (100 mL), dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography eluted with 0-100% ethyl acetate in cyclohexane to obtain the title compound (385 mg, 28%) as an orange solid. ESI-MS (M+H)+: 376.1, 374.1, 1 H NMR (400 MHz, DMSO) δ 8.56 (1H, d, J = 5.1 Hz), 8.22 - 8.21 (1H, m), 8.09 (1H, d, J = 8.8 Hz), 7.96 (1H, s), 7.83 (1H, dd, J = 2.0, 8.9 Hz), 7.23 - 7.22 (1H, m), 2.93 - 2.84 (2H, m), 2.44 (3H, s), 1.92 - 1.82 (2H, m).

[0220] Synthesis of 4-(azetidine-1-yl)-7-bromo-2-((1S,2S)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline [ka] Synthesis of 4-(azetidine-1-yl)-7-bromo-2-((1S,2S)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline A solution of 7-bromo-4-chloro-2-[(1S,2S)-2-(4-methylpyrimidine-2-yl)cyclopropyl]quinoline (120 mg, 0.32 mmol) and azetidine (0.11 mL, 1.6 mmol) in NMP (0.50 mL) was stirred in a microwave reactor at 140°C for 35 minutes. The mixture was diluted with DCM, water, and brine (saturated aqueous solution) to obtain an emulsion. The mixture was concentrated under vacuum, suspended in DCM, filtered, and concentrated under vacuum again. The residue was loaded into an SCX cartridge, washed with MeOH in DCM, and eluted with 7N NH3 (in MeOH) in DCM to obtain the title compound (90 mg, 71%) as a yellow solid. ESI-MS (M+H)+: 397.2, 395.2, 1 H NMR (400 MHz, DMSO) δ 8.55 (d, J=5.0 Hz, 1H), 7.95 - 7.90 (m, 2H), 7.52 - 7.49 (m, 1H), 7.22 (d, J=5.1 Hz, 1H), 6.30 (s, 1H), 4.47 - 4.41 (m, 4H), 2.86 - 2.82 (m, 1H), 2.73 - 2.67 (m, 1H), 2.45 - 2.43 (m, 5H), 1.96 - 1.85 (m, 1H), 1.77 - 1.73 (m, 1H).

[0221] The compounds in Table 1 were synthesized from 7-bromo-4-chloro-2-[(1S,2S)-2-(4-methylpyrimidine-2-yl)cyclopropyl]quinoline and a suitable amine coupling partner using the same method as described for 7-bromo-4-chloro-2-((1S,2S)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline. [Table 1-1] [Table 1-2]

[0222] Synthesis of rac-7-bromo-4-chloro-2-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline [ka] Synthesis of (E)-7-bromo-4-chloro-2-(2-(4-methylpyrimidine-2-yl)vinyl)quinoline (E)-4-methyl-2-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl)pyrimidine (110 mg, 0.41 mmol), 7-bromo-2,4-dichloroquinoline (100 mg, 0.41 mmol), and K3PO4 (170 mg, 0.81 mmol) were mixed in THF (4.0 mL) and water (1.0 mL). The mixture was degassed with N2, and then PdCl2(PPh3)2 (14 mg, 0.020 mmol) was added. The mixture was heated at 70°C for 18 hours. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over MgSO4, filtered, 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 (67 mg, 46%) as a yellow solid. 1H NMR (400 MHz, DMSO) δ 8.73 (d, J=5.1 Hz, 1H), 8.37 - 8.34 (m, 2H), 8.13 (d, J=8.9 Hz, 1H), 8.04 (d, J=16.3 Hz, 1H), 7.90 (dd, J=2.0, 9.0 Hz, 1H), 7.86 (d, J=16.1 Hz, 1H), 7.33 (d, J=5.0 Hz, 1H), 2.53 (s, 3H).

[0223] Synthesis of rac-7-bromo-4-chloro-2-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline NaH (60% in mineral oil, 140 mg, 3.6 mmol) was added to a stirred solution of Me3SOI (850 mg, 3.9 mmol) in DMSO (6.0 mL), and the mixture was stirred at room temperature under an N2 atmosphere for 1 hour. A slurry of (E)-7-bromo-4-chloro-2-(2-(4-methylpyrimidine-2-yl)vinyl)quinoline (470 mg, 1.3 mmol) in DMSO (7.0 mL) and THF (3.0 mL) was added, and the mixture was stirred at room temperature for 3 hours. The mixture was quenched with NH4Cl (saturated aqueous solution, 75 mL), and the mixture was extracted with HCl (3 × 75 mL). The combined organic matter was dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography eluting with 0-50% HCl in cyclohexane to obtain the title compound (210 mg, 44%) as a colorless rubbery substance. ESI-MS (M+H)+: 376.1, 374.1, 1 H NMR (400 MHz, DMSO) δ 8.57 - 8.55 (m, 1H), 8.22 - 8.21 (m, 1H), 8.11 - 8.08 (m, 1H), 7.97 (s, 1H), 7.85 - 7.81 (m, 1H), 7.22 (d, J=5.0 Hz, 1H), 2.94 - 2.84 (m, 2H), 2.45 - 2.44 (m, 3H), 1.92 - 1.83 (m, 2H).

[0224] Synthesis of rac-7-bromo-N,N-dimethyl-2-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline-4-amine [ka] Me2NH (5.6M in EtOH, 1.0 mL, 5.66 mmol) was added to a stirred mixture of rac-7-bromo-4-chloro-2-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline (210 mg, 0.57 mmol) in EtOH (0.57 mL). The mixture was sealed and stirred at 90°C for 18 hours. The mixture was cooled, and more Me2NH (5.6M in EtOH, 1.0 mL, 5.66 mmol) was added. The mixture was sealed and stirred at 90°C for 2 hours. The mixture was concentrated under vacuum, and the residue was purified by column chromatography using silica gel eluted with 1-20% MeOH in DCM to obtain the title compound (140 mg, 63%) as a colorless rubbery substance. ESI-MS (M+H)+: 385.2, 383.2, 1 H NMR (400 MHz, CDCl3) δ 8.45 (d, J=5.1 Hz, 1H), 8.09 (d, J=2.0 Hz, 1H), 7.83 (d, J=8.9 Hz, 1H), 7.45 - 7.41 (m, 1H), 6.95 - 6.93 (m, 1H), 6.70 (s, 1H), 2.98 (s, 6H), 2.96 - 2.90 (m, 1H), 2.81 - 2.76 (m, 1H), 2.48 (s, 3H), 1.99 - 1.93 (m, 1H), 1.89 - 1.84 (m, 1H).

[0225] Synthesis of rac-7-bromo-2-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)-4-(oxetane-3-yloxy)quinoline [ka] 3-Hydroxyoxetane (17 μL, 0.27 mmol) was added to a stirred suspension in DMF (1.0 mL) of rac-7-bromo-4-chloro-2-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline (100 mg, 0.267 mmol) and NaH (60% in mineral oil, 27 mg, 0.67 mmol), and the mixture was stirred at 100°C for 18 hours under an N2 atmosphere. The mixture was quenched with water and extracted with DCM (3 times). The combined organic matter was passed through a hydrophobic frit and concentrated under vacuum. The aqueous phase was further extracted with siRNA (3 times), the combined organic matter was dried over MgSO4, filtered, and combined with the DCM residue. The mixture was concentrated under vacuum to obtain the title compound (97 mg, 89%) as a brown solid, which was used without further purification. ESI-MS (M+H)+: 412, 414, 1 H NMR (400 MHz, DMSO) δ 8.59 (d, J=5.1 Hz, 1H), 8.15 (d, J=8.8 Hz, 1H), 8.10 (d, J=1.8 Hz, 1H), 7.70 (dd, J=2.0, 8.8 Hz, 1H), 7.25 (d, J=5.1 Hz, 1H), 6.91 (s, 1H), 5.64 - 5.58 (m, 1H), 5.15 - 5.07 (m, 2H), 4.77 - 4.71 (m, 2H), 2.91 - 2.83 (m, 2H), 2.48 (s, 3H), 1.91 - 1.80 (m, 2H).

[0226] Synthesis of rac-7-bromo-4-((1-methylpiperidine-4-yl)oxy)-2-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline [ka] To a solution of N-methyl-4-piperidinol (0.016 mL, 0.13 mmol) in DMF (0.50 mL), NaH (60% in mineral oil, 13 mg, 0.33 mmol) was added at room temperature under an N2 atmosphere. After 10 minutes, rac-7-bromo-4-chloro-2-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline (50 mg, 0.13 mmol) was added. The mixture was stirred at room temperature under an N2 atmosphere for 2 hours. Further addition of NaH (60% in mineral oil, 13 mg, 0.33 mmol) was added, and the mixture was stirred at room temperature under an N2 atmosphere for 18 hours. The mixture was quenched with water and extracted with DCM (3 times). The combined organic matter was passed through a hydrophobic frit and concentrated under vacuum. The above procedure was repeated, and then the residues from both reactions were loaded into an SCX cartridge and washed with MeOH. The compound was released using 7N NH3 in MeOH, concentrated under vacuum, and the title compound (93 mg, 77%) was obtained as a yellow, rubbery substance. ESI-MS (M +H)+: 453, 455.

[0227] Synthesis of rac-N-(7-bromo-2-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline-4-yl)-N-methylmethanesulfonamide [ka] Synthesis of rac-7-bromo-N-methyl-2-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline-4-amine MeNH2 (33% in EtOH, 0.83 mL, 6.7 mmol) was added to a stirred mixture of rac-7-bromo-4-chloro-2-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline (250 mg, 0.67 mmol) in EtOH (1.0 mL). The mixture was sealed and heated under reflux for 24 hours. The reaction mixture was concentrated under vacuum, and the residue was purified by silica gel column chromatography eluting with 0-10% 7N NH3 (in MeOH) in DCM to obtain the title compound (160 mg, 65%) as a pale yellow solid. ESI-MS (M+H)+: 369.1, 371.1, 1 H NMR (400 MHz, CDCl3) δ 8.44 (d, J=5.1 Hz, 1H), 8.05 (d, J=1.8 Hz, 1H), 7.48 (d, J=8.8 Hz, 1H), 7.40 (dd, J=1.9, 8.7 Hz, 1H), 6.93 (d, J=5.1 Hz, 1H), 6.33 (s, 1H), 4.95 - 4.93 (m, 1H), 3.01 (d, J=4.8 Hz, 3H), 2.95 - 2.90 (m, 1H), 2.81 - 2.74 (m, 1H), 2.47 (s, 3H), 1.97 - 1.82 (m, 2H).

[0228] Synthesis of rac-N-(7-bromo-2-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline-4-yl)-N-methylmethanesulfonamide LiHMDS (1.0 M, 0.49 mL, 0.49 mmol in THF) was added dropwise at 0°C to a stirred solution of rac-7-bromo-N-methyl-2-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline-4-amine (120 mg, 0.33 mmol) in THF (5.0 mL). After 15 minutes, MsCl (0.050 mL, 0.65 mmol) was added dropwise, and the reaction mixture was warmed to room temperature and stirred for 18 hours. The reaction mixture was quenched with water and extracted with DCM. The organic layer was dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography eluted with 0-100% ethyl ethyl ethyl elution in cyclohexane to obtain the title compound (50 mg, 34%). ESI-MS (M+H)+: 447.2, 449.2, 1H NMR (400 MHz, CDCl3) δ 8.46 (d, J=5.0 Hz, 1H), 8.20 (d, J=1.6 Hz, 1H), 7.96 (d, J=8.9 Hz, 1H), 7.63 - 7.59 (m, 1H), 7.35 (s, 1H), 6.97 (d, J=5.0 Hz, 1H), 3.37 (s, 3H), 3.03 (s, 3H), 3.03 - 2.95 (m, 1H), 2.87 - 2.82 (m, 1H), 2.49 (s, 3H), 2.06 - 1.91 (m, 2H).

[0229] Synthesis of rac-4-(7-bromo-2-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline-4-yl)morpholine [ka] A mixture of rac-7-bromo-4-chloro-2-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline (100 mg, 0.267 mmol) and morpholine (0.12 mL, 1.33 mmol) was heated to 140°C in a microwave reactor for 30 minutes twice. The mixture was diluted with DCM, washed with water, dried over MgSO4, concentrated under vacuum to obtain the title compound, which was used without further purification. ESI-MS (M+H)+: 425.3, 427.3.

[0230] Synthesis of (7-bromo-5-cyclopropylpyrazolo[1,5-a]pyridine-2-yl)methanol [ka] Synthesis of 4-cyclopropylpyridine-2-amine [ka] To a toluene / H2O (200 mL / 40 mL) solution of 4-bromopyridine-2-amine (20 g, 0.12 mol), cyclopropylboronic acid (20 g, 0.23 mol), Pd(OAc)2 (1.0 g, 4.6 mmol), K3PO4 (74 g, 0.35 mol), and PCy3 (2.6 g, 9.3 mmol) were added at room temperature. The reaction mixture was stirred under nitrogen at 90°C for 16 hours. The reaction mixture was concentrated under vacuum, diluted with water (150 mL), and then extracted with ethyl acetate (150 ml x 2). The combined organic layer was washed with brine (200 mL x 1), dried over Na2SO4, concentrated under vacuum to obtain the crude product, which was purified by silica gel chromatography (eluent: ethyl acetate / PE = 1 / 1) to obtain 4-cyclopropylpyridine-2-amine (16 g, quantitatively) as a yellow solid. ESI-MS [M + H] + : 135.1.

[0231] Synthesis of (1S,2S)-2-(2-((tert-butoxycarbonyl)amino)-6-methoxypyridine-4-yl)cyclopropane-1-carboxylic acid To a stirred HBr (40% in H2O, 70 mL) solution, 4-cyclopropylpyridine-2-amine (15 g, 0.11 mol) was added gradually at 0°C, followed by the dropwise addition of Br2 (52 g, 0.32 mol). After stirring at 0°C for 30 minutes, a solution of NaNO2 (19 g, 0.27 mol) in water (30 mL) was added dropwise while maintaining the temperature below 10°C. The resulting mixture was stirred at 0°C for a further 30 minutes. The reaction mixture was quenched with aqueous NaOH solution (60 g in water (100 mL)) until the pH reached 12, and then extracted with ELISA (100 mL x 2). The combined organic layers were washed with water (200 mL) and brine (200 mL), dried over Na2SO4, and concentrated under vacuum to obtain the crude product. This crude product was purified by silica gel chromatography (eluent: siRNA / PE = 1 / 10) to obtain 2-bromo-4-cyclopropylpyridine (15 g, 70%) as a yellow oil. ESI-MS [M + H] + : 198.1.

[0232] Synthesis of dimethyl 7-bromo-5-cyclopropylpyrazolo[1,5-a]pyridine-2,3-dicarboxylate To a stirred solution of O-(mesitylsulfonyl)hydroxylamine (34 g, 160 mol) in DCM (200 mL), a solution of 2-bromo-4-cyclopropylpyridine (15 g, 76 mmol) in DCM (50 mL) was slowly added at 0°C. The mixture was stirred at 0°C for 10 minutes, then warmed to room temperature and stirred for 14 hours. The reaction mixture was concentrated and dried under vacuum. The residue was dissolved in CH3CN (200 mL), DMAD (17 g, 120 mmol) was added, followed by the dropwise addition of DBU (18.2 g, 120 mol) at 0°C. The resulting mixture was stirred at 0°C for 10 minutes, then warmed to room temperature and stirred for 16 hours. The reaction mixture was concentrated under vacuum, diluted with water (300 mL), and extracted with ELISA (200 mL x 2). The combined organic layers were washed with water (400 mL) and brine (400 mL), dried over Na2SO4, and concentrated under vacuum to obtain the crude product. This crude product was purified by silica gel chromatography (eluent: siRNA / PE = 1 / 10) to obtain dimethyl 7-bromo-5-cyclopropyl pyrazolo[1,5-a]pyridine-2,3-dicarboxylate (6.5 g, 24%) as a yellow solid. ESI-MS [M + H] + : 353.0.

[0233] Synthesis of 7-bromo-5-cyclopropylpyrazolo[1,5-a]pyridine-2-carboxylic acid A mixture of dimethyl 7-bromo-5-cyclopropylpyrazolo[1,5-a]pyridine-2,3-dicarboxylate (6.0 g, 17 mmol) and LiOH·H2O (1.4 g, 34 mmol) in THF (50 mL) and water (10 mL) was stirred at 40°C for 2 hours. The mixture was concentrated under vacuum to remove THF, and then 1,4-dioxane (50 mL) and concentrated HCl (12 mL) were added. The resulting mixture was stirred at 100°C for 6 hours. The reaction mixture was poured into water (200 mL) and extracted with HCl (150 mL × 3). The combined organic layer was washed with brine (400 mL), dried over Na2SO4, then concentrated, and dried under vacuum to obtain 7-bromo-5-cyclopropylpyrazolo[1,5-a]pyridine-2-carboxylic acid (4.8 g, quantitatively) as a yellow solid. ESI-MS [M + H] + : 281.0.

[0234] Synthesis of methyl 7-bromo-5-cyclopropylpyrazolo[1,5-a]pyridine-2-carboxylate To a mixture of 7-bromo-5-cyclopropylpyrazolo[1,5-a]pyridine-2-carboxylic acid (4.8 g, 17 mmol) in MeOH (50 mL), SOCl2 (4.0 g, 34 mmol) was added dropwise at room temperature. The mixture was stirred at 70 °C for 3 hours. The reaction mixture was concentrated under vacuum, diluted with ethyl acetate (200 mL), washed with NaHCO3 (saturated aqueous solution, 150 mL) and brine (150 mL), dried over Na2SO4, and then concentrated under vacuum to obtain the crude product. This was purified by silica gel chromatography (eluent: ethyl acetate / PE = 1 / 10) to obtain methyl 7-bromo-5-cyclopropylpyrazolo[1,5-a]pyridine-2-carboxylate (3.8 g, 76% in two steps) as a yellow solid. ESI-MS [M + H] + : 295.0.

[0235] Synthesis of (7-bromo-5-cyclopropylpyrazolo[1,5-a]pyridine-2-yl)methanol To a stirred solution of methyl 7-bromo-5-cyclopropylpyrazolo[1,5-a]pyridine-2-carboxylate (3.3 g, 11 mmol) in THF (60 mL), DIBAl-H (1 M in hexane, 33 mL, 33 mmol) was added dropwise at -65°C. The mixture was stirred at -65°C for 2 hours. The reaction mixture was quenched at -65°C with NaOH (1 M in water, 50 mL), warmed to room temperature, and then extracted with Depositphotos (100 mL x 2). The combined organic layers were washed with brine (150 mL), dried over Na₂SO₄, and then concentrated under vacuum to obtain the crude product, which was purified by silica gel chromatography (eluent: Depositphotos / PE = 1 / 5) to obtain the desired product (2.8 g, 95%) as a yellow solid. ESI-MS [M + H] + : 267.0.

[0236] Example 1 Synthesis of N7-((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)-N4,N4-dimethyl-2-(2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline-4,7-diamine(I-1) [ka] Synthesis of 2-(3-bromo-2-oxopropyl)isoindoline-1,3-dione Br2 (3.8 mL, 74 mmol) in AcOH (45 mL) was added dropwise to a stirred solution of 2-(2-oxopropyl)isoindoline-1,3-dione (10 g, 49 mmol) at 70°C. The mixture was stirred at 70°C for 90 minutes, then allowed to cool and concentrated under vacuum. The residue was dissolved in DCM (100 mL) and washed with Na2S2O3 (1.0 M aqueous solution, 100 mL) and Na2CO3 (20% aqueous solution, 2 × 100 mL). The organic layer was passed through a phase separation cartridge and concentrated under vacuum. The residue was triturated with Et2O to obtain the title compound (12 g, 88%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.92 - 7.88 (m, 2H), 7.78 - 7.75 (m, 2H), 5.12 (s, 1H), 4.79 (s, 2H), 4.01 (s, 2H).

[0237] Synthesis of 2-((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)isoindoline-1,3-dione A mixture of 5-cyclopropylpyridine-2-amine (4.5 g, 34 mmol), 2-(3-bromo-2-oxopropyl)isoindoline-1,3-dione (10 g, 37 mmol), and DIPEA (8.8 mL, 50 mmol) in 1,4-dioxane (340 mL) was heated at 100 °C for 72 hours. The mixture was concentrated under vacuum, and the residue was purified by silica gel column chromatography eluted with 20-100% siRNA in Et2O to obtain the title compound (3.6 g, 33%) as a red solid. 1 H NMR (400 MHz, DMSO) δ 8.32 (s, 1H), 7.98 - 7.91 (m, 4H), 7.79 (s, 1H), 7.40 (d, J=9.3 Hz, 1H), 7.01 (dd, J=1.8, 9.3 Hz, 1H), 4.92 (s, 2H), 2.05 - 1.92 (m, 1H), 0.96 (ddd, J=4.4, 6.3, 8.4 Hz, 2H), 0.73 - 0.68 (m, 2H).

[0238] Synthesis of (6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methanamine N2H4·H2O (3.6 g, 56.72 mmol) was added to a solution of 2-((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)isoindoline-1,3-dione (3.6 g, 11.34 mmol) in EtOH (55 mL), and the mixture was heated at 80°C for 18 hours. The mixture was cooled, filtered through Celite®, and concentrated under vacuum. The residue was loaded into an SCX cartridge, washed with MeOH in DCM, eluted with 7N NH3 (in MeOH) in DCM, and then concentrated under vacuum to obtain the title compound (2.0 g, 94%) as an orange, rubbery substance. 1 H NMR (400 MHz, DMSO) δ 8.30 (s, 1H), 7.62 (s, 1H), 7.33 (d, J=9.3 Hz, 1H), 6.92 (dd, J=1.6, 9.2 Hz, 1H), 3.77 (s, 2H), 1.96 - 1.87 (m, 1H), 0.94 - 0.87 (m, 2H), 0.69 - 0.63 (m, 2H).

[0239] Synthesis of tert-butyl((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)carbamate Di-tert-butyl dicarbonate (1.4 g, 5.3 mmol) was added to a solution of (6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methaneamine (1.0 g, 5.3 mmol) in DCM (55 mL), and the mixture was stirred at room temperature for 18 hours. NaHCO3 (saturated aqueous solution, 50 mL) was added, and the mixture was extracted with DCM (3 × 50 mL). The combined organic matter was dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography eluted with 20-100% ethyl acetate in cyclohexane to obtain the title compound (930 mg, 60%) as a yellow solid. 1H NMR (400 MHz, DMSO) δ 8.32 (s, 1H), 7.57 (s, 1H), 7.35 (d, J=9.3 Hz, 1H), 7.26 (dd, J=5.7, 5.7 Hz, 1H), 6.95 (dd, J=1.9, 9.2 Hz, 1H), 4.19 (d, J=6.1 Hz, 2H), 1.95 - 1.87 (m, 1H), 1.39 (s, 9H), 0.91 (ddd, J=4.3, 6.3, 8.5 Hz, 2H), 0.69 - 0.64 (m, 2H).

[0240] Synthesis of rac-tert-butyl((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)(4-(dimethylamino)-2-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline-7-yl)carbamate A mixture of tert-butyl((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)carbamate (99 mg, 0.34 mmol), rac-7-bromo-N,N-dimethyl-2-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline-4-amine (110 mg, 0.28 mmol), Pd(OAc)2, Xantphos (17 mg, 0.028 mmol), and Cs2CO3 (190 mg, 0.029 mmol) in 1,4-dioxane (5.0 mL) was degassed with N2 and heated at 100°C for 18 hours. The mixture was filtered through Celite® and concentrated under vacuum. The residue was purified by silica gel column chromatography using elution with 0-20% 7N NH3 (in MeOH) in DCM to obtain the title compound (50 mg, 30%). 1H NMR (400 MHz, CDCl3) δ 8.43 (d, J=5.0 Hz, 1H), 7.89 - 7.84 (m, 2H), 7.78 (d, J=2.3 Hz, 1H), 7.44 - 7.40 (m, 3H), 6.93 - 6.87 (m, 2H), 6.61 (s, 1H), 5.12 (d, J=1.4 Hz, 2H), 2.96 (s, 6H), 2.93 - 2.87 (m, 2H), 2.80 - 2.74 (m, 1H), 2.46 (s, 3H), 1.92 - 1.80 (m, 3H), 1.45 (s, 9H), 0.96 - 0.91 (m, 2H), 0.69 - 0.64 (m, 2H).

[0241] rac-N 7 -((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)-N 4 ,N 4 Synthesis of -dimethyl-2-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline-4,7-diamine HCl (4.0 M in 1,4-dioxane, 0.19 mL, 0.76 mmol) was added to a solution of rac-tert-butyl((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)(4-(dimethylamino)-2-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline-7-yl)carbamate (45 mg, 0.076 mmol) in MeOH (1.0 mL), and the mixture was stirred at room temperature for 3 hours. The mixture was concentrated under vacuum and purified by preparative HPLC to obtain the title compound (3 mg, 8%) as formate. ESI-MS (M+H)+: 490.5, 1H NMR (400 MHz, DMSO) δ 8.50 (d, J=5.1 Hz, 1H), 8.31 (s, 2H), 7.70 - 7.67 (m, 2H), 7.40 (d, J=9.3 Hz, 1H), 7.16 (d, J=5.1 Hz, 1H), 6.99 - 6.91 (m, 2H), 6.70 (d, J=2.4 Hz, 1H), 6.62 (dd, J=5.7, 5.7 Hz, 1H), 6.59 (s, 1H), 4.44 (d, J=5.5 Hz, 2H), 2.88 (s, 6H), 2.75 - 2.65 (m, 2H), 2.61 - 2.55 (m, 2H), 2.40 (s, 3H), 1.94 - 1.86 (m, 1H), 1.77 - 1.63 (m, 2H), 1.23 (s, 1H), 0.92 - 0.87 (m, 2H), 0.68 - 0.63 (m, 2H).

[0242] Example 2 Synthesis of 2-((1S,2S)-2-(3-chlorophenyl)cyclopropyl)-7-(((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)amino)pyrido[4,3-d]pyrimidine-4(3H)-one(I-2) [ka] Synthesis of methyl 6-chloro-4-((1S,2S)-2-(3-chlorophenyl)cyclopropane-1-carboxamide)nicotinate (1S,2S)-2-(3-chlorophenyl)cyclopropane-1-carboxylic acid (0.45 g, 2.3 mmol) and DCM (10 mL) were cooled, and one drop of DMF was added at 0°C. The mixture was stirred for 2 hours. The mixture was concentrated under vacuum and added to a solution of methyl 4-amino-6-chloronicotinate (0.36 g, 1.92 mmol) in a mixture of THF (10 mL) and pyridine (1.6 mL, 19.2 mmol). The mixture was heated to 70°C for 18 hours. The mixture was diluted with NaHCO3 (saturated aqueous solution, 50 mL) and extracted with ELISA (3 × 50 mL). The organic phases were combined, dried over MgSO4, and concentrated under vacuum. The residue was purified by silica gel column chromatography eluting with a gradient of 0 to 100% ELISA in cyclohexane to obtain the title compound (335 mg, 48%). ESI-MS (M+H)+: 365.1, 1 H NMR (400 MHz, CDCl3) δ 11.45 (s, 1H), 8.94 (s, 1H), 8.73 (s, 1H), 7.24 - 7.21 (m, 2H), 7.10 (d, J=1.9 Hz, 1H), 7.05 - 6.99 (m, 1H), 3.97 (s, 3H), 2.62 (ddd, J=4.0, 6.5, 9.3 Hz, 1H), 1.91 - 1.86 (m, 1H), 1.79 - 1.74 (m, 1H), 1.49 - 1.44 (m, 1H).

[0243] Synthesis of 7-Chloro-2-((1S,2S)-2-(3-chlorophenyl)cyclopropyl)pyrido[4,3-d]pyrimidine-4(3H)-one Methyl 6-chloro-4-((1S,2S)-2-(3-chlorophenyl)cyclopropane-1-carboxamide)nicotinate was added to a mixture of 7N NH3 (13 mL) and MeOH (13 mL) in a sealed vial. The mixture was stirred at room temperature for 18 hours. The mixture was concentrated under vacuum, and the residue was purified by silica gel column chromatography eluting with a gradient of 20-100% RINKAN in cyclohexane to obtain the title compound (179 mg, 58%). ESI-MS (M+H)+: 332.1,1 H NMR (400 MHz, DMSO) δ 12.88 (s, 1H), 9.01 (s, 1H), 7.56 (s, 1H), 7.37 - 7.32 (m, 2H), 7.30 - 7.27 (m, 1H), 7.22 - 7.20 (m, 1H), 2.72 - 2.66 (m, 1H), 2.33 - 2.27 (m, 1H), 1.90 - 1.84 (m, 1H), 1.75 (ddd, J=4.5, 6.6, 8.4 Hz, 1H).

[0244] Synthesis of 7-Chloro-2-((1S,2S)-2-(3-chlorophenyl)cyclopropyl)-3-(2,4-dimethoxybenzyl)pyrido[4,3-d]pyrimidine-4(3H)-one A mixture of K2CO3 (0.15 g, 1.08 mmol), 7-chloro-2-((1S,2S)-2-(3-chlorophenyl)cyclopropyl)pyrido[4,3-d]pyrimidine-4(3H)-one (0.18 g, 0.542 mmol), and DMB-Cl (0.13 mL, 0.813 mmol) in a mixture of DMF (5 mL) and Et2O (2 mL) was heated to 80°C for 18 hours. The mixture was diluted with brine (50 mL) and water (75 mL) and extracted with HCl (3 × 25 mL). The organic phases were combined and concentrated under vacuum. The residue was purified by silica gel column chromatography with elution in cyclohexane under a gradient of 0 to 100% HCl to obtain the title compound (111 mg, 43%). ESI-MS (M+H)+: 482.1, 1H NMR (400 MHz, DMSO) δ 9.11 (s, 1H), 7.63 (s, 1H), 7.25 - 7.23 (m, 2H), 7.03 (s, 1H), 6.99 - 6.96 (m, 1H), 6.77 (d, J=8.5 Hz, 1H), 6.38 (d, J=2.4 Hz, 1H), 6.33 (dd, J=2.4, 8.4 Hz, 1H), 5.35 - 5.21 (m, 2H), 3.68 (s, 3H), 3.62 (s, 3H), 2.45 (ddd, J=4.1, 6.5, 9.0 Hz, 1H), 2.36 - 2.31 (m, 1H), 2.01 - 1.94 (m, 1H), 1.61 (ddd, J=4.4, 6.6, 8.1 Hz, 1H).

[0245] Synthesis of tert-butyl(2-((1S,2S)-2-(3-chlorophenyl)cyclopropyl)-3-(2,4-dimethoxybenzyl)-4-oxo-3,4-dihydropyrido[4,3-d]pyrimidine-7-yl)((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)carbamate A mixture containing 7-chloro-2-((1S,2S)-2-(3-chlorophenyl)cyclopropyl)-3-(2,4-dimethoxybenzyl)pyrido[4,3-d]pyrimidine-4(3H)-one (0.11 g, 0.22 mmol), tert-butyl((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)carbamate (0.079 g, 0.22 mmol), Pd2(dba)3 (0.021 g, 0.02 mmol), Xantphos (0.026 g, 0.045 mmol), and Cs2CO3 (0.15 g, 0.45 mmol) in toluene (2 mL) was heated at 110 °C for 18 hours. The mixture was filtered through Celite® and concentrated under vacuum. The residue was purified by silica gel column chromatography using a gradient of 0-100% siRNA in cyclohexane to obtain the title compound (64 mg, 38%) as a pale yellow, rubbery substance. ESI-MS (M+H)+: 733.5, 1H NMR (400 MHz, DMSO) δ 9.08 (s, 1H), 8.27 (s, 1H), 7.80 (s, 1H), 7.58 (d, J=4.4 Hz, 1H), 7.37 - 7.32 (m, 1H), 7.25 - 7.22 (m, 2H), 7.03 (s, 1H), 6.99 - 6.91 (m, 2H), 6.72 (d, J=8.4 Hz, 1H), 6.38 (d, J=2.3 Hz, 1H), 6.34 (dd, J=2.3, 8.4 Hz, 1H), 5.34 (s, 2H), 5.32 - 5.20 (m, 2H), 3.68 (s, 3H), 3.63 (s, 3H), 2.47 - 2.40 (m, 1H), 2.33 - 2.27 (m, 1H), 1.99 - 1.87 (m, 2H), 1.62 - 1.54 (m, 1H), 1.45 (s, 9H), 0.93 - 0.86 (m, 2H), 0.68 - 0.62 (m, 2H).

[0246] Synthesis of 2-((1S,2S)-2-(3-chlorophenyl)cyclopropyl)-7-(((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)amino)pyrido[4,3-d]pyrimidine-4(3H)-one To a solution of tert-butyl(2-((1S,2S)-2-(3-chlorophenyl)cyclopropyl)-3-(2,4-dimethoxybenzyl)-4-oxo-3,4-dihydropyrido[4,3-d]pyrimidine-7-yl)((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)carbamate (50 mg, 0.068 mmol) and anisole (0.074 mL, 0.68 mmol) in DCM (0.5 mL), TFA (0.5 mL) was added. The mixture was stirred at room temperature for 2 hours. The mixture was concentrated on silica under vacuum and purified by silica gel column chromatography eluting with a gradient of 0-10% 7N NH3 (in MeOH) in DCM, followed by preparative HPLC, to obtain the title compound (11 mg, 33%) as formate. ESI-MS (M+H)+: 483.5, 1H NMR (400 MHz, DMSO) δ 12.02 (s, 1H), 8.73 (s, 1H), 8.39 (s, 1H), 8.30 (s, 1H), 7.68 (dd, J=6.0, 6.0 Hz, 1H), 7.64 (s, 1H), 7.38 (d, J=9.3 Hz, 1H), 7.34 - 7.29 (m, 2H), 7.27 - 7.25 (m, 1H), 7.18 (d, J=7.7 Hz, 1H), 6.96 (dd, J=1.8, 9.3 Hz, 1H), 6.31 (s, 1H), 4.58 (d, J=3.8 Hz, 2H), 2.62 - 2.54 (m, 1H), 2.22 - 2.16 (m, 1H), 1.94 - 1.86 (m, 1H), 1.80 - 1.74 (m, 1H), 1.63 - 1.57 (m, 1H), 0.93 - 0.88 (m, 2H), 0.68 - 0.63 (m, 2H).

[0247] Example 3 Synthesis of rac-2-((1S*,2S*)-2-(3-chlorophenyl)cyclopropyl)-7-(((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)amino)pyrido[4,3-d]pyrimidine-4(3H)-one(I-3) [ka] The title compound was synthesized starting from methyl 2-amino-4-bromobenzoate and rac-(1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropan-1-carbonyl chloride (2.3 mg, 25%), using the same method as described for 2-((1S,2S)-2-(3-chlorophenyl)cyclopropyl)-7-(((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)amino)pyrido[4,3-d]pyrimidine-4(3H)-one. ESI-MS (M+H)+: 464.3, 1H NMR (400 MHz, DMSO) δ 11.87 (s, 1H), 8.53 (d, J=5.0 Hz, 1H), 8.31 (s, 1H), 7.72 (d, J=8.8 Hz, 1H), 7.67 (s, 1H), 7.39 (d, J=9.4 Hz, 1H), 7.20 (d, J=5.0 Hz, 1H), 7.10 (dd, J=5.8, 5.8 Hz, 1H), 6.98 (d, J=9.4 Hz, 1H), 6.79 (dd, J=2.3, 8.8 Hz, 1H), 6.51 (d, J=1.9 Hz, 1H), 4.44 (d, J=5.6 Hz, 2H), 2.77 - 2.71 (m, 1H), 2.48 - 2.45 (m, 1H), 2.41 (s, 3H), 1.94 - 1.86 (m, 1H), 1.74 - 1.61 (m, 2H), 0.93 - 0.87 (m, 2H), 0.69 - 0.63 (m, 2H).

[0248] Example 4 Synthesis of rac-1-(2-(((2-((1S*,2S*)-2-(3-chlorophenyl)cyclopropyl)-4-methoxyquinoline-7-yl)amino)methyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-yl)pyrrolidine-2-one (I-4) [ka] Synthesis of 1-(2-(aminomethyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-yl)pyrrolidine-2-one [ka] 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 eluting under a 20-100% ethyl chromatin gradient 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).

[0249] Synthesis of 1-(2-(aminomethyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-yl)pyrrolidine-2-one A solution of 2-((6-cyclopropyl-8-(2-oxopyrrolidine-1-yl)imidazo[1,2-a]pyridine-2-yl)methyl)isoindoline-1,3-dione (1.0 g, 2.50 mmol) and hydrazine hydrate (0.16 mL, 4.99 mmol) in EtOH (15 mL) was heated to 75°C for 2 hours. The mixture was cooled to room temperature and then applied to an SCX column, which was washed with 3:1 DCM:MeOH and then eluted with 3:1 7N NH3 (in MeOH):DCM to obtain the title compound (0.60 g, 89%). ESI-MS (M+H)+: 271.3, 1 ¹H NMR (400 MHz, CDCl3) δ values: 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.

[0250] Synthesis of 1-(2-amino-4-bromophenyl)ethane-1-one BCl3 (1.0 M, 32 mL, 32 mmol in DCM) was added dropwise to a stirred slurry of 3-bromoaniline (5.0 g, 29 mmol) in MeCN (15 mL, 290 mmol) and toluene (35 mL), while maintaining the temperature of the mixture below 10°C. AlCl3 (5.8 g, 44 mmol) was gradually added to the reaction mixture while cooling. The mixture was stirred at 90°C for 17 hours. The reaction mixture was cooled to room temperature, and HCl (2.0 M aqueous solution, 50 mL) was added. The reaction mixture was stirred at 50°C for 1 hour. The reaction mixture was cooled to room temperature, diluted with water (100 mL), and extracted with DCM (3 × 150 mL). The combined organic matter was dried over MgSO4 and concentrated under vacuum to obtain the title compound (4.6 g, 74%) as a brown solid. 1H NMR (400 MHz, CDCl3) δ 7.55 (d, J=8.6 Hz, 1H), 6.83 (d, J=1.8 Hz, 1H), 6.76 (dd, J=2.0, 8.6 Hz, 1H), 6.38 - 6.33 (m, 2H), 2.54 (s, 3H).

[0251] Synthesis of rac-(1S*,2S*)-N-(2-acetyl-5-bromophenyl)-2-(3-chlorophenyl)cyclopropane-1-carboxamide Oxalyl chloride (0.44 g, 5.1 mmol) was added dropwise to a 10 mL DCM solution of rac-(1S*,2S*)-2-(3-chlorophenyl)cyclopropane-1-carboxylic acid (500 mg, 2.5 mmol) and DMF (0.05 mL) and brought to 0°C. The reaction mixture was stirred at 0°C for 2.5 hours. The reaction mixture was warmed to room temperature and concentrated under vacuum. The residue was suspended in THF (10 mL) and pyridine (2.1 mL, 25 mmol) and 1-(2-amino-4-bromophenyl)ethane-1-one (520 mg, 2.4 mmol) were added. The reaction mixture was stirred at 50°C for 16 hours. The reaction mixture was cooled to room temperature, diluted with water (75 mL), and stirred for 2 hours. The resulting precipitate was collected by filtration, washed with water (100 mL), and dried under vacuum to obtain the title compound (850 mg, 85%). 1 H NMR (400 MHz, DMSO) δ 11.51 (s, 1H), 8.57 (d, J=2.0 Hz, 1H), 7.92 (d, J=8.6 Hz, 1H), 7.42 (dd, J=2.0, 8.3 Hz, 1H), 7.35 - 7.29 (m, 2H), 7.28 - 7.24 (m, 1H), 7.21 - 7.18 (m, 1H), 2.59 (s, 3H), 2.48 - 2.43 (m, 1H), 2.21 - 2.15 (m, 1H), 1.56 - 1.42 (m, 2H).

[0252] Synthesis of rac-7-bromo-2-((1S*,2S*)-2-(3-chlorophenyl)cyclopropyl)quinoline-4(1H)-one NaOH (100 mg, 2.6 mmol) was azeotropically mixed with toluene (twice) and added to a solution of rac-(1S*,2S*)-N-(2-acetyl-5-bromophenyl)-2-(3-chlorophenyl)cyclopropane-1-carboxamide (250 mg, 0.64 mmol) in 1,4-dioxane (5.0 mL) under an N2 atmosphere. The reaction mixture was stirred at 100 °C for 3 hours, then cooled to room temperature and diluted with NH4Cl (saturated aqueous solution, 20 mL). The resulting precipitate was collected by filtration, washed with water (50 mL), and dried under vacuum to obtain the title compound (200 mg, 83%) as a beige solid. 1 ¹H NMR (400 MHz, DMSO) δ 11.65 - 11.62 (m, 1H), 7.94 (d, J=8.6 Hz, 1H), 7.75 (d, J=1.3 Hz, 1H), 7.42 (dd, J=1.5, 8.6 Hz, 1H), 7.37 - 7.31 (m, 2H), 7.27 (dd, J=1.8, 6.8 Hz, 1H), 7.22 (d, J=7.8 Hz, 1H), 5.89 (s, 1H), 2.27 - 2.20 (m, 1H), 1.80 - 1.72 (m, 1H), 1.69 - 1.61 (m, 1H). One CH is hidden by the DMSO peak.

[0253] Synthesis of rac-7-bromo-2-((1S*,2S*)-2-(3-chlorophenyl)cyclopropyl)-4-methoxyquinoline A mixture of rac-7-bromo-2-((1S*,2S*)-2-(3-chlorophenyl)cyclopropyl)quinoline-4(1H)-one (100 mg, 0.27 mmol) and K2CO3 (74 mg, 0.53 mmol) in DMF (2.5 mL) was stirred at 50°C for 1.5 hours. The reaction mixture was cooled to room temperature and MeI (0.019 mL, 0.29 mmol) was added. The reaction mixture was stirred at 50°C for 5 hours, then cooled to room temperature, and MeI (0.019 mL, 0.29 mmol) was added again. The reaction mixture was stirred at 50°C for 16 hours. The reaction mixture was cooled to room temperature, quenched with water (25 mL), and extracted with ₹ (3 × 40 mL). The combined organic matter was dried over MgSO4 and concentrated under vacuum to obtain the title compound (82 mg, 79%) as a yellow oil. 1 H NMR (400 MHz, CDCl3) δ 8.09 (d, J=1.8 Hz, 1H), 7.96 (d, J=8.8 Hz, 1H), 7.48 (dd, J=1.9, 8.8 Hz, 1H), 7.24 - 7.14 (m, 3H), 7.07 (d, J=7.4 Hz, 1H), 6.67 (s, 1H), 4.02 (s, 3H), 2.67 - 2.61 (m, 1H), 2.38 - 2.33 (m, 1H), 2.01 - 1.96 (m, 1H), 1.54 - 1.49 (m, 1H).

[0254] Synthesis of rac-1-(2-(((2-((1S*,2S*)-2-(3-chlorophenyl)cyclopropyl)-4-methoxyquinoline-7-yl)amino)methyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-yl)pyrrolidine-2-one A mixture of rac-7-bromo-2-((1S*,2S*)-2-(3-chlorophenyl)cyclopropyl)-4-methoxyquinoline (41 mg, 0.11 mmol), 1-(2-(aminomethyl)-6-cyclopropylimidazo[1,2-a]pyrrolidine-8-yl)pyrrolidine-2-one (34 mg, 0.13 mmol), rac-BINAP (6.6 mg, 0.010 mmol), Pd2(dba)3 (4.8 mg, 0.0053 mmol), and tBuOK (24 mg, 0.21 mmol) in toluene (1.5 mL) was degassed for 5 minutes and stirred at 90°C for 4 hours. The reaction mixture was cooled to room temperature, filtered through Celite®, and concentrated under vacuum. The residue was dissolved in DCM (25 mL) and washed with NH4Cl (saturated aqueous solution, 3 × 50 mL). The combined organic compounds were passed through hydrophobic frit and concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with 5% MeOH in DCM, followed by 10% 7N NH3 (in MeOH) in DCM, to obtain the title compound (25 mg, 41%) as a yellow solid. ESI-MS (M+H)+: 578.5, 1 H NMR (400 MHz, DMSO) δ 8.24 (s, 1H), 7.75 - 7.69 (m, 2H), 7.32 - 7.15 (m, 5H), 7.13 (d, J=1.6 Hz, 1H), 6.95 (dd, J=2.2, 9.0 Hz, 1H), 6.75 - 6.70 (m, 2H), 4.45 (d, J=5.6 Hz, 2H), 4.19 (dd, J=7.3, 7.3 Hz, 2H), 3.94 (s, 3H), 2.48 - 2.42 (m, 2H), 2.18 - 2.09 (m, 2H), 1.94 - 1.86 (m, 1H), 1.82 - 1.77 (m, 1H), 1.54 - 1.43 (m, 1H), 0.93 - 0.88 (m, 2H), 0.66 - 0.61 (m, 2H) Two CH peaks are hidden by the solvent peak.

[0255] Example 5 Synthesis of rac-1-(2-(((2-((1S*,2S*)-2-(3-chlorophenyl)cyclopropyl)-4-oxo-1,4-dihydroquinoline-7-yl)amino)methyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-yl)-3-methylimidazolidin-2,4-dione (I-5) [ka] Synthesis of rac-tert-butyl(2-((1S*,2S*)-2-(3-chlorophenyl)cyclopropyl)-4-methoxyquinoline-7-yl)((6-cyclopropyl-8-(3-methyl-2,4-dioxoimidazolidine-1-yl)imidazo[1,2-a]pyridine-2-yl)methyl)carbamate rac-7-bromo-2-((1S*,2S*)-2-(3-chlorophenyl)cyclopropyl)-4-methoxyquinoline (100 mg, 0.26 mmol) was added to a mixture of tert-butyl((6-cyclopropyl-8-(3-methyl-2,4-dioxoimidazolidine-1-yl)imidazo[1,2-a]pyridine-2-yl)methyl)carbamate (123 mg, 0.31 mmol), Pd2(dba)3 (12 mg, 0.013 mmol), Xantphos (15 mg, 0.026 mmol), and Cs2CO3 (251 mg, 0.77 mmol) in 1,4-dioxane (5.0 mL), and the mixture was heated to 105°C for 18 hours. The mixture was filtered through Celite® and then concentrated under vacuum. The residue was purified by silica gel column chromatography using a gradient of 0-100% acetyl in cyclohexane to obtain the crude title compound, which was then proceeded to the next step without further purification. 1H NMR (400 MHz, CDCl3) δ 8.01 (d, J=9.0 Hz, 1H), 7.81 (d, J=1.9 Hz, 1H), 7.75 (d, J=0.4 Hz, 1H), 7.48 (s, 1H), 7.37 (d, J=1.8 Hz, 1H), 7.23 - 7.14 (m, 3H), 7.11 - 7.05 (m, 2H), 6.60 (s, 1H), 5.05 (s, 2H), 4.02 - 4.01 (m, 3H), 3.70 (s, 2H), 3.11 (s, 3H), 2.62 - 2.58 (m, 1H), 2.38 - 2.33 (m, 1H), 1.97 - 1.83 (m, 2H), 1.51 - 1.47 (m, 1H), 1.45 (s, 9H), 0.98 - 0.88 (m, 2H), 0.71 - 0.64 (m, 2H).

[0256] Synthesis of rac-1-(2-(((2-((1S*,2S*)-2-(3-chlorophenyl)cyclopropyl)-4-oxo-1,4-dihydroquinoline-7-yl)amino)methyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-yl)-3-methylimidazolidin-2,4-dione Pyridine HCl (392 mg, 3.39 mmol) was added to rac-tert-butyl(2-((1S*,2S*)-2-(3-chlorophenyl)cyclopropyl)-4-methoxyquinoline-7-yl)((6-cyclopropyl-8-(3-methyl-2,4-dioxoimidazolidine-1-yl)imidazo[1,2-a]pyridine-2-yl)methyl)carbamate (60 mg, 0.085 mmol), and the mixture was heated to 130°C for 2 hours. The mixture was diluted with water and 10% MeOH in DCM, and then extracted with 10% MeOH in DCM. The organic phases were combined, dried, and then concentrated under vacuum. The residue was purified by preparative HPLC to obtain the title compound (3 mg, 3%). ESI-MS (M+H)+: 593.3, Purity: 91.4%, 1H NMR (400 MHz, DMSO) δ 10.98 - 10.97 (m, 1H), 8.26 (d, J=1.1 Hz, 1H), 7.74 - 7.70 (m, 2H), 7.35 - 7.29 (m, 3H), 7.27 - 7.25 (m, 1H), 7.20 - 7.18 (m, 1H), 6.97 - 6.95 (m, 1H), 6.70 (dd, J=2.1, 8.8 Hz, 1H), 6.45 (d, J=2.0 Hz, 1H), 5.60 (d, J=1.7 Hz, 1H), 4.91 (s, 2H), 4.43 (d, J=5.4 Hz, 2H), 2.99 (s, 3H), 2.40 - 2.36 (m, 1H), 2.16 - 2.12 (m, 1H), 1.94 (dd, J=8.4, 8.4 Hz, 1H), 1.68 - 1.65 (m, 1H), 1.54 - 1.51 (m, 1H), 0.97 - 0.92 (m, 2H), 0.67 - 0.62 (m, 2H).

[0257] Example 6 Synthesis of 1-(2-(((2-((1S,2S)-2-(3-chlorophenyl)cyclopropyl)-4-oxo-3,4-dihydroquinazoline-7-yl)amino)methyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-yl)-3-methylimidazolidin-2,4-dione (I-6) [ka] Synthesis of methyl 4-bromo-2-((1S,2S)-2-(3-chlorophenyl)cyclopropane-1-carboxamide)benzoate (1S,2S)-2-(3-chlorophenyl)cyclopropane-1-carboxylic acid (1.0 g, 5.1 mmol) and oxalyl chloride (0.44 mL, 5.1 mmol) were cooled in 20 mL of DCM, to which one drop of DMF was added at 0°C, and the mixture was stirred for 1 hour. The mixture was concentrated and then redissolved in 20 mL of THF. Methyl 2-amino-4-bromobenzoate (1.2 g, 5.1 mmol), followed by pyridine (1.2 mL, 15.3 mmol), was added, and the mixture was heated at 70°C for 18 hours. The cooled mixture was diluted with water and then extracted with DCM. The combined organic matter was passed through a hydrophobic cartridge and concentrated on silica under vacuum, and then purified by silica gel column chromatography eluting with a gradient of 0 to 100% siRNA in cyclohexane to obtain the title compound (800 mg, 38%). ESI-MS (M+H)+: 410.1, 1 H NMR (400 MHz, DMSO) δ 10.88 (s, 1H), 8.50 (d, J=2.0 Hz, 1H), 7.83 (d, J=8.5 Hz, 1H), 7.41 (dd, J=2.0, 8.5 Hz, 1H), 7.35 - 7.30 (m, 2H), 7.28 - 7.25 (m, 1H), 7.20 (d, J=7.7 Hz, 1H), 3.84 (s, 3H), 2.48 - 2.43 (m, 1H), 2.25 - 2.19 (m, 1H), 1.56 - 1.43 (m, 2H).

[0258] Synthesis of 7-bromo-2-((1S,2S)-2-(3-chlorophenyl)cyclopropyl)quinazoline-4(3H)-one 7N NH3 (20 mL) in MeOH was added to a solution of methyl 4-bromo-2-((1S,2S)-2-(3-chlorophenyl)cyclopropane-1-carboxamide)benzoate (400 mg, 0.98 mmol) in MeOH (20 mL), and the mixture was heated to 80°C for 18 hours. The mixture was diluted with DCM, washed with brine, passed through a hydrophobic cartridge, concentrated on silica under vacuum, and then purified by silica gel column chromatography eluting with a gradient of 0-80% siRNA in cyclohexane to obtain the title compound, which was used directly in the next step. 1 H NMR (400 MHz, DMSO) δ 12.55 (s, 1H), 7.97 (d, J=8.4 Hz, 1H), 7.73 (s, 1H), 7.59 - 7.56 (m, 1H), 7.36 - 7.30 (m, 2H), 7.28 (d, J=7.8 Hz, 1H), 7.21 (d, J=7.5 Hz, 1H), 2.65 - 2.59 (m, 1H), 2.33 - 2.25 (m, 1H), 1.91 - 1.80 (m, 1H), 1.68 - 1.63 (m, 1H).

[0259] Synthesis of tert-butyl(2-((1S,2S)-2-(3-chlorophenyl)cyclopropyl)-4-oxo-3,4-dihydroquinazolin-7-yl)carbamate A 1,4-dioxane solution of methyl 4-bromo-2-((1S,2S)-2-(3-chlorophenyl)cyclopropane-1-carboxamide)benzoate (100 mg, 0.27 mmol), Xantphos (62 mg, 0.11 mmol), tert-butylcarbamate (34 mg, 0.29 mmol), and Cs2CO3 (260 mg, 0.8-0 mmol) was purged with N2 for 5 minutes and heated to 100°C for 18 hours. The mixture was filtered through Celite®, concentrated under vacuum, and then purified by silica gel column chromatography eluting with a gradient of 0-80% siRNA in cyclohexane to obtain the title compound (120 mg, quantitative). 1H NMR (400 MHz, CDCl3) δ 10.97 (s, 1H), 8.12 (d, J=8.8 Hz, 1H), 7.68 (d, J=2.0 Hz, 1H), 7.38 (dd, J=2.1, 8.8 Hz, 1H), 7.24 - 7.17 (m, 3H), 7.11 - 7.08 (m, 1H), 6.76 (s, 1H), 2.77 - 2.70 (m, 1H), 2.14 - 2.08 (m, 1H), 2.00 - 1.93 (m, 1H), 1.56 - 1.50 (m, 10H).

[0260] Synthesis of 7-amino-2-((1S,2S)-2-(3-chlorophenyl)cyclopropyl)quinazoline-4(3H)-one TFA (2.0 mL) was added to a mixture of tert-butyl(2-((1S,2S)-2-(3-chlorophenyl)cyclopropyl)-4-oxo-3,4-dihydroquinazolin-7-yl)carbamate (200 mg, 0.48 mmol) in CHCl3 (2 mL). The reaction mixture was heated to 70°C under microwave conditions for 30 minutes. The mixture was treated with NaHCO3 (saturated aqueous solution) and then extracted by DCM. The combined organic matter was passed through a hydrophobic cartridge and then concentrated under vacuum to obtain the title compound (124 mg, 82%). ESI-MS (M+H)+: 312.3

[0261] Synthesis of 1-(2-(((2-((1S,2S)-2-(3-chlorophenyl)cyclopropyl)-4-oxo-3,4-dihydroquinazoline-7-yl)amino)methyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-yl)-3-methylimidazolidin-2,4-dione Ti(OiPr)4 (0.079 mL, 0.27 mmol) was added to a mixture of 7-amino-2-((1S,2S)-2-(3-chlorophenyl)cyclopropyl)quinazoline-4(3H)-one (84 mg, 0.27 mmol) and 6-cyclopropyl-8-(3-methyl-2,4-dioxoimidazolidine-1-yl)imidazo[1,2-a]pyridine-2-carbaldehyde (80 mg, 0.27 mmol) in DCM (0.5 mL) and MeOH (0.5 mL), and the mixture was heated to 50°C for 18 hours. The reaction mixture was cooled to room temperature, and NaCNBH3 (34 mg, 0.27 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours, then diluted with water, filtered through Celite®, and concentrated under vacuum. The residue was dissolved in DCM, washed with water, then brine, passed through a hydrophobic cartridge, and then concentrated under vacuum. The residue was purified by silica gel column chromatography eluting under a gradient of 0-10% 7N NH3 (in MeOH) in DCM, followed by preparative HPLC to obtain the title compound (8 mg, 5%). ESI-MS (M+H)+: 594.4, 1 H NMR (400 MHz, DMSO) δ 11.85 (s, 1H), 8.25 (d, J=1.1 Hz, 1H), 7.74 - 7.71 (m, 2H), 7.36 - 7.26 (m, 4H), 7.18 - 7.11 (m, 2H), 6.79 (dd, J=2.3, 8.8 Hz, 1H), 6.51 (d, J=2.1 Hz, 1H), 4.92 (s, 2H), 4.46 (d, J=5.5 Hz, 2H), 2.97 (s, 3H), 2.56 - 2.53 (m, 1H), 2.21 - 2.15 (m, 1H), 1.97 - 1.90 (m, 1H), 1.77 - 1.72 (m, 1H), 1.53 (dd, J=4.3, 14.7 Hz, 1H), 0.96 - 0.91 (m, 2H), 0.66 - 0.62 (m, 2H).

[0262] The compounds listed in Table 2 were synthesized using rac-(1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropane-1-carboxylic acid and methyl 4-amino-6-chloronicotinate, following the same procedure as described above. [Table 2] The compounds in Table 3 were synthesized using rac-(1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropane-1-carboxylic acid and methyl 2-amino-4-bromobenzoate, following the same procedure as described above. [Table 3]

[0263] Example 9 Synthesis of 1-(6-cyclopropyl-2-(((2-(2-(4-methylpyrimidine-2-yl)cyclopropyl)-4-oxo-1,4-dihydropyrido[3,2-d]pyrimidine-7-yl)amino)methyl)imidazo[1,2-a]pyridine-8-yl)-3-methylimidazolidined-2,4-dione (I-9) [ka] Synthesis of rac-methyl 5-bromo-3-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropane-1-carboxamide) picolinate Oxalyl chloride (0.78 mL, 8.90 mmol) was added dropwise at 0°C to a stirred solution of rac-(1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropanecarboxylic acid (793 mg, 4.45 mmol) and DMF (0.050 mL) in THF (10 mL), and the mixture was stirred at 0°C for 30 minutes. The reaction mixture was then concentrated under vacuum. The residue was suspended in THF (20 mL), followed by the addition of methyl 3-amino-5-bromopyridine-2-carboxylate (1079 mg, 4.67 mmol), DMAP (109 mg, 0.890 mmol), and pyridine (3.6 mmol, 44.5 mmol). The mixture was heated to 70°C and stirred for 16 hours. It was then cooled to room temperature and diluted with siRNA and water. The organic matter was washed with NaHCO3 (saturated aqueous solution) and brine, dried with MgSO4, and concentrated in vacuum to obtain the title compound (1.26 g, 72%) as a black solid. ESI-MS (M+H)+: 391.2, 1 H NMR (400 MHz, CDCl3) δ 11.24 (s, 1H), 9.41 (d, J=2.0 Hz, 1H), 8.46 - 8.43 (m, 2H), 6.99 (d, J=5.1 Hz, 1H), 4.02 (s, 3H), 2.92 - 2.86 (m, 1H), 2.49 (s, 3H), 2.39 - 2.34 (m, 1H), 1.80 - 1.71 (m, 2H).

[0264] Synthesis of rac-5-bromo-3-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropane-1-carboxamide)picolinamide rac-methyl 5-bromo-3-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropane-1-carboxamide) picolinate (1.26 g, 3.22 mmol) was suspended in 7N NH3 (26 mL) in MeOH and stirred at 65°C for 18 hours. The reaction mixture was cooled to room temperature and concentrated under vacuum to obtain the title compound (1.2 g, 67%). ESI-MS (M+H)+: 376.1, 1H NMR (400 MHz, CDCl3) δ 12.18 (s, 1H), 9.39 (d, J=2.0 Hz, 1H), 8.43 (d, J=5.1 Hz, 1H), 8.26 (d, J=2.0 Hz, 1H), 8.00 - 8.00 (m, 1H), 6.97 (d, J=5.4 Hz, 1H), 5.56 (s, 1H), 2.88 - 2.83 (m, 1H), 2.47 (s, 3H), 2.39 - 2.34 (m, 1H), 1.78 - 1.69 (m, 2H).

[0265] Synthesis of rac-7-bromo-2-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)pyrido[3,2-d]pyrimidine-4(3H)-one NaOH (383 mg, 9.57 mmol) (azeotropically stirred three times with toluene) was added to a stirred mixture of rac-5-bromo-3-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropane-1-carboxamide)picolinamide (1200 mg, 3.19 mmol) in 1,4-dioxane (10 mL), and the reaction was stirred at 100 °C for 18 hours. The reaction was cooled to room temperature and partitioned between water and ethyl acetate. The aqueous layer was extracted with ethyl acetate (three times). The combined organic matter was dried over MgSO4 and concentrated under vacuum to obtain the title compound (0.9 g, 79%) as a grayish-white solid. ESI-MS (M+H)+: 358.1 1 H NMR (400 MHz, DMSO) δ 12.87 (s, 1H), 8.79 (d, J=2.1 Hz, 1H), 8.57 (d, J=5.1 Hz, 1H), 8.30 (d, J=2.1 Hz, 1H), 7.25 (d, J=5.0 Hz, 1H), 2.89 - 2.84 (m, 1H), 2.69 - 2.63 (m, 1H), 2.45 (s, 3H), 1.85 - 1.74 (m, 2H).

[0266] Synthesis of rac-tert-butyl(2-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)-4-oxo-3,4-dihydropyrido[3,2-d]pyrimidine-7-yl)carbamate rac-7-bromo-2-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)pyrido[3,2-d]pyrimidine-4(3H)-one (400 mg, 1.12 mmol), tert-butylcarbamate (196 mg, 1.68 mmol), Pd(OAc)2 (13 mg, 0.056 mmol), Xantphos (65 mg, 0.11 mmol), and Cs2CO3 (1092 mg, 3.35 mmol) were suspended in 1,4-dioxane (5 mL) and degassed with N2 for 5 minutes. The reaction mixture was then heated to 100 °C and stirred for 16 hours. Further addition of tert-butylcarbamate (196 mg, 1.68 mmol), Pd(OAc)2 (13 mg, 0.056 mmol), and Xantphos (65 mg, 0.11 mmol) was added, and the mixture was stirred at 100°C for a further 24 hours. The reaction mixture was cooled to room temperature and filtered through Celite®. The residue was purified by column chromatography using silica gel eluted with 0-10% MeOH in DCM to obtain the title compound (220 mg, 60%) as a yellow solid. ESI-MS (M+H)+: 395.3

[0267] Synthesis of rac-7-amino-2-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)pyrido[3,2-d]pyrimidine-4(3H)-one TFA (0.43 mL, 5.58 mmol) was added to a chloroform (6 mL) stirred solution of rac-tert-butyl(2-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)-4-oxo-3,4-dihydropyrido[3,2-d]pyrimidine-7-yl) carbamate (220 mg, 0.56 mmol) and stirred at room temperature for 16 hours. The reaction mixture was concentrated under vacuum, and the residue was loaded into an SCX cartridge and washed with a 3:1 DCM:MeOH mixture. The compound was released using 7N NH3 (in MeOH) in the DCM to obtain the title compound (150 mg), which was then removed without further purification and proceeded to the next step. ESI-MS (M+H)+: 295.2, 1 H NMR (400 MHz, DMSO) δ 8.58 - 8.55 (m, 1H), 8.09 (d, J=2.5 Hz, 1H), 7.24 (dd, J=4.8, 4.8 Hz, 2H), 6.78 (d, J=2.5 Hz, 1H), 6.28 (s, 2H), 3.18 (d, J=5.3 Hz, 1H), 2.81 - 2.75 (m, 1H), 2.58 - 2.54 (m, 1H), 2.44 (d, J=2.3 Hz, 3H), 1.83 - 1.67 (m, 2H).

[0268] Synthesis of rac-1-(6-cyclopropyl-2-(((2-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)-4-oxo-3,4-dihydropyrido[3,2-d]pyrimidine-7-yl)amino)methyl)imidazo[1,2-a]pyridine-8-yl)-3-methylimidazolidined-2,4-dione (I-9) The title compound (17.9 mg, 6%) was prepared from rac-7-amino-2-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)pyrido[3,2-d]pyrimidine-4(3H)-one and 6-cyclopropyl-8-(3-methyl-2,4-dioxoimidazolidine-1-yl)imidazo[1,2-a]pyridin-2-carbaldehyde using the same method as that used for 1-(2-(((2-((1S,2S*)-2-(3-chlorophenyl)cyclopropyl)pyrido[3,2-d]pyrimidine-4(3H)-one and 6-cyclopropyl-8-(3-methyl-2,4-dioxoimidazolidine-1-yl)imidazo[1,2-a]pyridin-2-carbaldehyde. ESI-MS (M+H): +577.4, 1 H NMR (400 MHz, DMSO) δ 12.19 (s, 1H), 8.55 (d, J=5.1 Hz, 1H), 8.28 (d, J=1.1 Hz, 1H), 8.24 (d, J=2.6 Hz, 1H), 7.81 (s, 1H), 7.44 (dd, J=6.0, 6.0 Hz, 1H), 7.37 (d, J=1.5 Hz, 1H), 7.23 (d, J=5.1 Hz, 1H), 6.81 (d, J=2.5 Hz, 1H), 4.93 (s, 2H), 4.51 (d, J=5.9 Hz, 2H), 2.99 (s, 3H), 2.80 - 2.74 (m, 1H), 2.56 (dd, J=4.5, 4.5 Hz, 1H), 2.43 (s, 3H), 1.99 - 1.92 (m, 1H), 1.77 - 1.65 (m, 2H), 0.98 - 0.93 (m, 2H), 0.69 - 0.64 (m, 2H).

[0269] Example 10 Synthesis of rac-1-(6-cyclopropyl-2-(((2-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)-4-oxo-1,4-dihydro-1,6-naphthyridine-7-yl)amino)methyl)imidazo[1,2-a]pyridine-8-yl)-3-methylimidazolidined-2,4-dione (I-10) [ka] Synthesis of rac-(1S*,2S*)-N-(5-acetyl-2-chloropyridine-4-yl)-2-(4-methylpyrimidine-2-yl)cyclopropane-1-carboxamide Oxalyl chloride (0.98 mL, 11.2 mmol) was added dropwise at 0°C to a stirred solution of 1-(4-amino-6-chloro-3-pyridyl)ethanone (1.00 g, 5.89 mmol) and DMF (0.050 mL) in THF (10 mL), and the mixture was stirred at 0°C for 30 minutes. The reaction mixture was then concentrated to dryness, suspended in THF (10 mL), and subsequently rac-(1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropane-1-carboxylic acid (1.00 g, 5.61 mmol) and pyridine (4.5 mL, 56.1 mmol) were added. The reaction mixture was then heated to 70°C and stirred for 16 hours. The reaction mixture was cooled to room temperature and diluted with ethyl acetate. The reaction mixture was washed with NaHCO3 (saturated aqueous solution) and brine. The organic matter was dried over MgSO4 and concentrated under vacuum. The residue was purified by column chromatography using silica gel eluted with 0-100% siRNA in cyclohexane to obtain the title compound (900 mg, 95%) as a pale blue solid. ESI-MS (M+H)+: 331.1, 1 H NMR (400 MHz, CDCl3) δ 12.10 - 12.05 (m, 1H), 8.85 (s, 1H), 8.76 (s, 1H), 8.44 (d, J=5.1 Hz, 1H), 6.98 (d, J=4.8 Hz, 1H), 2.91 - 2.84 (m, 1H), 2.68 (s, 3H), 2.48 (s, 3H), 2.39 - 2.33 (m, 1H), 1.81 - 1.72 (m, 2H).

[0270] Synthesis of rac-7-chloro-2-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)-1,6-naphthyrizine-4(1H)-one NaOH (435 mg, 10.9 mmol) (azeotropically distilled three times with toluene) was added to a stirred suspension of rac-(1S*,2S*)-N-(5-acetyl-2-chloropyridine-4-yl)-2-(4-methylpyrimidine-2-yl)cyclopropane-1-carboxamide (900 mg, 2.72 mmol) in 1,4-dioxane (20 mL). The reaction mixture was then heated to 100°C for 1 hour. The mixture was diluted with water and extracted with ethyl acetate. The organic matter was washed with NaHCO3 (saturated aqueous solution), then brine, dried over MgSO4, and then concentrated under vacuum to obtain the title compound (400 mg, 87%) as a pale yellow solid. ESI-MS (M+H)+: 313.1, 1 ¹H NMR (400 MHz, DMSO) δ 11.92 (s, 1H), 8.95 (s, 1H), 8.58 (d, J=5.1 Hz, 1H), 7.44 (s, 1H), 7.25 (d, J=5.4 Hz, 1H), 6.08 (s, 1H), 2.73 - 2.67 (m, 1H), 2.45 (s, 3H), 1.86 - 1.72 (m, 2H). The 1H signal is obscured by the DMSO signal.

[0271] Synthesis of rac-7-chloro-2-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)-4-((2-(trimethylsilyl)ethoxy)methoxy)-1,6-naphthyridine NaHMDS (1 M in THF, 1.2 mL, 1.25 mmol) was added dropwise to a stirred suspension of rac-7-chloro-2-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)-1,6-naphthyrizine-4(1H)-one (390 mg, 1.25 mmol) in DMF (3.00 mL) at room temperature, and the mixture was stirred for 10 minutes. Then, SEM-Cl (0.22 mL, 1.25 mmol) was added, and the reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was quenched with water and then extracted with ethyl acetate. The combined organic matter was washed with NaHCO3 (saturated aqueous solution) and brine, dried over MgSO4, and concentrated under vacuum. The residue was purified by column chromatography on silica gel eluted with 0-100% ethyl acetate in cyclohexane to obtain the title compound (300 mg, 54%) as an orange oil. ESI-MS (M+H)+: 443.3, 1 H NMR (400 MHz, CDCl3) δ 9.26 (s, 1H), 8.46 (d, J=5.1 Hz, 1H), 7.75 (s, 1H), 7.03 (s, 1H), 6.97 (d, J=5.1 Hz, 1H), 5.48 (d, J=1.8 Hz, 2H), 3.85 - 3.78 (m, 2H), 3.05 - 2.98 (m, 1H), 2.88 - 2.78 (m, 1H), 2.49 (s, 3H), 2.06 - 1.90 (m, 2H), 1.01 - 0.95 (m, 2H), 0.00 (s, 9H).

[0272] Synthesis of rac-tert-butyl(2-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)-4-((2-(trimethylsilyl)ethoxy)methoxy)-1,6-naphthyrizine-7-yl)carbamate rac-7-chloro-2-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)-4-((2-(trimethylsilyl)ethoxy)methoxy)-1,6-naphthirizine (300 mg, 0.68 mmol), tert-butylcarbamate (119 mg, 1.02 mmol), Pd(OAc)2 (7.6 mg, 0.034 mmol), Xantphos (39 mg, 0.068 mmol), and Cs2CO3 (662 mg, 2.03 mmol) were suspended in 1,4-dioxane (5.0 mL) and purged with N2 for 5 minutes. The reaction mixture was then heated to 100°C and stirred for 1 hour. The mixture was filtered through Celite® and then concentrated under vacuum. The residue was purified by column chromatography using silica gel eluted with 0-100% siRNA in cyclohexane to obtain the title compound (300 mg, 84%) as a white solid. ESI-MS (M+H)+: 524.4, 1 H NMR (400 MHz, CDCl3) δ 9.14 (s, 1H), 8.44 (d, J=5.1 Hz, 1H), 8.23 ​​(s, 1H), 7.40 (s, 1H), 6.94 (d, J=5.1 Hz, 1H), 6.86 (s, 1H), 5.44 (d, J=1.9 Hz, 2H), 3.83 - 3.78 (m, 2H), 2.99 - 2.94 (m, 1H), 2.78 - 2.72 (m, 1H), 2.47 (s, 3H), 2.08 - 2.03 (m, 1H), 1.90 - 1.84 (m, 1H), 1.46 (s, 9H), 1.43 - 1.40 (m, 1H), 1.30 - 1.21 (m, 1H), 1.00 - 0.95 (m, 2H), -0.01 (s, 9H).

[0273] Synthesis of rac-7-amino-2-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)-1,6-naphthyrizine-4(1H)-one TFA (0.44 mL, 5.73 mmol) was added to a solution of rac-tert-butyl(2-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)-4-((2-(trimethylsilyl)ethoxy)methoxy)-1,6-naphthyrizin-7-yl)carbamate (300 mg, 0.573 mmol) in CHCl3 (4.00 mL), and the resulting solution was stirred at room temperature for 4 hours. The reaction product was concentrated under vacuum. The residue was loaded into an SCX cartridge, washed with DCM in MeOH, and eluted with 7N NH3 (in MeOH) in DCM to obtain the title compound (100 mg, 60%) as a pale orange solid. ESI-MS (M+H)+: 294.2, 1 H NMR (400 MHz, DMSO) δ 11.14 (s, 1H), 8.63 (s, 1H), 8.57 (d, J=5.1 Hz, 1H), 7.24 (d, J=5.0 Hz, 1H), 6.39 (s, 2H), 6.22 (s, 1H), 5.64 (d, J=1.8 Hz, 1H), 2.62 - 2.57 (m, 1H), 2.45 (s, 4H), 1.75 - 1.66 (m, 2H).

[0274] Synthesis of rac-1-(6-cyclopropyl-2-(((2-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)-4-oxo-1,4-dihydro-1,6-naphthyridine-7-yl)amino)methyl)imidazo[1,2-a]pyridine-8-yl)-3-methylimidazolidined-2,4-dione Ti(OiPr)4 (0.20 mL, 0.682 mmol) was added to a stirred solution of rac-7-amino-2-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)-1,6-naphthyrizine-4(1H)-one (40 mg, 0.136 mmol) and 6-cyclopropyl-8-(3-methyl-2,4-dioxo-imidazolidin-1-yl)imidazo[1,2-a]pyridine-2-carbaldehyde (41 mg, 0.136 mmol) in a 1:1 mixture of MeOH (2.0 mL) and DCM (2.0 mL). The mixture was then heated in a sealed tube at 50°C for 12 hours. The reaction product was cooled to room temperature. NaCNBH3 (30 mg, 0.477 mmol) was added, and the mixture was then stirred at room temperature for 18 hours. The reaction mixture was diluted with water (1.0 mL), filtered through Celite®, and concentrated under vacuum. The residue was purified by column chromatography using silica gel eluted by 0-10% 7N NH3 (in MeOH) in DCM, followed by preparative HPLC, to obtain the title compound (10.6 mg, 12%). ESI-MS (M+H): +576.4, 1 H NMR (400 MHz, DMSO) δ 11.15 (s, 1H), 8.70 (s, 1H), 8.56 (d, J=5.1 Hz, 1H), 8.24 (d, J=1.1 Hz, 1H), 7.69 (s, 1H), 7.48 (dd, J=6.0, 6.0 Hz, 1H), 7.34 (d, J=1.5 Hz, 1H), 7.23 (d, J=5.1 Hz, 1H), 6.28 (s, 1H), 5.67 (s, 1H), 4.91 (s, 2H), 4.57 (d, J=5.9 Hz, 2H), 2.99 (s, 3H), 2.61 - 2.56 (m, 1H), 2.46 - 2.41 (m, 4H), 1.98 - 1.90 (m, 1H), 1.75 - 1.64 (m, 2H), 0.97 - 0.92 (m, 2H), 0.67 - 0.62 (m, 2H).

[0275] Examples 11-13 Synthesis of rac-1-(6-cyclopropyl-2-(((2-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)-4-oxo-1,4-dihydroquinoline-7-yl)amino)methyl)imidazo[1,2-a]pyridine-8-yl)-3-methylimidazolidined-2,4-dione (I-11) [ka] Synthesis of rac-(1S*,2S*)-N-(2-acetyl-5-chlorophenyl)-2-(4-methylpyrimidine-2-yl)cyclopropane-1-carboxamide Oxalyl chloride (0.71 mL, 5.61 mmol) was added dropwise at 0°C to a stirred solution of 1-(2-amino-4-bromophenyl)ethane-1-one (631 mg, 2.95 mmol) and DMF (0.050 mL) in THF (20 mL), and the mixture was stirred at 0°C for 30 minutes. The reaction mixture was then concentrated to dryness. The residue was suspended in THF (20 mL), followed by the addition of rac-(1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropane-1-carboxylic acid (500 mg, 2.81 mmol) and pyridine (2.3 mL, 28.1 mmol). The reaction mixture was then heated to 70°C and stirred for 16 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, and then washed with NaHCO3 (saturated aqueous solution) and brine. The organic matter was dried over MgSO4 and concentrated under vacuum. The residue was purified by column chromatography using silica gel eluted with 0-100% acetyl in cyclohexane to obtain the title compound (890 mg, 80%). ESI-MS (M+H)+: 376.1, 1H NMR (400 MHz, DMSO) δ 11.52 - 11.50 (m, 1H), 8.57 - 8.55 (m, 1H), 8.50 - 8.48 (m, 1H), 7.93 - 7.90 (m, 1H), 7.46 - 7.43 (m, 1H), 7.26 - 7.23 (m, 1H), 2.60 - 2.59 (m, 4H), 2.45 - 2.44 (m, 3H), 2.37 - 2.31 (m, 1H), 1.61 - 1.56 (m, 2H). From ED01395-188

[0276] Synthesis of rac-7-bromo-2-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline-4(1H)-one NaOH (435 mg, 10.9 mmol) (azeotropically distilled three times with toluene) was added to a stirred suspension of rac-(1S*,2S*)-N-(2-acetyl-5-bromophenyl)-2-(4-methylpyrimidine-2-yl)cyclopropane-1-carboxamide (890 mg, 2.38 mmol) in 1,4-dioxane (15 mL). The reaction mixture was then heated to 100 °C, stirred for 1 hour, cooled to room temperature, and quenched with NH4Cl (saturated aqueous solution). The resulting precipitate was filtered, washed with water, and dried under vacuum to obtain the title compound (680 mg, 87%) as a brown solid. ESI-MS (M+H)+: 358.1, 1 ¹H NMR (400 MHz, DMSO) δ 8.59 - 8.57 (m, 1H), 7.97 - 7.94 (m, 1H), 7.75 - 7.73 (m, 1H), 7.46 - 7.42 (m, 1H), 7.26 - 7.24 (m, 1H), 5.96 (s, 1H), 2.71 - 2.66 (m, 1H), 2.46 (s, 3H), 1.83 - 1.71 (m, 2H). 1H disappears (presumably under the DMSO peak), and no interchangeable 1H is observed.

[0277] Synthesis of rac-tert-butyl(2-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)-4-oxo-1,4-dihydroquinoline-7-yl)carbamate rac-7-bromo-2-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline-4(1H)-one (340 mg, 0.954 mmol), tert-butylcarbamate (168 mg, 1.43 mmol), Pd(OAc)2 (21 mg, 0.095 mmol), Xantphos (110 mg, 0.191 mmol), and Cs2CO3 (933 mg, 2.86 mmol) were suspended in 1,4-dioxane (10 mL) and purged with N2 for 5 minutes. The reaction mixture was then heated to 100 °C and stirred for 1 hour. The mixture was filtered through Celite®, concentrated under vacuum, and the residue was purified by column chromatography on silica gel eluted with 0-10% DCM in MeOH to obtain the title compound (150 mg, purity approximately 60%). This was then moved on to the next step without further refinement. ESI-MS (M+H)+: 393.3

[0278] Synthesis of rac-7-amino-2-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline-4(1H)-one TFA (0.35 mL, 4.59 mmol) was added to a chloroform (4.00 mL) stirred solution of rac-tert-butyl(2-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)-4-oxo-1,4-dihydroquinoline-7-yl)carbamate (60%, 150 mg, 0.229 mmol) and stirred at room temperature for 30 minutes. The reaction mixture was concentrated under vacuum. The residue was loaded into an SCX cartridge and washed with 3:1 DCM:MeOH, and eluted with 7N NH3 (in MeOH) in DCM to obtain 100 mg of the desired product with a purity of approximately 60%. This substance was purified by silica gel column chromatography eluting with a gradient of 0 to 100% siRNA in cyclohexane to obtain the title compound (50 mg, 43%) as an orange solid. ESI-MS (M+H)+: 293.3,1 ¹H NMR (400 MHz, DMSO) δ 11.03 (s, 1H), 8.56 (d, J=5.1 Hz, 1H), 7.68 (d, J=8.7 Hz, 1H), 7.23 (d, J=5.0 Hz, 1H), 6.53 (dd, J=2.1, 8.7 Hz, 1H), 6.46 (d, J=2.0 Hz, 1H), 5.82 (s, 2H), 5.58 (d, J=1.8 Hz, 1H), 2.58 - 2.54 (m, 1H), 2.45 (s, 3H), 1.71 - 1.66 (m, 2H). 1H is obscured by the DMSO signal.

[0279] Synthesis of rac-1-(6-cyclopropyl-2-(((2-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)-4-oxo-1,4-dihydroquinoline-7-yl)amino)methyl)imidazo[1,2-a]pyridine-8-yl)-3-methylimidazolidin-2,4-dione Ti(OiPr)4 (0.25 mL, 0.855 mmol) was added to a stirred solution of rac-7-amino-2-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline-4(1H)-one (50 mg, 0.171 mmol, 1.00 equivalent) and 6-cyclopropyl-8-(3-methyl-2,4-dioxoimidazolidine-1-yl)imidazo[1,2-a]pyridine-2-carbaldehyde (51 mg, 0.171 mmol, 1.00 equivalent) in a 1:1 mixture of MeOH (2.0 mL) and DCM (2.0 mL). The reaction mixture was then heated in a sealed tube at 50°C for 5 hours. Good conversion to imines was shown by LC-MS. The reaction mixture was cooled to room temperature. NaCNBH3 (38 mg, 0.599 mmol) was added, and the reaction mixture was stirred at room temperature for 1 hour. The mixture was quenched with water (1.0 mL) and filtered through Celite®. It was washed with MeOH (3 × 5 mL) and concentrated to obtain the crude residue. The residue was purified by column chromatography on silica gel eluted by 0-20% 7N NH3 (in MeOH) in DCM, followed by preparative HPLC, to obtain the title compound (28 mg, 28%) as a mixture of enantiomers. ESI-MS (M+H)+: 575.4, 1 H NMR (400 MHz, DMSO) δ 11.03 (s, 1H), 8.55 (d, J=5.0 Hz, 1H), 8.26 - 8.25 (m, 1H), 7.74 - 7.70 (m, 2H), 7.34 (d, J=1.6 Hz, 1H), 7.22 (d, J=5.1 Hz, 1H), 6.99 - 6.95 (m, 1H), 6.70 (dd, J=2.1, 8.9 Hz, 1H), 6.45 (d, J=2.1 Hz, 1H), 5.61 (d, J=1.6 Hz, 1H), 4.92 (s, 2H), 4.45 - 4.41 (m, 2H), 2.99 (s, 3H), 2.44 - 2.43 (m, 4H), 1.98 - 1.90 (m, 1H), 1.71 - 1.62 (m, 2H), 0.97 - 0.91 (m, 2H), 0.67 - 0.62 (m, 2H). The 1H peak is absent, suggesting it is below the DMSO peak.

[0280] Enantiomer of 1-(6-cyclopropyl-2-(((2-(2-(4-methylpyrimidine-2-yl)cyclopropyl)-4-oxo-1,4-dihydroquinoline-7-yl)amino)methyl)imidazo[1,2-a]pyridin-8-yl)-3-methylimidazolidin-2,4-dione (i.e., 1-(6-cyclopropyl-2-(((2-((1S,2S)-2-(4-methylpyrimidine-2-yl)cyclopropyl)-4-oxo-1,4-dihydro The following were obtained by SFC separation (LUX Cellulose-4 21.2×250mm, 5um 45 / 55 EtOH (0.1% DEA) / CO2, 100 mL / min, 120 bar, 40℃) of doroquinoline-7-yl)amino)methyl)imidazo[1,2-a]pyridine-8-yl)-3-methylimidazolidin-2,4-dione):

[0281] First isomer to elute: (4.4 mg) (Example 12, I-12) ESI-MS (M+H)+: 575.4, 1H NMR (400 MHz, DMSO) δ 11.03 (s, 1H), 8.55 (d, J=5.1 Hz, 1H), 8.26 (d, J=1.1 Hz, 1H), 7.72 (d, J=8.6 Hz, 1H), 7.70 (s, 1H), 7.34 (d, J=1.5 Hz, 1H), 7.22 (d, J=5.1 Hz, 1H), 6.97 (dd, J=5.8, 5.8 Hz, 1H), 6.70 (dd, J=2.1, 8.9 Hz, 1H), 6.45 (d, J=2.0 Hz, 1H), 5.62 (s, 1H), 4.92 (s, 2H), 4.43 (d, J=5.5 Hz, 2H), 2.99 (s, 3H), 2.56 - 2.54 (m, 1H), 2.43 (s, 4H), 1.98 - 1.90 (m, 1H), 1.71 - 1.62 (m, 2H), 0.97 - 0.91 (m, 2H), 0.67 - 0.62 (m, 2H).エナンチオマーRT = 20.7

[0282] Chapter 2: Dissolved heterosexual body: (4.4 mg) (Example 13, I-13) ESI-MS (M+H)+: 575.4, 1H NMR (400 MHz, DMSO) δ 11.05 (s, 1H), 8.57 - 8.53 (m, 1H), 8.26 (d, J=1.4 Hz, 1H), 7.72 (d, J=8.8 Hz, 1H), 7.70 (s, 1H), 7.34 (d, J=1.5 Hz, 1H), 7.21 (d, J=5.0 Hz, 1H), 6.97 (s, 1H), 6.71 - 6.70 (m, 1H), 6.45 (d, J=1.8 Hz, 1H), 5.61 (s, 1H), 4.92 (s, 2H), 4.42 (d, J=5.6 Hz, 2H), 2.99 (s, 3H), 2.58 - 2.55 (m, 1H), 2.43 (s, 4H), 1.98 - 1.90 (m, 1H), 1.70 - 1.65 (m, 2H), 0.97 - 0.91 (m, 2H), 0.67 - 0.62 (m, 2H). Enantiomer RT = 27.4

[0283] Example 14 Synthesis of rac-1-(6-cyclopropyl-2-(((6-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)-1,5-naphthyridine-3-yl)amino)methyl)imidazo[1,2-a]pyridine-8-yl)-3-methylimidazolidined-2,4-dione (I-14) [ka] Synthesis of 4-methyl-2-((trimethylsilyl)ethynyl)pyrimidine PdCl2(PPh3)2 (3.55 g, 5.06 mmol) was added to an N2-purged solution of 2-chloro-4-methylpyrimidine (13 g, 101.12 mmol), NEt3 (131.2 mL, 941.4 mmol), TMS-acetylene (16.8 mL, 121.35 mmol), and CuI (1.93 g, 10.11 mmol) in DMF (13 mL), and the mixture was heated to 60 °C for 18 hours. The reaction product was diluted with SiO2 and filtered through Celite®. The organic matter was washed with NaHCO3 (saturated aqueous solution, 2 × 200 mL) and brine (100 mL), dried over MgSO4, and then concentrated under vacuum. The residue was purified by column chromatography on silica gel eluted with 20-35% SiO2 in cyclohexane to obtain the title compound (6.98 g, 36%). ESI-MS (M+H)+: 191.2, 1 H NMR (400 MHz, CDCl3) δ 8.55 (d, J=5.1 Hz, 1H), 7.10 (d, J=5.1 Hz, 1H), 2.54 (s, 3H), 0.29 (s, 9H).

[0284] Synthesis of 2-ethynyl-4-methylpyrimidine TBAF (1M, 44 mL, 44.1 mmol) was added dropwise at 0°C to a chilled THF (75 mL) solution of 4-methyl-2-((trimethylsilyl)ethynyl)pyrimidine (7.00 g, 36.8 mmol), and the reaction mixture was stirred for 45 minutes. The reaction mixture was warmed to room temperature, quenched with water (75 mL), and extracted with RINKAN (3 × 200 mL). The combined organic matter was dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography on silica gel eluted with 20-85% RINKAN in cyclohexane to obtain the title compound (2.88 g, 66.3%) as a pale yellow solid. ESI-MS (M+H)+: 119.3, 1 H NMR (400 MHz, CDCl3) δ 8.57 (d, J=5.1 Hz, 1H), 7.15 (d, J=5.1 Hz, 1H), 3.11 (s, 1H), 2.55 (s, 3H).

[0285] Synthesis of (E)-4-methyl-2-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl)pyrimidine CuCl (60 mg, 0.609 mmol), Xantphos (353 mg, 0.609 mmol), and NaO t Bu (117 mg, 1.22 mmol) was suspended in THF (8.0 mL) and stirred at room temperature for 30 minutes. (BPin)2 (3.25 g, 12.8 mmol) was added to THF (4.0 mL) and the mixture was stirred at room temperature for 10 minutes. 2-Ethynyl-4-methylpyrimidine (1.44 g, 12.2 mmol) and MeOH (0.99 mL, 24.4 mmol) were added to THF (3.0 mL) and the reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was quenched with water (50 mL) and extracted with SiO2 (3 × 100 mL). The combined organic phase was washed with brine (100 mL), dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography on silica gel eluted with 0-40% SiO2 in cyclohexane to obtain the title compound (2.53 g, 76%) as a pale yellow oil. This solidified upon standing. ESI-MS (M+H)+: 247.3, 1 H NMR (400 MHz, CDCl3) δ 8.57 (d, J=5.1 Hz, 1H), 7.46 (d, J=18.2 Hz, 1H), 7.01 (m, 2H), 2.52 (s, 3H), 1.30 (s, 12H).

[0286] (E)-7-bromo-2-(2-(4-methylpyrimidine-2-yl)vinyl)-1,5-naphthyridine synthesis 7-Bromo-2-chloro-1,5-naphthyridine (470 mg, 1.93 mmol), (E)-4-methyl-2-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl)pyrimidine (475 mg, 1.93 mmol), PdCl2(PPh3)2 (68 mg, 0.0965 mmol), and K3PO4 (819 mg, 3.86 mmol) were suspended in THF (30 mL) and water (3.0 mL). The reaction mixture was then purged with N2 for 5 minutes and heated to 70°C for 1 hour. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, and then washed with NaHCO3 (saturated aqueous solution) and brine. The organic matter was dried over MgSO4 and concentrated under vacuum. The residue was purified by column chromatography using silica gel eluted with 0-100% ammonium cyclohexane to obtain the title compound (110 mg, 17%). ESI-MS (M+H)+: 327.1, 329.0, 1 H NMR (400 MHz, DMSO) δ 9.08 (d, J=2.3 Hz, 1H), 8.78 (dd, J=0.8, 2.2 Hz, 1H), 8.75 (d, J=5.1 Hz, 1H), 8.50 (d, J=8.8 Hz, 1H), 8.33 (d, J=8.8 Hz, 1H), 8.13 (d, J=16.1 Hz, 1H), 7.85 (d, J=15.7 Hz, 1H), 7.35 (d, J=5.0 Hz, 1H), 2.55 (s, 3H).

[0287] Synthesis of rac-7-bromo-2-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)-1,5-naphthyrizine NaH (60% in mineral oil, 38 mg, 0.941 mmol) was added to a stirred solution of trimethylsulfoxonium iodide (222 mg, 1.01 mmol) in DMSO (12 mL) at room temperature under nitrogen conditions, and the reaction mixture was stirred at room temperature for 1.5 hours. Next, (E)-7-bromo-2-(2-(4-methylpyrimidine-2-yl)vinyl)-1,5-naphthirizine (110 mg, 0.336 mmol) in DMSO (25 mL) was added, and the mixture was stirred at room temperature for 18 hours. The reaction mixture was quenched with NH4Cl (saturated aqueous solution) and extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO4, and concentrated under vacuum to obtain the crude title compound (100 mg), which was then proceeded to the next step without further purification. ESI-MS (M+H)+: 341.1, 343.1, 1 H NMR (400 MHz, CDCl3) δ 8.87 (d, J=2.3 Hz, 1H), 8.47 - 8.45 (m, 2H), 8.21 (d, J=8.4 Hz, 1H), 7.58 (d, J=8.8 Hz, 1H), 6.97 (d, J=5.1 Hz, 1H), 3.03 - 2.98 (m, 1H), 2.93 - 2.88 (m, 1H), 2.49 (s, 3H), 2.01 - 1.93 (m, 2H).

[0288] Synthesis of rac-tert-butyl(6-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)-1,5-naphthyrizine-3-yl)carbamate rac-7-bromo-2-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)-1,5-naphthirizine (100 mg, 0.293 mmol), tert-butylcarbamate (52 mg, 0.440 mmol), Pd(OAc)2 (3.3 mg, 0.0147 mmol), Xantphos (17 mg, 0.0293 mmol), and Cs2CO3 (286 mg, 0.879 mmol) were suspended in 1,4-dioxane (5.00 mL) and purged with N2 for 5 minutes. The reaction mixture was then heated to 100°C for 1 hour. The reaction mixture was cooled to room temperature, filtered through Celite®, and concentrated under vacuum. The residue was purified by column chromatography using silica gel eluted with 0-10% MeOH in DCM to obtain the title compound (100 mg, 80%) as a yellow solid. ESI-MS (M+H)+: 378.3, 1 H NMR (400 MHz, CDCl3) δ 8.78 (d, J=2.5 Hz, 1H), 8.45 (d, J=5.1 Hz, 1H), 8.40 - 8.37 (m, 1H), 8.14 (d, J=8.9 Hz, 1H), 7.43 (d, J=9.0 Hz, 1H), 6.95 (d, J=4.9 Hz, 1H), 6.82 (s, 1H), 3.01 - 2.95 (m, 1H), 2.90 - 2.84 (m, 1H), 2.48 (s, 3H), 2.02 - 1.83 (m, 2H), 1.57 (s, 9H).

[0289] Synthesis of rac-6-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)-1,5-naphthyrizine-3-amine TFA (0.20 mL, 2.65 mmol) was added to a chloroform (3 mL) stirred solution of rac-tert-butyl(6-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)-1,5-naphthirizine-3-yl)carbamate (100 mg, 0.265 mmol) and stirred at room temperature for 2 hours. The mixture was concentrated under vacuum, the residue was purified using an SCX cartridge, washed with 3:1 DCM (in MeOH), and eluted with 7N NH3 (in MeOH) in DCM to obtain the title compound (45 mg, 61%). ESI-MS (M+H)+: 278.2, 1 H NMR (400 MHz, CDCl3) δ 8.46 - 8.42 (m, 2H), 8.07 (d, J=8.6 Hz, 1H), 7.34 (d, J=2.5 Hz, 1H), 7.28 (s, 1H), 6.95 (d, J=5.1 Hz, 1H), 4.06 (s, 2H), 2.99 - 2.93 (m, 1H), 2.89 - 2.83 (m, 1H), 2.48 (s, 3H), 1.96 - 1.88 (m, 2H).

[0290] Synthesis of rac-1-(6-cyclopropyl-2-(((6-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)-1,5-naphthyridine-3-yl)amino)methyl)imidazo[1,2-a]pyridine-8-yl)-3-methylimidazolidin-2,4-dione Ti(OiPr)4 (0.24 mL, 0.811 mmol) was added to a stirred solution of rac-6-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)-1,5-naphthyrizine-3-amine (45 mg, 0.162 mmol) and 6-cyclopropyl-8-(3-methyl-2,4-dioxoimidazolidine-1-yl)imidazo[1,2-a]pyridine-2-carbaldehyde (48 mg, 0.162 mmol) in a 1:1 mixture of MeOH (2.0 mL) and DCM (2.0 mL). The mixture was then heated to 50°C in a sealed tube for 12 hours. The reaction was cooled to room temperature, and then NaCNBH3 (36 mg, 0.568 mmol) was added. The mixture was then stirred at room temperature for 18 hours, quenched with water (1 mL), filtered through Celite®, and concentrated under vacuum. The residue was purified by silica gel column chromatography eluting 0-10% 7N NH3 (in MeOH) in DCM, followed by preparative HPLC, to obtain the title compound (14.7 mg, 16%). ESI-MS (M+H)+: 560.4, 1 H NMR (400 MHz, DMSO) δ 8.55 - 8.50 (m, 2H), 8.25 (s, 1H), 8.00 (d, J=8.3 Hz, 1H), 7.81 (s, 1H), 7.37 - 7.34 (m, 2H), 7.16 (dd, J=4.7, 4.7 Hz, 2H), 7.03 (d, J=2.3 Hz, 1H), 4.93 (s, 2H), 4.51 (d, J=5.6 Hz, 2H), 2.97 (s, 3H), 2.73 (dd, J=7.1, 7.1 Hz, 2H), 2.40 (s, 3H), 1.97 - 1.89 (m, 1H), 1.80 - 1.70 (m, 2H), 0.96 - 0.89 (m, 2H), 0.64 (q, J=5.2 Hz, 2H).

[0291] The compounds in Table 4 were synthesized from (E)-4-methyl-2-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl)pyrimidine and 7-bromo-2-chloro-1,6-naphthiridine using the same method as rac-1-(6-cyclopropyl-2-(((6-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)-1,5-naphthiridine-3-yl)amino)methyl)imidazo[1,2-a]pyridin-8-yl)-3-methylimidazolidined-2,4-dione. [Table 4]

[0292] Examples 16-17 rac-1-(2-(((6-(2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline-3-yl)amino)methyl)imidazo[1,2-a]pyridine-8-yl)imidazolidin-2,4-dione (I-16) and Synthesis of rac-1-(2-((methyl(6-(2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline-3-yl)amino)methyl)imidazo[1,2-a]pyridine-8-yl)imidazolidin-2,4-dione (I-17) [ka] Synthesis of tert-butyl(6-bromoquinoline-3-yl)carbamate 6-bromo-3-iodoquinoline (1.00 g, 2.99 mmol), tert-butylcarbamate (0.35 g, 2.99 mmol), Xantphos (0.69 g, 1.20 mmol), Cs2CO3 (2.93 g, 8.98 mmol), and Pd2(dba)3 (0.55 g, 0.60 mmol) were purged with N2 in 1,4-dioxane (5.0 mL) and stirred overnight at 100°C. The mixture was filtered through Celite® and concentrated under vacuum. The residue was purified by column chromatography on silica gel eluted with 0-100% siRNA in cyclohexane to obtain the title compound (0.55 g, 51%) as a grayish-white solid. ESI-MS (M+H)+: 323.1, 325.0, 1 H NMR (400 MHz, DMSO) δ 9.98 (s, 1H), 8.88 - 8.86 (m, 1H), 8.48 (s, 1H), 8.21 (d, J=2.1 Hz, 1H), 7.89 - 7.85 (m, 1H), 7.73 - 7.69 (m, 1H), 1.54 (s, 9H)

[0293] Synthesis of tert-butyl(E)-(6-(2-(4-methylpyrimidine-2-yl)vinyl)quinoline-3-yl)carbamate tert-butyl(6-bromoquinoline-3-yl)carbamate (540 mg, 1.67 mmol), (E)-4-methyl-2-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl)pyrimidine (411 mg, 1.67 mmol), PdCl2(PPh3)2 (59 mg, 0.0835 mmol), and K3PO4 (709 mg, 3.34 mmol) were suspended in THF (30 mL) and H2O (3.0 mL). The mixture was purged with N2 and then heated to 70°C for 18 hours. The mixture was then cooled to room temperature, diluted with ethyl acetate, and washed with NaHCO3 (saturated aqueous solution) and then brine. The organic matter was passed through a hydrophobic frit and concentrated under vacuum. The residue was purified by column chromatography using silica gel eluted with 0-100% siRNA in cyclohexane to obtain the title compound (420 mg, 56%) as a pale yellow solid. ESI-MS (M+H)+: 363.3, 1 H NMR (400 MHz, CDCl3) 8.62 - 8.59 (m, 2H), 8.51 - 8.48 (m, 1H), 8.12 (d, J=16.1 Hz, 1H), 8.03 - 8.00 (m, 1H), 7.95 - 7.89 (m, 2H), 7.34 (d, J=15.9 Hz, 1H), 7.03 - 7.00 (m, 1H), 6.73 (s, 1H), 2.58 (s, 3H), 1.58 (s, 9H).

[0294] Synthesis of rac-tert-butyl(6-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline-3-yl)carbamate and rac-tert-butylmethyl(6-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline-3-yl)carbamate NaH (60% of mineral oil, 62 mg, 1.55 mmol) was added to a stirred solution of trimethylsulfoxonium iodide (364 mg, 1.66 mmol) in DMSO (5.0 mL) at room temperature over 1.5 hours. Tert-butyl(E)-(6-(2-(4-methylpyrimidine-2-yl)vinyl)quinoline-3-yl)carbamate (200 mg, 0.552 mmol) in DMSO (5.0 mL) was added, and the mixture was stirred at room temperature for 18 hours. A mixture of sodium hydride (60% of mineral oil, 22 mg, 0.552 mmol) and trimethylsulfoxonium iodide (121 mg, 0.552 mmol) in DMSO (5.0 mL) (which had been stirred at room temperature for 1 hour beforehand) was added to the reaction mixture, and the resulting mixture was heated to 60°C over 3 hours. The mixture was quenched with NH4Cl (saturated aqueous solution) and extracted with siRNA. The combined organic matter was passed through hydrophobic frit and then concentrated under vacuum. The residue was purified by silica gel column chromatography eluting with 0-100% siRNA in cyclohexane to obtain a mixture of the title compound (90 mg), which was used without further purification.

[0295] Synthesis of rac-6-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline-3-amine and rac-N-methyl-6-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline-3-amine TFA (0.037 mL, 0.478 mmol) was added to a mixture of rac-tert-butyl(6-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline-3-yl)carbamate and rac-tert-butylmethyl(6-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline-3-yl)carbamate (90 mg) in DCM (5.0 mL). The reaction mixture was stirred at room temperature for 3 hours. The mixture was quenched with NaHCO3 (saturated aqueous solution) and extracted with DCM. The combined organic matter was passed through a hydrophobic frit and then concentrated under vacuum to obtain a mixture of the title compound (85 mg) as a brown solid, which was used without further purification.

[0296] Synthesis of rac-1-(6-cyclopropyl-2-(((6-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline-3-yl)amino)methyl)imidazo[1,2-a]pyridine-8-yl)-3-methylimidazolidin-2,4-dione and rac-1-(6-cyclopropyl-2-((methyl(6-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline-3-yl)amino)methyl)imidazo[1,2-a]pyridine-8-yl)-3-methylimidazolidin-2,4-dione A crude mixture of rac-6-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline-3-amine and rac-N-methyl-6-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline-3-amine (90 mg, 0.310 mmol), 6-cyclopropyl-8-(3-methyl-2,4-dioxoimidazolidine-1-yl)imidazo[1,2-a]pyridine-2-carbaldehyde (111 mg, 0.372 mmol), and Ti(OiPr)4 (0.092 mL, 0.310 mmol) in DCM (0.50 mL) and MeOH (0.50 mL) was stirred in a sealed tube at 50°C for 18 hours. The reaction mixture was cooled to room temperature, and NaCNBH3 (39 mg, 0.620 mmol) was added. The mixture was stirred at room temperature for 2 hours, then diluted with water (1 mL), filtered through Celite®, and concentrated under vacuum. The residue was purified by preparative HPLC to obtain the title compound.

[0297] rac-1-(6-cyclopropyl-2-(((6-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline-3-yl)amino)methyl)imidazo[1,2-a]pyridine-8-yl)-3-methylimidazolidined-2,4-dione (4.8 mg, 2%) ESI-MS (M+H)+: 559.3, 1H NMR (400 MHz, DMSO) δ 8.54 - 8.49 (m, 2H), 8.25 (d, J=1.1 Hz, 1H), 7.80 (s, 1H), 7.71 - 7.68 (m, 1H), 7.44 (d, J=1.9 Hz, 1H), 7.36 (d, J=1.5 Hz, 1H), 7.19 - 7.15 (m, 2H), 7.07 (d, J=2.6 Hz, 1H), 6.83 (t, J=5.8 Hz, 1H), 4.96 - 4.95 (m, 2H), 4.47 (d, J=5.8 Hz, 2H), 3.00 - 2.99 (m, 3H), 2.61 - 2.57 (m, 1H), 2.50 - 2.47 (m, 1H), 2.43 - 2.42 (m, 3H), 1.98 - 1.90 (m, 1H), 1.77 - 1.71 (m, 1H), 1.65 - 1.59 (m, 1H), 0.97 - 0.91 (m, 2H), 0.67 - 0.62 (m, 2H).

[0298] rac-1-(6-cyclopropyl-2-((methyl(6-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline-3-yl)amino)methyl)imidazo[1,2-a]pyridine-8-yl)-3-methylimidazolidinedion-2,4-dione (3.7 mg, 2%) ESI-MS (M+H)+: 573.4, 1H NMR (400 MHz, DMSO) δ 8.78 (d, J=3.0 Hz, 1H), 8.55 (s, 1H), 8.19 (d, J=1.0 Hz, 1H), 7.74 - 7.70 (m, 2H), 7.53 (d, J=1.9 Hz, 1H), 7.37 (d, J=1.5 Hz, 1H), 7.30 (d, J=2.6 Hz, 1H), 7.25 - 7.18 (m, 2H), 4.89 (s, 2H), 4.82 (s, 2H), 3.19 (s, 3H), 2.97 (s, 3H), 2.64 - 2.58 (m, 1H), 2.43 (s, 3H), 1.95 - 1.88 (m, 1H), 1.79 - 1.73 (m, 1H), 1.66 - 1.61 (m, 1H), 0.95 - 0.89 (m, 2H), 0.65 - 0.60 (m, 2H). The cPr CH signal is obscured by the DMSO signal.

[0299] Example 18 Synthesis of 1-(2-(((2-((1S,2S)-2-(3-chlorophenyl)cyclopropyl)-4-methoxy-1,6-naphthyrizin-7-yl)amino)methyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-yl)-3-methylimidazolidin-2,4-dione (I-18) [ka] Synthesis of 1-(6-chloro-4-((2,4-dimethoxybenzyl)amino)pyridine-3-yl)ethane-1-one (2,4-dimethoxyphenyl)methaneamine (0.47 mL, 3.16 mmol) was added dropwise at 0°C to a cooled mixture of 1-(4,6-dichloropyridine-3-yl)ethane-1-one (400 mg, 2.11 mmol) and NEt3 (0.44 mL, 3.16 mmol) in MeCN (10 mL). The mixture was warmed to room temperature and stirred for 18 hours. Water was added, and the mixture was extracted with ethyl acetate. The combined organic matter was passed through a hydrophobic frit and then concentrated under vacuum to obtain the title compound (420 mg, 62%). ESI-MS (M+H)+: 321, 1 H NMR (400 MHz, CDCl3) δ 9.47 - 9.44 (m, 1H), 8.58 (s, 1H), 7.10 (d, J=8.3 Hz, 1H), 6.66 (s, 1H), 6.49 (d, J=2.3 Hz, 1H), 6.44 (dd, J=2.5, 8.3 Hz, 1H), 4.34 (d, J=5.8 Hz, 2H), 3.86 (s, 3H), 3.80 (s, 3H), 2.57 (s, 3H).

[0300] Synthesis of 1-(4-amino-6-chloropyridine-3-yl)ethane-1-one TFA (1.0 mL, 1.31 mmol) was added to a solution of 1-(6-chloro-4-((2,4-dimethoxybenzyl)amino)pyridine-3-yl)ethane-1-one (420 mg, 1.31 mmol) in DCM (20 mL), and the mixture was stirred at room temperature for 18 hours. NaHCO3 (saturated aqueous solution) was added, and the mixture was extracted with DCM. The combined organic matter was passed through a hydrophobic frit and then concentrated under vacuum to obtain the title compound (260 mg, quantitative). 1 1H NMR (400 MHz, DMSO): δ, 8.69 (s, 1H), 6.79 (s, 1H), 2.59 (s, 3H). 2H(NH2) has disappeared.

[0301] Synthesis of (1S,2S)-N-(5-acetyl-2-chloropyridine-4-yl)-2-(3-chlorophenyl)cyclopropane-1-carboxamide Oxalyl chloride (0.44 mL, 5.09 mmol) was added dropwise at 0°C to a cooled and stirred solution of (1S,2S)-2-(4-methylpyrimidine-2-yl)cyclopropanecarboxylic acid (1.00 g, 5.09 mmol) and DMF (0.050 mL) in THF (25 mL), and the mixture was stirred at 0°C for 30 minutes. The reaction mixture was then concentrated under vacuum. The residue was suspended in THF (20 mL), and 1-(2-amino-4-bromophenyl)ethanone (87 mg, 5.09 mmol) and pyridine (1.2 mL, 15.26 mmol) were added. The mixture was then heated to 70°C for 18 hours. The mixture was cooled to room temperature and quenched with water (50 mL). The resulting precipitate was filtered, washed with water, and dried to obtain the title compound (860 mg, 48%). 1 H NMR (400 MHz, DMSO) δ 11.74 (s, 1H), 9.00 (s, 1H), 8.46 (s, 1H), 7.33 - 7.20 (m, 4H), 2.67 (s, 3H), 2.56 - 2.53 (m, 1H), 2.35 - 2.29 (m, 1H), 1.60 - 1.48 (m, 2H).

[0302] Synthesis of 7-chloro-2-((1S,2S)-2-(3-chlorophenyl)cyclopropyl)-1,6-naphthyrizine-4(1H)-one NaOH (229 mg, 5.73 mmol) (azeotropically stirred three times with toluene) was added to a stirred suspension of (1S,2S)-N-(5-acetyl-2-chloropyridine-4-yl)-2-(3-chlorophenyl)cyclopropane-1-carboxamide (500 mg, 1.43 mmol) in 1,4-dioxane (5 mL). The reaction mixture was heated at 100 °C for 1 hour. The reaction mixture was cooled to room temperature and poured into NH4Cl (saturated aqueous solution, 50 mL). The resulting precipitate was filtered and dried to obtain the title compound (450 mg, 94%). 1H NMR (400 MHz, DMSO) δ 11.90 (s, 1H), 8.93 (s, 1H), 7.47 (s, 1H), 7.37 - 7.32 (m, 2H), 7.29 - 7.21 (m, 2H), 6.02 (s, 1H), 2.57 - 2.54 (m, 1H), 2.33 - 2.21 (m, 1H), 1.83 - 1.76 (m, 1H), 1.72 - 1.66 (m, 1H).

[0303] Synthesis of 7-chloro-2-((1S,2S)-2-(3-chlorophenyl)cyclopropyl)-4-methoxy-1,6-naphthyridine MeI (0.093 mL, 1.49 mmol) was added to a stirred mixture of 7-chloro-2-((1S,2S)-2-(3-chlorophenyl)cyclopropyl)-1,6-naphthyrizine-4(1H)-one (450 mg, 1.36 mmol) and K2CO3 (376 mg, 2.71 mmol) in DMF (5.0 mL). The reaction mixture was heated to 50°C for 1 hour. The reaction mixture was cooled to room temperature, diluted with water, and then extracted with ethyl acetate. The combined organic matter was dried over MgSO4 and concentrated under vacuum to obtain the title compound (185 mg, 39%), which was used in the next step without further purification. 1 H NMR (400 MHz, DMSO) δ 9.22 (s, 1H), 7.80 (s, 1H), 7.37 - 7.23 (m, 5H), 4.10 (s, 3H), 2.75 - 2.64 (m, 2H), 2.01 - 1.93 (m, 1H), 1.75 - 1.69 (m, 1H).

[0304] Synthesis of N-(2-((1S,2S)-2-(3-chlorophenyl)cyclopropyl)-4-methoxy-1,6-naphthyrizin-7-yl)-1,1-diphenylmethanymine Xantphos (124 mg, 0.214 mmol), benzophenone imine (0.099 mL, 0.589 mmol), Cs2CO3 (524 mg, 1.61 mmol), and Pd2(dba)3 (98 mg, 0.107 mmol) were added to a solution of 7-chloro-2-((1S,2S)-2-(3-chlorophenyl)cyclopropyl)-4-methoxy-1,6-naphthirizine (185 mg, 0.536 mmol) in 1,4-dioxane (5 mL). The solution was degassed with N2 and heated at 100°C for 18 hours. The mixture was allowed to cool to room temperature, filtered through Celite®, and concentrated under vacuum. The residue was purified by silica gel column chromatography eluted with 0-50% siRNA in cyclohexane to obtain the title compound (60 mg, 21%) as a grayish-white solid. ESI-MS (M+H)+: 490.3, 1 H NMR (400 MHz, CDCl3) 9.20 (s, 1H), 7.85 - 7.80 (m, 2H), 7.51 - 7.38 (m, 4H), 7.07 - 7.03 (m, 8H), 6.94 - 6.94 (m, 1H), 6.54 (s, 1H), 4.00 - 3.99 (m, 3H), 2.65 - 2.59 (m, 1H), 2.33 - 2.28 (m, 1H), 1.97 - 1.92 (m, 1H), 1.54 - 1.48 (m, 1H).

[0305] Synthesis of 2-((1S,2S)-2-(3-chlorophenyl)cyclopropyl)-4-methoxy-1,6-naphthyridine-7-amine HCl (1M aqueous solution, 1.2 mL, 1.22 mmol) was added to a THF (1 mL) stirred solution of N-(2-((1S,2S)-2-(3-chlorophenyl)cyclopropyl)-4-methoxy-1,6-naphthyridine-7-yl)-1,1-diphenylmethaneimine (60 mg, 0.122 mmol), and the reaction mixture was stirred at 0°C for 30 minutes. The reaction mixture was quenched with NaHCO3 (saturated aqueous solution) and extracted by DCM. The organic matter was passed through hydrophobic frit and concentrated under vacuum. The residue was purified by silica gel column chromatography eluting with 0-10% 7N NH3 (in MeOH) in DCM to obtain the title compound (40 mg, quantitative). ESI-MS (M+H)+: 326.1 1 H NMR (400 MHz, CDCl3) δ 9.05 (s, 1H), 7.09 - 7.05 (m, 4H), 6.74 - 6.74 (m, 1H), 6.44 (s, 1H), 4.56 (s, 2H), 4.01 (s, 3H), 2.67 - 2.62 (m, 1H), 2.33 - 2.27 (m, 1H), 2.00 - 1.95 (m, 1H), 1.53 - 1.49 (m, 1H).

[0306] Synthesis of 1-(2-(((2-((1S,2S)-2-(3-chlorophenyl)cyclopropyl)-4-methoxy-1,6-naphthyrizin-7-yl)amino)methyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-yl)-3-methylimidazolidin-2,4-dione Ti(OiPr)4 (0.036 mL, 0.123 mmol) was added to a stirred solution of 2-((1S,2S)-2-(3-chlorophenyl)cyclopropyl)-4-methoxy-1,6-naphthyrizine-7-amine (40 mg, 0.123 mmol) and 6-cyclopropyl-8-(3-methyl-2,4-dioxoimidazolidine-1-yl)imidazo[1,2-a]pyridine-2-carbaldehyde (44 mg, 0.147 mmol) in DCM (0.50 mL) and MeOH (0.50 mL). The mixture was stirred in a sealed tube at 50°C for 16 hours and then cooled to room temperature. NaCNBH3 (15 mg, 0.246 mmol) was added and the mixture was stirred at room temperature for 2 hours. The reaction product was diluted with water (1.0 mL), filtered through Celite®, and then concentrated under vacuum. The residue was purified by preparative HPLC to obtain the title compound (6.5 mg, 9%). ESI-MS (M+H)+: 608.2, 1 H NMR (400 MHz, DMSO) δ 8.93 (s, 1H), 8.25 - 8.24 (m, 1H), 7.72 (s, 1H), 7.36 - 7.19 (m, 6H), 6.80 (s, 1H), 6.54 (s, 1H), 4.94 (s, 2H), 4.59 (d, J=5.9 Hz, 2H), 4.00 (s, 3H), 2.99 (s, 3H), 2.59 - 2.55 (m, 1H), 1.96 - 1.90 (m, 1H), 1.87 - 1.81 (m, 1H), 1.58 - 1.52 (m, 1H), 0.97 - 0.91 (m, 2H), 0.67 - 0.62 (m, 2H).

[0307] Example 19 Synthesis of rac-N-((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)-2-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline-7-amine(I-19) [ka] Synthesis of (E)-7-bromo-2-(2-(4-methylpyrimidine-2-yl)vinyl)quinoline (E)-4-methyl-2-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl)pyrimidine (500 mg, 2.0 mmol), 7-bromo-2-chloroquinoline (490 mg, 2.0 mmol), Pd(PPh3)2Cl2 (71 mg, 0.10 mmol), and K3PO4 (860 mg, 4.1 mmol) were mixed in THF (20 mL) and water (2.0 mL) and degassed with N2 for 5 minutes, then stirred at 70°C for 3 hours. The reaction mixture was cooled to room temperature, diluted with ELISA (100 mL), and then washed with NaHCO3 (saturated aqueous solution, 100 mL) and brine (saturated aqueous solution, 150 mL). The combined organic layers were dried over MgSO4 and concentrated under vacuum. The residue was purified by silica gel column chromatography using a gradient of 0-100% acetyl in cyclohexane to obtain the title compound (300 mg, 45%). ESI-MS (M+H)+: 326.0, 327.9, 1 H NMR (400 MHz, DMSO) δ 8.72 (d, J=5.1 Hz, 1H), 8.45 (d, J=8.6 Hz, 1H), 8.25 (d, J=1.8 Hz, 1H), 8.10 - 8.05 (m, 2H), 7.97 (d, J=8.8 Hz, 1H), 7.81 - 7.74 (m, 2H), 7.31 (d, J=5.1 Hz, 1H), 2.53 (s, 3H).

[0308] Synthesis of rac-7-bromo-2-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline To a solution of trimethylsulfoxonium iodide (200 mg, 0.92 mmol) in DMSO (2.5 mL), NaH (60% in mineral oil, 34 mg, 0.86 mmol) was added, and the reaction mixture was stirred at room temperature for 1.5 hours. (E)-7-bromo-2-(2-(4-methylpyrimidine-2-yl)vinyl)quinoline (100 mg, 0.31 mmol) was heated in DMSO (2.5 mL) until dissolved, and then added to the reaction mixture. The mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with NH4Cl (saturated aqueous solution, 50 mL), and then diluted with HCl (20 mL). The mixture was extracted with HCl (3 × 50 mL), and the combined organic layers were dried over MgSO4 and concentrated under vacuum. The residue was purified by column chromatography on silica gel eluting with a gradient of 0 to 100% HCl in cyclohexane to obtain the title compound (35 mg, 34%). ESI-MS (M+H)+: 340.0, 341.9, 1 H NMR (400 MHz, CDCl3) δ 8.45 (d, J=5.1 Hz, 1H), 8.16 (d, J=2.0 Hz, 1H), 7.97 (d, J=8.6 Hz, 1H), 7.60 (d, J=8.8 Hz, 1H), 7.52 (dd, J=2.0, 8.6 Hz, 1H), 7.32 (d, J=8.6 Hz, 1H), 6.95 (d, J=5.1 Hz, 1H), 3.01 - 2.95 (m, 1H), 2.90 - 2.84 (m, 1H), 2.48 (s, 3H), 2.01 - 1.89 (m, 2H).

[0309] Synthesis of rac-N-((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)-2-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline-7-amine A mixture of rac-7-bromo-2-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline (35 mg, 0.10 mmol), (6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methanamine (23 mg, 0.12 mmol), rac-BINAP (6.4 mg, 0.01 mmol), Pd2(dba)3 (4.7 mg, 0.005 mmol), and KOtBu (23 mg, 0.21 mmol) in toluene (3.0 mL) was degassed with N2 for 5 minutes and stirred at 90°C for 4 hours. The reaction mixture was cooled to room temperature, filtered through Celite®, and concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting under a gradient of 0-20% 7N NH3 (in MeOH) in DCM, followed by preparative HPLC, to obtain the title compound (13 mg, 28%). ESI-MS (M+H)+: 447.4, 1 H NMR (400 MHz, DMSO) δ 8.53 (d, J=5.1 Hz, 1H), 8.33 - 8.31 (m, 1H), 7.92 (d, J=8.2 Hz, 1H), 7.71 (s, 1H), 7.58 (d, J=8.9 Hz, 1H), 7.42 (d, J=9.4 Hz, 1H), 7.19 (d, J=5.0 Hz, 1H), 7.12 (d, J=8.3 Hz, 1H), 7.06 (dd, J=2.3, 8.9 Hz, 1H), 6.99 (dd, J=1.8, 9.3 Hz, 1H), 6.80 - 6.76 (m, 2H), 4.48 (d, J=5.8 Hz, 2H), 2.76 - 2.65 (m, 2H), 2.42 (s, 3H), 1.95 - 1.88 (m, 1H), 1.80 - 1.70 (m, 2H), 0.94 - 0.88 (m, 2H), 0.70 - 0.65 (m, 2H).

[0310] Example 20 Synthesis of rac-N-((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)-4-methoxy-2-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline-7-amine(I-20) [ka] Synthesis of methyl 2-acetamido-4-bromobenzoate Ac2O (8.0 mL, 85 mmol) was added to a solution of methyl 2-amino-4-bromobenzoate (13 g, 56 mmol) in toluene (150 mL), and the mixture was stirred at 80°C for 18 hours. The mixture was cooled to room temperature and concentrated under vacuum. The residue was washed with cyclohexane and toluene (10:1), and concentrated under vacuum to obtain the title compound (13 g, 85%). ESI-MS (M+H)+: 274.0, 1 H NMR (400 MHz, CDCl3) δ 11.06 (s, 1H), 8.97 (d, J=2.0 Hz, 1H), 7.87 (d, J=8.6 Hz, 1H), 7.21 (dd, J=1.9, 8.5 Hz, 1H), 3.93 (s, 3H), 2.24 (s, 3H).

[0311] Synthesis of 7-bromo-4-hydroxyquinoline-2(1H)-one A suspension of methyl 2-acetamido-4-bromobenzoate (10 g, 37 mmol) in THF (100 mL) was added to KHMDS solution (1.0 M in THF, 110 mL, 110 mmol) at -78°C. The reaction mixture was stirred at -78°C for 1 hour and then warmed to room temperature. The reaction mixture was quenched with water (150 mL) and washed with siRNA (200 mL). The aqueous phase was acidified with HCl (2.0 M aqueous solution) until a precipitate formed. The precipitate was collected by filtration, washed with siRNA, and then dried under high vacuum for 24 hours to obtain the title compound (4.6 g, 52%). ESI-MS (M+H)+: 240.0, 242.0, 1H NMR (400 MHz, DMSO) δ 11.00 - 10.95 (m, 1H), 7.75 (d, J=8.3 Hz, 1H), 7.44 (d, J=1.8 Hz, 1H), 7.28 (dd, J=1.9, 8.5 Hz, 1H), 5.58 (s, 1H).

[0312] Synthesis of 7-bromo-4-methoxyquinoline-2(1H)-one A mixture of 7-bromo-4-hydroxyquinoline-2(1H)-one (6.6 g, 27 mmol) and K2CO3 (7.5 g, 55 mmol) in acetone (120 mL) was stirred under reflux for 3 hours. Dimethyl sulfate (2.6 mL, 27 mmol) was added, and the suspension was stirred under reflux for 3 hours. The reaction mixture was cooled to room temperature and quenched with water (150 mL). The reaction mixture was concentrated to remove the acetone, and the remaining aqueous mixture was filtered. The collected precipitate was washed with water under high vacuum for 18 hours to obtain the title compound (5.6 g, 81%). ESI-MS (M+H)+: 254.0, 256.0, 1 H NMR (400 MHz, DMSO) δ 11.45 - 11.39 (m, 1H), 7.69 (d, J=8.6 Hz, 1H), 7.46 (d, J=1.8 Hz, 1H), 7.32 (dd, J=2.0, 8.6 Hz, 1H), 5.92 (s, 1H), 3.92 (s, 3H).

[0313] Synthesis of 7-bromo-2-chloro-4-methoxyquinoline A mixture of 7-bromo-4-methoxyquinoline-2(1H)-one (5.5 g, 22 mmol) in POCl3 (10 mL, 110 mmol) was stirred at 80°C for 2 hours. The reaction mixture was diluted with toluene (10 mL) and stirred at 80°C for 2 hours. The reaction mixture was cooled to room temperature and concentrated under vacuum. The residue was washed with water (50 mL), basicized with NaHCO3 (saturated aqueous solution), and extracted with toluene (3 × 100 mL). The combined organic layers were passed through hydrophobic frit and concentrated under vacuum to obtain the title compound (5.1 g, 86%). ESI-MS (M+H)+: 273.9,1 H NMR (400 MHz, DMSO) δ 8.13 (d, J=1.9 Hz, 1H), 8.06 (d, J=8.9 Hz, 1H), 7.77 (dd, J=2.0, 8.9 Hz, 1H), 7.19 (s, 1H), 4.11 (s, 3H).

[0314] Synthesis of (E)-7-bromo-4-methoxy-2-(2-(4-methylpyrimidine-2-yl)vinyl)quinoline (E)-4-methyl-2-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl)pyrimidine (500 mg, 2.0 mmol), 7-bromo-2-chloro-4-methoxyquinoline (550 mg, 2.0 mmol), Pd(PPh3)2Cl2 (71 mg, 0.10 mmol), and K3PO4 (860 mg, 4.1 mmol) were mixed in THF (20 mL) and water (2.0 mL) and degassed with N2 for 5 minutes, then stirred at 70°C for 8 hours. The reaction mixture was cooled to room temperature, diluted with ELISA (100 mL), and washed with NaHCO3 (saturated aqueous solution, 100 mL). The organic layer was dried over MgSO4 and concentrated under vacuum. The residue was purified by silica gel column chromatography using a gradient of 0-100% acetyl in cyclohexane to obtain the title compound (200 mg, 28%). ESI-MS (M+H)+: 356.1, 358.1, 1 H NMR (400 MHz, CDCl3) δ 8.62 (d, J=5.0 Hz, 1H), 8.22 (d, J=1.6 Hz, 1H), 8.15 (d, J=16.2 Hz, 1H), 8.02 (d, J=8.8 Hz, 1H), 7.71 (d, J=15.4 Hz, 1H), 7.56 (dd, J=1.9, 8.8 Hz, 1H), 7.09 (s, 1H), 7.04 (d, J=5.0 Hz, 1H), 4.08 (s, 3H), 2.58 (s, 3H).

[0315] Synthesis of rac-7-bromo-4-methoxy-2-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline To a solution of trimethylsulfoxonium iodide (370 mg, 1.7 mmol) in DMSO (5.0 mL), NaH (60% in mineral oil, 63 mg, 1.6 mmol) was added, and the reaction mixture was stirred at room temperature for 1.5 hours. A mixture of (E)-7-bromo-4-methoxy-2-(2-(4-methylpyrimidine-2-yl)vinyl)quinoline (200 mg, 0.56 mmol) in DMSO (3.0 mL) was added dropwise to the reaction mixture. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was quenched with NH4Cl (saturated aqueous solution, 80 mL) and extracted with ethyl acetate (3 × 100 mL). The combined organic layers were 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 with a gradient of 0 to 100% ethyl acetate in cyclohexane to obtain the title compound (50 mg, 24%). ESI-MS (M+H)+: 370.1, 372.1, 1 H NMR (400 MHz, CDCl3) δ 8.45 (d, J=5.1 Hz, 1H), 8.08 (d, J=1.6 Hz, 1H), 7.96 (d, J=8.9 Hz, 1H), 7.47 (dd, J=1.9, 8.8 Hz, 1H), 6.95 (d, J=5.1 Hz, 1H), 6.67 (s, 1H), 4.00 (s, 3H), 2.98 - 2.93 (m, 1H), 2.87 - 2.79 (m, 1H), 2.48 (s, 3H), 2.00 - 1.86 (m, 2H).

[0316] Synthesis of rac-N-((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)-4-methoxy-2-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline-7-amineformate A mixture of rac-7-bromo-4-methoxy-2-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline (50 mg, 0.14 mmol), (6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methanamine hydrochloride (36 mg, 0.16 mmol), rac-BINAP (8.4 mg, 0.01 mmol), Pd2(dba)3 (6.2 mg, 0.008 mmol), and KOtBu (45 mg, 0.41 mmol) in toluene (3.0 mL) was degassed with N2 for 5 minutes and stirred at 90°C for 16 hours. The reaction mixture was cooled to room temperature, filtered through Celite®, and concentrated under vacuum. The residue was purified by silica gel column chromatography eluting under a gradient of 0-20% 7N NH3 (in MeOH) in DCM, followed by preparative HPLC, to obtain the title compound (5.0 mg, 8%). ESI-MS (M+H)+: 477.3, 1 H NMR (400 MHz, DMSO) δ 8.51 (d, J=5.1 Hz, 1H), 8.45 (s, 1H), 8.30 (d, J=0.4 Hz, 1H), 7.73 (d, J=9.0 Hz, 1H), 7.68 (s, 1H), 7.40 (d, J=9.2 Hz, 1H), 7.17 (d, J=5.1 Hz, 1H), 6.99 - 6.94 (m, 2H), 6.73 - 6.69 (m, 3H), 4.44 (d, J=5.9 Hz, 2H), 3.94 (s, 3H), 2.74 - 2.61 (m, 2H), 2.41 (s, 3H), 1.92 - 1.88 (m, 1H), 1.80 - 1.65 (m, 2H), 0.92 - 0.87 (m, 2H), 0.68 - 0.63 (m, 2H).

[0317] Examples 21-23 Synthesis of rac-1-(6-cyclopropyl-2-(((4-methoxy-2-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline-7-yl)amino)methyl)imidazo[1,2-a]pyridine-8-yl)-3-methylimidazolidin-2,4-dione (I-21) [ka] Synthesis of rac-tert-butyl(4-methoxy-2-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline-7-yl)carbamate A suspension of rac-7-bromo-4-methoxy-2-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline (70 mg, 0.19 mmol), tert-butylcarbamate (24 mg, 0.21 mmol), Xantphos (44 mg, 0.08 mmol), and Cs2CO3 (190 mg, 0.57 mmol) in 1,4-dioxane (3.0 mL) was degassed with N2 for 10 minutes. Pd2(dba)3 (35 mg, 0.04 mmol) was added, and the reaction mixture was stirred at 100°C for 16 hours. The reaction mixture was cooled to room temperature, filtered through Celite®, and concentrated under vacuum. The residue was purified by column chromatography on silica gel eluted in cyclohexane with a gradient of 0 to 100% ethyl acetate to obtain the title compound (91 mg, quantitative). ESI-MS (M+H)+: 407.4, 1 H NMR (400 MHz, CDCl3) δ 8.44 (d, J=5.0 Hz, 1H), 8.02 (d, J=8.9 Hz, 1H), 7.70 (d, J=2.1 Hz, 1H), 7.63 (d, J=9.2 Hz, 1H), 6.94 (d, J=5.0 Hz, 1H), 6.65 (s, 1H), 6.56 (s, 1H), 3.99 (s, 3H), 2.96 - 2.77 (m, 2H), 2.47 (s, 3H), 2.00 - 1.94 (m, 1H), 1.88 - 1.82 (m, 1H), 1.55 (s, 9H).

[0318] Synthesis of rac-4-methoxy-2-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline-7-amine rac-tert-butyl(4-methoxy-2-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline-7-yl)carbamate (91 mg, 0.22 mmol) and TFA (0.34 mL, 4.5 mmol) were dissolved in CHCl3 (2.0 mL), the mixture was stirred at room temperature for 1.5 hours, and then concentrated under vacuum. The residue was washed with NaHCO3 (saturated aqueous solution, 25 mL) and extracted with DCM (3 × 40 mL). The combined organic matter was dried over MgSO4 and concentrated under vacuum to obtain the title compound (62 mg, 90%), which was used without further purification. ESI-MS (M+H)+: 307.2, 1 H NMR (400 MHz, CDCl3) δ 8.44 (d, J=5.1 Hz, 1H), 7.90 (d, J=8.8 Hz, 1H), 7.05 (d, J=2.1 Hz, 1H), 6.93 (d, J=5.1 Hz, 1H), 6.82 (dd, J=2.3, 8.8 Hz, 1H), 6.43 (s, 1H), 3.95 (s, 2H), 2.94 - 2.77 (m, 2H), 2.47 (s, 3H), 1.95 - 1.82 (m, 2H).

[0319] Synthesis of rac-1-(6-cyclopropyl-2-(((4-methoxy-2-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline-7-yl)amino)methyl)imidazo[1,2-a]pyridine-8-yl)-3-methylimidazolidin-2,4-dione Ti(iPrO)4 (0.30 mL, 1.0 mmol) was added to a solution of rac-4-methoxy-2-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline-7-amine (62 mg, 0.20 mmol) and 6-cyclopropyl-8-(3-methyl-2,4-dioxoimidazolidine-1-yl)imidazo[1,2-a]pyridine-2-carbaldehyde (60 mg, 0.20 mmol) in DCM (3.0 mL) and MeOH (3.0 mL). The reaction mixture was stirred in a sealed vial at 50°C for 16 hours. The reaction mixture was cooled to room temperature, diluted with MeOH (1.0 mL), and NaCNBH3 was added (45 mg, 0.71 mmol). The reaction mixture was stirred at room temperature for 40 minutes. The reaction mixture was quenched with water (1.0 mL), diluted with MeOH (5.0 mL), filtered through Celite® using MeOH (3 × 3.0 mL), and concentrated under vacuum. The residue was purified by silica gel column chromatography eluting under a gradient of 0–10% 7N NH3 (in MeOH) in DCM, followed by preparative HPLC, to obtain the title compound (41 mg, 38%) as a mixture of enantiomers. ESI-MS (M+H)+: 589.4, 1 H NMR (400 MHz, DMSO) δ 8.53 (d, J=5.0 Hz, 1H), 8.27 (s, 1H), 7.78 - 7.73 (m, 2H), 7.36 (s, 1H), 7.19 (d, J=5.0 Hz, 1H), 6.98 (d, J=9.0 Hz, 1H), 6.78 - 6.73 (m, 3H), 4.96 (s, 2H), 4.48 (d, J=5.4 Hz, 2H), 3.96 (s, 3H), 2.99 (s, 3H), 2.74 - 2.70 (m, 1H), 2.68 - 2.63 (m, 1H), 2.42 (s, 3H), 1.97 - 1.91 (m, 1H), 1.81 - 1.77 (m, 1H), 1.71 - 1.67 (m, 1H), 0.96 - 0.92 (m, 2H), 0.66 (d, J=5.0 Hz, 2H).

[0320] The mixture was SFC (YMC Cellulose-C 10×250mm, 5μm 55 / 45 Separation using MeOH (0.1% DEA) / CO2, 15 mL / min, 120 bar, 40°C) yielded two enantiomers: 1-(6-cyclopropyl-2-(((4-methoxy-2-((1S,2S)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline-7-yl)amino)methyl)imidazo[1,2-a]pyridin-8-yl)-3-methylimidazolidin-2,4-dione and 1-(6-cyclopropyl-2-(((4-methoxy-2-((1R,2R)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline-7-yl)amino)methyl)imidazo[1,2-a]pyridin-8-yl)-3-methylimidazolidin-2,4-dione.

[0321] The first isomer to elute (Example 22, I-22) ESI-MS (M+H)+: 589.6, 1 H NMR (400 MHz, DMSO) δ 8.51 (d, J=5.1 Hz, 1H), 8.25 (d, J=1.1 Hz, 1H), 7.74 (d, J=8.3 Hz, 2H), 7.35 (d, J=1.5 Hz, 1H), 7.17 (d, J=5.1 Hz, 1H), 6.96 (dd, J=2.3, 9.0 Hz, 1H), 6.74 - 6.70 (m, 3H), 4.94 (s, 2H), 4.46 (d, J=5.4 Hz, 2H), 3.94 (s, 3H), 2.97 (s, 3H), 2.73 - 2.61 (m, 2H), 2.40 (s, 3H), 1.96 - 1.89 (m, 1H), 1.80 - 1.65 (m, 2H), 0.95 - 0.89 (m, 2H), 0.66 - 0.61 (m, 2H). RT=2.64 minutes, 100%ee.

[0322] The second isomer to elute (Example 23, I-23) ESI-MS (M+H)+: 589.5, 1H NMR (400 MHz, DMSO) δ 8.44 (d, J=5.1 Hz, 1H), 8.18 (d, J=1.1 Hz, 1H), 7.67 (d, J=8.4 Hz, 2H), 7.28 (d, J=1.5 Hz, 1H), 7.10 (d, J=5.0 Hz, 1H), 6.90 (dd, J=2.3, 9.0 Hz, 1H), 6.67 - 6.64 (m, 3H), 4.88 (s, 2H), 4.39 (d, J=5.4 Hz, 2H), 3.87 (s, 3H), 2.91 (s, 3H), 2.67 - 2.54 (m, 2H), 2.34 (s, 3H), 1.90 - 1.82 (m, 1H), 1.73 - 1.58 (m, 2H), 0.89 - 0.83 (m, 2H), 0.60 - 0.55 (m, 2H). RT=8.46 minutes, 100% ee.

[0323] Example 24 Synthesis of rac-1-(6-cyclopropyl-2-(((3-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline-6-yl)amino)methyl)imidazo[1,2-a]pyridine-8-yl)-3-methylimidazolidin-2,4-dione (I-24) [ka] Synthesis of 6-bromo-3-iodoquinoline NIS (3.2 g, 14 mmol) was gradually added to a stirred solution of 6-bromoquinoline (2.0 g, 9.6 mmol) in AcOH (20 mL), and the reaction mixture was stirred at 100 °C for 16 hours. The reaction mixture was cooled to room temperature and concentrated under vacuum. The residue was dissolved in DCM (150 mL) and washed with NaHCO3 (saturated aqueous solution, 2 × 100 mL), Na2SO3 (saturated aqueous solution, 100 mL), and brine (saturated aqueous solution, 150 mL). The organic layer was dried over MgSO4 and concentrated under vacuum. The residue was purified by silica gel column chromatography eluting under a gradient of 0 to 100% ethyl acetate in cyclohexane to obtain the title compound (1.0 g, 31%) as a grayish-white solid. ESI-MS (M+H)+: 333.9, 335.9, 1 H NMR (400 MHz, CDCl3) δ 9.04 (d, J=2.0 Hz, 1H), 8.45 (d, J=1.9 Hz, 1H), 7.93 (d, J=9.0 Hz, 1H), 7.88 (d, J=2.1 Hz, 1H), 7.81 - 7.77 (m, 1H).

[0324] Synthesis of (E)-6-bromo-3-(2-(4-methylpyrimidine-2-yl)vinyl)quinoline A suspension of 6-bromo-3-iodoquinoline (1.0 g, 3.0 mmol), (E)-4-methyl-2-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl)pyrimidine (740 mg, 3.0 mmol), Pd(PPh3)2Cl2 (110 mg, 0.15 mmol), and K3PO4 (1300 mg, 6.0 mmol) in THF (30 mL) and water (3.0 mL) was degassed with N2 for 5 minutes, and the reaction mixture was stirred at 70°C for 16 hours. The reaction mixture was cooled to room temperature, diluted with ELISA (100 mL), and washed with NaHCO3 (saturated aqueous solution, 2 × 100 mL) and brine (saturated aqueous solution, 150 mL). The organic layer was dried over MgSO4 and concentrated under vacuum. The residue was purified by silica gel column chromatography using a gradient of 0-100% siRNA in cyclohexane to obtain the title compound (600 mg, 58%) as a pale yellow solid. ESI-MS (M+H)+: 326.0, 328.0, 1 H NMR (400 MHz, DMSO) δ 9.37 (d, J=2.1 Hz, 1H), 8.73 - 8.68 (m, 2H), 8.29 (d, J=2.3 Hz, 1H), 8.10 (d, J=16.5 Hz, 1H), 7.99 (d, J=8.9 Hz, 1H), 7.92 - 7.89 (m, 1H), 7.58 (d, J=16.1 Hz, 1H), 7.30 (d, J=5.0 Hz, 1H), 2.54 (s, 3H).

[0325] Synthesis of rac-6-bromo-3-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline (E)-6-bromo-3-(2-(4-methylpyrimidine-2-yl)vinyl)quinoline (420 mg, 1.3 mmol), triethylammonium bis(catecholate)iodomethyl silicate (1.9 g, 3.9 mmol), and 4CzIPN (100 mg, 0.13 mmol) were suspended in DMSO (30 mL) and degassed with N2 for 5 minutes. The stirred mixture was irradiated with a blue LED for 16 hours. The mixture was cooled to room temperature and diluted with ELISA (100 mL) and NaHCO3 (saturated aqueous solution, 100 mL). The mixture was stirred, Celite® (10 g) was added, and the mixture was filtered to obtain a two-phase mixture. The layers were separated, the organic layer 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 using a gradient of 0-100% siRNA in cyclohexane to obtain the title compound (100 mg, 23%), which was used directly in the next step without further purification. ESI-MS (M+H)+: 340.1, 342.1

[0326] Synthesis of rac-tert-butyl(3-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline-6-yl)carbamate A mixture of rac-6-bromo-3-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline (160 mg, 0.47 mmol), tert-butylcarbamate (83 mg, 0.71 mmol), Pd(OAc)2 (5.3 mg, 0.02 mmol), Xantphos (27 mg, 0.05 mmol), and Cs2CO3 (460 mg, 1.4 mmol) in 1,4-dioxane (5.0 mL) was degassed with N2 for 5 minutes. The reaction mixture was stirred at 100 °C for 1 hour. The reaction mixture was cooled to room temperature, filtered through Celite®, and concentrated under vacuum. The residue was purified by column chromatography using silica gel eluting under a gradient of 0-10% MeOH in DCM to obtain the title compound (135 mg, 51%) as a yellow solid. ESI-MS (M+H)+: 377.3

[0327] Synthesis of rac-3-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline-6-amine TFA (0.27 mL, 3.6 mmol) was added to a stirred solution of rac-tert-butyl(3-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline-6-yl)carbamate (140 mg, 0.36 mmol) in CHCl3 (3.0 mL), 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 1:3 MeOH (in DCM), and eluted with 7N NH3 (in DCM) in 1:3 MeOH to obtain the title compound (75 mg, 52%). ESI-MS (M+H)+: 277.2

[0328] Synthesis of rac-1-(6-cyclopropyl-2-(((3-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline-6-yl)amino)methyl)imidazo[1,2-a]pyridine-8-yl)-3-methylimidazolidin-2,4-dione Ti(PrO)4 (0.40 mL, 1.4 mmol) was added to a stirred solution of rac-3-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline-6-amine (75 mg, 0.27 mmol) and 6-cyclopropyl-8-(3-methyl-2,4-dioxoimidazolidine-1-yl)imidazo[1,2-a]pyridine-2-carbaldehyde (81 mg, 0.27 mmol) in MeOH (2.0 mL) and DCM (2.0 mL). The reaction mixture was stirred in a sealed tube at 50°C for 4 hours, then cooled to room temperature, and NaCNBH3 (60 mg, 0.95 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours, then quenched with water (1.0 mL), filtered through Celite®, and concentrated under vacuum. The residue was purified by silica gel column chromatography eluting under a gradient of 0-10% 7N NH3 (in MeOH) in DCM, followed by two preparative HPLC steps, to obtain the title compound (17 mg, 11%) as formate. ESI-MS (M+H): +599.4, 1 H NMR (400 MHz, DMSO) δ 8.58 (d, J=5.1 Hz, 1H), 8.46 (d, J=1.8 Hz, 1H), 8.30 (s, 1H), 7.82 (s, 1H), 7.77 - 7.71 (m, 2H), 7.39 (s, 1H), 7.30 - 7.22 (m, 2H), 6.80 - 6.74 (m, 2H), 4.99 (s, 2H), 4.51 (d, J=5.6 Hz, 2H), 3.04 (s, 3H), 2.67 - 2.61 (m, 1H), 2.47 (s, 3H), 2.02 - 1.94 (m, 1H), 1.82 - The peaks are 1.68 (m, 2H), 1.01 - 0.95 (m, 2H), and 0.69 (q, J=5.1 Hz, 2H). The 1H peak is obscured by the DMSO signal.

[0329] Example 25 Synthesis of rac-1-(2-(((4-(1H-imidazole-1-yl)-2-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline-7-yl)amino)methyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-yl)-3-methylimidazolidinedion-2,4-dione (I-25) [ka] Synthesis of rac-tert-butyl(2-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)-4-oxo-1,4-dihydroquinoline-7-yl)carbamate A mixture of rac-7-bromo-2-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline-4(1H)-one (3.0 g, 8.4 mmol), tert-butylcarbamate (1.5 g, 13 mmol), Pd(OAc)2 (95 mg, 0.42 mmol), Xantphos (490 mg, 0.84 mmol), and Cs2CO3 (8.2 g, 25 mmol) in 1,4-dioxane (84 mL) was degassed with N2 for 10 minutes and stirred at 90°C for 16 hours. The reaction mixture was cooled to room temperature and degassed with N2 for 10 minutes. Further addition of tert-butylcarbamate (1.5 g, 13 mmol), Pd(OAc)2 (95 mg, 0.42 mmol), and Xantphos (490 mg, 0.84 mmol) was added, and the reaction mixture was stirred at 100°C for 16 hours. The mixture was cooled to room temperature and degassed with N2. Further addition of tert-butylcarbamate (1.5 g, 13 mmol), Pd(OAc)2 (95 mg, 0.42 mmol), Xantphos (490 mg, 0.84 mmol), and Cs2CO3 (8.2 g, 25 mmol) was added, and the resulting mixture was stirred at 100°C for 16 hours. The reaction mixture was cooled to room temperature, filtered through Celite® using DCM and MeOH (9:1, 100 mL), and concentrated under vacuum. The residue was purified by column chromatography using silica gel eluted under a gradient of 0-10% MeOH in DCM to obtain the title compound (790 mg, 24%) as a creamy solid. ESI (M+H)+: 393.4,1 ¹H NMR (400 MHz, DMSO) δ values: 11.49 (s, 1H), 9.78 (s, 1H), 8.58 - 8.56 (m, 1H), 7.95 - 7.93 (m, 1H), 7.88 (d, J=8.8 Hz, 1H), 7.24 - 7.23 (m, 1H), 7.20 (q, J=3.6 Hz, 1H), 5.79 (d, J=1.8 Hz, 1H), 2.65 - 2.59 (m, 1H), 2.45 (s, 3H), 1.79 - 1.67 (m, 2H), 1.52 - 1.51 (m, 9H). One cyclopropyl signal is obscured by the DMSO signal.

[0330] Synthesis of rac-tert-butyl(4-bromo-2-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline-7-yl)carbamate PBr3 (0.28 mL, 3.0 mmol) was added dropwise to a mixture of rac-tert-butyl(2-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)-4-oxo-1,4-dihydroquinoline-7-yl)carbamate (790 mg, 2.0 mmol) in DMF (20 mL). The reaction mixture was placed under an N2 atmosphere and stirred at room temperature for 16 hours. The mixture was quenched with NaHCO3 (saturated aqueous solution, 50 mL) and extracted with ethyl acetate (3 × 100 mL). The combined organic layers were dried over MgSO4 and concentrated under vacuum. The residue was purified by column chromatography on silica gel eluted with a gradient of 5–40% ethyl acetate in cyclohexane to obtain the title compound (280 mg, 30%). 1H NMR (400 MHz, DMSO) δ 9.89 (s, 1H), 8.54 (d, J=5.1 Hz, 1H), 8.14 (d, J=1.8 Hz, 1H), 7.94 (d, J=9.1 Hz, 1H), 7.86 (s, 1H), 7.68 (dd, J=2.3, 9.1 Hz, 1H), 7.20 (d, J=5.6 Hz, 1H), 2.83 - 2.77 (m, 2H), 2.42 (s, 3H), 1.88 - 1.77 (m, 2H), 1.52 (s, 9H).

[0331] Synthesis of rac-4-(1H-imidazole-1-yl)-2-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline-7-amine A mixture of rac-tert-butyl(4-bromo-2-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline-7-yl)carbamate (75 mg, 0.17 mmol), 1H-imidazole (13 mg, 0.18 mmol), CuI (3.1 mg, 0.017 mmol), DMEDA (0.0035 mL, 0.033 mmol), and K2CO3 (46 mg, 0.33 mmol) in DMF (1.7 mL) was degassed with N2 for 15 minutes and stirred at 150°C for 12 hours under an N2 atmosphere. Further CuI (3.1 mg, 0.017 mmol) was added, the mixture was degassed with N2 for 5 minutes, and then stirred at 150°C for 4 hours. The reaction mixture was cooled to room temperature, diluted with toluene (25 mL), and washed with NaHCO3 (saturated aqueous solution, 25 mL) and brine (saturated aqueous solution, 25 mL). The combined aqueous layer was extracted with toluene (20 mL). The combined organic layer was dried over MgSO4 and concentrated under vacuum to obtain the title compound (50 mg, 89%) as a yellow, rubbery substance, which was used without further purification. ESI (M+H)+: 343.2.

[0332] Synthesis of rac-1-(2-(((4-(1H-imidazole-1-yl)-2-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline-7-yl)amino)methyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-yl)-3-methylimidazolidin-2,4-dione Ti(OiPr)4 (0.22 mL, 0.73 mmol) was added to a solution of rac-4-(1H-imidazole-1-yl)-2-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline-7-amine (50 mg, 0.15 mmol) and 6-cyclopropyl-8-(3-methyl-2,4-dioxoimidazolidine-1-yl)imidazo[1,2-a]pyridine-2-carbaldehyde (44 mg, 0.15 mmol) in MeOH (2.2 mL) and DCM (2.2 mL). The solution was sealed and stirred at 50°C for 16 hours. The reaction mixture was cooled to room temperature and NaCNBH3 (32 mg, 0.51 mmol) was added. The mixture was stirred at room temperature for 5 hours. Water (2.0 mL) was added, the mixture was filtered through Celite®, and then concentrated under vacuum. The residue was purified by silica gel column chromatography eluting under a gradient of 1-20% 7N NH3 (in MeOH) in DCM, followed by preparative HPLC, to obtain the title compound (8 mg, 9%) as a yellow lyophilized solid. ESI (M+H)+: 625.4, 1H NMR (400 MHz, DMSO) δ 8.52 (d, J=5.1 Hz, 1H), 8.27 - 8.25 (m, 1H), 8.06 - 8.05 (m, 1H), 7.77 (s, 1H), 7.62 - 7.61 (m, 1H), 7.41 (d, J=9.1 Hz, 1H), 7.35 (d, J=1.5 Hz, 1H), 7.22 (s, 1H), 7.20 - 7.11 (m, 3H), 7.06 (t, J=6.0 Hz, 1H), 6.90 (d, J=2.3 Hz, 1H), 4.94 (s, 2H), 4.52 (d, J=5.8 Hz, 2H), 2.97 (s, 3H), 2.81 - 2.72 (m, 2H), 2.41 (s, 3H), 1.97 - 1.90 (m, 1H), 1.86 - 1.72 (m, 2H), 0.96 - 0.90 (m, 2H), 0.67 - 0.62 (m, 2H).

[0333] Example 26 Synthesis of rac-1-(6-cyclopropyl-2-(((2-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)-4-(1H-1,2,4-triazole-1-yl)quinoline-7-yl)amino)methyl)imidazo[1,2-a]pyridine-8-yl)-3-methylimidazolidin-2,4-dione (I-26) [ka] Synthesis of rac-2-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)-4-(1H-1,2,4-triazole-1-yl)quinoline-7-amine A mixture of rac-tert-butyl(4-bromo-2-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline-7-yl)carbamate (63 mg, 0.14 mmol), 1,2,4-triazole (10 mg, 0.14 mmol), DEMDA (1.5 μL, 0.014 mmol), CuI (1.3 mg, 6.9 μmol), and K2CO3 (38 mg, 0.28 mmol) in DMF (3.00 mL) was placed under an N2 atmosphere and stirred at 150 °C for 16 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (50 mL), and washed with saturated aqueous solution of NaHCO3 (50 mL) and saturated aqueous solution of brine (50 mL). The combined organic layer was dried over MgSO4 and concentrated under vacuum. The residue was loaded into an SCX cartridge, washed with MeOH in DCM (1:1), eluted with 7N NH3 (in MeOH) in DCM (1:1), and concentrated under vacuum to obtain the title compound (54 mg, quantitative). ESI (M+H)+: 344.2, 1 H NMR (400 MHz, CDCl3) δ 8.51 (s, 1H), 8.45 (d, J=5.1 Hz, 1H), 8.24 - 8.22 (m, 1H), 7.71 (d, J=8.8 Hz, 1H), 7.19 (d, J=2.3 Hz, 1H), 7.11 - 7.10 (m, 1H), 6.97 - 6.92 (m, 2H), 4.21 - 4.17 (m, 2H), 3.01 - 2.94 (m, 1H), 2.89 - 2.83 (m, 1H), 2.48 (s, 3H), 2.03 - 1.96 (m, 1H), 1.95 - 1.89 (m, 1H).

[0334] Synthesis of rac-1-(6-cyclopropyl-2-(((2-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)-4-(1H-1,2,4-triazole-1-yl)quinoline-7-yl)amino)methyl)imidazo[1,2-a]pyridine-8-yl)-3-methylimidazolidin-2,4-dione Ti(OiPr)4 (0.23 mL, 0.79 mmol) was added to a mixture of rac-2-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)-4-(1H-1,2,4-triazole-1-yl)quinoline-7-amine (54 mg, 0.16 mmol) and 6-cyclopropyl-8-(3-methyl-2,4-dioxoimidazolidine-1-yl)imidazo[1,2-a]pyridine-2-carbaldehyde (47 mg, 0.16 mmol) in MeOH (2.5 mL) and DCM (2.5 mL). The reaction mixture was degassed with N2 for 10 minutes and stirred in a sealed vial at 50°C for 16 hours. The reaction mixture was cooled to room temperature, diluted with MeOH (1.0 mL), and NaCNBH3 (35 mg, 0.55 mmol) was added. The reaction mixture was stirred at room temperature for 4 hours. NaCNBH3 (35 mg, 0.55 mmol) was then added, and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with water (2.0 mL), filtered through a Celite® pad, and concentrated under vacuum. The residue was purified by preparative HPLC to obtain the title compound (19 mg, 19%) as a yellow solid. ESI (M+H)+: 626.4, 1H NMR (400 MHz, DMSO) δ 9.14 (s, 1H), 8.52 (d, J=5.0 Hz, 1H), 8.38 (s, 1H), 8.26 (d, J=1.1 Hz, 1H), 7.77 (s, 1H), 7.73 (d, J=9.2 Hz, 1H), 7.37 (s, 1H), 7.35 (d, J=1.5 Hz, 1H), 7.18 (d, J=5.1 Hz, 1H), 7.14 (dd, J=2.2, 9.2 Hz, 1H), 7.08 (t, J=6.0 Hz, 1H), 6.91 (d, J=2.0Hz, 1H), 4.94 (s, 2H), 4.52 (d, J=5.6 Hz, 2H), 2.97 (s, 3H), 2.81 - 2.74 (m, 2H), 2.41 (s, 3H), 1.95 - 1.90 (m, 1H), 1.87 - 1.83 (m, 1H), 1.79 - 1.74 (m, 1H), 0.96 - 0.90 (m, 2H), 0.66 - 0.62 (m, 2H).

[0335] Example 27 Synthesis of 1-(6-cyclopropyl-2-(((4-(1-methyl-1H-pyrazole-4-yl)-2-((1S,2S)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline-7-yl)amino)methyl)imidazo[1,2-a]pyridine-8-yl)-3-methylimidazolidin-2,4-dione (I-27) [ka] Synthesis of tert-butyl(4-(1-methyl-1H-pyrazole-4-yl)-2-((1S,2S)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline-7-yl)carbamate tert-butyl(4-bromo-2-((1S,2S)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline-7-yl)carbamate (48mg, 0.11mmol) (rac-tert-butyl(4-bromo-2-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline-7-yl)carbamate) is administered via the same route as rac-tert-butyl(4-bromo-2-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline-7-yl)carbamate, (1S,2 A mixture of (prepared from S)-2-(4-methylpyrimidine-2-yl)cyclopropane-1-carboxylic acid, 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (24 mg, 0.12 mmol), and K3PO4 (67 mg, 0.32 mmol) in dioxane (1.0 mL) and water (0.2 mL) was degassed with N2 for 5 minutes. PdCl2(dppf)2 (4.3 mg, 0.0053 mmol) was added, and the mixture was heated in a microwave reactor at 100°C for 30 minutes. The mixture was cooled to room temperature, filtered through Celite®, and then concentrated under vacuum. The residue was purified by silica gel column chromatography eluting in cyclohexane with a gradient of 0 to 100% siRNA to obtain the title compound (32 mg, 67%) as a golden rubbery substance. ESI (M+H)+: 457.5

[0336] Synthesis of 4-(1-methyl-1H-pyrazole-4-yl)-2-((1S,2S)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline-7-amine tert-butyl(4-(1-methyl-1H-pyrazole-4-yl)-2-((1S,2S)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline-7-yl)carbamate (32 mg, 0.070 mmol) was dissolved in DCM (2.0 mL) and TFA (0.4 mL) was added. The mixture was stirred for 90 minutes and then concentrated under vacuum. The residue was loaded into an SCX cartridge and washed with DCM, then 10% MeOH in DCM, eluted with 10% 7N NH3 (in MeOH) in DCM, and then concentrated under vacuum to obtain the title compound (20 mg, 80%) as a yellow solid. ESI (M+H)+: 357.3

[0337] Synthesis of 1-(6-cyclopropyl-2-(((4-(1-methyl-1H-pyrazole-4-yl)-2-((1S,2S)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline-7-yl)amino)methyl)imidazo[1,2-a]pyridine-8-yl)-3-methylimidazolidin-2,4-dione Using a procedure similar to that used for rac-1-(6-cyclopropyl-2-(((2-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)-4-(1H-1,2,4-triazole-1-yl)quinoline-7-yl)amino)methyl)imidazo[1,2-a]pyridin-8-yl)-3-methylimidazolidin-2,4-dione, the title compound was converted to 4-(1-methyl-1H-pyrazole-4 Prepared (as formate) from 6-cyclopropyl-8-(3-methyl-2,4-dioxoimidazolidine-1-yl)imidazo[1,2-a]pyridine-2-carbaldehyde (17 mg, 0.056 mmol) and then purified by preparative HPLC (19 mg, 53%). ESI (M+H)+: 639.5, 1 H NMR (400 MHz, DMSO) δ 8.53 (d, J=5.0 Hz, 1H), 8.28 - 8.18 (m, 2H), 7.91 - 7.86 (m, 2H), 7.78 (s, 1H), 7.37 (d, J=1.5 Hz, 1H), 7.20 - 7.14 (m, 2H), 7.09 (dd, J=2.4, 9.2 Hz, 1H), 6.85 - 6.83 (m, 2H), 4.97 (s, 2H), 4.52 (d, J=5.6 Hz, 2H), 3.95 (s, 3H), 2.99 (s, 3H), 2.77 - 2.65 (m, 2H), 2.43 (s, 3H), 1.98 - 1.91 (m, 1H), 1.83 - 1.69 (m, 2H), 0.97 - 0.91 (m, 2H), 0.68 - 0.63 (m, 2H).

[0338] Example 28 Synthesis of 1-(6-cyclopropyl-2-(((5-methoxy-2-((1S,2S)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline-7-yl)amino)methyl)imidazo[1,2-a]pyridine-8-yl)-3-methylimidazolidin-2,4-dione (I-28) [ka] Synthesis of 1-(6-cyclopropyl-2-(((5-methoxy-2-((1S,2S)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline-7-yl)amino)methyl)imidazo[1,2-a]pyridine-8-yl)-3-methylimidazolidin-2,4-dione [ka] Synthesis of (1S,2S)-N-methoxy-N-methyl-2-(4-methylpyrimidine-2-yl)cyclopropane-1-carboxamide Oxalyl chloride (7.3 mL, 84.2 mmol) was added dropwise at 0°C to a stirred solution of (1S,2S)-2-(4-methylpyrimidine-2-yl)cyclopropanecarboxylic acid (7.50 g, 42.1 mmol) and DMF (0.050 mL) in THF (10 mL), and the mixture was stirred at 0°C for 30 minutes. The reaction mixture was then concentrated to dryness. The residue was suspended in THF (20 mL), followed by the addition of N,O-dimethylhydroxylamine hydrochloride (4.93 g, 50.5 mmol) and pyridine (14 mL, 0.168 mol). The reaction mixture was then heated to 50°C, stirred for 3 hours, cooled to room temperature, and partitioned between water and DCM. The layers were separated, and the aqueous solution was further extracted with DCM. The combined organic matter was dried over MgSO4 and concentrated. The residue was purified by silica gel column chromatography eluting with 0-10% MeOH in DCM to obtain the title compound (7.4 g, 79%) as a brown oily substance. ESI-MS (M+H)+: 222.3, 1H NMR (400 MHz, CDCl3) δ 8.43 (d, J=5.1 Hz, 1H), 6.95 (d, J=5.1 Hz, 1H), 3.71 (s, 3H), 3.26 - 3.21 (m, 3H), 2.81 - 2.71 (m, 2H), 2.47 (s, 3H), 1.73 - 1.66 (m, 1H), 1.64 - 1.58 (m, 1H).

[0339] Synthesis of 1-((1S,2S)-2-(4-methylpyrimidine-2-yl)cyclopropyl)ethane-1-one A methylmagnesium bromide solution (3M in Et2O, 20 mL, 60.2 mmol) was added dropwise over 5 minutes at 0°C to a stirred solution of (1S,2S)-N-methoxy-N-methyl-2-(4-methylpyrimidine-2-yl)cyclopropane-1-carboxamide (7.40 g, 33.4 mmol) in THF (60 mL), and the reaction mixture was stirred at 0°C for 1 hour. The reaction mixture was warmed to room temperature and quenched with NH4Cl (saturated aqueous solution). The mixture was then extracted with ELISA (3 times). The combined organic matter was dried over MgSO4 and concentrated under vacuum. The residue was purified by silica gel column chromatography eluted with 0-100% ethyl acetate in cyclohexane to obtain the title compound (4.76 g, 81%) as a blue oil. ESI-MS (M+H)+: 177.2, 1 H NMR (400 MHz, DMSO) δ 8.50 (d, J=5.0 Hz, 1H), 7.19 (d, J=5.4 Hz, 1H), 2.58 - 2.52 (m, 2H), 2.40 (s, 3H), 2.24 (s, 3H), 1.57 - 1.48 (m, 2H).

[0340] Synthesis of 4-bromo-2-hydroxy-6-nitrobenzaldehyde 3-Bromo-5-nitrophenol (2.0 g, 9.17 mmol) and hexamethylenetetramine (2.57 g, 18.3 mmol) were suspended in TFA (10 mL, 0.131 mol) and heated in a sealed tube at 100°C for 24 hours. The reaction mixture was cooled to room temperature and poured into ice / water. The solution was then extracted with DCM (three times). The combined organic compounds were dried over MgSO4 and concentrated under vacuum. The residue was purified by silica gel column chromatography eluted with 0-100% ethyl acetate in cyclohexane to obtain the title product as a mixture of two positional isomers (1.15 g, 51%). ESI-MS (M+H)+: 244.0 / 246.0, positional isomer A 1 H NMR (400 MHz, CDCl3) δ 12.21 (s, 1H), 10.29 (s, 1H), 7.69 (d, J=1.8 Hz, 1H), 7.49 (d, J=1.5 Hz, 1H), Positional isomer B 1 H NMR (400 MHz, CDCl3) δ 12.11 (s, 1H), 10.42 (s, 1H), 7.99 (d, J=2.1 Hz, 1H), 7.78 (d, J=1.8 Hz, 1H), 1.43 (s, 1H).

[0341] Synthesis of 4-bromo-2-methoxy-6-nitrobenzaldehyde 1,8-Diazabicyclo[5.4.0]undeca-7-ene (1.4 mL, 9.35 mmol) and iodomethane (0.87 mL, 14.0 mmol) were added to a stirred solution of 4-bromo-2-hydroxy-6-nitrobenzaldehyde (1.15 g, 4.67 mmol) in acetone (20 mL). The reaction mixture was then stirred at room temperature for 16 hours. The reaction mixture was concentrated and then suspended in siRNA and NaHCO3. The aqueous layer was further extracted with siRNA. The combined organic matter was dried over MgSO4 and concentrated under vacuum. The crude residue was purified by silica gel column chromatography eluting with 0-100% siRNA in hexane to obtain a mixture of positional isomers (1.0 g, 82%). Isomer A 1H NMR (400 MHz, CDCl3) δ 10.30 (s, 1H), 7.55 (s, 1H), 7.36 (s, 1H), 3.96 (s, 3H). Isomer B 1 H NMR (400 MHz, CDCl3) δ 10.38 (s, 1H), 8.10 (d, J=1.8 Hz, 1H), 7.79 (d, J=1.8 Hz, 1H), 4.03 (s, 3H).

[0342] Synthesis of 2-amino-4-bromo-6-methoxybenzaldehyde Hydrogen chloride (2M, 10 mL, 2.00 mmol) was added to a stirred mixture of iron (322 mg, 5.77 mmol) and 4-bromo-2-methoxy-6-nitrobenzaldehyde (500 mg, 1.92 mmol) in EtOH (10 mL) and water (2.5 mL). The reaction mixture was then heated to 60°C and stirred for 5 hours. The reaction mixture was cooled to room temperature, concentrated, and the residue was diluted with DCM and NaHCO3. The aqueous layer was further extracted with DCM. The combined organic matter was dried over MgSO4 and concentrated under vacuum. The residue was purified by silica gel column chromatography with elution under a gradient of 0-10% MeOH in DCM to obtain the title compound (160 mg, 36%). ESI-MS (M+H)+: 230.1, 232.1, 1 H NMR (400 MHz, DMSO) δ 10.26 - 10.26 (m, 1H), 7.60 (s, 2H), 6.63 (d, J=1.8 Hz, 1H), 6.39 (d, J=1.5 Hz, 1H), 3.89 (s, 3H).

[0343] Synthesis of 7-bromo-5-methoxy-2-((1S,2S)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline KOH (25.4 mg, 0.45 mmol) was added to a stirred solution of 1-((1S,2S)-2-(4-methylpyrimidine-2-yl)cyclopropyl)ethane-1-one (80 mg, 0.45 mmol) and 2-amino-4-bromo-6-methoxybenzaldehyde (104 mg, 0.45 mmol) in EtOH (3.0 mL), and the mixture was stirred at 70°C for 30 minutes. The reaction mixture was cooled to room temperature and concentrated under vacuum. The residue was dissolved in DCM and washed with NaHCO3. The organic matter was dried over MgSO4 and concentrated under vacuum. The residue was purified by silica gel column chromatography eluted with 0-100% siRNA in cyclohexane to obtain the title compound (80 mg, 48%). ESI-MS (M+H)+: 370.2, 372.2, 1 H NMR (400 MHz, CDCl3) δ 8.44 (d, J=5.1 Hz, 1H), 8.33 (d, J=8.3 Hz, 1H), 7.75 (s, 1H), 7.28 (d, J=8.6 Hz, 1H), 6.94 (d, J=5.1 Hz, 1H), 6.87 - 6.84 (m, 1H), 3.97 (s, 3H), 2.99 - 2.93 (m, 1H), 2.89 - 2.82 (m, 1H), 2.47 (s, 3H), 1.99 - 1.87 (m, 2H).

[0344] Synthesis of tert-butyl(5-methoxy-2-((1S,2S)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline-7-yl)carbamate 7-Bromo-5-methoxy-2-((1S,2S)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline (80 mg, 0.216 mmol), tert-butylcarbamate (38 mg, 0.324 mmol), Pd(OAc)2 (2.4 mg, 0.011 mmol), Xantphos (13 mg, 0.022 mmol), and Cs2CO3 (211 mg, 0.648 mmol) were suspended in 1,4-dioxane (5.0 mL) and degassed for 5 minutes. The reaction mixture was then heated to 100 °C and stirred for 3 hours. The reaction mixture was cooled to room temperature, filtered through Celite®, and concentrated under vacuum. The residue was purified by silica gel column chromatography eluted with 0-100% ethyl acetate in cyclohexane to obtain the title compound (75 mg, 85%). ESI-MS (M+H)+: 407.4, 1 H NMR (400 MHz, CDCl3) δ 8.44 (d, J=5.1 Hz, 1H), 8.28 (d, J=8.6 Hz, 1H), 7.38 - 7.35 (m, 1H), 7.17 (s, 1H), 7.13 (d, J=8.6 Hz, 1H), 6.93 (d, J=5.1 Hz, 1H), 6.69 (s, 1H), 3.99 (s, 3H), 2.97 - 2.91 (m, 1H), 2.86 - 2.80 (m, 1H), 2.47 (s, 3H), 1.96 - 1.84 (m, 2H), 1.57 (s, 9H).

[0345] Synthesis of 5-Methoxy-2-((1S,2S)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline-7-amine TFA (0.14 mL, 1.85 mmol) was added to a stirred solution of tert-butyl-(5-methoxy-2-((1S,2S)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline-7-yl)carbamate (75 mg, 0.185 mmol) in CHCl3 (3 mL). The reaction was stirred at room temperature for 3 hours, then concentrated under vacuum and loaded into an SCX cartridge. This was washed with 3:1 DCM:MeOH, eluted with 7N NH3 in 3:1 DCM:MeOH, and then concentrated under vacuum to obtain the title compound (52 mg, 92%). 1 H NMR (400 MHz, DMSO) δ 8.57 (d, J=5.1 Hz, 1H), 8.10 (d, J=8.3 Hz, 1H), 7.23 (d, J=5.6 Hz, 1H), 7.07 (d, J=8.3 Hz, 1H), 6.50 (d, J=1.3 Hz, 1H), 6.43 (d, J=1.8 Hz, 1H), 5.72 (s, 2H), 4.14 (q, J=5.2 Hz, 1H), 3.92 (s, 3H), 2.79 - 2.67 (m, 2H), 2.47 (s, 3H), 1.83 - 1.74 (m, 2H).

[0346] Synthesis of 1-(6-cyclopropyl-2-(((5-methoxy-2-((1S,2S)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline-7-yl)amino)methyl)imidazo[1,2-a]pyridine-8-yl)-3-methylimidazolidin-2,4-dione Ti(iPrO)4 (0.25 mL, 0.849 mmol) was added to a stirred solution of 5-methoxy-2-((1S,2S)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline-7-amine (52 mg, 0.170 mmol) and 6-cyclopropyl-8-(3-methyl-2,4-dioxoimidazolidine-1-yl)imidazo[1,2-a]pyridine-2-carbaldehyde (51 mg, 0.170 mmol) in a 1:1 mixture of MeOH (4.0 mL) and DCM (4.0 mL). The reaction mixture was then heated in a sealed tube at 50°C for 16 hours. The reaction mixture was cooled to room temperature, NaCNBH3 (37 mg, 0.594 mmol) was added, and the reaction mixture was then stirred at room temperature for 2 hours. The reaction mixture was quenched with water (1.0 mL). Next, the reaction mixture was filtered through Celite® and then concentrated under vacuum. The residue was purified by silica gel column chromatography eluting 0-10% 7N NH3 (in MeOH) in DCM, followed by preparative HPLC, to obtain the title compound (50 mg, 46%). ESI-MS (M+H)+: 598.5, 1 H NMR (400 MHz, DMSO) δ 8.56 (d, J=5.1 Hz, 1H), 8.32 (d, J=1.0 Hz, 1H), 8.11 (d, J=8.8 Hz, 1H), 7.83 (s, 1H), 7.40 (d, J=1.5 Hz, 1H), 7.22 (d, J=5.1 Hz, 1H), 7.11 (d, J=8.6 Hz, 1H), 6.78 (dd, J=5.8, 5.8 Hz, 1H), 6.60 (d, J=1.8 Hz, 1H), 6.45 (d, J=1.5 Hz, 1H), 5.01 (s, 2H), 4.54 (d, J=5.6 Hz, 2H), 3.94 (s, 3H), 3.03 (s, 3H), 2.77 - 2.66 (m, 2H), 2.46 (s, 3H), 2.03 - 1.95 (m, 1H), 1.81 - 1.72 (m, 2H), 0.99 (ddd, J=4.3, 6.3, 8.3 Hz, 2H), 0.73 - 0.68 (m, 2H).

[0347] Example 29 Synthesis of rac-1-(6-cyclopropyl-2-(((4-(dimethylamino)-2-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline-7-yl)amino)methyl)imidazo[1,2-a]pyridine-8-yl)-3-methylimidazolidin-2,4-dione (I-29) [ka] Synthesis of rac-tert-butyl(4-(dimethylamino)-2-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline-7-yl)carbamate A mixture of rac-7-bromo-N,N-dimethyl-2-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline-4-amine (150 mg, 0.39 mmol), tert-butylcarbamate (69 mg, 0.59 mmol), Pd2(dba)3 (36 mg, 0.039 mmol), Xantphos (45 mg, 0.078 mmol), and Cs2CO3 (260 mg, 0.78 mmol) in 1,4-dioxane (4.0 mL) was degassed with N2 and heated at 100°C for 18 hours. The mixture was filtered through Celite®, then concentrated under vacuum, and purified by silica gel column chromatography eluting with 0-100% siRNA in cyclohexane to obtain the title compound (120 mg, 70%) as a yellow rubbery substance. ESI-MS (M+H)+: 420.4, 1H NMR (400 MHz, DMSO) δ 9.65 (s, 1H), 8.54 (d, J=5.1 Hz, 1H), 7.99 - 7.96 (m, 1H), 7.88 (d, J=9.2 Hz, 1H), 7.47 (dd, J=2.3, 9.2 Hz, 1H), 7.20 - 7.18 (m, 1H), 6.81 (s, 1H), 2.95 (s, 6H), 2.78 - 2.65 (m, 2H), 2.43 (s, 3H), 1.86 - 1.80 (m, 1H), 1.76 - 1.70 (m, 1H), 1.53 (s, 9H).

[0348] rac-N 4 ,N 4 Synthesis of -dimethyl-2-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline-4,7-diamine A solution of rac-tert-butyl(4-(dimethylamino)-2-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline-7-yl)carbamate (115 mg, 0.274 mmol) in TFA (2.5 mL) and CHCl3 (2.7 mL) was stirred at room temperature for 2 hours and then concentrated under vacuum. The residue was dissolved in NaHCO3 (saturated aqueous solution, 50 mL) and extracted with DCM (3 × 50 mL). The combined organic layers were dried in (MgSO4), filtered, and concentrated under vacuum to obtain the title compound (79 mg, 90%) as a yellow rubbery substance. ESI-MS (M+H)+: 320.2, 1 H NMR (400 MHz, DMSO) δ 8.53 (d, J=5.0 Hz, 1H), 7.71 - 7.66 (m, 1H), 7.20 - 7.17 (m, 1H), 6.81 - 6.79 (m, 2H), 6.58 (s, 1H), 5.58 (s, 2H), 2.91 (br s, 6H), 2.75 - 2.69 (m, 1H), 2.64 - 2.57 (m, 1H), 2.43 (s, 3H), 1.82 - 1.75 (m, 1H), 1.73 - 1.65 (m, 1H).

[0349] Synthesis of rac-1-(6-cyclopropyl-2-(((4-(dimethylamino)-2-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline-7-yl)amino)methyl)imidazo[1,2-a]pyridine-8-yl)-3-methylimidazolidin-2,4-dione Ti(iPrO)4 (0.26 mL, 0.88 mmol) was added to a stirred solution of rac-N,N-dimethyl-2-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline-4,7-diamine (49 mg, 0.18 mmol) and 6-cyclopropyl-8-(3-methyl-2,4-dioxoimidazolidine-1-yl)imidazo[1,2-a]pyridine-2-carbaldehyde (53 mg, 0.178 mmol) in DCM (1.8 mL) and MeOH (1.8 mL). The reaction mixture was sealed and stirred at 50°C for 18 hours. The mixture was cooled to room temperature, and then Ti(iPrO)4 (0.26 mL, 0.88 mmol) was added. The mixture was stirred at 50°C for 2 hours, and then cooled to room temperature. NaCNBH3 (39 mg, 0.62 mmol) was added, and the mixture was stirred at room temperature for 18 hours. Water (1.0 mL) was added, and the mixture was concentrated on silica under vacuum. The mixture was then purified by silica gel column chromatography eluting with 1-20% 7N NH3 (in MeOH) in DCM, followed by preparative HPLC, to obtain the title compound (12 mg, 12%) as a yellow solid (as formate). ESI-MS (M+H)+: 560.3, 1H NMR (400 MHz, DMSO) δ 8.85 - 8.84 (m, 1H), 8.54 (d, J=5.1 Hz, 1H), 8.45 (s, 0.5H), 8.25 - 8.24 (m, 1H), 8.12 - 8.08 (m, 1H), 7.74 (s, 1H), 7.35 (d, J=1.6 Hz, 1H), 7.28 (t, J=6.1 Hz, 1H), 7.23 - 7.19 (m, 2H), 6.63 (s, 1H), 4.95 (s, 2H), 4.62 (d, J=6.0 Hz, 2H), 2.99 (s, 3H), 2.81 - 2.70 (m, 2H), 2.43 (s, 3H), 1.97 - 1.90 (m, 1H), 1.84 - 1.75 (m, 2H), 0.97 - 0.91 (m, 2H), 0.67 - 0.62 (m, 2H).

[0350] The compounds in Table 1 were synthesized from 6-cyclopropyl-8-(3-methyl-2,4-dioxoimidazolidine-1-yl)imidazo[1,2-a]pyridine-2-carbaldehyde and a suitable coupling partner, using the same method as for rac-1-(6-cyclopropyl-2-(((4-(dimethylamino)-2-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline-7-yl)amino)methyl)imidazo[1,2-a]pyridine-8-yl)-3-methylimidazolidin-2,4-dione. [Table 5-1] [Table 5-2] [Table 5-3] [Table 5-4] [Table 5-5] [Table 5-6]

[0351] Examples 40-42 Synthesis of rac-1-(6-cyclopropyl-2-(((2-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)-4-morpholinoquinoline-7-yl)amino)methyl)imidazo[1,2-a]pyridine-8-yl)-3-methylimidazolidin-2,4-dione (I-40) [ka] The title compound was prepared from rac-4-(7-bromo-2-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline-7-yl)amino)methyl)imidazo[1,2-a]pyridin-8-yl)-3-methylimidazolidin-2,4-dione using a procedure similar to that used for rac-4-(7-bromo-2-((1S*,2S*)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline-4-yl)morpholine as a mixture of enantiomers (26 mg, 23%). ESI-MS (M+H)+: 644.3, purity 99.7%, 1H NMR (400 MHz, DMSO): δ 8.52 (1H, d, J = 5.1 Hz), 8.27 (1H, d, J = 1.0 Hz), 7.77 (1H, s), 7.69 (1H, d, J = 9.2 Hz), 7.36 (1H, d, J = 1.5 Hz), 7.18 (1H, d, J = 5.4 Hz), 7.00 (1H, dd, J = 2.4, 9.0 Hz), 6.76 - 6.71 (3H, m), 4.96 (2H, s), 4.48 (2H, d, J = 5.6 Hz), 3.86 - 3.81 (4H, m), 3.10 - 3.07 (4H, m), 2.99 (3H, s), 2.73 - 2.68 (1H, m), 2.65 - 2.60 (1H, m), 2.42 (3H, s), 1.98 - 1.91 (1H, m), 1.79 - 1.73 (1H, m), 1.71 - 1.66 (1H, m), 0.97 - 0.91 (2H, m), 0.68 - 0.63 (2H, m).

[0352] SFC(YMC Amylose-C 10×250mm, 5um 50 / 50 The enantiomers were separated using IPA (0.1% DEA) / CO2, 15 ml / min, 120 bar, 40℃ to obtain two enantiomers: 1-(6-cyclopropyl-2-(((2-((1S,2S)-2-(4-methylpyrimidine-2-yl)cyclopropyl)-4-morpholinoquinoline-7-yl)amino)methyl)imidazo[1,2-a]pyridine-8-yl)-3-methylimidazolidin-2,4-dione and 1-(6-cyclopropyl-2-(((2-((1R,2R)-2-(4-methylpyrimidine-2-yl)cyclopropyl)-4-morpholinoquinoline-7-yl)amino)methyl)imidazo[1,2-a]pyridine-8-yl)-3-methylimidazolidin-2,4-dione.

[0353] The first isomer to elute (7.5 mg) (Example 41, I-41) ESI-MS (M+H)+: 644.6, 1H NMR (400 MHz, DMSO): d, ppm 8.52 (1H, d, J = 5.0 Hz), 8.27 (1H, s), 7.77 (1H, s), 7.70 (1H, d, J = 9.0 Hz), 7.36 (1H, d, J = 1.6 Hz), 7.18 (1H, d, J = 5.1 Hz), 7.00 (1H, dd, J = 2.3, 9.0 Hz), 6.76 - 6.71 (3H, m), 4.96 (2H, s), 4.48 (2H, d, J = 5.5 Hz), 3.86 - 3.82 (4H, m), 3.11 - 3.07 (4H, m), 2.99 (3H, s), 2.73 - 2.68 (1H, m), 2.65 - 2.60 (1H, m), 2.42 (3H, s), 1.98 - 1.91 (1H, m), 1.79 - 1.66 (2H, m), 0.97 - 0.92 (2H, m), 0.68 - 0.63 (2H, m), RT=6.40 points, 100% ee.

[0354] Chapter 2, soluble heterosexual body (7.3 mg) (Example 42, I-42) ESI-MS (M+H)+: 644.5, 1H NMR (400 MHz, DMSO): d, ppm 8.52 (1H, d, J = 5.1 Hz), 8.27 (1H, d, J = 1.1 Hz), 7.77 (1H, s), 7.69 (1H, d, J = 9.0 Hz), 7.36 (1H, d, J = 1.5 Hz), 7.18 (1H, d, J = 5.1 Hz), 7.00 (1H, dd, J = 2.4, 9.0 Hz), 6.77 - 6.71 (3H, m), 4.96 (2H, s), 4.48 (2H, d, J = 5.9 Hz), 3.84 (4H, dd, J = 4.4, 4.4 Hz), 3.09 (4H, dd, J = 4.1, 4.1 Hz), 2.99 (3H, s), 2.73 - 2.68 (1H, m), 2.65 - 2.60 (1H, m), 2.42 (3H, s), 1.98 - 1.91 (1H, m), 1.79 - 1.74 (1H, m), 1.71 - 1.66 (1H, m), 0.97 - 0.91 (2H, m), 0.68 - 0.63 (2H, m). RT=8.70 minutes, 98.9%ee.

[0355] Example 43 Synthesis of 1-[6-cyclopropyl-2-[[2-[(1S,2S)-2-(4-methylpyrimidine-2-yl)cyclopropyl]-4-(2-oxa-6-azaspiro[3,3]heptan-6-yl)-7-quinolyl]oxymethyl]imidazo[1,2-a]pyridine-8-yl]-3-methylimidazolidined-2,4-dione (I-43) [ka] Synthesis of 1-(6-cyclopropyl-2-(((2-((1S,2S)-2-(4-methylpyrimidine-2-yl)cyclopropyl)-4-(2-oxa-6-azaspiro[3,3]heptan-6-yl)quinoline-7-yl)oxy)methyl)imidazo[1,2-a]pyridine-8-yl)-3-methylimidazolidin-2,4-dione A 1,4-dioxane (1.0 mL) suspension of 6-(7-bromo-2-((1S,2S)-2-(4-methylpyrimidine-2-yl)cyclopropyl)quinoline-4-yl)-2-oxa-6-azaspiro[3.3]heptane (110 mg, 0.24 mmol), 1-(6-cyclopropyl-2-(hydroxymethyl)imidazo[1,2-a]pyridine-8-yl)-3-methylimidazolidine-2,4-dione (72 mg, 0.24 mmol), Cs2CO3 (240 mg, 0.72 mmol), and Adamantyl-BippyPhos (32 mg, 0.048 mmol) was degassed with N2 for 10 minutes. Pd(OAc)2 (5.4 mg, 0.024 mmol) was added, and the reaction mixture was stirred at 90°C for 18 hours. The reaction mixture was filtered through a Celite® pad and concentrated under vacuum. The residue was purified by silica gel column chromatography eluting 0-20% 7N NH3 (in MeOH) in DCM, followed by preparative HPLC, to obtain the title compound (16 mg, 10%) as a white solid (formate). ESI-MS (M+H)+: 657, 1 H NMR (400 MHz, DMSO) δ 8.51 (d, J=5.1 Hz, 1H), 8.30 (d, J=1.0 Hz, 1H), 8.18 (s, 1H), 7.98 (s, 1H), 7.80 (d, J=9.3 Hz, 1H), 7.39 (d, J=1.5 Hz, 1H), 7.28 (d, J=2.5 Hz, 1H), 7.17 (d, J=5.1 Hz, 1H), 7.00 (dd, J=2.7, 9.2 Hz, 1H), 6.24 (s, 1H), 5.30 (s, 2H), 4.91 (s, 2H), 4.74 (s, 4H), 4.46 (s, 4H), 2.97 (s, 3H), 2.75 - 2.69 (m, 1H), 2.62 - 2.57 (m, 1H), 2.41 (s, 3H), 2.00 - 1.90 (m, 1H), 1.80 - 1.75 (m, 1H), 1.70 - 1.64 (m, 1H), 0.98 - 0.92 (m, 2H), 0.69 - 0.64 (m, 2H).

[0356] Example 44 Synthesis of 8-((1S,2S)-2-(3-chlorophenyl)cyclopropyl)-7-((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)-7H-purine (I-44) [ka] Synthesis of 4-chloro-N-((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)pyrimidine-5-amine To a solution of 4-chloropyrimidine-5-amine (1.2 g, 9.3 mmol) in DMF (40 mL), NaH (0.48 g, 12 mmol, 60% dispersion in mineral oil) was added at 0°C. After stirring at room temperature under N2 for 1 hour, a solution of 2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine (1.6 g, 7.7 mmol) in DMF (10 mL) was added to the reaction mixture. The resulting mixture was stirred at room temperature for a further 2 hours. The reaction mixture was quenched with water (60 mL). The aqueous phase was extracted with ELISA (60 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, and then concentrated under vacuum to obtain the crude product. This was purified by column chromatography using silica gel eluted with 0-50% siRNA / PE to obtain 4-chloro-N-((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)pyrimidine-5-amine (330 mg, 14%) as a yellow oil. ESI-MS [M +H]+: 300.1

[0357] Synthesis of 8-((1S,2S)-2-(3-chlorophenyl)cyclopropyl)-7-((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)-7H-purine 4-Chloro-N-((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)pyrimidine-5-amine (50 mg, 0.17 mmol), (1S,2S)-2-(3-chlorophenyl)cyclopropane-1-carboxamide (40 mg, 0.20 mmol), and Cs2CO3 (166 mg, 0.51 mmol) were mixed in 1,4-dioxane (5.0 mL). Pd2(dba)3 (31 mg, 0.034 mmol) and Xantphos (20 mg, 0.034 mmol) were added to the mixture. The reaction mixture was stirred at 95°C for 12 hours under N2. The reaction mixture was filtered through Celite®, and the filter cake was washed with DCM / MeOH (V / V=10 / 1, 50 mL). The filtrate was concentrated under vacuum to obtain a crude product, which was purified by preparative TLC with elution in 6% MeOH / DCM to obtain 8-((1S,2S)-2-(3-chlorophenyl)cyclopropyl)-7-((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)-7H-purine (20 mg, 27%) as a yellow solid. ESI-MS [M +H]+: 441.2, 1 H NMR (400 MHz, DMSO) δ 9.16 (s, 1H), 8.93 (s, 1H), 8.21 (s, 1H), 7.75 (s, 1H), 7.40 - 7.25 (m, 4H), 7.21 - 7.12 (m, 1H), 7.06 - 6.94 (m, 1H), 5.90 - 5.75 (m, 2H), 3.05 - 2.92 (m, 1H), 2.75 - 2.63 (m, 1H), 2.05 - 1.89 (m, 2H), 1.85 - 1.72 (m, 1H), 1.04 - 0.88 (m, 2H), 0.78 - 0.63 (m, 2H).

[0358] Example 45 Synthesis of 2-((1S,2S)-2-(3-chlorophenyl)cyclopropyl)-N-((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)-1H-benzo[d]imidazole-6-amine (I-45) [ka] Synthesis of (1S,2S)-N-(2-amino-4-nitrophenyl)-2-(3-chlorophenyl)cyclopropane-1-carboxamide A mixture of (1S,2S)-2-(3-chlorophenyl)cyclopropane-1-carboxylic acid (236 mg, 1.2 mmol), 4-nitrobenzene-1,2-diamine (153 mg, 1 mol), HATU (950 mg, 2.5 mmol), and DIPEA (645 mg, 5 mmol) in DMF (5 mL) was stirred at 60°C for 14 hours under N2. Water (50 mL) was added, and the mixture was extracted with ELISA (30 mL x 3). The combined organic layer was washed with brine (30 mL), dried over Na2SO4, and concentrated under vacuum. The residue was purified by column chromatography (eluent: DCM / MeOH = 0-5%) to obtain (1S,2S)-N-(2-amino-4-nitrophenyl)-2-(3-chlorophenyl)cyclopropane-1-carboxamide (200 mg, 60%) as a yellow oil. ESI-MS [M +H]+: 332.1.

[0359] Synthesis of 2-((1S,2S)-2-(3-chlorophenyl)cyclopropyl)-6-nitro-1H-benzo[d]imidazole A solution of (1S,2S)-N-(2-amino-4-nitrophenyl)-2-(3-chlorophenyl)cyclopropane-1-carboxamide (200 mg, 0.6 mmol) in AcOH (10 mL) was stirred at 110°C for 14 hours. The mixture was evaporated to remove the AcOH, and the residue was diluted with NaHCO3 (saturated aqueous solution, 50 mL) and extracted with ELISA (30 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, and concentrated under vacuum. The residue was purified by preparative TLC (eluent: DCM / MeOH = 20 / 1) to obtain 2-((1S,2S)-2-(3-chlorophenyl)cyclopropyl)-6-nitro-1H-benzo[d]imidazole (180 mg, 95%) as a yellow solid. ESI-MS [M +H]+: 314.1.

[0360] Synthesis of 2-((1S,2S)-2-(3-chlorophenyl)cyclopropyl)-1H-benzo[d]imidazole-6-amine A mixture of 2-((1S,2S)-2-(3-chlorophenyl)cyclopropyl)-6-nitro-1H-benzo[d]imidazole (180 mg, 0.57 mmol), Fe (160 mg, 2.85 mmol), and NH4Cl (302 mg, 5.7 mmol) in MeOH / H2O (6 mL / 2 mL) was stirred at 65°C for 18 hours under N2. The reaction mixture was filtered through Celite® and the filtrate was washed with DCM / MeOH (10 / 1, 50 mL). Water (30 mL) was added to the filtrate and extracted with DCM / MeOH (10 / 1, 50 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, and concentrated under vacuum to obtain 2-((1S,2S)-2-(3-chlorophenyl)cyclopropyl)-1H-benzo[d]imidazole-6-amine (160 mg, crude) as a brown solid, which was used in the next step without further purification. ESI-MS [M +H] + : 284.1.

[0361] Synthesis of 2-((1S,2S)-2-(3-chlorophenyl)cyclopropyl)-N-((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)-1H-benzo[d]imidazole-6-amine 2-((1S,2S)-2-(3-chlorophenyl)cyclopropyl)-1H-benzo[d]imidazole-6-amine (100 mg, 0.35 mmol) and 6-cyclopropylimidazo[1,2-a]pyridine-2-carbaldehyde (65 mg, 0.35 mol) were mixed in THF (15 mL), to which acetic acid (0.1 mL) was added. The resulting solution was stirred at room temperature for 16 hours. NaBH(OAc)3 (148 mg, 0.7 mmol) was added, and the solution was stirred for a further 1 hour. The reaction product was quenched with NaHCO3 (saturated aqueous solution, 50 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, and concentrated under vacuum to obtain a crude product, which was purified by preparative TLC (eluent: DCM / MeOH = 10 / 1) to obtain 2-((1S,2S)-2-(3-chlorophenyl)cyclopropyl)-N-((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)-1H-benzo[d]imidazole-6-amine (23 mg, 14%) as a red solid. ESI-MS [M+H] + : 454.2, 1 H NMR (400 MHz, DMSO) δ 11.71 (s, 1H), 8.28 (s, 1H), 7.61 (s, 1H), 7.37 (d, J = 9.3 Hz, 1H), 7.33 - 7.27 (m, 2H), 7.25 - 7.22 (m, 1H), 7.18-7.14 (m, 2H), 6.95 (dd, J = 9.3, 1.7 Hz, 1H), 6.59 - 6.42 (m, 2H), 5.86 (s, 1H), 4.33 (d, J = 3.8 Hz, 2H), 2.46 - 2.41 (m, 1H), 2.29 - 2.24 (m, 1H), 1.93 - 1.86 (m, 1H), 1.73 - 1.68 (m, 1H), 1.58 - 1.53 (m, 1H), 0.92 - 0.83 (m, 2H), 0.70 - 0.60 (m, 2H)

[0362] Example 46 Synthesis of 2-((1S,2S)-2-(3-chlorophenyl)cyclopropyl)-N-((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)-1H-benzo[d]imidazole-7-amine (I-46) [ka] Synthesis of (1S,2S)-N-(2-amino-6-nitrophenyl)-2-(3-chlorophenyl)cyclopropane-1-carboxamide (1S,2S)-2-(3-chlorophenyl)cyclopropane-1-carboxylic acid (480 mg, 2.45 mmol) and 3-nitrobenzene-1,2-diamine (306 mg, 2.0 mol) were mixed in DMF (20 mL), to which HATU (1.94 g, 5.08 mmol) and DIPEA (1.3 g, 10.15 mmol) were added. The resulting reaction mixture was stirred under N2 at room temperature for 14 hours. The reaction mixture was poured into water (200 mL) and extracted with ELISA (30 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, and concentrated under vacuum to obtain the crude product. This was purified by column chromatography (eluent: MeOH / DCM = 0-5%) to obtain (1S,2S)-N-(2-amino-6-nitrophenyl)-2-(3-chlorophenyl)cyclopropane-1-carboxamide (520 mg, 78%) as a yellow oil. ESI-MS [M +H]+: 332.1.

[0363] Synthesis of 2-((1S,2S)-2-(3-chlorophenyl)cyclopropyl)-7-nitro-1H-benzo[d]imidazole A mixture of (1S,2S)-N-(2-amino-6-nitrophenyl)-2-(3-chlorophenyl)cyclopropane-1-carboxamide (520 mg, 1.57 mmol) in AcOH (20 mL) was stirred at 110°C for 12 hours. The mixture was concentrated under vacuum to remove the AcOH, and the residue was diluted with NaHCO3 (saturated aqueous solution, 50 mL) and extracted with ELISA (30 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, concentrated under vacuum to obtain the crude product, which was purified by column chromatography (eluent: MeOH / DCM = 0-5%) to obtain 2-((1S,2S)-2-(3-chlorophenyl)cyclopropyl)-7-nitro-1H-benzo[d]imidazole (450 mg, 92%) as a yellow solid. ESI-MS [M +H]+: 314.1.

[0364] Synthesis of 2-((1S,2S)-2-(3-chlorophenyl)cyclopropyl)-1H-benzo[d]imidazole-7-amine To a solution of 2-((1S,2S)-2-(3-chlorophenyl)cyclopropyl)-7-nitro-1H-benzo[d]imidazole (375 mg, 1.2 mmol) in MeOH / water (15 mL / 5 mL), Fe (336 mg, 6.0 mmol) and NH4Cl (320 mg, 6.0 mmol) were added. The reaction mixture was stirred under N2 at 65°C for 18 hours. The reaction mixture was filtered through Celite® and the filtrate was washed with DCM / MeOH (10 / 1, 50 mL). Water (30 mL) was added to the filtrate and extracted with DCM / MeOH (10 / 1, 30 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, and concentrated under vacuum to obtain 2-((1S,2S)-2-(3-chlorophenyl)cyclopropyl)-1H-benzo[d]imidazole-7-amine (320 mg, crude) as a brown solid, which was used without further purification. ESI-MS [M +H] + : 284.2

[0365] Synthesis of 2-((1S,2S)-2-(3-chlorophenyl)cyclopropyl)-N-((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)-1H-benzo[d]imidazole-7-amine 2-((1S,2S)-2-(3-chlorophenyl)cyclopropyl)-1H-benzo[d]imidazole-7-amine (120 mg, crude) and 6-cyclopropylimidazo[1,2-a]pyridine-2-carbaldehyde (65 mg, 0.35 mol) were mixed in THF (15 mL), to which acetic acid (0.1 mL) was added. The resulting solution was stirred at room temperature for 16 hours. NaBH(OAc)3 (148 mg, 0.7 mmol) was added, and the mixture was stirred for a further 1 hour. The reaction product was quenched with NaHCO3 (saturated aqueous solution, 50 mL) and extracted with ELISA (30 ml x 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, and then concentrated under vacuum to obtain the crude product, which was purified by preparative TLC (eluent: DCM / MeOH = 10 / 1) to obtain 2-((1S,2S)-2-(3-chlorophenyl)cyclopropyl)-N-((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)-1H-benzo[d]imidazole-7-amine (6.8 mg, 4%) as a yellow solid. ESI-MS [M +H] + : 454.1[M +H]+, 1H NMR (400 MHz, DMSO) δ 12.09 (s, 1H), 8.30 (s, 1H), 7.66 (s, 1H), 7.40 (d, J = 9.3 Hz, 1H), 7.35 - 7.31 (m, 2H), 7.25 (d, J = 8.6 Hz, 1H), 7.20 (d, J = 7.7 Hz, 1H), 6.97 - 6.95 (m, 1H), 6.86 (t, J = 7.8 Hz, 1H), 6.64 (s, 1H), 6.27 (s, 1H), 5.70 - 5.67 (m, 1H), 4.48 (d, J = 5.4 Hz, 2H), 2.48 - 2.45 (m, 1H), 2.41 - 2.36 (m, 1H), 1.94 - 1.87 (m, 1H), 1.79 (s, 1H), 1.64 - 1.59 (m, 1H), 0.92 - 0.88 (m, 2H), 0.68 - 0.64 (m, 2H).

[0366] Example 47 Synthesis of rac-tert-butyl(2-((1S*,2S*)-2-(3-chlorophenyl)cyclopropyl)-4-methoxyquinoline-7-yl)((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)carbamate (I-47) [ka] Synthesis of rac-2-((1S*,2S*)-2-(3-chlorophenyl)cyclopropyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane [ka] Synthesis of (E)-2-(3-chlorostyryl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane [ka] CuCl (287 mg, 2.9 mmol), t-BuONa (557 mg, 5.8 mmol), and Xantphos (1.7 g, 2.9 mmol) were placed in an oven-dried Schlenk tube under nitrogen, and THF (60 mL) was added. The reaction mixture was stirred at room temperature for 30 minutes, and then bis(pinacolato)diborone (7.4 g, 29 mmol) in THF (30 mL) was added. The reaction mixture was stirred for 10 minutes, and then 1-chloro-3-ethynylbenzene (4 g, 29 mmol) was added, followed by MeOH (1.8 g, 58 mmol). The mixture was stirred at room temperature for 18 hours. After completi...

Claims

1. Equation (I): 【Chemistry 1】 Compounds or pharmaceutically acceptable salts thereof [In the formula: Cy Ａ teeth, 【Chemistry 2】 Selected from, where * represents a bond site to the cyclopropyl ring; Each R Ａ is independently selected from oxo, halogen, -CN, -C(O)R, -C(O) ２ R, -C(O)N(R) ２ , -NO ２ , -N(R) ２ , -N(R)C(O)R, -N(R)C(O) ２ R, -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 an optionally substituted group independently selected from C １ to ６ aliphatic, phenyl, 5- to 6-membered heteroaryl having 1 to 4 heteroatoms independently selected from oxygen, nitrogen and sulfur, 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 6- to 12-membered spirocyclic ring system having 0 to 4 heteroatoms independently selected from oxygen, nitrogen and sulfur; Each R is independently either hydrogen or C １～６ An optionally substituted group selected from aliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyls, and 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyls having 1 to 2 heteroatoms selected from oxygen, nitrogen, and sulfur; X is -N= or -NR-, where X is a Cy bonded to a cyclopropyl ring. Ａ It is adjacent to the ring atom; Each R Ｙ and R Ｙ’ C is hydrogen, halogen, and optionally substituted C １～６ Selected independently from aliphatic groups; Each R ｘ and R ｘ ' is independently selected from hydrogen, halogen, or CN; Cy Ｂ This is selected from phenyl, 8-10 membered bicyclic aryls, 5-6 membered heteroaryls 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 (where Cy Ｂ This includes 0 to 5 -R values. Ｂ (Substituted with the base); or Cy Ｂ and R ｘ These, together with the intervening atoms, form a 6-12 membered spirocyclic ring system having 0-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, where Cy Ｂ and R ｘ The ring(s) formed by this process contain 0 to 4 -R Ｂ It is also acceptable if it is substituted with the base; Each R Ｂ These are oxo, halogen, -CN, -C(O)R, and -C(O). ２ R, -C(O)N(R) ２ , -NO ２ , -N(R) ２ , -N(R)C(O)R, -N(R)C(O) ２ R, -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 3-7 member saturated or partially unsaturated monocyclic heterocyclyls having 1-2 heteroatoms selected from aliphatic, oxygen, nitrogen, and sulfur, and optionally substituted groups selected from 5-6 member heteroaryls having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur; L is an arbitrarily substituted C １～３ Hydrocarbon chain (1 to 3 methylene units are arbitrarily and independently -O-, -NR ｚ -, -S-, -SO-, or -SO ２ (substituted with -); or L is an optionally substituted five- or six-membered saturated or partially unsaturated heterocyclene having one to three heteroatoms independently selected from oxygen, nitrogen, and sulfur; Each R ｚ is hydrogen, -(CH ２ ) ０～３ OR, -(CH ２ ) ０～３ C(O)OR, and any substituted C １～６ Selected independently from aliphatic groups; Cy Ｃ This is a 7-10 membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, or a 6-12 membered saturated or partially unsaturated bicyclic heterocycline having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, where Cy Ｃ This includes 0 to 6 -L Ｃ -R Ｃ It is substituted with the base; Each L Ｃ This is a covalent bond, and optionally substituted C １～６ A hydrocarbon chain (in which 1 to 3 methylene units are arbitrarily and independently replaced with -O- or -NR-) is independently selected; Each R Ｃ These are halogen, -CN, -C(O)R, -C(O) ２ R, -C(O)N(R) ２ , -NO ２ , -N(R) ２ , -N(R)C(O)R, -N(R)C(O) ２ R, -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 Ｄ , and C １ ~ ６ A group independently selected from any substituted group chosen from aliphatic groups; Each Cy Ｄ This is 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- or 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, a 6-12 member saturated or partially unsaturated bicyclic heterocyclyl having 1-3 heteroatoms independently selected from phenyl, oxygen, nitrogen, or sulfur, a bridging biscycle, and a 6-12 member saturated or partially unsaturated bicyclic spiroheterocyclyl having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, where Cy Ｄ There are 0 to 4 L Ｄ -R Ｄ It is substituted with the base; Each L Ｄ This is a covalent bond, and optionally substituted C １～６ A hydrocarbon chain (in which 1 to 3 methylene units are arbitrarily and independently replaced with -O- or -NR-) is independently selected; each R Ｄ is independently selected from oxo, halogen, -CN, -C(O)R, -C(O) ２ R, -C(O)N(R) ２ , -NO ２ , -N(R) ２ , -N(R)C(O)R, -N(R)C(O) ２ R, -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, 3-7 membered saturated or partially unsaturated monocyclic carbocyclyl, and 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen and sulfur].

2. each R Ａ is independently selected from oxo, halogen, -CN, -N(R) ２ , -N(R)S(O) ２ R, -OR, and C １ - ６ aliphatic, optionally substituted groups selected from 5- or 6-membered heteroaryl having 1 to 4 heteroatoms independently selected from oxygen, nitrogen and sulfur, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 2 heteroatoms selected from oxygen, nitrogen and sulfur, and 6- to 12-membered spirocyclic ring system having 0 to 4 heteroatoms independently selected from oxygen, nitrogen and sulfur, the compound according to claim 1.

3. Cy Ｂ However, it is selected from phenyl and a 5-membered or 6-membered heteroaryl having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, where Cy Ｂ However, there are 0 to 4 -R Ｂ The compound according to claim 1 or 2, which is substituted with a group.

4. Cy Ｂ but, 【Transformation 3】 The compound according to any one of claims 1 to 3.

5. Each R Ｂ However, halogens and optionally substituted C １ ~ ６ A compound according to any one of claims 1 to 4, independently selected from aliphatic compounds.

6. L, i) C as arbitrarily substituted １～３ It is a hydrocarbon chain, where 1 to 3 methylene units are -O-, -NR ｚ -, -S-, or -SO ２ It is arbitrarily replaced with -, or ii) *-NHCH(Me)-, *-NHCH ２ -, *-OCH(Me)-, or *-OCH ２ - and in the formula, * is Cy Ａ Represents a connection point to, or iii) The compound according to any one of claims 1 to 5, which is an optionally substituted five-membered saturated or partially unsaturated heterocyclene having one heteroatom independently selected from oxygen, nitrogen, and sulfur.

7. Cy Ｃ However, it is a biring aryl with 8 to 10 members, and here, Cy Ｃ However, there are 0 to 6 -L Ｃ -R Ｃ A compound according to any one of claims 1 to 6, which is substituted with a group.

8. Cy Ｃ but, 【Chemistry 4】 A compound according to any one of claims 1 to 7, selected from the group consisting of the following.

9. The aforementioned compound is given by formula II: 【Transformation 5】 A compound of or a pharmaceutically acceptable salt thereof, wherein each R ３ , R ４ , R ５ , R ６ , and R ７ However, hydrogen and -L Ｃ -R Ｃ A compound according to any one of claims 1 to 8, independently selected from the above.

10. R ３ , R ４ , R ５ , R ６ , and R ７ Each of them is hydrogen and -L Ｃ -R Ｃ Selected independently from, where each L Ｃ However, covalent bonds and optionally substituted C １～６ A hydrocarbon chain (in which 1 to 3 methylene units are arbitrarily and independently replaced with -O- or -NR-) is independently selected; each R Ｃ However, halogen, -CN, -C(O)R, -C(O) ２ R, -C(O)N(R) ２ , -N(R) ２ , -N(R)C(O)R, -N(R)C(O) ２ R, -N(R)S(O) ２ R, -S(O) ２ R, -S(O) ２ N(R) ２ Cy Ｄ , and C １ ~ ６ A compound according to any one of claims 1 to 9, independently selected from optionally substituted groups selected from aliphatic groups.

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

12. R ４ However, hydrogen and -L Ｃ -R Ｃ Selected from, here, L Ｃ However, it is a covalent bond, R Ｃ However, halogen, -CN, -C(O)R, -C(O) ２ R, -C(O)N(R) ２ , -N(R) ２ , -N(R)C(O)R, -N(R)C(O) ２ R, -N(R)S(O) ２ R, -OR, -S(O) ２ R, -S(O) ２ N(R) ２ Cy Ｄ , and C １ ~ ６ A compound according to any one of claims 1 to 11, selected from optionally substituted groups selected from aliphatic groups.

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

14. R ６ However, hydrogen and L Ｃ -R Ｃ Selected from, here, L Ｃ However, it is a covalent bond, R Ｃ However, halogen, -N(R) ２ , -OR,Cy Ｄ , and optionally substituted C １～６ A compound according to any one of claims 1 to 13, selected from aliphatic groups.

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

16. The aforementioned compound, i) Equation III: 【Transformation 6】 It is a compound of, In the formula, X １ However, N, CH, or C-L Ｃ -R Ｃ And; Each X ２ However, N, CH, or C-L Ｃ -R Ｃ Selected independently of; X ３ and X ４ However, independently, N is either N or C, where X ３ or X ４ At least one of them is C; X ５ , X ６ , X ７ , and X ８ Each of these is N, CH, or C-L Ｃ -R Ｃ Selected independently of; n is a compound, where n is 1 or 2, or ii) Formulas IV-a, IV-b, or IV-c: 【Transformation 7】 It is a compound of, or iii) Formulas V-a, V-b, or V-c: 【Transformation 8】 It is a compound of, or iv) Forms VI-a, VI-b, or VI-c: 【Chemistry 9】 It is a compound of, R ４ However, hydrogen or L Ｃ -R Ｃ And here, L Ｃ The bond is covalent, and R Ｃ is halogen or Cy Ｄ And Cy Ｄ However, it is a 5-membered saturated or partially unsaturated monocyclic heterocycline having 1 to 2 nitrogen atoms, and Cy Ｄ However, there are 0 to 4 -L Ｄ -R Ｄ It is a compound that is substituted with a group. The compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof.

17. Cy Ｄ but, 【Chemistry 10】 A compound according to any one of claims 1 to 16, wherein the ring is selected from the rings. 【Request Item 18】 【Chemistry 11】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 A compound or a pharmaceutically acceptable salt thereof, selected from the following: When "&" and a number follow the center of a 3D shape, it indicates that both R and S configurations are present at that location. If two solid centers are represented by the same symbol, their arrangements are relative to each other, and A compound or a pharmaceutically acceptable salt thereof, in which the arrangements of each stereocenter can be independent of each other, if each stereocenter is indicated by a different symbol.

19. A pharmaceutical composition comprising the compound described in any one of claims 1 to 18.

20. The pharmaceutical composition according to claim 19, for use in treating a disease or disorder mediated by plasma kallikrein.

21. The pharmaceutical composition according to claim 20, wherein the disease or disorder is hereditary angioedema or diabetic macular edema.

22. A compound according to any one of claims 1 to 18, for use in treating a disease or disorder mediated by plasma kallikrein.

23. The compound according to claim 22, wherein the disease or disorder is hereditary angioedema or diabetic macular edema.

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