Polycyclic inhibitors 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 TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 63 / 162,483, filed March 17, 2021, which is incorporated herein by reference in its entirety. [Background technology]

[0002] I. Background technology Plasma kallikrein (pKa) is a serine protease zymogen in blood that is converted to its catalytically active form by coagulation factor XIIa and contributes to the innate inflammatory response and the intrinsic blood coagulation cascade. In vivo mechanisms leading to activation of this pathway include interaction with polyphosphate released from activated platelets and the absence of C1 inhibitor (C1-INH), the primary physiological inhibitor of PKa. PKa-mediated cleavage of high-molecular-weight kininogen generates bradykinin (BK), a potent vasodilatory and proinflammatory nonapeptide, which activates the bradykinin 2 receptor. Subsequent cleavage of BK by carboxypeptidases generates des-Arg9-BK, which activates the B1 receptor. Both B1 and B2 receptors are expressed by vascular, glial, and neuronal cell types, with the highest levels of retinal expression detected in the ganglion cell layer and the inner and outer nuclear layers. Activation of B1 and B2 receptors causes vasodilation and increases vascular permeability.

[0003] PKa is also associated with numerous disorders, including hereditary angioedema (HAE), an autosomal dominant disease characterized by painful, unpredictable, recurrent attacks of inflammation affecting the hands, feet, face, abdomen, genitourinary tract, and larynx. The prevalence of HAE is uncertain but estimated to be approximately 1 case per 50,000 people, with no known differences between racial groups. HAE is caused by 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 leads to painful, debilitating, and potentially fatal swelling attacks. If left untreated, HAE can result in a mortality rate as high as 40%, primarily due to upper airway obstruction. Summary of the Invention

[0004] II. Summary of the Invention The present disclosure is based, at least in part, on the development of a number of compounds that bind to and effectively inhibit the activity of plasma kallikrein. Accordingly, provided herein are compounds and uses thereof for targeting plasma kallikrein and / or treating diseases and disorders mediated by plasma kallikrein, novel intermediates, and processes for preparing the compounds disclosed herein. The present disclosure also extends to pharmaceutical compositions comprising any one of them, and to 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 provides a compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof, wherein Cy A , X, Cy B , Cy C , L, R x , R x’ , R Y , and R Y’Each of the following, both alone and in combination, is defined and described in classes and subclasses herein. In certain embodiments, the invention provides compounds of formulae (I) to (VI-c), as defined and described in classes and subclasses herein.

[0006] In some embodiments, the present invention also provides methods of using the compounds of Formulas (I)-(VI-c).

[0007] Advantageously, the compounds of the present disclosure have therapeutic activity and a suitable level of bioavailability and / or suitable half-life for use as therapeutic agents. DETAILED DESCRIPTION OF THE INVENTION

[0008] III. MODE FOR CARRYING OUT THE INVENTION A.Definition Compounds of the present invention include those generally described above as well as those further exemplified by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise indicated. For purposes of this invention, chemical elements are defined as defined in the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75 th Further, the general principles of organic chemistry are identified in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry", 5 th Ed., Ed.: Smith, MB 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 ordinary meaning within the chemical and biological arts. The chemical structures and formulas set forth herein are constructed according to the standard rules of chemical valency known in the chemical arts.

[0010] As used herein, the term "aliphatic" or "aliphatic group" means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is fully saturated or contains one or more units of unsaturation, or a monocyclic or bicyclic hydrocarbon that is fully saturated or contains one or more units of unsaturation, but is not aromatic (also referred to herein as "carbocyclyl," "alicyclic," or "cycloalkyl"), and has a single point of attachment to the remainder of the molecule. Unless otherwise specified, aliphatic groups contain 1-6 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms, and in yet other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms. In some embodiments, "alicyclic" (or "carbocyclyl" or "cycloalkyl") refers to a monocyclic C3-C7 hydrocarbon that is fully saturated or contains one or more units of unsaturation, but is not aromatic, and has a single point of attachment to the rest of the molecule. Suitable aliphatic groups include, but are not limited to, straight-chain or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups, and hybrids thereof, such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl, or (cycloalkyl)alkenyl.

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

[0012] As used herein, the term "unsaturated" means that a moiety has one or more units of unsaturation.

[0013] The term "alkylene" refers to a divalent alkyl group. An "alkylene chain" is a polymethylene group, i.e., -(CH) n -, where n is a positive integer, preferably 1 to 6, 1 to 4, 1 to 3, 1 to 2, or 2 to 3. A substituted alkylene chain is a polymethylene group in which one or more methylene group hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for substituted aliphatic groups.

[0014] The term "halogen" means 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, an 8- to 10-membered bicyclic aryl group is an optionally substituted naphthyl ring. In certain embodiments of the present invention, "aryl" refers to an aromatic ring system that may bear one or more substituents, including, but not limited to, phenyl, biphenyl, naphthyl, anthracyl, and the like. As used herein, the term "aryl" also includes within its scope groups in which an aromatic ring is fused to one or more non-aromatic rings, such as, for example, indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl.

[0016] The terms "heteroaryl" and "heteroar-" refer to groups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms, having 6, 10, or 14 pi electrons shared in a cyclic arrangement, and having 1 to 5 heteroatoms in addition to the carbon atoms. Heteroaryl groups include, but are not limited to, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. As used herein, the terms "heteroaryl" and "heteroar-" also include groups in which a heteroaromatic ring is fused to one or more aryl, alicyclic, or heterocyclyl rings, where the radical or point of attachment is on the heteroaromatic ring (or in the case of a divalent fused heteroarylene ring system, at least one radical or point of attachment is on the heteroaromatic ring). Non-limiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzothiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-1,4-oxazin-3(4H)-one. Heteroaryl groups can be monocyclic or bicyclic. The term "heteroaryl" can be used interchangeably with the terms "heteroaryl ring," "heteroaryl group," or "heteroaromatic," and any of these terms include optionally substituted rings.

[0017] As used herein, the terms "heterocyclyl," "heterocyclic radical," and "heterocyclic ring" are used interchangeably and refer to a stable 5- to 7-membered monocyclic or 7- to 10-membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated and has, in addition to carbon atoms, one or more, preferably one to four, heteroatoms as defined above. In this context, the term "nitrogen," when used in reference to a ring atom, includes substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 0 to 3 heteroatoms selected from oxygen, sulfur, or nitrogen, the nitrogen can be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or + It may be NR (as in N-substituted pyrrolidinyl).

[0018] A heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure, and any of the ring atoms can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl. The terms "heterocyclyl," "heterocyclyl ring," "heterocyclic group," "heterocyclic moiety," and "heterocyclic radical" are used interchangeably herein and include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl, or alicyclic rings, such as indolinyl, 3H-indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl, where the radical or point of attachment is on the heterocyclyl ring. Heterocyclyl groups can be monocyclic or bicyclic. The term "heterocyclylalkyl" refers to an alkyl group substituted by a heterocyclyl, where the alkyl and heterocyclyl portions independently are optionally substituted.

[0019] As used herein, the term "partially unsaturated" refers to a ring moiety that contains at least one double or triple bond. The term "partially unsaturated" is intended to encompass rings with multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties as defined herein.

[0020] As used herein, and unless otherwise stated, 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 a divalent version of that moiety. For example, a divalent carbocycle is a "carbocyclylene," a divalent aryl ring is an "arylene," a divalent benzene ring is a "phenylene," a divalent heterocycle is a "heterocyclylene," a divalent heteroaryl ring is a "heteroarylene," a divalent alkyl chain is an "alkylene," a divalent alkenyl chain is an "alkenylene," a divalent alkynyl chain is an "alkynylene," etc.

[0021] As described herein, the compounds of the invention may contain "optionally substituted" moieties when specified. In general, the term "substituted," whether preceded by the term "optionally," means that one or more hydrogens of the specified moiety have been replaced with a suitable substituent. "Substituted" applies to one or more hydrogens that are evident or implied from the structure (e.g., [ka] At least [ka] refers to, [ka] At least [ka] In addition, in polycyclic ring systems, unless otherwise specified, substituents can replace a hydrogen on any individual ring (e.g., [ka] At least [ka] (refers to "optionally substituted"). Unless otherwise indicated, an "optionally substituted" group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituents may be the same or different at all positions. Combinations of substituents envisioned by the present invention are preferably those that result in the formation of stable or chemically feasible compounds. The term "stable," as used herein, refers to compounds that remain substantially unchanged when subjected to conditions that permit their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.

[0022] Suitable monovalent substituents on a substitutable carbon atom of an "optionally substituted" group are independently halogen; -(CH) 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°; optionally substituted with R° -(CH2) 0~4 Ph; optionally substituted with R° -(CH2) 0~4 O(CH2) 0~1 Ph; optionally substituted with R° -CH=CHPh; optionally substituted with 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 linear or branched alkylene)C(O)ON(R°)2, where each R° is optionally substituted as defined below and independently represents hydrogen, C 1~6 Aliphatic, -CH2Ph, -O(CH2) 0~1Ph, -CH2- (a 5-6 membered heteroaryl ring), or a 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or, notwithstanding the above definitions, two independent occurrences of R° together with their intervening atom(s) form a 3-12 membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below.

[0023] Suitable monovalent substituents on R° (or the ring formed by two independent occurrences of R° together with the intervening atoms) are independently halogen, —(CH2), 0~2 R ● ,-(Halo R ● ), -(CH2) 0~2 OH, -(CH2) 0~2 OR ● , -(CH2) 0~2 CH(OR ● )2;-O(HaloR ● ), -CN, -N3, -(CH2) 0~2 C(O)R ● , -(CH2) 0~2 C(O)OH, -(CH2) 0~2 C(O)OR ● , -(CH2) 0~2 SR ● , -(CH2) 0~2 SH, -(CH2) 0~2 NH2, -(CH2) 0~2 NHR ● , -(CH2) 0~2 NR ● 2, -NO2, -SiR ● 3. -OSiR ● 3. -C(O)SR ● , -(C 1~4 Linear or branched alkylene)C(O)OR ● , or -SSR ● where each R ● is unsubstituted or, if preceded by "halo", substituted only with one or more halogens, and C 1~4Aliphatic, -CH2Ph, -O(CH2) 0~1 or a 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on a saturated carbon atom of R° include =0 and =S.

[0024] Suitable 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 R # is hydrogen, optionally substituted as defined below, C 1~6 The "optionally substituted" group is selected from an aliphatic or unsubstituted 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Preferred divalent substituents attached to adjacent substitutable carbon atoms of the "optionally substituted" group include -O(CR # 2) 2-3 O-, wherein each R # is hydrogen, optionally substituted as defined below, C 1~6 It is selected from aliphatic or unsubstituted 5-6 membered saturated, partially unsaturated, or aryl rings having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0025] R # Suitable substituents on the aliphatic group include halogen, -R ● ,-(Halo R ● ), -OH, -OR ● , -O(HaloR ● ), -CN, -C(O)OH, -C(O)OR ●, -NH2, -NHR ● , -NR ● 2, or -NO2, wherein each R ● is unsubstituted or, if preceded by "halo", substituted with only one or more halogens, and independently, C 1~4 Aliphatic, -CH2Ph, -O(CH2) 0~1 Ph, or a 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0026] Suitable substituents on a substitutable nitrogen of an "optionally substituted" group include -R † , -NR † 2. -C(O)R † , -C(O)OR † , -C(O)C(O)R † , -C(O)CHC(O)R † , -S(O)2R † , -S(O)NR † 2. -C(S)NR † 2. -C(NH)NR † 2, or -N(R † )S(O)2R † wherein each R † are independently hydrogen, optionally substituted as defined below, C 1~6 aliphatic, unsubstituted -OPh, or an unsubstituted 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, regardless of the above definition, two R † Independent occurrences of together with their intervening atom(s) form an unsubstituted 3-12 membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0027] R † Suitable substituents on the aliphatic group are independently halogen, —R ● ,-(Halo R ● ), -OH, -OR ●, -O(HaloR ● ), -CN, -C(O)OH, -C(O)OR ● , -NH2, -NHR ● , -NR ● 2, or -NO2, where each R ● is unsubstituted or, if preceded by "halo", substituted with only one or more halogens, and independently, C 1~4 Aliphatic, -CH2Ph, -O(CH2) 0~1 Ph, or a 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0028] As used herein, the term "pharmaceutically acceptable salt" refers to a salt that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, etc., and is commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, which is incorporated herein by reference.

[0029] In certain embodiments, the neutral forms of the compounds are regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. In some embodiments, the parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents.

[0030] Unless otherwise stated, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Accordingly, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the compounds of the invention are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention. Additionally, unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, replacement of hydrogen by deuterium or tritium, or 13 C-enriched carbon or 14 Compounds having the structures of the present invention, including the replacement of a carbon with a C-enriched carbon, are within the scope of the present invention. Such compounds are useful, for example, as analytical tools, 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 single enantiomers or single diastereoisomers. A single enantiomer refers to an enantiomeric excess of 80% or greater, for example, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99%. A single diastereomeric excess refers to an excess of 80% or greater, 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 an oxygen that is double bonded to a carbon atom, thereby forming a carbonyl.

[0032] symbol" [ka] " indicates the point of attachment of a chemical moiety to the rest of the molecule or chemical formula, except when used as a bond to indicate unknown or mixed stereochemistry.

[0033] As used herein, the articles "a" and "an" are used to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element.

[0034] A "dosing regimen" (or "treatment regimen"), as that term is used herein, is a set of unit doses (usually two or more) that are administered individually to a subject, usually spaced apart by a period of time. In some embodiments, a given therapeutic agent has a recommended dosing regimen that may require one or more doses. In some embodiments, the dosing regimen is made up of multiple doses, each separated by the same length of time from each other; in some embodiments, the dosing regimen is made up of multiple doses, with at least two different time periods separating the individual doses.

[0035] As understood from the context, a "reference" compound is a compound that is sufficiently similar to the particular compound of interest to allow a relevant comparison. In some embodiments, the information about the reference compound is obtained contemporaneously with the 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, comparison of the particular compound of interest to the reference compound establishes the identity, similarity, or difference of the particular compound of interest relative to the reference compound.

[0036] As used herein, the phrase "therapeutic agent" refers to any agent that has a therapeutic effect and / or induces a desired biological and / or pharmacological effect when administered to a subject.

[0037] As used herein, the term "therapeutically effective amount" refers to an amount of a therapeutic agent that confers a therapeutic effect on a treated subject at a reasonable benefit / risk ratio applicable to any medical treatment. The therapeutic effect can be objective (i.e., measurable by some test or marker) or subjective (i.e., the subject gives an indication of or feels an effect). In particular, a "therapeutically effective amount" refers to an amount of a therapeutic agent effective to treat, ameliorate, or prevent a desired disease or condition, or to exhibit a therapeutic or prophylactic effect that is detectable, 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 symptoms of the disease. A therapeutically effective amount is generally administered in a dosage regimen that may consist of multiple unit doses. For any particular therapeutic agent, the therapeutically effective amount (and / or an appropriate unit dose within an effective dosage regimen) may vary depending, for example, on the route of administration and combination with other pharmaceutical agents. In addition, the particular therapeutically effective amount (and / or unit dose) for any particular subject will depend on a variety of factors, including the disorder being treated and the severity of the disorder; the activity of the particular therapeutic agent used; the particular composition used; the age, weight, health, sex, and diet of the subject; the time of administration, route of administration, and / or excretion or metabolic rate of the particular therapeutic agent used; the duration of treatment; and similar factors well known in the medical arts.

[0038] As used herein, the term "treatment" (also "treat" or "treating") refers to any administration of a substance (e.g., a provided composition) that partially or completely relieves, ameliorates, 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 subjects who do not exhibit symptoms of the associated disease, disorder, and / or condition and / or subjects who exhibit only early signs of the disease, disorder, and / or condition. Alternatively or additionally, such treatment may be treatment of subjects who exhibit one or more established signs of the associated disease, disorder, and / or condition. In some embodiments, treatment may be treatment of subjects who have been diagnosed with the associated disease, disorder, and / or condition. In some embodiments, treatment may be treatment of subjects known to have one or more susceptibility factors that statistically correlate with an increased risk of developing the associated disease, disorder, and / or condition.

[0039] B. Compound In some embodiments, provided compounds have formula (I): [ka] or a pharmaceutically acceptable salt thereof, During the ceremony: Cy A is an 8- to 10-membered bicyclic heteroarylene having 1 to 5 heteroatoms independently selected from oxygen, nitrogen, and sulfur, a 10- to 14-membered tricyclic heteroarylene having 1 to 6 heteroatoms independently selected from oxygen, nitrogen, and sulfur, an 8- to 14-membered saturated or partially unsaturated bicyclic heterocyclyl having 1 to 6 heteroatoms independently selected from oxygen, nitrogen, or sulfur, or a 10- to 15-membered saturated or partially unsaturated tricyclic heterocyclyl having 1 to 6 heteroatoms independently selected from oxygen, nitrogen, or sulfur, wherein Cy A 0 to 6 -R A substituted with a group; Each R Ais independently selected from oxo, halogen, —CN, —C(O)R, —C(O)R, —C(O)N(R), —NO, —N(R), —N(R)C(O)R, —N(R)C(O)R, —N(R)S(O)R, —OR, —OC(O)R, —OC(O)N(R), —SR, —S(O)R, —S(O)R, —S(O)N(R), —S(O)N(R), or C1-6 aliphatic, phenyl, oxygen, nitrogen, and sulfur. an optionally substituted group selected from a 5-6 membered heteroaryl having up to 4 heteroatoms, a 3-7 membered saturated or partially unsaturated monocyclic carbocyclyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur, or a 6-12 membered spirocyclic ring system having 0-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur; Each R is independently hydrogen or C 1~6 an optionally substituted group selected from aliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, or 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl 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 adjacent to a ring atom of; Each R Y and R Y’ is hydrogen, halogen, and optionally substituted C 1~6 independently selected from aliphatic groups; Each R x and R x ' are independently selected from hydrogen, halogen, or CN; Cy B is selected from phenyl, 8-10 membered bicyclic aryl, 5-6 membered heteroaryl having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, or 7-10 membered heteroaryl having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, where Cy is B 0 to 5 -R B substituted with a group); or Cy B and R x together with the intervening atoms form a 6-12 membered spirocyclic ring system having 0-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein Cy B and R x The ring(s) formed by B optionally substituted with a group; Each R B are independently selected from oxo, halogen, —CN, —C(O)R, —C(O)R, —C(O)N(R), —NO, —N(R), —N(R)C(O)R, —N(R)C(O)R, —N(R)S(O)R, —OR, —OC(O)R, —OC(O)N(R), —SR, —S(O)R, —S(O)R, —S(O)N(R), —S(O)N(R), or an optionally substituted group selected from a 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from a C1-6 aliphatic, oxygen, nitrogen, or sulfur, or a 5-6 membered heteroaryl having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur; L is an optionally substituted C 1~3 A hydrocarbon chain (1 to 3 methylene units optionally and independently -O-, -NR z -, -S-, -SO-, or -SO2-); or L is an optionally substituted 5-6 membered 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 optionally substituted C 1~6 independently selected from aliphatic groups; Cy Cis 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 heterocyclyl having 1-4 heteroatoms independently selected from oxygen, nitrogen, or sulfur, wherein Cy C 0 to 6 -L C -R C substituted with a group; Each L C is a covalent bond or an optionally substituted C 1~6 independently selected from hydrocarbon chains in which 1 to 3 methylene units are optionally and independently replaced with -O- or -NR-; 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 or an optionally substituted group selected from C1-6 aliphatic groups; Each Cy D are independently selected from a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 2 heteroatoms independently selected from oxygen, nitrogen, or sulfur, a 5- to 6-membered monocyclic heteroaryl having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, a 6- to 12-membered saturated or partially unsaturated bicyclic heterocyclyl having 1 to 3 heteroatoms independently selected from phenyl, oxygen, nitrogen, or sulfur, a bridged bicycle, or a 6- to 12-membered saturated or partially unsaturated bicyclic spiroheterocyclyl having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, or sulfur, wherein Cy D 0 to 4 L D -R D substituted with a group; Each L D is a covalent bond or an optionally substituted C1~6 independently selected from hydrocarbon chains in which 1 to 3 methylene units are optionally and independently replaced with -O- or -NR-; Each R D are independently selected from oxo, halogen, —CN, —C(O)R, —C(O)R, —C(O)N(R), —NO, —N(R), —N(R)C(O)R, —N(R)C(O)R, —N(R)S(O)R, —OR, —OC(O)R, —OC(O)N(R), —SR, —S(O)R, —S(O)R, —S(O)N(R), —S(O)N(R), or an optionally substituted group selected from C aliphatic, phenyl, 3-7 membered saturated or partially unsaturated monocyclic carbocyclyl, 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 a double-bonded oxygen on the carbon "C=O" and is understood to be part of a structure or group where this carbon atom is substituted by oxo. For example, Cy C Ga-L D -R D is replaced by L D is a covalent bond and R D is oxo, the carbon atom substituted with oxo (i.e., the carbon in C=O) is C Some of the (e.g., cyclopentyl at the 2-position is -L D -R D Cy substituted with C (component of L D is a covalent bond and R D teeth, [ka] is the oxo equivalent.

[0041] With respect to Formula I, "Cy attached to a cyclopropyl ring" A It will be understood that references to "a ring atom of" refer to the ring atom marked with an "*" below. [ka]

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

[0043] In some embodiments, Cy A is a 10-14 membered tricyclic heteroarylene having 1-6 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein Cy A 0 to 5 -R A is substituted with a group.

[0044] In some embodiments, Cy A teeth, [ka] wherein the compound is selected from the group consisting of: each Y is independently selected from =C(H)- or =N-; W is selected from -C(O)- or -S(O)2-; V is selected from =CH- or =N-; * denotes the point of attachment to the cyclopropyl ring.

[0045] In some embodiments, Cy A teeth, [ka] wherein the compound is selected from the group consisting of: * denotes the point of attachment to the cyclopropyl ring.

[0046] In some embodiments, CyA teeth, [ka] wherein * represents the point of attachment to the cyclopropyl ring.

[0047] In some embodiments, Cy A teeth, [ka] wherein * represents the point of attachment to the cyclopropyl ring.

[0048] In some embodiments, Cy A teeth, [ka] wherein * represents the point of attachment to the cyclopropyl ring.

[0049] In some embodiments, Cy A teeth, [ka] wherein * represents the point of attachment to the cyclopropyl ring.

[0050] In some embodiments, each R A are independently selected from oxo, halogen, —CN, —N(R)2, —N(R)S(O)2R, —OR, or an optionally substituted group selected from a 5-6 membered heteroaryl having 1-4 heteroatoms independently selected from C1-6 aliphatic, oxygen, nitrogen, and sulfur, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from oxygen, nitrogen, or sulfur, or a 6-12 membered spirocyclic ring system having 0-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur.

[0051] In some embodiments, R A One example of R is oxo. A One example of R is halogen. A One example of is -CN. In some embodiments, R A One example of is -N(R). In some embodiments, R A One example of is -N(R)2, where each R is independently hydrogen or an optionally substituted C 1~6 In some embodiments, R A One example of is -N(R)S(O)R. In some embodiments, R A One example of is -N(R)S(O)R, where each R is an optionally substituted C 1~6 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'R A is oxo, and one or more additional R A Included are embodiments that may include groups.

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

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

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

[0055] In some embodiments, R A One example of R is an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur. A One example of is azetidinyl. In some embodiments, R A One example of is piperazinyl. In some embodiments, R A One example of is morpholinyl. In some embodiments, R A One example of is thiomorpholinyl.

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

[0057] In some embodiments, optionally substituted R A The substituents on the group are independently -(CH2) 0~4 R°, -(CH2)0~4 OR°, or —CN, where each R° is independently as defined above and described in 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 is selected from phenyl, 5-6 membered heteroaryl having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, or 7-10 membered heteroaryl having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein Cy B 0 to 4 -R B is substituted with a group.

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

[0061] In some embodiments, Cy B is phenyl, where Cy B 0 to 4 -R B In some embodiments, Cy is substituted with a group. B is phenyl, where Cy B 0 to 3 -R B is substituted with a group.

[0062] In some embodiments, Cy B is a 6-membered heteroaryl having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein Cy B 0 to 4 -R B In some embodiments, Cy is substituted with a group. B is a 6-membered heteroaryl having 1 to 3 nitrogen atoms, where Cy B 0 to 4 -R B In some embodiments, Cy is substituted with a group. B 0 to 2 -R B In some embodiments, Cy is a pyrimidinyl group substituted with a cysteine ​​group. B 0 to 2 -R B In some embodiments, Cy is a pyridinyl group substituted with a cysteine ​​group. B is 0 to 1 -R B In some embodiments, Cy is a pyrazinyl group substituted with a cysteine ​​group. B is 0 to 1 -R B In some embodiments, Cy is a pyridazinyl group substituted with a group. B is 0 to 1 -R B It is a 1,3,5-triazinyl group substituted with a group.

[0063] In some embodiments, Cy B is a 5-membered heteroaryl having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein Cy B 0 to 4 -R B In some embodiments, Cy is substituted with a group. B is a 5-membered heteroaryl having 1 to 2 heteroatoms independently selected from sulfur and nitrogen, wherein Cy B 0 to 4 -R B In some embodiments, Cy is substituted with a group. B 0 to 2 -R B In some embodiments, Cy is a thienyl group substituted with a thienyl group. B is 0 to 1 -R BIn some embodiments, Cy is a thiazolyl group substituted with a thiazolyl group. B is 0 to 1 -R B It is a thiadiazolyl group substituted with a group.

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

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

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

[0067] In some embodiments, Cy B and R x together with the intervening atoms form a 6-12 membered spirocyclic ring system having 0-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein Cy B and R x The ring(s) formed by B It will be understood that any reference herein to the number of atoms in a spirocyclic ring system (e.g., 6-12 members) includes the cyclopropyl ring shown.

[0068] In some embodiments, Cy B and Rx together with the intervening atoms form a 6- to 12-membered spirocyclic ring system containing 0-1 nitrogen heteroatom, wherein Cy B and R x The ring(s) formed by B It may be substituted with a group.

[0069] In some embodiments, Cy B and R x are, together with the atoms intervening between them, [ka] Forms a 6- to 12-membered spirocyclic ring system selected from:

[0070] In some embodiments, each R B are independently selected from oxo, halogen, —CN, —NO, —N(R), —N(R)C(O)R, —OR, or an optionally substituted group selected from a C aliphatic or 5-membered heteroaryl having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur.

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

[0072] In some embodiments, R B One example of R is oxo. B One example of R is halogen. B One example of R is chloro. B One example of is -CN. In some embodiments, R B One example of is -NO. In some embodiments, R BOne example of is -N(R). In some embodiments, R B One example of is -N(R)C(O)R. In some embodiments, R B One example of is -OR.

[0073] In some embodiments, R B One example of R is optionally substituted C1-6 aliphatic. B One example of R is a C1-6 aliphatic substituted with halogen. B One example of is methyl.

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

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

[0076] In some embodiments, R B One example of R is a 5-membered heteroaryl having 1 to 4 heteroatoms independently selected from oxygen, nitrogen, and sulfur. B One example is tetrazolyl.

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

[0078] In some embodiments, R Y and R Y’ are each independently selected from hydrogen and halogen.

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

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

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

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

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

[0084] In some embodiments, L is -CH-. In some embodiments, L is optionally substituted [ka] where * represents Cy A In some embodiments, L represents a point of attachment to an optionally substituted [ka] where * represents Cy A In some embodiments, L represents a point of attachment to an optionally substituted [ka] where * represents Cy A In some embodiments, L represents a point of attachment to [ka] where * represents Cy A In some embodiments, L represents a point of attachment to [ka] where * represents Cy A In some embodiments, L represents a point of attachment to [ka] where * represents Cy A Represents a point of attachment to

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

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

[0087] In some embodiments, L is *-NHCH(Me)-, where * is Cy A In some embodiments, L represents a point of attachment to [ka] where * represents Cy A In some embodiments, L represents a point of attachment to [ka] where * represents Cy A In some embodiments, L is *-NHCH2-, where * represents a point of attachment to Cy AIn some embodiments, L is *-N(CH3)CH2-, where * represents a point of attachment to Cy A In some embodiments, L represents a point of attachment to [ka] where * represents Cy A In some embodiments, L represents a point of attachment to [ka] where * represents Cy A In some embodiments, L is *-OCH(Me)-, where * represents a point of attachment to Cy A In some embodiments, L is *-OCH2-, where * represents a point of attachment to Cy A Represents the attachment point to

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

[0089] In some embodiments, L is an optionally substituted 5-6 membered 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 membered saturated or partially unsaturated heterocyclene having one heteroatom independently selected from oxygen, nitrogen, and sulfur. In some embodiments, L is an optionally substituted pyrrolidinediyl group. In some embodiments, L is an optionally substituted [ka] where * represents Cy A Represents the attachment point to

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

[0091] In some embodiments, Cy C is an 8-10 membered bicyclic aryl, where Cy C 0 to 6 -L C -R C In some embodiments, Cy is substituted with a group. C 0 to 6 -L C -R C and quinolinyl substituted with a group.

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

[0093] In some embodiments, Cy C is triazolopyridinyl, where Cy C 0 to 4 -L C -R C In some embodiments, Cy is substituted with a group. C is pyrazolopyridinyl, where Cy C 0 to 5 -L C -R C In some embodiments, Cy is substituted with a group. C is pyrazolopyrimidinyl, where Cy C 0 to 4 -L C -R C In some embodiments, Cy is substituted with a group. C is triazolopyridazinyl, where Cy C 0 to 3 -L C -R C In some embodiments, Cy is substituted with a group. C is imidazopyridazinyl, where Cy C 0 to 4 -L C -R C In some embodiments, Cy is substituted with a group. C is imidazopyrimidinyl, where CyC 0 to 4 -L C -R C In some embodiments, Cy is substituted with a group. C is an imidazopyrimidinone, where Cy C 0 to 4 -L C -R C In some embodiments, Cy is substituted with a group. C is imidazopyrazinyl, where Cy C 0 to 4 -L C -R C In some embodiments, Cy is substituted with a group. C is benzimidazolyl, where Cy C 0 to 4 -L C -R C In some embodiments, Cy is substituted with a group. C is triazolopyrimidinyl, where Cy C 0 to 3 -L C -R C In some embodiments, Cy is substituted with a group. C is thienopyridinyl, where Cy C 0 to 6 -L C -R C In some embodiments, Cy is substituted with a group. C is quinolinyl, where Cy C 0 to 6 -L C -R C is substituted with a group.

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

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

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

[0097] In some embodiments, provided compounds have Formula II: [ka] or a pharmaceutically acceptable salt thereof, wherein Cy A , Cy B , L, X, R x , R x’ , R Y , and R Y’ Each of the R 3 , R 4 , R 5 , R 6 , and R 7 is hydrogen or -L C -R C are independently selected from

[0098] Unless otherwise specified or prohibited by the preceding definition of Formula II, the variable moieties Cy, as defined above and described in 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 be understood that the above embodiment also applies to compounds of formula II, both alone and in combination.

[0099] In some embodiments, R 3 , R 4, R 5 , R 6 , and R 7 Each of C -R C where each L C is a covalent bond or an optionally substituted C 1~6 hydrocarbon chains (in which 1 to 3 methylene units are optionally and independently replaced by -O- or -NR-); C is 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 or an optionally substituted group selected from C1-6 aliphatic.

[0100] In some embodiments, R 3 is hydrogen or L C -R C where L C is a covalent bond and R C is halogen. In some embodiments, R 3 is hydrogen.

[0101] In some embodiments, R 4 is hydrogen or -L C -R C where L C is a covalent bond or an optionally substituted C 1~6 hydrocarbon chains in which 1 to 3 methylene units are optionally and independently replaced by -O- or -NR-; R C is 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 an optionally substituted group selected from C1-6 aliphatic groups.

[0102] In some embodiments, R 4 is hydrogen or -L C -R C where L C is a covalent bond and R C is 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 an optionally substituted group selected from C1-6 aliphatic groups.

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

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

[0105] R 4 In some embodiments, Cy Dis selected from a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 2 heteroatoms independently selected from oxygen, nitrogen, or sulfur, a 5- to 6-membered monocyclic heteroaryl having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, a 6- to 12-membered saturated or partially unsaturated fused bicyclic heterocyclyl having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, or sulfur, a bridged bicycle, or a 6- to 12-membered saturated or partially unsaturated bicyclic spiroheterocyclyl having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, or sulfur, wherein Cy D 0 to 4 L D -R D substituted with R 4 In some embodiments, Cy D is a 5-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 2 heteroatoms selected from oxygen, nitrogen, or sulfur.

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

[0107] R 4 In some embodiments of D is selected from oxo, halogen, —C(O)R, —N(R), —OR, or an optionally substituted group selected from C aliphatic, phenyl, 3-7 membered saturated or partially unsaturated monocyclic carbocyclyl, or 3-7 membered 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 group, R D The optional substituents on the above are halogen, -(CH2)0~4 R°, -(CH2) 0~4 OR°, -(CH2) 0~4 N(R°)2, -(CH2) 0~4 and —O—P(O)(O—R°), where each R° is independently as defined above and described in classes and subclasses herein.

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

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

[0111] In some embodiments, R 5 L C -R C where L C is a covalent bond and R C Cy D In some embodiments, Cy D is a cyclopropyl group.

[0112] In some embodiments, R 6 is hydrogen or L C -R C where L C is a covalent bond and R C is halogen, -N(R)2, -OR, Cy D , or an optionally substituted C 1~6 The alkyl group is selected from aliphatic groups.

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

[0114] In some embodiments, R 7 is hydrogen or L C -R C where L C is a covalent bond and R C Cy D is.

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

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

[0117] In some embodiments, provided compounds have Formula III: [ka] 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 alone and in combination, is defined and described in classes and subclasses herein, and wherein: X 1 is N, CH, or CL C -R C and; each X 2 is N, CH, or CL C -R C are independently selected from; X 3 and X 4 are independently N or C, where X 3 or X 4 at least one of is C; X 5 , X6 , X 7 , and X 8 Each of C -R C are independently selected from; n is 1 or 2.

[0118] In some embodiments, X 1 is N. In some embodiments, X 1 is CH. In some embodiments, X 1 is CL C -R C where L C and R C are as defined above and described in classes and subclasses herein, both alone and in combination.

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

[0120] In some embodiments, X 5 is N. In some embodiments, X 5 is CH. In some embodiments, X 5 is CL C -R C where L C and R C are as defined above and described in classes and subclasses herein, both alone and in combination. In some embodiments, X 6 is N. In some embodiments, X6 is CH. In some embodiments, X 6 is CL C -R C where L C and R C are as defined above and described in classes and subclasses herein, both alone and in combination. In some embodiments, X 7 is N. In some embodiments, X 7 is CH. In some embodiments, X 7 is CL C -R C where L C and R C are as defined above and described in classes and subclasses herein, both alone and in combination. In some embodiments, X 8 is N. In some embodiments, X 8 is CH. In some embodiments, X 8 is CL C -R C where L C and R C are as defined above and described in classes and subclasses herein, both alone and in combination.

[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 In some embodiments, n is 1 and X 8 is CL C -R C where L C and R C are as defined above and described in classes and subclasses herein, both alone and in combination.

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

[0124] In some embodiments, provided compounds have formula IV-a, IV-b, or IV-c: [ka] or a pharmaceutically acceptable salt thereof, wherein 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 the following, both alone and in combination, is defined and described in classes and subclasses herein.

[0125] Unless otherwise specified or prohibited by the preceding definitions of Formula IV-a, IV-b, or IV-c, the variables Cy, as defined above and described in classes and subclasses herein, 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 be understood that the above embodiment also applies to compounds of formula IV-a, IV-b, or IV-c, both alone and in combination.

[0126] In some embodiments, provided compounds have formula Va, Vb, or Vc: [ka] or a pharmaceutically acceptable salt thereof, wherein 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 alone and in combination, is defined and described in 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 preceding definitions of Formula Va, Vb, or Vc, the variables Cy, as defined above and described in classes and subclasses herein, 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 be understood that the embodiment of also applies to compounds of formula Va, Vb, or Vc, both alone and in combination.

[0128] In some embodiments, provided compounds have formula VI-a, VI-b, or VI-c: [ka] or a pharmaceutically acceptable salt thereof, wherein Cy A , R B Each of, L, and X, both alone and in combination, is as defined and described in the classes and subclasses herein; R 4 is hydrogen or L C -R C where L C is a covalent bond and R C is halogen or Cy D and Cy D is a 5-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 2 heteroatoms selected from nitrogen, and Cy D 0 to 4 -L D -R D is substituted with a group.

[0129] Unless otherwise specified or prohibited by the preceding definitions of Formula VI-a, VI-b, or VI-c, the variables Cy, as defined above and described in classes and subclasses herein, A , R B , L, R 4 It will be understood that the embodiments of X, X, and X also apply to compounds of formula VI-a, VI-b, or VI-c, both alone and in combination.

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

[0131] In certain embodiments of the provided compounds (i.e., any species of compound not otherwise defined, and any compound of Formulas (I)-(VI-c)), the moiety: [ka] (R x , R x’ , R Y , or R Y’ (including when one or more of these are hydrogen) is a Cy bonded to two stereocenters marked with an *. B and Cy A In other words, the moiety: [ka] "Trans" in this context means [ka] It will be understood that the term "compound" refers to a compound comprising a mixture of In some embodiments, the mixture is a racemic mixture.

[0132] In certain embodiments of the provided compounds (i.e., any species of compound not otherwise defined, and any compound of Formulas (I)-(VI-c)), the moiety: [ka] The absolute stereochemistry of is as follows: [ka] As stated above.

[0133] In certain embodiments of the provided compounds (i.e., any species of compound not otherwise defined, and any compound of Formulas (I)-(VI-c)), the moiety: [ka] The absolute stereochemistry of [ka] As stated above.

[0134] In some embodiments, the compound provided is selected from Table A. Table A. rac-N 7 -((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N 4 ,N 4 -dimethyl-2-((1S*,2S*)-2-(4-methylpyrimidin-2-yl)cyclopropyl)quinoline-4,7-diamine (I-1); 2-((1S,2S)-2-(3-chlorophenyl)cyclopropyl)-7-(((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)amino)pyrido[4,3-d]pyrimidin-4(3H)-one (I-2); rac-2-((1S*,2S*)-2-(3-chlorophenyl)cyclopropyl)-7-(((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)amino)pyrido[4,3-d]pyrimidin-4(3H)-one (I-3); rac-1-(2-(((2-((1S*,2S*)-2-(3-chlorophenyl)cyclopropyl)-4-methoxyquinolin-7-yl)amino)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)pyrrolidin-2-one (I-4); rac-1-(2-(((2-((1S*,2S*)-2-(3-chlorophenyl)cyclopropyl)-4-oxo-1,4-dihydroquinolin-7-yl)amino)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)-3-methylimidazolidine-2,4-dione (I-5); 1-(2-(((2-((1S,2S)-2-(3-chlorophenyl)cyclopropyl)-4-oxo-3,4-dihydroquinazolin-7-yl)amino)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)-3-methylimidazolidine-2,4-dione (I-6); rac-1-(6-cyclopropyl-2-(((2-((1S*,2S*)-2-(4-methylpyrimidin-2-yl)cyclopropyl)-4-oxo-3,4-dihydropyrido[4,3-d]pyrimidin-7-yl)amino)methyl)imidazo[1,2-a]pyridin-8-yl)-3-methylimidazolidine-2,4-dione (I-7); rac-1-(6-cyclopropyl-2-(((2-((1S*,2S*)-2-(4-methylpyrimidin-2-yl)cyclopropyl)-4-oxo-1,4-dihydroquinazolin-7-yl)amino)methyl)imidazo[1,2-a]pyridin-8-yl)-3-methylimidazolidine-2,4-dione (I-8); rac-1-(6-cyclopropyl-2-(((2-((1S*,2S*)-2-(4-methylpyrimidin-2-yl)cyclopropyl)-4-oxo-3,4-dihydropyrido[3,2-d]pyrimidin-7-yl)amino)methyl)imidazo[1,2-a]pyridin-8-yl)-3-methylimidazolidine-2,4-dione (I-9); rac-1-(6-cyclopropyl-2-(((2-((1S*,2S*)-2-(4-methylpyrimidin-2-yl)cyclopropyl)-4-oxo-1,4-dihydro-1,6-naphthyridin-7-yl)amino)methyl)imidazo[1,2-a]pyridin-8-yl)-3-methylimidazolidine-2,4-dione (I-10); rac-1-(6-cyclopropyl-2-(((2-((1S*,2S*)-2-(4-methylpyrimidin-2-yl)cyclopropyl)-4-oxo-1,4-dihydroquinolin-7-yl)amino)methyl)imidazo[1,2-a]pyridin-8-yl)-3-methylimidazolidine-2,4-dione (I-11); 1-(6-cyclopropyl-2-(((2-((1S*,2S*)-2-(4-methylpyrimidin-2-yl)cyclopropyl)-4-oxo-1,4-dihydroquinolin-7-yl)amino)methyl)imidazo[1,2-a]pyridin-8-yl)-3-methylimidazolidine-2,4-dione, first-eluting isomer (I-12); 1-(6-cyclopropyl-2-(((2-((1S*,2S*)-2-(4-methylpyrimidin-2-yl)cyclopropyl)-4-oxo-1,4-dihydroquinolin-7-yl)amino)methyl)imidazo[1,2-a]pyridin-8-yl)-3-methylimidazolidine-2,4-dione, second-eluting isomer (I-13); 1-(6-cyclopropyl-2-(((2-((1S,2S)-2-(4-methylpyrimidin-2-yl)cyclopropyl)-4-oxo-1,4-dihydroquinolin-7-yl)amino)methyl)imidazo[1,2-a]pyridin-8-yl)-3-methylimidazolidine-2,4-dione; 1-(6-cyclopropyl-2-(((2-((1R,2R)-2-(4-methylpyrimidin-2-yl)cyclopropyl)-4-oxo-1,4-dihydroquinolin-7-yl)amino)methyl)imidazo[1,2-a]pyridin-8-yl)-3-methylimidazolidine-2,4-dione; 1-(6-cyclopropyl-2-(((2-((1S,2S)-2-(4-methylpyrimidin-2-yl)cyclopropyl)-4-oxo-1,4-dihydroquinolin-7-yl)amino)methyl)imidazo[1,2-a]pyridin-8-yl)-3-methylimidazolidine-2,4-dione; 1-(6-cyclopropyl-2-(((2-((1R,2R)-2-(4-methylpyrimidin-2-yl)cyclopropyl)-4-oxo-1,4-dihydroquinolin-7-yl)amino)methyl)imidazo[1,2-a]pyridin-8-yl)-3-methylimidazolidine-2,4-dione; rac-1-(6-cyclopropyl-2-(((6-((1S*,2S*)-2-(4-methylpyrimidin-2-yl)cyclopropyl)-1,5-naphthyridin-3-yl)amino)methyl)imidazo[1,2-a]pyridin-8-yl)-3-methylimidazolidine-2,4-dione (I-14); rac-1-(6-cyclopropyl-2-(((2-((1S*,2S*)-2-(4-methylpyrimidin-2-yl)cyclopropyl)-1,6-naphthyridin-7-yl)amino)methyl)imidazo[1,2-a]pyridin-8-yl)-3-methylimidazolidine-2,4-dione formate (I-15); rac-1-(6-cyclopropyl-2-(((6-((1S*,2S*)-2-(4-methylpyrimidin-2-yl)cyclopropyl)quinolin-3-yl)amino)methyl)imidazo[1,2-a]pyridin-8-yl)-3-methylimidazolidine-2,4-dione (I-16); rac-1-(6-cyclopropyl-2-((methyl(6-((1S*,2S*)-2-(4-methylpyrimidin-2-yl)cyclopropyl)quinolin-3-yl)amino)methyl)imidazo[1,2-a]pyridin-8-yl)-3-methylimidazolidine-2,4-dione (I-17); 1-(2-(((2-((1S,2S)-2-(3-chlorophenyl)cyclopropyl)-4-methoxy-1,6-naphthyridin-7-yl)amino)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)-3-methylimidazolidine-2,4-dione (I-18); rac-N-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-2-((1S*,2S*)-2-(4-methylpyrimidin-2-yl)cyclopropyl)quinolin-7-amine (I-19); rac-N-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-4-methoxy-2-((1S*,2S*)-2-(4-methylpyrimidin-2-yl)cyclopropyl)quinolin-7-amine formate (I-20); rac-1-(6-cyclopropyl-2-(((4-methoxy-2-((1S*,2S*)-2-(4-methylpyrimidin-2-yl)cyclopropyl)quinolin-7-yl)amino)methyl)imidazo[1,2-a]pyridin-8-yl)-3-methylimidazolidine-2,4-dione (I-21); rac-1-(6-cyclopropyl-2-(((4-methoxy-2-((1S*,2S*)-2-(4-methylpyrimidin-2-yl)cyclopropyl)quinolin-7-yl)amino)methyl)imidazo[1,2-a]pyridin-8-yl)-3-methylimidazolidine-2,4-dione (I-22), first-eluting isomer; rac-1-(6-cyclopropyl-2-(((4-methoxy-2-((1S*,2S*)-2-(4-methylpyrimidin-2-yl)cyclopropyl)quinolin-7-yl)amino)methyl)imidazo[1,2-a]pyridin-8-yl)-3-methylimidazolidine-2,4-dione (I-23), the second-eluting isomer; 1-(6-cyclopropyl-2-(((4-methoxy-2-((1S,2S)-2-(4-methylpyrimidin-2-yl)cyclopropyl)quinolin-7-yl)amino)methyl)imidazo[1,2-a]pyridin-8-yl)-3-methylimidazolidine-2,4-dione; 1-(6-cyclopropyl-2-(((4-methoxy-2-((1R,2R)-2-(4-methylpyrimidin-2-yl)cyclopropyl)quinolin-7-yl)amino)methyl)imidazo[1,2-a]pyridin-8-yl)-3-methylimidazolidine-2,4-dione; rac-1-(6-cyclopropyl-2-(((3-((1S*,2S*)-2-(4-methylpyrimidin-2-yl)cyclopropyl)quinolin-6-yl)amino)methyl)imidazo[1,2-a]pyridin-8-yl)-3-methylimidazolidine-2,4-dione (I-24); rac-1-(2-(((4-(1H-imidazol-1-yl)-2-((1S*,2S*)-2-(4-methylpyrimidin-2-yl)cyclopropyl)quinolin-7-yl)amino)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)-3-methylimidazolidine-2,4-dione (I-25); rac-1-(6-cyclopropyl-2-(((2-((1S*,2S*)-2-(4-methylpyrimidin-2-yl)cyclopropyl)-4-(1H-1,2,4-triazol-1-yl)quinolin-7-yl)amino)methyl)imidazo[1,2-a]pyridin-8-yl)-3-methylimidazolidine-2,4-dione (I-26); 1-(6-cyclopropyl-2-(((4-(1-methyl-1H-pyrazol-4-yl)-2-((1S,2S)-2-(4-methylpyrimidin-2-yl)cyclopropyl)quinolin-7-yl)amino)methyl)imidazo[1,2-a]pyridin-8-yl)-3-methylimidazolidine-2,4-dione (I-27); 1-(6-cyclopropyl-2-(((5-methoxy-2-((1S,2S)-2-(4-methylpyrimidin-2-yl)cyclopropyl)quinolin-7-yl)amino)methyl)imidazo[1,2-a]pyridin-8-yl)-3-methylimidazolidine-2,4-dione (I-28); rac-1-(6-cyclopropyl-2-(((4-(dimethylamino)-2-((1S*,2S*)-2-(4-methylpyrimidin-2-yl)cyclopropyl)quinolin-7-yl)amino)methyl)imidazo[1,2-a]pyridin-8-yl)-3-methylimidazolidine-2,4-dione (I-29); 1-(2-(((4-(azetidin-1-yl)-2-((1S,2S)-2-(4-methylpyrimidin-2-yl)cyclopropyl)quinolin-7-yl)amino)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)-3-methylimidazolidine-2,4-dione, formate salt (I-30); 1-(2-(((4-(azetidin-1-yl)-2-((1S,2S)-2-(4-methylpyrimidin-2-yl)cyclopropyl)quinolin-7-yl)amino)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)-3-methylimidazolidine-2,4-dione; 1-(6-cyclopropyl-2-(((4-(3-hydroxyazetidin-1-yl)-2-((1S,2S)-2-(4-methylpyrimidin-2-yl)cyclopropyl)quinolin-7-yl)amino)methyl)imidazo[1,2-a]pyridin-8-yl)-3-methylimidazolidine-2,4-dione (I-31); rac-1-(6-cyclopropyl-2-(((4-(methylamino)-2-((1S*,2S*)-2-(4-methylpyrimidin-2-yl)cyclopropyl)quinolin-7-yl)amino)methyl)imidazo[1,2-a]pyridin-8-yl)-3-methylimidazolidine-2,4-dione, formate (I-32); rac-1-(6-cyclopropyl-2-(((2-((1S*,2S*)-2-(4-methylpyrimidin-2-yl)cyclopropyl)-4-(oxetan-3-yloxy)quinolin-7-yl)amino)methyl)imidazo[1,2-a]pyridin-8-yl)-3-methylimidazolidine-2,4-dione (I-33); rac-N-(7-(((6-cyclopropyl-8-(3-methyl-2,4-dioxoimidazolidin-1-yl)imidazo[1,2-a]pyridin-2-yl)methyl)amino)-2-((1S*,2S*)-2-(4-methylpyrimidin-2-yl)cyclopropyl)quinolin-4-yl)-N-methylmethanesulfonamide, formate salt (I-34); rac-N-(7-(((6-cyclopropyl-8-(3-methyl-2,4-dioxoimidazolidin-1-yl)imidazo[1,2-a]pyridin-2-yl)methyl)amino)-2-((1S*,2S*)-2-(4-methylpyrimidin-2-yl)cyclopropyl)quinolin-4-yl)-N-methylmethanesulfonamide; rac-1-(6-cyclopropyl-2-(((4-((1-methylpiperidin-4-yl)oxy)-2-((1S*,2S*)-2-(4-methylpyrimidin-2-yl)cyclopropyl)quinolin-7-yl)amino)methyl)imidazo[1,2-a]pyridin-8-yl)-3-methylimidazolidine-2,4-dione (I-35); 1-(6-cyclopropyl-2-(((2-((1S,2S)-2-(4-methylpyrimidin-2-yl)cyclopropyl)-4-(2-oxa-6-azaspiro[3.3]heptan-6-yl)quinolin-7-yl)amino)methyl)imidazo[1,2-a]pyridin-8-yl)-3-methylimidazolidine-2,4-dione, formate (I-36); 1-(6-cyclopropyl-2-(((2-((1S,2S)-2-(4-methylpyrimidin-2-yl)cyclopropyl)-4-(2-oxa-6-azaspiro[3.3]heptan-6-yl)quinolin-7-yl)amino)methyl)imidazo[1,2-a]pyridin-8-yl)-3-methylimidazolidine-2,4-dione; 1-(6-cyclopropyl-2-(((4-(1,1-dioxidothiomorpholino)-2-((1S,2S)-2-(4-methylpyrimidin-2-yl)cyclopropyl)quinolin-7-yl)amino)methyl)imidazo[1,2-a]pyridin-8-yl)-3-methylimidazolidine-2,4-dione, formate (I-37); 1-(6-cyclopropyl-2-(((4-(1,1-dioxidothiomorpholino)-2-((1S,2S)-2-(4-methylpyrimidin-2-yl)cyclopropyl)quinolin-7-yl)amino)methyl)imidazo[1,2-a]pyridin-8-yl)-3-methylimidazolidine-2,4-dione; 1-(6-cyclopropyl-2-(((4-((2-hydroxy-2-methylpropyl)amino)-2-((1S,2S)-2-(4-methylpyrimidin-2-yl)cyclopropyl)quinolin-7-yl)amino)methyl)imidazo[1,2-a]pyridin-8-yl)-3-methylimidazolidine-2,4-dione (I-38); 1-(6-cyclopropyl-2-(((4-(4-methylpiperazin-1-yl)-2-((1S,2S)-2-(4-methylpyrimidin-2-yl)cyclopropyl)quinolin-7-yl)amino)methyl)imidazo[1,2-a]pyridin-8-yl)-3-methylimidazolidine-2,4-dione, formate salt (I-39); 1-(6-cyclopropyl-2-(((4-(4-methylpiperazin-1-yl)-2-((1S,2S)-2-(4-methylpyrimidin-2-yl)cyclopropyl)quinolin-7-yl)amino)methyl)imidazo[1,2-a]pyridin-8-yl)-3-methylimidazolidine-2,4-dione; rac-1-(6-cyclopropyl-2-(((2-((1S*,2S*)-2-(4-methylpyrimidin-2-yl)cyclopropyl)-4-morpholinoquinolin-7-yl)amino)methyl)imidazo[1,2-a]pyridin-8-yl)-3-methylimidazolidine-2,4-dione (I-40); rac-1-(6-cyclopropyl-2-(((2-((1S*,2S*)-2-(4-methylpyrimidin-2-yl)cyclopropyl)-4-morpholinoquinolin-7-yl)amino)methyl)imidazo[1,2-a]pyridin-8-yl)-3-methylimidazolidine-2,4-dione, first-eluting isomer (I-41); rac-1-(6-cyclopropyl-2-(((2-((1S*,2S*)-2-(4-methylpyrimidin-2-yl)cyclopropyl)-4-morpholinoquinolin-7-yl)amino)methyl)imidazo[1,2-a]pyridin-8-yl)-3-methylimidazolidine-2,4-dione (I-42), the second-eluting isomer (I-42); 1-(6-cyclopropyl-2-(((2-((1S,2S)-2-(4-methylpyrimidin-2-yl)cyclopropyl)-4-morpholinoquinolin-7-yl)amino)methyl)imidazo[1,2-a]pyridin-8-yl)-3-methylimidazolidine-2,4-dione; 1-(6-cyclopropyl-2-(((2-((1R,2R)-2-(4-methylpyrimidin-2-yl)cyclopropyl)-4-morpholinoquinolin-7-yl)amino)methyl)imidazo[1,2-a]pyridin-8-yl)-3-methylimidazolidine-2,4-dione; 1-[6-cyclopropyl-2-[[2-[(1S,2S)-2-(4-methylpyrimidin-2-yl)cyclopropyl]-4-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-7-quinolyl]oxymethyl]imidazo[1,2-a]pyridin-8-yl]-3-methyl-imidazolidine-2,4-dione (I-43); 8-((1S,2S)-2-(3-chlorophenyl)cyclopropyl)-7-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-7H-purine (I-44); 2-((1S,2S)-2-(3-chlorophenyl)cyclopropyl)-N-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-benzo[d]imidazol-6-amine (I-45); 2-((1S,2S)-2-(3-chlorophenyl)cyclopropyl)-N-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-benzo[d]imidazol-7-amine (I-46); rac-tert-butyl(2-((1S*,2S*)-2-(3-chlorophenyl)cyclopropyl)-4-methoxyquinolin-7-yl)((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)carbamate (I-47); rac-2-((1S*,2S*)-2-(3-chlorophenyl)cyclopropyl)-N-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-4-methoxyquinolin-7-amine (I-48); rac-2-((1S*,2S*)-2-(3-chlorophenyl)cyclopropyl)-7-(((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)amino)quinolin-4(1H)-one (I-49); 2-((1S,2S)-2-(3-chlorophenyl)cyclopropyl)-7-(((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)amino)quinazolin-4(1H)-one (I-50); 2-((1S,2S)-2-(3-chlorophenyl)cyclopropyl)-7-(((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)amino)quinolin-4-ol (I-51); 7-((2R,4S)-4-((tert-butyldimethylsilyl)oxy)-2-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)pyrrolidin-1-yl)-4-methoxy-2-((1RS,2RS)-2-(4-methylpyrimidin-2-yl)cyclopropyl)quinoline (I-52); (3S,5R)-5-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)-1-(4-methoxy-2-(rac(1S*,2S*)-2-(4-methylpyrimidin-2-yl)cyclopropyl)quinolin-7-yl)pyrrolidin-3-ol (I-53); rac-7-((2R,4S)-2-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)-4-hydroxypyrrolidin-1-yl)-2-((1S*,2S*)-2-(4-methylpyrimidin-2-yl)cyclopropyl)quinolin-4-ol (I-54); rac-6-(((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)amino)-3-((1S*,2S*)-2-(4-methylpyrimidin-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]pyridin-6-yl)-5-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)pyrrolidin-3-ol (I-56); rac-1-(6-cyclopropyl-2-(((2-((1S*,2S*)-2-(4-methylpyrimidin-2-yl)cyclopropyl)quinolin-7-yl)amino)methyl)imidazo[1,2-a]pyridin-8-yl)-3-methylimidazolidine-2,4-dione (I-57); 1-(6-cyclopropyl-2-(((2-((1R,2R)-2-(4-methylpyrimidin-2-yl)cyclopropyl)quinolin-7-yl)amino)methyl)imidazo[1,2-a]pyridin-8-yl)-3-methylimidazolidine-2,4-dione, first-eluting isomer (I-58); 1-(6-cyclopropyl-2-(((2-((1S,2S)-2-(4-methylpyrimidin-2-yl)cyclopropyl)quinolin-7-yl)amino)methyl)imidazo[1,2-a]pyridin-8-yl)-3-methylimidazolidine-2,4-dione, second-eluting isomer (I-59); rac-1-(6-cyclopropyl-2-(((2-((1S*,2S*)-2-(4-methylpyrimidin-2-yl)cyclopropyl)quinazolin-7-yl)amino)methyl)imidazo[1,2-a]pyridin-8-yl)-3-methylimidazolidine-2,4-dione (I-60); rac-1-(6-cyclopropyl-2-(((3-((1S*,2S*)-2-(4-methylpyrimidin-2-yl)cyclopropyl)-1,1-dioxide-4H-benzo[b][1,4]thiazin-6-yl)amino)methyl)imidazo[1,2-a]pyridin-8-yl)-3-methylimidazolidine-2,4-dione (I-61); rac-1-(6-cyclopropyl-2-(((3-((1S*,2S*)-2-(4-methylpyrimidin-2-yl)cyclopropyl)quinoxalin-6-yl)amino)methyl)imidazo[1,2-a]pyridin-8-yl)-3-methylimidazolidine-2,4-dione (I-62); rac-1-(6-cyclopropyl-2-(((2-((1S*,2S*)-2-(4-methylpyrimidin-2-yl)cyclopropyl)pyrido[4,3-d]pyrimidin-7-yl)amino)methyl)imidazo[1,2-a]pyridin-8-yl)-3-methylimidazolidine-2,4-dione (I-63); rac-6-(((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)amino)-3-((1S*,2S*)-2-(4-methylpyrimidin-2-yl)cyclopropyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (I-64); rac-6-(((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)amino)-3-((1S*,2S*)-2-(4-methylpyrimidin-2-yl)cyclopropyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide, first-eluting isomer (I-65); rac-6-(((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)amino)-3-((1S*,2S*)-2-(4-methylpyrimidin-2-yl)cyclopropyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide, the second-eluting isomer (I-66); 6-(((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)amino)-3-((1S,2S)-2-(4-methylpyrimidin-2-yl)cyclopropyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 6-(((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)amino)-3-((1R,2R)-2-(4-methylpyrimidin-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-methylpyrimidin-2-yl)cyclopropyl)quinolin-7-yl)pyrrolidin-2-yl)imidazo[1,2-a]pyridin-8-yl)-3-methylimidazolidine-2,4-dione (I-67); rac-1-(6-cyclopropyl-2-((2R,4S)-4-hydroxy-1-(2-((1S*,2S*)-2-(4-methylpyrimidin-2-yl)cyclopropyl)quinolin-7-yl)pyrrolidin-2-yl)imidazo[1,2-a]pyridin-8-yl)-3-methylimidazolidine-2,4-dione (I-68); rac-1-(6-cyclopropyl-2-(((4-(2-hydroxyethoxy)-2-((1S*,2S*)-2-(4-methylpyrimidin-2-yl)cyclopropyl)quinolin-7-yl)amino)methyl)imidazo[1,2-a]pyridin-8-yl)-3-methylimidazolidine-2,4-dione (I-69); rac-1-(6-cyclopropyl-2-(((2-((1S*,2S*)-2-(4-methylpyrimidin-2-yl)cyclopropyl)quinolin-8-yl)amino)methyl)imidazo[1,2-a]pyridin-8-yl)-3-methylimidazolidine-2,4-dione (I-70); rac-1-(6-cyclopropyl-2-((5-((1S*,2S*)-2-(4-methylpyrimidin-2-yl)cyclopropyl)-3H-imidazo[4,5-b]pyridin-3-yl)methyl)imidazo[1,2-a]pyridin-8-yl)-3-methylimidazolidine-2,4-dione (I-71); rac-1-(6-cyclopropyl-2-((5-((1S*,2S*)-2-(4-methylpyrimidin-2-yl)cyclopropyl)-1H-imidazo[4,5-b]pyridin-1-yl)methyl)imidazo[1,2-a]pyridin-8-yl)-3-methylimidazolidine-2,4-dione (I-72); 1-(6-cyclopropyl-2-((5-((1S,2S)-2-(4-methylpyrimidin-2-yl)cyclopropyl)-1H-imidazo[4,5-b]pyridin-1-yl)methyl)imidazo[1,2-a]pyridin-8-yl)-3-methylimidazolidine-2,4-dione; 1-(6-cyclopropyl-2-((5-((1R,2R)-2-(4-methylpyrimidin-2-yl)cyclopropyl)-1H-imidazo[4,5-b]pyridin-1-yl)methyl)imidazo[1,2-a]pyridin-8-yl)-3-methylimidazolidine-2,4-dione; rac-7-(((6-cyclopropyl-8-(3-methyl-2,4-dioxoimidazolidin-1-yl)imidazo[1,2-a]pyridin-2-yl)methyl)amino)-2-((1S*,2S*)-2-(4-methylpyrimidin-2-yl)cyclopropyl)quinoline-4-carbonitrile (I-73); rac-N-((6-cyclopropyl-8-(4-ethylpiperazin-1-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-2-((1S*,2S*)-2-(4-methylpyrimidin-2-yl)cyclopropyl)quinolin-7-amine (I-74); rac-1-(6-cyclopropyl-2-(((5-(methoxymethyl)-2-((1S*,2S*)-2-(4-methylpyrimidin-2-yl)cyclopropyl)quinolin-7-yl)amino)methyl)imidazo[1,2-a]pyridin-8-yl)-3-methylimidazolidine-2,4-dione (I-75); rac-1-(6-cyclopropyl-2-(((4-(methoxymethyl)-2-((1S*,2S*)-2-(4-methylpyrimidin-2-yl)cyclopropyl)quinolin-7-yl)amino)methyl)imidazo[1,2-a]pyridin-8-yl)-3-methylimidazolidine-2,4-dione (I-76); rac-1-(6-cyclopropyl-2-(((4-(hydroxymethyl)-2-((1S*,2S*)-2-(4-methylpyrimidin-2-yl)cyclopropyl)quinolin-7-yl)amino)methyl)imidazo[1,2-a]pyridin-8-yl)-3-methylimidazolidine-2,4-dione (I-77); rac-1-(6-cyclopropyl-2-(((2-((1S*,2S*)-2-(4-methylpyrimidin-2-yl)cyclopropyl)quinolin-7-yl)amino)methyl)imidazo[1,2-a]pyridin-8-yl)-3-(oxetan-3-yl)imidazolidine-2,4-dione (I-78); rac-1-(6-cyclopropyl-2-(((2-((1S*,2S*)-2-(4-methylpyrimidin-2-yl)cyclopropyl)-4,4-dioxide-1H-pyrido[3,4-b][1,4]thiazin-7-yl)amino)methyl)imidazo[1,2-a]pyridin-8-yl)-3-methylimidazolidine-2,4-dione (I-79); rac-6-(((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)(methyl)amino)-3-((1S*,2S*)-2-(4-methylpyrimidin-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-methylpyrimidin-2-yl)cyclopropyl)quinolin-7-yl)amino)methyl)imidazo[1,2-a]pyridin-8-yl)imidazolidine-2,4-dione (I-81); rac-7-(((6-cyclopropyl-8-(3-methyl-2,4-dioxoimidazolidin-1-yl)imidazo[1,2-a]pyridin-2-yl)methyl)amino)-2-((1S*,2S*)-2-(4-methylpyrimidin-2-yl)cyclopropyl)quinoline-5-carbonitrile (I-82); rac-4-chloro-2-((1S*,2S*)-2-(7-(((6-cyclopropyl-8-(3-methyl-2,4-dioxoimidazolidin-1-yl)imidazo[1,2-a]pyridin-2-yl)methyl)amino)quinolin-2-yl)cyclopropyl)benzonitrile (I-83); rac-1-(6-cyclopropyl-2-(((6-methoxy-2-((1S*,2S*)-2-(4-methylpyrimidin-2-yl)cyclopropyl)quinolin-7-yl)amino)methyl)imidazo[1,2-a]pyridin-8-yl)-3-methylimidazolidine-2,4-dione (I-84); rac-2-(7-(((6-cyclopropyl-8-(3-methyl-2,4-dioxoimidazolidin-1-yl)imidazo[1,2-a]pyridin-2-yl)methyl)amino)-2-((1S*,2S*)-2-(4-methylpyrimidin-2-yl)cyclopropyl)quinolin-4-yl)acetonitrile (I-85); rac-1-(6-cyclopropyl-2-(((5-hydroxy-7-((1S*,2S*)-2-(4-methylpyrimidin-2-yl)cyclopropyl)pyrido[2,3-d]pyrimidin-2-yl)amino)methyl)imidazo[1,2-a]pyridin-8-yl)-3-methylimidazolidine-2,4-dione (I-86); 6-((1-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)ethyl)amino)-3-((1S,2S)-2-(4-methylpyrimidin-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-methylpyrimidin-2-yl)cyclopropyl)quinolin-7-yl)amino)methyl)imidazo[1,2-a]pyridin-8-yl)-3-methylimidazolidine-2,4-dione (I-88); rac-7-chloro-6-(((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)amino)-3-((1S*,2S*)-2-(4-methylpyrimidin-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-methylpyrimidin-2-yl)cyclopropyl)quinolin-7-yl)amino)methyl)imidazo[1,2-a]pyridin-8-yl)-5-(3-hydroxyoxetan-3-yl)-3-methylimidazolidine-2,4-dione (I-90); 6-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methoxy)-3-((1S,2S)-2-(4-methylpyrimidin-2-yl)cyclopropyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (I-91); rac-6-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methoxy)-3-((1S*,2S*)-2-(4-methylpyrimidin-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-dioxoimidazolidin-1-yl)imidazo[1,2-a]pyridin-2-yl)methyl)amino)quinolin-2-yl)cyclopropyl)benzonitrile (I-93); 6-(((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)amino)-4-methyl-3-((1S,2S)-2-(4-methylpyrimidin-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-methylpyrimidin-2-yl)cyclopropyl)quinolin-7-yl)amino)methyl)imidazo[1,2-a]pyridin-8-yl)-3-methylimidazolidine-2,4-dione (I-95); 3-methyl-1-(6-methyl-2-(((2-((1S,2S)-2-(4-methylpyrimidin-2-yl)cyclopropyl)-4-(2-oxa-6-azaspiro[3.3]heptan-6-yl)quinolin-7-yl)oxy)methyl)imidazo[1,2-a]pyridin-8-yl)imidazolidine-2,4-dione (I-96); 1-(6-cyclopropyl-2-(((4-((2-hydroxy-2-methylpropyl)amino)-2-((1S,2S)-2-(4-methylpyrimidin-2-yl)cyclopropyl)quinolin-7-yl)oxy)methyl)imidazo[1,2-a]pyridin-8-yl)-3-methylimidazolidine-2,4-dione (I-97); 1-(6-cyclopropyl-2-((methyl(2-((1S,2S)-2-(4-methylpyrimidin-2-yl)cyclopropyl)-4-(2-oxa-6-azaspiro[3.3]heptan-6-yl)quinolin-7-yl)amino)methyl)imidazo[1,2-a]pyridin-8-yl)-3-methylimidazolidine-2,4-dione (I-98); 1-(6-cyclopropyl-2-(1-((2-((1S,2S)-2-(4-methylpyrimidin-2-yl)cyclopropyl)-4-(2-oxa-6-azaspiro[3.3]heptan-6-yl)quinolin-7-yl)amino)ethyl)imidazo[1,2-a]pyridin-8-yl)-3-methylimidazolidine-2,4-dione (I-99); 1-(6-cyclopropyl-2-(((4-((2-hydroxy-2-methylpropyl)(methyl)amino)-2-((1S,2S)-2-(4-methylpyrimidin-2-yl)cyclopropyl)quinolin-7-yl)amino)methyl)imidazo[1,2-a]pyridin-8-yl)-3-methylimidazolidine-2,4-dione (I-100); 1-(6-cyclopropyl-2-((R)-1-((2-((1S,2S)-2-(4-methylpyrimidin-2-yl)cyclopropyl)-4-(2-oxa-6-azaspiro[3.3]heptan-6-yl)quinolin-7-yl)amino)ethyl)imidazo[1,2-a]pyridin-8-yl)-3-methylimidazolidine-2,4-dione (I-101); rac-1-(6-cyclopropyl-2-(((5-methoxy-2-((1S*,2S*)-2-(4-methylpyrimidin-2-yl)cyclopropyl)quinolin-7-yl)oxy)methyl)imidazo[1,2-a]pyridin-8-yl)-3-methylimidazolidine-2,4-dione (I-102); 1-(6-cyclopropyl-2-(((2-((1S,2S)-2-(4-methylpyrimidin-2-yl)cyclopropyl)-4-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-1,6-naphthyridin-7-yl)oxy)methyl)imidazo[1,2-a]pyridin-8-yl)-3-methylimidazolidine-2,4-dione (I-103); rac-1-(2-(((5-methoxy-2-((1S*,2S*)-2-(4-methylpyrimidin-2-yl)cyclopropyl)quinolin-7-yl)amino)methyl)-6-methylimidazo[1,2-a]pyridin-8-yl)-3-methylimidazolidine-2,4-dione (I-104); 6-(((6-cyclopropyl-8-fluoroimidazo[1,2-a]pyridin-2-yl)methyl)amino)-3-((1S,2S)-2-(4-methylpyrimidin-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-methylpyrimidin-2-yl)cyclopropyl)quinolin-7-yl)amino)methyl)imidazo[1,2-a]pyrazin-8-yl)-3-methylimidazolidine-2,4-dione (I-106); 1-(5-cyclopropyl-2-(((2-((1S,2S)-2-(4-methylpyrimidin-2-yl)cyclopropyl)-4-(2-oxa-6-azaspiro[3.3]heptan-6-yl)quinolin-7-yl)amino)methyl)pyrazolo[1,5-a]pyridin-7-yl)-3-methylimidazolidine-2,4-dione (I-107); 1-(5-cyclopropyl-2-(((2-((1S,2S)-2-(4-methylpyrimidin-2-yl)cyclopropyl)-4-(2-oxa-6-azaspiro[3.3]heptan-6-yl)quinolin-7-yl)oxy)methyl)pyrazolo[1,5-a]pyridin-7-yl)-3-methylimidazolidine-2,4-dione (I-108); or pharmaceutical salts thereof.

[0135] Compounds explicitly 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 a compound according to the present disclosure, e.g., a compound of Formula (I)-(VI-c), or a pharmaceutical composition comprising a compound or compounds of Formula (I)-(VI-c) named in the examples in combination with a pharmaceutically acceptable excipient (e.g., carrier).

[0137] The pharmaceutical composition comprises an optical isomer, diastereomer, or pharmaceutically acceptable salt of the inhibitor disclosed herein. The compound of Formula (I)-(VI-c) contained in the pharmaceutical composition can be covalently bound to a carrier moiety as described above. Alternatively, the compound of Formula (I)-(VI-c) contained in the pharmaceutical composition is not covalently bound to a carrier moiety.

[0138] As used herein, "pharmaceutically acceptable carrier" refers to a pharmaceutical excipient, e.g., a pharmaceutically and physiologically acceptable organic or inorganic carrier substance suitable for enteral or parenteral administration that does not adversely react with the active agent. Suitable pharmaceutically acceptable carriers include water, salt solutions (e.g., Ringer's solution), alcohol, oils, gelatin, and carbohydrates such as lactose, amylose, or starch, fatty acid esters, hydroxymethylcellulose, and polyvinylpyrrolidine. Such preparations may be sterilized and, if necessary, may be mixed with auxiliary substances, such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring agents, and / or flavoring agents, which do not adversely react with the compounds of the present invention.

[0139] The compounds of the present invention can be administered to a subject alone or co-administered. Co-administration means that the compounds are administered individually or in combination (two or more compounds), simultaneously or sequentially. Also, the preparation can be combined with other active substances (for example, to reduce metabolic degradation) if necessary.

[0140] In some embodiments, test agents as described herein can be incorporated into pharmaceutical compositions for administration by methods known to those of skill in the art and described herein for the provided compounds.

[0141] D. Formulation The compounds of the present invention can be prepared into a wide variety of oral, parenteral, and topical dosage forms and can be administered in a wide variety of oral, parenteral, and topical dosage forms. Thus, the compounds of the present invention can be administered by injection (e.g., intravenously, intramuscularly, intradermally, subcutaneously, intraduodenally, or intraperitoneally). 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 transdermally. It is also contemplated that multiple routes of administration (e.g., intramuscularly, orally, transdermally) can be used to administer the compounds of the present invention. Thus, 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 can be solid or liquid.Solid preparations include powder, tablets, pills, capsules, cachets, suppositories and dispersible granules.Solid carriers can be one or more substances that can also function as diluents, flavoring agents, binders, preservatives, tablet disintegrating agents or encapsulating materials.

[0143] In powders, the carrier is a finely divided solid in admixture with the finely divided active ingredient. In tablets, the active ingredient is mixed with a carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.

[0144] Powders and tablets preferably contain 5% to 70% of the active compound. Suitable carriers include magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, low-melting waxes, cocoa butter, and the like. The term "preparation" is intended to include a combination of the active compound with an encapsulating material as a carrier, in which the active ingredient is surrounded by a carrier, with or without other carriers, thereby providing a capsule in which the carrier is associated with the active ingredient. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.

[0145] For preparing suppositories, a low-melting wax, such as a mixture of fatty acid glycerides or cocoa butter, is first melted and the active ingredient is dispersed homogeneously therein as by stirring, etc. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool, and thereby solidify.

[0146] Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water / propylene glycol solutions.For parenteral injection, liquid preparations can be formulated in solution in aqueous polyethylene glycol solution.

[0147] When 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, as well as suspensions, emulsions, or inserts (including suppositories). In particular, carriers for parenteral administration include aqueous dextrose solutions, saline, purified water, ethanol, glycerol, propylene glycol, peanut oil, sesame oil, polyoxyethylene block polymers, etc. Ampoules are convenient unit doses. The compounds of the present invention can 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 WO 96 / 05309, the teachings of 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 adding suitable colorants, flavors, stabilizers, and thickeners, if desired. Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active ingredient in water with viscous materials, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well-known suspending agents.

[0149] Also included are solid preparations that are intended to be converted immediately before use into liquid form preparations for oral administration. Such liquid forms include solutions, suspensions, and emulsions. These preparations may contain, in addition to the active ingredient, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizers, etc.

[0150] Pharmaceutical preparations are preferably in unit dosage form.In this form, the preparation is subdivided into unit doses containing appropriate amounts of active ingredients.The unit dosage form can be a packaged preparation, and the package contains individual amounts of the preparation, for example, packaged tablets, capsules, and powders in vials or ampoules.The unit dosage form can also be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.

[0151] The quantity of active ingredient in a unit dose preparation may be varied or adjusted according to the particular use and potency of the active ingredient. The composition may also contain other compatible therapeutic agents, if desired.

[0152] Some compounds may have limited water solubility and therefore may require a surfactant or other suitable cosolvent in the composition. Such cosolvents include polysorbates 20, 60, and 80; Pluronic F-68, F-84, and P-103; cyclodextrin; and polyoxyl 35 castor oil. Such cosolvents are typically used at levels between about 0.01% and about 2% by weight.

[0153] A viscosity greater than that of a simple aqueous solution may be desirable to reduce variability in dispensing the formulation, to reduce physical separation of the components of a suspension or emulsion formulation, and / or to otherwise improve the formulation. Examples of such viscosity-enhancing agents include polyvinyl alcohol, polyvinylpyrrolidone, methylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, carboxymethylcellulose, hydroxypropylcellulose, chondroitin sulfate and its salts, hyaluronic acid and its salts, and combinations of the foregoing. Such agents are typically used at levels between about 0.01% and about 2% by weight.

[0154] The compositions of the present invention may additionally contain ingredients that provide sustained release and / or comfort. Such ingredients include high molecular weight anionic mucus-mimetic polymers, gelling polysaccharides, and micronized drug carrier substrates. These ingredients are described in more detail in U.S. Patent Nos. 4,911,920; 5,403,841; 5,212,162; and 4,861,760. The entire contents of these patents are incorporated herein by reference in their entirety 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 purpose. The actual amount effective for a particular application will depend, inter alia, on the condition being treated. For example, when administered in a method for treating HAE, such compositions will contain an amount of active ingredient effective to achieve the desired result (e.g., inhibiting PKa and / or reducing the amount of bradykinin in a subject).

[0156] The dosage and frequency (single or multiple doses) of the compound administered can vary depending on a variety of factors, including the route of administration; the size, age, sex, health, weight, body mass index, and diet of the recipient; the nature and extent of symptoms of the disease being treated (e.g., a disease responsive 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 regimen. Other therapeutic regimens or agents may be used in conjunction with the methods and compounds of the invention.

[0157] For any provided compound or test agent, the therapeutically effective amount can be initially determined by cell culture assays. The target concentration is the concentration of active compound(s) that can reduce PKa enzyme activity, as measured, for example, using the methods described.

[0158] The therapeutically effective amount used in humans can be determined from animal models.For example, the dose for humans can be formulated to achieve the concentration that has been found to be effective in animals.The dosage for humans can be adjusted by monitoring PKa inhibition and adjusting the dosage upward or downward as described above.

[0159] Dosage can vary depending on the requirements of the patient and the compound used. In the context of the present invention, the dose administered to a patient should be sufficient to bring about a beneficial therapeutic response in the patient over time. The size of the dose will also be determined by the existence, nature, and extent of any adverse side effects. In some embodiments, the compound of the present disclosure or a pharmaceutical composition comprising the same is provided as a unit dose.

[0160] In one aspect, the compounds provided herein exhibit one or more pharmacokinetic (PK) properties (e.g., C max , t max , C min , t 1 / 2In 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 No. WO2019 / 178129.

[0161] F. Treatment Method The present disclosure provides compounds and pharmaceutical compositions comprising the same for use in medicine, i.e., for use in treatment. The present disclosure further provides the use of any compound described herein to inhibit the activity of PKa, which is beneficial in treating diseases and conditions mediated by PKa. Exemplary PKa-mediated disorders include edema, which refers to swelling in a subject's entire body or part of it due to inflammation or injury when small blood vessels become leaky and release fluid into surrounding tissues. In some examples, the edema is HAE. In other examples, the edema occurs in the eye (e.g., diabetic macular edema (DME)). The present disclosure provides methods for inhibiting the activity of PKa. In certain embodiments, the present application provides methods 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, the present application provides methods for inhibiting the activity of PKa in vivo by delivering an effective amount of any of the compounds described herein to a subject in need of treatment via a suitable route.

[0162] In certain embodiments, the methods comprise administering any of the compounds described herein, or a pharmaceutically acceptable salt thereof, to a subject in need thereof (e.g., a subject such as a human patient (e.g., having edema)). In certain embodiments, the methods comprise administering a compound of Formula (I)-(VI-c), or a pharmaceutically acceptable salt or composition thereof, to a subject in need thereof. In some embodiments, the methods comprise administering a pharmaceutical composition comprising a compound of Formula (I)-(VI-c) or a pharmaceutically acceptable salt thereof to a subject in need thereof.

[0163] In certain embodiments, the subject treated by any of the methods described herein is a human patient who has, is suspected of having, or is at risk of having edema, such as HAE or diabetic macular edema (DME).Subjects with edema can be identified by routine medical examination, for example, clinical examination.Subjects suspected of having edema can show one or more symptoms of disease / disorder.Subjects at risk of edema can be subjects who have one or more of the risk factors associated with disease, for example, C1-INH deficiency for HAE.

[0164] In certain embodiments, provided herein are methods for alleviating one or more symptoms of HAE in a human patient suffering from an HAE attack. Such patients can be identified through routine medical procedures. An effective amount of one or more of the provided compounds can be administered to a human patient by a suitable route, such as the routes described herein. The compounds described herein can be used alone or in combination with other anti-HAE agents, such as C1 esterase inhibitors (e.g., Cinryze® or Berinert®), PKa inhibitors (e.g., ecallantide or lanadelumab), or bradykinin B2 receptor antagonists (e.g., Firazyr®).

[0165] In another embodiment, provided herein is a method for reducing the risk of HAE attacks in a human HAE patient in a quiescent state. Such patients can be identified based on various factors, including a history of HAE attacks. An effective amount of one or more of the compounds can be administered to a human patient by a suitable route, such as the routes described herein. The compounds described herein can be used alone or in combination with other anti-HAE agents, such as C1 esterase inhibitors (e.g., Cinryze® or Berinert®), PKa inhibitors (e.g., ecallantide or lanadelumab), or bradykinin B2 receptor antagonists (e.g., Firazyr®).

[0166] In yet other embodiments, provided herein is prophylactic treatment of HAE in human patients at risk for HAE attacks using one or more of the compounds described herein. In some embodiments, patients suitable for prophylactic treatment of HAE are human subjects suffering from HAE (e.g., with a history of HAE attacks). In some embodiments, patients suitable for such prophylactic treatment are human subjects whose history of HAE attacks makes them worthy of a prophylactic approach, as determined by a physician (e.g., a human subject experiencing more than a certain average number of attacks over a period of time, including, but not limited to, one, two, or more attacks per month). Alternatively, patients suitable for prophylactic treatment may be human subjects without a history of HAE attacks but with one or more risk factors for HAE (e.g., a family history, a genetic defect in the C1-INH gene, etc.). Such prophylactic treatment may require a compound described herein as the sole active agent or may require an additional anti-HAE agent, such as those described herein.

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

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

[0169] In certain embodiments, the subject to be treated is an animal. The animal may be of either sex and at any stage of development. In certain embodiments, the subject is a mammal. In certain embodiments, the subject to be treated is a human. In certain embodiments, the subject is a 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 livestock animal, such as a cow, pig, horse, sheep, or goat. In certain embodiments, the subject is a zoo animal. In other embodiments, the subject is a research animal, such as a rodent (e.g., mouse, rat), dog, pig, or non-human primate. In certain embodiments, the animal is a genetically engineered animal. In certain embodiments, the animal is a transgenic animal.

[0170] Certain methods described herein may include administering one or more additional pharmaceutical agents(s) in combination with a compound described herein. The additional pharmaceutical agent(s) may be administered simultaneously with the compound of Formula (I)-(VI-c) or at a different time than the compound of Formula (I)-(VI-c). For example, the compound of Formula (I)-(VI-c) and any additional pharmaceutical agent(s) may be on the same administration schedule or different administration schedules. All or a portion of the dose of the compound of Formula (I)-(VI-c) may be administered before all or a portion of the dose of the additional pharmaceutical agent, after all or a portion of the dose of the additional pharmaceutical agent, within the administration schedule of the additional pharmaceutical agent, or a combination thereof. The timing of administration of the compound of Formula (I)-(VI-c) and the additional pharmaceutical agent may vary depending on the additional pharmaceutical agent.

[0171] In certain embodiments, the additional pharmaceutical agent comprises an agent useful in the treatment of edema, e.g., HAE or DME. Examples of such agents are provided herein.

[0172] Also provided is the use of a compound of the present disclosure for the manufacture of a medicament for a condition / disease disclosed herein.

[0173] In the context of this specification, "comprising" should be interpreted as "including." Embodiments of the invention comprising particular features / elements are also intended to cover alternative embodiments that "consist" or "consist essentially of" the relevant elements / features. Where technically appropriate, embodiments of the invention may be combined.

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

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

[0176] The Background Art section of this specification contains relevant technical information and may be used as a basis for revision. Subject headings are used herein to divide the document into sections and are not intended to be used to interpret the meaning of the disclosure provided herein.

[0177] This application claims priority to U.S. Provisional Patent Application No. 63 / 162,483, filed March 17, 2021, which is incorporated herein by reference. This application may be used as a basis for any amendment to this application, particularly with respect to the chemical structures disclosed therein. [Example]

[0178] IV. Working Examples In certain embodiments, the Examples describe compounds containing one or more stereocenters, and the particular stereocenter is designated as "S*" or "R*." In either case, the "*" designation generally indicates that the exact configuration is unknown (e.g., for a compound with a single stereocenter, the R*- or S*- designation indicates that either the R- or S-isomer has been isolated, but the configuration of the stereocenter in the particular isomer isolated has not been determined).

[0179] It will be understood that the compounds described within the examples may contain two or more stereocenters. As noted above, single stereochemical isomers, as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the compounds of the invention, are within the scope of the present invention. When more than one "S*" or "R*" appears within a pair of parentheses within a particular compound name (e.g., "(1S*,2S*)"), it is understood that the S* and / or R* configurations are relative to one another. For example, a compound designated "(1S*,2S*)-" or "(1R*,2R*)-" will be understood to specifically refer to either the "(1S,2S)-" isomer or the "(1R,2R)-" isomer, but not the "(1S,2R)-" or "(1R,2S)-" isomer. Furthermore, compounds designated "rac-(1S*,2S*)-" or "rac-(1R*,2R*)-" will be understood to include a racemic mixture of the "(1S,2S)-" and "(1R,2R)-" isomers. Similarly, compounds designated "(1S*,2R*)-" or "(1R*,2S*)-" will be understood to specifically refer to either the "(1R,2S)-" isomer or the "(1S,2R)-" isomer, but not to the "(1S,2S)-" or "(1R,2R)-" isomers. Additionally, compounds designated "rac-(1R*,2S*)-" or "rac-(1S*,2R*)-" will be understood to include a racemic mixture of the "(1R,2S)-" and "(1S,2R)-" isomers. In certain embodiments, the examples include schemes showing compounds with one or more stereocenters. In some embodiments, the symbol "&" followed by a number appears adjacent to the stereocenter. In such cases, it is understood that a mixture of both configurations (e.g., R- and S-) is included at that position.

[0180] In some embodiments, the term "or" is followed by a number adjacent to the stereogenic center. In such cases, it is understood that either the "R-" or "S-" isomer is indicated, and that the particular isomer has not been determined.

[0181] In some embodiments, the numbering following the symbol "&" or the term "or" refers to the relationship of one stereocenter to another in the compound. For example, when two stereocenters in a compound are each designated with the same number (e.g., two instances of "&1"), it is understood that the configurations are relative to one another (e.g., when a structure is depicted as (S,S) and both stereocenters are designated as "&1", it is understood that a mixture of the (S,S) and (R,R) isomers is included, but not the (S,R) or (R,S) isomers. However, when each stereocenter is designated with a different number (e.g., one instance of "&1" and one instance of "&2"), it is understood that the configurations can be independent of one another (e.g., when a structure is depicted as (S,S) and one stereocenter is designated as "&1" and one stereocenter is designated as "&2", it is understood that a mixture of the (S,S), (S,R), (R,S), and (R,R) isomers is included).

[0182] Synthesis of intermediates Synthesis of (1S,2S)-2-(4-methylpyrimidin-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)Cl-DCM (2 g, 2.5 mmol), and KCO (17.25 g, 125 mmol) in dioxane (100 mL) and HO (5 mL) was stirred at 90 °C for 12 h. The reaction mixture was treated with HO (50 mL) and extracted with EA (50 mL × 3). The combined organic layers were washed with brine (50 mL), dried over NaSO, and concentrated in vacuo (at 30 °C). The crude product was purified by silica column chromatography (PE / EtOAc = 5 / 1) to give 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-methylpyrimidin-2-yl)cyclopropane-1-carboxylate [ka] A solution of 4-methyl-2-vinylpyrimidine (4.8 g, 40 mmol) and ethyl 2-diazoacetate (9.12 g, 80 mmol) in toluene (70 mL) was refluxed at 110 °C for 8 hours. The reaction was concentrated in vacuo, and the crude product was purified by silica gel column (PE / EA = 5 / 1) to give rac-ethyl (1S*,2S*)-2-(4-methylpyrimidin-2-yl)cyclopropane-1-carboxylate (3.6 g, 43.7%) as a yellow oil. ESI-MS [M + H] + : 207.2.

[0184] Synthesis of rac-(1S*,2S*)-2-(4-methylpyrimidin-2-yl)cyclopropane-1-carboxylic acid [ka] A mixture of rac-ethyl (1S*,2S*)-2-(4-methylpyrimidin-2-yl)cyclopropane-1-carboxylate (3.6 g, 17.5 mmol) and LiOH—OH (1.4 g, 35 mmol) in THF / HO (20 mL / 10 mL) was stirred at room temperature for 12 h. The reaction was concentrated in vacuo to remove THF, and the pH of the residue was adjusted to 3 with HCl (2N). A white solid precipitated, and the mixture was filtered and dried to give rac-(1S*,2S*)-2-(4-methylpyrimidin-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-methylpyrimidin-2-yl)cyclopropane-1-carboxylic acid [ka] The racemic mixture of rac-(1S,2S)-2-(4-methylpyrimidin-2-yl)cyclopropane-1-carboxylic acid (2.4 g) was separated by SFC to give (1S,2S)-2-(4-methylpyrimidin-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-methylpyrimidin-2-yl)cyclopropane-1-carboxamide [ka] To a solution of (1S,2S)-2-(4-methylpyrimidin-2-yl)cyclopropane-1-carboxylic acid (1.1 g, 6.1 mmol) in dry DCM (20 mL) was slowly added (COCl) (1.56 g, 12.3 mmol) at 0 °C and stirred for an additional 1 h at 0 °C. The reaction mixture was concentrated in vacuo, and the resulting acid chloride was dissolved in dry THF (20 mL), cooled to 0 °C, and then NH (20 mL, 2 M solution in iPrOH) was added. The resulting solution was stirred for an additional 1 h at room temperature and concentrated in vacuo to give the crude product, which was purified by silica gel chromatography (eluent: DCM / MeOH = 20 / 1) to give (1S,2S)-2-(4-methylpyrimidin-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 (first-eluting isomer) [ka] rac-(1S*,2S*)-2-(3-chlorophenyl)cyclopropane-1-carboxylic acid (10 g) was separated using SFC (SFC80, Daicel CHIRALPAK AD-H 250 mm × 20 mm i.d., 5 μm, CO / EtOH = 86 / 14, 50 g / min, 35 °C) to give (1S,2S)-2-(3-chlorophenyl)cyclopropane-1-carboxylic acid (4.5 g, first-eluting isomer, Rt = 3.0 min, 99.9% ee) and (1R,2R)-2-(3-chlorophenyl)cyclopropane-1-carboxylic acid (4.3 g, second-eluting isomer, Rt = 4.0 min, 99.9% ee).

[0188] Synthesis of 6-cyclopropylimidazo[1,2-a]pyridine-2-carbaldehyde [ka] Synthesis of 5-cyclopropylpyridin-2-amine 5-Bromopyridin-2-amine (10 g, 58 mmol), cyclopropylboronic acid (12 g, 120 mmol), SPhos (2.4 g, 5.8 mmol), and KPO (43 g, 200 mmol) were placed under a N atmosphere and suspended in toluene (220 mL) and water (22 mL). The resulting suspension was degassed for 10 min, and Pd(OAc) (0.65 g, 2.9 mmol) was added. The reaction mixture was stirred at 95 °C under a N atmosphere for 16 h. 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 through a hydrophobic frit, and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with a gradient of 10–95% EtOAc in hexanes to afford 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-cyclopropylpyridin-2-amine (5.3 g, 40 mmol) and ethyl 3-bromo-2-oxopropanoate (5.9 mL, 47 mmol) in ethanol (110 mL) was stirred at reflux for 1 h. The mixture was cooled to room temperature and concentrated in vacuo. The residue was dissolved in DCM (100 mL), washed with Na2CO3 (sat. aq., 60 mL), dried through a hydrophobic frit, and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with a gradient of 20-80% EtOAc in hexanes to give 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]pyridin-2-yl)methanol LiAlH4 (1 M in THF, 42.99 mmol, 42.99 mL) 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 h, then EtOAc (5 mL) was added dropwise. The mixture was stirred at room temperature for 1 h, then washed with water (30 mL) and brine (30 mL). The organics were dried over MgSO4 and then concentrated in vacuo to give 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 A suspension of (6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methanol (2.0 g, 11 mmol) and manganese(IV) oxide (9.2 g, 110 mmol) in chloroform (25 mL) and MeCN (25 mL) was stirred for 1 h at 50° C. The mixture was cooled to room temperature, filtered through Celite®, and concentrated in vacuo to give 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]pyridin-2-yl)methanol (0.13 g, 0.69 mmol) in DCM (3.0 mL) was added SOCl (1.0 mL) slowly at 0 °C. The reaction mixture was stirred at room temperature for 2 h. The resulting mixture was concentrated in vacuo to give 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]pyridin-2-yl)methyl)isoindoline-1,3-dione [ka] Synthesis of 2-(3-bromo-2-oxopropyl)isoindoline-1,3-dione A few drops of a solution of bromine (7.6 mL, 150 mmol) in AcOH (80 mL) was added to a stirred solution of 2-(2-oxopropyl)isoindoline-1,3-dione (20 g, 98 mmol) at 70 °C. The reaction was stirred until the solution was colorless. The remaining bromine / AcOH solution was added dropwise over 2 h. The reaction mixture was stirred at 70 °C for an additional 2 h. The mixture was cooled to room temperature and concentrated in vacuo. The residue was dissolved in DCM (300 mL) and washed with NaSO solution (1.0 M, 75 mL) and NaCO solution (10% aqueous, 2 × 150 mL). The combined organics were dried over MgSO and concentrated in vacuo. The residue was triturated with hot diethyl ether, filtered, and dried to give 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]pyridin-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-cyclopropylpyridin-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 h. The mixture was cooled to room temperature and reduced to half its volume by concentration in vacuo. The mixture was diluted with DCM (200 mL) and washed with NaHCO solution (saturated, aqueous, 150 mL) and brine (150 mL). The organics were dried over MgSO and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with a gradient of 0 to 100% EtOAc in cyclohexane to give 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]pyridin-2-yl)methyl)isoindoline-1,3-dione [ka] Synthesis of 3-chloro-5-cyclopropylpyridin-2-amine A mixture of toluene (120 mL) and water (12 mL) was degassed for 50 minutes. 5-Bromo-3-chloropyridin-2-amine (5.0 g, 24 mmol), cyclopropylboronic acid (2.1 g, 24 mmol), SPhos (0.99 g, 2.4 mmol), and KPO (18 g, 84 mmol) were added to the solvent mixture, which was heated to 100 °C. Pd(OAc) (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 and filtered through Celite®, which was washed with toluene. The combined organics were dried over MgSO and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with a gradient of 5–30% EtOAc in cyclohexane to give 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]pyridin-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-cyclopropylpyridin-2-amine (530 mg, 3.1 mmol) in 1,4-dioxane (11 mL) was heated at 98 °C for 17 h. The mixture was cooled to room temperature and concentrated in vacuo. The mixture was partitioned between DCM (2 × 50 mL) and NaHCO (saturated aqueous solution, 50 mL). The organics were dried over MgSO and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with a gradient of 10–50% EtOAc in isohexane to give 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]pyridin-2-yl)methyl)carbamate [ka] Synthesis of 8-bromo-2-(bromomethyl)-6-cyclopropylimidazo[1,2-a]pyridine [ka] A mixture of 3-bromo-5-cyclopropylpyridin-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 under N for 16 h. The reaction mixture was warmed to room temperature, quenched with saturated NaHCO solution (50 mL), and extracted with EtOAc (3 × 50 ml). The combined organics were washed with brine (50 mL), dried over NaSO, and concentrated in vacuo. The crude residue was purified by column chromatography (eluent: DCM / MeOH = 50 / 1 to 30 / 1) to give 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 NaN (244 mg, 3.75 mmol) in DMF (10.0 mL) was stirred under N at room temperature for 16 hours. The mixture was diluted with EtOAc (100 mL) and washed with brine (3 × 50 mL). The organic layer was dried over NaSO and concentrated in vacuo to give 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]pyridin-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 at reflux for 2 hours. The mixture was concentrated in vacuo and purified by preparative TLC (eluent: DCM / MeOH = 10 / 1) to give (8-bromo-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methanamine (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]pyridin-2-yl)methyl)carbamate [ka] A mixture of (8-bromo-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methanamine (550 mg, 2.08 mmol), (Boc)O (679 mg, 3.11 mmol), and EtN (630 mg, 6.24 mmol) in DCM (20 mL) was stirred at room temperature for 16 h. The mixture was quenched with water (50 mL) and extracted with DCM (3 × 50 mL). The combined organics were washed with brine (50 mL), dried over NaSO, and concentrated in vacuo. The residue was purified by preparative TLC (eluent: DCM / MeOH = 20 / 1) to give tert-butyl ((8-bromo-6-cyclopropylimidazo[1,2-a]pyridin-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]pyridin-8-yl)-3-methylimidazolidine-2,4-dione [ka] To a reaction mixture of imidazolidine-2,4-dione (1 g, 10 mmol) in dry toluene (25 mL) was added 1,1-dimethoxy-N,N-dimethylethan-1-amine (4 g, 30 mmol). The reaction was stirred at 110° C. under N for 3 hours. The reaction was cooled to 0° C. in 15 minutes and filtered. The organic layer was concentrated and purified by silica gel chromatography (eluent: DCM / MeOH=10 / 1) to give 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-dioxoimidazolidin-1-yl)imidazo[1,2-a]pyridin-2-yl)methyl)carbamate [ka] To a mixture of 3-methylimidazolidine-2,4-dione (224 mg, 2 mmol), tert-butyl ((8-bromo-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)carbamate (365 mg, 1 mmol), and CsCO (975 mg, 3 mmol) in dry dioxane (10 mL) was added Pd(dba) (183 mg, 0.2 mmol) and XantPhos (116 mg, 0.2 mmol). The reaction was stirred at 100 °C under N for 16 h. The reaction was quenched with water (50 mL) and extracted with EtOAc (30 mL × 3). The organic layer was washed with brine (30 mL), dried over NaSO, concentrated in vacuo, and purified by silica gel chromatography (eluent: DCM / MeOH=10 / 1) to give tert-butyl ((6-cyclopropyl-8-(3-methyl-2,4-dioxoimidazolidin-1-yl)imidazo[1,2-a]pyridin-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]pyridin-8-yl)-3-methylimidazolidine-2,4-dione [ka] To a reaction mixture of tert-butyl ((6-cyclopropyl-8-(3-methyl-2,4-dioxoimidazolidin-1-yl)imidazo[1,2-a]pyridin-2-yl)methyl)carbamate (500 mg, 1.25 mmol) in dry DCM (10 mL) was added TFA (2 mL). The reaction was stirred at room temperature under N for 16 hours. The reaction mixture was neutralized with NH in MeOH, then concentrated in vacuo and purified by silica gel chromatography (eluent: DCM / MeOH=10 / 1) to give 1-(2-(aminomethyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)-3-methylimidazolidine-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-dioxoimidazolidin-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-cyclopropyl-pyridin-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 h. The mixture was allowed to cool and concentrated in vacuo. The residue was dissolved in DCM, washed with water, dried over MgSO, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with 10-60% EtOAc in cyclohexane to give 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]pyridin-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) at −10° C. under a N atmosphere. The mixture was allowed to warm to room temperature over 2 hours. Rochelle's salt (saturated aqueous solution) was added and the mixture was stirred for 18 hours. The mixture was extracted with DCM (3×), and the combined organics were dried over MgSO, filtered through Celite®, and concentrated in vacuo to afford the title compound (3.0 g, 73%) as an off-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]pyridin-8-yl)-3-methylimidazolidine-2,4-dione A mixture of (8-bromo-6-cyclopropyl-imidazo[1,2-a]pyridin-2-yl)methanol (2.44 g, 9.13 mmol), 3-methylimidazolidine-2,4-dione (1.20 g, 10 mmol), Pd(dba) (420 mg, 0.46 mmol), Xantphos (530 mg, 0.91 mmol), and CsCO (8.9 g, 27 mmol) in 1,4-dioxane (110 mL) was degassed with N and heated at 100 °C for 18 h. Water (200 mL) was added, and the mixture was extracted into EtOAc (3 × 100 mL). The combined organic layers were dried (MgSO), filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with 0-10% MeOH in DCM to give 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-dioxoimidazolidin-1-yl)imidazo[1,2-a]pyridine-2-carbaldehyde To a stirred solution of 1-(6-cyclopropyl-2-(hydroxymethyl)imidazo[1,2-a]pyridin-8-yl)-3-methylimidazolidine-2,4-dione (1.2 g, 4.0 mmol) in DCM (40 mL) was added MnO (3.5 g, 40 mmol) and the mixture was stirred at room temperature for 18 hours. Further MnO (3.5 g, 40 mmol) was added and the mixture was stirred at room temperature for 5 hours. Further MnO (690 mg, 7.8 mmol) was added and the mixture was stirred at room temperature for 18 hours. The mixture was filtered through Celite® and concentrated in vacuo to give the title compound (800 mg, 67%) as an off-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]pyridin-8-yl)-3-methylimidazolidine-2,4-dione [ka] To a solution of 1-(6-cyclopropyl-2-(hydroxymethyl)imidazo[1,2-a]pyridin-8-yl)-3-methylimidazolidine-2,4-dione (0.40 g, 1.3 mmol) in DCM (10 mL) was added SOCl (3.0 mL). The resulting mixture was stirred under N at 25 °C for 2 h. The reaction mixture was concentrated in vacuo to give 1-(2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)-3-methylimidazolidine-2,4-dione (0.42 g, quantitative) 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]pyridin-8-yl)-3-methylimidazolidine-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]pyridin-2-yl)methanol (10 g, 37.45 mmol) and MnO (9.8 g, 112 mmol) was stirred at room temperature for 12 h. A second batch of MnO (9.8 g, 112 mmol) was added and stirred at room temperature for an additional 12 h. The reaction mixture was filtered through a short silica pad and washed with EtOAc (500 mL). The filtrate was concentrated in vacuo to give 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]pyridin-2-yl)ethan-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) was slowly added MeMgBr (30 mL, 3 M solution in EtO, 90 mmol) at −65° C., and the resulting solution was stirred for 2 h at −65° C. The reaction was quenched with saturated aqueous NH4Cl (70 mL) at −65° C., stirred and warmed to room temperature, and then extracted with EtOAc (4 × 75 mL). The combined organic layers were washed with brine (75 mL), dried over NaSO, and then concentrated in vacuo to give the crude product, which was purified by silica gel chromatography (eluent: DCM / MeOH=15 / 1) to give 1-(8-bromo-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)ethan-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]pyridin-8-yl)-3-methylimidazolidine-2,4-dione A mixture of 1-(8-bromo-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)ethan-1-ol (7.3 g, 25.98 mmol), 3-methylimidazolidine-2,4-dione (8.9 g, 77.9 mmol), Pd(dba) (2.38 g, 2.6 mmol), Xantphos (3 g, 5.2 mmol), and CsCO (25 g, 77 mmol) in dioxane (75 mL) was stirred at 95° C. for 18 h. The reaction mixture was cooled to room temperature and filtered through Celite®, washing with EtoAc (3 × 75 mL). The combined filtrate was washed with brine (80 mL), dried over NaSO, and then concentrated in vacuo to give the crude product, which was purified by silica gel chromatography (eluent: DCM / MeOH=15 / 1) to give 1-(6-cyclopropyl-2-(1-hydroxyethyl)imidazo[1,2-a]pyridin-8-yl)-3-methylimidazolidine-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]pyrazin-8-yl)-3-methylimidazolidine-2,4-dione [ka] Synthesis of 5-cyclopropylpyrazin-2-amine To a mixture of 5-bromopyrazin-2-amine (10 g, 57 mmol) in toluene / HO (V / V = 1 / 1, 400 mL), cyclopropylboronic acid (15 g, 0.17 mol), S-phos (2.4 g, 5.8 mmol), KPO (36 g, 0.17 mol), and Pd(OAc) (1.3 g, 5.8 mmol) were added. The mixture was stirred at 100 °C under N for 16 h and then cooled to room temperature. The reaction mixture was filtered through Celite®, and the filter cake was washed with DCM / MeOH (10 / 1, 100 mL). The filtrate was concentrated in vacuo to give the crude product, which was purified by silica gel chromatography (eluent: PE / EtOAc = 10 / 1 to 5 / 1) to give 5-cyclopropylpyrazin-2-amine (5.6 g, 72%) as a yellow solid. ESI-MS [M + H] + : 136.1.

[0213] Synthesis of 3-bromo-5-cyclopropylpyrazin-2-amine To a stirred solution of 5-cyclopropylpyrazin-2-amine (5.6 g, 41 mmol) in CHCN (40 mL) was added NBS (7.4 g, 42 mmol) at 0 °C. The mixture was stirred at room temperature for 30 min. The reaction mixture was poured into water (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organics were washed with saturated brine solution (100 mL) and dried over NaSO. The organic layer was concentrated and purified by column chromatography on silica gel (eluent: PE / EtOAc = 10 / 1) to give 3-bromo-5-cyclopropylpyrazin-2-amine (2.0 g, 23% yield). 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-cyclopropylpyrazin-2-amine (2.0 g, 9.3 mmol) in DME (30 mL) was added ethyl 3-bromo-2-oxopropanoate (2.0 g, 10 mmol). The mixture was stirred at 90 °C for 16 hours and cooled to room temperature. The mixture was then poured into water (50 mL) and extracted with EtOAc (3 × 50 mL). The combined organics were washed with saturated brine solution (100 mL), dried over NaSO, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluent: PE / EtOAc = 2 / 1) to give 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]pyrazin-2-yl)methanol To a mixture of 8-bromo-6-cyclopropylimidazo[1,2-a]pyrazine-2-carboxylate (1.0 g, 3.2 mmol) in THF (20 mL) was added DIBAL-H (11 mL, 11 mmol) at −65° C. The mixture was stirred at −65° C. for 1 h, then warmed to 25° C. and stirred for an additional 1 h. The reaction mixture was poured into ice-water (20 mL) and extracted with EtOAc (3×50 mL). The combined organics were washed with saturated brine solution (50 mL), dried over NaSO, and concentrated in vacuo to give a residue that was purified by column chromatography on silica gel (eluent: PE / EtOAc=5 / 1) to give (8-bromo-6-cyclopropylimidazo[1,2-a]pyrazin-2-yl)methanol (0.49 g, 57% yield). ESI-MS [M +H]: 268.0

[0216] Synthesis of 1-(6-cyclopropyl-2-(hydroxymethyl)imidazo[1,2-a]pyrazin-8-yl)-3-methylimidazolidine-2,4-dione To a mixture of (8-bromo-6-cyclopropylimidazo[1,2-a]pyrazin-2-yl)methanol (0.49 g, 1.8 mmol) in dioxane (15 mL) was added 3-methylimidazolidine-2,4-dione (0.83 g, 7.3 mmol), Pd(dba) (0.34 g, 0.37 mmol), Xant-Phos (0.38 g, 0.66 mmol), and CsCO (1.8 g, 5.5 mmol). After stirring at 90 °C under N for 16 h, the reaction mixture was filtered, and the filter cake was washed with DCM / MeOH (10 / 1, 50 mL). The filtrate was concentrated in vacuo to give a crude product, which was purified by column chromatography on silica gel (eluent: DCM / MeOH = 30 / 1 to 10 / 1) to give 1-(6-cyclopropyl-2-(hydroxymethyl)imidazo[1,2-a]pyrazin-8-yl)-3-methylimidazolidine-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-methylpyrimidin-2-yl)cyclopropyl)quinoline [ka] Synthesis of (1S,2S)-N-(2-acetyl-5-bromophenyl)-2-(4-methylpyrimidin-2-yl)cyclopropane-1-carboxamide Oxalyl chloride (0.98 mL, 11 mmol) was added dropwise to a stirred solution of (1S,2S)-2-(4-methylpyrimidin-2-yl)cyclopropane-1-carboxylic acid (1.00 g, 5.6 mmol) and DMF (0.050 mL) in THF (10 mL) at 0 °C and stirred at 0 °C for 30 minutes. The reaction was then concentrated in vacuo. The residue was suspended in THF (20 mL), 1-(2-amino-4-bromo-phenyl)ethanone (1300 mg, 5.9 mmol) and pyridine (4.5 mL, 56 mmol) were added, and the mixture was heated at 70 °C for 18 hours. The mixture was cooled to room temperature and quenched with water (50 mL). The precipitate that formed was filtered, washed with water, dried over MgSO4, and concentrated in vacuo to give 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-methylpyrimidin-2-yl)cyclopropyl)quinolin-4(1H)-one NaOH (440 mg, 11 mmol) was azeotroped with toluene (3 times) and then added to a stirred suspension of (1S,2S)—N-(2-acetyl-5-bromophenyl)-2-(4-methylpyrimidin-2-yl)cyclopropane-1-carboxamide (1.70 g, 4.5 mmol) in 1,4-dioxane (20 mL). The reaction was heated at 100° C. for 1 h. The reaction was cooled to room temperature and poured into NH4Cl (sat. aq., 50 mL). The resulting precipitate was filtered and dried under high vacuum to give 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-methylpyrimidin-2-yl)cyclopropyl)quinoline 7-Bromo-2-((1S,2S)-2-(4-methylpyrimidin-2-yl)cyclopropyl)quinolin-4(1H)-one (1.30 g, 3.65 mmol) in POCl (8.5 mL, 91.2 mmol) was stirred at 100° C. for 90 min, cooled to room temperature over 30 min, and then stirred at 100° C. for 30 min. The mixture was cooled and concentrated in vacuo. The residue was dissolved in DCM (500 mL) and washed with NaHCO (saturated aqueous solution, 150 mL), water (100 mL), brine (saturated aqueous solution, 150 mL), water (100 mL), dried over MgSO, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with 0–100% EtOAc in cyclohexane to give 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-(azetidin-1-yl)-7-bromo-2-((1S,2S)-2-(4-methylpyrimidin-2-yl)cyclopropyl)quinoline [ka] Synthesis of 4-(azetidin-1-yl)-7-bromo-2-((1S,2S)-2-(4-methylpyrimidin-2-yl)cyclopropyl)quinoline A solution of 7-bromo-4-chloro-2-[(1S,2S)-2-(4-methylpyrimidin-2-yl)cyclopropyl]quinoline (120 mg, 0.32 mmol) and azetidine (0.11 mL, 1.6 mmol) in NMP (0.50 mL) was stirred at 140° C. for 35 minutes in a microwave reactor. The mixture was diluted with DCM, water, and brine (saturated aqueous solution) to give an emulsion. The mixture was concentrated in vacuo, suspended in DCM, filtered, and concentrated in vacuo. The residue was loaded onto an SCX cartridge, washed with MeOH in DCM, and eluted with 7N NH in MeOH to give 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-methylpyrimidin-2-yl)cyclopropyl]quinoline and the appropriate amine coupling partner in a manner similar to that described for 7-bromo-4-chloro-2-((1S,2S)-2-(4-methylpyrimidin-2-yl)cyclopropyl)quinoline. [Table 1-1] [Table 1-2]

[0222] Synthesis of rac-7-bromo-4-chloro-2-((1S*,2S*)-2-(4-methylpyrimidin-2-yl)cyclopropyl)quinoline [ka] Synthesis of (E)-7-bromo-4-chloro-2-(2-(4-methylpyrimidin-2-yl)vinyl)quinoline A mixture of (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 KPO (170 mg, 0.81 mmol) in THF (4.0 mL) and water (1.0 mL) was degassed with N, and then PdCl(PPh) (14 mg, 0.020 mmol) was added. The mixture was heated at 70 °C for 18 h. The mixture was diluted with water and extracted with EtOAc. The organic layer was dried over MgSO, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with 0–30% EtOAc in cyclohexane to give 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-methylpyrimidin-2-yl)cyclopropyl)quinoline NaH (60% in mineral oil, 140 mg, 3.6 mmol) was added to a stirred solution of MeSOI (850 mg, 3.9 mmol) in DMSO (6.0 mL), and the mixture was stirred at room temperature for 1 h under a N atmosphere. A slurry of (E)-7-bromo-4-chloro-2-(2-(4-methylpyrimidin-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 h. The mixture was quenched with NH4Cl (sat. aq., 75 mL), and the mixture was extracted with EtOAc (3 × 75 mL). The combined organics were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with 0–50% EtOAc in cyclohexane to afford the title compound (210 mg, 44%) as a colorless gum. 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-methylpyrimidin-2-yl)cyclopropyl)quinolin-4-amine [ka] MeNH (5.6 M 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-methylpyrimidin-2-yl)cyclopropyl)quinoline (210 mg, 0.57 mmol) in EtOH (0.57 mL), and the mixture was sealed and stirred at 90 °C for 18 h. The mixture was cooled, and more MeNH (5.6 M in EtOH, 1.0 mL, 5.66 mmol) was added. The mixture was sealed and stirred at 90 °C for 2 h. The mixture was concentrated in vacuo, and the residue was purified by column chromatography on silica gel eluting with 1-20% MeOH in DCM to give the title compound (140 mg, 63%) as a colorless gum. 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-methylpyrimidin-2-yl)cyclopropyl)-4-(oxetan-3-yloxy)quinoline [ka] 3-Hydroxyoxetane (17 μL, 0.27 mmol) was added to a stirred suspension of rac-7-bromo-4-chloro-2-((1S*,2S*)-2-(4-methylpyrimidin-2-yl)cyclopropyl)quinoline (100 mg, 0.267 mmol) and NaH (60% in mineral oil, 27 mg, 0.67 mmol) in DMF (1.0 mL) and stirred at 100° C. under a N atmosphere for 18 h. The mixture was quenched with water and extracted with DCM (3×). The combined organics were passed through a hydrophobic frit and concentrated in vacuo. The aqueous phase was further extracted with EtOAc (3×), and the combined organics were dried over MgSO4, filtered, combined with the DCM residue, and concentrated in vacuo to give 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-methylpiperidin-4-yl)oxy)-2-((1S*,2S*)-2-(4-methylpyrimidin-2-yl)cyclopropyl)quinoline [ka] To a solution of N-methyl-4-piperidinol (0.016 mL, 0.13 mmol) in DMF (0.50 mL) was added NaH (60% in mineral oil, 13 mg, 0.33 mmol) at room temperature under a N atmosphere. After 10 min, rac-7-bromo-4-chloro-2-((1S*,2S*)-2-(4-methylpyrimidin-2-yl)cyclopropyl)quinoline (50 mg, 0.13 mmol) was added. The mixture was stirred at room temperature under a N atmosphere for 2 h. Further NaH (60% in mineral oil, 13 mg, 0.33 mmol) was added, and the mixture was stirred at room temperature under a N atmosphere for 18 h. The mixture was quenched with water and extracted with DCM (3×). The combined organics were passed through a hydrophobic frit and concentrated in vacuo. The above procedure was repeated, and then the combined residues from both reactions were loaded onto an SCX cartridge, which was washed with MeOH. The compound was released using 7N NH3 in MeOH and concentrated in vacuo to give the title compound (93 mg, 77%) as a yellow gum. ESI-MS (M +H)+: 453, 455.

[0227] Synthesis of rac-N-(7-bromo-2-((1S*,2S*)-2-(4-methylpyrimidin-2-yl)cyclopropyl)quinolin-4-yl)-N-methylmethanesulfonamide [ka] Synthesis of rac-7-bromo-N-methyl-2-((1S*,2S*)-2-(4-methylpyrimidin-2-yl)cyclopropyl)quinolin-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-methylpyrimidin-2-yl)cyclopropyl)quinoline (250 mg, 0.67 mmol) in EtOH (1.0 mL). The mixture was sealed and heated to reflux for 24 h. The reaction mixture was concentrated in vacuo, and the residue was purified by silica gel column chromatography eluting with 0-10% 7N NH3 (in MeOH) in DCM to give 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-methylpyrimidin-2-yl)cyclopropyl)quinolin-4-yl)-N-methylmethanesulfonamide LiHMDS (1.0 M in THF, 0.49 mL, 0.49 mmol) was added dropwise to a stirred solution of rac-7-bromo-N-methyl-2-((1S*,2S*)-2-(4-methylpyrimidin-2-yl)cyclopropyl)quinolin-4-amine (120 mg, 0.33 mmol) in THF (5.0 mL) at 0°C. After 15 min, MsCl (0.050 mL, 0.65 mmol) was added dropwise, and the reaction mixture was warmed to room temperature and stirred for 18 h. The reaction mixture was quenched with water and extracted with DCM. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with 0-100% EtOAc in cyclohexane to give 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-methylpyrimidin-2-yl)cyclopropyl)quinolin-4-yl)morpholine [ka] A mixture of rac-7-bromo-4-chloro-2-((1S*,2S*)-2-(4-methylpyrimidin-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 two 30 min periods. The mixture was diluted with DCM and then washed with water, dried over MgSO4, and concentrated in vacuo to give 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]pyridin-2-yl)methanol [ka] Synthesis of 4-cyclopropylpyridin-2-amine [ka] To a solution of 4-bromopyridin-2-amine (20 g, 0.12 mol) in toluene / HO (200 mL / 40 mL), cyclopropylboronic acid (20 g, 0.23 mol), Pd(OAc) (1.0 g, 4.6 mmol), KPO (74 g, 0.35 mol), and PCy (2.6 g, 9.3 mmol) were added at room temperature. The reaction mixture was stirred under nitrogen at 90 °C for 16 h. The reaction mixture was concentrated in vacuo, diluted with water (150 mL), and then extracted with EtOAc (150 mL × 2). The combined organic layers were washed with brine (200 mL × 1), dried over NaSO, and concentrated in vacuo to give the crude product, which was purified by silica gel chromatography (eluent: EtOAc / PE = 1 / 1) to give 4-cyclopropylpyridin-2-amine (16 g, quantitative) as a yellow solid. ESI-MS [M + H] + : 135.1.

[0231] Synthesis of (1S,2S)-2-(2-((tert-butoxycarbonyl)amino)-6-methoxypyridin-4-yl)cyclopropane-1-carboxylic acid To a stirred solution of HBr (40% in HO, 70 mL), 4-cyclopropylpyridin-2-amine (15 g, 0.11 mol) was added portionwise at 0 °C, followed by dropwise addition of Br (52 g, 0.32 mol). After stirring at 0 °C for 30 min, a solution of NaNO (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 an additional 30 min. The reaction mixture was quenched with aqueous NaOH (60 g in water (100 mL)) until pH = 12 and extracted with EtOAc (100 mL × 2). The combined organic layers were washed with water (200 mL) and brine (200 mL), dried over Na2SO4, and concentrated in vacuo to give the crude product, which was purified by silica gel chromatography (eluent: EtOAc / PE=1 / 10) to give 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) was slowly added a solution of 2-bromo-4-cyclopropylpyridine (15 g, 76 mmol) in DCM (50 mL) at 0 °C. The mixture was stirred at 0 °C for 10 min, then warmed to room temperature and stirred for 14 h. The reaction mixture was concentrated and dried in vacuo. The residue was dissolved in CHCN (200 mL) and 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 min, warmed to room temperature and stirred for 16 h. The reaction mixture was concentrated in vacuo, diluted with water (300 mL), and extracted with EtOAc (200 mL × 2). The combined organic layers were washed with water (400 mL) and brine (400 mL), dried over Na2SO4, and concentrated in vacuo to give the crude product, which was purified by silica gel chromatography (eluent: EtOAc / PE = 1 / 10) to give dimethyl 7-bromo-5-cyclopropylpyrazolo[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·HO (1.4 g, 34 mmol) in THF (50 mL) and water (10 mL) was stirred at 40 °C for 2 h. The mixture was concentrated in vacuo to remove THF, and then 1,4-dioxane (50 mL) and HCl (concentrated, 12 mL) were added. The resulting mixture was stirred at 100 °C for 6 h. The reaction mixture was poured into water (200 mL) and extracted with EtOAc (150 mL × 3). The combined organic layers were washed with brine (400 mL), dried over NaSO, and then concentrated and dried in vacuo to give 7-bromo-5-cyclopropylpyrazolo[1,5-a]pyridine-2-carboxylic acid (4.8 g, quantitative) 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) was added SOCl (4.0 g, 34 mmol) dropwise at room temperature. The mixture was stirred at 70 °C for 3 h. The reaction mixture was concentrated in vacuo, diluted with EtOAc (200 mL), washed with NaHCO (saturated aqueous solution, 150 mL) and brine (150 mL), dried over NaSO, and then concentrated in vacuo to give the crude product. This was purified by silica gel chromatography (eluent: EtOAc / PE = 1 / 10) to give methyl 7-bromo-5-cyclopropylpyrazolo[1,5-a]pyridine-2-carboxylate (3.8 g, 76% over two steps) as a yellow solid. ESI-MS [M + H] + : 295.0.

[0235] Synthesis of (7-bromo-5-cyclopropylpyrazolo[1,5-a]pyridin-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) was added DIBAl-H (1 M in hexane, 33 mL, 33 mmol) dropwise at −65° C. The mixture was stirred at −65° C. for 2 h. The reaction mixture was quenched with NaOH (1 M in water, 50 mL) at −65° C., warmed to room temperature, and then extracted with EtOAc (100 mL × 2). The combined organic layers were washed with brine (150 mL), dried over NaSO, and then concentrated in vacuo to give the crude product, which was purified by silica gel chromatography (eluent: EtOAc / PE = 1 / 5) to give 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]pyridin-2-yl)methyl)-N4,N4-dimethyl-2-(2-(4-methylpyrimidin-2-yl)cyclopropyl)quinoline-4,7-diamine (I-1) [ka] Synthesis of 2-(3-bromo-2-oxopropyl)isoindoline-1,3-dione Br (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 min, then allowed to cool and concentrated in vacuo. The residue was dissolved in DCM (100 mL) and washed with NaSO (1.0 M aqueous solution, 100 mL) and NaCO (20% aqueous solution, 2 × 100 mL). The organic layer was passed through a phase separation cartridge and then concentrated in vacuo. The residue was triturated with EtO to give 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]pyridin-2-yl)methyl)isoindoline-1,3-dione A mixture of 5-cyclopropylpyridin-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 h. The mixture was concentrated in vacuo, and the residue was purified by silica gel column chromatography eluting with 20 to 100% EtOAc in EtO to give 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]pyridin-2-yl)methanamine N2H4·H2O (3.6 g, 56.72 mmol) was added to a solution of 2-((6-cyclopropylimidazo[1,2-a]pyridin-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 h. The mixture was cooled, filtered through Celite® and concentrated in vacuo. The residue was loaded onto an SCX cartridge, washed with MeOH in DCM, eluted with 7N NH3 in MeOH in DCM and then concentrated in vacuo to give the title compound (2.0 g, 94%) as an orange gum. 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]pyridin-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]pyridin-2-yl)methanamine (1.0 g, 5.3 mmol) in DCM (55 mL), and the mixture was stirred at room temperature for 18 h. NaHCO3 (saturated aqueous solution, 50 mL) was added, and the mixture was extracted with DCM (3 × 50 mL). The combined organics were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with 20–100% EtOAc in cyclohexane to afford 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]pyridin-2-yl)methyl)(4-(dimethylamino)-2-((1S*,2S*)-2-(4-methylpyrimidin-2-yl)cyclopropyl)quinolin-7-yl)carbamate A mixture of tert-butyl ((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)carbamate (99 mg, 0.34 mmol), rac-7-bromo-N,N-dimethyl-2-((1S,2S)-2-(4-methylpyrimidin-2-yl)cyclopropyl)quinolin-4-amine (110 mg, 0.28 mmol), Pd(OAc), Xantphos (17 mg, 0.028 mmol), and CsCO (190 mg, 0.029 mmol) in 1,4-dioxane (5.0 mL) was degassed with N and heated at 100° C. for 18 h. The mixture was filtered through Celite® and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with 0-20% 7N NH3 (in MeOH) in DCM to give 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]pyridin-2-yl)methyl)-N 4 ,N 4 Synthesis of 1-dimethyl-2-((1S*,2S*)-2-(4-methylpyrimidin-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]pyridin-2-yl)methyl)(4-(dimethylamino)-2-((1S*,2S*)-2-(4-methylpyrimidin-2-yl)cyclopropyl)quinolin-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 in vacuo and purified by preparative HPLC to give the title compound (3 mg, 8%) as the formate salt. 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]pyridin-2-yl)methyl)amino)pyrido[4,3-d]pyrimidin-4(3H)-one (I-2) [ka] Synthesis of methyl 6-chloro-4-((1S,2S)-2-(3-chlorophenyl)cyclopropane-1-carboxamido)nicotinate To a cooled solution of (1S,2S)-2-(3-chlorophenyl)cyclopropane-1-carboxylic acid (0.45 g, 2.3 mmol) and DCM (10 mL) at 0 °C, one drop of DMF was added, and the mixture was stirred for 2 h. The mixture was concentrated in vacuo 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), and heated to 70 °C for 18 h. The mixture was diluted with NaHCO (saturated aqueous solution, 50 mL) and extracted with EtOAc (3 × 50 mL). The organic phases were combined, dried over MgSO, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a gradient of 0–100% EtOAc in cyclohexane to give 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]pyrimidin-4(3H)-one Methyl 6-chloro-4-((1S,2S)-2-(3-chlorophenyl)cyclopropane-1-carboxamide)nicotinate was added to a mixture of 7N NH3 in MeOH (13 mL) and MeOH (13 mL) in a sealed vial. The mixture was stirred at room temperature for 18 hours. The mixture was concentrated in vacuo, and the residue was purified by silica gel column chromatography eluting with a gradient of 20 to 100% EtOAc in cyclohexane to give 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]pyrimidin-4(3H)-one A mixture of KCO (0.15 g, 1.08 mmol), 7-chloro-2-((1S,2S)-2-(3-chlorophenyl)cyclopropyl)pyrido[4,3-d]pyrimidin-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 EtO (2 mL) was heated to 80 °C for 18 h. The mixture was diluted with brine (50 mL), water (75 mL), and extracted with EtOAc (3 × 25 mL). The organic phases were combined and concentrated in vacuo, and the residue was purified by silica gel column chromatography eluting with a gradient of 0–100% EtOAc in cyclohexane to give 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]pyrimidin-7-yl)((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)carbamate A mixture of 7-chloro-2-((1S,2S)-2-(3-chlorophenyl)cyclopropyl)-3-(2,4-dimethoxybenzyl)pyrido[4,3-d]pyrimidin-4(3H)-one (0.11 g, 0.22 mmol), tert-butyl ((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)carbamate (0.079 g, 0.22 mmol), Pd(dba) (0.021 g, 0.02 mmol), Xantphos (0.026 g, 0.045 mmol), and CsCO (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 in vacuo. The residue was purified by silica gel column chromatography eluting with a gradient of 0-100% EtOAc in cyclohexane to afford the title compound (64 mg, 38%) as a pale yellow gum. 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]pyridin-2-yl)methyl)amino)pyrido[4,3-d]pyrimidin-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]pyrimidin-7-yl)((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)carbamate (50 mg, 0.068 mmol) and anisole (0.074 mL, 0.68 mmol) in DCM (0.5 mL) was added TFA (0.5 mL). The mixture was stirred at room temperature for 2 hours. The mixture was concentrated in vacuo onto silica gel 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 afford the title compound (11 mg, 33%) as the formate salt. 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]pyridin-2-yl)methyl)amino)pyrido[4,3-d]pyrimidin-4(3H)-one (I-3) [ka] The title compound was synthesized in a similar manner as described for 2-((1S,2S)-2-(3-chlorophenyl)cyclopropyl)-7-(((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)amino)pyrido[4,3-d]pyrimidin-4(3H)-one, starting from methyl 2-amino-4-bromobenzoate and rac-(1S,2S)-2-(4-methylpyrimidin-2-yl)cyclopropane-1-carbonyl chloride (2.3 mg, 25%). 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-methoxyquinolin-7-yl)amino)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)pyrrolidin-2-one (I-4) [ka] Synthesis of 1-(2-(aminomethyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)pyrrolidin-2-one [ka] Synthesis of 2-((6-cyclopropyl-8-(2-oxopyrrolidin-1-yl)imidazo[1,2-a]pyridin-2-yl)methyl)isoindoline-1,3-dione Pyrrolidin-2-one (0.65 mL, 8.5 mmol), 2-((8-chloro-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)isoindoline-1,3-dione (2000 mg, 5.7 mmol), Xantphos (660 mg, 1.1 mmol), and K2CO3 (1600 mg, 11 mmol) in 1,4-dioxane (20 mL) were degassed with N2 for 5 minutes. Pd(OAc)2 (130 mg, 0.57 mmol) was added, and the reaction mixture was heated at 160 °C in a microwave for 2 hours. The mixture was cooled to room temperature, filtered through Celite®, and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with a gradient of 20 to 100% EtOAc in cyclohexane to give 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]pyridin-8-yl)pyrrolidin-2-one A solution of 2-((6-cyclopropyl-8-(2-oxopyrrolidin-1-yl)imidazo[1,2-a]pyridin-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 h. 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 NH in MeOH:DCM to give the title compound (0.60 g, 89%). ESI-MS (M+H)+: 271.3, 1 H NMR (400 MHz, CDCl3) δ 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). No NH2 was observed.

[0250] Synthesis of 1-(2-amino-4-bromophenyl)ethan-1-one BCl3 (1.0 M in DCM, 32 mL, 32 mmol) 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 added portionwise to the reaction mixture with cooling. The mixture was stirred at 90 °C for 17 h. 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 h. The reaction mixture was cooled to room temperature, diluted with water (100 mL), and extracted with DCM (3 × 150 mL). The combined organics were dried over MgSO4 and concentrated in vacuo to give 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 solution of rac-(1S*,2S*)-2-(3-chlorophenyl)cyclopropane-1-carboxylic acid (500 mg, 2.5 mmol) and DMF (0.05 mL) in DCM (10 mL) at 0° C. The reaction mixture was stirred at 0° C. for 2.5 hours. The reaction mixture was warmed to room temperature and concentrated in vacuo. The residue was suspended in THF (10 mL), and pyridine (2.1 mL, 25 mmol) and 1-(2-amino-4-bromophenyl)ethan-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 in vacuo to give 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)quinolin-4(1H)-one NaOH (100 mg, 2.6 mmol) was azeotroped 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) placed under a N atmosphere. The reaction mixture was stirred at 100° C. for 3 h, then cooled to room temperature and diluted with NH4Cl (sat. aq., 20 mL). The resulting precipitate was collected by filtration, washed with water (50 mL), and dried in vacuo to give the title compound (200 mg, 83%) as a beige solid. 1 H 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)quinolin-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 h. 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 h, then cooled to room temperature and more MeI (0.019 mL, 0.29 mmol) was added. The reaction mixture was stirred at 50° C. for 16 h. The reaction mixture was cooled to room temperature, quenched with water (25 mL) and extracted with EtOAc (3×40 mL). The combined organics were dried over MgSO4 and concentrated in vacuo to give 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-methoxyquinolin-7-yl)amino)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)pyrrolidin-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]pyridin-8-yl)pyrrolidin-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 min and stirred at 90 °C for 4 h. The reaction mixture was cooled to room temperature, filtered through Celite®, and concentrated in vacuo. The residue was dissolved in DCM (25 mL) and washed with NH4Cl (sat. aq., 3 × 50 mL). The combined organics were passed through a hydrophobic frit and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with 5% MeOH in DCM then 10% 7N NH3 in MeOH in DCM to give 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 CHs 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-dihydroquinolin-7-yl)amino)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)-3-methylimidazolidine-2,4-dione (I-5) [ka] Synthesis of rac-tert-butyl (2-((1S*,2S*)-2-(3-chlorophenyl)cyclopropyl)-4-methoxyquinolin-7-yl)((6-cyclopropyl-8-(3-methyl-2,4-dioxoimidazolidin-1-yl)imidazo[1,2-a]pyridin-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-dioxoimidazolidin-1-yl)imidazo[1,2-a]pyridin-2-yl)methyl)carbamate (123 mg, 0.31 mmol), Pd(dba) (12 mg, 0.013 mmol), Xantphos (15 mg, 0.026 mmol), and CsCO (251 mg, 0.77 mmol) in 1,4-dioxane (5.0 mL), and the mixture was heated to 105° C. for 18 h. The mixture was filtered through Celite® and then concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a gradient of 0-100% EtOAc in cyclohexane to give the crude title compound, which was carried on 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-dihydroquinolin-7-yl)amino)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)-3-methylimidazolidine-2,4-dione Pyridine HCl (392 mg, 3.39 mmol) was added to rac-tert-butyl (2-((1S*,2S*)-2-(3-chlorophenyl)cyclopropyl)-4-methoxyquinolin-7-yl)((6-cyclopropyl-8-(3-methyl-2,4-dioxoimidazolidin-1-yl)imidazo[1,2-a]pyridin-2-yl)methyl)carbamate (60 mg, 0.085 mmol) and the mixture was heated to 130° C. for 2 h. 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 in vacuo. The residue was purified by preparative HPLC to give 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-dihydroquinazolin-7-yl)amino)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)-3-methylimidazolidine-2,4-dione (I-6) [ka] Synthesis of methyl 4-bromo-2-((1S,2S)-2-(3-chlorophenyl)cyclopropane-1-carboxamido)benzoate To a cooled solution of (1S,2S)-2-(3-chlorophenyl)cyclopropane-1-carboxylic acid (1.0 g, 5.1 mmol) and oxalyl chloride (0.44 mL, 5.1 mmol) in DCM (20 mL) was added one drop of DMF at 0 °C, and the mixture was stirred for 1 h. The mixture was concentrated and then redissolved in THF (20 mL). Methyl 2-amino-4-bromobenzoate (1.2 g, 5.1 mmol) was added, followed by pyridine (1.2 mL, 15.3 mmol), and the mixture was heated at 70 °C for 18 h. The cooled mixture was diluted with water and then extracted with DCM. The combined organics were passed through a hydrophobic cartridge, concentrated onto silica in vacuo, and then purified by silica gel column chromatography eluting with a gradient of 0–100% EtOAc in cyclohexane to give 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)quinazolin-4(3H)-one 7N NH3 in MeOH (20 mL) was added to a solution of methyl 4-bromo-2-((1S,2S)-2-(3-chlorophenyl)cyclopropane-1-carboxamido)benzoate (400 mg, 0.98 mmol) in MeOH (20 mL) and the mixture was heated to 80°C for 18 h. The mixture was diluted with DCM, washed with brine, passed through a hydrophobic cartridge, concentrated onto silica in vacuo, and then purified by silica gel column chromatography eluting with a gradient of 0-80% EtOAc in cyclohexane to give 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 solution of methyl 4-bromo-2-((1S,2S)-2-(3-chlorophenyl)cyclopropane-1-carboxamido)benzoate (100 mg, 0.27 mmol), Xantphos (62 mg, 0.11 mmol), tert-butyl carbamate (34 mg, 0.29 mmol), and CsCO (260 mg, 0.8-0 mmol) in 1,4-dioxane was purged with N for 5 minutes and heated to 100 °C for 18 hours. The mixture was filtered through Celite®, concentrated in vacuo, and then purified by silica gel column chromatography eluting with a gradient of 0-80% EtOAc in cyclohexane to give 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)quinazolin-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 CHCl (2 mL). The reaction was heated to 70° C. under microwave conditions for 30 minutes. The mixture was treated with NaHCO (sat. aq.) and then extracted with DCM. The combined organics were passed through a hydrophobic cartridge and then concentrated in vacuo to give 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-dihydroquinazolin-7-yl)amino)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)-3-methylimidazolidine-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)quinazolin-4(3H)-one (84 mg, 0.27 mmol) and 6-cyclopropyl-8-(3-methyl-2,4-dioxoimidazolidin-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 heated to 50 °C for 18 h. The reaction was cooled to room temperature and NaCNBH3 (34 mg, 0.27 mmol) was added. The reaction was stirred at room temperature for 2 h, then diluted with water, filtered through Celite®, and concentrated in vacuo. The residue was dissolved in DCM, washed with water, then brine, passed through a hydrophobic cartridge, and then concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a gradient of 0-10% 7N NH3 (in MeOH) in DCM, followed by preparative HPLC to give 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 in Table 2 were synthesized using a procedure similar to that described above using rac-(1S*,2S*)-2-(4-methylpyrimidin-2-yl)cyclopropane-1-carboxylic acid and methyl 4-amino-6-chloronicotinate. [Table 2] The compounds in Table 3 were synthesized using a procedure similar to that described above using rac-(1S*,2S*)-2-(4-methylpyrimidin-2-yl)cyclopropane-1-carboxylic acid and methyl 2-amino-4-bromobenzoate. [Table 3]

[0263] Example 9 Synthesis of 1-(6-cyclopropyl-2-(((2-(2-(4-methylpyrimidin-2-yl)cyclopropyl)-4-oxo-1,4-dihydropyrido[3,2-d]pyrimidin-7-yl)amino)methyl)imidazo[1,2-a]pyridin-8-yl)-3-methylimidazolidine-2,4-dione (I-9) [ka] Synthesis of rac-methyl 5-bromo-3-((1S*,2S*)-2-(4-methylpyrimidin-2-yl)cyclopropane-1-carboxamido)picolinate Oxalyl chloride (0.78 mL, 8.90 mmol) was added dropwise to a stirred solution of rac-(1S*,2S*)-2-(4-methylpyrimidin-2-yl)cyclopropanecarboxylic acid (793 mg, 4.45 mmol) and DMF (0.050 mL) in THF (10 mL) at 0° C. and stirred at 0° C. for 30 minutes. The reaction was then concentrated in vacuo. The residue was suspended in THF (20 mL), followed by the addition of methyl 3-amino-5-bromo-pyridine-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 EtOAc and water. The organics were washed with NaHCO3 (sat. aq.) and brine, dried over MgSO4 and concentrated in vacuo to give 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-methylpyrimidin-2-yl)cyclopropane-1-carboxamide)picolinamide rac-Methyl 5-bromo-3-((1S*,2S*)-2-(4-methylpyrimidin-2-yl)cyclopropane-1-carboxamide)picolinate (1.26 g, 3.22 mmol) was suspended in 7N NH3 in MeOH (26 mL) and stirred at 65° C. for 18 h. The reaction was cooled to room temperature and concentrated in vacuo to give 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-methylpyrimidin-2-yl)cyclopropyl)pyrido[3,2-d]pyrimidin-4(3H)-one NaOH (383 mg, 9.57 mmol) (azeotroped three times with toluene) was added to a stirred mixture of rac-5-bromo-3-((1S*,2S*)-2-(4-methylpyrimidin-2-yl)cyclopropane-1-carboxamide)picolinamide (1200 mg, 3.19 mmol) in 1,4-dioxane (10 mL), and the reaction was then stirred at 100° C. for 18 h. The reaction was cooled to room temperature and partitioned between water and EtOAc. The aqueous layer was extracted with EtOAc (three times). The combined organics were dried over MgSO4 and concentrated in vacuo to give the title compound (0.9 g, 79%) as an off-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-methylpyrimidin-2-yl)cyclopropyl)-4-oxo-3,4-dihydropyrido[3,2-d]pyrimidin-7-yl)carbamate rac-7-Bromo-2-((1S,2S)-2-(4-methylpyrimidin-2-yl)cyclopropyl)pyrido[3,2-d]pyrimidin-4(3H)-one (400 mg, 1.12 mmol), tert-butyl carbamate (196 mg, 1.68 mmol), Pd(OAc) (13 mg, 0.056 mmol), Xantphos (65 mg, 0.11 mmol), and CsCO (1092 mg, 3.35 mmol) were suspended in 1,4-dioxane (5 mL) and degassed with N for 5 min. The reaction was then heated to 100 °C and stirred for 16 h. Additional tert-butyl carbamate (196 mg, 1.68 mmol), Pd(OAc) (13 mg, 0.056 mmol), and Xantphos (65 mg, 0.11 mmol) were added, and the mixture was stirred at 100° C. for an additional 24 h. The reaction was cooled to room temperature and filtered through Celite®. The residue was purified by column chromatography on silica gel eluting with 0-10% MeOH in DCM to give 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-methylpyrimidin-2-yl)cyclopropyl)pyrido[3,2-d]pyrimidin-4(3H)-one TFA (0.43 mL, 5.58 mmol) was added to a stirred solution of rac-tert-butyl (2-((1S*,2S*)-2-(4-methylpyrimidin-2-yl)cyclopropyl)-4-oxo-3,4-dihydropyrido[3,2-d]pyrimidin-7-yl)carbamate (220 mg, 0.56 mmol) in chloroform (6 mL) and stirred at room temperature for 16 h. The reaction was concentrated in vacuo and the residue was loaded onto an SCX cartridge, which was washed with 3:1 DCM:MeOH. The compound was released using 7N NH3 in MeOH in DCM to give the title compound (150 mg), which was carried on to the next step without further purification. 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-methylpyrimidin-2-yl)cyclopropyl)-4-oxo-3,4-dihydropyrido[3,2-d]pyrimidin-7-yl)amino)methyl)imidazo[1,2-a]pyridin-8-yl)-3-methylimidazolidine-2,4-dione (I-9) Using a method similar to that used for 1-(2-(((2-((1S,2S)-2-(3-chlorophenyl)cyclopropyl)-4-oxo-3,4-dihydroquinazolin-7-yl)amino)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)-3-methylimidazolin-2,4-dione, the title compound (17.9 mg, 6%) was prepared from rac-7-amino-2-((1S,2S)-2-(4-methylpyrimidin-2-yl)cyclopropyl)pyrido[3,2-d]pyrimidin-4(3H)-one and 6-cyclopropyl-8-(3-methyl-2,4-dioxoimidazolin-1-yl)imidazo[1,2-a]pyridine-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-methylpyrimidin-2-yl)cyclopropyl)-4-oxo-1,4-dihydro-1,6-naphthyridin-7-yl)amino)methyl)imidazo[1,2-a]pyridin-8-yl)-3-methylimidazolidine-2,4-dione (I-10) [ka] Synthesis of rac-(1S*,2S*)-N-(5-acetyl-2-chloropyridin-4-yl)-2-(4-methylpyrimidin-2-yl)cyclopropane-1-carboxamide Oxalyl chloride (0.98 mL, 11.2 mmol) was added dropwise 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) at 0 °C and stirred for 30 minutes at 0 °C. The reaction was then concentrated to dryness and then suspended in THF (10 mL), followed by the addition of rac-(1S*,2S*)-2-(4-methylpyrimidin-2-yl)cyclopropane-1-carboxylic acid (1.00 g, 5.61 mmol) and pyridine (4.5 mL, 56.1 mmol). The reaction was then heated to 70 °C and stirred for 16 hours. The reaction was cooled to room temperature and diluted with EtOAc. The reaction was washed with NaHCO3 (sat. aq.) and brine. The organics were dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with 0-100% EtOAc in cyclohexane to give 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-methylpyrimidin-2-yl)cyclopropyl)-1,6-naphthyridin-4(1H)-one NaOH (435 mg, 10.9 mmol) (azeotroped three times with toluene) was added to a stirred suspension of rac-(1S*,2S*)-N-(5-acetyl-2-chloropyridin-4-yl)-2-(4-methylpyrimidin-2-yl)cyclopropane-1-carboxamide (900 mg, 2.72 mmol) in 1,4-dioxane (20 mL). The reaction was then heated to 100° C. for 1 h. The mixture was diluted with water and extracted with EtOAc. The organics were washed with NaHCO (sat. aq.), then brine, dried over MgSO, and then concentrated in vacuo to give the title compound (400 mg, 87%) as a pale yellow solid. ESI-MS (M+H)+: 313.1, 1 H 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), 1H obscured by DMSO signals.

[0271] Synthesis of rac-7-chloro-2-((1S*,2S*)-2-(4-methylpyrimidin-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-methylpyrimidin-2-yl)cyclopropyl)-1,6-naphthyridin-4(1H)-one (390 mg, 1.25 mmol) in DMF (3.00 mL) at room temperature and stirred for 10 min. SEM-Cl (0.22 mL, 1.25 mmol) was then added and the reaction was stirred at room temperature for 18 h. The reaction was quenched with water and then extracted with EtOAc. The combined organics were washed with NaHCO3 (sat. aq.) and brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with 0–100% EtOAc in cyclohexane to give 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-methylpyrimidin-2-yl)cyclopropyl)-4-((2-(trimethylsilyl)ethoxy)methoxy)-1,6-naphthyridin-7-yl)carbamate rac-7-Chloro-2-((1S*,2S*)-2-(4-methylpyrimidin-2-yl)cyclopropyl)-4-((2-(trimethylsilyl)ethoxy)methoxy)-1,6-naphthyridine (300 mg, 0.68 mmol), tert-butyl carbamate (119 mg, 1.02 mmol), Pd(OAc) (7.6 mg, 0.034 mmol), Xantphos (39 mg, 0.068 mmol), and CsCO (662 mg, 2.03 mmol) were suspended in 1,4-dioxane (5.0 mL) and purged with N for 5 minutes. The reaction was then heated to 100 °C and stirred for 1 hour. The mixture was filtered through Celite® and then concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with 0-100% EtOAc in cyclohexane to give 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-methylpyrimidin-2-yl)cyclopropyl)-1,6-naphthyridin-4(1H)-one TFA (0.44 mL, 5.73 mmol) was added to a solution of rac-tert-butyl (2-((1S*,2S*)-2-(4-methylpyrimidin-2-yl)cyclopropyl)-4-((2-(trimethylsilyl)ethoxy)methoxy)-1,6-naphthyridin-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 was concentrated in vacuo. The residue was loaded onto an SCX cartridge, which was washed with DCM in MeOH and eluted with 7N NH3 in DCM (in MeOH) to give the product 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-methylpyrimidin-2-yl)cyclopropyl)-4-oxo-1,4-dihydro-1,6-naphthyridin-7-yl)amino)methyl)imidazo[1,2-a]pyridin-8-yl)-3-methylimidazolidine-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-methylpyrimidin-2-yl)cyclopropyl)-1,6-naphthyridin-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 at 50 °C in a sealed tube for 12 h. The reaction was cooled to room temperature. NaCNBH3 (30 mg, 0.477 mmol) was added, and the mixture was then stirred at room temperature for 18 h. The reaction was diluted with water (1.0 mL), filtered through Celite®, and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with 0-10% 7N NH3 (in MeOH) in DCM followed by preparative HPLC to give 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 to 13 Synthesis of rac-1-(6-cyclopropyl-2-(((2-((1S*,2S*)-2-(4-methylpyrimidin-2-yl)cyclopropyl)-4-oxo-1,4-dihydroquinolin-7-yl)amino)methyl)imidazo[1,2-a]pyridin-8-yl)-3-methylimidazolidine-2,4-dione (I-11) [ka] Synthesis of rac-(1S*,2S*)-N-(2-acetyl-5-chlorophenyl)-2-(4-methylpyrimidin-2-yl)cyclopropane-1-carboxamide Oxalyl chloride (0.71 mL, 5.61 mmol) was added dropwise to a stirred solution of 1-(2-amino-4-bromophenyl)ethan-1-one (631 mg, 2.95 mmol) and DMF (0.050 mL) in THF (20 mL) at 0 °C and stirred for 30 minutes at 0 °C. The reaction was then concentrated to dryness. The residue was suspended in THF (20 mL), followed by the addition of rac-(1S*,2S*)-2-(4-methylpyrimidin-2-yl)cyclopropane-1-carboxylic acid (500 mg, 2.81 mmol) and pyridine (2.3 mL, 28.1 mmol). The reaction was then heated to 70 °C and stirred for 16 hours. The reaction was cooled to room temperature, diluted with EtOAc, and then washed with NaHCO3 (sat. aq.) and brine. The organics were dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with 0-100% EtOAc in cyclohexane to give 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-methylpyrimidin-2-yl)cyclopropyl)quinolin-4(1H)-one NaOH (435 mg, 10.9 mmol) (azeotroped three times with toluene) was added to a stirred suspension of rac-(1S*,2S*)-N-(2-acetyl-5-bromophenyl)-2-(4-methylpyrimidin-2-yl)cyclopropane-1-carboxamide (890 mg, 2.38 mmol) in 1,4-dioxane (15 mL). The reaction was then heated to 100° C. and stirred for 1 h, then cooled to room temperature and quenched with NH4Cl (sat. aq.). The precipitate that formed was filtered, washed with water, and dried under vacuum to give the title compound (680 mg, 87%) as a brown solid. ESI-MS (M+H)+: 358.1, 1 H 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 is missing (assumed to be under the DMSO peak), and no exchangeable 1H is observed.

[0277] Synthesis of rac-tert-butyl (2-((1S*,2S*)-2-(4-methylpyrimidin-2-yl)cyclopropyl)-4-oxo-1,4-dihydroquinolin-7-yl)carbamate rac-7-Bromo-2-((1S*,2S*)-2-(4-methylpyrimidin-2-yl)cyclopropyl)quinolin-4(1H)-one (340 mg, 0.954 mmol), tert-butyl carbamate (168 mg, 1.43 mmol), Pd(OAc) (21 mg, 0.095 mmol), Xantphos (110 mg, 0.191 mmol), and CsCO (933 mg, 2.86 mmol) were suspended in 1,4-dioxane (10 mL) and purged with N for 5 minutes. The reaction was then heated to 100 °C and stirred for 1 hour. The mixture was filtered through Celite®, concentrated in vacuo, and the residue was purified by column chromatography on silica gel eluting with 0-10% DCM in MeOH to give the title compound (150 mg, approximately 60% pure). This was carried on to the next step without further purification. ESI-MS (M+H)+: 393.3

[0278] Synthesis of rac-7-amino-2-((1S*,2S*)-2-(4-methylpyrimidin-2-yl)cyclopropyl)quinolin-4(1H)-one TFA (0.35 mL, 4.59 mmol) was added to a stirred solution of rac-tert-butyl (2-((1S*,2S*)-2-(4-methylpyrimidin-2-yl)cyclopropyl)-4-oxo-1,4-dihydroquinolin-7-yl)carbamate (60%, 150 mg, 0.229 mmol) in chloroform (4.00 mL) and stirred at room temperature for 30 minutes. The reaction was concentrated in vacuo. The residue was loaded onto an SCX cartridge, which was washed with 3:1 DCM:MeOH and eluted with 7N NH3 in DCM (in MeOH) to give 100 mg of the desired product in approximately 60% purity. This material was purified by silica gel column chromatography eluting with a gradient of 0 to 100% EtOAc in cyclohexane to give the title compound (50 mg, 43%) as an orange solid. ESI-MS (M+H)+: 293.3,1 H 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-methylpyrimidin-2-yl)cyclopropyl)-4-oxo-1,4-dihydroquinolin-7-yl)amino)methyl)imidazo[1,2-a]pyridin-8-yl)-3-methylimidazolidine-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-methylpyrimidin-2-yl)cyclopropyl)quinolin-4(1H)-one (50 mg, 0.171 mmol, 1.00 equiv.) and 6-cyclopropyl-8-(3-methyl-2,4-dioxoimidazolidin-1-yl)imidazo[1,2-a]pyridine-2-carbaldehyde (51 mg, 0.171 mmol, 1.00 equiv.) in a 1:1 mixture of MeOH (2.0 mL) and DCM (2.0 mL). The reaction was then heated in a sealed tube at 50°C for 5 hours. LCMS showed good conversion to the imine. The reaction was cooled to room temperature. NaCNBH3 (38 mg, 0.599 mmol) was added, and the reaction was then stirred at room temperature for 1 hour. It was quenched with water (1.0 mL) and filtered through Celite®. It was washed with MeOH (3 x 5 mL) and concentrated to give a crude residue. The residue was purified by column chromatography on silica gel eluting with 0-20% 7N NH3 (in MeOH) in DCM, followed by preparative HPLC to give 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). 1H is missing, and is assumed to be under the DMSO peak.

[0280] The enantiomers of 1-(6-cyclopropyl-2-(((2-(2-(4-methylpyrimidin-2-yl)cyclopropyl)-4-oxo-1,4-dihydroquinolin-7-yl)amino)methyl)imidazo[1,2-a]pyridin-8-yl)-3-methylimidazolidine-2,4-dione (i.e., 1-(6-cyclopropyl-2-(((2-((1S,2S)-2-(4-methylpyrimidin-2-yl)cyclopropyl)-4-oxo-1,4-dihydroquinolin-7-yl)amino)methyl)imidazo[1,2-a]pyridin-8-yl)-3-methylimidazolidine-2,4-dione SFC separation (LUX Cellulose-4 21.2 x 250 mm, 5 um 45 / 55 EtOH (0.1% DEA) / CO2, 100 mL / min, 120 bar, 40 °C) of 1-(6-cyclopropyl-2-(((2-((1R,2R)-2-(4-methylpyrimidin-2-yl)cyclopropyl)-4-oxo-1,4-dihydroquinolin-7-yl)amino)methyl)imidazo[1,2-a]pyridin-8-yl)-3-methylimidazolidine-2,4-dione and 1-(6-cyclopropyl-2-(((2-((1R,2R)-2-(4-methylpyrimidin-2-yl)cyclopropyl)-4-oxo-1,4-dihydroquinolin-7-yl)amino)methyl)imidazo[1,2-a]pyridin-8-yl)-3-methylimidazolidine-2,4-dione) gave the following:

[0281] First-eluting isomer: (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-methylpyrimidin-2-yl)cyclopropyl)-1,5-naphthyridin-3-yl)amino)methyl)imidazo[1,2-a]pyridin-8-yl)-3-methylimidazolidine-2,4-dione (I-14) [ka] Synthesis of 4-methyl-2-((trimethylsilyl)ethynyl)pyrimidine PdCl(PPh) (3.55 g, 5.06 mmol) was added to an N-purged solution of 2-chloro-4-methylpyrimidine (13 g, 101.12 mmol), NEt (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 h. The reaction was diluted with EtOAc and filtered through Celite. The organics were washed with NaHCO (sat. aq., 2 × 200 mL) and brine (100 mL), dried over MgSO, and then concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with 20–35% EtOAc in cyclohexane to give 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 (1 M, 44 mL, 44.1 mmol) was added dropwise to a cooled solution of 4-methyl-2-((trimethylsilyl)ethynyl)pyrimidine (7.00 g, 36.8 mmol) in THF (75 mL) at 0 °C, and the reaction mixture was stirred for 45 min. The reaction mixture was warmed to room temperature, quenched with water (75 mL), and extracted with EtOAc (3 × 200 mL). The combined organics were dried over MgSO, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with 20–85% EtOAc in cyclohexane to afford 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 min. (BPin)2 (3.25 g, 12.8 mmol) in THF (4.0 mL) was added, and the mixture was stirred at room temperature for 10 min. 2-Ethynyl-4-methylpyrimidine (1.44 g, 12.2 mmol) and MeOH (0.99 mL, 24.4 mmol) in THF (3.0 mL) were added, and the reaction mixture was stirred at room temperature for 18 h. The reaction mixture was quenched with water (50 mL) and extracted with EtOAc (3 × 100 mL). The combined organic phases were washed with brine (100 mL), dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with 0–40% EtOAc in cyclohexane to give the title compound (2.53 g, 76%) as a pale yellow oil, which solidified on 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] Synthesis of (E)-7-bromo-2-(2-(4-methylpyrimidin-2-yl)vinyl)-1,5-naphthyridine 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), PdCl(PPh) (68 mg, 0.0965 mmol), and KPO (819 mg, 3.86 mmol) were suspended in THF (30 mL) and water (3.0 mL). The reaction mixture was then purged with N for 5 minutes and heated to 70 °C for 1 hour. The reaction was cooled to room temperature, diluted with EtOAc, and then washed with NaHCO (sat. aq.) and brine. The organics were dried over MgSO and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with 0-100% EtOAc in cyclohexane to give 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-methylpyrimidin-2-yl)cyclopropyl)-1,5-naphthyridine 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 a nitrogen atmosphere, and the reaction was stirred at room temperature for 1.5 hours. (E)-7-Bromo-2-(2-(4-methylpyrimidin-2-yl)vinyl)-1,5-naphthyridine (110 mg, 0.336 mmol) in DMSO (25 mL) was then added, and the mixture was stirred at room temperature for 18 hours. The reaction was quenched with NH4Cl (saturated aqueous solution) and extracted with EtOAc. The organic phase was washed with brine, dried over MgSO4, and concentrated in vacuo to give the crude title compound (100 mg), which was carried on 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-methylpyrimidin-2-yl)cyclopropyl)-1,5-naphthyridin-3-yl)carbamate rac-7-Bromo-2-((1S*,2S*)-2-(4-methylpyrimidin-2-yl)cyclopropyl)-1,5-naphthyridine (100 mg, 0.293 mmol), tert-butyl carbamate (52 mg, 0.440 mmol), Pd(OAc) (3.3 mg, 0.0147 mmol), Xantphos (17 mg, 0.0293 mmol), and CsCO (286 mg, 0.879 mmol) were suspended in 1,4-dioxane (5.00 mL) and purged with N for 5 minutes. The reaction was then heated to 100° C. for 1 hour. The reaction was cooled to room temperature, filtered through Celite®, and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with 0-10% MeOH in DCM to give the product 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-methylpyrimidin-2-yl)cyclopropyl)-1,5-naphthyridin-3-amine TFA (0.20 mL, 2.65 mmol) was added to a stirred solution of rac-tert-butyl (6-((1S*,2S*)-2-(4-methylpyrimidin-2-yl)cyclopropyl)-1,5-naphthyridin-3-yl)carbamate (100 mg, 0.265 mmol) in chloroform (3 mL) and stirred at room temperature for 2 hours. The mixture was concentrated in vacuo and the residue was purified using an SCX cartridge, washed with 3:1 DCM in MeOH, and eluted with 7N NH3 in DCM in MeOH to give 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-methylpyrimidin-2-yl)cyclopropyl)-1,5-naphthyridin-3-yl)amino)methyl)imidazo[1,2-a]pyridin-8-yl)-3-methylimidazolidine-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-methylpyrimidin-2-yl)cyclopropyl)-1,5-naphthyridin-3-amine (45 mg, 0.162 mmol) and 6-cyclopropyl-8-(3-methyl-2,4-dioxoimidazolidin-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 h. 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, then quenched with water (1 mL), filtered through Celite®, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with 0-10% 7N NH3 (in MeOH) in DCM followed by preparative HPLC to give 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-naphthyridine in a manner similar to that for rac-1-(6-cyclopropyl-2-(((6-((1S*,2S*)-2-(4-methylpyrimidin-2-yl)cyclopropyl)-1,5-naphthyridin-3-yl)amino)methyl)imidazo[1,2-a]pyridin-8-yl)-3-methylimidazolidine-2,4-dione. [Table 4]

[0292] Examples 16-17 rac-1-(2-(((6-(2-(4-methylpyrimidin-2-yl)cyclopropyl)quinolin-3-yl)amino)methyl)imidazo[1,2-a]pyridin-8-yl)imidazolidine-2,4-dione (I-16) and Synthesis of rac-1-(2-((methyl(6-(2-(4-methylpyrimidin-2-yl)cyclopropyl)quinolin-3-yl)amino)methyl)imidazo[1,2-a]pyridin-8-yl)imidazolidine-2,4-dione (I-17) [ka] Synthesis of tert-butyl (6-bromoquinolin-3-yl)carbamate A solution of 6-bromo-3-iodoquinoline (1.00 g, 2.99 mmol), tert-butyl carbamate (0.35 g, 2.99 mmol), Xantphos (0.69 g, 1.20 mmol), CsCO (2.93 g, 8.98 mmol), and Pd(dba) (0.55 g, 0.60 mmol) in 1,4-dioxane (5.0 mL) was purged with N and stirred at 100 °C overnight. The mixture was filtered through Celite® and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with 0 to 100% EtOAc in cyclohexane to give the title compound (0.55 g, 51%) as an off-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-methylpyrimidin-2-yl)vinyl)quinolin-3-yl)carbamate tert-Butyl (6-bromoquinolin-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), PdCl(PPh) (59 mg, 0.0835 mmol), and KPO (709 mg, 3.34 mmol) were suspended in THF (30 mL) and HO (3.0 mL). The mixture was purged with N and then heated to 70 °C for 18 h. The mixture was then cooled to room temperature, diluted with EtOAc, and washed with NaHCO (sat. aq.) followed by brine. The organics were passed through a hydrophobic frit and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with 0-100% EtOAc in cyclohexane to give 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-methylpyrimidin-2-yl)cyclopropyl)quinolin-3-yl)carbamate and rac-tert-butylmethyl (6-((1S*,2S*)-2-(4-methylpyrimidin-2-yl)cyclopropyl)quinolin-3-yl)carbamate NaH (60% in 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-methylpyrimidin-2-yl)vinyl)quinolin-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% in mineral oil, 22 mg, 0.552 mmol) and trimethylsulfoxonium iodide (121 mg, 0.552 mmol) in DMSO (5.0 mL) (previously stirred at room temperature for 1 hour) was added to the reaction mixture, and the resulting mixture was heated to 60° C. for 3 hours. The mixture was quenched with NH4Cl (saturated aqueous solution) and extracted with EtOAc. The combined organics were passed through a hydrophobic frit and then concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with 0-100% EtOAc in cyclohexane to give a mixture of the title compounds (90 mg), which was used without further purification.

[0295] Synthesis of rac-6-((1S*,2S*)-2-(4-methylpyrimidin-2-yl)cyclopropyl)quinolin-3-amine and rac-N-methyl-6-((1S*,2S*)-2-(4-methylpyrimidin-2-yl)cyclopropyl)quinolin-3-amine TFA (0.037 mL, 0.478 mmol) was added to a mixture of rac-tert-butyl (6-((1S*,2S*)-2-(4-methylpyrimidin-2-yl)cyclopropyl)quinolin-3-yl)carbamate and rac-tert-butyl methyl (6-((1S*,2S*)-2-(4-methylpyrimidin-2-yl)cyclopropyl)quinolin-3-yl)carbamate (90 mg) in DCM (5.0 mL). The reaction was stirred at room temperature for 3 h. The mixture was quenched with NaHCO3 (sat. aq.) and extracted with DCM. The combined organics were passed through a hydrophobic frit then concentrated in vacuo to give the mixture of title compounds (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-methylpyrimidin-2-yl)cyclopropyl)quinolin-3-yl)amino)methyl)imidazo[1,2-a]pyridin-8-yl)-3-methylimidazolidine-2,4-dione and rac-1-(6-cyclopropyl-2-((methyl(6-((1S*,2S*)-2-(4-methylpyrimidin-2-yl)cyclopropyl)quinolin-3-yl)amino)methyl)imidazo[1,2-a]pyridin-8-yl)-3-methylimidazolidine-2,4-dione A crude mixture of rac-6-((1S*,2S*)-2-(4-methylpyrimidin-2-yl)cyclopropyl)quinolin-3-amine and rac-N-methyl-6-((1S*,2S*)-2-(4-methylpyrimidin-2-yl)cyclopropyl)quinolin-3-amine (90 mg, 0.310 mmol), 6-cyclopropyl-8-(3-methyl-2,4-dioxoimidazolidin-1-yl)imidazo[1,2-a]pyridine-2-carbaldehyde (111 mg, 0.372 mmol), and Ti(OiPr) (0.092 mL, 0.310 mmol) in DCM (0.50 mL) and MeOH (0.50 mL) was stirred at 50 °C in a sealed tube for 18 h. The reaction was cooled to room temperature and NaCNBH (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 in vacuo. The residue was purified by preparative HPLC to give the title compound.

[0297] rac-1-(6-cyclopropyl-2-(((6-((1S*,2S*)-2-(4-methylpyrimidin-2-yl)cyclopropyl)quinolin-3-yl)amino)methyl)imidazo[1,2-a]pyridin-8-yl)-3-methylimidazolidine-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-methylpyrimidin-2-yl)cyclopropyl)quinolin-3-yl)amino)methyl)imidazo[1,2-a]pyridin-8-yl)-3-methylimidazolidine-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), cPr CH signal was obscured by the DMSO signal.

[0299] Example 18 Synthesis of 1-(2-(((2-((1S,2S)-2-(3-chlorophenyl)cyclopropyl)-4-methoxy-1,6-naphthyridin-7-yl)amino)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)-3-methylimidazolidine-2,4-dione (I-18) [ka] Synthesis of 1-(6-chloro-4-((2,4-dimethoxybenzyl)amino)pyridin-3-yl)ethan-1-one To a cooled mixture of 1-(4,6-dichloropyridin-3-yl)ethan-1-one (400 mg, 2.11 mmol) and NEt3 (0.44 mL, 3.16 mmol) in MeCN (10 mL) was added (2,4-dimethoxyphenyl)methanamine (0.47 mL, 3.16 mmol) dropwise at 0 °C. The mixture was allowed to warm to room temperature and stirred for 18 h. Water was added and the mixture was extracted with EtOAc. The combined organics were passed through a hydrophobic frit and then concentrated in vacuo to give 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-chloropyridin-3-yl)ethan-1-one TFA (1.0 mL, 1.31 mmol) was added to a solution of 1-(6-chloro-4-((2,4-dimethoxybenzyl)amino)pyridin-3-yl)ethan-1-one (420 mg, 1.31 mmol) in DCM (20 mL) and the mixture was stirred at room temperature for 18 h. NaHCO3 (sat. aq.) was added and the mixture extracted with DCM. The combined organics were passed through a hydrophobic frit and then concentrated in vacuo to give the title compound (260 mg, quant.). 1 H NMR (400 MHz, DMSO) δ 8.69 (s, 1H), 6.79 (s, 1H), 2.59 (s, 3H). 2H (NH2) is missing.

[0301] Synthesis of (1S,2S)-N-(5-acetyl-2-chloropyridin-4-yl)-2-(3-chlorophenyl)cyclopropane-1-carboxamide Oxalyl chloride (0.44 mL, 5.09 mmol) was added dropwise to a cooled, stirred solution of (1S,2S)-2-(4-methylpyrimidin-2-yl)cyclopropanecarboxylic acid (1.00 g, 5.09 mmol) and DMF (0.050 mL) in THF (25 mL) at 0 °C and stirred at 0 °C for 30 minutes. The reaction was then concentrated in vacuo. The residue was suspended in THF (20 mL), and 1-(2-amino-4-bromo-phenyl)ethanone (87 mg, 5.09 mmol) and pyridine (1.2 mL, 15.26 mmol) were added, and 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 give 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-naphthyridin-4(1H)-one NaOH (229 mg, 5.73 mmol) (azeotroped three times with toluene) was added to a stirred suspension of (1S,2S)—N-(5-acetyl-2-chloropyridin-4-yl)-2-(3-chlorophenyl)cyclopropane-1-carboxamide (500 mg, 1.43 mmol) in 1,4-dioxane (5 mL). The reaction was heated at 100° C. for 1 h. The reaction was cooled to room temperature and poured into NH4Cl (sat. aq., 50 mL). The resulting precipitate was filtered and dried to give 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-naphthyridin-4(1H)-one (450 mg, 1.36 mmol) and KCO (376 mg, 2.71 mmol) in DMF (5.0 mL). The reaction was heated to 50 °C for 1 h. The reaction was cooled to room temperature, diluted with water, and then extracted with EtOAc. The combined organics were dried over MgSO and concentrated in vacuo to give 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-naphthyridin-7-yl)-1,1-diphenylmethanimine Xantphos (124 mg, 0.214 mmol), benzophenone imine (0.099 mL, 0.589 mmol), CsCO (524 mg, 1.61 mmol), and Pd(dba) (98 mg, 0.107 mmol) were added to a solution of 7-chloro-2-((1S,2S)-2-(3-chlorophenyl)cyclopropyl)-4-methoxy-1,6-naphthyridine (185 mg, 0.536 mmol) in 1,4-dioxane (5 mL). The solution was degassed with N and heated at 100 °C for 18 h. The mixture was allowed to cool to room temperature, filtered through Celite®, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with 0–50% EtOAc in cyclohexane to afford the title compound (60 mg, 21%) as an off-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-naphthyridin-7-amine HCl (1 M aqueous solution, 1.2 mL, 1.22 mmol) was added to a stirred solution of N-(2-((1S,2S)-2-(3-chlorophenyl)cyclopropyl)-4-methoxy-1,6-naphthyridin-7-yl)-1,1-diphenylmethanimine (60 mg, 0.122 mmol) in THF (1 mL) and the reaction was stirred at 0 °C for 30 min. The reaction mixture was quenched with NaHCO (sat. aq.) and extracted with DCM. The organics were passed through a hydrophobic frit and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with 0-10% 7N NH (in MeOH) in DCM to give 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-naphthyridin-7-yl)amino)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)-3-methylimidazolidine-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-naphthyridin-7-amine (40 mg, 0.123 mmol) and 6-cyclopropyl-8-(3-methyl-2,4-dioxoimidazolidin-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 h and then cooled to room temperature. NaCNBH3 (15 mg, 0.246 mmol) was added, and the mixture was stirred at room temperature for 2 h. The reaction was diluted with water (1.0 mL), filtered through Celite®, and then concentrated in vacuo. The residue was purified by preparative HPLC to give 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]pyridin-2-yl)methyl)-2-((1S*,2S*)-2-(4-methylpyrimidin-2-yl)cyclopropyl)quinolin-7-amine (I-19) [ka] Synthesis of (E)-7-bromo-2-(2-(4-methylpyrimidin-2-yl)vinyl)quinoline A mixture of (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(PPh)Cl (71 mg, 0.10 mmol), and KPO (860 mg, 4.1 mmol) in THF (20 mL) and water (2.0 mL) was degassed with N for 5 minutes and stirred at 70 °C for 3 hours. The reaction mixture was cooled to room temperature, diluted with EtOAc (100 mL), and then washed with NaHCO (saturated aqueous solution, 100 mL) and brine (saturated aqueous solution, 150 mL). The combined organic layers were dried over MgSO and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a gradient of 0-100% EtOAc in cyclohexane to afford 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-methylpyrimidin-2-yl)cyclopropyl)quinoline To a solution of trimethylsulfoxonium iodide (200 mg, 0.92 mmol) in DMSO (2.5 mL) was added NaH (60% in mineral oil, 34 mg, 0.86 mmol), and the reaction mixture was stirred at room temperature for 1.5 h. A mixture of (E)-7-bromo-2-(2-(4-methylpyrimidin-2-yl)vinyl)quinoline (100 mg, 0.31 mmol) in DMSO (2.5 mL) was heated until dissolved and added to the reaction mixture. The mixture was stirred at room temperature for 16 h. The reaction mixture was quenched with NH4Cl (saturated aqueous solution, 50 mL) and then diluted with EtOAc (20 mL). The mixture was extracted with EtOAc (3 × 50 mL), and the combined organic layers were dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with a gradient of 0 to 100% EtOAc in cyclohexane to give 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]pyridin-2-yl)methyl)-2-((1S*,2S*)-2-(4-methylpyrimidin-2-yl)cyclopropyl)quinolin-7-amine A mixture of rac-7-bromo-2-((1S*,2S*)-2-(4-methylpyrimidin-2-yl)cyclopropyl)quinoline (35 mg, 0.10 mmol), (6-cyclopropylimidazo[1,2-a]pyridin-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 in vacuo. The residue was purified by silica gel column chromatography eluting with a gradient of 0-20% 7N NH3 (in MeOH) in DCM followed by preparative HPLC to give 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]pyridin-2-yl)methyl)-4-methoxy-2-((1S*,2S*)-2-(4-methylpyrimidin-2-yl)cyclopropyl)quinolin-7-amine (I-20) [ka] Synthesis of methyl 2-acetamido-4-bromobenzoate AcO (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 h. The mixture was cooled to room temperature and concentrated in vacuo. The residue was washed with cyclohexane and EtOAc (10:1) and concentrated in vacuo to give 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-hydroxyquinolin-2(1H)-one A suspension of methyl 2-acetamido-4-bromobenzoate (10 g, 37 mmol) in THF (100 mL) was added to a 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 EtOAc (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 EtOAc, and then dried under high vacuum for 24 hours to give 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-methoxyquinolin-2(1H)-one A mixture of 7-bromo-4-hydroxyquinolin-2(1H)-one (6.6 g, 27 mmol) and K2CO3 (7.5 g, 55 mmol) in acetone (120 mL) was stirred at reflux for 3 hours. Dimethyl sulfate (2.6 mL, 27 mmol) was added, and the suspension was stirred at 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 acetone, and the remaining aqueous mixture was filtered. The collected precipitate was washed with water under high vacuum for 18 hours to give 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-methoxyquinolin-2(1H)-one (5.5 g, 22 mmol) in POCl (10 mL, 110 mmol) was stirred at 80° C. for 2 h. The reaction mixture was diluted with toluene (10 mL) and stirred at 80° C. for 2 h. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was washed with water (50 mL), basified with NaHCO (sat. aq.) and extracted with EtOAc (3×100 mL). The combined organic layers were passed through a hydrophobic frit and concentrated in vacuo to give 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-methylpyrimidin-2-yl)vinyl)quinoline A mixture of (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(PPh)Cl (71 mg, 0.10 mmol), and KPO (860 mg, 4.1 mmol) in THF (20 mL) and water (2.0 mL) was degassed with N for 5 minutes and stirred at 70 °C for 8 hours. The reaction mixture was cooled to room temperature, diluted with EtOAc (100 mL), and washed with NaHCO (sat. aq., 100 mL). The organic layer was dried over MgSO and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a gradient of 0-100% EtOAc in cyclohexane to give 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-methylpyrimidin-2-yl)cyclopropyl)quinoline To a solution of trimethylsulfoxonium iodide (370 mg, 1.7 mmol) in DMSO (5.0 mL) was added NaH (60% in mineral oil, 63 mg, 1.6 mmol), and the reaction mixture was stirred at room temperature for 1.5 h. A mixture of (E)-7-bromo-4-methoxy-2-(2-(4-methylpyrimidin-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 h. The reaction mixture was quenched with NH4Cl (saturated aqueous solution, 80 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (saturated aqueous solution, 100 mL), dried over MgSO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a gradient of 0 to 100% EtOAc in cyclohexane to give 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]pyridin-2-yl)methyl)-4-methoxy-2-((1S*,2S*)-2-(4-methylpyrimidin-2-yl)cyclopropyl)quinolin-7-amine formate A mixture of rac-7-bromo-4-methoxy-2-((1S*,2S*)-2-(4-methylpyrimidin-2-yl)cyclopropyl)quinoline (50 mg, 0.14 mmol), (6-cyclopropylimidazo[1,2-a]pyridin-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 in vacuo. The residue was purified by silica gel column chromatography eluting with a gradient of 0-20% 7N NH3 (in MeOH) in DCM followed by preparative HPLC to give 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 to 23 Synthesis of rac-1-(6-cyclopropyl-2-(((4-methoxy-2-((1S*,2S*)-2-(4-methylpyrimidin-2-yl)cyclopropyl)quinolin-7-yl)amino)methyl)imidazo[1,2-a]pyridin-8-yl)-3-methylimidazolidine-2,4-dione (I-21) [ka] Synthesis of rac-tert-butyl (4-methoxy-2-((1S*,2S*)-2-(4-methylpyrimidin-2-yl)cyclopropyl)quinolin-7-yl)carbamate A suspension of rac-7-bromo-4-methoxy-2-((1S*,2S*)-2-(4-methylpyrimidin-2-yl)cyclopropyl)quinoline (70 mg, 0.19 mmol), tert-butyl carbamate (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 min. Pd2(dba)3 (35 mg, 0.04 mmol) was added, and the reaction mixture was stirred at 100 °C for 16 h. The reaction mixture was cooled to room temperature, filtered through Celite®, and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with a gradient of 0 to 100% EtOAc in cyclohexane to give 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-methylpyrimidin-2-yl)cyclopropyl)quinolin-7-amine rac-tert-Butyl (4-methoxy-2-((1S*,2S*)-2-(4-methylpyrimidin-2-yl)cyclopropyl)quinolin-7-yl)carbamate (91 mg, 0.22 mmol) and TFA (0.34 mL, 4.5 mmol) were dissolved in CHCl3 (2.0 mL) and the mixture was stirred at room temperature for 1.5 h, then concentrated in vacuo. The residue was washed with NaHCO3 (sat. aq., 25 mL) and extracted with DCM (3 x 40 mL). The combined organics were dried over MgSO4 and concentrated in vacuo to give 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-methylpyrimidin-2-yl)cyclopropyl)quinolin-7-yl)amino)methyl)imidazo[1,2-a]pyridin-8-yl)-3-methylimidazolidine-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-methylpyrimidin-2-yl)cyclopropyl)quinolin-7-amine (62 mg, 0.20 mmol) and 6-cyclopropyl-8-(3-methyl-2,4-dioxoimidazolidin-1-yl)imidazo[1,2-a]pyridine-2-carbaldehyde (60 mg, 0.20 mmol) in DCM (3.0 mL) and MeOH (3.0 mL), and the reaction mixture was stirred at 50 °C for 16 h in a sealed vial. The reaction mixture was cooled to room temperature, diluted with MeOH (1.0 mL), and NaCNBH3 (45 mg, 0.71 mmol) was added. The reaction mixture was stirred at room temperature for 40 min. The reaction mixture was quenched with water (1.0 mL), diluted with MeOH (5.0 mL), filtered through Celite® with MeOH (3 × 3.0 mL), and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a gradient of 0 to 10% 7N NH3 (in MeOH) in DCM, followed by preparative HPLC to afford 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) / CO, 15 mL / min, 120 bar, 40° C. afforded the two enantiomers: 1-(6-cyclopropyl-2-(((4-methoxy-2-((1S,2S)-2-(4-methylpyrimidin-2-yl)cyclopropyl)quinolin-7-yl)amino)methyl)imidazo[1,2-a]pyridin-8-yl)-3-methylimidazolidine-2,4-dione and 1-(6-cyclopropyl-2-(((4-methoxy-2-((1R,2R)-2-(4-methylpyrimidin-2-yl)cyclopropyl)quinolin-7-yl)amino)methyl)imidazo[1,2-a]pyridin-8-yl)-3-methylimidazolidine-2,4-dione.

[0321] First-eluting isomer (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] Second-eluting isomer (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-methylpyrimidin-2-yl)cyclopropyl)quinolin-6-yl)amino)methyl)imidazo[1,2-a]pyridin-8-yl)-3-methylimidazolidine-2,4-dione (I-24) [ka] Synthesis of 6-bromo-3-iodoquinoline NIS (3.2 g, 14 mmol) was added portionwise 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 h. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was dissolved in DCM (150 mL) and washed with NaHCO (saturated aqueous solution, 2 × 100 mL), NaSO (saturated aqueous solution, 100 mL), and brine (saturated aqueous solution, 150 mL). The organic layer was dried over MgSO and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a gradient of 0 to 100% EtOAc in cyclohexane to afford the title compound (1.0 g, 31%) as an off-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-methylpyrimidin-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(PPh)Cl (110 mg, 0.15 mmol), and KPO (1300 mg, 6.0 mmol) in THF (30 mL) and water (3.0 mL) was degassed with N 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 EtOAc (100 mL), and washed with NaHCO (sat. aq., 2 × 100 mL) and brine (sat. aq., 150 mL). The organic layer was dried over MgSO and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a gradient of 0-100% EtOAc in cyclohexane to afford 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-methylpyrimidin-2-yl)cyclopropyl)quinoline A suspension of (E)-6-bromo-3-(2-(4-methylpyrimidin-2-yl)vinyl)quinoline (420 mg, 1.3 mmol), triethylammonium bis(catecholato)iodomethylsilicate (1.9 g, 3.9 mmol), and 4CzIPN (100 mg, 0.13 mmol) in DMSO (30 mL) was degassed with N 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 EtOAc (100 mL) and NaHCO (saturated, aqueous, 100 mL). The mixture was stirred, Celite® (10 g) was added, and filtered to give a biphasic mixture. The layers were separated, and the organic layer was washed with brine (saturated, aqueous, 100 mL), dried over MgSO, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a gradient of 0-100% EtOAc in cyclohexane to afford 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-methylpyrimidin-2-yl)cyclopropyl)quinolin-6-yl)carbamate A mixture of rac-6-bromo-3-((1S*,2S*)-2-(4-methylpyrimidin-2-yl)cyclopropyl)quinoline (160 mg, 0.47 mmol), tert-butyl carbamate (83 mg, 0.71 mmol), Pd(OAc) (5.3 mg, 0.02 mmol), Xantphos (27 mg, 0.05 mmol), and CsCO (460 mg, 1.4 mmol) in 1,4-dioxane (5.0 mL) was degassed with N 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 in vacuo. The residue was purified by column chromatography on silica gel eluting with a gradient of 0–10% MeOH in DCM to afford 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-methylpyrimidin-2-yl)cyclopropyl)quinolin-6-amine TFA (0.27 mL, 3.6 mmol) was added to a stirred solution of rac-tert-butyl (3-((1S*,2S*)-2-(4-methylpyrimidin-2-yl)cyclopropyl)quinolin-6-yl)carbamate (140 mg, 0.36 mmol) in CHCl3 (3.0 mL), and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated in vacuo, and the residue was loaded onto an SCX cartridge, washed with 1:3 MeOH in DCM, and eluted with 1:3 7N NH3 in MeOH in DCM to give 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-methylpyrimidin-2-yl)cyclopropyl)quinolin-6-yl)amino)methyl)imidazo[1,2-a]pyridin-8-yl)-3-methylimidazolidine-2,4-dione Ti(PrO) (0.40 mL, 1.4 mmol) was added to a stirred solution of rac-3-((1S*,2S*)-2-(4-methylpyrimidin-2-yl)cyclopropyl)quinolin-6-amine (75 mg, 0.27 mmol) and 6-cyclopropyl-8-(3-methyl-2,4-dioxoimidazolidin-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 NaCNBH (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 in vacuo. The residue was purified by silica gel column chromatography eluting with a gradient of 0-10% 7N NH3 (in MeOH) in DCM followed by two preparative HPLC runs to afford the title compound (17 mg, 11%) as the formate salt. 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 - 1.68 (m, 2H), 1.01 - 0.95 (m, 2H), 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-imidazol-1-yl)-2-((1S*,2S*)-2-(4-methylpyrimidin-2-yl)cyclopropyl)quinolin-7-yl)amino)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)-3-methylimidazolidine-2,4-dione (I-25) [ka] Synthesis of rac-tert-butyl (2-((1S*,2S*)-2-(4-methylpyrimidin-2-yl)cyclopropyl)-4-oxo-1,4-dihydroquinolin-7-yl)carbamate A mixture of rac-7-bromo-2-((1S*,2S*)-2-(4-methylpyrimidin-2-yl)cyclopropyl)quinolin-4(1H)-one (3.0 g, 8.4 mmol), tert-butyl carbamate (1.5 g, 13 mmol), Pd(OAc) (95 mg, 0.42 mmol), Xantphos (490 mg, 0.84 mmol), and CsCO (8.2 g, 25 mmol) in 1,4-dioxane (84 mL) was degassed with N for 10 min and stirred at 90 °C for 16 h. The reaction mixture was cooled to room temperature and degassed with N for 10 min. Additional tert-butyl carbamate (1.5 g, 13 mmol), Pd(OAc) (95 mg, 0.42 mmol), and Xantphos (490 mg, 0.84 mmol) were added, and the reaction mixture was stirred at 100 °C for 16 h. The mixture was cooled to room temperature and degassed with N. Additional tert-butyl carbamate (1.5 g, 13 mmol), Pd(OAc) (95 mg, 0.42 mmol), Xantphos (490 mg, 0.84 mmol), and CsCO (8.2 g, 25 mmol) were added, and the resulting mixture was stirred at 100 °C for 16 h. The reaction mixture was cooled to room temperature, filtered through Celite® with DCM and MeOH (9:1, 100 mL), and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with a gradient of 0-10% MeOH in DCM to give the title compound (790 mg, 24%) as a cream solid. ESI (M+H)+: 393.4,1 H NMR (400 MHz, DMSO) δ 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-methylpyrimidin-2-yl)cyclopropyl)quinolin-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-methylpyrimidin-2-yl)cyclopropyl)-4-oxo-1,4-dihydroquinolin-7-yl)carbamate (790 mg, 2.0 mmol) in DMF (20 mL), and the reaction mixture was placed under a N2 atmosphere and stirred at room temperature for 16 h. The mixture was quenched with NaHCO3 (saturated aqueous solution, 50 mL) and extracted with EtOAc (3 × 100 mL). The combined organic layers were dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with a gradient of 5–40% EtOAc in cyclohexane to give 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-imidazol-1-yl)-2-((1S*,2S*)-2-(4-methylpyrimidin-2-yl)cyclopropyl)quinolin-7-amine A mixture of rac-tert-butyl (4-bromo-2-((1S*,2S*)-2-(4-methylpyrimidin-2-yl)cyclopropyl)quinolin-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 KCO (46 mg, 0.33 mmol) in DMF (1.7 mL) was degassed with N for 15 min and stirred at 150 °C under N atmosphere for 12 h. Additional CuI (3.1 mg, 0.017 mmol) was added, and the mixture was degassed with N for 5 min and then stirred at 150 °C for 4 h. The reaction mixture was cooled to room temperature, diluted with EtOAc (25 mL), and washed with NaHCO (saturated aqueous solution, 25 mL) and brine (saturated aqueous solution, 25 mL). The combined aqueous layers were extracted with EtOAc (20 mL). The combined organic layers were dried over MgSO and concentrated in vacuo to afford the title compound (50 mg, 89%) as a yellow gum, which was used without further purification. ESI (M+H)+: 343.2.

[0332] Synthesis of rac-1-(2-(((4-(1H-imidazol-1-yl)-2-((1S*,2S*)-2-(4-methylpyrimidin-2-yl)cyclopropyl)quinolin-7-yl)amino)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)-3-methylimidazolidine-2,4-dione Ti(OiPr)4 (0.22 mL, 0.73 mmol) was added to a solution of rac-4-(1H-imidazol-1-yl)-2-((1S*,2S*)-2-(4-methylpyrimidin-2-yl)cyclopropyl)quinolin-7-amine (50 mg, 0.15 mmol) and 6-cyclopropyl-8-(3-methyl-2,4-dioxoimidazolidin-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 h. 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 h. Water (2.0 mL) was added, and the mixture was filtered through Celite® and then concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a gradient of 1 to 20% 7N NH3 (in MeOH) in DCM, followed by preparative HPLC to afford 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-methylpyrimidin-2-yl)cyclopropyl)-4-(1H-1,2,4-triazol-1-yl)quinolin-7-yl)amino)methyl)imidazo[1,2-a]pyridin-8-yl)-3-methylimidazolidine-2,4-dione (I-26) [ka] Synthesis of rac-2-((1S*,2S*)-2-(4-methylpyrimidin-2-yl)cyclopropyl)-4-(1H-1,2,4-triazol-1-yl)quinolin-7-amine A mixture of rac-tert-butyl (4-bromo-2-((1S*,2S*)-2-(4-methylpyrimidin-2-yl)cyclopropyl)quinolin-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 a N2 atmosphere and stirred at 150 °C for 16 h. The reaction mixture was cooled to room temperature, diluted with EtOAc (50 mL), and washed with NaHCO3 (sat. aq., 50 mL) and brine (sat. aq., 50 mL). The combined organic layers were dried over MgSO4 and concentrated in vacuo. The residue was loaded onto an SCX cartridge, washed with MeOH in DCM (1:1), eluted with 7N NH3 (in MeOH) in DCM (1:1) and concentrated in vacuo to give 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-methylpyrimidin-2-yl)cyclopropyl)-4-(1H-1,2,4-triazol-1-yl)quinolin-7-yl)amino)methyl)imidazo[1,2-a]pyridin-8-yl)-3-methylimidazolidine-2,4-dione Ti(OiPr)4 (0.23 mL, 0.79 mmol) was added to a mixture of rac-2-((1S*,2S*)-2-(4-methylpyrimidin-2-yl)cyclopropyl)-4-(1H-1,2,4-triazol-1-yl)quinolin-7-amine (54 mg, 0.16 mmol) and 6-cyclopropyl-8-(3-methyl-2,4-dioxoimidazolidin-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. Further NaCNBH3 (35 mg, 0.55 mmol) was 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 pad of Celite®, and concentrated in vacuo. The residue was purified by preparative HPLC to give 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-pyrazol-4-yl)-2-((1S,2S)-2-(4-methylpyrimidin-2-yl)cyclopropyl)quinolin-7-yl)amino)methyl)imidazo[1,2-a]pyridin-8-yl)-3-methylimidazolidine-2,4-dione (I-27) [ka] Synthesis of tert-butyl (4-(1-methyl-1H-pyrazol-4-yl)-2-((1S,2S)-2-(4-methylpyrimidin-2-yl)cyclopropyl)quinolin-7-yl)carbamate tert-Butyl (4-bromo-2-((1S,2S)-2-(4-methylpyrimidin-2-yl)cyclopropyl)quinolin-7-yl)carbamate (48 mg, 0.11 mmol) was prepared using the same route as (rac-tert-butyl (4-bromo-2-((1S,2S)-2-(4-methylpyrimidin-2-yl)cyclopropyl)quinolin-7-yl)carbamate (1S,2 A mixture of (S)-2-(4-methylpyrimidin-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 KPO (67 mg, 0.32 mmol) in dioxane (1.0 mL) and water (0.2 mL) was degassed with N for 5 min. PdCl(dppf) (4.3 mg, 0.0053 mmol) was added, and the mixture was heated at 100 °C in a microwave reactor for 30 min. The mixture was cooled to room temperature, filtered through Celite®, and then concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a gradient of 0 to 100% EtOAc in cyclohexane to afford the title compound (32 mg, 67%) as a golden gum. ESI (M+H)+: 457.5

[0336] Synthesis of 4-(1-methyl-1H-pyrazol-4-yl)-2-((1S,2S)-2-(4-methylpyrimidin-2-yl)cyclopropyl)quinolin-7-amine tert-Butyl (4-(1-methyl-1H-pyrazol-4-yl)-2-((1S,2S)-2-(4-methylpyrimidin-2-yl)cyclopropyl)quinolin-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 in vacuo. The residue was loaded onto an SCX cartridge, washed with DCM, then 10% MeOH in DCM, eluted with 10% 7N NH3 (in MeOH) in DCM, and then concentrated in vacuo to give 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-pyrazol-4-yl)-2-((1S,2S)-2-(4-methylpyrimidin-2-yl)cyclopropyl)quinolin-7-yl)amino)methyl)imidazo[1,2-a]pyridin-8-yl)-3-methylimidazolidine-2,4-dione The title compound was obtained from 4-(1-methyl-1H-pyrazole-4-yl)-2-(4-methylpyrimidin-2-yl)cyclopropyl)-4-(1H-1,2,4-triazol-1-yl)quinolin-7-yl)amino)methyl)imidazo[1,2-a]pyridin-8-yl)-3-methylimidazolidine-2,4-dione using a procedure similar to that used for rac-1-(6-cyclopropyl-2-(((2-((1S*,2S*)-2-(4-methylpyrimidin-2-yl)cyclopropyl)-4-(1H-1,2,4-triazol-1-yl)quinolin-7-yl)amino)methyl)imidazo[1,2-a]pyridin-8-yl)-3-methylimidazolidine-2,4-dione. -yl)-2-((1S,2S)-2-(4-methylpyrimidin-2-yl)cyclopropyl)quinolin-7-amine (20 mg, 0.056 mmol) and 6-cyclopropyl-8-(3-methyl-2,4-dioxoimidazolidin-1-yl)imidazo[1,2-a]pyridine-2-carbaldehyde (17 mg, 0.056 mmol) (as the formate salt) 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-methylpyrimidin-2-yl)cyclopropyl)quinolin-7-yl)amino)methyl)imidazo[1,2-a]pyridin-8-yl)-3-methylimidazolidine-2,4-dione (I-28) [ka] Synthesis of 1-(6-cyclopropyl-2-(((5-methoxy-2-((1S,2S)-2-(4-methylpyrimidin-2-yl)cyclopropyl)quinolin-7-yl)amino)methyl)imidazo[1,2-a]pyridin-8-yl)-3-methylimidazolidine-2,4-dione [ka] Synthesis of (1S,2S)-N-methoxy-N-methyl-2-(4-methylpyrimidin-2-yl)cyclopropane-1-carboxamide Oxalyl chloride (7.3 mL, 84.2 mmol) was added dropwise to a stirred solution of (1S,2S)-2-(4-methylpyrimidin-2-yl)cyclopropanecarboxylic acid (7.50 g, 42.1 mmol) and DMF (0.050 mL) in THF (10 mL) at 0 °C and stirred at 0 °C for 30 min. The reaction 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 was then heated to 50 °C and stirred for 3 h, then cooled to room temperature and partitioned between water and DCM. The layers were separated and the aqueous was further extracted with DCM. The combined organics were dried over MgSO and concentrated. The residue was purified by silica gel column chromatography eluting with 0-10% MeOH in DCM to give the title compound (7.4 g, 79%) as a brown oil. 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-methylpyrimidin-2-yl)cyclopropyl)ethan-1-one A solution of methylmagnesium bromide (3 M in EtO, 20 mL, 60.2 mmol) was added dropwise over 5 min to a stirred solution of (1S,2S)-N-methoxy-N-methyl-2-(4-methylpyrimidin-2-yl)cyclopropane-1-carboxamide (7.40 g, 33.4 mmol) in THF (60 mL) at 0 °C, and the reaction was stirred at 0 °C for 1 h. The reaction was warmed to room temperature and quenched with NH Cl (sat. aq.). The mixture was then extracted with EtOAc (3 x). The combined organics were dried over MgSO and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with 0-100% ethyl acetate in cyclohexane to give 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-nitro-phenol (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 h. The reaction was cooled to room temperature and poured into ice / water. The solution was then extracted with DCM (3 times). The combined organics were dried over MgSO and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with 0-100% EtOAc in cyclohexane to give the title product as a mixture of two regioisomers (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]undec-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-nitro-benzaldehyde (1.15 g, 4.67 mmol) in acetone (20 mL). The reaction was then stirred at room temperature for 16 h. The reaction was concentrated and then suspended in EtOAc and NaHCO. The aqueous layer was further extracted with EtOAc. The combined organics were dried over MgSO and concentrated in vacuo. The crude residue was purified by silica gel column chromatography eluting with 0–100% EtOAc in hexanes to give a mixture of regioisomers (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 (2 M, 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 was then heated to 60 °C and stirred for 5 h. The reaction was cooled to room temperature, concentrated, and the residue was diluted with DCM and NaHCO. The aqueous layer was further extracted with DCM. The combined organics were dried over MgSO and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a gradient of 0 to 10% MeOH in DCM to give 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-methylpyrimidin-2-yl)cyclopropyl)quinoline KOH (25.4 mg, 0.45 mmol) was added to a stirred solution of 1-((1S,2S)-2-(4-methylpyrimidin-2-yl)cyclopropyl)ethan-1-one (80 mg, 0.45 mmol) and 2-amino-4-bromo-6-methoxybenzaldehyde (104 mg, 0.45 mmol) in EtOH (3.0 mL), which was then stirred at 70 °C for 30 min. The reaction was cooled to room temperature and concentrated in vacuo. The residue was dissolved in DCM and washed with NaHCO. The organics were dried over MgSO and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with 0-100% EtOAc in cyclohexane to give 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-methylpyrimidin-2-yl)cyclopropyl)quinolin-7-yl)carbamate 7-Bromo-5-methoxy-2-((1S,2S)-2-(4-methylpyrimidin-2-yl)cyclopropyl)quinoline (80 mg, 0.216 mmol), tert-butyl carbamate (38 mg, 0.324 mmol), Pd(OAc) (2.4 mg, 0.011 mmol), Xantphos (13 mg, 0.022 mmol), and CsCO (211 mg, 0.648 mmol) were suspended in 1,4-dioxane (5.0 mL) and degassed for 5 minutes. The reaction was then heated to 100 °C and stirred for 3 hours. The reaction was cooled to room temperature, filtered through Celite®, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with 0 to 100% EtOAc in cyclohexane to give 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-methylpyrimidin-2-yl)cyclopropyl)quinolin-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-methylpyrimidin-2-yl)cyclopropyl)quinolin-7-yl)carbamate (75 mg, 0.185 mmol) in CHCl (3 mL). The reaction was stirred at room temperature for 3 hours, then concentrated in vacuo and loaded onto an SCX cartridge. This was washed with 3:1 DCM:MeOH and eluted with 7N NH in 3:1 DCM:MeOH, then concentrated in vacuo to give 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-methylpyrimidin-2-yl)cyclopropyl)quinolin-7-yl)amino)methyl)imidazo[1,2-a]pyridin-8-yl)-3-methylimidazolidine-2,4-dione Ti(iPrO) (0.25 mL, 0.849 mmol) was added to a stirred solution of 5-methoxy-2-((1S,2S)-2-(4-methylpyrimidin-2-yl)cyclopropyl)quinolin-7-amine (52 mg, 0.170 mmol) and 6-cyclopropyl-8-(3-methyl-2,4-dioxoimidazolidin-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 was then heated in a sealed tube at 50° C. for 16 hours. The reaction was cooled to room temperature, NaCNBH (37 mg, 0.594 mmol) was added, and the reaction was then stirred at room temperature for 2 hours. The reaction was quenched with water (1.0 mL). The reaction mixture was then filtered through Celite® and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with 0-10% 7N NH3 (in MeOH) in DCM followed by preparative HPLC to give 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-methylpyrimidin-2-yl)cyclopropyl)quinolin-7-yl)amino)methyl)imidazo[1,2-a]pyridin-8-yl)-3-methylimidazolidine-2,4-dione (I-29) [ka] Synthesis of rac-tert-butyl (4-(dimethylamino)-2-((1S*,2S*)-2-(4-methylpyrimidin-2-yl)cyclopropyl)quinolin-7-yl)carbamate A mixture of rac-7-bromo-N,N-dimethyl-2-((1S,2S)-2-(4-methylpyrimidin-2-yl)cyclopropyl)quinolin-4-amine (150 mg, 0.39 mmol), tert-butyl carbamate (69 mg, 0.59 mmol), Pd(dba) (36 mg, 0.039 mmol), Xantphos (45 mg, 0.078 mmol), and CsCO (260 mg, 0.78 mmol) in 1,4-dioxane (4.0 mL) was degassed with N and heated at 100 °C for 18 h. The mixture was filtered through Celite®, then concentrated in vacuo and purified by silica gel column chromatography eluting with 0–100% EtOAc in cyclohexane to give the title compound (120 mg, 70%) as a yellow gum. 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 1-dimethyl-2-((1S*,2S*)-2-(4-methylpyrimidin-2-yl)cyclopropyl)quinoline-4,7-diamine A solution of rac-tert-butyl (4-(dimethylamino)-2-((1S*,2S*)-2-(4-methylpyrimidin-2-yl)cyclopropyl)quinolin-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 h and then concentrated in vacuo. The residue was dissolved in NaHCO3 (sat. aq., 50 mL) and extracted with DCM (3 x 50 mL). The combined organic layers were dried (MgSO4), filtered, and concentrated in vacuo to give the title compound (79 mg, 90%) as a yellow gum. 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-methylpyrimidin-2-yl)cyclopropyl)quinolin-7-yl)amino)methyl)imidazo[1,2-a]pyridin-8-yl)-3-methylimidazolidine-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-methylpyrimidin-2-yl)cyclopropyl)quinoline-4,7-diamine (49 mg, 0.18 mmol) and 6-cyclopropyl-8-(3-methyl-2,4-dioxoimidazolidin-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 was sealed and stirred at 50 °C for 18 h. The mixture was cooled to room temperature, and additional Ti(iPrO)4 (0.26 mL, 0.88 mmol) was added. The mixture was stirred at 50 °C for 2 h and then cooled to room temperature. NaCNBH3 (39 mg, 0.62 mmol) was added and the mixture was stirred at room temperature for 18 h. Water (1.0 mL) was added and the mixture was concentrated in vacuo onto silica gel and then purified by silica gel column chromatography eluting with 1-20% 7N NH3 (in MeOH) in DCM followed by preparative HPLC to give the title compound (12 mg, 12%) as a yellow solid (as the formate salt). 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-dioxoimidazolidin-1-yl)imidazo[1,2-a]pyridine-2-carbaldehyde and the appropriate coupling partner in a manner similar to rac-1-(6-cyclopropyl-2-(((4-(dimethylamino)-2-((1S*,2S*)-2-(4-methylpyrimidin-2-yl)cyclopropyl)quinolin-7-yl)amino)methyl)imidazo[1,2-a]pyridin-8-yl)-3-methylimidazolidine-2,4-dione. [Table 5-1] [Table 5-2] [Table 5-3] [Table 5-4] [Table 5-5] [Table 5-6]

[0351] Examples 40 to 42 Synthesis of rac-1-(6-cyclopropyl-2-(((2-((1S*,2S*)-2-(4-methylpyrimidin-2-yl)cyclopropyl)-4-morpholinoquinolin-7-yl)amino)methyl)imidazo[1,2-a]pyridin-8-yl)-3-methylimidazolidine-2,4-dione (I-40) [ka] Using a procedure similar to that used for rac-1-(6-cyclopropyl-2-(((4-(dimethylamino)-2-((1S*,2S*)-2-(4-methylpyrimidin-2-yl)cyclopropyl)quinolin-7-yl)amino)methyl)imidazo[1,2-a]pyridin-8-yl)-3-methylimidazolidine-2,4-dione, the title compound was prepared from rac-4-(7-bromo-2-((1S*,2S*)-2-(4-methylpyrimidin-2-yl)cyclopropyl)quinolin-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°C) to give the two enantiomers: 1-(6-cyclopropyl-2-(((2-((1S,2S)-2-(4-methylpyrimidin-2-yl)cyclopropyl)-4-morpholinoquinolin-7-yl)amino)methyl)imidazo[1,2-a]pyridin-8-yl)-3-methylimidazolidine-2,4-dione and 1-(6-cyclopropyl-2-(((2-((1R,2R)-2-(4-methylpyrimidin-2-yl)cyclopropyl)-4-morpholinoquinolin-7-yl)amino)methyl)imidazo[1,2-a]pyridin-8-yl)-3-methylimidazolidine-2,4-dione.

[0353] First-eluting isomer (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: Absorbed heterogeneous 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-methylpyrimidin-2-yl)cyclopropyl]-4-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-7-quinolyl]oxymethyl]imidazo[1,2-a]pyridin-8-yl]-3-methyl-imidazolidine-2,4-dione (I-43) [ka] Synthesis of 1-(6-cyclopropyl-2-(((2-((1S,2S)-2-(4-methylpyrimidin-2-yl)cyclopropyl)-4-(2-oxa-6-azaspiro[3.3]heptan-6-yl)quinolin-7-yl)oxy)methyl)imidazo[1,2-a]pyridin-8-yl)-3-methylimidazolidine-2,4-dione A suspension of 6-(7-bromo-2-((1S,2S)-2-(4-methylpyrimidin-2-yl)cyclopropyl)quinolin-4-yl)-2-oxa-6-azaspiro[3.3]heptane (110 mg, 0.24 mmol), 1-(6-cyclopropyl-2-(hydroxymethyl)imidazo[1,2-a]pyridin-8-yl)-3-methylimidazolidine-2,4-dione (72 mg, 0.24 mmol), CsCO (240 mg, 0.72 mmol), and Adamantyl-BippyPhos (32 mg, 0.048 mmol) in 1,4-dioxane (1.0 mL) was degassed with N for 10 min. Pd(OAc) (5.4 mg, 0.024 mmol) was added, and the reaction mixture was stirred at 90 °C for 18 h. The reaction mixture was filtered through a pad of Celite® and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with 0-20% 7N NH3 (in MeOH) in DCM followed by preparative HPLC to give the title compound (16 mg, 10%) as a white solid (formate salt). 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]pyridin-2-yl)methyl)-7H-purine (I-44) [ka] Synthesis of 4-chloro-N-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)pyrimidin-5-amine To a solution of 4-chloropyrimidin-5-amine (1.2 g, 9.3 mmol) in DMF (40 mL) was added NaH (0.48 g, 12 mmol, 60% dispersion in mineral oil) at 0 °C. After stirring at room temperature for 1 h under N2, 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 an additional 2 h. The reaction mixture was quenched with water (60 mL). The aqueous phase was extracted with EtOAc (60 mL × 3). The combined organic layers were washed with brine (100 mL), dried over NaSO, and then concentrated in vacuo to give the crude material, which was purified by column chromatography on silica gel eluting with 0-50% EtOAc / PE to give 4-chloro-N-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)pyrimidin-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]pyridin-2-yl)methyl)-7H-purine To a mixture of 4-chloro-N-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)pyrimidin-5-amine (50 mg, 0.17 mmol), (1S,2S)-2-(3-chlorophenyl)cyclopropane-1-carboxamide (40 mg, 0.20 mmol), and CsCO (166 mg, 0.51 mmol) in 1,4-dioxane (5.0 mL) was added Pd(dba) (31 mg, 0.034 mmol) and Xantphos (20 mg, 0.034 mmol). The reaction mixture was stirred at 95 °C under N for 12 h. 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 in vacuo to give the crude material, which was purified by preparative TLC eluting with 6% MeOH / DCM to give 8-((1S,2S)-2-(3-chlorophenyl)cyclopropyl)-7-((6-cyclopropylimidazo[1,2-a]pyridin-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]pyridin-2-yl)methyl)-1H-benzo[d]imidazol-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 h under N. Water (50 mL) was added, and the mixture was extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (30 mL), dried over NaSO, and concentrated in vacuo. The residue was purified by column chromatography (eluent: DCM / MeOH = 0-5%) to give (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 h. The mixture was evaporated to remove AcOH, and the residue was diluted with NaHCO (saturated aqueous solution, 50 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (30 mL), dried over NaSO, and concentrated in vacuo. The residue was purified by preparative TLC (eluent: DCM / MeOH = 20 / 1) to give 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]imidazol-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 / HO (6 mL / 2 mL) was stirred at 65 °C for 18 h under N2. The reaction mixture was filtered through Celite®, and the filter cake was washed with DCM / MeOH (10 / 1, 50 mL). Water (30 mL) was added to the filtrate, and the mixture was extracted with DCM / MeOH (10 / 1, 50 mL × 3). The combined organic layers were washed with brine (30 mL), dried over NaSO, and concentrated in vacuo to give 2-((1S,2S)-2-(3-chlorophenyl)cyclopropyl)-1H-benzo[d]imidazol-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]pyridin-2-yl)methyl)-1H-benzo[d]imidazol-6-amine To a mixture of 2-((1S,2S)-2-(3-chlorophenyl)cyclopropyl)-1H-benzo[d]imidazol-6-amine (100 mg, 0.35 mmol) and 6-cyclopropylimidazo[1,2-a]pyridine-2-carbaldehyde (65 mg, 0.35 mol) in THF (15 mL) was added acetic acid (0.1 mL). The resulting solution was stirred at room temperature for 16 h. NaBH(OAc) (148 mg, 0.7 mmol) was added, and the solution was stirred for an additional 1 h. The reaction was quenched with NaHCO (saturated aqueous solution, 50 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic layers were washed with brine (30 mL), dried over NaSO and concentrated in vacuo to give the crude product, which was purified by preparative TLC (eluent: DCM / MeOH=10 / 1) to give 2-((1S,2S)-2-(3-chlorophenyl)cyclopropyl)-N-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-benzo[d]imidazol-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]pyridin-2-yl)methyl)-1H-benzo[d]imidazol-7-amine (I-46) [ka] Synthesis of (1S,2S)-N-(2-amino-6-nitrophenyl)-2-(3-chlorophenyl)cyclopropane-1-carboxamide To a mixture of (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) in DMF (20 mL) was added HATU (1.94 g, 5.08 mmol) and DIPEA (1.3 g, 10.15 mmol). The resulting reaction mixture was stirred at room temperature under N for 14 hours. The reaction mixture was poured into water (200 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (30 mL), dried over NaSO, and concentrated in vacuo to give a crude product, which was purified by column chromatography (eluent: MeOH / DCM = 0-5%) to give (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 h. The mixture was concentrated in vacuo to remove AcOH, and the residue was diluted with NaHCO (saturated aqueous solution, 50 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (30 mL), dried over NaSO, and concentrated in vacuo to give the crude product, which was purified by column chromatography (eluent: MeOH / DCM = 0-5%) to give 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]imidazol-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) was added Fe (336 mg, 6.0 mmol) and NH4Cl (320 mg, 6.0 mmol). The reaction was stirred at 65 °C under N2 for 18 h. The reaction mixture was filtered through Celite® and the filter cake 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 NaSO, and concentrated in vacuo to give 2-((1S,2S)-2-(3-chlorophenyl)cyclopropyl)-1H-benzo[d]imidazol-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]pyridin-2-yl)methyl)-1H-benzo[d]imidazol-7-amine To a mixture of 2-((1S,2S)-2-(3-chlorophenyl)cyclopropyl)-1H-benzo[d]imidazol-7-amine (120 mg, crude) and 6-cyclopropylimidazo[1,2-a]pyridine-2-carbaldehyde (65 mg, 0.35 mol) in THF (15 mL) was added acetic acid (0.1 mL). The resulting solution was stirred at room temperature for 16 h. NaBH(OAc) (148 mg, 0.7 mmol) was added, and the mixture was stirred for an additional 1 h. The reaction was quenched with NaHCO (saturated aqueous solution, 50 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (30 mL), dried over NaSO, and then concentrated in vacuo to give the crude product, which was purified by preparative TLC (eluent: DCM / MeOH=10 / 1) to give 2-((1S,2S)-2-(3-chlorophenyl)cyclopropyl)-N-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-benzo[d]imidazol-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-methoxyquinolin-7-yl)((6-cyclopropylimidazo[1,2-a]pyridin-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, followed by the addition of bis(pinacolato)diboron (7.4 g, 29 mmol) in THF (30 mL). The reaction mixture was stirred for 10 minutes, and 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. Upon completion, the reaction mixture was quenched with water (80 mL) and extracted with EtOAc (80 mL × 3). The combined organic layers were washed with brine (80 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluent: EtOAc / PE = 0-3%) to give (£)-2-(3-chlorostyryl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (4.4 g, 57%) as a pale yellow viscous oil. ESI-MS [M + H]: 265.1.

[0367] Synthesis of rac-2-((1S*,2S*)-2-(3-chlorophenyl)cyclopropyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane [ka] To a solution of ZnEt (20 mL, 20 mmol, 1 M in hexane) in dry DCM (25 mL) was added (very slowly) a solution of trifluoroacetic acid (2.3 g, 20 mmol) in DCM (15 mL) at 0 °C. After the addition (25 min), the reaction mixture was stirred at 0 °C for an additional 30 min. Then, a solution of diiodomethane (5.4 g, 20 mmol) in DCM (15 mL) was added to it. After stirring at 0 °C for an additional 30 min, a solution of (E)-2-(3-chlorostyryl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.7 g, 10 mmol) in DCM (15 mL) was added to the above reaction mixture, and the reaction mixture was warmed to room temperature and stirred overnight. The reaction mixture was quenched with NH Cl (saturated aqueous solution, 50 mL) and extracted with DCM (50 mL × 3). The organic layer was dried over anhydrous NaSO and then concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluent: PE / EtOAc = 20:1) to give 2-(2-(3-chlorophenyl)cyclopropyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.1 g, yield 75%) as a colorless oil. ESI-MS [M +H]+: 279.1, 1 H NMR (400 MHz, DMSO) δ 7.27 - 7.23 (m, 1H), 7.19 - 7.16 (m, 2H), 7.06 - 7.04 (m, 1H), 2.04 - 2.00 (m, 1H), 1.20 - 1.15 (m, 12H), 1.07 - 1.01 (m, 2H), 0.23 - 0.18(m, 1H).

[0368] Synthesis of 7-bromo-4-hydroxyquinolin-2(1H)-one and 5-bromo-4-hydroxyquinolin-2(1H)-one To an oven-dried 100 mL round-bottom flask were added 3-bromoaniline (10 g, 58 mmol) and 2,2-dimethyl-1,3-dioxane-4,6-dione (10 g, 69 mmol) and heated at 80 °C for 6 h. After the starting material was consumed (TLC), the reaction was diluted with NaHCO (saturated aqueous solution, 50 mL) and washed with EtOAc (100 mL × 3). The organic layer was discarded. The pH of the aqueous layer was adjusted to pH = 1 with concentrated HCl and then extracted with DCM (75 mL × 3). The combined organic layers were washed with brine (70 mL), dried over anhydrous NaSO, and concentrated in vacuo to give the crude product, which was treated with Eaton's reagent (80 g) at 80 °C for 6 h. Upon completion, the reaction mixture was cooled to 0 °C, quenched with cold water (100 mL), and stirred for 30 min until a solid precipitated. The mixture was filtered and the filter cake was dried to give 7-bromo-4-hydroxyquinolin-2(1H)-one (6.5 g crude, mixture with 5-bromo-4-hydroxyquinolin-2(1H)-one) as a white solid. ESI-MS: [M + H] + , 240.0

[0369] Synthesis of 7-bromo-4-methoxyquinolin-2(1H)-one [ka] A mixture of 7-bromo-4-hydroxyquinolin-2(1H)-one (6.5 g crude, mixture with 5-bromo-4-hydroxyquinolin-2(1H)-one) and K2CO3 (7.5 g, 54 mmol) in acetone (120 mL) was refluxed for 3 hours. The reaction was cooled to room temperature, dimethyl sulfate (3.4 g, 27 mmol) was added, and the mixture was refluxed for an additional 3 hours. The reaction was concentrated in vacuo to remove the solvent, and the residue was diluted with HO (80 mL) and extracted with EtOAc (80 mL × 3). The combined organic layers were washed with brine (80 mL), dried over anhydrous Na2SO4, and then concentrated in vacuo to give 7-bromo-4-methoxyquinolin-2(1H)-one (3.3 g crude), which was used without further purification. ESI-MS: [M + H] + , 254.0

[0370] Synthesis of 7-bromo-2-chloro-4-methoxyquinoline and 5-bromo-2-chloro-4-methoxyquinoline [ka] A mixture of 7-bromo-4-methoxyquinolin-2(1H)-one (2.4 g, crude) and POCl3 (7.2 g, 47 mmol) was stirred at 80 °C for 2 h. After removing excess POCl3, the dark brown liquid was added to cold water (150 mL) and neutralized with NaHCO3 (saturated aqueous solution, 50 mL), followed by extraction with EtOAc (100 mL × 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, and concentrated in vacuo to give a white solid, which was purified by preparative HPLC (chromatography column: Kromasil-C18 100 × 21.2 mm × 5 μm, mobile phase: ACN-HO (0.1% FA), gradient: 60–70) to give 7-bromo-2-chloro-4-methoxyquinoline (640 mg, 6% over 3 steps) as a white solid. ESI-MS: [M + H]+, 272.0, 1 H NMR (400 MHz, DMSO) δ 8.11 (d, J = 1.9 Hz, 1H), 8.04 (d, J = 8.9 Hz, 1H), 7.74 (dd, J = 8.9, 2.0 Hz, 1H), 7.17 (s, 1H), 4.09 (s, 3H).

[0371] Synthesis of rac-7-bromo-2-((1S*,2S*)-2-(3-chlorophenyl)cyclopropyl)-4-methoxyquinoline A mixture of 7-bromo-2-chloro-4-methoxyquinoline (300 mg, 1.1 mmol), Pd(PPh) (380 mg, 0.33 mmol), 2-(2-(3-chlorophenyl)cyclopropyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (473 mg, 1.7 mmol), and NaCO (350 mg, 3.3 mmol) in DME (8 mL) and HO (2 mL) was stirred in a sealed tube and irradiated in a microwave oven at 95 °C for 1.5 h. The mixture was diluted with water (60 mL) and extracted with DCM (50 mL × 3). The combined organic layers were washed with brine (80 mL), dried over NaSO and concentrated in vacuo to give the crude product, which was purified by column chromatography on silica gel (eluent: EA / PE=1 / 15) to give 7-bromo-2-(2-(3-chlorophenyl)cyclopropyl)-4-methoxyquinoline (90 mg, 21% yield) as a colorless oil. ESI-MS: [M + H]+, 388.0, 1 H NMR (400 MHz, DMSO) δ 8.01 - 7.98 (m, 2H), 7.59 (dd, J = 8.8, 2.0 Hz, 1H), 7.34 - 7.13 (m, 5H), 4.04 (s, 3H), 2.64 - 2.57 (m, 2H), 1.92 - 1.88 (m, 1H), 1.64-1.59 (m,1H).

[0372] Synthesis of rac-tert-butyl (2-((1S*,2S*)-2-(3-chlorophenyl)cyclopropyl)-4-methoxyquinolin-7-yl)((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)carbamate A mixture of tert-butyl ((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)carbamate (59 mg, 0.21 mmol), 7-bromo-2-(2-(3-chlorophenyl)cyclopropyl)-4-methoxyquinoline (80 mg, 0.21 mmol), Pd(dba) (38 mg, 0.041 mmol), Xantphos (47 mg, 0.082 mmol), and CsCO (200 mg, 0.62 mmol) in toluene (8 mL) was stirred at 110 °C under N overnight. The reaction was filtered and concentrated in vacuo. The residue was diluted with water (30 mL) and then extracted with EtOAc (30 mL × 3). The organic layer was dried over NaSO and concentrated in vacuo. The residue was purified by preparative TLC (eluent: DCM / MeOH=20 / 1) to give rac-tert-butyl (2-((1S*,2S*)-2-(3-chlorophenyl)cyclopropyl)-4-methoxyquinolin-7-yl)((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)carbamate (20 mg, 16% yield) as a white solid. ESI-MS [M +H]+: 595.3. 1 H NMR (400 MHz, MeOD) δ 8.14 (s, 1H), 8.04 (d, J = 8.9 Hz, 1H), 7.72 (d, J = 1.8 Hz, 1H), 7.64 (s, 1H), 7.42 - 7.39 (m, 1H), 7.35 (d, J = 9.3 Hz, 1H), 7.27 - 7.23 (m, 1H), 7.20 - 7.16 (m, 2H), 7.12 (d, J = 7.7 Hz, 1H), 7.04 (dd, J = 9.4, 1.6 Hz, 1H), 6.79 (s, 1H), 5.06 (s, 2H), 4.05 (s, 3H), 2.61 - 2.56 (m, 1H), 2.49 - 2.45 (m, 1H), 1.92 - 1.83 (m, 2H), 1.57 - 1.53 (m, 1H), 1.46 (s, 9H), 0.97 - 0.92 (m, 2H), 0.69 - 0.67 (m, 2H).

[0373] Example 48 Synthesis of rac-2-((1S*,2S*)-2-(3-chlorophenyl)cyclopropyl)-N-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-4-methoxyquinolin-7-amine (I-48) [ka] To a solution of rac-tert-butyl ...

Claims

1. Formula (I): 【Chemistry 1】 or a pharma- ceutically acceptable salt thereof [In the formula: Cy Ａ is an 8-10 membered bicyclic heteroarylene having 1 to 5 heteroatoms independently selected from oxygen, nitrogen, and sulfur, a 10-14 membered tricyclic heteroarylene having 1 to 6 heteroatoms independently selected from oxygen, nitrogen, and sulfur, an 8-14 membered saturated or partially unsaturated bicyclic heterocyclyl having 1 to 6 heteroatoms independently selected from oxygen, nitrogen, and sulfur, or a 10-15 membered saturated or partially unsaturated tricyclic heterocyclyl having 1 to 6 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein Cy is Ａ is 0 to 6 -R Ａ is substituted with a group; Each R Ａ is 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 C １ ~ ６ optionally substituted groups selected from aliphatic, phenyl, 5-6 membered heteroaryl having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, 3-7 membered saturated or partially unsaturated monocyclic carbocyclyl, 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from oxygen, nitrogen, and sulfur, and 6-12 membered spirocyclic ring systems having 0-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur; Each R is independently hydrogen or C １～６ an optionally substituted group selected from aliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, and 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 2 heteroatoms selected from oxygen, nitrogen, and sulfur; X is -N= or -NR-, where X is a Cy bonded to a cyclopropyl ring. Ａ adjacent to a ring atom of; Each R Ｙ and R Ｙ’ is hydrogen, halogen, and optionally substituted C １～６ independently selected from aliphatic groups; Each R ｘ and R ｘ ' is independently selected from hydrogen, halogen, or CN; Cy Ｂ is selected from phenyl, 8-10 membered bicyclic aryl, 5-6 membered heteroaryl having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, and 7-10 membered heteroaryl having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, where Cy is Ｂ is 0 to 5 -R Ｂ substituted with a group; or Cy Ｂ and R ｘ 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 Ｂ may be substituted with a group; Each R Ｂ is 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 C １ ~ ６ optionally substituted groups selected from 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from aliphatic, oxygen, nitrogen, and sulfur, and 5-6 membered heteroaryl having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur; L is an optionally substituted C １～３ A hydrocarbon chain (1 to 3 methylene units optionally and independently -O-, -NR ｚ -, -S-, -SO-, or -SO ２ -, or L is an optionally substituted 5- or 6-membered saturated or partially unsaturated heterocyclene having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur; Each R ｚ is hydrogen, -(CH ２ ) ０～３ OR, -(CH ２ ) ０～３ C(O)OR and optionally substituted C １～６ independently selected from aliphatic groups; Cy Ｃ 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 heterocyclyl having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, where Cy is Ｃ 0 to 6 -L Ｃ -R Ｃ is substituted with a group; Each L Ｃ represents a covalent bond and an optionally substituted C １～６ independently selected from a hydrocarbon chain in which 1 to 3 methylene units are optionally and independently replaced by -O- or -NR-; Each R Ｃ is 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 an optionally substituted group selected from aliphatic; Each Cy Ｄ are independently selected from 3-7 membered saturated or partially unsaturated monocyclic carbocyclyl, 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, and sulfur, 5- or 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, 6-12 membered saturated or partially unsaturated bicyclic heterocyclyl having 1-3 heteroatoms independently selected from phenyl, oxygen, nitrogen, or sulfur, bridged bicycle, and 6-12 membered saturated or partially unsaturated bicyclic spiroheterocyclyl having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein Cy is Ｄ 0 to 4 L Ｄ -R Ｄ is substituted with a group; Each L Ｄ represents a covalent bond and an optionally substituted C １～６ independently selected from a hydrocarbon chain in which 1 to 3 methylene units are optionally and independently replaced by -O- or -NR-; Each R Ｄ is 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 C １ ~ ６ and optionally substituted groups selected from aliphatic, phenyl, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, and 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 2 heteroatoms selected from oxygen, nitrogen, and sulfur.

2. Cy Ａ but, 【Chemistry 2】 is selected from the group consisting of During the ceremony: each Y is independently selected from ═C(H)— or ═N—; W is -C(O)- or -S(O) ２ - selected from; V is selected from ═CH— or ═N—; 2. The compound of claim 1, wherein * represents the point of attachment to the cyclopropyl ring.

3. 【Chemistry 3】 3. The compound of claim 1 or 2, wherein the compound is selected from the group consisting of:

4. Cy Ａ but, 【Chemistry 4】 wherein the compound is selected from the group consisting of:

3. The compound of claim 1 or 2, wherein * represents the point of attachment to the cyclopropyl ring.

5. Cy Ａ but, 【Chemistry 5】 The compound according to any one of claims 1 to 4, wherein the compound is selected from the group consisting of:

6. Each R Ａ is oxo, halogen, -CN, -N(R) ２ , -N(R)S(O) ２ R, -OR, and C １ ~ ６ 6. The compound of any one of claims 1 to 5, wherein the optionally substituted groups are selected from: a 5- or 6-membered heteroaryl having 1-4 heteroatoms independently selected from aliphatic, oxygen, nitrogen, and sulfur; a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from oxygen, nitrogen, and sulfur; and a 6- to 12-membered spirocyclic ring system having 0-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur.

7. Cy Ｂ is selected from phenyl and 5- or 6-membered heteroaryl having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, where Cy Ｂ 0 to 4 -R Ｂ The compound according to any one of claims 1 to 6, which is substituted with a group.

8. Cy Ｂ but, 【Chemistry 6】 The compound according to any one of claims 1 to 7,

9. Each R Ｂ is halogen and optionally substituted C １ ~ ６ The compound according to any one of claims 1 to 8, independently selected from aliphatic.

10. L is optionally substituted C １～３ A hydrocarbon chain in which 1 to 3 methylene units are -O-, -NR ｚ -, -S-, or -SO ２ 10. The compound according to any one of claims 1 to 9, optionally replaced by -.

11. L is *-NHCH(Me)-, *-NHCH ２ -, *-OCH(Me)-, or *-OCH ２ -, wherein * is Cy Ａ A compound according to any one of claims 1 to 10, which represents a point of attachment to:

12. 10. The compound of any one of claims 1 to 9, wherein L is an optionally substituted 5-membered saturated or partially unsaturated heterocyclene having one heteroatom independently selected from oxygen, nitrogen, and sulfur.

13. Cy Ｃ is an 8-10 membered bicyclic aryl, where Cy Ｃ However, 0 to 6 -L Ｃ -R Ｃ The compound according to any one of claims 1 to 12, which is substituted with a group.

14. Cy Ｃ but, 【Chemistry 7】 The compound according to any one of claims 1 to 13, selected from the group consisting of:

15. The compound has formula II: 【Chemistry 8】 or a pharma- ceutically acceptable salt thereof, ３ , R ４ , R ５ , R ６ , and R ７ is hydrogen and -L Ｃ -R Ｃ The compound according to any one of claims 1 to 14, independently selected from:

16. R ３ , R ４ , R ５ , R ６ , and R ７ Each of -L Ｃ -R Ｃ where each L Ｃ is a covalent bond and optionally substituted C １～６ a hydrocarbon chain in which 1 to 3 methylene units are optionally and independently replaced by -O- or -NR-; Ｃ is 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 16. The compound of any one of claims 1 to 15, wherein each of the groups is independently selected from: an optionally substituted group selected from aliphatic.

17. R ３ The compound according to any one of claims 1 to 16, wherein is hydrogen.

18. R ４ is hydrogen and -L Ｃ -R Ｃ wherein L is selected from Ｃ is a covalent bond, R Ｃ is 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 18. The compound according to any one of claims 1 to 17, wherein the compound is selected from the group consisting of: an optionally substituted group selected from aliphatic;

19. R ５ The compound according to any one of claims 1 to 18, wherein is hydrogen.

20. R ６ is hydrogen and L Ｃ -R Ｃ wherein L is selected from Ｃ is a covalent bond, R Ｃ is halogen, -N(R ２ , -OR, Cy Ｄ and optionally substituted C １～６ A compound according to any one of claims 1 to 19, selected from aliphatic groups.

21. R ７ The compound according to any one of claims 1 to 20, wherein is hydrogen.

22. The compound has formula III: 【Chemistry 9】 or a pharma- ceutically acceptable salt thereof, In the formula, X １ is N, CH, or C-L Ｃ -R Ｃ and each X ２ is N, CH, or C-L Ｃ -R Ｃ are independently selected from; X ３ and X ４ is independently N or C, where X ３ or X ４ at least one of is C; X ５ , X ６ , X ７ , and X ８ Each of is N, CH, or C-L Ｃ -R Ｃ are independently selected from; The compound according to any one of claims 1 to 21, wherein n is 1 or 2.

23. The compound has formula IV-a, IV-b, or IV-c: 【Chemistry 10】 23. The compound according to any one of claims 1 to 22, which is a compound of the formula:

24. The compound has formula Va, Vb, or Vc: 【Chemistry 11】 or a pharma- ceutically acceptable salt thereof.

25. The compound has the formula VI-a, VI-b, or VI-c: 【Chemistry 12】 or a pharma- ceutically acceptable salt thereof, R ４ is hydrogen or L Ｃ -R Ｃ where L Ｃ is a covalent bond, R Ｃ is halogen or Cy Ｄ and Cy Ｄ is a 5-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 2 nitrogen atoms, and Cy Ｄ However, 0 to 4 -L Ｄ -R Ｄ The compound according to any one of claims 1 to 24, which is substituted with a group.

26. Cy Ｄ but, 【Chemistry 13】 The compound according to any one of claims 1 to 25, wherein the ring is selected from the group consisting of:

27. The compound is 【Chemistry 14-1】 【Chemistry 14-2】 【Chemistry 14-3】 【Chemistry 14-4】 【Chemistry 14-5】 【Chemistry 14-6】 【Chemistry 14-7】 【Chemistry 14-8】 【Chemistry 14-9】 【Chemistry 14-10】 【Chemistry 14-11】 【Chemistry 14-12】 【Chemistry 14-13】 【Chemistry 14-14】 【Chemistry 14-15】 【Chemistry 14-16】 【Chemistry 14-17】 27. The compound according to any one of claims 1 to 26, or a pharma- ceutically acceptable salt thereof, selected from:

28. A pharmaceutical composition comprising a compound according to any one of claims 1 to 27.

29. A compound or composition according to any one of claims 1 to 28 for use in treating a disease or disorder mediated by plasma kallikrein.

30. 30. The compound or composition of claim 29, wherein the disease or disorder is hereditary angioedema or diabetic macular edema.

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