Mrgprx2 inhibitors and methods of use thereof

Abstract

Disclosed are compounds, compositions, and methods useful for preventing or treating an MRGPRX2-mediated disease or disorder.

Description

[0001] MRGPRX2 INHIBITORS AND METHODS OF USE THEREOF CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of priority to U.S. Provisional Application Nos. 63 / 462,418, filed on April 27, 2023; 63 / 546,090, filed on October 27, 2023; and 63 / 614,730, filed on December 26, 2023; each of which is hereby incorporated by reference in its entirety.

[0003] BACKGROUND

[0004] Mature mammalian mast cells ordinarily reside near blood vessels or nerves, beneath or within epithelia, within airways, gastrointestinal and genitourinary tracts, and near smooth muscle and mucus-producing glands. Classically, mast cells are activated by IgE antibodies, secreting a wide range of substances with local and systemic effects, including histamine, serotonin, proteases, chemokines, and cytokines. Indeed, mast cells are implicated in the progression and / or maintenance of many diseases.

[0005] Recent work has emphasized the role of the Mas-related G protein-coupled receptor (MRGPR) family, specifically, Mrgprb2, in mast cell activation. Mrgprb2 is the mouse receptor for several cationic molecules, collectively called basic secretagogues, and the ortholog of the human receptor MRGPRX2). To date, Mrgprb2 and MRGPRX2 have been reported to be expressed only on certain populations of mast cells. This knowledge provides an opportunity to target mast cell degranulation in a very precise manner.

[0006] Natural endogenous ligands of Mrgprb2 / MRGPRX2 have been reported and are mostly neuropeptides, including substance P (SP), vasoactive intestinal polypeptide (VIP), Corti statin- 14, and pituitary adenylate cyclase activating polypeptide (PACAP). Others include P-defensin, cathelicidin (LL-37), and proadrenomedullin N-terminal 20 peptide (PAMP[9-20]). Given the close proximity between mast cells and sensory nerves in various pathological conditions, it follows that neuropeptide-activated MRGPRX2 could contribute to symptoms of neurogenic inflammation including pain, swelling and pruritus. Various observations using knock-out (KO) mice are consistent with the Mrgprb2 / MRGPRX2 receptors playing a role in mast cell-mediated neurogenic inflammation. For instance, Mrgprb2 / MRGPRX2 agonists induce various symptoms such as flushing, swelling and itch in wild type mice, but not in Mrgprb2-deficient mice. Mrgprb2-deficent mice have also demonstrated significant reductions in inflammation (leukocyte infiltration, including mast cells), swelling, pain and overall clinical score in various disease models. An important and relevant observation was the demonstration that Substance P injection could stimulate the infiltration of leukocytes in wild type and NKR1 (canonical Substance P receptor) KO mice

[0007] - 1 - whereas the response was substantially blunted in Mrgprb2 null mice. This observation extends the role of Mrgprb2 / MRGPRX2 as a key receptor in mediating Substance P-induced inflammatory responses, including pain. Indeed, a Substance P / Mrgprb2 sensory cluster was demonstrated to be critical in driving the clinical score of a severe preclinical model of atopic dermatitis.

[0008] In addition to the various reports using Mrgprb2-deficient mice, further evidence suggests a role for various ligands of MRGPRX2 in human disease. For example, in addition to the number of MRGPRX2-expressing mast cells being significantly increased in severe chronic urticaria, PACAP nerve fibres were demonstrated to be in close proximity to tryptase-positive mast cells, providing the morphological basis for increased mast cell - sensory interactions. In support of this, patients with urticaria exhibit enhanced wheal reactions vs healthy individuals to MRGPRX2 agonists (e.g., Substance P) when injected intradermally. In addition, PACAP and the antimicrobial peptide, LL-37, which is implicated in cutaneous inflammation, were both demonstrated to be upregulated in rosacea. Indeed, mast cell-deficient mice do not develop inflammation / flushing following LL-37 injection thus inferring a role for Mrgprb2.

[0009] In addition to skin disorders, mast cell involvement has been highlighted for inflammatory bowel disease (IBD) and arthritis as well as asthma and migraine. In patients with rheumatoid arthritis (RA), the number of degranulated mast cells is increased in synovial tissue and is correlated with disease activity, as it is for patients with IBD. A positive correlation between serum Substance P levels and chronic pain intensity has been noted in both osteoarthritic and RA patients and a recent article suggested that the SP- MRGPRX2 axis may play a role in the pathogenesis of RA, especially in the regulation of inflammation and pain. Finally, there is a growing body of evidence for a role of PACAP in migraine pathogenesis and that it is mediated via activation of mast cells.

[0010] Accordingly, there is a need for small-molecule agonists of MRGPRX2 that block IgE-independent mast cell de-granulation, which are expected to provide therapeutic benefit in mast-cell driven pathologies including skin disorders such as urticaria, atopic dermatitis and rosacea as well as additional indications like inflammatory bowel disease, arthritis and migraine. Accordingly, there is a need in the art to provide small molecule therapeutics that modulate MRGPRX2. SUMMARY

[0011] One aspect of the invention provides compounds that are antagonists of MRGPRX2, compositions comprising them, and methods useful for preventing or treating MRGPRX2- mediated diseases or disorders.

[0012] Accordingly, provided herein in some embodiments is a compound having the structure of Formula (la) or (lb): or a pharmaceutical salt thereof; wherein:

[0013] X is N or CRX;

[0014] X1, X2, and X3are each independently N or CRX;

[0015] Rxis independently for each occurrence hydrogen, fluoro, or chloro;

[0016] Y is C(=O), C(=O)CH2, CH2, or a bond;

[0017] R1is -R1aor -CH2R1a; wherein R1ais phenyl, (C1-C6)alkyl, 5- to 6-membered heteroaryl, or (C3-C8)cycloalkyl(C1-C6)alkyl; each of which is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, chloro, (C1- C6)alkyl, (C3-C8)cycloalkyl, and (C1-C6)alkoxy;

[0018] R2is 4-, 5- or 6- membered heterocycloalkyl, 9- or 10-membered bicyclic heterocycloalkyl, 5- or 6- membered heteroaryl, 9- or 10-membered bicyclic heteroaryl, (C3- C8)cycloalkyl, or phenyl; each of which is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, chloro, cyano, hydroxy, (C1-C6)alkyl, (C1-C6)alkenyl, -C(=O)NH2, -NH2, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)hydroxy alkyl, (C1-C6)halohydroxyalkyl, (C1-C6)hydroxyalkoxy, (C1-C6)carboxyalkyl (C1-C6)haloalkoxy, (C3-C8)cycloalkyl, and 4- to 7-membered heterocycloalkyl; wherein (C1- C6)alkyl is optionally substituted with phenyl, 4- to 7-membered heterocycloalkyl, and - NHR2a; or R2is (C1-C6)alkyl;

[0019] R2ais C(=O)R2b, (C1-C6)alkyl, or (C3-C8)cycloalkyl, wherein (C1-C6)alkyl or (C3-C8)cycloalkyl is optionally substituted with one or more independent instances of halo;

[0020] R2bis (C1-C6)alkyl; R3and R4are each independently hydrogen, (C1-C6)alkyl, (C1-C6)alkoxyalkyl, or (C1- C6)haloalkyl; or taken together with the carbon atom to which they are attached form a (C3- C6)cycloalkyl;

[0021] R5is hydrogen, (C1-C6)alkyl, (C1-C6)alkoxyalkyl, or (C1-C6)haloalkyl; or R5taken together with R3or R4forms -(CH2)n-; wherein n is 1, 2, or 3; and

[0022] R6and R7are independently for each occurrence hydrogen or (C1-C6)alkyl; or R6and R7taken together with the carbon atom to which they are attached form a (C3-C6)cycloalkyl.

[0023] In some embodiments, provided here in is a compound of Formula (la) or (lb): or a pharmaceutical salt thereof; wherein:

[0024] X is N or CRX;

[0025] X1, X2, and X3are each independently N or CRX;

[0026] Rxis independently for each occurrence hydrogen, fluoro, or chloro;

[0027] Y is C(=O), C(=O)CH2, CH2, or a bond;

[0028] R1is -OR1aor -CH2R1a; wherein R1ais phenyl, 5- to 6-membered heteroaryl, or (C3- C8)cycloalkyl(C1-C6)alkyl; each of which is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, chloro, (C1-C6)alkyl, (C3-C8)cycloalkyl, and (C1-C6)alkoxy;

[0029] R2is 5- or 6- membered heterocycloalkyl, 9- or 10-membered bicyclic heterocycloalkyl (e.g., indoline, octahydroindole, tetrahydroquinoline, or decahydroquinoline), 5- or 6- membered heteroaryl, 9- or 10-membered bicyclic heteroaryl, or phenyl; each of which is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, chloro, cyano, hydroxy, (C1- C6)alkyl, (C1-C6)alkenyl, -C(=O)NH2, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)hydroxy alkyl, and (C1-C6)haloalkoxy; wherein (C1-C6)alkyl is optionally substituted with phenyl or -NHR2a;

[0030] R2ais or (C3-C8)cycloalkyl, optionally substituted with one or more independent instances of halo; R3and R4are each independently hydrogen, (C1-C6)alkyl, (C1-C6)alkoxyalkyl, or (C1- C6)haloalkyl; or taken together with the carbon atom to which they are attached form a (C3- C6)cycloalkyl;

[0031] R5is hydrogen, (C1-C6)alkyl, (C1-C6)alkoxyalkyl, or (C1-C6)haloalkyl; or R5taken together with R3or R4forms -(CH2)n-; wherein n is 1, 2, or 3; and

[0032] R6and R7are independently for each occurrence hydrogen or (C1-C6)alkyl; or R6and R7taken together with the carbon atom to which they are attached form a (C3-C6)cycloalkyl.

[0033] Also provided herein are pharmaceutical compositions comprising a compound of Formula (la) or (lb); and at least one pharmaceutically acceptable excipient.

[0034] Additionally, methods of preventing or treating an MRGPRX2-mediated disease or disorder, comprise administering to a subject in need thereof a therapeutically effective amount of the compound of Formula (la) or (lb). For example, an MRGPRX2-mediated disease or disorder may be chronic spontaneous urticaria, prurigo nodularis, irritable bowel syndrome, chronic inducible urticaria, atopic dermatitis, osteoarthritis, rosacea, migraine, pseudo-analphylaxis, mast cell activation syndrome, mastocytosis, pruritus, neurodermatitis, contact urticaria, allergic rhinitis, asthma, acute contact dermatitis, ulcerative colitis, crohns disease, idiopathic chronic cough, rheumatoid arthritis, multiple sclerosis, geographic atrophy, endometriosis, seborrheic dermatitis, psoriasis, chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, neuropathic itch, periodontitis, autism, abdominal aortic aneurysms, deep vein thrombosis, amyotrophic lateral sclerosis, interstitial cystitis, coronary artery disease, cancer, sickle cell disease, obesity, or ulcers.

[0035] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.

[0036] Other features, objects, and advantages of the invention will be apparent from the detailed description, and from the claims. DETAILED DESCRIPTION

[0037] Definitions

[0038] For convenience, before further description of the present invention, certain terms employed in the specification, examples and appended claims are collected here. These definitions should be read in light of the remainder of the disclosure and as understood by a person of skill in the art. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by a person of ordinary skill in the art.

[0039] In order for the present invention to be more readily understood, certain terms and phrases are defined below and throughout the specification.

[0040] The articles “a” and “an” are used herein 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.

[0041] The phrase “and / or,” as used herein in the specification and in the claims, should be understood to mean “either or both” of the elements so conjoined, i.e., elements that are conjunctively present in some cases and disjunctively present in other cases. Multiple elements listed with “and / or” should be construed in the same fashion, i.e., “one or more” of the elements so conjoined. Other elements may optionally be present other than the elements specifically identified by the “and / or” clause, whether related or unrelated to those elements specifically identified. Thus, as a non-limiting example, a reference to “A and / or B”, when used in conjunction with open-ended language such as “comprising” can refer, in one embodiment, to A only (optionally including elements other than B); in another embodiment, to B only (optionally including elements other than A); in yet another embodiment, to both A and B (optionally including other elements); etc.

[0042] As used herein in the specification and in the claims, “or” should be understood to have the same meaning as “and / or” as defined above. For example, when separating items in a list, “or” or “and / or” shall be interpreted as being inclusive, i.e., the inclusion of at least one, but also including more than one, of a number or list of elements, and, optionally, additional unlisted items. Only terms clearly indicated to the contrary, such as “only one of’ or “exactly one of,” or, when used in the claims, “consisting of,” will refer to the inclusion of exactly one element of a number or list of elements. In general, the term “or” as used herein shall only be interpreted as indicating exclusive alternatives (i.e., “one or the other but not both”) when preceded by terms of exclusivity, such as “either,” “one of,” “only one of,” or "exactly one of.” “Consisting essentially of,” when used in the claims, shall have its ordinary meaning as used in the field of patent law.

[0043] As used herein in the specification and in the claims, the phrase “at least one,” in reference to a list of one or more elements, should be understood to mean at least one element selected from any one or more of the elements in the list of elements, but not necessarily including at least one of each and every element specifically listed within the list of elements and not excluding any combinations of elements in the list of elements. This definition also allows that elements may optionally be present other than the elements specifically identified within the list of elements to which the phrase “at least one” refers, whether related or unrelated to those elements specifically identified. Thus, as a non-limiting example, “at least one of A and B” (or, equivalently, “at least one of A or B,” or, equivalently “at least one of A and / or B”) can refer, in one embodiment, to at least one, optionally including more than one, A, with no B present (and optionally including elements other than B); in another embodiment, to at least one, optionally including more than one, B, with no A present (and optionally including elements other than A); in yet another embodiment, to at least one, optionally including more than one, A, and at least one, optionally including more than one, B (and optionally including other elements); etc.

[0044] It should also be understood that, unless clearly indicated to the contrary, in any methods claimed herein that include more than one step or act, the order of the steps or acts of the method is not necessarily limited to the order in which the steps or acts of the method are recited.

[0045] In the claims, as well as in the specification above, all transitional phrases such as “comprising,” “including,” “carrying,” “having,” “containing,” “involving,” “holding,” “composed of,” and the like are to be understood to be open-ended, i.e., to mean including but not limited to. Only the transitional phrases “consisting of" and “consisting essentially of’ shall be closed or semi-closed transitional phrases, respectively, as set forth in the United States Patent Office Manual of Patent Examining Procedures, Section 2111.03.

[0046] Certain compounds contained in compositions of the present invention may exist in particular geometric or stereoisomeric forms. In addition, polymers of the present invention may also be optically active. The present invention contemplates all such compounds, including cis- and trans-isomers, R- and S-enantiomers, diastereomers, (D)-isomers, (in- isomers, the racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the invention. Additional asymmetric carbon atoms may be present in a substituent such as an alkyl group. All such isomers, as well as mixtures thereof, are intended to be included in this invention.

[0047] “Geometric isomer" means isomers that differ in the orientation of substituent atoms in relationship to a carbon-carbon double bond, to a cycloalkyl ring, or to a bridged bicyclic system. Atoms (other than H) on each side of a carbon- carbon double bond may be in an E (substituents are on opposite sides of the carbon- carbon double bond) or Z (substituents are oriented on the same side) configuration. "R," "S," "S*," "R*," "E," "Z," "cis," and "bans," indicate configurations relative to the core molecule. Certain of the disclosed compounds may exist in “atropisomeric” forms or as “atropisomers.” Atropisomers are stereoisomers resulting from hindered rotation about single bonds where the steric strain barrier to rotation is high enough to allow for the isolation of the conformers. The compounds of the invention may be prepared as individual isomers by either isomer-specific synthesis or resolved from a mixture of isomers. Conventional resolution techniques include forming the salt of a free base of each isomer of an isomeric pair using an optically active acid (followed by fractional crystallization and regeneration of the free base), forming the salt of the acid form of each isomer of an isomeric pair using an optically active amine (followed by fractional crystallization and regeneration of the free acid), forming an ester or amide of each of the isomers of an isomeric pair using an optically pure acid, amine or alcohol (followed by chromatographic separation and removal of the chiral auxiliary), or resolving an isomeric mixture of either a starting material or a final product using various well known chromatographic methods.

[0048] If, for instance, a particular enantiomer of compound of the present invention is desired, it may be prepared by asymmetric synthesis, or by derivation with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomers. Alternatively, where the molecule contains a basic functional group, such as amino, or an acidic functional group, such as carboxyl, diastereomeric salts are formed with an appropriate optically- active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic means well known in the art, and subsequent recovery of the pure enantiomers.

[0049] Percent purity by mole fraction is the ratio of the moles of the enantiomer (or diastereomer) or over the moles of the enantiomer (or diastereomer) plus the moles of its optical isomer. When the stereochemistry of a disclosed compound is named or depicted by structure, the named or depicted stereoisomer is at least about 60%, about 70%, about 80%, about 90%, about 99% or about 99.9% by mole fraction pure relative to the other stereoisomers. When a single enantiomer is named or depicted by structure, the depicted or named enantiomer is at least about 60%, about 70%, about 80%, about 90%, about 99% or about 99.9% by mole fraction pure. When a single diastereomer is named or depicted by structure, the depicted or named diastereomer is at least about 60%, about 70%, about 80%, about 90%, about 99% or about 99.9% by mole fraction pure.

[0050] When a disclosed compound is named or depicted by structure without indicating the stereochemistry, and the compound has at least one chiral center, it is to be understood that the name or structure encompasses either enantiomer of the compound free from the corresponding optical isomer, a racemic mixture of the compound or mixtures enriched in one enantiomer relative to its corresponding optical isomer. When a disclosed compound is named or depicted by structure without indicating the stereochemistry and has two or more chiral centers, it is to be understood that the name or structure encompasses a diastereomer free of other diastereomers, a number of diastereomers free from other diastereomeric pairs, mixtures of diastereomers, mixtures of diastereomeric pairs, mixtures of diastereomers in which one diastereomer is enriched relative to the other diastereomer(s) or mixtures of diastereomers in which one or more diastereomer is enriched relative to the other diastereomers. The invention embraces all of these forms.

[0051] Structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds produced by the replacement of a hydrogen with deuterium or tritium, or of a carbon with a13C- or14C- enriched carbon are within the scope of this invention.

[0052] The term “prodrug” as used herein encompasses compounds that, under physiological conditions, are converted into therapeutically active agents. A common method for making a prodrug is to include selected moieties that are hydrolyzed under physiological conditions to reveal the desired molecule. In other embodiments, the prodrug is converted by an enzymatic activity of the host animal.

[0053] The phrase “pharmaceutically acceptable excipient” or “pharmaceutically acceptable carrier” as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting the subject chemical from one organ or portion of the body, to another organ or portion of the body. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation, not injurious to the patient, and substantially non-pyrogenic. Some examples of materials which can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol, and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide;

[0054] (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer’s solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances employed in pharmaceutical formulations. In certain embodiments, pharmaceutical compositions of the present invention are non-pyrogenic, i.e., do not induce significant temperature elevations when administered to a patient.

[0055] The term “pharmaceutically acceptable salts” refers to the relatively non-toxic, inorganic and organic acid addition salts of the compound(s). These salts can be prepared in situ during the final isolation and purification of the compound(s), or by separately reacting a purified compound(s) in its free base form with a suitable organic or inorganic acid, and isolating the salt thus formed. Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactobionate, and laurylsulphonate salts, and the like. (See, for example, Berge et al. (1977) “Pharmaceutical Salts”, J. Pharm. Sci. 66:1-19.)

[0056] In other cases, the compounds useful in the methods of the present invention may contain one or more acidic functional groups and, thus, are capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable bases. The term “pharmaceutically acceptable salts” in these instances refers to the relatively non-toxic inorganic and organic base addition salts of a compound(s). These salts can likewise be prepared in situ during the final isolation and purification of the compound(s), or by separately reacting the purified compound(s) in its free acid form with a suitable base, such as the hydroxide, carbonate, or bicarbonate of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, or tertiary amine. Representative alkali or alkaline earth salts include the lithium, sodium, potassium, calcium, magnesium, and aluminum salts, and the like. Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like (see, for example, Berge et al., supra). The term “pharmaceutically acceptable cocrystals” refers to solid coformers that do not form formal ionic interactions with the small molecule.

[0057] A “therapeutically effective amount” (or “effective amount”) of a compound with respect to use in treatment, refers to an amount of the compound in a preparation which, when administered as part of a desired dosage regimen (to a mammal, preferably a human) alleviates a symptom, ameliorates a condition, or slows the onset of disease conditions according to clinically acceptable standards for the disorder or condition to be treated or the cosmetic purpose, e.g., at a reasonable benefit / risk ratio applicable to any medical treatment.

[0058] The term “prophylactic or therapeutic” treatment is art-recognized and includes administration to the host of one or more of the subject compositions. If it is administered prior to clinical manifestation of the unwanted condition (e.g., disease or other unwanted state of the host animal) then the treatment is prophylactic, (i.e., it protects the host against developing the unwanted condition), whereas if it is administered after manifestation of the unwanted condition, the treatment is therapeutic, (i.e., it is intended to diminish, ameliorate, or stabilize the existing unwanted condition or side effects thereof).

[0059] The term “patient” or “subject” refers to a mammal in need of a particular treatment. In certain embodiments, a patient is a primate, canine, feline, or equine. In certain embodiments, a patient is a human.

[0060] An aliphatic chain comprises the classes of alkyl, alkenyl and alkynyl defined below. A straight aliphatic chain is limited to unbranched carbon chain moieties. As used herein, the term “aliphatic group” refers to a straight chain, branched-chain, or cyclic aliphatic hydrocarbon group and includes saturated and unsaturated aliphatic groups, such as an alkyl group, an alkenyl group, or an alkynyl group.

[0061] “Alkyl” refers to a fully saturated cyclic or acyclic, branched or unbranched carbon chain moiety having the number of carbon atoms specified, or up to 30 carbon atoms if no specification is made. For example, alkyl of 1 to 8 carbon atoms refers to moieties such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, and octyl, and those moieties which are positional isomers of these moieties. Alkyl of 10 to 30 carbon atoms includes decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl, heneicosyl, docosyl, tricosyl and tetracosyl. In certain embodiments, a straight chain or branched chain alkyl has 30 or fewer carbon atoms in its backbone (e.g., C1-C30 for straight chains, C3-C30 for branched chains), and more preferably 20 or fewer. Alkyl goups may be substituted or unsubstituted. As used herein, the term “heteroalkyl” refers to an alkyl moiety as hereinbefore defined which contain one or more oxygen, sulfur, nitrogen, phosphorus, or silicon atoms in place of carbon atoms.

[0062] As used herein, the term “haloalkyl” refers to an alkyl group as hereinbefore defined substituted with at least one halogen.

[0063] As used herein, the term “haloalkoxy” refers to an alkoxy group as defined herein substituted with at least one halogen atom. For example, haloalkoxy groups include fluoroalkoxy groups, such as trifluoromethoxy, difluoromethoxy, and the like.

[0064] As used herein, the term “hydroxyalkyl” refers to an alkyl group as hereinbefore defined substituted with at least one hydroxyl.

[0065] As used herein, the term “alkylene” refers to an alkyl group having the specified number of carbons, for example from 2 to 12 carbon atoms, that contains two points of attachment to the rest of the compound on its longest carbon chain. Non-limiting examples of alkylene groups include methylene -(CH2)-, ethylene -(CH2CH2)-, n-propylene - (CH2CH2CH2)-, isopropylene -(CH2CH(CH3))-, and the like. Alkylene groups can be cyclic or acyclic, branched or unbranched carbon chain moiety, and may be optionally substituted with one or more substituents.

[0066] "Cycloalkyl" means mono- or bicyclic or bridged or spirocyclic, or polycyclic saturated carbocyclic rings, each having from 3 to 12 carbon atoms. Preferred cycloalkyls have from 3-10 carbon atoms in their ring structure, and more preferably have 3-6 carbons in the ring structure. Cycloalkyl groups may be substituted or unsubstituted.

[0067] “1,2-Disubstituted cyclohexyl” as used herein refers to a cyclohexane ring that contains points of attachment at the 1 and 2 positions of the cyclohexane ring to the rest of the compound. Similarly, “1,2-disubstituted cyclopentyl” as used herein refers to a cyclopentane ring that contains points of attachment at the 1 and 2 positions of the cyclopentane ring to the rest of the compound. 1 ,2-Disubstituted cyclohexyl and 1 ,2- disubstituted cyclopentyl can also be referred to as 1 ,2-cyclohexylene and 1 ,2- cyclopentylene, respectively.

[0068] As used herein, the term “halocyclo alkyl” refers to a cycloalkyl group as hereinbefore defined substituted with at least one halogen.

[0069] "Cycloheteroalkyl" refers to an cycloalkyl moiety as hereinbefore defined which contain one or more oxygen, sulfur, nitrogen, phosphorus, or silicon atoms in place of carbon atoms. Preferred cycloheteroalkyls have from 4-8 carbon atoms and heteroatoms in their ring structure, and more preferably have 4-6 carbons and heteroatoms in the ring structure. Cycloheteroalkyl groups may be substituted or unsubstituted.

[0070] Unless the number of carbons is otherwise specified, “lower alkyl,” as used herein, means an alkyl group, as defined above, but having from one to ten carbons, more preferably from one to six carbon atoms in its backbone structure such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. Likewise, “lower alkenyl” and “lower alkynyl” have similar chain lengths. Throughout the application, preferred alkyl groups are lower alkyls. In certain embodiments, a substituent designated herein as alkyl is a lower alkyl.

[0071] “Alkenyl” refers to any cyclic or acyclic, branched or unbranched unsaturated carbon chain moiety having the number of carbon atoms specified, or up to 26 carbon atoms if no limitation on the number of carbon atoms is specified; and having one or more double bonds in the moiety. Alkenyl of 6 to 26 carbon atoms is exemplified by hexenyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodenyl, tridecenyl, tetradecenyl, pentadecenyl, hexadecenyl, heptadecenyl, octadecenyl, nonadecenyl, eicosenyl, heneicosoenyl, docosenyl, tricosenyl, and tetracosenyl, in their various isomeric forms, where the unsaturated bond(s) can be located anywhere in the moiety and can have either the (Z) or the (E) configuration about the double bond(s).

[0072] “Alkynyl” refers to hydrocarbyl moieties of the scope of alkenyl, but having one or more triple bonds in the moiety.

[0073] The term “aryl” as used herein includes 3- to 12-membered substituted or unsubstituted single-ring aromatic groups in which each atom of the ring is carbon (i.e., carbocyclic aryl) or where one or more atoms are heteroatoms (i.e., heteroaryl). Preferably, aryl groups include 5- to 12-membered rings, more preferably 6- to 10-membered rings The term “aryl” also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is aromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and / or heterocyclyls. Carboycyclic aryl groups include benzene, naphthalene, phenanthrene, phenol, aniline, and the like. Heteroaryl groups include substituted or unsubstituted aromatic 3- to 12-membered ring structures, more preferably 5- to 12- membered rings, more preferably 5- to 10-membered rings, whose ring structures include one to four heteroatoms. Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine, pyrimidine, indazole, quinoline, benzofuran, and the like. Aryl and heteroaryl can be monocyclic, bicyclic, or polycyclic. The term “halo”, “halide”, or “halogen” as used herein means halogen and includes, for example, and without being limited thereto, fluoro, chloro, bromo, iodo and the like, in both radioactive and non-radioactive forms. In a preferred embodiment, halo is selected from the group consisting of fluoro, chloro and bromo.The terms “heterocyclyl” or “heterocyclic group” or “heterocycloalkyl” refer to 3- to 12-membered ring structures, more preferably 5- to 12- membered rings, more preferably 5- to 10-membered rings, whose ring structures include one to four heteroatoms. Heterocycles can be monocyclic, bicyclic, spirocyclic, or polycyclic. Heterocyclyl groups include, for example, thiophene, thianthrene, furan, pyran, isobenzofuran, chromene, xanthene, phenoxathiin, pyrrole, imidazole, pyrazole, isothiazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, pyrimidine, phenanthroline, phenazine, phenarsazine, phenothiazine, furazan, phenoxazine, pyrrolidine, oxolane, thiolane, oxazole, piperidine, piperazine, morpholine, lactones, lactams such as azetidinones and pyrrolidinones, sultams, sultones, and the like. Heterocycloalkyl groups can be fully saturated or partially saturated. Heterocycloalkyl groups include, for example, bicyclic ring systems having either or both constituent rings saturated (e.g., 2,3-dihydroindole, 4, 5,6,7- tetrahydro-benzofuran, decahydroquinoline, and the like) or partially saturated (e.g., octahydroquinoline and the like).

[0074] The heterocyclic ring can be substituted at one or more positions with such substituents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphate, phosphonate, phosphinate, carbonyl, carboxyl, silyl, sulfamoyl, sulfinyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, a heterocyclyl, an aromatic or heteroaromatic moiety, -CF3, -CN, and the like.

[0075] The term “substituted” refers to moieties having substituents replacing a hydrogen on one or more carbons of the backbone. It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. As used herein, the term “substituted” is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this invention, the heteroatoms such as nitrogen may have hydrogen substituents and / or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. Substituents can include any substituents described herein, for example, a halogen, a hydroxyl, a carbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an alkoxy, a phosphoryl, a phosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, or an aromatic or heteroaromatic moiety. In preferred embodiments, the substituents on substituted alkyls are selected from C1-6 alkyl, C3-6 cycloalkyl, halogen, carbonyl, cyano, or hydroxyl. In more preferred embodiments, the substituents on substituted alkyls are selected from fluoro, carbonyl, cyano, or hydroxyl. It will be understood by those skilled in the art that substituents can themselves be substituted, if appropriate. Unless specifically stated as “unsubstituted,” references to chemical moieties herein are understood to include substituted variants. For example, reference to an “aryl” group or moiety implicitly includes both substituted and unsubstituted variants.

[0076] As used herein, the definition of each expression, e.g., alkyl, m, n, etc., when it occurs more than once in any structure, is intended to be independent of its definition elsewhere in the same structure.

[0077] As used herein, “small molecules” refers to small organic or inorganic molecules of molecular weight below about 3,000 Daltons. In general, small molecules useful for the invention have a molecular weight of less than 3,000 Daltons (Da). The small molecules can be, e.g., from at least about 100 Da to about 3,000 Da (e.g., between about 100 to about 3,000 Da, about 100 to about 2500 Da, about 100 to about 2,000 Da, about 100 to about 1,750 Da, about 100 to about 1,500 Da, about 100 to about 1,250 Da, about 100 to about 1,000 Da, about 100 to about 750 Da, about 100 to about 500 Da, about 200 to about 1500, about 500 to about 1000, about 300 to about 1000 Da, or about 100 to about 250 Da).

[0078] In some embodiments, a “small molecule” refers to an organic, inorganic, or organometallic compound typically having a molecular weight of less than about 1000. In some embodiments, a small molecule is an organic compound, with a size on the order of 1 nm. In some embodiments, small molecule drugs of the invention encompass oligopeptides and other biomolecules having a molecular weight of less than about 1000. An “effective amount” is an amount sufficient to effect beneficial or desired results.

[0079] For example, a therapeutic amount is one that achieves the desired therapeutic effect. This amount can be the same or different from a prophylactically effective amount, which is an amount necessary to prevent onset of disease or disease symptoms. An effective amount can be administered in one or more administrations, applications or dosages. A therapeutically effective amount of a composition depends on the composition selected. The compositions can be administered from one or more times per day to one or more times per week; including once every other day. The skilled artisan will appreciate that certain factors may influence the dosage and timing required to effectively treat a subject, including but not limited to the severity of the disease or disorder, previous treatments, the general health and / or age of the subject, and other diseases present. Moreover, treatment of a subject with a therapeutically effective amount of the compositions described herein can include a single treatment or a series of treatments.

[0080] The terms “decrease,” “reduce,” “reduced”, “reduction”, “decrease,” and “inhibit” are all used herein generally to mean a decrease by a statistically significant amount relative to a reference. However, for avoidance of doubt, “reduce,” “reduction” or “decrease” or “inhibit” typically means a decrease by at least 10% as compared to a reference level and can include, for example, a decrease by at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, up to and including, for example, the complete absence of the given entity or parameter ascompared to the reference level, or any decrease between 10-99% as compared to the absence of a given treatment.

[0081] The terms “increased”, “increase” or “enhance” or “activate” are all used herein to generally mean an increase by a statically significant amount; for the avoidance of any doubt, the terms “increased”, “increase” or “enhance” or “activate” means an increase of at least 10% as compared to a reference level, for example an increase of at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 80%, or at least about 90% or up to and including a 100% increase or any increase between 10-100% as compared to a reference level, or at least about a 2-fold, or at least about a 3-fold, or at least about a 4-fold, or at least about a 5-fold or at least about a 10- fold increase, or any increase between 2-fold and 10-fold or greater as compared to a reference level. As used herein, the term “modulate” includes up-regulation and down-regulation, e.g., enhancing or inhibiting a response.

[0082] A “radiopharmaceutical agent,” as defined herein, refers to a pharmaceutical agent which contains at least one radiation-emitting radioisotope. Radiopharmaceutical agents are routinely used in nuclear medicine for the diagnosis and / or therapy of various diseases. The radiolabelled pharmaceutical agent, for example, a radiolabelled antibody, contains a radioisotope (RI) which serves as the radiation source. As contemplated herein, the term “radioisotope” includes metallic and non-metallic radioisotopes. The radioisotope is chosen based on the medical application of the radiolabeled pharmaceutical agents. When the radioisotope is a metallic radioisotope, a chelator is typically employed to bind the metallic radioisotope to the rest of the molecule. When the radioisotope is a non-metallic radioisotope, the non-metallic radioisotope is typically linked directly, or via a linker, to the rest of the molecule.

[0083] For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 67th Ed., 1986-87, inside cover.

[0084] Compounds of the Invention

[0085] In some embodiments, provided here in is a compound of Formula (la) or (lb): or a pharmaceutical salt thereof; wherein:

[0086] X is N or CRX;

[0087] X1, X2, and X3are each independently N or CRX;

[0088] Rxis independently for each occurrence hydrogen, fluoro, or chloro;

[0089] Y is C(=O), C(=O)CH2, CH2, or a bond;

[0090] R1is -OR1aor -CH2R1a; wherein R1ais phenyl, (C1-C6)alkyl, 5- to 6-membered heteroaryl, or (C3-C8)cycloalkyl(C1-C6)alkyl; each of which is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, chloro, (C1- C6)alkyl, (C3-C8)cycloalkyl, and (C1-C6)alkoxy;

[0091] R2is 4-, 5- or 6- membered heterocycloalkyl, 9- or 10-membered bicyclic heterocycloalkyl, 5- or 6- membered heteroaryl, 9- or 10-membered bicyclic heteroaryl, (C3- C8)cycloalkyl, or phenyl; each of which is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, chloro, cyano, hydroxy, (C1-C6)alkyl, (C1-C6)alkenyl, -C(=O)NH2, -NH2, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)hydroxy alkyl, (C1-C6)halohydroxyalkyl, (C1-C6)hydroxyalkoxy, (C1-C6)carboxyalkyl (C1-C6)haloalkoxy, (C3-C8)cycloalkyl, and 4- to 7-membered heterocycloalkyl; wherein (C1- C6)alkyl is optionally substituted with phenyl, 4- to 7-membered heterocycloalkyl, and - NHR2a; or R2is (C1-C6)alkyl;

[0092] R2ais C(=O)R2b, (C1-C6)alkyl, or (C3-C8)cycloalkyl, wherein (C1-C6)alkyl or (C3- C8)cycloalkyl is optionally substituted with one or more independent instances of halo;

[0093] R2bis (C1-C6)alkyl;

[0094] R3and R4are each independently hydrogen, (C1-C6)alkyl, (C1-C6)alkoxyalkyl, or (C1- C6)haloalkyl; or taken together with the carbon atom to which they are attached form a (C3- C6)cycloalkyl;

[0095] R5is hydrogen, (C1-C6)alkyl, (C1-C6)alkoxyalkyl, or (C1-C6)haloalkyl; or R5taken together with R3or R4forms -(CH2)n-; wherein n is 1, 2, or 3; and

[0096] R6and R7are independently for each occurrence hydrogen or (C1-C6)alkyl; or R6and R7taken together with the carbon atom to which they are attached form a (C3-C6)cycloalkyl.

[0097] In some embodiments, provided here in is a compound of Formula (la) or (lb): or a pharmaceutical salt thereof; wherein:

[0098] X is N or CRX;

[0099] X1, X2, and X3are each independently N or CRX;

[0100] Rxis independently for each occurrence hydrogen, fluoro, or chloro; Y is C(=O), C(=O)CH2, CH2, or a bond;

[0101] R1is -OR1aor -CH2R1a; wherein R1ais phenyl, 5- to 6-membered heteroaryl, or (C3- C8)cycloalkyl(C1-C6)alkyl; each of which is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, chloro, (C1-C6)alkyl, (C3-C8)cycloalkyl, and (C1-C6)alkoxy;

[0102] R2is 5- or 6- membered heterocycloalkyl, 9- or 10-membered bicyclic heterocycloalkyl (e.g., indoline, octahydroindole, tetrahydroquinoline, or decahydroquinoline), 5- or 6- membered heteroaryl, 9- or 10-membered bicyclic heteroaryl, or phenyl; each of which is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, chloro, cyano, hydroxy, (C1- C6)alkyl, (C1-C6)alkenyl, -C(=O)NH2, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)hydroxy alkyl, and (C1-C6)haloalkoxy; wherein (C1-C6)alkyl is optionally substituted with phenyl or -NHR2a;

[0103] R2ais (C3-C8)cycloalkyl, optionally substituted with one or more independent instances of halo;

[0104] R3and R4are each independently hydrogen, (C1-C6)alkyl, (C1-C6)alkoxyalkyl, or (C1- C6)haloalkyl; or taken together with the carbon atom to which they are attached form a (C3- C6)cycloalkyl;

[0105] R5is hydrogen, (C1-C6)alkyl, (C1-C6)alkoxyalkyl, or (C1-C6)haloalkyl; or R5taken together with R3or R4forms -(CH2)n-; wherein n is 1, 2, or 3; and

[0106] R6and R7are independently for each occurrence hydrogen or (C1-C6)alkyl; or R6and R7taken together with the carbon atom to which they are attached form a (C3-C6)cycloalkyl.

[0107] In some embodiments, the compound is

[0108] In certain embodiments of the compound of formula (la), X1is N, while in other embodiments, X1is CH.

[0109] In some embodiments, X2is CH.

[0110] In some embodiments, X3is CH. In some embodiments, X1is N; X2is CH; and X3is CH.

[0111] In some embodiments, X1is CH; X2is CH; and X3is CH.

[0112] In other embodiments, the compound is:

[0113] In certain embodiments of the compound of Formula (lb), X is CH.

[0114] In some embodiments of the compound of Formula (la) or (lb), Y is C(=O).

[0115] In some preferred embodiments, R1is -OR1a.

[0116] In some embodiments, R1ais phenyl optionally substituted with one or two instances of fluoro or chloro. In certain preferred embodiments, R1ais 4-fluorophenyl, while in other embodimetns, R1ais 2,4-difluorophenyl or 4-chlorophenyl.

[0117] In some embodiments, R1ais 6-membered heteroaryl optionally substituted with one or two instances of fluoro or chloro. In some embodiments, R1ais pyridyl optionally substituted with one or two fluoro or chloro. More particularly, in some embodiments, R1ais 4-fluoropyridyl.

[0118] In some embodiments, R1ais (C3-C8)cycloalkyl(C1-C6)alkyl. In some embodiments, R1ais cyclopropylmethyl.

[0119] In some embodiments, R2is 9- or 10-membered bicyclic heteroaryl optionally substituted with one or more substituents independently selected from the group consisting of fluoro, chloro, cyano, hydroxy, (C1-C6)alkyl, (C1-C6)alkenyl, -C(=O)NH2, -NH2, (C1- C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)hydroxy alkyl, (C1-C6)halohydroxyalkyl, (C1- C6)hydroxyalkoxy, (C1-C6)carboxy alkyl (C1-C6)haloalkoxy, (C3-C8)cycloalkyl, and 4- to 7- membered heterocycloalkyl; wherein (C1-C6)alkyl is optionally substituted with phenyl, 4- to 7-membered heterocycloalkyl, and -NHR2a.

[0120] In more particular embodiments, R2is [l,2,4]triazolo[4,3-a]pyridine, [l,2,4]triazolo[l,5-a]pyridine, [l,2,4]triazolo[l,5-a]pyrazine, [l,2,4]triazolo[l,5- a]pyrimidine, [l,2,4]triazolo[4,3-a]pyrimidine, [l,2,4]triazolo[l,5-b]pyridazine, 1H- pyrazolo[3,4-b]pyridine 7-oxide, 3H-imidazo[4,5-b]pyridine 4-oxide, benzo[d]oxazole, 1H- benzo[d]imidazole, benzo [d] thiazole, lH-benzo[d][l,2,3]triazole, [l,2,3]oxadiazolo[4,5- b]pyridine, oxazolo[4,5-b]pyridine, IH-indazole, lH-pyrazolo[3,4-b]pyridine, or oxoisoindolin-1-yl; each of which is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, chloro, cyano, hydroxy, (C1- C6)alkyl, (C1-C6)alkenyl, -C(=O)NH2, -NH2, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1- C6)hydroxyalkyl, (C1-C6)halohydroxyalkyl, (C1-C6)hydroxyalkoxy, (C1-C6)carboxyalkyl (C1- C6)haloalkoxy, (C3-C8)cycloalkyl, and 4- to 7-membered heterocycloalkyl; wherein (C1- C6)alkyl is optionally substituted with phenyl, 4- to 7-membered heterocycloalkyl, or - NHR2a.

[0121] In other embodiments, R2is 9- or 10-membered bicyclic heterocycloalkyl optionally substituted with one or more substituents independently selected from the group consisting of fluoro, chloro, cyano, hydroxy, (C1-C6)alkyl, (C1-C6)alkenyl, -C(=O)NH2, -NH2, (C1- C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)hydroxy alkyl, (C1-C6)halohydroxyalkyl, (C1- C6)hydroxyalkoxy, (C1-C6)carboxy alkyl (C1-C6)haloalkoxy, (C3-C8)cycloalkyl, and 4- to 7- membered heterocycloalkyl; wherein (C1-C6)alkyl is optionally substituted with phenyl, 4- to 7-membered heterocycloalkyl, or -NHR2a.

[0122] In more particular embodiments, R2is 6,7-dihydro-5H-cyclopenta[b]pyridine 1- oxide, 5,6,7,8-tetrahydro-[l,2,4]triazolo[l,5-a]pyridine, 4,5,6,7-tetrahydropyrazolo[l,5- a]pyridine, 4,5,6,7-tetrahydro-[l,2,3]triazolo[l,5-a]pyridine, 5,6,7,8-tetrahydroimidazo[l,2- a]pyridine, 4,5,6,7-tetrahydro-lH-benzo[d]imidazole, 4,5,6,7-tetrahydrobenzo[d]oxazole, 4,5,6,7-tetrahydro-112-benzo[d][l,2,3]triazole, 6,7-dihydro-5H-[l,2,4]triazolo[5,l- b][l,3]oxazine, 4,5,6,7-tetrahydro-2H-benzo[d][l,2,3]triazole, isoindolin-1-one, or 7-oxo-6,7- dihydro-lH-pyrazolo[4,3-d]pyrimidine, each of which is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, chloro, cyano, hydroxy, (C1-C6)alkyl, (C1-C6)alkenyl, -C(=O)NH2, -NH2, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)hydroxy alkyl, (C1-C6)halohydroxyalkyl, (C1-C6)hydroxyalkoxy, (C1-C6)carboxyalkyl (C1-C6)haloalkoxy, (C3-C8)cycloalkyl, and 4- to 7-membered heterocycloalkyl; wherein (C1- C6)alkyl is optionally substituted with phenyl, 4- to 7-membered heterocycloalkyl, or - NHR2a.

[0123] In some embodiments, R2is pyridin-2(lH)-one, pyridine oxide, pyrimidine oxide, 1,5- dihydro-2H-pyrrol-2-one, phenyl, isoindolin-1-one, IH-indazole, tetrahydro-2H-pyran, pyridine, IH-pyrazole, 2-oxo-2,3-dihydro-lH-imidazole, 5-oxomorpholine, tetrahydropyrimidin-2(lH)-one, piperidin-2-one, pyrimidin-2(lH)-one, pyridazin-3(2H)-one, or pyrazin-2(lH)-one; each of which is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, chloro, cyano, hydroxy, (C1- C6)alkyl, (C1-C6)alkenyl, -C(=O)NH2, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)hydroxy alkyl, and (C1-C6)haloalkoxy; wherein (C1-C6)alkyl is optionally substituted with phenyl or -NHR2a.

[0124] In some embodiments, R2is pyridin-2(lH)-one, pyridine oxide, pyrimidine oxide, 1,5- dihydro-2H-pyrrol-2-one, phenyl, isoindolin-1-one, IH-indazole, tetrahydro-2H-pyran, pyridine, or IH-pyrazole; each of which is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, chloro, cyano, hydroxy, (C1-C6)alkyl, (C1-C6)alkenyl, -C(=O)NH2, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1- C6)hydroxyalkyl, and (C1-C6)haloalkoxy; wherein (C1-C6)alkyl is optionally substituted with phenyl or -NHR2a. Preferably, R2is pyridin-2(lH)-one or pyridine oxide; each of which is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, chloro, cyano, hydroxy, (C1-C6)alkyl, (C1-C6)alkenyl, -C(=O)NH2, (C1- C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)hydroxy alkyl, and (C1-C6)haloalkoxy; wherein (C1- C6)alkyl is optionally substituted with phenyl or -NHR2a. In some preferred embodiments, R2is unsubstituted pyridin-2(lH)-one or pyridine oxide. In other preferred embodiments, R2is unsubstituted pyridin-2(lH)-one or pyridine oxide.

[0125] In some embodiments, R2ais methyl. In other embodiments, R2ais cyclobutyl optionally substituted with at least one fluoro.

[0126] In some embodiments, R2bis methyl.

[0127] In some embodiments, R3and R4are each hydrogen.

[0128] In other embodiments, R3and R4are each independently (C1-C6)alkyl, preferably R3and R4are each methyl.

[0129] In some embodiments, one of R3and R4is hydrogen.

[0130] In some embodiments, one of R3and R4is (C1-C6)fluoroalkyl, preferably trifluoromethyl.

[0131] In other embodiments, R3and R4taken together with the carbon atom to which they are attached form a (C3-C6)cycloalkyl. In some embodiments, R3and R4taken together with the carbon atom to which they are attached form cyclopropyl, while in other embodiments, R3and R4taken together with the carbon atom to which they are attached form cyclobutyl.

[0132] In some embodiments, R5is hydrogen. In other embodiments, R5taken together with one of R3or R4forms -(CH2)n-, preferably wherein n is 2.

[0133] In some embodiments, one of R6or R7is hydrogen.

[0134] In other embodiments, one of R6or R7is (C1-C6)alkyl, preferably one of R6or R7is methyl. In other embodiments, one of R6or R7is ethyl.

[0135] In some embodiments, R6and R7are each hydrogen.

[0136] In other embodiments, each of R6and R7is (C1-C6)alkyl, preferably each of R6and R7is methyl.

[0137] In other embodiments, R6and R7taken together with the carbon atom to which they are attached form a (C3-C6)cycloalkyl, preferably a cyclopropyl.

[0138] In more particular embodiments, a compound of the invention has the structure: or a pharmaceutically acceptable salt thereof.

[0139] In some embodiments, a compound of the invention has the structure:

[0140]

[0141] or a pharmaceutically acceptable salt thereof.

[0142] In other embodiments, a compound of the invention has the structure: or a pharmaceutically acceptable salt thereof.

[0143] In certain embodiments, the compounds are atropisomers. 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, compounds produced by the replacement of a hydrogen with deuterium or tritium, or of a carbon with a13C- or14C-enriched carbon are within the scope of this invention. Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents in accordance with the present invention. For example, in the case of variable R1, the (C1-C4)alkyl or the -O-(C1-C4)alkyl can be suitably deuterated (e.g., -CD3, or -OCD3, respectively).

[0144] Any compound of the invention can also be radiolabed for the preparation of a radiopharmaceutical agent.

[0145] Methods of Treatment

[0146] One aspect of the invention provides compounds, compositions, and methods useful for preventing or treating a disease Additionally, methods of preventing or treating an MRGPRX2-mediated disease or disorder, comprise administering to a subject in need thereof a therapeutically effective amount of the compound of Formula (la) or (lb), or a pharmaceutically acceptable salt thereof. For example, an MRGPRX2-mediated disease or disorder may be chronic spontaneous urticaria, prurigo nodularis, irritable bowel syndrome, chronic inducible urticaria, atopic dermatitis, osteoarthritis, rosacea, migraine, pseudo- analphylaxis, mast cell activation syndrome, mastocytosis, pruritus, neurodermatitis, contact urticaria, allergic rhinitis, asthma, acute contact dermatitis, ulcerative colitis, crohns disease, idiopathic chronic cough, rheumatoid arthritis, multiple sclerosis, geographic atrophy, endometriosis, seborrheic dermatitis, psoriasis, chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, neuropathic itch, periodontitis, autism, abdominal aortic aneurysms, deep vein thrombosis, amyotrophic lateral sclerosis, interstitial cystitis, coronary artery disease, cancer, sickle cell disease, obesity, or ulcers.

[0147] In certain embodiments, the compound is administered orally to the subject.

[0148] In certain embodiments, the compound is administered parenterally to the subject.

[0149] In certain embodiments, the disease is prevented. In other embodiments, the disease is treated.

[0150] Pharmaceutical Compositions, Routes of Administration, and Dosing

[0151] In certain embodiments, the invention is directed to a pharmaceutical composition, comprising a compound of the invention, e.g. a compound of Formula (la) or (lb), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0152] In certain embodiments, the invention is directed to a pharmaceutical composition, comprising a compound of any of the disclosed embodiments, and a pharmaceutically acceptable carrier.

[0153] In certain embodiments, the pharmaceutical composition comprises a plurality of compounds of the invention and a pharmaceutically acceptable carrier.

[0154] Pharmaceutical compositions of the invention can be prepared by combining one or more compounds of the invention with a pharmaceutically acceptable carrier and, optionally, one or more additional pharmaceutically active agents.

[0155] As stated above, an “effective amount” refers to any amount that is sufficient to achieve a desired biological effect. Combined with the teachings provided herein, by choosing among the various active compounds and weighing factors such as potency, relative bioavailability, patient body weight, severity of adverse side-effects and mode of administration, an effective prophylactic or therapeutic treatment regimen can be planned which does not cause substantial unwanted toxicity and yet is effective to treat the particular subject. The effective amount for any particular application can vary depending on such factors as the disease or condition being treated, the particular compound of the invention being administered, the size of the subject, or the severity of the disease or condition. One of ordinary skill in the art can empirically determine the effective amount of a particular compound of the invention and / or other therapeutic agent without necessitating undue experimentation. A maximum dose may be used, that is, the highest safe dose according to some medical judgment. Multiple doses per day may be contemplated to achieve appropriate systemic levels of compounds. Appropriate systemic levels can be determined by, for example, measurement of the patient’s peak or sustained plasma level of the drug. “Dose” and “dosage” are used interchangeably herein.

[0156] In certain embodiments, intravenous administration of a compound may typically be from 0.1 mg / kg / day to 20 mg / kg / day. In one embodiment, intravenous administration of a compound may typically be from 0.1 mg / kg / day to 2 mg / kg / day. In one embodiment, intravenous administration of a compound may typically be from 0.5 mg / kg / day to 5 mg / kg / day. In one embodiment, intravenous administration of a compound may typically be from 1 mg / kg / day to 20 mg / kg / day. In one embodiment, intravenous administration of a compound may typically be from 1 mg / kg / day to 10 mg / kg / day.

[0157] Generally, daily oral doses of a compound will be, for human subjects, from about 0.01 milligrams / kg per day to 1000 milligrams / kg per day. It is expected that oral doses in the range of 0.5 to 50 milligrams / kg, in one or more administrations per day, will yield therapeutic results. Dosage may be adjusted appropriately to achieve desired drug levels, local or systemic, depending upon the mode of administration. For example, it is expected that intravenous administration would be from one order to several orders of magnitude lower dose per day. In the event that the response in a subject is insufficient at such doses, even higher doses (or effective higher doses by a different, more localized delivery route) may be employed to the extent that patient tolerance permits. Multiple doses per day are contemplated to achieve appropriate systemic levels of the compound.

[0158] For any compound described herein the therapeutically effective amount can be initially determined from animal models. A therapeutically effective dose can also be determined from human data for compounds which have been tested in humans and for compounds which are known to exhibit similar pharmacological activities, such as other related active agents. Higher doses may be required for parenteral administration. The applied dose can be adjusted based on the relative bioavailability and potency of the administered compound. Adjusting the dose to achieve maximal efficacy based on the methods described above and other methods as are well-known in the art is well within the capabilities of the ordinarily skilled artisan. The formulations of the invention can be administered in pharmaceutically acceptable solutions, which may routinely contain pharmaceutically acceptable concentrations of salt, buffering agents, preservatives, compatible carriers, adjuvants, and optionally other therapeutic ingredients.

[0159] For use in therapy, an effective amount of the compound can be administered to a subject by any mode that delivers the compound to the desired surface. Administering a pharmaceutical composition may be accomplished by any means known to the skilled artisan. Routes of administration include but are not limited to intravenous, intramuscular, intraperitoneal, intravesical (urinary bladder), oral, subcutaneous, direct injection (for example, into a tumor or abscess), mucosal (e.g., topical to eye), inhalation, and topical.

[0160] For intravenous and other parenteral routes of administration, a compound of the invention can be formulated as a lyophilized preparation, as a lyophilized preparation of liposome-intercalated or -encapsulated active compound, as a lipid complex in aqueous suspension, or as a salt complex. Lyophilized formulations are generally reconstituted in suitable aqueous solution, e.g., in sterile water or saline, shortly prior to administration.

[0161] For oral administration, the compounds can be formulated readily by combining the active compound(s) with pharmaceutically acceptable carriers well known in the art. Such carriers enable the compounds of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a subject to be treated. Pharmaceutical preparations for oral use can be obtained as solid excipient, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and / or polyvinylpyrrolidone (PVP). If desired, disintegrating agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate. Optionally the oral formulations may also be formulated in saline or buffers, e.g., EDTA for neutralizing internal acid conditions or may be administered without any carriers.

[0162] Also specifically contemplated are oral dosage forms of the above component or components. The component or components may be chemically modified so that oral delivery of the derivative is efficacious. Generally, the chemical modification contemplated is the attachment of at least one moiety to the component molecule itself, where said moiety permits (a) inhibition of acid hydrolysis; and (b) uptake into the blood stream from the stomach or intestine. Also desired is the increase in overall stability of the component or components and increase in circulation time in the body. Examples of such moieties include: polyethylene glycol, copolymers of ethylene glycol and propylene glycol, carboxymethyl cellulose, dextran, polyvinyl alcohol, polyvinyl pyrrolidone and polyproline. Abuchowski and Davis, “Soluble Polymer-Enzyme Adducts”, In: Enzymes as Drugs, Hocenberg and Roberts, eds., Wiley-Interscience, New York, N.Y., pp. 367-383 (1981); Newmark et al., J Appl Biochem 4:185-9 (1982). Other polymers that could be used are poly- 1,3 -dioxolane and poly-1, 3, 6-tioxocane. For pharmaceutical usage, as indicated above, polyethylene glycol moieties are suitable.

[0163] For the component (or derivative) the location of release may be the stomach, the small intestine (the duodenum, the jejunum, or the ileum), or the large intestine. One skilled in the art has available formulations which will not dissolve in the stomach, yet will release the material in the duodenum or elsewhere in the intestine. Preferably, the release will avoid the deleterious effects of the stomach environment, either by protection of the compound of the invention (or derivative) or by release of the biologically active material beyond the stomach environment, such as in the intestine.

[0164] To ensure full gastric resistance a coating impermeable to at least pH 5.0 is essential. Examples of the more common inert ingredients that are used as enteric coatings are cellulose acetate trimellitate (CAT), hydroxypropylmethylcellulose phthalate (HPMCP), HPMCP 50, HPMCP 55, polyvinyl acetate phthalate (PVAP), Eudragit L30D, Aquateric, cellulose acetate phthalate (CAP), Eudragit L, Eudragit S, and shellac. These coatings may be used as mixed films.

[0165] A coating or mixture of coatings can also be used on tablets, which are not intended for protection against the stomach. This can include sugar coatings, or coatings which make the tablet easier to swallow. Capsules may consist of a hard shell (such as gelatin) for delivery of dry therapeutic (e.g., powder); for liquid forms, a soft gelatin shell may be used. The shell material of cachets could be thick starch or other edible paper. For pills, lozenges, molded tablets or tablet triturates, moist massing techniques can be used.

[0166] The therapeutic can be included in the formulation as fine multi-particulates in the form of granules or pellets of particle size about 1 mm. The formulation of the material for capsule administration could also be as a powder, lightly compressed plugs or even as tablets. The therapeutic could be prepared by compression. Colorants and flavoring agents may all be included. For example, the compound of the invention (or derivative) may be formulated (such as by liposome or microsphere encapsulation) and then further contained within an edible product, such as a refrigerated beverage containing colorants and flavoring agents.

[0167] One may dilute or increase the volume of the therapeutic with an inert material. These diluents could include carbohydrates, especially mannitol, a-lactose, anhydrous lactose, cellulose, sucrose, modified dextrans and starch. Certain inorganic salts may be also be used as fillers including calcium triphosphate, magnesium carbonate and sodium chloride. Some commercially available diluents are Fast-Flo, Emdex, STA-Rx 1500, Emcompress and Avicell.

[0168] Disintegrants may be included in the formulation of the therapeutic into a solid dosage form. Materials used as disintegrates include but are not limited to starch, including the commercial disintegrant based on starch, Explotab. Sodium starch glycolate, Amberlite, sodium carboxymethylcellulose, ultramylopectin, sodium alginate, gelatin, orange peel, acid carboxymethyl cellulose, natural sponge and bentonite may all be used. Another form of the disintegrants are the insoluble cationic exchange resins. Powdered gums may be used as disintegrants and as binders and these can include powdered gums such as agar, Karaya or tragacanth. Alginic acid and its sodium salt are also useful as disintegrants.

[0169] Binders may be used to hold the therapeutic agent together to form a hard tablet and include materials from natural products such as acacia, tragacanth, starch and gelatin. Others include methyl cellulose (MC), ethyl cellulose (EC) and carboxymethyl cellulose (CMC). Polyvinyl pyrrolidone (PVP) and hydroxypropylmethyl cellulose (HPMC) could both be used in alcoholic solutions to granulate the therapeutic.

[0170] An anti-frictional agent may be included in the formulation of the therapeutic to prevent sticking during the formulation process. Lubricants may be used as a layer between the therapeutic and the die wall, and these can include but are not limited to; stearic acid including its magnesium and calcium salts, polytetrafluoroethylene (PTFE), liquid paraffin, vegetable oils and waxes. Soluble lubricants may also be used such as sodium lauryl sulfate, magnesium lauryl sulfate, polyethylene glycol of various molecular weights, Carbowax 4000 and 6000.

[0171] Glidants that might improve the flow properties of the drug during formulation and to aid rearrangement during compression might be added. The glidants may include starch, talc, pyrogenic silica and hydrated silicoaluminate. To aid dissolution of the therapeutic into the aqueous environment a surfactant might be added as a wetting agent. Surfactants may include anionic detergents such as sodium lauryl sulfate, dioctyl sodium sulfosuccinate and dioctyl sodium sulfonate. Cationic detergents which can be used and can include benzalkonium chloride and benzethonium chloride. Potential non-ionic detergents that could be included in the formulation as surfactants include lauromacrogol 400, polyoxyl 40 stearate, polyoxyethylene hydrogenated castor oil 10, 50 and 60, glycerol monostearate, polysorbate 40, 60, 65 and 80, sucrose fatty acid ester, methyl cellulose and carboxymethyl cellulose. These surfactants could be present in the formulation of the compound of the invention or derivative either alone or as a mixture in different ratios.

[0172] Pharmaceutical preparations which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and / or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added. Microspheres formulated for oral administration may also be used. Such microspheres have been well defined in the art. All formulations for oral administration should be in dosages suitable for such administration.

[0173] For buccal administration, the compositions may take the form of tablets or lozenges formulated in conventional manner.

[0174] For topical administration, the compound may be formulated as solutions, gels, ointments, creams, suspensions, etc. as are well-known in the art. Systemic formulations include those designed for administration by injection, e.g., subcutaneous, intravenous, intramuscular, intrathecal or intraperitoneal injection, as well as those designed for transdermal, transmucosal oral or pulmonary administration.

[0175] For administration by inhalation, compounds for use according to the present invention may be conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol the dosage unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges of e.g., gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch. Also contemplated herein is pulmonary delivery of the compounds disclosed herein (or salts thereof). The compound is delivered to the lungs of a mammal while inhaling and traverses across the lung epithelial lining to the blood stream. Other reports of inhaled molecules include Adjei et al., Pharm Res 7:565-569 (1990); Adjei et al., Int J Pharmaceutics 63:135-144 (1990) (leuprolide acetate); Braquet et al., J Cardiovasc Pharmacol 13(suppl. 5): 143-146 (1989) (endothelin-1); Hubbard et al., Annal Int Med 3:206-212 (1989) (□ 1- antitrypsin); Smith et al., 1989, J Clin Invest 84:1145-1146 (a- 1 -proteinase); Oswein et al., 1990, "Aerosolization of Proteins", Proceedings of Symposium on Respiratory Drug Delivery II, Keystone, Colorado, March, (recombinant human growth hormone); Debs et al., 1988, J Immunol 140:3482-3488 (interferon-gamma and tumor necrosis factor alpha) and Platz et al., U.S. Pat. No. 5,284,656 (granulocyte colony stimulating factor; incorporated by reference). A method and composition for pulmonary delivery of drugs for systemic effect is described in U.S. Pat. No. 5,451,569 (incorporated by reference), issued Sep. 19, 1995 to Wong et al.

[0176] Contemplated for use in the practice of this invention are mechanical devices designed for pulmonary delivery of therapeutic products, including but not limited to nebulizers, metered dose inhalers, and powder inhalers, all of which are familiar to those skilled in the art.

[0177] Some specific examples of commercially available devices suitable for the practice of this invention are the Ultravent nebulizer, manufactured by Mallinckrodt, Inc., St. Louis, Mo.; the Acorn II nebulizer, manufactured by Marquest Medical Products, Englewood, Colo.; the Ventolin metered dose inhaler, manufactured by Glaxo Inc., Research Triangle Park, North Carolina; and the Spinhaler powder inhaler, manufactured by Fisons Corp., Bedford, Mass.

[0178] All such devices require the use of formulations suitable for the dispensing of the compounds of the invention. Typically, each formulation is specific to the type of device employed and may involve the use of an appropriate propellant material, in addition to the usual diluents, adjuvants and / or carriers useful in therapy. Also, the use of liposomes, microcapsules or microspheres, inclusion complexes, or other types of carriers is contemplated. Chemically modified compound of the invention may also be prepared in different formulations depending on the type of chemical modification or the type of device employed.

[0179] Formulations suitable for use with a nebulizer, either jet or ultrasonic, will typically comprise a compound of the invention (or derivative) dissolved in water at a concentration of about 0.1 to 25 mg of biologically active compound of the invention per mL of solution. The formulation may also include a buffer and a simple sugar (e.g., for inhibitor stabilization and regulation of osmotic pressure). The nebulizer formulation may also contain a surfactant, to reduce or prevent surface induced aggregation of the compound of the invention caused by atomization of the solution in forming the aerosol.

[0180] Formulations for use with a metered-dose inhaler device will generally comprise a finely divided powder containing the compound of the invention (or derivative) suspended in a propellant with the aid of a surfactant. The propellant may be any conventional material employed for this purpose, such as a chlorofluorocarbon, a hydrochlorofluorocarbon, a hydrofluorocarbon, or a hydrocarbon, including trichlorofluoromethane, dichlorodifluoromethane, dichlorotetrafluoroethanol, and 1,1,1,2-tetrafluoroethane, or combinations thereof. Suitable surfactants include sorbitan trioleate and soya lecithin. Oleic acid may also be useful as a surfactant.

[0181] Formulations for dispensing from a powder inhaler device will comprise a finely divided dry powder containing a compound of the invention (or derivative) and may also include a bulking agent, such as lactose, sorbitol, sucrose, or mannitol in amounts which facilitate dispersal of the powder from the device, e.g., 50 to 90% by weight of the formulation. The compound of the invention (or derivative) should advantageously be prepared in particulate form with an average particle size of less than 10 micrometers (μm), most preferably 0.5 to 5 μm, for most effective delivery to the deep lung.

[0182] Nasal delivery of a pharmaceutical composition of the present invention is also contemplated. Nasal delivery allows the passage of a pharmaceutical composition of the present invention to the blood stream directly after administering the therapeutic product to the nose, without the necessity for deposition of the product in the lung. Formulations for nasal delivery include those with dextran or cyclodextran.

[0183] For nasal administration, a useful device is a small, hard bottle to which a metered dose sprayer is attached. In one embodiment, the metered dose is delivered by drawing the pharmaceutical composition of the present invention solution into a chamber of defined volume, which chamber has an aperture dimensioned to aerosolize and aerosol formulation by forming a spray when a liquid in the chamber is compressed. The chamber is compressed to administer the pharmaceutical composition of the present invention. In a specific embodiment, the chamber is a piston arrangement. Such devices are commercially available.

[0184] Alternatively, a plastic squeeze bottle with an aperture or opening dimensioned to aerosolize an aerosol formulation by forming a spray when squeezed is used. The opening is usually found in the top of the bottle, and the top is generally tapered to partially fit in the nasal passages for efficient administration of the aerosol formulation. Preferably, the nasal inhaler will provide a metered amount of the aerosol formulation, for administration of a measured dose of the drug.

[0185] The compounds, when it is desirable to deliver them systemically, may be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and / or dispersing agents.

[0186] Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Additionally, suspensions of the active compounds may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.

[0187] Alternatively, the active compounds may be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.

[0188] The compounds may also be formulated in rectal or vaginal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.

[0189] In addition to the formulations described above, a compound may also be formulated as a depot preparation. Such long acting formulations may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.

[0190] The pharmaceutical compositions also may comprise suitable solid or gel phase carriers or excipients. Examples of such carriers or excipients include but are not limited to calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols.

[0191] Suitable liquid or solid pharmaceutical preparation forms are, for example, aqueous or saline solutions for inhalation, microencapsulated, encochleated, coated onto microscopic gold particles, contained in liposomes, nebulized, aerosols, pellets for implantation into the skin, or dried onto a sharp object to be scratched into the skin. The pharmaceutical compositions also include granules, powders, tablets, coated tablets, (micro)capsules, suppositories, syrups, emulsions, suspensions, creams, drops or preparations with protracted release of active compounds, in whose preparation excipients and additives and / or auxiliaries such as disintegrants, binders, coating agents, swelling agents, lubricants, flavorings, sweeteners or solubilizers are customarily used as described above. The pharmaceutical compositions are suitable for use in a variety of drug delivery systems. For a brief review of methods for drug delivery, see Langer R, Science 249:1527-33 (1990).

[0192] The compound of the invention and optionally other therapeutics may be administered per se (neat) or in the form of a pharmaceutically acceptable salt or cocrystal. When used in medicine the salts or cocrystals should be pharmaceutically acceptable, but non- pharmaceutically acceptable salts or cocrystals may conveniently be used to prepare pharmaceutically acceptable salts or cocrystals thereof. Such salts include, but are not limited to, those prepared from the following acids: hydrochloric, hydrobromic, sulphuric, nitric, phosphoric, maleic, acetic, salicylic, p-toluene sulphonic, tartaric, citric, methane sulphonic, formic, malonic, succinic, naphthalene-2-sulphonic, and benzene sulphonic. Also, such salts can be prepared as alkaline metal or alkaline earth salts, such as sodium, potassium or calcium salts of the carboxylic acid group.

[0193] Suitable buffering agents include: acetic acid and a salt (1-2% w / v); citric acid and a salt (1-3% w / v); boric acid and a salt (0.5-2.5% w / v); and phosphoric acid and a salt (0.8-2% w / v). Suitable preservatives include benzalkonium chloride (0.003-0.03% w / v); chlorobutanol (0.3-0.9% w / v); parabens (0.01-0.25% w / v) and thimerosal (0.004-0.02% w / v).

[0194] Pharmaceutical compositions of the invention contain an effective amount of a compound as described herein and optionally therapeutic agents included in a pharmaceutically acceptable carrier. The term “pharmaceutically acceptable carrier” means one or more compatible solid or liquid filler, diluents or encapsulating substances which are suitable for administration to a human or other vertebrate animal. The term “carrier” denotes an organic or inorganic ingredient, natural or synthetic, with which the active ingredient is combined to facilitate the application. The components of the pharmaceutical compositions also are capable of being commingled with the compounds of the present invention, and with each other, in a manner such that there is no interaction which would substantially impair the desired pharmaceutical efficiency. The therapeutic agent(s), including specifically but not limited to a compound of the invention, may be provided in particles. Particles as used herein means nanoparticles or microparticles (or in some instances larger particles) which can consist in whole or in part of the compound of the invention or the other therapeutic agent(s) as described herein. The particles may contain the therapeutic agent(s) in a core surrounded by a coating, including, but not limited to, an enteric coating. The therapeutic agent(s) also may be dispersed throughout the particles. The therapeutic agent(s) also may be adsorbed into the particles. The particles may be of any order release kinetics, including zero-order release, first-order release, second-order release, delayed release, sustained release, immediate release, and any combination thereof, etc. The particle may include, in addition to the therapeutic agent(s), any of those materials routinely used in the art of pharmacy and medicine, including, but not limited to, erodible, nonerodible, biodegradable, or nonbiodegradable material or combinations thereof. The particles may be microcapsules which contain the compound of the invention in a solution or in a semi-solid state. The particles may be of virtually any shape.

[0195] Both non-biodegradable and biodegradable polymeric materials can be used in the manufacture of particles for delivering the therapeutic agent(s). Such polymers may be natural or synthetic polymers. The polymer is selected based on the period of time over which release is desired. Bioadhesive polymers of particular interest include bioerodible hydrogels described in Sawhney H S et al. (1993) Macromolecules 26:581-7, the teachings of which are incorporated herein. These include polyhyaluronic acids, casein, gelatin, glutin, poly anhydrides, polyacrylic acid, alginate, chitosan, poly(methyl methacrylates), poly(ethyl methacrylates), poly(butylmethacrylate), poly(isobutyl methacrylate), poly (hexylmethacrylate), poly(isodecyl methacrylate), poly(lauryl methacrylate), poly(phenyl methacrylate), poly(methyl acrylate), poly (isopropyl acrylate), poly(isobutyl acrylate), and poly (octadecyl acrylate).

[0196] The therapeutic agent(s) may be contained in controlled release systems. The term “controlled release” is intended to refer to any drug-containing formulation in which the manner and profile of drug release from the formulation are controlled. This refers to immediate as well as non-immediate release formulations, with non-immediate release formulations including but not limited to sustained release and delayed release formulations. The term “sustained release” (also referred to as “extended release”) is used in its conventional sense to refer to a drug formulation that provides for gradual release of a drug over an extended period of time, and that preferably, although not necessarily, results in substantially constant blood levels of a drug over an extended time period. The term “delayed release” is used in its conventional sense to refer to a drug formulation in which there is a time delay between administration of the formulation and the release of the drug there from. “Delayed release” may or may not involve gradual release of drug over an extended period of time, and thus may or may not be “sustained release.”

[0197] Use of a long-term sustained release implant may be particularly suitable for treatment of chronic conditions. “Long-term” release, as used herein, means that the implant is constructed and arranged to deliver therapeutic levels of the active ingredient for at least 7 days, and preferably 30-60 days. Long-term sustained release implants are well-known to those of ordinary skill in the art and include some of the release systems described above.

[0198] It will be understood by one of ordinary skill in the relevant arts that other suitable modifications and adaptations to the compositions and methods described herein are readily apparent from the description of the invention contained herein in view of information known to the ordinarily skilled artisan, and may be made without departing from the scope of the invention or any embodiment thereof. Having now described the present invention in detail, the same will be more clearly understood by reference to the following examples, which are included herewith for purposes of illustration only and are not intended to be limiting of the invention.

[0199] EXAMPLES

[0200] The invention is further described in the following examples, which do not limit the scope of the invention described in the claims.

[0201] Abbreviations

[0202] AIBN: Azobisisobutyronitrile

[0203] DCC: N,N'-Dicyclohexylcarbodiimide

[0204] DCM: Dichloromethane

[0205] DIEA: N,N-diisopropylethylamine

[0206] DMA: N,N-dimethylacetamide

[0207] DMAP: 4-dimethylaminopyridine

[0208] DME: Dimethoxyethane

[0209] DMF: N.N-dimethylformamide

[0210] DMSO: Dimethylsulfoxide EA: Ethyl acetate

[0211] EDCI: l-Ethyl-3-(3-dimethylaminopropyl)carbodiimide

[0212] HATU : 1 - [Bis(dimethylamino)methylene] - 1 H- 1 ,2 ,3-triazolo [4,5 -b]pyridinium 3-oxide hexafluorophosphate m-CPBA: Meta-chloroperbenzoic acid

[0213] MTBE: Methyl tert-butyl ether

[0214] NBS: N-bromosuccinimide

[0215] PE: Petroleum ether

[0216] Py: Pyridine

[0217] PTS A: Para- toluenesulfonic acid

[0218] RuPhos-Pd: 2-Dicyclohexylphosphino-2',6'-diisopropoxy-l,T-biphenyl)[2-(2'-amino-l,r- biphenyl)]palladium(II) methanesulfonate

[0219] TEA: Triethylamine

[0220] Experimental Procedures

[0221] Example 1: N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-(4-(6-oxo-l,6-dihydropyridine-3- carbonyl)piperazin- 1 -yl)propanamide

[0222] Synthetic Scheme

[0223] 5-(4-fluorophenoxy)pyridin-2-amine To a stirred solution of 5-bromopyridin-2-amine (3 g, 17.340 mmol, 1.0 equiv) in dioxane was added 4-fluorophenol (2.33 g, 20.808 mmol, 1.2 equiv), dimethylglycine (0.18 g, 1.734 mmol, 0.1 equiv), CS2CO3(8.47 g, 26.010 mmol, 1.5 equiv) and Cui (0.66 g, 3.468 mmol, 0.2 equiv) at room temperature. The reaction mixture was stirred at 110 °C for a period of overnight under N2. After cooling to room temperature, the reaction mixture was quenched by addition of water (50 mL). The aqueous layer was extracted with ethyl acetate (100 mL x 3). The combined organic phase was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue obtained was purified by silica gel chromatography (0-60% PE / EA) to afford 5-(4-fluorophenoxy)pyridin-2-amine (450 mg, 12.69%). MS (ESI): mass calcd. For C11H9FN2O: 204.07 m / z, found: 205.10 [M+H]+.

[0224] 2-bromo-N-(5-(4-fluorophenoxy)pyridin-2-yl)propanamide

[0225] To a stirred solution of 5-(4-fluorophenoxy)pyridin-2-amine (500 mg, 2.45 mmol, 1.0 equiv) in anhydrous DCM (15 mL) was added 2-bromopropanoic acid (450 mg, 2.94 mmol, 1.2 equiv) and DCC (610 mg, 2.94 mmol, 1.2 equiv) and AgNO3(60 mg, 0.37 mmol, 0.15 equiv) at room temperature. After completion of reaction, the reaction mixture was quenched by addition of water (50 mL). The aqueous layer was extracted with DCM (100 mL x 3). The combined organic phase was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue obtained was purified by silica gel chromatography (0-80% PE / EA) to afford 2-bromo-N-(5-(4-fluorophenoxy)pyridin-2-yl)propanamide (581 mg, 70.00%). MS (ESI): mass calcd. For C14H12BrFN2O2: 338.01 m / z, found: 339.05 [M+H]+. tert-butyl 4-(6-oxo-l,6-dihydropyridine-3-carbonyl)piperazine-1-carboxylate

[0226] To a stirred solution of tert-butyl piperazine- 1 -carboxylate (600 mg, 3.221 mmol, 1.0 equiv) in pyridine (2 mL) was added 6-oxo-l,6-dihydropyridine-3-carboxylic acid (582 mg, 4.187 mmol, 1.3 equiv) and EDCI (83 mg, 0.435 mmol, 1.5 equiv) at room temperature. The reaction mixture was stirred at room temperature for a period of overnight. After completion of reaction, the reaction mixture was quenched by addition of water (20 mL). The aqueous layer was extracted with ethyl acetate (30 mL). The combined organic phase was washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue obtained was purified by silica gel chromatography (0-60% PE / EA) to afford tert -butyl 4-(6- oxo- l,6-dihydropyridine-3-carbonyl)piperazine-l -carboxylate (140 mg, 13.07%) as a white solid. MS (ESI): mass calcd. for C15H21N3O4: 307.15 m / z, found: 308.15 [M+H]+. 5-(piperazine-1-carbonyl)pyridin-2(lH)-one

[0227] To a stirred solution of tert-butyl 4-(6-oxo-1,6-dihydropyridine-3- carbonyl)piperazine-l -carboxylate (140 mg, 0.456 mmol, 1.0 equiv) in EA (5 mL) was added HC1 (4 M in EA, 5 mL). The reaction mixture was stirred at room temperature for 1 h. The product was precipitated by the addition of diethyl ether. The product was obtained (90 mg, 54.24%) by filtration and drying of the HC1 salt and used without further purification. MS (ESI): mass calcd. for C10H13N3O2: 207.10, m / z, found: 208.15 [M+H]+.

[0228] N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-(4-(6-oxo-l,6-dihydropyridine-3-carbonyl)pipera zin- 1 -yl)propanamide

[0229] To a stirred solution of 5-(piperazine-1-carbonyl)pyridin-2(lH)-one (90 mg, 0.483 mmol, 1.0 equiv) in DMF was added K2CO3(67 mg, 0.483 mmol, 1.0 equiv) and KI (240 mg, 1.449 mmol, 3.0 equiv) at room temperature. The reaction mixture was stirred at room temperature for 0.5 h. To the above mixture was added 2-bromo-N-(5-(4- fluorophenoxy)pyridin-2-yl)propanamide (176 mg, 0.531 mmol, 1.1 equiv) at room temperature. The resulting mixture was stirred for 5 h at room temperature. After completion of reaction, the reaction mixture was quenched by addition of water (5 mL). The aqueous layer was extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate filtered and concentrated. The residue obtained was purified by silica gel chromatography (0-100% PE / EA) and Prep-HPLC using a Column: XSelect CSH C18 Column, 30*150 mm, 5μm (eluent: 20% to 50% (v / v) CH3CN and H2O, 0.1% FA) to afford N-(5-(4-fhiorophenoxy)pyridin-2-yl)-2-(4-(6-oxo-l,6- dihydropyridine-3-carbonyl)piperazin-1-yl)propanamide (20.9 mg, 8.32%) as a white solid. MS (ESI): mass calcd. for C24H24FN5O4: 465.18, m / z, found: 466.05 [M+H]+,1H NMR (300 MHz, DMSO-d6) δ 11.84 (s, 1H), 10.25 (s, 1H), 8.13 (dd, J = 6.0, 2.9 Hz, 2H), 7.43 - 7.60 (m, 3H), 7.16 - 7.29 (m, 2H), 7.02 - 7.15 (m, 2H), 6.33 (d, J = 9.4 Hz, 1H), 3.44 - 3.58 (m, 5H), 2.58 (tt, J = 9.3, 4.9 Hz, 4H), 1.19 (d, J = 6.9 Hz, 3H).19F NMR (282 MHz, DMSO-d6) δ - 119.85.

[0230] Example 2: 2-(4-(4-cyanobenzoyl)piperazin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2- yl)propanamide tert-butyl 4-(4-cyanobenzoyl)piperazine-1-carboxylate

[0231] To a stirred solution of tert-butyl piperazine- 1 -carboxylate (500 mg, 2.684 mmol, 1.0 equiv) in pyridine (3 mL) was added 4-cyanobenzoic acid (513 mg, 3.489 mmol, 1.3 equiv) and EDO (711 mg, 4.00 mmol, 1.5 equiv). The reaction mixture was stirred at room temperature for a period of 5 h. The reaction was quenched by water (20 mL) and extracted with EA (30 mL x 3). The combined organic extracts were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue obtained was purified by silica gel chromatography (0-50% PE / EA) to afford tert-butyl 4-(4- cyanobenzoyl)piperazine-l -carboxylate (700 mg, 82.68%). MS (ESI): mass calcd. for: C17H21N3O3:315.16 m / z, found: 260.05 [M+H]+.

[0232] 4-(piperazine-1-carbonyl)benzonitrile

[0233] To a stirred solution of tert-butyl 4-(4-cyanobenzoyl)piperazine- 1 -carboxylate (600 mg, 1.903 mmol, 1.0 equiv) in EA (5 mL) was added 4 N HC1 (in EA, 5 mL). The reaction mixture was stirred at room temperature for a period of 2 h. The product was precipitated by the addition of diethyl ether to afford 4- (piperazine- l-carbonyl)benzonitrile (400 mg, 95.11%) as an HC1 salt and used without further purification. MS (ESI): mass calcd. for: C12H13N3O: 215.11 m / z, found: 216.05[M+H]+.

[0234] 2-(4-(4-cyanobenzoyl)piperazin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propanamide

[0235] To a stirred solution of 4- (piperazine- l-carbonyl)benzonitrile (150 mg, 0.697 mmol, 1.0 equiv) in DMF was added 2-bromo-N-[5-(4- fluorophenoxy )pyridin-2-yl]propanamide (260 mg, 0.767 mmol, 1.1 equiv) and TEA (211 mg, 2.091 mmol, 3.0 equiv) at room temperature. The reaction mixture was stirred for 3 h at 60 °C. After cooling to room temperature, the reaction was quenched by water (20 mL) and extracted with EA (20 mL x 3). The combined organic extracts were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue obtained was further purified by silica gel chromatography (0-20% DCM / MeOH) & C18 column to afford 2-[4-(4- cyanobenzoyl)piperazin-1-yl]-N-[5-(4-fluorophenoxy)pyridin-2-yl]propanamide (20.9 mg, 6.30%) as a white solid. MS (ESI): mass calcd. for C26H24FN5O3: 473.19 m / z, found: 474.05 [M+H]+.1H NMR (300 MHz, DMSO-d6) δ 10.23 (s, 1H), 8.13 (dd, J = 6.0, 2.9 Hz, 2H), 7.92 (d, J = 7.9 Hz, 2H), 7.58 (d, J = 7.9 Hz, 2H), 7.52 (dd, J = 9.1, 2.9 Hz, 1H), 7.23 (t, J = 8.8 Hz, 2H), 7.08 (dd, J = 9.1, 4.4 Hz, 2H), 3.67 (s, 2H), 3.52 (d, J = 6.9 Hz, 3H), 2.51 - 2.79 (m, 4H), 1.19 (d, J = 6.8 Hz, 3H).19F NMR (282 MHz, DMSO-d6) δ -119.856.

[0236] Example 3: 2-(4-(lH-pyrazole-4-carbonyl)piperazin-1-yl)-N-(5-(4- fluorophenoxy)pyridin-2-yl)propanamide

[0237] Synthetic Scheme tert-butyl 4-(l-((5-(4-fluorophenoxy)pyridin-2-yl)amino)-1-oxopropan-2-yl)piperazine- 1-carboxylate

[0238] To a solution of tert-butyl piperazine- 1 -carboxylate (0.91 g, 4.886 mmol, 1.1 equiv) in DMA (10 mL) was added 2-bromo-N-(5-(4-fluorophenoxy)pyridin-2-yl)propanamide (1.5 g, 4.423 mmol, 1.0 equiv) and TEA (1.34 g, 13.269 mmol, 3.0 equiv) at rt. The resulting mixture was stirred for 3 h at 60 °C. After cooling to room temperature, the reaction was quenched by water (20 mL) and extracted with EA (20 mL x 3). The combined organic extracts were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The residue obtained was purified by silica gel chromatography (0-60% PE / EA) to afford tert- butyl 4-(l -((5-(4-fhiorophenoxy)pyridin-2-yl)amino)- 1 -oxopropan-2-yl)piperazine- 1 - carboxylate (1.0 g, 50.23%) as yellow oil. MS (ESI): mass calcd. For C23H29FN4O4: 444.22 m / z, found: 445.20 [M+H]+.

[0239] N-[5-(4-fluorophenoxy)pyridin-2-yl]-2-(piperazin-1-yl)propanamide hydrochloride

[0240] To a solution of tert-butyl 4-(l-((5-(4-fluorophenoxy)pyridin-2-yl)amino)-1- oxopropan-2-yl)piperazine-l -carboxylate (2.0 g, 4.499 mmol, 1.0 equiv) in EA (15 mL) was added 4N HC1 (in EA, 15 mL) at 0 °C. The resulting mixture was stirred for 2 h at rt. The product was precipitated by the addition of anhydrous ether to afford N-[5-(4- fluorophenoxy)pyridin-2-yl]-2-(piperazin-1-yl)propanamide hydrochloride (1.7 g, crude) which was used without further purification. MS (ESI): mass calcd. For C18H21FN4O2: 344.16 m / z, found: 345.15 [M+H]+

[0241] 2-(4-(lH-pyrazole-4-carbonyl)piperazin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2- yl)propanamide To a solution of N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-(piperazin-1-yl)propanamide (100 mg, 0.290 mmol, 1 equiv) in pyridine (3 mL) was added lH-pyrazole-4-carboxylic acid (36 mg, 0.319 mmol, 1.1 equiv) and EDCI (111 mg, 0.580 mmol, 2 equiv) at rt. The resulting mixture was stirred for 2 h at rt. The reaction was quenched with water (10 mL). The resulting mixture was extracted with ethyl acetate (3 x 10 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The residue obtained was purified by silica gel chromatography (0-100% PE / EA) and Prep-HPLC using a column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm (eluent: 26% to 56% (v / v) CH3CN and H2O with lOmmol / L NH4HCO3) to afford 2-(4-(lH-pyrazole-4-carbonyl)piperazin-1-yl)-N-(5-(4- fluorophenoxy)pyridin-2-yl)propanamide (14.3 mg, 11.30%) as a white solid. MS (ESI): mass calcd. for C22H23FN6O3: 438.18 m / z, found: 439.10 [M+H]+.1H NMR (300 MHz, DMSO-d6) δ 13.17 (s, 1H), 10.24 (s, 1H), 8.14 (dd, J = 5.9, 2.9 Hz, 2H), 8.06 (s, 1H), 7.72 (s, 1H), 7.53 (dd, J = 9.1, 2.9 Hz, 1H), 7.16 - 7.31 (m, 2H), 7.04 - 7.16 (m, 2H), 3.64 (t, J = 4.9 Hz, 4H),

[0242] 3.51 (q, J = 6.8 Hz, 1H), 2.51 - 2.66 (m, 4H), 1.20 (d, J = 6.8 Hz, 3H).

[0243] Example 4: (S)-N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-(4-(6-oxo-l,6-dihydropyridine-3- carbonyl)piperazin-1-yl)propanamide and Example 5 (SPT-0009347): (R)-N-(5-(4- fluorophenoxy)pyridin-2-yl)-2-(4-(6-oxo-1,6-dihydropyridine-3-carbonyl)piperazin-1- yl)propanamide

[0244] (S)-N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-(4-(6-oxo-l,6-dihydropyridine-3- carbonyl) piperazin- 1 -yl)propanamide and (R)-N - (5- (4-fluorophenoxy)pyridin-2-yl) -2- (4- (6-oxo- 1 ,6-dihydropyridine-3-carbonyl)piperazin- 1 -yl)propanamide

[0245] N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-(4-(6-oxo-l,6-dihydropyridine-3- carbonyl)piperazin-1-yl)propanamide was separated by Chiral-Prep-HPLC (CHIRALPAK IF 2*25 cm, 5 μm; Mobile Phase A: MTBE (0.5% 2M NH3-MeOH)-HPLC, Mobile Phase B: EtOH-HPLC; Flow rate: 15 mL / min; Gradient: isocratic 50; Wave Length: 220 / 254 nm) to afford (S)-N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-(4-(6-oxo-l,6-dihydropyridine-3- carbonyl)piperazin-1-yl)propanamide (2.0 mg), MS (ESI): mass calcd. for C24H24FN5O4:

[0246] 465.18 m / z, found: 466.10 [M+H]+,1H NMR (300 MHz, DMSO-d6) δ 11.84 (s, 1H), 10.25 (s,

[0247] 1H), 8.13 (dd, J = 6.0, 2.9 Hz, 2H), 7.42 - 7.60 (m, 3H), 7.17 - 7.29 (m, 2H), 7.02 - 7.16 (m, 2H), 6.33 (d, J = 9.4 Hz, 1H), 3.45 - 3.59 (m, 5H), 2.50 - 2.67 (m, 4H), 1.19 (d, J = 6.9 Hz, 3H).19F NMR (282 MHz, DMSO-d6) δ -60.37, -105.68, -119.86. and (R)-N-(5-(4- fluorophenoxy)pyridin-2-yl)-2-(4-(6-oxo- 1 ,6-dihydropyridine-3-carbonyl)piperazin- 1 - yl)propanamide (2.6 mg). MS (ESI): mass calcd. for C24H24FN5O4: 465.18 m / z, found: 466.15 [M+H]+,1H NMR (300 MHz, DMSO-d6) δ 11.84 (s, 1H), 10.25 (s, 1H), 8.13 (dd, J = 6.0, 2.9 Hz, 2H), 7.42 - 7.60 (m, 3H), 7.17 - 7.29 (m, 2H), 7.02 - 7.17 (m, 2H), 6.33 (d, J = 9.4 Hz, 1H), 3.44 - 3.59 (m, 5H), 2.50 - 2.67 (m, 4H), 1.21 (d, J = 6.9 Hz, 3H).19F NMR (282 MHz, DMSO-d6) δ -27.14, -30.73, -119.85, -167.23.

[0248] Example 6 : 2-(4-(4-cyanobenzyl)piperazin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2- yl)propanamide

[0249] 2-(4-(4-cyanobenzyl)piperazin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propanamide

[0250] To a solution of N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-(piperazin-1-yl)propanamide (120 mg, 0.348 mmol, 1.0 equiv) in DMF (3 mL) was added K2CO3(97 mg, 0.696 mmol, 2.0 equiv) and 4-(bromomethyl)benzonitrile (102 mg, 0.522 mmol, 1.5 equiv) at rt. The resulting mixture was stirred for 2 hours at 100 °C. After cooling to room temperature the reaction was quenched by water (10 mL) and extracted with EA (10 mL x 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue obtained was purified by silica gel chromatography (0-100% PE / EA) and Prep-HPLC using a Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm (eluent: 45% to 75% CH3CN and H2O with 10 mmol / L NH4HCO3) to afford 2-(4-(4- cyanobenzyl)piperazin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propanamide (17.2 mg, 10.75%) as a white solid. MS (ESI): mass calcd. for C26H26FN5O2: 459.525 m / z, found 460.10 [M+H]+.1H NMR (300 MHz, DMSO-d6) δ 10.12 (s, 1H), 8.09 - 8.18 (m, 2H), 7.84 - 7.75 (m, 2H), 7.58 - 7.47 (m, 3H), 7.30 - 7.16 (m, 2H), 7.15 - 7.02 (m, 2H), 3.58 (s, 2H), 3.42 (q, J = 6.8 Hz, 1H), 2.53 - 2.61 (m, 4H), 2.40 - 2.46 (m, 4H), 1.18 (d, J = 6.9 Hz, 3H).19F NMR (282 MHz, DMSO-d6) δ -119.896.

[0251] Example 7 : N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-(4-isonicotinoylpiperazin-1- yl)propanamide

[0252] N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-(4-isonicotinoylpiperazin-1-yl)propanamide

[0253] To a solution of N-(5-(4- fluorophenoxy )pyridin-2-yl)-2-(piperazin-1-yl)propanamide (80 mg, 0.232 mmol, 1.0 equiv) in pyridine (3mL) was added isonicotinic acid (43 mg, 0.348 mmol, 1.5 equiv) and EDCI (89 mg, 0.464 mmol, 2.0 equiv) at rt. The resulting mixture was stirred for 2 hours at rt. The reaction mixture was quenched by water (10 mF) and extracted with EA (10 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The residue obtained was purified by silica gel chromatography (0-20% DCM / MeOH) and Prep-HPLC using a column: Column: XBridge Prep OBD C18 Column, 30*150 mm (eluent: 27% to 57% (v / v) CH3CN and H2O with lOmmol / L NH4HCO3) to afford N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-(4- isonicotinoylpiperazin-1-yl)propanamide (27.5 mg, 25.96%) as a white solid. MS (ESI): mass calcd. for C24H24FN5O3: 449.19 m / z, found 450.15 [M+H]+.1H NMR (300 MHz, DMSO-d6) δ 10.25 (s, 1H), 8.62 - 8.70 (m, 2H), 8.09 - 8.18 (m, 2H), 7.52 (dd, J = 9.1, 2.9 Hz, 1H), 7.34 - 7.42 (m, 2H), 7.16 - 7.31 (m, 2H), 7.03 - 7.15 (m, 2H), 3.64 - 3.69 (m, 2H), 3.52 (d, J = 7.0 Hz, 1H), 3.26 - 3.36 (m, 2H), 3.53 - 3.68 (m, 4H), 1.19 (d, J = 6.9 Hz, 3H).19F NMR (282 MHz, DMSO-d6) δ -119.84. Example 8: N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-(4-((6-oxo-l,6-dihydropyridin-3- yl)methyl)piperazin- 1 -yl)propanamide

[0254] N-[5-(4-fluorophenoxy)pyridin-2-yl]-4-[(6-oxo-lH-pyridin-3-yl)methyl]-l,4-diazepane-1- carboxamide

[0255] To a solution of N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-(piperazin-1-yl)propanamide (150 mg, 0.436 mmol, 1.0 equiv) in DCM (5 mL) was added 6-oxo-l,6-dihydropyridine-3- carbaldehyde (100 mg, 0.812 mmol, 1.8 equiv) and TEA (88 mg, 0.872 mmol, 2.0 equiv) at rt. The resulting mixture was stirred for 1 h at rt. NaBH(OAc)3(369 mg, 1.744 mmol, 4.0 equiv) was added the mixture at 0 °C. The resulting mixture was stirred for 12 h at rt. The reaction mixture was quenched by water (10 mL) and extracted with DCM / MeOH (4:1) (10 mL x 3). The combined organic extracts were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The residue obtained was purified by silica gel chromatography (0-20% DCM / MeOH) to afford crude product as a yellow oil, and then purified by Prep-HPLC using a Column: XBridge C18 5 μm (eluent: 33% to 63% CH3CN and H2O with 10 mmol / L NH4HCO3) to afford N-[5-(4-fluorophenoxy)pyridin-2-yl]-4-[(6- oxo-lH-pyridin-3-yl)methyl]-l,4-diazepane-1-carboxamide as a white solid. MS (ESI): mass calcd: For C24H26FN5O3: 451.20 m / z, found: 452.15 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 11.46 (s, 1H), 10.11 (s, 1H), 8.10 - 8.17 (m, 2H), 7.49 - 7.57 (m, 1H), 7.33 - 7.40 (m, 1H), 7.18 - 7.29 (m, 3H), 7.04 - 7.14 (m, 2H), 6.29 (d, J = 9.4 Hz, 1H), 3.36 - 3.45 (m, 1H), 3.17 - 3.22 (m, 2H), 2.52 - 2.57 (m, 4H), 2.37 - 2.41 (m, 4H), 1.17 (d, J = 6.9 Hz, 3H).19F NMR (376 MHz, DMSO-d6) δ -119.90.

[0256] Example 9: N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-(4-(4-hydroxybenzoyl)piperazin-1- yl)propanamide

[0257] N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-(4-(4-hydroxybenzoyl)piperazin-1- yl)propanamide

[0258] To a solution of N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-(piperazin-1-yl)propanamide (90 mg, 0.261 mmol, 1.0 equiv) in pyridine (2 mL) was added 4-hydroxybenzoic acid (54 mg, 0.392 mmol, 1.5 equiv) and EDO (100 mg, 0.522 mmol, 2.0 equiv) at rt. The resulting mixture was stirred for 2 h at rt. The reaction was quenched by water (10 mL) and extracted with EA (10 mL x 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue obtained was purified by silica gel chromatography (0-20% DCM / MeOH) and Prep-HPLC using a Column: XBridge Shield RP 18 OBD Column, 30*150 mm, 5μm (eluent: 30% to 60% CH3CN and H2O with 10 mmol / L NH4HCO3+0.1% NH3H2O) to afford N-(5-(4-fhiorophenoxy)pyridin-2-yl)-2-(4-(4- hydroxybenzoyl)piperazin-1-yl)propanamide (5.6 mg, 4.62%) as a white solid. MS (ESI): mass calcd. for C25H25FN4O4: 464.19 m / z, found 465.15 [M+H]+.1H NMR (400 MHz, DMSO- d ) δ 10.23 (s, 1H), 9.83 (s, 1H), 8.10 - 8.17 (m, 2H), 7.49 - 7.55 (m, 1H), 7.18 - 7.28 (m, 4H), 7.05 - 7.17 (m, 2H), 6.74 - 6.81 (m, 2H), 3.43 - 3.60(m, 5H), 2.50 - 2.64 (m, 4H), 1.19 (d, J = 6.8 Hz, 3H).19F NMR (376 MHz, DMSO-d6) δ -119.873.

[0259] Example 10: 4-(4-(l-((5-(4-fluorophenoxy)pyridin-2-yl)amino)-1-oxopropan-2- yl) piperazine- 1 -carbonyl)pyridine 1 -oxide

[0260] 4-(4-(l-((5-(4-fluorophenoxy)pyridin-2-yI)amino)-1-oxopropan-2-yI)piperazine-1- carbonyl)pyridine 1 -oxide

[0261] To a solution of N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-(piperazin-1-yl)propanamide (80 mg, 0.232 mmol, 1.0 equiv) in pyridine (2 mL) was added 4-carboxypyridine-l -oxide (48 mg, 0.348 mmol, 1.5 equiv) and EDO (89 mg, 0.464 mmol, 2.0 equiv) at rt. The resulting mixture was stirred for 2 h at rt. The reaction was quenched by water (10 mL) and extracted with EA (10 mL x 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue obtained was purified by silica gel chromatography (0-20% DCM / MeOH) and Prep-HPLC using a Column: XBridge Shield RP 18 OBD Column, 30*150 mm, 5μm; (eluent: 23% to 53% CH3CN and H2O with 10 mmol / L NH4HCO3+0.1% NH3H2O) to afford 4-(4-(l-((5-(4-fhiorophenoxy)pyridin-2- yl)amino)-1-oxopropan-2-yl)piperazine-1-carbonyl)pyridine 1 -oxide (22.7 mg, 21.29%) as a white solid. MS (ESI): mass calcd. for C24H24FN5O4: 465.18 m / z, found 466.10 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 10.25 (s, 1H), 8.24 (d, J = 6.6 Hz, 2H), 8.11 - 8.16 (m, 2H), 7.49 - 7.55 (m, 1H), 7.45 (d, J = 6.5 Hz, 2H), 7.19 - 7.22 (m, 2H), 7.05 - 7.14 (m, 2H), 3.40 - 3.65 (m, 5H), 2.45 - 2.65 (m, 4H), 1.19 (d, J = 6.9 Hz, 3H).19F NMR (376 MHz, DMSO-d6) δ -119.856.

[0262] Example 11: N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-(4-(tetrahydro-2H-pyran-4- carbonyl)piperazin- 1 -yl)propanamide

[0263] N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-(4-(tetrahydro-2H-pyran-4-carbonyl)piperazin-

[0264] 1 -yl)propanamide

[0265] To a solution of N-[5-(4-fluorophenoxy)pyridin-2-yl]-2-(piperazin-1-yl)propanamide hydrochloride (80 mg, 0.232 mmol, 1 equiv) in pyridine (2mL) was added tetrahydro-2H- pyran-4-carboxylic acid (36 mg, 0.278 mmol, 1.2 equiv) and EDO (89 mg, 0.464 mmol, 2.0 equiv) at rt. The resulting mixture was stirred for 3 h at rt. The reaction was quenched by water (10 mL) and extracted with EA (10 mL x 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue obtained was purified by silica gel chromatography (0-20% DCM / MeOH) and Prep-HPLC using a Column: XBridge Prep OBD Cl 8 Column, 30*150 mm, 5μm; (eluent: 24% to 54% CH3CN and H2O with 10 mmol / L NH4HCO3) to afford N-(5-(4-fluorophenoxy)pyridin-2-yl)- 2-(4-(tetrahydro-2H-pyran-4-carbonyl)piperazin-1-yl)propanamide (17.2 mg, 16.03%) as a white solid. MS (ESI): mass calcd. for C24H29FN4O4: 456.22 m / z, found 457.15 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 10.26 (s, 1H), 8.10 - 8.17 (m, 2H), 7.53 (dd, J = 8.9, 3.0 Hz, 1H), 7.19 - 7.31 (m, 2H), 7.04 - 7.14 (m, 2H), 3.79 - 3.87 (m, 2H), 3.44 - 3.58 (m, 5H), 3.31 - 3.41 (m, 2H), 2.80 - 2.90 (m, 1H), 2.66 - 2.69 (m, 2H), 2.32 - 2.35 (m, 2H) 1.46 - 1.51 (m, 4H), 1.18 (d, J = 6.9 Hz, 3H).19F NMR (376 MHz, DMSO-d6) δ -119.859.

[0266] Example 12: 2-(4-(lH-indazole-5-carbonyl)piperazin-1-yl)-N-(5-(4- fluorophenoxy)pyridin-2-yl)propanamide

[0267] 2-(4-(lH-indazole-5-carbonyl)piperazin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2- yl)propanamide

[0268] To a solution of N-[5-(4- fluorophenoxy )pyridin-2-yl]-2-(piperazin-1-yl)propanamide hydrochloride (80 mg, 0.232 mmol, 1 equiv) in pyridine (3 mL) was added lH-indazole-5- carboxylic acid (45 mg, 0.278 mmol, 1.2 equiv) and EDO (66 mg, 0.348 mmol, 1.5 equiv). The mixture was stirred at room temperature for 2 h. The mixture was concentrated to dryness under reduced pressure to provide the crude product, which was purified by Prep- HPLC using for a Column: XBridge Shield RP 18 OBD Column, 30*150 mm, 5μm (eluent: 31% to 61% (v / v) CH3CN and H2O with lOmmol / L NH4HCO3+ 0.1% NH3H2O) to afford 2- (4-(lH-indazole-5-carbonyl)piperazin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2- yl)propanamide (14.5 mg, 12.77%) as a white solid. MS (ESI): mass calcd. for C26H25FN6O3: 488.20 m / z, found: 489.10 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 13.26 (s, 1H), 10.27 (s, 1H), 8.12 - 8.18 (m, 3H), 7.85 (s, 1H), 7.49 - 7.62 (m, 2H), 7.38 (dd, J = 8.6, 1.5 Hz, 1H), 7.24 (t, J = 8.8 Hz, 2H), 7.04 - 7.14 (m, 2H), 3.43 - 3.58 (m, 4H), 2.62 (s, 1H), 2.41 - 2.61 (m, 4H), 1.20 (d, J = 6.8 Hz, 3H).

[0269] Example 13: N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-(4-(6-oxo-1-(2,2,2-trifluoroethyl)- 1 ,6-dihydropyridine-3-carbonyl)piperazin- 1 -yl)propanamide

[0270] Synthetic Scheme

[0271]

[0272] 6-oxo-1-(2,2,2-trifluoroethyl)-l,6-dihydropyridine-3-carboxylic acid

[0273] To a solution of methyl 6-oxo-1-(2,2,2-trifluoroethyl)pyridine-3-carboxylate (251 mg,

[0274] 1.067 mmol, 1.0 equiv) in methanol (1 mL), tetrahydrofuran (2 mL) and water (1 mL) was added LiOH (128 mg, 5.335 mmol, 5 equiv) at room temperature. The reaction mixture was stirred at room temperature for 2 h. The mixture was acidified pH = 5 with HC1 (IN). The aqueous layer was extracted with ethyl acetate (30 mL x 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue obtained was purified by silica gel chromatography (0-100% PE / EA) to afford 6-oxo-1-(2,2,2-trifluoroethyl)-l,6-dihydropyridine-3-carboxylic acid (220 mg, 95.65%) as a white solid. MS (ESI): mass calcd. for C8H6F NO3: 221.14 m / z, found 222.05

[0275] 6-oxo-1-(2,2,2-trifluoroethyl)-l,6-dihydropyridine-3-carboxylic acid

[0276] To a solution of methyl 6-oxo-1-(2,2,2-trifluoroethyl)pyridine-3-carboxylate (251 mg, 1.067 mmol, 1.0 equiv) in methanol (1 mL), tetrahydrofuran (2 mL) and water (1 mL) was added LiOH (128 mg, 5.335 mmol, 5 equiv) at room temperature. The reaction mixture was stirred at room temperature for 2 h. The mixture was acidified pH = 5 with HC1 (IN). The aqueous layer was extracted with ethyl acetate (30 mL x 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue obtained was purified by silica gel chromatography (0-100% PE / EA) to afford 6-oxo-1-(2,2,2-trifluoroethyl)-l,6-dihydropyridine-3-carboxylic acid (220 mg, 95.65%) as a white solid. MS (ESI): mass calcd. for C8H6F NO3: 221.14 m / z, found 222.05 [M+H]+.

[0277] N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-(4-(6-oxo-1-(2,2,2-trifluoroethyl)-l,6- dihydropyridine-3-carbonyI)piperazin-1-yI)propanamide

[0278] To a solution of 6-oxo-1-(2,2,2-trifluoroethyl)-l,6-dihydropyridine-3-carboxylic acid (60 mg, 0.271 mmol, 1.0 equiv) in pyridine (3 mL) was added N-[5-(4-fluorophenoxy)pyridin- 2-yl]-2-(piperazin-1-yl)propanamide hydrochloride (93 mg, 0.271 mmol, 1.0 equiv) and EDO (78 mg, 0.407 mmol, 1.5 equiv) at rt. The resulting mixture was stirred for 5 h at rt. The reaction was quenched with H2O (10 mL) at rt. The resulting mixture was extracted with EA (20 mL x 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4. The resulting mixture was filtered. The filtrate was concentrated and purified by flash chromatography (0-20% DCM / MeOH) & Prep-HPLC using a column: XBridge C18 5 m, 19 mm X 250 mm, 30*150 mm, 5μm (eluent: 35% to 60% CH3CN and H2O with 10 mmol / L NH4HCO3) to afford N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-(4-(6-oxo- 1 -(2,2,2-trifluoroethyl)- 1 ,6-dihydropyridine-3-carbonyl)piperazin- 1 -yl)propanamide (31.3 mg, 21.08%) as a white solid. MS (ESI): mass calcd. for C26H25F4N5O4: 547.18 m / z, found 548.10 [M+H]+.1H NMR (300 MHz, DMSO-d6) δ 10.25 (s, 1H), 8.13 (dd, J = 6.0, 2.9 Hz, 2H), 7.97 (d, J = 2.5 Hz, 1H), 7.47 - 7.61 (m, 2H), 7.16 - 7.31 (m, 2H), 7.02 - 7.15 (m, 2H), 6.51 (d, J = 9.5 Hz, 1H), 4.89 (q, 7= 9.1 Hz, 2H), 3.46 - 3.58 (m, 5H), 2.52 - 2.68 (m, 4H), 1.19 (d, J = 6.9 Hz, 3H).19F NMR (282 MHz, DMSO-d6) δ -69.44, -119.86.

[0279] Example 14: 2-(4-(l-benzyl-6-oxo-l,6-dihydropyridine-3-carbonyl)piperazin-1-yl)-N-(5- (4-fluorophenoxy)pyridin-2-yl)propanamide l-benzyl-6-oxo-l,6-dihydropyridine-3-carboxylic acid

[0280] To a solution of 6-oxo-lH-pyridine-3-carboxylic acid (400 mg, 2.875 mmol, 1.0 equiv) in methanol (10 mL) and water (2 mL) was added KOH (564 mg, 10.063 mmol, 3.5 equiv). The resulting solution was heated at reflux for 5 minutes and then benzyl bromide (983 mg, 5.750 mmol, 2.0 equiv) was added. Heating was continued for an additional 90 minutes, the reaction was then cooled to room temperature and the methanol removed under reduced pressure. The aqueous phase was acidified with 2 M HC1, and the resulting white precipitate was isolated by vacuum filtration, washed with water and air dried to give a white solid (410 mg, 56.60%) as a white solid. MS (ESI): mass calcd. for C13H11NO3: 229.07 m / z, found 230.15 [M+H]+.

[0281] 2-(4-(l-benzyl-6-oxo-l,6-dihydropyridine-3-carbonyl)piperazin-1-yl)-N-(5-(4- fluorophenoxy)pyridin-2-yl)propanamide

[0282] To a solution of l-benzyl-6-oxo-l,6-dihydropyridine-3-carboxylic acid (60 mg, 0.262 mmol, 1.0 equiv) in pyridine (5 mL) was added N-(5-(4-fluorophenoxy)pyridin-2-yl)-2- (piperazin-1-yl)propanamide (90 mg, 0.262 mmol, 1.00 equiv) and EDCI (75 mg, 0.393 mmol, 1.5 equiv). The mixture was stirred at room temperature for 2 h. The mixture was concentrated to dryness under reduced pressure to provide the crude product, which was purified by Column: XBridge Shield RP 18 OBD Column, 30*150 mm, 5 μm (eluent: 35% to 65% CH3CN and H2O with 10 mmol / L NH4HCO3+ 0.1%NH3H2O) to afford 2-(4-(l-benzyl-6-oxo- l,6-dihydropyridine-3-carbonyl)piperazin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2- yl)propanamide (11.7 mg, 8.03%) as a white solid. MS (ESI): mass calcd. for C31H30FN5O4: 555.23 m / z, found 556.15 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 10.27 (s, 1H), 8.15 (dd, J = 6.1, 2.9 Hz, 2H), 8.10 (d, J = 2.6 Hz, 1H), 7.46 - 7.56 (m, 2H), 7.26 - 7.39 (m, 4H), 7.24 (t, J = 8.7 Hz, 2H), 7.09 (dd, J = 9.0, 4.5 Hz, 2H), 6.45 (d, J = 9.3 Hz, 1H), 5.14 (s, 2H), 3.53 (t, J = 6.1 Hz, 5H), 2.43 - 2.67 (m, 4H), 1.19 (d, J = 6.8 Hz, 3H).

[0283] Example 15: N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-(4-(l-oxoisoindolin-4-yl)piperazin-

[0284] 1 -yl)propanamide

[0285] N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-(4-(l-oxoisoindolin-4-yl)piperazin-1- yl)propanamide

[0286] To a stirring solution 4-iodoisoindolin-1-one (92 mg, 0.436 mmol, 1.0 equiv) in 1,4- dioxane (2 mF) was added a solution of N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-(piperazin-1- yl)propanamide (150 mg, 0.436 mmol, 1.0 equiv) and CS2CO3(425 mg, 1.308 mmol, 3.0 equiv) and (SP-4-1)-[1,3-Bis[2,6-bis(l-ethylpropyl)phenyl]-4,5-dichloro-l,3-dihydro-2H-imidazol- 2-ylidene]dichloro(2-methylpyridine)palladium (36 mg, 0.0436 mmol, 0.1 equiv). The mixture was stirred at 100 °C for 5 h under N2. The mixture was concentrated to dryness under reduced pressure to provide the crude product, which was purified by Cl 8 column (eluent: CH3CN and H2O) and Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; (eluent: 33% to 63% CH3CN and H2O with 10 mmol / L NH4HCO3) to afford N-(5-(4-fluorophenoxy)pyridin-2-yl)- 2-(4-(l-oxoisoindolin-4-yl)piperazin-1-yl)propanamide (6.8 mg, 3.22%) as a white solid. MS (ESI): mass calcd. for C26H26FN5O3: 475.20 m / z, found 476.10 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 10.26 (s, 1H), 8.57 (s, 1H), 8.12 - 8.20 (m, 2H), 7.50 - 7.58 (m, 1H), 7.40 (t, J = 7.7 Hz, 1H), 7.19 - 7.30 (m, 3H), 7.05 - 7.17 (m, 3H), 4.36 (s, 2H), 3.09 - 3.13 (m, 4H), 2.66 - 2.80 (m, 4H), 1.24 (d, J = 6.8 Hz, 3H).19F NMR (376 MHz, DMSO-d6) δ -119.87.

[0287] Example 16: 2-(4-(5-(((3,3-difluorocyclobutyl)amino)methyl)-6-oxo-l,6- dihydropyridine-3-carbonyl)piperazin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2- yl)propanamide

[0288] Synthetic Scheme

[0289]

[0290] 2-(4-(5-bromo-6-methoxynicotinoyl)piperazin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2- yl)propanamide

[0291] To a stirring solution 5-bromo-6-methoxynicotinic acid (337 mg, 1.452 mmol, 1.0 equiv) in DMF (5 mL) was added a solution of N-(5-(4-fluorophenoxy)pyridin-2-yl)-2- (piperazin-1-yl)propanamide (500 mg, 1.452 mmol, 1.0 equiv), HATU (828 mg, 2.178 mmol, 1.5 equiv) and DIEA (563 mg, 4.356 mmol, 3.0 equiv). The resulting mixture was stirred at room temperature for 6 h. After completion of reaction, the reaction mixture was quenched by addition of water (20 mL). The aqueous layer was extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue obtained was purified by silica gel chromatography (0-100% PE / EA) to afford 2-(4-(5-bromo-6-methoxynicotinoyl)piperazin-1- yl)-N-(5-(4- fluorophenoxy )pyridin-2-yl)propanamide (500 mg, 61.67%). MS (ESI): mass calcd. for C25H25BrFN5O4: 557.11 m / z, found: 558.20 [M+H]+.

[0292] N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-(4-(5-formyl-6-methoxynicotinoyl)piperazin-1- yl)propanamide

[0293] To a stirring solution 2-(4-(5-bromo-6-methoxynicotinoyl)piperazin-1-yl)-N-(5-(4- fluorophenoxy)pyridin-2-yl)propanamide (500 mg, 0.895 mmol, 1.0 equiv) in DMSO (7 mL) was added a solution of tert-butyl isocyanide (112 mg, 1.343 mmol, 1.5 equiv), (acetyloxy)palladio acetate (20 mg, 0.090 mmol, 0.1 equiv), sodium formate (91 mg, 1.343 mmol, 1.5 equiv) and dppb (38 mg, 0.090 mmol, 0.1 equiv). The resulting mixture was maintained under nitrogen and stirred at 100 °C for 5 h. After cooled to room temperature, the reaction was quenched by water (20 mL) and extracted with EA (20 mL x 3). The combined organic extracts were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue obtained was purified by silica gel chromatography (0-100% PE / EA) to afford N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-(4-(5-formyl-6- methoxynicotinoyl)piperazin-1-yl)propanamide (350 mg, 77.02%) as a white solid. MS (ESI): mass calcd. for C26H26FN5O5: 507.19 m / z, found: 508.15 [M+H]+.

[0294] 2-(4-(5-(((3,3-difluorocyclobutyl)amino)methyl)-6-methoxynicotinoyl)piperazin-1-yl)-N- (5-(4-fluorophenoxy)pyridin-2-yl)propanamide

[0295] To a stirring solution N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-(4-(5-formyl-6- methoxynicotinoyl)piperazin-1-yl)propanamide (350 mg, 0.690 mmol, 1.0 equiv) in DCM (3 mL) was added 3,3-difluorocyclobutan-1-amine (74 mg, 0.690 mmol, 1.0 equiv) and HOAc (12 mg, 0.207 mmol, 0.3 equiv). The reaction was stirred for 0.5 h at rt. NaBH(OAc)3(292 mg, 1.380 mmol, 2.0 equiv) was added into the solution. The resulting mixture was stirred at room temperature for 5 h. After completion of reaction, the reaction mixture was quenched by addition of water (20 mL). The aqueous layer was extracted with DCM (30 mL x 3). The combined organic phase was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue obtained was purified by silica gel chromatography (0- 10% DCM / MeOH) to afford 2-(4-(5-(((3,3-difhiorocyclobutyl)amino)methyl)-6- methoxynicotinoyl)piperazin- 1 -yl)-N-(5 -(4-fluorophenoxy)pyridin-2-yl)propanamide (170 mg, 41.18%). MS (ESI): mass calcd. for C30H33F3N6O4: 598.25 m / z, found: 599.15 [M+H]+.

[0296] 2-(4-(5-(((3,3-difluorocyclobutyl)amino)methyl)-6-oxo-l,6-dihydropyridine-3- carbonyl)piperazin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propanamide

[0297] To a stirring solution 2-(4-(5-(((3,3-difhiorocyclobutyl)amino)methyl)-6- methoxynicotinoyl)piperazin- 1 -yl)-N-(5 -(4-fluorophenoxy)pyridin-2-yl)propanamide (170 mg, 0.284 mmol, 1.0 equiv) in DMF (2 mL) was added a solution of HBrPy (454 mg, 2.840 mmol, 10 equiv). After cooled to room temperature, the reaction was quenched by water (10 mL) and extracted with EA (20 mL x 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue obtained was purified by silica gel chromatography (0-10% DCM / MeOH) and Prep-HPLC using a Column: XBridge Prep OBD C18 Column, 30*150 mm, 5.0 μm (eluent: 28% to 58% CH3CN and H2O with 10 mmol / L NH4HCO3+0.05%NH3H2O) to afford 2-(4-(5-(((3,3- difluorocyclobutyl)amino)methyl)-6-oxo- 1 ,6-dihydropyridine-3-carbonyl)piperazin- 1 -yl)-N- (5-(4-fluorophenoxy)pyridin-2-yl)propanamide (6.1 mg, 3.63%) as a white solid. MS (ESI): mass calcd. for C29H31F3N6O4: 584.24 m / z, found: 585.20 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 11.84 (s, 1H), 10.28 (s, 1H), 8.14 (dd, J = 6.1, 2.9 Hz, 2H), 7.53 (dd, J = 9.1, 2.9 Hz, 1H), 7.47 (q, J = 2.5 Hz, 2H), 7.24 (t, J = 8.8 Hz, 2H), 7.04 - 7.17 (m, 2H), 3.54 (t, J = 5.2 Hz, 5H),3.38 - 3.51(m,2H) 3.08 - 3.18 (m, 1H), 2.67 - 2.79 (m, 2H), 2.52 - 2.64 (m, 5H), 2.22 - 2.40 (m, 2H), 1.16 - 1.26 (m, 3H).19F NMR (376 MHz, DMSO-d6) δ -80.25, -94.97, -119.86.

[0298] Example 17: 3-(4-(l-((5-(4-fluorophenoxy)pyridin-2-yl)amino)-1-oxopropan-2- yl)piperazin-1-yl)benzamide

[0299] Synthetic Scheme

[0300] 2-(4-(3-cyanophenyl)piperazin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propanamide

[0301] To a solution of N-(5-(4-fhiorophenoxy)pyridin-2-yl)-2-(piperazin-1-yl)propanamide (hydrogen chloride salt, 100 mg, 0.26 mmol, 1.0 equiv) in 1,4-dioxane (3 mL) was added CS2CO3(170 mg, 0.52 mmol, 2.0 equiv) at rt. To the mixture was added 3-bromobenzonitrile (57 mg, 0.31 mmol, 1.2 equiv), RuPhos (13 mg, 0.026 mmol, 0.1 equiv), RuPhos-Pd (21 mg, 0.026 mmol, 1.2 equiv) and DMF (0.5 mL). The reaction was stirred for 16 h at 90 °C under N2. After cooled to room temperature, The reaction mixture was quenched by water (10 mL) and extracted with EA (20 mL x 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated under vacuum to yield a crude product which was directly purified by flash chromatographyto (0-20% DCM / MeOH) afford 2-(4-(3-cyanophenyl)piperazin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propanamide (70 mg, 60.3%) as a white solid. MS (ESI): mass calcd. for C25H24FN5O2: 445.19 m / z, found: 446.15 [M+H]+.

[0302] 3-(4-(l-((5-(4-fluorophenoxy)pyridin-2-yl)amino)-1-oxopropan-2-yl)piperazin-1- yl)benzamide

[0303] To a solution of 2-(4-(3-cyanophenyl)piperazin-1-yl)-N-(5-(4-fluorophenoxy)pyridin- 2-yl)propanamide (70 mg, 0.157 mmol, 1.0 equiv) in DMSO (2 mL) was added K2CO3(65 mg, 0.471 mmol, 3.0 equiv) and 30% H2O2(2 mL) at rt. The resulting mixture was stirred for 2 h at rt. After completion of reaction, the reaction was quenched by ice water (10 mL) and extracted with EA (20 mL x 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue obtained was purified by silica gel chromatography (0-100% PE / EA) and Prep-HPLC using a Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm (eluent: 31% to 67% CH3CN and H2O with 10 mmol / L NH4HCO3) to afford 3-(4-(l-((5-(4-fluorophenoxy)pyridin-2-yl)amino)-1- oxopropan-2-yl)piperazin-1-yl)benzamide (2.7 mg, 3.69%) as a white solid. MS (ESI): mass calcd. for C25H26FN5O3: 463.20 m / z, found: 464.15 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 10.25 (s, 1H), 8.11 - 8.20 (m, 2H), 7.92 (s, 1H), 7.54 (dd, J = 9.0, 3.0 Hz, 1H), 7.16 - 7.32 (m, 5H), 7.04 - 7.16 (m, 3H), 3.52 (q, J = 6.8 Hz, 1H), 3.22 (d, J =5.1Hz, 4H), 2.61 - 2.79 (m, 4H), 1.24 (d, J = 6.8 Hz, 3H).19F NMR (376 MHz, DMSO-d6) δ - 119.1390.

[0304] Example 18: N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-(4-(6-oxo-5-(trifluoromethyl)-l,6- dihydropyridine-3-carbonyl)piperazin-1-yl)propanamide

[0305] Synthetic Scheme

[0306]

[0307] N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-(4-(6-methoxy-5-(trifluoromethyl)nicotinoyl)pipe razin- 1 -yl)propanamide

[0308] To a solution of N-[5-(4-fluorophenoxy)pyridin-2-yl]-2-(piperazin-1-yl)propanamide hydrochloride (200 mg, 0.581 mmol, 1.0 equiv) in pyridine (10 mL) was added 6-methoxy-5- (trifluoromethyl)nicotinic acid (154 mg, 0.697 mmol, 1.2 equiv) and EDCI (167 mg, 0.871 mmol, 1.5 equiv) at rt. The resulting mixture was stirred for 2 hours at rt. The reaction mixture was quenched by water (10 mL) and extracted with EA (20 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The residue obtained was purified by silica gel chromatography (0-10% DCM / MeOH) to give N-(5-(4- fluorophenoxy)pyridin-2-yl)-2-(4-(6-methoxy-5-(trifluoromethyl)nicotinoyl)piperazin- 1 - yl)propanamide (180 mg, 52.65%) as a yellow solid. MS (ESI): mass calcd. for C26H25F4N5O4: 547.18 m / z, found: 548.25 [M+H]+.

[0309] N-(5-(4-fluorophenoxy)pyridin-2-yI)-2-(4-(6-oxo-5-(trifluoromethyI)-l,6-dihydropyridin e-3-carbonyl)piperazin-1-yl)propanamide

[0310] To a solution of N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-(4-(6-methoxy-5- (trifluoromethyl)nicotinoyl)piperazin-1-yl)propanamide (200 mg, 0.365 mmol, 1.0 equiv) in DMF (7 mL) the mixture was added HBrPy (880 mg, 3.650 mmol, 10 equiv). The mixture was stirred at 100 °C for 2 h. After cooled to room temperature, the reaction was quenched by water (10 mL) and extracted with 5 : 1 DCM / MeOH (10 mL x 3). The combined organic extracts were washed with brine (5 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue obtained was purified by silica gel chromatography (0-20% DCM / MeOH) and Prep-HPLC using a column: XBridge Shield RP 18 OBD Column, 30*150 mm, 5μm; (eluent: 5% to 20% CH3CN and H2O with 10 mmol / L NH4HCO3) to afford N-(5-(4- fhiorophenoxy)pyridin-2-yl)-2-(4-(6-oxo-5-(trifluoromethyl)-l,6-dihydropyridine-3- carbonyl)piperazin-1-yl)propanamide (61.9 mg, 31.70%) as a white solid. MS (ESI): mass calcd. for C25H23F4N5O4: 533.17, found: 534.10 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 12.25 (br, 1H), 10.27 (s, 1H), 8.11 - 8.18 (m, 2H), 7.88 - 7.92 (m, 2H), 7.52 (dd, J = 9.0, 3.0 Hz, 1H), 7.19-7.23 (m , 2H), 7.08 (dd, J = 9.0, 4.5 Hz, 2H), 3.39-3.57 (m , 5H), 2.58 (tq, J = 11.7, 5.9, 5.2 Hz, 4H), 1.19 (d, J = 6.8 Hz, 3H).

[0311] Example 19: (R)-4-(4-(l-((5-(4-fluorophenoxy)pyridin-2-yl)amino)-1-oxopropan-2- yl)piperazine-1-carbonyl)pyridine 1-oxide and Example 20: (S)-4-(4-(l-((5-(4- fluorophenoxy)pyridin-2-yl)amino) - 1 -oxopropan- 2- yl) piperazine- 1 -carbonyl)pyridine 1 - oxide

[0312] (R)-4-(4-(l-((5-(4-fluorophenoxy)pyridin-2-yl)amino)-1-oxopropan-2-yl)piperazine-1- carbonyl)pyridine 1-oxide and (S)-4-(4-(l-((5-(4-fluorophenoxy)pyridin-2-yl)amino)-1- oxopropan-2-yl)piperazine-1-carbonyl)pyridine 1-oxide

[0313] 4-(4-( 1 -((5-(4-fluorophenoxy)pyridin-2-yl)amino)- 1 -oxopropan-2-yl)piperazine- 1 - carbonyl)pyridine 1-oxide was separated by Chiral-Prep-HPLC Column (CHIRALPAK ID, 2*25 cm, 5 μm; Mobile Phase A: MtBE(0.5% 2M NH3-MeOH)-HPLC, Mobile Phase B: IPA- -HPLC; Flow rate: 20 mL / min; Gradient: isocratic 50; Wave Length: 220 / 254 nm) to afford (R)-4-(4-(l-((5-(4-fluorophenoxy)pyridin-2-yl)amino)-1-oxopropan-2-yl)piperazine-1- carbonyl)pyridine 1-oxide (6.1 mg, first peak), MS (ESI): mass calcd. for C24H24FN5O4: 465.18 m / z, found: 466.10 [M+H]+,1H NMR (400 MHz, DMSO-d6) δ 10.26 (s, 1H), 8.21 - 8.28 (m, 2H), 8.10 - 8.17 (m, 2H), 7.53 (dd, J = 9.2, 2.9 Hz, 1H), 7.42 - 7.48 (m, 2H), 7.24 (t, J = 8.8 Hz, 2H), 7.05 - 7.14 (m, 2H), 3.42 - 3.63 (m, 5H), 2.53 - 2.68 (m, 4H), 1.20 (d, J = 6.9 Hz, 3H).19F NMR (376 MHz, DMSO-d6) S -119.856. and (S)-4-(4-(l-((5-(4- fluorophenoxy)pyridin-2-yl)amino)-1-oxopropan-2-yl)piperazine-1-carbonyl)pyridine 1- oxide (2.8 mg, second peak), MS (ESI): mass calcd. for C24H24FN5O4: 465.18 m / z, found: 466.10 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 10.26 (s, 1H), 8.21 - 8.28 (m, 2H), 8.10 - 8.17 (m, 2H), 7.53 (dd, J = 9.2, 2.9 Hz, 1H), 7.42 - 7.48 (m, 2H), 7.24 (t, J = 8.8 Hz, 2H), 7.05 - 7.14 (m, 2H), 3.42 - 3.63 (m, 5H), 2.53 - 2.68 (m, 4H), 1.20 (d, J = 6.9 Hz, 3H).19F NMR (376 MHz, DMSO-d6) δ -119.856.

[0314] Example 21: 2-(4-(2-chloro-6-oxo-l,6-dihydropyridine-3-carbonyl)piperazin-1-yl)-N-(5- (4-fluorophenoxy)pyridin-2-yl)propanamide

[0315] 2-(4-(2-chloro-6-oxo-l,6-dihydropyridine-3-carbonyl)piperazin-1-yl)-N-(5-(4- fluorophenoxy)pyridin-2-yl)propanamide

[0316] To a solution of N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-(piperazin-1-yl)propanamide (119 mg, 0.346 mmol, 1.2 equiv) in Py (3 mL) was added 2-chloro-6-oxo-l,6-dihydropyridine- 3-carboxylic acid (50 mg, 0.288 mmol, 1.0 equiv) and EDO (83 mg, 0.432 mmol, 1.5 equiv). The mixture was stirred at room temperature for 5 h. The reaction mixture was quenched by water (10 mL) and extracted with 5:1 DCM / MeOH (10 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The residue obtained was purified by silica gel chromatography (0-20% DCM / MeOH) and Prep-HPLC using a column: Column: XBridge Shield RP 18 OBD Column, 30*150 mm, 5.0 μm (eluent: 21% to 51% (v / v) CH3CN and H2O with 10 mmol / L NH4HCO3+0.1%NH3.H2O) to afford 2- (4-(2-chloro-6-oxo-l,6-dihydropyridine-3-carbonyl)piperazin-1-yl)-N-(5-(4- fluorophenoxy)pyridin-2-yl)propanamide (21.5 mg, 14.90%) as a white solid. MS (ESI): mass calcd. for C24H23CIFN5O4: 499.14 m / z, found: 500.05 [M+H]+.1H NMR (400 MHz, DMSO- t / 6) 8 10.28 (s, 1H), 8.10 - 8.17 (m, 2H), 7.61 (d, J = 8.2 Hz, 1H), 7.53 (dd, J = 9.0, 3.0 Hz, 1H), 7.19 - 7.29 (m, 2H), 7.04 - 7.14 (m, 2H), 6.62 (d, J = 8.3 Hz, 1H), 3.58 - 3.64 (m, 2H), 3.46 - 356 (m, 1H), 3.17 - 3.42 (m,2H), 2.52 - 2.71 (m, 4H), 1.18 (d, J = 6.9 Hz, 3H).19F NMR (376 MHz, DMSO-d6) δ -119.86.

[0317] Example 22: N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-(4-(6-oxo-4-(trifluoromethyl)-l,6- dihydropyridine-3-carbonyl)piperazin-1-yl)propanamide

[0318] N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-(4-(6-oxo-4-(trifluoromethyl)-l,6- dihydropyridine-3-carbonyl)piperazin-1-yl)propanamide

[0319] To a solution of N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-(piperazin-1-yl)propanamide (100 mg, 0.289 mmol, 1.2 equiv) in Py (3 mL) was added a solution of 6-oxo-4- (trifluoromethyl)-l,6-dihydropyridine-3-carboxylic acid (50 mg, 0.241 mmol, 1.0 equiv) and EDCI (69 mg, 0.361 mmol, 1.5 equiv). The mixture was stirred at room temperature for 3 h. The reaction mixture was quenched by water (10 mL) and extracted with 5:1 DCM / MeOH (10 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The residue obtained was purified by silica gel chromatography (0-100% PE / EA) and Prep-HPLC using a column: Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm (eluent: 26% to 56% (v / v) CH3CN and H2O with 10 mmol / L NH4HCO3) to afford N-(5-(4- fhiorophenoxy)pyridin-2-yl)-2-(4-(6-oxo-4-(trifluoromethyl)-l,6-dihydropyridine-3- carbonyl)piperazin-1-yl)propanamide (32.7 mg, 25.31%) as a white solid. MS (ESI): mass calcd. for C25H23F4N5O4: 533.17 m / z, found: 534.10 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 12.34 (s, 1H), 10.27 (s, 1H), 8.10 - 8.17 (m, 2H), 7.70 (s, 1H), 7.53 (dd, J = 8.9, 3.0 Hz, 1H), 7.19 - 7.30 (m, 2H), 7.04 - 7.14 (m, 2H), 6.79 (s, 1H), 3.66 - 3.70 (m, 1H), 3.51 (q, J = 6.8 Hz, 1H), 3.32 - 3.43 (m, 3H), 2.54 - 2.76 (m, 4H), 1.18 (d, J = 6.9 Hz, 3H).19F NMR (376 MHz, DMSO-d6) δ -62.26, -119.86.

[0320] Example 23: 4-(4-(l-((5-(4-fluorophenoxy)pyridin-2-yl)amino)-1-oxopropan-2- yI)piperazine-1-carbonyI)-3-(trifluoromethyI)pyridine 1-oxide

[0321] Synthetic Scheme

[0322] 4-carboxy-3-(trifluoromethyl)pyridine 1-oxide

[0323] To a solution of 3-(trifluoromethyl)isonicotinic acid (300 mg, 0.244 mmol, 1.0 equiv) in HOAc (3 mL) was added 30% H2O2(0.6 mL) at 0 °C. The resulting mixture was stirred for 4 h at 80 °C. After cooled to room temperature, the mixture was purified by C18 column to afford 4-carboxy-3-(trifluoromethyl)pyridine 1-oxide as a white solid. MS (ESI): mass calcd. for C7H4F3NO3: 207.108 m / z, found: 208.00 [M+H]+.

[0324] 4-(4-(l-((5-(4-fluorophenoxy)pyridin-2-yl)amino)-1-oxopropan-2-yl)piperazine-1- carbonyI)-3-(trifluoromethyI)pyridine 1-oxide

[0325] To a solution of 4-carboxy-3-(trifluoromethyl)pyridine 1-oxide (100 mg, 0.483 mmol, 1.0 equiv) in Py (3 mL) was added N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-(piperazin-1- yl)propanamide (166 mg, 0.483 mmol, 1.0 equiv) and EDCI (138 mg, 0.724 mmol, 1.5 equiv) at rt. The resulting mixture was stirred for 3 h at rt. The reaction mixture was quenched by water (10 mL) and extracted with EA (20 mL x 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated under vacuum to yield a crude product which was directly purified by Cl 8 column to afford 4-(4-(l- ((5-(4-fluorophenoxy)pyridin-2-yl)amino)- 1 -oxopropan-2-yl)piperazine- 1 -carbonyl)-3- (trifluoromethyl)pyridine 1-oxide as a white solid. MS (ESI): mass calcd. for C25H23F4N5O4: 533.484 m / z, found 534.15 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 10.29 (s, 1H), 8.75 (d, J = 1.7 Hz, 1H), 8.48 - 8.55 (m, 1H), 8.09 - 8.17 (m, 2H), 7.50 - 7.62 (m, 2H), 7.19 - 7.30 (m, 2H), 7.04 - 7.14 (m, 2H), 3.71 (s, 1H), 3.48 - 3.59 (m, 2H), 3.25 - 3.27 (m, 2H), 2.65 - 2.75 (m, 2H), 2.30 - 2.39 (m, 2H), 1.15 - 1.21 (m, 3H).19F NMR (376 MHz, DMSO-d6) δ -59.64, -119.85.

[0326] Example 24: 4-(4-(l-((5-(4-fluorophenoxy)pyridin-2-yl)amino)-1-oxopropan-2- yl)piperazine-1-carbonyl)-2-(2,2,2-trifluoroethyl)pyridine 1-oxide Synthetic Scheme methyl 2-(2,2,2-trifluoro-1-hydroxyethyl)isonicotinate

[0327] To a solution of methyl 2-formylisonicotinate (1.0 g, 6.06 mmol, 1.0 equiv) in THF (15 mL) was added trimethyl(trifluoromethyl)silane (1.7 g, 12.12 mmol, 2.0 equiv) and CsF (1.8 g, 12.12 mmol, 2.0 equiv) at 0 °C. The resulting mixture was stirred for 16 h at rt under N2. The reaction mixture was quenched by water (30 mL) and extracted with EA (30 mL x 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated under vacuum to yield a crude product which was directly purified by flash chromatography to afford crude product as a white solid. MS (ESI): mass calcd. for C9H8F3NO3: 235.162 m / z, found 236.15 [M+H]+. methyl 2-(2,2,2-trifluoro-1-((methylsulfonyl)oxy)ethyl)isonicotinate

[0328] To a solution of methyl 2-(2,2,2-trifluoro-1-hydroxyethyl)isonicotinate (400 mg, 1.701 mmol, 1.0 equiv) in DCM (5 mL) was added TEA (516 mg, 5.103 mmol, 3.0 equiv) and methanesulfonylmethanesulfonylmethane (439 mg, 2.551 mmol, 1.5 equiv) at rt. The resulting mixture was stirred for overnight rt. The reaction mixture was quenched by water (10 mL) and extracted with EA (20 mL x 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated under vacuum to yield a crude product which was directly purified by flash chromatography (5-60% PE / EA) to afford methyl 2-(2,2,2-trifluoro-1-((methylsulfonyl)oxy)ethyl)isonicotinate as yellow oil. MS (ESI): mass calcd. for C10H10F3NO5S: 313.25 m / z, found 314.10 [M+H]+. methyl 2-(2,2,2-trifluoroethyl)isonicotinate

[0329] To a solution of methyl 2-(2,2,2-trifluoro-1-((methylsulfonyl)oxy)ethyl)isonicotinate (160 mg, 0.511 mmol, 1.0 equiv) in toluene (5 mL) was added AIBN (17 mg, 0.102 mmol, 0.2 equiv) and tributylstannane (223 mg, 0.766 mmol, 1.5 equiv) at rt. The resulting mixture was stirred for 5 h at 80 °C. After cooled to room temperature, the reaction mixture was quenched by water (10 mL) and extracted with EA (20 mL x 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated under vacuum to yield a crude product which was directly purified by flash chromatography to (5- 60% PE / EA) to afford methyl 2-(2,2,2-trifluoroethyl)isonicotinate as a white solid. MS (ESI): mass calcd. For: C9H8F3NO2: 219.163 m / z, found: 220.15 [M+H]+.

[0330] 2-(2,2,2-trifluoroethyl)isonicotinic acid

[0331] To a solution of methyl 2-(2,2,2-trifluoroethyl)isonicotinate (60 mg, 0.274 mmol, 1.0 equiv) in THF / McOH / lLC) (1 mL / 1 mL / 1 mL) was added LiOH (65 mg, 2.740 mmol, 10.0 equiv) at rt. The mixture was stirred for 3 h at rt. The mixture was adjusted to pH 4~5 with 2N HC1. The resulting solution was extracted with EA (30 mL x 3) and concentrated under vacuum. The crude product was used in the next step directly without further purification. MS (ESI): mass calcd. for C9H8F3NO2: 205.136 m / z, found: 206.00 [M+H]+.

[0332] 4-carboxy-2-(2,2,2-trifluoroethyl)pyridine 1-oxide

[0333] To a solution of 2-(2,2,2-trifluoroethyl)isonicotinic acid (50 mg, 0.244 mmol, 1.0 equiv) in HOAc (2 mL) was added 30% H2O2(0.4 mL) at rt . The resulting mixture was stirred for 3 h at 80 °C. After cooled to room temperature, the reaction was concentrated under vacuum and purified by C18 column to afford 4-carboxy-2-(2,2,2-trifluoroethyl)pyridine 1- oxide as a white solid. MS (ESI): mass calcd. For: C8H6F3NO3: 221.14 m / z, found: 222.05 [M+H]+.

[0334] 4-(4-(l-((5-(4-fluorophenoxy)pyridin-2-yl)amino)-1-oxopropan-2-yl)piperazine-1- carbonyI)-2-(2,2,2-trifluoroethyI)pyridine 1-oxide

[0335] To a solution of 4-carboxy-2-(2,2,2-trifluoroethyl)pyridine 1-oxide (50 mg, 0.226 mmol, 1.0 equiv) in Py (3 mL) was added N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-(piperazin- l-yl)propanamide (78 mg, 0.226 mmol, 1 equiv) and EDO (87 mg, 0.452 mmol, 2.0 equiv) at rt .The resulting mixture was stirred for 3 h at rt. The reaction mixture was quenched by water (10 mL) and extracted with EA (20 mL x 3). The combined organic extracts were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered and concentrated under vacuum to yield a crude product which was directly purified by flash chromatography & Cl 8 column to afford 4- (4-( 1 -((5-(4-fluorophenoxy)pyridin-2-yl)amino)- 1 -oxopropan-2-yl)piperazine- 1 -carbonyl)-2- (2,2,2-trifluoroethyl)pyridine 1-oxide as a white solid. MS (ESI): mass calcd. for C26H25F4N5O4: 547.511 m / z, found: 548.15 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 10.26 (s, 1H), 8.39 (d, J = 6.7 Hz, 1H), 8.10 - 8.17 (m, 2H), 7.67 (d, J = 2.4 Hz, 1H), 7.45 - 7.56 (m, 2H), 7.18 - 7.28 (m, 2H), 7.05 - 7.12 (m, 2H), 4.02 - 4.05 (m, 2H), 3.32 - 3.68 (m, 5H), 2.52 - 2.68 (s, 4H), 1.19 (d, J = 6.9 Hz, 3H).19F NMR (376 MHz, DMSO-d6) δ -62.54, -119.86. Example 25: 2-(4-(4-chloro-6-oxo-l,6-dihydropyridine-3-carbonyl)piperazin-1-yl)-N-(5- (4-fluorophenoxy)pyridin-2-yl)propanamide

[0336] 2-(4-(4-chloro-6-methoxynicotinoyl)piperazin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2- yl)propanamide

[0337] To a solution of N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-(piperazin-1-yl)propanamide (100 mg, 0.290 mmol, 1.0 equiv) in Py (3 mL) was added 4-chloro-6-methoxynicotinic acid (54 mg, 0.290 mmol, 1.0 equiv) and EDO (111 mg, 0.580 mmol, 2.0 equiv) at rt. The resulting mixture concentrated under vacuum and purified by silica gel column to afford 2-(4-(4-chloro- 6-methoxynicotinoyl)piperazin- l-yl)-N-(5-(4- fluorophenoxy )pyridin-2-yl)propanamide as a white solid. MS (ESI): mass calcd. for C25H25CIFN5O4: 513.95 m / z, found: 514.20 [M+H]+.

[0338] 2-(4-(4-chloro-6-oxo-l,6-dihydropyridine-3-carbonyl)piperazin-1-yl)-N-(5-(4- fluorophenoxy)pyridin-2-yl)propanamide

[0339] To a solution of 2-(4-(4-chloro-6-methoxynicotinoyl)piperazin-1-yl)-N-(5-(4- fluorophenoxy)pyridin-2-yl)propanamide (190 mg, 0.370 mmol, 1.0 equiv) in DMF (5 mL) was added Pyridine hydrobromide (591 mg, 3.700 mmol, 10.0 equiv) at rt. The resulting mixture was stirred for 3 h at 100 °C. After cooled to room temperature, the reaction mixture was quenched by water (10 mL) and extracted with EA (20 mL x 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated under vacuum to yield a crude product which was directly purified by Cl 8 column to afford 2-(4-(4-chloro-6-oxo-l,6-dihydropyridine-3-carbonyl)piperazin-1-yl)-N-(5-(4- fluorophenoxy)pyridin-2-yl)propanamide (60 mg, 32.43% )as a white solid. MS (ESI): mass calcd. for C24H23CIFN5O4: 499.93 m / z, found: 500.05 [M+H]+.1H NMR (300 MHz, DMSO- d6δ 12.08 (s, 1H), 10.27 (s, 1H), 8.09 - 8.18 (m, 2H), 7.60 (s, 1H), 7.49 - 7.56 (m, 1H), 7.17 - 7.31 (m, 2H), 7.03 - 7.16 (m, 2H), 6.56 (s, 1H), 3.62 (s, 2H), 3.48 - 3.56 (m, 1H), 3.48 - 3.40 (m, 2H), 2.53 - 2.56 (m, 4H), 1.19 (d, J = 6.8 Hz, 3H).19F NMR (282 MHz, DMSO-d6) δ -119.85.

[0340] Example 26: 4-(4-(l-((5-(4-fluorophenoxy)pyridin-2-yl)amino)-1-oxopropan-2- yl)piperazine-1-carbonyl)-2-(trifluoromethyl)pyridine 1-oxide

[0341] 4-(methoxycarbonyl)-2-(trifluoromethyl)pyridine 1-oxide

[0342] In a 50-mL round bottom flask, to a solution of methyl 2-(trifluoromethyl)isonicotinate (500 mg, 2.437 mmol, 1.0 equiv) in HOAc (8 mL) was added H2O2(2 mL) at rt. The resulting mixture was stirred for 2 hours at 80 °C. After cooled to room temperature, the reaction was quenched with water (10 mL) and extracted with EA (30 mL x 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous Na2SO4, and concentrated under vacuum to yield a crude product which was directly purified by flash chromatography (0-10% DCM / MeOH) to afford 4-(methoxycarbonyl)-2-(trifluoromethyl)pyridine 1-oxide (150 mg, 27.83%) as a yellow solid. MS (ESI): mass calcd. for C8H6F3NO3: 221.11 m / z, found: 222.00 [M+H]+.

[0343] 4-carboxy-2-(trifluoromethyl)pyridine 1-oxide

[0344] In a 50-mL round bottom flask, to a solution of 4-(methoxycarbonyl)-2- (trifluoromethyl)pyridine 1-oxide (150 mg, 0.678 mmol, 1.0 equiv) in MeOH (1 mL), THF (3 mL) and H2O (1 mL) was added LiOH (48 mg, 2.034 mmol, 3.0 equiv) at rt. The reaction mixture was stirred for 4 h at rt. The mixture was acidified to pH = 5 with 4 N HC1. The mixture was concentrated under vacuum and purified by Cl 8 Column (Mobile Phase A: Water (0.05% HCOOH), Mobile Phase B: ACN; Gradient: 5% B to 70% B) to afford 4-carboxy-2- (trifluoromethyl)pyridine 1-oxide (80 mg, 56.95%) as a yellow solid. MS (ESI): mass calcd. for:C8H6F3NO3: 221.11 m / z, found: 222.00 [M+H]+.

[0345]

[0346] 4-(4-(l-((5-(4-fluorophenoxy)pyridin-2-yl)amino)-1-oxopropan-2-yl)piperazine-1- carbonyl)-2-(trifluoromethyl)pyridine 1-oxide

[0347] To a solution of 4-carboxy-2-(trifluoromethyl)pyridine 1-oxide (100 mg, 0.483 mmol, 1.0 equiv) in Pyridine (5 mL) was added N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-(piperazin-1- yl)propanamide (166 mg, 0.483 mmol, 1.0 equiv) and EDCI (139 mg, 0.724 mmol, 1.5 equiv) at rt. The resulting mixture was stirred for 2 h at rt. The reaction was quenched with H2O (10 mL) at rt. The resulting mixture was extracted with EA (30 mL x 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue obtained was purified by flash chromatography (0-20% DCM / MeOH) and Prep-HPLC using a Column: XBridge Prep OBD Cl 8 Column, 30*150 mm, 5μm (eluent: 26% to 56% CH3CN and H2O with 10 mmol / L NH4HCO3) to afford 4-(4- ( 1 -((5 -(4-fluorophenoxy)pyridin-2-yl)amino)- 1 -oxopropan-2-yl)piperazine- 1 -carbonyl)-2- (trifhioromethyl)pyridine 1-oxide (22.4 mg, 8.67%) as a white solid. MS (ESI): mass calcd. for: C25H23F4N5O4: 533.14 m / z, found: 534.10 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 10.26 (s, 1H), 8.48 (d, J = 6.7 Hz, 1H), 8.13 (dd, J= 6.0, 2.9 Hz, 2H), 7.97 (d, J = 2.4 Hz, 1H), 7.73 (dd, J = 6.7, 2.5 Hz, 1H), 7.52 (dd, J = 9.1, 2.9 Hz, 1H), 7.18 - 7.29 (m, 2H), 7.04 - 7.13 (m, 2H), 3.30 - 3.67 (m, 5H), 2.59 - 2.64 (m, 4H), 1.19 (d, J = 6.9 Hz, 3H).19F NMR (376 MHz, DMSO-d6) δ -67.708, -119.860.

[0348] Example 27: N-(5-(4-chlorophenoxy)pyridin-2-yl)-2-(4-(6-oxo-l,6-dihydropyridine-3- carbonyl)piperazin- 1 -yl)propanamide

[0349] Synthetic Scheme

[0350]

[0351] 5-(4-chlorophenoxy)pyridin-2-amine

[0352] To a stirred solution of 4-chlorophenol (2 g, 15.557 mmol, 1.2 equiv) in dioxane (70 mL) was added dimethylglycine (0.13 g, 1.296 mmol, 0.1 equiv) and 5-bromopyridin-2-amine (2.24 g, 12.964 mmol, 1.0 equiv) and CS2CO3(6.34 g, 19.446 mmol, 1.5 equiv) followed by catalytic amount of Cui (0.49 g, 2.593 mmol, 0.2 equiv) at room temperature. The reaction mixture was stirred at 110 °C overnight under N2. After cooled to room temperature, the reaction was quenched by water (50 mL) and extracted with EA (70 mL x 3). The combined organic extracts were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue obtained was purified by silica gel chromatography (35- 50% PE / EA) to afford 5-(4-chlorophenoxy)pyridin-2-amine (1 g, 22.72%) as a yellow solid. MS (ESI): mass calcd. for: C11H9CIN2O: 220.04 m / z, found: 221.15 [M+H]+.

[0353] 2-bromo-N-(5-(4-chlorophenoxy)pyridin-2-yl)propanamide To a stirred solution of 5-(4-chlorophenoxy)pyridin-2-amine (1 g, 4.532 mmol, 1.0 equiv) in DCM (20 mL) was added 2-bromopropanoic acid (0.83 g, 5.438 mmol, 1.2 equiv), DCC (1.12 g, 5.438 mmol, 1.2 equiv) and AgNO3(0.12 g, 0.680 mmol, 0.15 equiv). The reaction mixture was stirred at room temperature for a period of overnight. After completion of reaction, the reaction was quenched by water (20 mL) and extracted with DCM (30 mL x 3). The combined organic extracts were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue obtained was purified by silica gel chromatography (0-20% PE / EA) to afford 2-bromo-N-(5-(4-chlorophenoxy)pyridin-2- yl)propanamide (1.1 g, 67.56%) as a pink solid. MS (ESI): mass calcd. for: C14H12BrClN2O2: 353.98 m / z, found: 355.05 [M+H]+. tert-butyl 4-(l-((5-(4-chlorophenoxy)pyridin-2-yl)amino)-1-oxopropan-2-yl)piperazine- 1-carboxylate

[0354] To a stirred solution of 2-bromo-N-[5-(4-chlorophenoxy)pyridin-2-yl]propanamide (520 mg, 1.462 mmol, 1.0 equiv) in anhydrous DMF (5 mL) was added tert-butyl piperazine- 1-carboxylate (326 mg, 1.754 mmol, 1.2 equiv) and TEA (888 mg, 8.772 mmol, 6.0 equiv). The reaction mixture was stirred at 50 °C for 5 h. After cooled to room temperature the reaction was quenched by water (30 mL) and extracted with EA (30 mL x 3). The combined organic extracts were washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue obtained was purified by silica gel chromatography (30-50% PE / EA) to afford tert-butyl 4-(l-{ [5-(4-chlorophenoxy)pyridin-2-yl]carbamoyl}ethyl)piperazine-1- carboxylate (570 mg, 84.07%) as a colorless oil. MS (ESI): mass calcd. for:C23H29QN4O4: 460.19 m / z, found: 461.30 [M+H]+.

[0355]

[0356] N-(5-(4-chlorophenoxy)pyridin-2-yl)-2-(piperazin-1-yl)propanamide

[0357] To a stirred solution of tert-butyl 4-(l-{ [5-(4-chlorophenoxy)pyridin-2- yl] carbamoyl }ethyl)piper azine- 1 -carboxylate (520 mg, 1.128 mmol, 1.0 equiv) in anhydrous EA (6 mL) was added hydrogen chloride (4M in EA, 1.0 mL). The reaction mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure to afford N-(5-(4-chlorophenoxy)pyridin-2-yl)-2-(piperazin-1-yl)propanamide (400 mg, 97.32%). MS (ESI): mass calcd. for: C18H21CIN4O2: 360.14 m / z, found: 361.20 [M+H]+.

[0358] N-(5-(4-chlorophenoxy)pyridin-2-yl)-2-(4-(6-oxo-l,6-dihydropyridine-3- carbonyl)piperazin- 1 -yl)propanamide

[0359] To a stirred solution of N-[5-(4-chlorophenoxy)pyridin-2-yl]-2-(piperazin-1- yl)propanamide (100 mg, 0.277 mmol, 1.0 equiv) in pyridine (2 mL) was added 6-oxo-lH- pyridine-3-carboxylic acid (46 mg, 0.332 mmol, 1.2 equiv) and EDO (80 mg, 0.416 mmol, 1.5 equiv) at room temperature. The reaction mixture was stirred at room temperature overnight. After completion of reaction, the reaction was quenched by water (20 mL) and extracted with EA (20 mL x 3). The combined organic extracts were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue obtained was purified by silica gel chromatography (5-60% PE / EA) and Prep-HPLC using a Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm (eluent: 29% to 59% CH3CN and H2O with 10 mmol / L NH4HCO3) to afford N-(5-(4-chlorophenoxy)pyridin-2-yl)-2-(4-(6-oxo-l,6- dihydropyridine-3-carbonyl)piperazin-1-yl)propanamide (9.1 mg, 6.81%) as a white solid. MS (ESI): mass calcd. for: : 482.15 m / z, found: 482.15 [M+H]+.1H NMR (300 MHz, DMSO-d6) δ 11.85 (s, 1H), 10.30 (s, 1H), 8.12 - 8.22 (m, 2H), 7.54 - 7.64 (m, 2H), 7.38 - 7.52 (m, 3H), 7.00 - 7.11 (m, 2H), 6.34 (d, J = 9.4 Hz, 1H), 3.50 - 3.55 (m, 5H), 2.55 - 2.59 (m, 4H), 1.19 (d, J = 6.8 Hz, 3H).

[0360] Example 28: 2-chloro-4-(4-(l-((5-(4-fluorophenoxy)pyridin-2-yl)amino)-1-oxopropan-2- yl) piperazine- 1 -carbonyl)pyridine 1 -oxide

[0361] 2-chloro-4-(methoxycarbonyl)pyridine 1-oxide

[0362] To a solution of methyl 2-chloroisonicotinate (500 mg, 2.914 mmol, 1.0 equiv) in DCM (5 mL) was added m-CPBA (1.51 g, 8.742 mmol, 3.0 equiv) at 0 °C. The resulting mixture was stirred for 3 h at rt. After completion of reaction, the reaction mixture was quenched by addition of water (10 mL). The aqueous layer was extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue obtained was purified by silica gel chromatography (0-100% PE / EA) to afford 2-chloro-4-(methoxycarbonyl)pyridine 1-oxide (370 mg, 67.69%) as yellow oil. MS (ESI): mass calcd. for C7H6CINO3: 187.00 m / z, found: 188.00 [M+H]+.

[0363] 4-carboxy-2-chloropyridine 1 -oxide

[0364] To a solution of 2-chloro-4-(methoxycarbonyl)pyridine 1-oxide (180 mg, 0.960 mmol, 1.0 equiv) in tetrahydrofuran (1 mL), water (1 mL) and methanol (1 mL) was added LiOH (69 mg, 2.880 mmol, 3.0 equiv). The resulting mixture was stirred for 2 h at rt. The mixture was acidified pH = 5 with HC1 (IN). The resulting mixture was concentrated under vacuum and purified by C18 column to afford (120 mg, 72.06%) as a yellow solid. MS (ESI): mass calcd. for C6H4CINO3: 172.99 m / z, found: 174.10 [M+H]+. 2-chloro-4-(4-(l-((5-(4-fluorophenoxy)pyridin-2-yl)amino)-1-oxopropan-2-yl)piperazine- l-carbonyl)pyridine 1 -oxide

[0365] To a solution of 4-carboxy-2-chloropyridine 1-oxide (150 mg, 0.864 mmol, 1.0 equiv) in pyridine (5 mL) in Py (3 mL) was added N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-(piperazin- l-yl)propanamide (149 mg, 0.432 mmol, 0.5 equiv) and EDO (331 mg, 1.728 mmol, 2.0 equiv) at rt. The resulting mixture was stirred for 2 h at rt. The resulting mixture was purified by C18 column & Prep-HPLC using for a Column: YMC Triart C18 ExRs Column, 30*150mm, 5μm (eluent: 27% to 57% (v / v) CH3CN and H2O with 10 mmol / L NH4HCO3) to afford 2-chloro-4-(4-( 1 -((5-(4-fhiorophenoxy)pyridin-2-yl)amino)- 1 -oxopropan-2- yl)piperazine-1-carbonyl)pyridine 1-oxide (13.4 mg, 6.20%) as a white solid. MS (ESI): mass calcd. for C24H23CIFN5O4: 499.14 m / z, found: 500.10 [M+H]+.1H NMR (300 MHz, DMSO- d6) δ 10.28 (s, 1H), 8.47 (d, J = 6.7 Hz, 1H), 8.14 (dd, J = 6.0, 2.9 Hz, 2H), 7.89 (d, J = 2.4 Hz, 1H), 7.53 (dd, J = 9.1, 2.9 Hz, 1H), 7.45 (dd, J = 6. , 2.4 Hz, 1H), 7.17 - 7.30 (m, 2H), 7.02 - 7.16 (m, 2H), 3.34 - 3.68 (m, 5H), 2.54 - 2.65 (4H), 1.19 (d, J = 6.8 Hz, 3H).19H NMR (282 MHz, DMSO-d6) δ -119.847.

[0366] Example 29: N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-(8-(6-oxo-l,6-dihydropyridine-3- carbonyI)-3,8-diazabicycIo[3.2.1]octan-3-yI)propanamide

[0367] Synthetic Scheme tert-butyl 8-(6-oxo-l,6-dihydropyridine-3-carbonyl)-3,8-diazabicyclo[3.2.1]octane-3- carboxylate

[0368] To a solution of tert-butyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate (500 mg, 2.355 mmol, 1.0 equiv) in pyridine (5 mL) the mixture was added 6-oxo-lH-pyridine-3-carboxylic acid (327 mg, 2.355 mmol, 1.0 equiv) and EDO (677 mg, 3.532 mmol, 1.5 equiv) at rt. The resulting mixture was stirred for 3 h at rt. The reaction mixture was quenched by water (30 mL) and extracted with EA (30 mL x 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated under vacuum to yield a crude product which was directly purified by silica gel column (0-80% PE / EA) to afford tert- butyl 8-(6-oxo-l,6-dihydropyridine-3-carbonyl)-3,8-diazabicyclo[3.2.1]octane-3- carboxylate as yellow oil. MS (ESI): mass calcd. for C17H23N3O4: 333.17 m / z, found: 334.25 [M+H]+.

[0369] 5-(3,8-diazabicyclo[3.2.1]octane-8-carbonyl)pyridin-2(lH)-one

[0370] To a solution of tert-butyl 8-(6-oxo-l,6-dihydropyridine-3-carbonyl)-3,8- diazabicyclo[3.2.1]octane-3-carboxylate (200 mg, 0.600 mmol, 1.0 equiv) in DCM (10 mL) was added TFA (10 mL). The resulting mixture was stirred for 2 hours at rt. The solvent was removed to give 5-(3,8-diazabicyclo[3.2.1]octane-8-carbonyl)pyridin-2(lH)-one as yellow solid. MS (ESI): mass calcd. for C12H15N3O2: 233.12 m / z, found: 234.20 [M+H]+.

[0371] N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-(8-(6-oxo-l,6-dihydropyridine-3-carbonyl)-3,8- diazabicyclo[3.2.1]octan-3-yl)propanamide

[0372] To a solution of 5-(3,8-diazabicyclo[3.2.1]octane-8-carbonyl)pyridin-2(lH)-one (100 mg, 0.429 mmol, 1.0 equiv) in DMA (10 mL) was added 2-bromo-N-(5-(4- fluorophenoxy)pyridin-2-yl)propanamide (145 mg, 0.429 mmol, 1.0 equiv) and TEA (130 mg, 1.287 mmol, 3.0 equiv) at rt. The resulting mixture was stirred for 2 hours at 60 °C. The reaction mixture was quenched by water (10 mL) and extracted with EA (20 mL x 3). The combined organic extracts were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered and concentrated under vacuum to yield a crude product which was directly purified by Column: XBridge Prep OBD Cl 8 Column, 30*150 mm, 5μm; Mobile Phase A: Water(10mmol / L NH4HCO3+0.05%NH3H2O), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 29% B to 45% B in 10 min to afford N-(5-(4-fluorophenoxy)pyridin-2-yl)- 2-(8-(6-oxo-l,6-dihydropyridine-3-carbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)propanamide (18.7 mg, 8.79%) as a white solid. MS: mass calcd. for C26H26FN5O4: 491.20, found: 492.10 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 11.86 (s, 1H), 10.16 (s, 1H), 8.19 - 8.10 (m, 2H), 7.63 (d, J = 2.5 Hz, 1H), 7.54 (ddd, J = 9.0, 7.9, 2.8 Hz, 2H), 7.28 - 7.19 (m, 2H), 7.13 - 7.05 (m, 2H), 6.35 (d, J = 9.5 Hz, 1H), 4.34 - 4.38 (m, 2H), 3.44 (d, J = 7.1 Hz, 1H), 2.68 - 2.76 (m, 2H), 2.51 - 2.58 (m, 2H), 1.89 - 1.98 (m, 2H), 1.78 - 1.85 (m, 2H), 1.17 (d, J = 6.9 Hz, 3H).

[0373] Example 30: N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-(4-(5-oxo-1-(2,2,2-trifluoroethyl)- 2,5-dihydro-lH-pyrrole-3-carbonyl)piperazin-1-yl)propanamide dimethyl 2-(bromomethyl)fumarate

[0374] To a solution of dimethyl 2-methylfumarate (1 g, 6.323 mmol, 1.0 equiv) in carbon tetrachloride (20 mL) was added NBS (1.68 g, 9.485 mmol, 1.5 equiv) and AIBN (21 mg, 0.126 mmol, 0.02 equiv). The mixture was stirred at 75 °C for 4 h. After cooled to room temperature, the mixture was filtered and the filtrate was concentrated in vacuo. The resulting residue was purified by silica gel chromatography (0-10% PE / EA) to give dimethyl 2- (bromomethyl)fumarate (1.2 g, 80.06%) as colorless oil. methyl 5-oxo-1-(2,2,2-trifluoroethyl)-2,5-dihydro-lH-pyrrole-3-carboxylate

[0375] To a solution of dimethyl 2-(bromomethyl)fumarate (100 mg, 0.422 mmol, 1.0 equiv) in CH3CN (10 mL) was added 2,2, 2-trifluoroethan- 1 -amine hydrochloride (68 mg, 0.506 mmol, 1.2 equiv) and DIEA (82 mg, 0.633 mmol, 1.5 equiv). The reaction was stirred at 80 °C for 6 h. After cooled to room temperature, the reaction was quenched by water (10 mL) and extracted with EA (10 mL x 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue obtained was purified by silica gel chromatography (0-30% PE / EA) to afford methyl 5-oxo-1-(2,2,2- trifluoroethyl)-2,5-dihydro-lH-pyrrole-3-carboxylate (60 mg, 63.74%) as a pink solid. MS (ESI): mass calcd. for C8H8F3NO3: 223.05 m / z, found: 224.15 [M+H]+.

[0376] N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-(4-(5-oxo-1-(2,2,2-trifluoroethyl)-2,5-dihydro-lH- pyrrole-3-carbonyl)piperazin-1-yl)propanamide

[0377] To a solution of methyl 5-oxo-1-(2,2,2-trifluoroethyl)-2,5-dihydro-lH-pyrrole-3- carboxylate (60 mg, 0.269 mmol, 1.0 equiv) in toluene (10 mL) was added trimethylaluminium (2M, in toluene, 0.538 mmol, 2 equiv) at 0 °C. The reaction was stirred at 100 °C for 4 h. After cooled to room temperature the reaction, the reaction was quenched by ice water (5 mL) and extracted with EA (10 mL x 3). The combined organic extracts were washed with brine (5 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue obtained was purified by silica gel chromatography (0-25% DCM / MeOH) and Prep- HPLC using a Column: YMC Triart C18 ExRs Column, 30*150mm, 5μm; (eluent: 31% to 61% (v / v) CH3CN and H2O with lOmmol / L NH4HCO3) to afford N-(5-(4- fhiorophenoxy)pyridin-2-yl)-2-(4-(5-oxo-1-(2,2,2-trifluoroethyl)-2,5-dihydro-lH-pyrrole-3- carbonyl)piperazin-1-yl)propanamide (14.7 mg, 6.10%) as a white solid. MS (ESI): mass calcd. for C25H25F4N5O4: 535.18 m / z, found: 536.15 [M+H]+,1H NMR (300 MHz, DMSO-d6) 3 10.28 (d, J = 3.3 Hz, 1H), 8.14 (dd, J = 5.9, 2.9 Hz, 2H), 7.53 (dd, J = 9.1, 2.9 Hz, 1H), 7.32 - 7.17 (m, 2H), 7.09 - 7.15 (m, 2H), 6.34 - 6.41 (m, 1H), 4.27 - 4.44(m,2H), 4.21 (t, J = 9.7 Hz, 1H), 3.39 - 3.63 (m, 6H) , 2.59 (dt, J = 9.4, 5.2 Hz, 4H), 1.19 (d, J = 6.8 Hz, 3H).

[0378] Example 31: 2-(4-(5-chloro-6-oxo-l,6-dihydropyridine-3-carbonyl)piperazin-1-yl)-N-(5- (4-fluorophenoxy)pyridin-2-yI)propanamide 2-(4-(5-chloro-6-methoxynicotinoyl)piperazin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2- yl)propanamide

[0379] To a solution of N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-(piperazin-1-yl)propanamide (120 mg, 0.348 mmol, 1.0 equiv) in Py (3 mL) was added 5-chloro-6-methoxynicotinic acid (65 mg, 0.348 mmol, 1.0 equiv) and EDO (133 mg, 0.696 mmol, 2.0 equiv) at rt. The resulting mixture was stirred for 3 h at rt. The reaction mixture was quenched by water (10 mL) and extracted with EA (20 mL x 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated under vacuum to yield a crude product which was directly purified by flash chromatographyto (0-20% DCM / MeOH) afford 2-(4-(5-chloro-6-methoxynicotinoyl)piperazin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2- yl)propanamide as a white solid. MS (ESI): mass calcd. for C25H25CIFN5O4: 513.95 m / z, found: 514.20 [M+H]+.

[0380] To a solution of 2-(4-(5-chloro-6-methoxynicotinoyl)piperazin-1-yl)-N-(5-(4- fluorophenoxy)pyridin-2-yl)propanamide (180 mg, 0.350 mmol, 1.0 equiv) in DMF (5 mL) was added Pyridine hydrobromide (560 mg, 3.50 mmol, 10.0 equiv) at rt .The resulting mixture was stirred for 3 h at 100 °C. The reaction mixture was quenched by water (10 mL) and extracted with 5:1 DCM / MeOH (20 mL x 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated under vacuum to yield a crude product which was directly purified by silica gel column & Cl 8 column to afford 2-(4-(5-chloro-6-oxo-l,6-dihydropyridine-3-carbonyl)piperazin-1-yl)-N-(5-(4- fluorophenoxy)pyridin-2-yl)propanamide as a white solid. MS (ESI): mass calcd. for C24H23CIFN5O4: 499.93 m / z, found: 500.05 [M+H]+.1H NMR (300 MHz, DMSO-d6) δ 12.40 (s, 1H), 10.27 (s, 1H), 8.10 - 8.18 (m, 2H), 7.79 (d, J = 2.3 Hz, 1H), 7.58 - 7.63 (m, 1H), 7.49 - 7.56 (m, 1H), 7.17 - 7.31 (m, 2H), 7.02 - 7.16 (m, 2H), 3.45 - 3.60(m, 5H), 2.50 - 2.65 (m, 4H), 1.19 (d, J = 6.8 Hz, 3H).19F NMR (282 MHz, DMSO-d6) δ -119.85.

[0381] Example 32: N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-(4-(6-oxo-5-(2,2,2-trifluoroethyl)- 1 ,6-dihydropyridine-3-carbonyl)piperazin- 1 -yl)propanamide

[0382] Synthetic Scheme

[0383]

[0384] (2-methoxy-5-(methoxycarbonyl)pyridin-3-yl)boronic acid

[0385] In a 40- mL round bottom flask, to a solution of methyl 5-bromo-6-methoxynicotinate (2.0 g, 8.128 mmol, 1.0 equiv) in dioxane (20 mL) was added 4,4,4',4',5,5,5',5'-octamethyl- 2,2'-bi(l,3,2-dioxaborolane) (2.27 g, 8.941 mmol, 1.1 equiv), Pd(dppf)Ch (0.59 g, 0.813 mmol, 0.1 equiv) and potassium acetate (2.39 g, 24.384 mmol, 3.0 equiv) at room temprature under. The reaction mixture was stirred at 90 °C for 2 h under N2. After completion of reaction, the reaction was quenched by water (10 mL) and extracted with EA (10 mL x 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue obtained was purified by silica gel chromatography (0-20% DCM / MeOH) to afford 2-methoxy-5-(methoxycarbonyl)pyridin-3-ylboronic acid (1.6 g, 86.77%). MS (ESI): mass calcd. for C8H10BNO5: 210.98 m / z. found 212.20 [M+H]+. In a 40-mL round bottom flask, to a solution of (2-methoxy-5- (methoxycarbonyl)pyridin-3-yl)boronic acid (1 g, 4.740 mmol, 1.0 equiv) in DME (20 mL) was added 2,2'-bipyridine (1.11 g, 7.110 mmol, 1.5 equiv), l,l,l-trifluoro-2-iodoethane (1.49 g, 7.110 mmol, 1.5 equiv) and Ni Bn (2.07 g, 9.480 mmol, 2.0 equiv) at rt. The reaction mixture was stirred at 80 °C for 1 h under N2. After cooled to room temperature, the methanol removed under reduced pressure. The reaction was quenched by water (10 mL) and extracted with EA (10 mL x 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue obtained was purified by silica gel chromatography (0-50% EA / PE) to afford desired compound methyl 6-methoxy-5- (2,2,2-trifluoroethyl)nicotinate (53 mg, 4.49%). MS (ESI): mass calcd. for: C8H10BNO5: 210.98 m / z. found: 250.00 [M+H]+.

[0386] To a stirred solution of methyl 6-methoxy-5-(2,2,2-trifluoroethyl)nicotinate (50 mg, 0.201 mmol, 1.0 equiv) and LiOH (48 mg, 2.010 mmol, 10.0 equiv) in methanol (1 mL), H2O (1 mL) and THF (1 mL) at room temperature. The reaction mixture was stirred at room temperature for a period of 3 h. The mixture was concentrated to dryness under reduced pressure to provide the crude product, which was purified by Cl 8 column (0-20% H2O / ACN) to afford 6-methoxy-5-(2,2,2-trifluoroethyl)pyridine-3-carboxylic acid (30 mg, 63.58%). MS (ESI): mass calcd. for C9H8F3NO3: 235.162 m / z. found 236.20 [M+H]+.

[0387] N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-(4-(6-methoxy-5-(2,2,2-trifluoroethyl)-l,6- dihydropyridine-3-carbonyl)piperazin-1-yl)propanamide

[0388] To a stirred solution of 6-methoxy-5-(2,2,2-trifluoroethyl)pyridine-3-carboxylic acid (30 mg, 0.128 mmol, 1.0 equiv) in pyridine (5 mL) was added N-(5-(4-fluorophenoxy)pyridin-2- yl)-2-(piperazin-1-yl)propanamide (66 mg, 0.192 mmol, 1.5 equiv) and EDO (73 mg, 0.384 mmol, 3.0 equiv) at room temperature. The reaction mixture was stirred at room temperature for a period of 3 h. The reaction was quenched by water (10 mL) and extracted with EA (10 mL x 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue obtained was purified by silica gel chromatography (0-50% EA / PE) to afford N-(5-(4-fluorophenoxy)pyridin-2-yl)-2- (4-(6-methoxy-5-(2,2,2-trifluoroethyl)-l,6-dihydropyridine-3-carbonyl)piperazin-1- yl)propanamide (30 mg, 41.73%).

[0389] N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-(4-(6-oxo-5-(2,2,2-trifluoroethyl)-l,6- dihydropyridine-3-carbonyl)piperazin-1-yl)propanamide

[0390] To a stirred solution of N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-(4-(6-methoxy-5- (2,2,2-trifluoroethyl)- 1 ,6-dihydropyridine-3-carbonyl)piperazin- 1 -yl)propanamide (30 mg, 0.053 mmol, 1.0 equiv) in DMF (5 mL) was added pyridine hydrobromide (85 mg, 0.530 mmol, 10.0 equiv) at room temperature. The reaction mixture was stirred at 90 °C for a period of 3 h. After cooled to room temperature, the reaction was quenched by water (10 mL) and extracted with EA (10 mL x 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue obtained was purified by silica gel chromatography (0-20% DCM / MeOH) and Prep-HPLC using a Column: XBridge Shield RP 18 OBD Column, 30*150 mm, 5μm (eluent: 32% to 62% CH3CN and H2O with 10 mmol / L NH4HCO3+0.1 % NH3.H2O) to afford N-(5-(4-fluorophenoxy)pyridin-2-yl)- 2-(4-(6-oxo-5-(2,2,2-trifluoroethyl)-l,6-dihydropyridine-3-carbonyl)piperazin-1- yl)propanamide (1.7 mg, 7.23%) as a white solid. MS (ESI): mass calcd. for C26H25F4N5O4: 547.51 m / z found: 548.10 [M+H]+.1H NMR (400 MHz, Acetonitrile-*) δ 8.18 (d, 7 = 9.1 Hz, 1H), 8.09 (d, J = 2.6 Hz, 1H), 7.62 (s, 1H), 7.55 (d, J = 2.4 Hz, 1H), 7.44 (dd, J = 9.0, 2.7 Hz, 1H), 7.03 - 7.15 (m,4H), 3.64 - 3.71 (m, 4H), 3.33 - 3.67 (m, 3H), 3.26 (s, 2H), 2.54 - 2.76 (m, 3H), 2.61 (s, 2H),1.27 (d, J = 7.3 Hz, 3H).19F NMR (376 MHz, Acetonitrile-*) -66.28, -121.48 (d, J = 4.0 Hz).

[0391] Example 33: 3-chloro-4-(4-(l-((5-(4-fluorophenoxy)pyridin-2-yl)amino)-1-oxopropan-2- yl)piperazine- 1 -carbonyl) pyridine 1 -oxide

[0392] 3-chloroisonicotinic acid

[0393] To a solution of methyl 3-chloropyridine-4-carboxylate (500 mg, 2.914 mmol, 1.0 equiv) in tetrahydrofuran (4 mL), water (2 mL) and methanol (2 mL) was added LiOH (349 mg, 14.570 mmol, 5.0 equiv) at rt. The resulting mixture was stirred for 1 h at rt. The resulting mixture was concentrated under vacuum. The resulting mixture was acidified pH = 6 with HC1 (IN). The aqueous layer was extracted with EA (3 X 20 mL), concentrated under reduced pressure to afford 3-chloroisonicotinic acid (160 mg, 34.85%) as yellow oil. MS (ESI): mass calcd. for: C6H4CINO2: 156.99 m / z, found: 158.05 [M+H]+.

[0394] 4-carboxy-3-chloropyridine 1-oxide

[0395] To a solution of 3-chloroisonicotinic acid (74 mg, 0.47. mmol, 1.0 equiv) in HO Ac (1 mL) was added 30% H2O2(0.2 mL) at rt. The resulting mixture was stirred for 3 h at 90 °C. After cooled to room temperature, the residue was purified by Cl 8 column to afford 4-carboxy- 3 -chloropyridine 1-oxide (60 mg, 73.18%) as a yellow solid. MS (ESI): mass calcd. for: C6H4CINO3: 172.99 m / z, found: 174.15 [M+H]+.

[0396] N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-(4-(6-oxo-5-(2,2,2-trifluoroethyl)-l,6- dihydropyridine-3-carbonyl)piperazin-1-yl)propanamide

[0397] To a solution of 4-carboxy-3-chloropyridine 1-oxide (60 mg, 0.346 mmol, 1.0 equiv) in pyridine (4 mL) was added N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-(piperazin-1- yl)propanamide (119 mg, 0.346 mmol, 1.0 equiv) and EDO (132 mg, 0.692 mmol, 2.0 equiv) at rt. The resulting mixture was stirred for 3 h at rt. The reaction was quenched by water (10 mL) and extracted with EA (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, and concentrated under vacuum to afford product which was directly purified by flash chromatography (0-100% PE / EA) & Cl 8 column to afford N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-(4-(6-oxo-5-(2,2,2-trifluoroethyl)-l,6- dihydropyridine-3-carbonyl)piperazin-1-yl)propanamide (28.2 mg, 16.21%) as a white solid. MS (ESI): mass calcd. for: C24H23CIFN5O4: 499.14 m / z, found: 500.05 [M+H]+.1H NMR (400

[0398] MHz, DMSO-d6) δ 10.26 (s, 1H), 8.60 (d, J = 1.7 Hz, 1H), 8.23 - 8.28 (m, 1H), 8.09 - 8.16

[0399] (m, 2H), 7.45 - 7.56 (m, 2H), 7.18 - 7.28 (m, 2H), 7.05 - 7.14 (m, 2H), 3.54 (q, J = 6.8 Hz, 1H), 3.49 - 3.58 (m, 2H), 3.24 - 3.31 (m, 2H), 2.53 - 2.60 (m, 4H), 1.19 (d, J = 6.8 Hz, 3H).19F NMR (376 MHz, DMSO-d6) δ -119.853.

[0400] Example 34: 2-(3,3-dimethyl-4-(6-oxo-l,6-dihydropyridine-3-carbonyl)piperazin-1-yl)- N-(5-(4-fluorophenoxy)pyridin-2-yl)propanamide

[0401] Synthetic Scheme tert-butyl 3,3-dimethyl-4-(6-oxo-l,6-dihydropyridine-3-carbonyl)piperazine-1- carboxylate

[0402] To a solution of tert-butyl 3,3-dimethylpiperazine-1-carboxylate (500 mg, 2.333 mmol, 1.0 equiv) in EA (5 mL) was added 6-oxo-l,6-dihydropyridine-3-carboxylic acid (324 mg, 2.333 mmol, 1.0 equiv), T3P (1.48 g, 4.666 mmol, 2.0 equiv) and TEA (944 mg, 9.332 mmol, 4.0 equiv) at rt. The resulting mixture was at room temperature for 6 h. The reaction mixture was quenched by addition of water (20 mL). The aqueous layer was extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give crude product which was further purified by column chromatography (0-15% DCM / MeOH) to afford tert-butyl 3,3-dimethyl-4-(6-oxo-l,6-dihydropyridine-3-carbonyl)piperazine-1-carboxylate (95 mg, 12.14%). MS (ESI): mass calcd. for C17H25N3O4: 335.18 m / z, found 336.20 [M+H]+.

[0403] 5-(2,2-dimethylpiperazine-1-carbonyl)pyridin-2(lH)-one

[0404] To a solution of tert-butyl 3,3-dimethyl-4-(6-oxo-l,6-dihydropyridine-3- carbonyl)piperazine-l -carboxylate (95 mg, 0.283 mmol, 1.0 equiv) in EA (2 mL) was added 4N HC1 (in EA, 2 mL). The resulting mixture was at room temperature for 2 h. After the reaction is complete, the product is precipitated with ethyl ether to afford 5-(2,2- dimethylpiperazine-1-carbonyl)pyridin-2(lH)-one (60 mg, 90.03%). MS (ESI): mass calcd. for C12H17N3O2: 235.13 m / z, found 236.05 [M+H]+.

[0405] 2-(3,3-dimethyl-4-(6-oxo-l,6-dihydropyridine-3-carbonyl)piperazin-1-yl)-N-(5-(4- fluorophenoxy)pyridin-2-yl)propanamide

[0406] To a solution of 5-(2,2-dimethylpiperazine-1-carbonyl)pyridin-2(lH)-one (50 mg, 0.213 mmol, 1.0 equiv) in DMA (2 mL) was added a solution of 2-bromo-N-(5-(4- fluorophenoxy)pyridin-2-yl)propanamide (86 mg, 0.256 mmol, 1.2 equiv) and TEA (86 mg, 0.852 mmol, 4.0 equiv). The mixture was stirred at 50 °C for 3 h. After cooled to room temperature, the reaction mixture was quenched by water (10 mL) and extracted with EA (50 mL x 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated under vacuum to yield a crude product which was directly purified by flash chromatographyto (0-20% DCM / MeOH) & Prep-HPLC using a Column: XBridge Prep OBD C18 Column, 30* 150mm 5.0 μm (eluent: 33% to 55% CH3CN and H2O with 10 mmol / L NH4HCO3) to afford 2-(3,3-dimethyl-4-(6-oxo-l,6-dihydropyridine-3- carbonyl)piperazin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propanamide (16.1 mg, 15.28%) as a white solid. MS (ESI): mass calcd. for C26H28FN5O4: 493.21 m / z, found: 494.15 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 11.84 (s, 1H), 10.19 (s, 1H), 8.16 (d, J = 8.6 Hz, 2H), 7.44 - 7.59 (m, 3H), 7.14 - 7.20 (m, 4H), 6.32 (d, J = 9.6 Hz, 1H), 3.46 - 3.52 (m, 1H), 2.73 (s, 2H), 2.41 (s, 4H), 1.41 (s, 6H), 1.18 - 1.24 (m, 3H).19F NMR (376 MHz, DMSO-d6) δ -119.84.

[0407] Example 35: N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-(4-(6-oxo-l,6-dihydropyridine-3- carbonyl)piperazin- 1 -yl)butanamide

[0408] 2-bromo-N-(5-(4-fluorophenoxy)pyridin-2-yl)butanamide

[0409] To a stirred solution of 5-(4-fluorophenoxy)pyridin-2-amine (200 mg, 0.979 mmol, 1.0 equiv) in anhydrous DCM (20 mL) was added 2-bromobutyric acid (196 mg, 1.175 mmol, 1.2 equiv) and DCC (242 mg, 1.175 mmol, 1.2 equiv) and AgNO3(25 mg, 0.147 mmol, 0.15 equiv). The reaction mixture was stirred at room temperature overnight. After completion of reaction, the reaction was quenched by water (20 mL) and extracted with DCM (20 mL x 3). The combined organic extracts were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue obtained was purified by silica gel chromatography (0-20% PE / EA) to afford 2-bromo-N-[5-(4-fluorophenoxy)pyridin-2- yl]butanamide (250 mg, 71.48%) as a pink solid. MS (ESI): mass calcd. for: C15H14BrFN2O2: 352.02 m / z, found: 353.10 [M+H]+.

[0410] N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-(4-(6-oxo-l,6-dihydropyridine-3- carbonyl) piperazin- 1 -yl)butanamide

[0411] To a stirred solution of 5-(piperazine-1-carbonyl)pyridin-2(lH)-one (100 mg, 0.483 mmol, 1.0 equiv) in anhydrous DMA (2 mL) was added TEA (293 mg, 2.898 mmol, 6.0 equiv) and 2-bromo-N-[5-(4-fluorophenoxy)pyridin-2-yl]butanamide (170 mg, 0.483 mmol, 1.0 equiv). The reaction mixture was stirred at 60 °C for a period of 3 h. After cooled to room temperature, the reaction was quenched by water (20 mL) and extracted with EA (20 mL x 3). The combined organic extracts were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue obtained was purified by silica gel chromatography (0-100% PE / EA) and Prep-HPLC using a column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; (eluent: 31% to 61% CH3CN and H2O with 10 mmol / L NH4HCO3) to afford N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-(4-(6-oxo-l,6-dihydropyridine-3- carbonyl)piperazin-1-yl)butanamid as a white solid. MS (ESI): mass calcd. for C25H26FN5O4: 479.20 m / z, found: 480.15[M+H]+.1H NMR (300 MHz, DMSO-d6) δ 10.51 (s, 1H), 8.10 - 8.21 (m, 2H), 7.45 - 7.57 (m, 3H), 7.24 (t, J = 8.8 Hz, 2H), 7.04 - 7.16 (m, 2H), 6.33 (d, J = 9.5 Hz, 1H), 3.44 - 3.57 (m, 5H), 2.61 (dd, J = 11.2, 5.3 Hz, 4H), 1.69 - 1.79 (m, 1H), 1.54 - 1.64 (m, 1H), 0.87 (t, J = 7.3 Hz, 3H).

[0412] Example 36: N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-methyl-2-(4-(6-oxo-l,6- dihydropyridine-3-carbonyI)piperazin-1-yI)propanamide

[0413] 2-bromo-N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-methylpropanamide

[0414] To a solution of 5-(4-fluorophenoxy)pyridin-2-amine (1.0 g, 4.9 mmol, 1.0 equiv) in DCM (15 mL) was added 2-bromo-2-methylpropanoic acid (981 mg, 5.9 mmol, 1.2 equiv), AgNO3(125 mg, 0.7 mmol, 0.15 equiv) and DCC (1.2 g, 5.9 mmol, 1.2 equiv) at 0 °C. The reaction was stirred at room temperature for 3 h. Quenched with water (50 mL) and extracted with DCM (50 mL x 3). The combined extracts were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel with PE / EA (0-100%) to give 2-bromo-N-(5-(4-fluorophenoxy)pyridin-2-yl)-2- methylpropanamide as yellow oil. tert-butyl 4-(l-((5-(4-fluorophenoxy)pyridin-2-yl)amino)-2-methyl-1-oxopropan-2- yl)piperazine- 1 -carboxylate

[0415] To a solution of 2-bromo-N-[5-(4-fluorophenoxy)pyridin-2-yl]-2-methylpropanamide (500 mg, 1.416 mmol, 1.0 equiv) in DMF (5 mL) was added tert-butyl piperazine-1- carboxylate (263 mg, 1.416 mmol, 1.0 equiv) and K2CO3(591 mg, 4.248 mmol, 3.0 equiv) at rt. The resulting mixture was stirred for 2 hours at 50 °C. After cooled to room temperature, the reaction was quenched by water (20 mL) and extracted with EA (30 mL x 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue obtained was purified by silica gel chromatography (0-100% PE / EA) to give tert-butyl 4-(l-((5-(4-fluorophenoxy)pyridin-2-yl)amino)-2-methyl-1- oxopropan-2-yl)piperazine- 1 -carboxylate (279 mg, 43.15%) as a yellow solid. MS (ESI): mass calcd. for C24H31FN4O4: 458.23 m / z, found: 459.30 [M+H]+.

[0416] N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-methyl-2-(piperazin-1-yl)propanamide

[0417] To a solution of tert-butyl 4-(l-((5-(4-fluorophenoxy)pyridin-2-yl)amino)-2-methyl-1- oxopropan-2-yl)piperazine-l -carboxylate (0.2 g, 0.436 mmol, 1.0 equiv) in EA (3 mL) was added 4N HC1 (in EA, 3 mL). The mixture was stirred at room temperature for 2 h. The mixture was concentrated to dryness under reduced pressure to provide the N-(5-(4- fluorophenoxy)pyridin-2-yl)-2-methyl-2-(piperazin-1-yl)propanamide as a white solid. MS (ESI): mass calcd. for C19H23FN4O2: 358.18 m / z, found: 359.25 [M+H]+.

[0418] N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-methyl-2-(4-(6-oxo-l,6-dihydropyridine-3- carbonyl)piperazin- 1 -yl)propanamide

[0419] To a solution of N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-methyl-2-(piperazin-1- yl)propanamide (100 mg, 0.279 mmol, 1.0 equiv) in pyridine (5 mL) was added 6-oxo-l,6- dihydropyridine-3-carboxylic acid (39 mg, 0.279 mmol, 1.0 equiv) and EDCI (80.23 mg, 0.419 mmol, 1.5 equiv) at rt. The resulting mixture was stirred for 2 hours at rt. The reaction mixture was quenched by water (10 mL) and extracted with EA (10 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The residue obtained was purified by silica gel chromatography (0-20% DCM / MeOH) and Prep-HPLC using a column: Column: XBridge Prep OBD C18 Column, 19*250 mm, 5μm (eluent: 35% to 65% CH3CN and H2O with 10 mmol / L NH4HCO3) to afford N-(5-(4-fluorophenoxy)pyridin- 2-yl)-2-methyl-2-(4-(6-oxo-l,6-dihydropyridine-3-carbonyl)piperazin-1-yl)propanamide (10 mg, 7.46%) as a white solid. MS (ESI): mass calcd. for C25H26FN5O4: 479.20, found: 480.10 [M+H]+,1H NMR (400 MHz, DMSO-d6) δ 11.87 (s, 1H), 9.85 (s, 1H), 8.07 - 8.18 (m, 2H), 7.47 - 7.62 (m, 3H), 7.24 (t, J = 8.8 Hz, 2H), 7.04 - 7.14 (m, 2H), 6.34 (d, J = 9.5 Hz, 1H), 3.46 - 3.80 (s, 4H), 2.49 (d, J = 4.1 Hz, 4H), 1.22 (s, 6H).

[0420] Example 37: 2-cyclopropyl-N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-(4-(6-oxo-l,6- dihydropyridine-3-carbonyI)piperazin-1-yI)acetamide ethyl 2-cyclopropyl-2-(4-(6-methoxynicotinoyl)piperazin-1-yl)acetate

[0421] To a stirred solution of l-(6-methoxypyridine-3-carbonyl)piperazine (200 mg, 0.904 mmol, 1.0 equiv) in DMA (3 mL) was added ethyl 2-bromo-2-cyclopropylacetate (187 mg, 0.904 mmol, 1.0 equiv) and TEA (548 mg, 5.424 mmol, 6.0 equiv). The reaction mixture was stirred at 50 °C for 5 h. After cooled to room temperature, the reaction was quenched by water (20 mL) and extracted with EA (20 mL x 3). The combined organic extracts were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue obtained was purified by silica gel chromatography (0-80% PE / EA) to afford ethyl 2- cyclopropyl-2-(4-(6-methoxynicotinoyl)piperazin-1-yl)acetate (50 mg, 15.92%) as a white solid. MS (ESI): mass calcd. for C18H25N3O4: 347.18 m / z, found: 348.30 [M+H]+.

[0422] 2-cyclopropyl-2-(4-(6-methoxynicotinoyl)piperazin-1-yl)acetic acid

[0423] To a stirred solution of ethyl 2-cyclopropyl-2-[4-(6-methoxypyridine-3- carbonyl)piperazin-1-yl] acetate (35 mg, 0.101 mmol, 1.0 equiv) in anhydrous MeOH (0.2 mL) and THF (0.8 mL) and H2O (0.2 mL) was added LiOH (12 mg, 0.505 mmol, 5.0 equiv). The reaction mixture was stirred at 40 °C for 1 h. After cooled to room temperature, the reaction was quenched by water (2 mL) then adjusted to pH 4~5 with 2N HC1. The resulting solution was extracted with EA (20 mL x 3). The combined organic extracts were washed with brine (5 mL), dried over anhydrous sodium sulfate, filtered and concentrated to afford 2-cyclopropyl- 2-(4-(6-methoxynicotinoyl)piperazin-1-yl)acetic acid (30 mg, 83.92%) as a white solid. MS (ESI): mass calcd. for C16H21N3O4: 319.15 m / z, found: 320.10 [M+H]+.

[0424] 2-cyclopropyl-N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-(4-(6- methoxynicotinoyl)piperazin- 1 -yl)acetamide

[0425] To a solution of 2-cyclopropyl-2-(4-(6-methoxynicotinoyl)piperazin-1-yl)acetic acid (27 mg, 0.085 mmol, 1.0 equiv) in pyridine (1 mL) was added 5-(4-fluorophenoxy)pyridin-2- amine (20 mg, 0.102 mmol, 1.2 equiv) and EDCI (24 mg, 0.128 mmol, 1.5 equiv). The mixture was stirred at rt for 2 h. After completion of reaction, the reaction was quenched by water (10 mL) and extracted with EA (10 mL x 3). The combined organic extracts were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue obtained was purified by silica gel chromatography (0-25% DCM / MeOH) to afford 2- cyclopropyl-N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-(4-(6-methoxynicotinoyl)piperazin-1- yl)acetamide (27 mg, 58.49%) as a white solid. MS (ESI): mass calcd. for C27H28FN5O4: 505.21 m / z, found 506.20 [M+H]+.

[0426] 2-cyclopropyl-N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-(4-(6-oxo-l,6-dihydropyridine-3- carbonyl)piperazin- 1 -yl)acetamide

[0427] To a stirred solution of 2-cyclopropyl-N-[5-(4-fluorophenoxy)pyridin-2-yl]-2-[4-(6- methoxypyridine-3-carbonyl)piperazin-1-yl]acetamide (27 mg, 0.053 mmol, 1.0 equiv) in DMF was added EiCl (11 mg, 0.265 mmol, 5.0 equiv) and PTSA (46 mg, 0.265 mmol, 5.0 equiv). The reaction mixture was stirred at 80 °C for 5 h. After cooled to room temperature, the crude product was purified by Prep-HPEC using a column: XBridge Shield RP 18 OBD Column, 30*150 mm, 5μm; (eluent: 28% to 58% CH3CN and H2O with 10 mmol / L NH4HCO3+0.1%NH3.H2O) to afford 2-cyclopropyl-N-(5-(4-fhiorophenoxy)pyridin-2-yl)-2- (4-(6-oxo-l,6-dihydropyridine-3-carbonyl)piperazin-1-yl)acetamide (6.2 mg, 23.53%) as a white solid. MS (ESI): mass calcd. for: C26H26FN5O4: 491.20 m / z, found: 492.15 [M+H]+.1H NMR (300 MHz, DMSO-d6) δ 11.71 (s, 1H), 10.20 (s, 1H), 8.10 - 8.20 (m, 2H), 7.40 - 7.66 (m, 3H), 7.17 - 7.30 (m, 2H), 7.04 - 7.16 (m, 2H), 6.34 (d, J = 9.5 Hz, 1H), 3.43 - 3.54 (m, 5H), 2.71 - 2.82 (m, 2H), 2.28 - 2.32 (m, 1H), 2.19 - 2.23 (m, 1H), 1.10 (d, J = 8.1 Hz, 1H), 0.66 (d, J = 8.8 Hz, 1H), 0.46 (d, J = 8.8 Hz, 1H), 0.33 (d, J = 4.0 Hz, 2H).19F NMR (282 MHz, DMSO-d6) δ -45.65, -119.88, -120.39.

[0428] Example 38: (S)-N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-((R)-3-methyl-4-(6-oxo-l,6- dihydropyridine-3-carbonyl)piperazin-1-yl)propanamide and Example 39: (R)-N-(5-(4- fluorophenoxy)pyridin-2-yl)-2-((R)-3-methyl-4-(6-oxo-l,6-dihydropyridine-3- carbonyl)piperazin- 1 -yl)propanamide tert-butyl (R)-3-methyl-4-(6-oxo-l,6-dihydropyridine-3-carbonyl)piperazine-1- carboxylate

[0429] To a solution of tert-butyl (R)-3-methylpiperazine-1-carboxylate (500 mg, 2.496 mmol, 1.0 equiv) in Pyridine (20 mL) was added 6-oxo-lH-pyridine-3-carboxylic acid (347 mg, 2.496 mmol, 1.0 equiv) and EDCI (718 mg, 3.744 mmol, 1.5 equiv) at rt. The resulting mixture was stirred for 2 hours at rt. The reaction mixture was quenched by water (10 mL) and extracted with EA (10 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The residue obtained was purified by silica gel chromatography (0- 20% DCM / MeOH) to give tert-butyl (R)-3-methyl-4-(6-oxo-l,6-dihydropyridine-3- carbonyl)piperazine-l -carboxylate (600 mg, 73.44%) as yellow oil. MS (ESI): mass calcd. for C16H23N3O4: 321.17 m / z, found: 344.10 [M+Na]+.

[0430] (R) -5- (2-methylpiperazine- 1 -carbonyl)pyridin-2(lH) -one

[0431] To a solution of tert-butyl (R)-3-methyl-4-(6-oxo-l,6-dihydropyridine-3-carbonyl)piperazine- 1 -carboxylate (200 mg, 0.622 mmol, 1.0 equiv) in DCM (15 mL) was added TFA (3 mL) at rt. The resulting mixture was stirred for 2 hours at rt. The solvent was removed to give (R)-5-(2- methylpiperazine-1-carbonyl)pyridin-2(lH)-one (120 mg, 87.15%) as a yellow solid. MS (ESI): mass calcd. for C11H15N3O2: 221.12 m / z, found: 222.10 [M+H]+.

[0432] (S)-N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-((R)-3-methyl-4-(6-oxo-l,6-dihydropyridine- 3-carbonyl)piperazin-1-yl)propanamide and (R)-N-(5-(4-fluorophenoxy)pyridin-2-yl)-2- ((R)-3-methyl-4-(6-oxo-l,6-dihydropyridine-3-carbonyl)piperazin-1-yl)propanamide

[0433] To a solution of (R)-5-(2-methylpiperazine-1-carbonyl)pyridin-2(lH)-one (100 mg, 0.452 mmol, 1.0 equiv) in DMA (20 mL) was added 2-bromo-N-(5-(4-fluorophenoxy)pyridin- 2-yl)propanamide (153 mg, 0.452 mmol, 1.0 equiv) and TEA (137 mg, 1.356 mmol, 3.0 equiv) at rt. The resulting mixture was stirred for 2 hours at 50 °C. After cooled to room temperature the reaction was quenched by water (10 mL) and extracted with EA (10 mL x 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue obtained was purified by silica gel chromatography (0-20% DCM / MeOH) to give N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-((R)-3- methyl-4-(6-oxo-l,6-dihydropyridine-3-carbonyl)piperazin-1-yl)propanamide as a white solid. The product was separated by Chiral-Prep-HPLC (CHIRALPAK IF 2*25 cm, 5 μm; Mobile Phase A: (HEX: DCM=3: l)(0.05% 2M NlL-McOH). Mobile Phase B: EtOH; Flow rate: 20 mL / min; Gradient: isocratic 20; Wave Length: 220 / 254 nm; RTl(min): 9.91; RT2(min): 14.786; Sample Solvent: EtOH; Injection Volume: 1.5 mL to afford (S)-N-(5-(4- fluorophenoxy)pyridin-2-yl)-2-((R)-3-methyl-4-(6-oxo-l,6-dihydropyridine-3- carbonyl)piperazin-1-yl)propanamide (13.9 mg, 6.34%) as a white solid. MS (ESI): mass calcd. for C25H26FN5O4: 479.20 m / z, found: 480.15 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 11.83 (s, 1H), 10.19 (s, 1H), 8.11 - 8.18 (m, 2H), 7.50 - 7.57 (m, 2H), 7.46 (dd, J = 9.4, 2.6 Hz, 1H), 7.24 (t, 7 = 8.8 Hz, 2H), 7.04 - 7.17 (m, 2H), 6.34 (d, J = 9.4 Hz, 1H), 4.34 (s, 1H), 3.83 (d, J = 12.9 Hz, 1H), 3.38 - 3.47 (m,lH), 3.35 (s,lH), 3.24 (t, J = 12.6 Hz, 1H), 2.84 (d, J = 11.1 Hz, 1H), 2.72 (d, J= 11.5 Hz, 1H), 2.22 (td, J = 11.6, 3.3 Hz, 1H), 1.31 (d, J = 6.7 Hz, 3H), 1.19 (d, J = 7.0 Hz, 3H). And (R)-N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-((R)-3-methyl- 4-(6-oxo-l,6-dihydropyridine-3-carbonyl)piperazin-1-yl)propanamide (7.4 mg, 3.32%) as a white solid MS (ESI): mass calcd. for C25H26FN5O4: 479.20 m / z, found: 480.15 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 11.83 (s, 1H), 10.16 (s, 1H), 8.14 (dd, J= 6.0, 2.9 Hz, 2H), 7.43 - 7.58 (m, 3H), 7.18 - 7.29 (m, 2H), 7.04 - 7.14 (m, 2H), 6.34 (d, J = 9.5 Hz, 1H), 4.33 (s, 1H), 3.85 (d, J = 13.0 Hz, 1H), 3.54 (q, J = 6.8 Hz, 1H), 3.21 - 3.32 (m, 1H), 2.85 (d, J = 11.4 Hz, 1H), 2.58 (d, J = 11.4 Hz, 1H), 2.36 - 2.48 (m, 2H), 1.31 (d, J = 6.7 Hz, 3H), 1.16 (d, J = 6.9 Hz, 3H).

[0434] Example 40: N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-(4-(2-(6-oxo-l,6-dihydropyridin-3- yl)acetyl)piperazin- 1 -yl)propanamide

[0435] N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-(4-(2-(6-methoxypyridin-3-yl)acetyl)piperazin-1- yl)propanamide To a solution of N-(5-(4-fhiorophenoxy)pyridin-2-yl)-2-(piperazin-1-yl)propanamide (100 mg, 0.290 mmol, 1.0 equiv) in pyridine (5 mL ) was added 2-(6-methoxypyridin-3- yl)acetic acid (48 mg, 0.290 mmol, 1.0 equiv) and EDCI (111 mg, 0.580 mmol, 2.0 equiv) was added at rt. The resulting mixture was stirred for 2 h at rt. The resulting mixture concentrated under vacuum to yield a crude product which was directly purified by flash chromatography (0- 20% DCM / MeOH) to afford N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-(4-(2-(6- methoxypyridin-3-yl)acetyl)piperazin-1-yl)propanamide (40 mg, 27.91%) as a white solid. MS (ESI): C26H28FN5O4: 493.21 m / z, found: 494.15 [M+H]+.

[0436] N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-(4-(2-(6-oxo-l,6-dihydropyridin-3- yl)acetyl)piperazin- 1 -yl)propanamide

[0437] To a solution of N-(5-(4-fhiorophenoxy)pyridin-2-yl)-2-(4-(2-(6-methoxypyridin-3- yl)acetyl)piperazin-1-yl)propanamide (40 mg, 0.081 mmol, 1.0 equiv) in DMF (2 mF) was added lithium chloride (17 mg, 0.405 mmol, 5.0 equiv) and PTSA (70 mg, 0.405 mmol, 5.0 equiv) at rt. The resulting mixture was stirred for 12 h at 80 °C. The residue was purified by C18 column to afford N-(5-(4- fluorophenoxy )pyridin-2-yl)-2-(4-(2-(6-oxo- 1,6- dihydropyridin-3-yl)acetyl)piperazin-1-yl)propanamide (9.6 mg, 24.66%) as a white solid. MS (ESI): mass calcd. for: C25H26FN5O4: 479.20 m / z, found: 480.10 [M+H]+.1H NMR (300 MHz, DMSO-d6) δ11.38 (s, 1H), 10.25 (s, 1H), 8.09 - 8.17 (m, 2H), 7.53 (dd, 7 = 9.0, 3.0 Hz, 1H), 7.15 - 7.32 (m, 4H), 7.04 - 7.15 (m, 2H), 6.26 (d, J = 9.3 Hz, 1H), 3.41 - 3.57 (m, 7H), 2.56 - 2.58 (m, 3H), 2.46 - 2.49 (m, 1H), 1.14 - 1.27 (m, 3H).19F NMR (282 MHz, DMSO-d6) δ - 119.866.

[0438] Example 41: (S)-2-(4-(4-chloro-6-oxo-l,6-dihydropyridine-3-carbonyl)piperazin-1-yl)- N-(5-(4-fluorophenoxy)pyridin-2-yl)propanamide and Example 42: (R)-2-(4-(4-chloro- 6-oxo-l,6-dihydropyridine-3-carbonyl)piperazin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2- yl)propanamide

[0439] (S)-2-(4-(4-chloro-6-oxo-l,6-dihydropyridine-3-carbonyl)piperazin-1-yl)-N-(5-(4- fluorophenoxy)pyridin-2-yl)propanamide and (R)-2-(4-(4-chloro-6-oxo-l,6- dihydropyridine-3-carbonyl)piperazin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2- yl)propanamide

[0440] 2-(4-(4-chloro-6-oxo-l,6-dihydropyridine-3-carbonyl)piperazin-1-yl)-N-(5-(4- fluorophenoxy)pyridin-2-yl)propanamide was separated by Chiral-HPEC (Column: CHIRAEPAK IA, 2*25 cm, 5 μm; Mobile Phase A: Hex (0.5% 2M NH3-MeOH)-HPEC, Mobile Phase B: EtOH— HPEC; Flow rate: 20 mE / min) to afford (S)-2-(4-(4-chloro-6-oxo-l,6- dihydropyridine-3-carbonyl)piperazin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2- yl)propanamide (25.0 mg, 13.51%). MS (ESI): mass calcd. for C24H23CIFN5O4: 499.93 m / z, found: 500.05 [M+H]+.1H NMR (300 MHz, DMSO-d6) δ 12.08 (s, 1H), 10.27 (s, 1H), 8.09 - 8.18 (m, 2H), 7.60 (s, 1H), 7.49 - 7.56 (m, 1H), 7.17 - 7.31 (m, 2H), 7.03 - 7.16 (m, 2H), 6.56 (s, 1H), 3.62 (s, 2H), 3.48 - 3.56 (m, 1H), 3.48 - 3.40 (m, 2H), 2.53 - 2.56 (m, 4H), 1.19 (d, J = 6.8 Hz, 3H).19F NMR (282 MHz, DMSO-d6) δ -119.85. And (R)-2-(4-(4-chloro-6-oxo-l,6- dihydropyridine-3-carbonyl)piperazin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2- yl)propanamide (25.0 mg, 13.51%). MS (ESI): mass calcd. for C24H23C1FN5O4: 499.93 m / z, found: 500.05 [M+H]+.1H NMR (300 MHz, DMSO-d6) δ 12.08 (s, 1H), 10.27 (s, 1H), 8.09 - 8.18 (m, 2H), 7.60 (s, 1H), 7.49 - 7.56 (m, 1H), 7.17 - 7.31 (m, 2H), 7.03 - 7.16 (m, 2H), 6.56 (s, 1H), 3.62 (s, 2H), 3.48 - 3.56 (m, 1H), 3.48 - 3.40 (m, 2H), 2.53 - 2.56 (m, 4H), 1.19 (d, J = 6.8 Hz, 3H).19F NMR (282 MHz, DMSO-d6) δ -119.85.

[0441] Example 43: (R)-4-(4-(l-((5-(4-fluorophenoxy)pyridin-2-yl)amino)-1-oxopropan-2- yl)piperazine-1-carbonyl)-2-(trifluoromethyl)pyridine 1-oxide and Example 44: (S)-4-(4- (l-((5-(4-fluorophenoxy)pyridin-2-yl)amino)-1-oxopropan-2-yl)piperazine-1-carbonyl)- 2-(trifluoromethyl)pyridine 1-oxide

[0442]

[0443] (R)-4-(4-(l-((5-(4-fluorophenoxy)pyridin-2-yl)amino)-1-oxopropan-2-yl)piperazine-1- carbonyl)-2-(trifluoromethyl)pyridine 1-oxide and (S)-4-(4-(l-((5-(4- fluorophenoxy)pyridin-2-yl)amino)-1-oxopropan-2-yl)piperazine-1-carbonyl)-2- (trifluoromethyl)pyridine 1-oxide

[0444] 4-(4-( 1 -((5-(4-fluorophenoxy)pyridin-2-yl)amino)- 1 -oxopropan-2-yl)piperazine- 1 - carbonyl)-2-(trifluoromethyl)pyridine 1-oxide was separated by Chiral-HPLC (Column: CHIRALPAK IA 5*25 cm, 5 μm; Mobile Phase A: Hex: DCM=3: 1(0.5% 2M NH3-MeOH)- HPLC, Mobile Phase B: EtOH— HPLC; Flow rate: 20 mL / min) to afford (R)-4-(4-(l-((5-(4- fluorophenoxy)pyridin-2-yl)amino)-1-oxopropan-2-yl)piperazine-1-carbonyl)-2- (trifhioromethyl)pyridine 1-oxide (9.9 mg, 7.67%, first peak) as a white solid, MS (ESI): mass calcd. for C25H23F4N5O4: 533.11 m / z, found 534.05 [M+H]+.1H NMR (300 MHz, DMSO-d6) 10.27 (s, 1H), 8.49 (d, J = 6.7 Hz, 1H), 8.09 - 8.18 (m, 2H), 7.97 (d, J = 2.4 Hz, 1H), 7.74 (dd, J = 6.7, 2.5 Hz, 1H), 7.53 (dd, J = 9.1, 2.9 Hz, 1H), 7.17 - 7.31 (m, 2H), 7.02 - 7.16 (m, 2H), 3.61 - 3.64 (m, 2H), (s, 2H), 3.47 - 3.60 (m, 2H), 3.37 - 3.46 (m, 2H), 2.62 (s, 3H), 1.20 (d, J= 6.9 Hz, 3H).19F NMR (282 MHz, DMSO-d6) δ -67.702, -119.850. And (S)-4-(4-(l-((5- (4-fluorophenoxy)pyridin-2-yl)amino)- 1 -oxopropan-2-yl)piperazine- 1 -carbonyl)-2- (trifhioromethyl)pyridine 1-oxide (10.8 mg, 8.38%, second peak) as a white solid, MS (ESI): mass calcd. for C25H23F4N5O4: 533.11 m / z, found 534.10 [M+H]+.1H NMR (300 MHz, DMSO-d6) δ 10.27 (s, 1H), 8.49 (d, J = 6.7 Hz, 1H), 8.09 - 8.18 (m, 2H), 7.97 (d, J = 2.4 Hz,

[0445] 1H), 7.74 (dd, 7 = 6.7, 2.5 Hz, 1H), 7.53 (dd, J = 9.1, 2.9 Hz, 1H), 7.17 - 7.31 (m, 2H), 7.02 - 7.16 (m, 2H), 3.61 - 3.64 (m, 2H), 3.47 - 3.60 (m, 2H), 3.37 - 3.46 (m, 2H), 2.62 (s, 3H), 1.20 (d, J= 6.9 Hz, 3H).19F NMR (282 MHz, DMSO-d6) δ -67.702, -119.850.

[0446] Example 45: (R)-2-chloro-4-(4-(l-((5-(4-fluorophenoxy)pyridin-2-yl)amino)-1- oxopropan-2-yl)piperazine-1-carbonyl)pyridine 1-oxide and Example 46: (S)-2-chloro- 4-(4-(l-((5-(4-fluorophenoxy)pyridin-2-yl)amino)-1-oxopropan-2-yl)piperazine-1- carbonyl)pyridine 1-oxide

[0447]

[0448] (R)-2-chloro-4-(4-(l-((5-(4-fluorophenoxy)pyridin-2-yl)amino)-1-oxopropan-2- yl)piperazine-1-carbonyl)pyridine 1-oxide and (S)-2-chloro-4-(4-(l-((5-(4- fluorophenoxy)pyridin-2-yl)amino)-1-oxopropan-2-yl)piperazine-1-carbonyl)pyridine 1- oxide

[0449] 2-chloro-4-(4-(l-((5-(4-fluorophenoxy)pyridin-2-yl)amino)-1-oxopropan-2- yl)piperazine-1-carbonyl)pyridine 1 -oxide was separated by Chiral-HPLC to afford (R)-2- chloro-4-(4-(l-((5-(4-fluorophenoxy)pyridin-2-yl)amino)-1-oxopropan-2-yl)piperazine-1- carbonyl)pyridine 1-oxide (2.0 mg). MS (ESI): mass calcd. for C24H23CIFN5O4: 499.14 m / z, found: 500.10 [M+H]+.1H NMR (300 MHz, DMSO-d6) δ 10.27 (s, 1H), 8.47 (d, J = 6.7 Hz, 1H), 8.14 (dd, J = 6.0, 2.9 Hz, 2H), 7.89 (d, J = 2.3 Hz, 1H), 7.53 (dd, J = 9.1, 2.9 Hz, 1H), 7.44 (dd, 7 = 6.7, 2.4 Hz, 1H), 7.31 - 7.17 (m, 2H), 7.16 - 7.02 (m, 2H), 3.39 - 3.67 (m, 5H), 2.51 - 2.64 (m, 4H), 1.19 (d, J= 6.8 Hz, 3H).19F NMR (282 MHz, DMSO-d6) δ -119.855. And (S)-2-chloro-4-(4-(l-((5-(4-fluorophenoxy)pyridin-2-yl)amino)-1-oxopropan-2-yl)piperazine- l-carbonyl)pyridine 1-oxide (2.0 mg). MS (ESI): mass calcd. for C24H23CIFN5O4: 499.14 m / z, found: 500.10 [M+H]+.1H NMR (300 MHz, DMSO-d6) δ 10.27 (s, 1H), 8.47 (d, J = 6.7 Hz, 1H), 8.14 (dd, J = 6.0, 2.9 Hz, 2H), 7.89 (d, J = 2.3 Hz, 1H), 7.53 (dd, J = 9.1, 2.9 Hz, 1H), 7.44 (dd, 7 = 6.7, 2.4 Hz, 1H), 7.31 - 7.17 (m, 2H), 7.16 - 7.02 (m, 2H), 3.39 - 3.67 (m, 5H), 2.51 - 2.64 (m, 4H), 1.19 (d, 7= 6.8 Hz, 3H).19F NMR (282 MHz, DMSO-d6) δ -119.859.

[0450] Example 47: (R)-N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-((S)-3-methyl-4-(6-oxo-1,6- dihydropyridine-3-carbonyl)piperazin-1-yl)propanamide and Example 48: (S)-N-(5-(4- fluorophenoxy)pyridin-2-yl)-2-((S)-3-methyl-4-(6-oxo-l,6-dihydropyridine-3- carbonyl)piperazin- 1 -yl)propanamide tert-butyl (2S)-4-(l-((5-(4-fluorophenoxy)pyridin-2-yl)amino)-1-oxopropan-2-yl)-2- methylpiperazine- l-carboxylate

[0451] To a solution of tert-butyl (S)-2-methylpiperazine- l-carboxylate (200 mg, 0.999 mmol, 1.0 equiv) in DMA (5 mL) was added TEA (303 mg, 2.997 mmol, 3.0 equiv) and 2-bromo-N- (5-(4-fluorophenoxy)pyridin-2-yl)propanamide (339 mg, 0.999 mmol, 1.0 equiv) at rt. The mixture was stirred for overnight at 60 °C. After cooled to room temperature, the reaction was quenched by water (15 mL) and extracted with EA (30 mL x 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated under vacuum to yield a crude product which was directly purified by flash chromatography (0-80% PE / EA) to afford tert-butyl (2S)-4-(l-((5-(4-fluorophenoxy)pyridin-2-yl)amino)-1-oxopropan- 2-yl)-2-methylpiperazine- l-carboxylate (180 mg, 39.31%) as a yellow solid. MS (ESI): mass calcd. for:C24H31FN4O4: 458.23 m / z, found: 459.20 [M+H]+.

[0452] N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-((S)-3-methylpiperazin-1-yl)propanamide

[0453] To a solution of tert-butyl (2S)-4-(l-((5-(4-fluorophenoxy)pyridin-2-yl)amino)-1- oxopropan-2-yl)-2-methylpiperazine-l -carboxylate (180 mg, 0.393 mmol, 1.0 equiv) in EA (3 mL) as added HC1 (4M, in EA, 3 mL) at rt. The mixture was stirred for 3 h at rt. The reaction mixture was concentrated under vacuum to yield a crude product N-(5-(4- fhiorophenoxy)pyridin-2-yl)-2-((S)-3-methylpiperazin-1-yl)propanamide (120 mg, 85.29%) as a yellow solid. MS (ESI): mass calcd. for: C19H23FN4O2: 358.11 m / z, found: 359.25 [M+H]+.

[0454] N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-((S)-4-(6-methoxynicotinoyl)-3-methylpiperazin-

[0455] 1 -yl)propanamide To a solution of N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-((S)-3-methylpiperazin-1- yl)propanamide (150 mg, 0.419 mmol, 1.0 equiv) in DCM (5 mL) was added TEA (127 mg, 1.257 mmol, 3.0 equiv) and 6-methoxynicotinoyl chloride (107 mg, 0.628 mmol, 1.5 equiv) at rt. The mixture was stirred for 4 h at rt. The reaction mixture was quenched by water (10 mL) and extracted with EA (20 mL x 3). The combined organic extracts were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under vacuum to yield a crude product which was directly purified by flash chromatography (0-20% DCM / MeOH) to afford N-(5-(4- fluorophenoxy )pyridin-2-yl)-2-((S)-4-(6-methoxynicotinoyl)-3- methylpiperazin-1-yl)propanamide (100 mg, 48.41%) as a yellow solid. MS (ESI): mass calcd. for: C26H28FN5O4: 493.23 m / z, found: 494.20 [M+H]+.

[0456] (R)-N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-((S)-3-methyl-4-(6-oxo-l,6-dihydropyridine- 3-carbonyl)piperazin-1-yl)propanamide and (S)-N-(5-(4-fluorophenoxy)pyridin-2-yl)-2- ((S)-3-methyl-4-(6-oxo-l,6-dihydropyridine-3-carbonyl)piperazin-1-yl)propanamide

[0457] To a solution of N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-((S)-4-(6-methoxynicotinoyl)- 3-methylpiperazin-1-yl)propanamide (90 mg, 0.182 mmol, 1.0 equiv) in DMF (3 mL) was added LiCl (39 mg, 0.910 mmol, 5.0 equiv), TsOH (157 mg, 0.910 mmol, 5.0 equiv) at rt. The resulting mixture was stirred for overnight at 80 °C. After cooled to room temperature, the reaction was quenched by water (10 mL) and extracted with EA (20 mL x 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated under vacuum to yield a crude product which was directly purified by flash chromatography (0-20% DCM / MeOH) & Cl 8 column to afford racemic product as a white solid. The racemic product was separated by Chiral-HPLC (column, CHIRALPAK IA 5*25 cm, 5 μm, Mobile Phase A: Hex: DCM=3: 1(0.5% 2M NH3-MeOH)-HPLC, Mobile Phase B: EtOH— HPLC; Flow rate: 20 mL / min) to afford (R)-N-(5-(4-fluorophenoxy)pyridin-2-yl)-2- ((S)-3-methyl-4-(6-oxo-l,6-dihydropyridine-3-carbonyl)piperazin-1-propanamide (17.1 mg, 19.52%) as a white solid. MS (ESI): mass calcd. for C25H26FN5O4479.11 m / z, found 480.10 [M+H]+.1H NMR (300 MHz, DMSO-d6) δ 11.80 (s, 1H), 10.18 (s, 1H), 8.10 - 8.19 (m, 2H), 7.48 - 7.58 (m, 2H), 7.46 (dd, J = 9.4, 2.6 Hz, 1H), 7.17 - 7.31 (m, 2H), 7.03 - 7.16 (m, 2H), 6.34 (d, J = 9.4 Hz, 1H), 4.34 (s, 1H), 3.84 (d, J = 13.2 Hz, 1H), 3.42 (q, J = 6.9 Hz, 1H), 3.24 (t, J = 12.4 Hz, 1H), 2.84 (d, J = 11.1 Hz, 1H), 2.72 (d, J = 11.3 Hz, 1H), 2.53 (s, 1H), 2.22 (t, J = 11.1 Hz, 1H), 1.31 (d, J = 6.7 Hz, 3H), 1.15 - 1.27 (m, 3H).19F NMR (282 MHz, DMSO- d6) δ -119.867. And (S)-N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-((S)-3-methyl-4-(6-oxo-l,6- dihydropyridine-3-carbonyl)piperazin-1-yl)propanamide (25.0 mg, 28.51%) as a white solid. MS (ESI): mass calcd. for C25H26FN5O4479.1 Im / z, found 480.10 [M+H]+.1H NMR (300 MHz, DMSO-d6) δ 11.81 (s, 1H), 10.15 (s, 1H), 8.14 (dd, J = 6.0, 2.9 Hz, 2H), 7.48 - 7.58 (m, 2H), 7.47 (dd, J = 9.4, 2.6 Hz, 1H), 7.17 - 7.31 (m, 2H), 7.03 - 7.16 (m, 2H), 6.34 (d, J = 9.4 Hz, 1H), 4.29 - 4.37 (m, 1H), 3.85 (d, J = 13.0 Hz, 1H), 3.54 (q, J = 6.7 Hz, 1H), 2.85 (d, J = 11.1 Hz, 1H), 2.58 (d, J = 11.4 Hz, 1H), 2.35 - 2.50 (m, 2H), 1.32 (d, 7 = 6.7 Hz, 3H), 1.16 (d, J = 6.9 Hz, 3H).19F NMR (282 MHz, DMSO-d6) δ -119.867.

[0458] Example 49: N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-((R)-4-((6-oxo-l,6-dihydropyridin- 3-yl)methyl)-3-(trifluoromethyl)piperazin-1-yl)propanamide tert-butyl (R)-4-((6-methoxypyridin-3-yl)methyl)-3-(trifluoromethyl)piperazine-1- carboxylate

[0459] To a stirred solution of tert-butyl (R)-3-(trifluoromethyl)piperazine-l -carboxylate (100 mg, 0.393 mmol, 1.0 equiv) in DCM (3 mF) was added 6-methoxypyridine-3-carbaldehyde (108 mg, 0.786 mmol, 2.0 equiv) and HOAc (20 mg). The reaction was stirred for 0.5 h at rt. STAB (125 mg, 0.590 mmol, 1.5 equiv) was added into the solution. The reaction mixture was stirred at room temperature for a period of 5 h. After completion of reaction, the reaction mixture was quenched by addition of water (10 mL). The aqueous layer was extracted with DCM (20 mL x 3). The combined organic phase was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give crude product which was further purified by column chromatography (0-50% PE / EA) to afford desired compound tert-butyl (R)-4-((6-methoxypyridin-3-yl)methyl)-3- (trifluoromethyl)piperazine-l -carboxylate (30 mg, 20.32%) as colorless oil. MS (ESI): mass calcd. for: C17H24F3N3O3: 375.18 m / z, found: 376.15 [M+H]+. (R) - 1 -((6-methoxypyridin-3-yl)methyl) -2- (trifluoromethyl)piperazine

[0460] To a stirred solution of tert-butyl (R)-4-((6-methoxypyridin-3-yl)methyl)-3- (trifluoromethyl)piperazine-l -carboxylate (28 mg, 0.075 mmol, 1.0 equiv) in EA (1 mL) was added 4N HC1 (10 in EA, 1 mL). The reaction mixture was stirred at room temperature for a period of 1 h. The resulting mixture was concentrated under reduced pressure to afford (R)-1- ((6-methoxypyridin-3-yl)methyl)-2-(trifluoromethyl)piperazine (30 mg, crude) as a white solid. The crude product mixture was used in the next step directly without further purification. MS (ESI): mass calcd. for C12H16F3N3O3: 275.12 m / z, found 276.10 [M+H]+.

[0461] N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-((R)-4-((6-methoxypyridin-3-yl)methyl)-3- (trifluoromethyl)piperazin- 1 -yl)propanamide

[0462] To a solution of (R)-1-((6-methoxypyridin-3-yl)methyl)-2-(trifluoromethyl)piperazine (28 mg, 0.102 mmol, 1.0 equiv) in DMA (1 mL) was added TEA (62 mg, 0.612 mmol, 6.0 equiv) and 2-bromo-N-[5-(4-fluorophenoxy)pyridin-2-yl]propanamide (41 mg, 0.122 mmol, 1.2 equiv) at rt. The resulting mixture was stirred for 3 hours at 50 °C. After cooled to room temperature, the reaction was quenched by water (10 mL) and extracted with EA (10 mL x 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue obtained was purified by silica gel chromatography (0-80% PE / EA) to afford N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-((R)-4-((6- methoxypyridin-3-yl)methyl)-3-(trifluoromethyl)piperazin- 1 -yl)propanamide (20 mg, 35.18%) as a white solid. MS (ESI): mass calcd. for C26H27F4N5O3: 533.21 m / z, found 534.20 [M+H]+. N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-((R)-4-((6-oxo-l,6-dihydropyridin-3-yl)methyl)- 3-(trifluoromethyl)piperazin-1-yl)propanamide

[0463] To a stirred solution of N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-((R)-4-((6- methoxypyridin-3-yl)methyl)-3-(trifluoromethyl)piperazin-1-yl)propanamide (20 mg, 0.036 mmol, 1.0 equiv) in DMF (1 mL) was added LiCl (8 mg, 0.180 mmol, 5.0 equiv) and PTSA (31 mg, 0.180 mmol, 5.0 equiv). The reaction mixture was stirred at 80 °C for a period of 5 h. After cooled to room temperature, the reaction was purified by Prep-HPLC using a Column: YMC Triart C18 ExRs Column, 20*250mm, 5μm(eluent: 43% to 73% CH3CN and H2O with 10 mmol / L NH4HCO3) to afford N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-((R)-4-((6-oxo-l,6- dihydropyridin-3-yl)methyl)-3-(trifluoromethyl)piperazin-1-yl)propanamide (3.1 mg, 15.48%) as a white solid. MS (ESI): mass calcd. for C25H25F4N5O3: 519.19 m / z, found 520.10 [M+H]+.1H NMR (300 MHz, DMSO-d6) δ 11.33 (s, 1H), 10.07 (d, J = 18.4 Hz, 1H), 8.10 - 8.18 (m, 2H), 7.43 - 7.57 (m, 1H), 7.39 (dd, J = 9.5, 2.3 Hz, 1H), 7.17 - 7.31 (m, 3H), 7.03 - 7.16 (m, 2H), 6.32 (d, J = 9.4 Hz, 1H), 3.36 - 3.68 (m, 5H), 2.78 - 3.02 (m, 2H), 2.53 - 2.73 (m, 2H), 2.32 (d, J = 18.5 Hz, 1H), 1.17 (d, J = 6.8 Hz, 3H).19F NMR (282 MHz, DMSO-d6) 3 -62.90, -63.24, -119.82, -119.88.

[0464] Example 50: N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-((S)-4-((6-oxo-l,6-dihydropyridin-3- yI)methyI)-3-(trifluoromethyI)piperazin-1-yI)propanamide tert-butyl (S)-4-((6-methoxypyridin-3-yl)methyl)-3-(trifluoromethyl)piperazine-1- carboxylate

[0465] To a stirred solution of tert-butyl (S)-3-(trifluoromethyl)piperazine-1-carboxylate (100 mg, 0.393 mmol, 1.0 equiv) in DCM (3 mL) was added 6-methoxypyridine-3-carbaldehyde (108 mg, 0.786 mmol, 2.0 equiv) and HOAc (20 mg). The reaction was stirred for 0.5 h at rt. STAB (125 mg, 0.590 mmol, 1.5 equiv) was was added into the solution. The reaction mixture was stirred at room temperature for a period of 5 h. After completion of reaction, the reaction mixture was quenched by addition of water (10 mL). The aqueous layer was extracted with DCM (20 mL x 3). The combined organic phase was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give crude product which was further purified by column chromatography (0-50% PE / EA) to afford desired compound tert-butyl (S)-4-((6-methoxypyridin-3-yl)methyl)-3- (trifluoromethyl)piperazine-l -carboxylate (30 mg, 20.32%) as colorless oil. MS (ESI): mass calcd. for: C17H24F3N3O3: 375.18 m / z, found: 376.30 [M+H]+.

[0466] (S)-1-((6-methoxypyridin-3-yl)methyl)-2-(trifluoromethyl)piperazine

[0467] To a stirred solution of tert-butyl (S)-4-((6-methoxypyridin-3-yl)methyl)-3- (trifluoromethyl)piperazine-l -carboxylate (28 mg, 0.075 mmol, 1.0 equiv) in EA (1 mL) was added 4N HC1 (10 in EA, 1 mL). The reaction mixture was stirred at room temperature for a period of 1 h. The resulting mixture was concentrated under reduced pressure to afford (S)-1- ((6-methoxypyridin-3-yl)methyl)-2-(trifluoromethyl)piperazine (30 mg, crude) as a white solid. The crude product mixture was used in the next step directly without further purification. MS (ESI): mass calcd. for C12H16F3N3O3: 275.12 m / z, found 276.10 [M+H]+.

[0468] N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-((S)-4-((6-methoxypyridin-3-yl)methyl)-3- (trifluoromethyl)piperazin- 1 -yl)propanamide

[0469] To a solution of (S)-1-((6-methoxypyridin-3-yl)methyl)-2-(trifluoromethyl)piperazine (28 mg, 0.102 mmol, 1.0 equiv) in DMA (1 mL) was added TEA (61 mg, 0.612 mmol, 6.0 equiv) and 2-bromo-N-[5-(4-fluorophenoxy)pyridin-2-yl]propanamide (41 mg, 0.122 mmol, 1.2 equiv) at rt. The resulting mixture was stirred for 3 hours at 50 °C. After the reaction cooled to room temperature, which was quenched by water (10 mL) and extracted with EA (10 mL x 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue obtained was purified by silica gel chromatography (0-100% PE / EA) to afford N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-((S)-4-((6- methoxypyridin-3-yl)methyl)-3-(trifluoromethyl)piperazin- 1 -yl)propanamide (20 mg, 35.18%) as a white solid. MS (ESI): mass calcd. for C26H27F4N5O3: 533.21 m / z, found 534.20 [M+H]+.

[0470] N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-((S)-4-((6-oxo-l,6-dihydropyridin-3-yl)methyl)-3- (trifluoromethyl)piperazin- 1 -yl)propanamide

[0471] To a stirred solution of N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-((S)-4-((6- methoxypyridin-3-yl)methyl)-3-(trifluoromethyl)piperazin-1-yl)propanamide (20 mg, 0.036 mmol, 1.0 equiv) in anhydrous DMF (1 mL) was added LiCl (8 mg, 0.180 mmol, 5 equiv) and PTS A (31 mg, 0.180 mmol, 5 equiv). The reaction mixture was stirred at 80 °C for a period of 5 h. After the reaction cooled to room temperature, the reaction was quenched by water (10 mL) and extracted with EA (10 mL x 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue obtained was purified by silica gel chromatography (0-100% PE / EA) and Prep-HPLC using a Column: XBridge Prep Phenyl OBD Cl 8 Column, 19*250 mm, 5μm(eluent: 50% to 80% CH3CN and H2O with 10 mmol / L NH4HCO3) to afford N-(5-(4-fluorophenoxy)pyridin-2-yl)- 2-((S)-4-((6-oxo-l,6-dihydropyridin-3-yl)methyl)-3-(trifluoromethyl)piperazin-1- yl)propanamide (3.1 mg, 15.25%) as a white solid. MS (ESI): mass calcd. for C25H25F4N5O3: 519.19 m / z, found 520.10 [M+H]+.1H NMR (300 MHz, DMSO-d6) δ 11.43 (s, 1H), 10.07 (d, J = 18.4 Hz, 1H), 8.11 - 8.18 (m, 2H), 7.43 - 7.57 (m, 1H), 7.39 (dd, J = 9.5, 2.3 Hz, 1H), 7.18 - 7.29 (m, 3H), 7.03 - 7.14 (m, 2H), 6.32 (d, J = 9.4 Hz, 1H), 3.36 - 3.68 (m, 4H), 2.77 - 3.01 (m, 2H), 2.52 - 2.71 (m, 2H), 2.32 (d, J = 18.5 Hz, 1H), 1.17 (d, J = 6.8 Hz, 3H).19F NMR (282 MHz, DMSO-d6) δ -62.90, -63.24, -119.82, -119.88.

[0472] Example 51: 4-(4-(l-((5-(4-fluorophenoxy)pyridin-2-yl)amino)-1-oxopropan-2- yl)piperazine-1-carbonyl)pyrimidine 1-oxide

[0473] 4-carboxypyrimidine 1-oxide

[0474] To a solution of pyrimidine-4-carboxylic acid (500 mg, 4.029 mmol, 1.0 equiv) in DCM (3 mL) was added m-CPBA (2.1 g, 12.087 mmol, 3.0 equiv) at 0 °C. The resulting mixture was stirred for 3 h at rt. The combined organic extracts were concentrated under vacuum and purified by Cl 8 column to afford 4-carboxypyrimidine 1 -oxide as a white solid.

[0475] MS (ESI): mass calcd. for C5H4N2O3140.09 m / z, found 141.10 [M+H]+.

[0476] 4-(4-(l-((5-(4-fluorophenoxy)pyridin-2-yl)amino)-1-oxopropan-2-yl)piperazine-1- carbonyl)pyrimidine 1-oxide

[0477] To a solution of 4-carboxypyrimidine 1-oxide (100 mg, 0.714 mmol, 1.0 equiv) in Py (3 mL) was added N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-(piperazin-1-yl)propanamide (246 mg, 0.714 mmol, 1.0 equiv) and EDO (410 mg, 2.142 mmol, 3.0 equiv) at rt. The resulting mixture was stirred for 3 h at rt. The reaction mixture was quenched by water (10 mL) and extracted with EA (20 mL x 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated under vacuum to yield a crude product which was directly purified by C18 column to afford 4-(4-(l-((5-(4- fluorophenoxy)pyridin-2-yl)amino)-1-oxopropan-2-yl)piperazine-1-carbonyl)pyrimidine 1- oxide (52 mg, 15.6%) as a white solid. MS (ESI): mass calcd. for C23H23FN6O4: 466.473 m / z, found: 467.05 [M+H]+.1H NMR (300 MHz, DMSO-d6) δ 12.62 (s, 1H), 10.28 (s, 1H), 8.22

[0478] (d, J = 1.1 Hz, 1H), 8.09 - 8.18 (m, 2H), 7.48 - 7.55 (m, 1H), 7.17 - 7.31 (m, 2H), 7.03 - 7.13

[0479] (m, 2H), 6.36 (d, J = 1.1 Hz, 1H), 3.49 - 3.63 (m, 3H), 3.27 - 3.41 (m, 2H), 2.52 - 2.64 (m, 4H), 1.19 (d, J = 6.9 Hz, 3H).19F NMR (282 MHz, DMSO-d6) δ -119.874.

[0480] Example 52: (R)-2-(3,3-dimethyl-4-(6-oxo-l,6-dihydropyridine-3-carbonyl)piperazin-1- yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propanamide and Example 53: (S)-2-(3,3- dimethyl-4-(6-oxo-l,6-dihydropyridine-3-carbonyl)piperazin-1-yl)-N-(5-(4- fluorophenoxy)pyridin-2-yl)propanamide (R)-2-(3,3-dimethyl-4-(6-oxo-l,6-dihydropyridine-3-carbonyl)piperazin-1-yl)-N-(5-(4- fluorophenoxy)pyridin-2-yl)propanamide and (S)-2-(3,3-dimethyl-4-(6-oxo- 1,6- dihydropyridine-3-carbonyl)piperazin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2- yl)propanamide

[0481] 2-(3,3-dimethyl-4-(6-oxo-l,6-dihydropyridine-3-carbonyl)piperazin-1-yl)-N-(5-(4- fluorophenoxy)pyridin-2-yl)propanamide was separated by Chiral-HPLC (Column: CHIRALPAK IG, 2*25 cm, 5 μm; Mobile Phase A: ( HEX: DCM=3: l)(0.5% 2M NH3- MeOH), Mobile Phase B: IPA; Flow rate: 18 mL / min; Gradient: isocratic 50; Wave Length: 220 / 254 nm) to afford (R)-2-(3,3-dimethyl-4-(6-oxo-l,6-dihydropyridine-3- carbonyl)piperazin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propanamide (21.1 mg) as a white solid. MS (ESI): mass calcd. for C26H28FN5O4: 493.21 found: 494.10 [M+H]+.1H NMR (300 MHz, DMSO-d6) δ 11.84 (s, 1H), 10.18 (s, 1H), 8.11 - 8.20 (m, 2H), 7.40 - 7.60 (m, 3H), 7.17 - 7.31 (m, 2H), 7.03 - 7.16 (m, 2H), 6.32 (d, J = 9.5 Hz, 1H), 3.49 (q, J = 6.8 Hz, 1H), 3.34 - 3.40 (m,2H), 2.68 - 2.79 (m, 1H), 2.57 - 2.67 (m, 1H), 2.41 (s, 2H), 1.41 (d, J = 2.0 Hz, 6H), 1.21 (d, J = 6.9 Hz, 3H).19F NMR (282 MHz, DMSO-d6) δ -119.82. And (S)-2-(3,3- dimethyl-4-(6-oxo-l,6-dihydropyridine-3-carbonyl)piperazin-1-yl)-N-(5-(4- fluorophenoxy)pyridin-2-yl)propanamide (77.3 mg) as a white solid. MS (ESI): mass calcd. for C26H28FN5O4: 493.21 found: 494.05 [M+H]+.1H NMR (300 MHz, DMSO-d6) δ 11.84 (s, 1H), 10.18 (s, 1H), 8.11 - 8.20 (m, 2H), 7.40 - 7.60 (m, 3H), 7.17 - 7.31 (m, 2H), 7.03 - 7.16 (m, 2H), 6.32 (d, J = 9.5 Hz, 1H), 3.49 (q, J = 6.8 Hz, 1H), 3.34 - 3.40 (m, 2H), 2.68 - 2.79 (m, 1H), 2.57 - 2.67 (m, 1H), 2.41 (s, 2H), 1.41 (d, J = 2.0 Hz, 6H), 1.21 (d, J = 6.9 Hz, 3H).19F NMR (282 MHz, DMSO-d6) δ -119.82.

[0482] Example 54: (R)-4-(4-(l-((5-(4-fluorophenoxy)pyridin-2-yl)amino)-1-oxopropan-2-yl)- 2,2-dimethylpiperazine-1-carbonyl)pyridine 1-oxide and Example 55: (S)-4-(4-(l-((5-(4- fluorophenoxy)pyridin-2-yl)amino)-1-oxopropan-2-yl)-2,2-dimethylpiperazine-1- carbonyl)pyridine 1-oxide

[0483] Synthetic Scheme

[0484] 4-(4-(tert-butoxycarbonyl)-2,2-dimethylpiperazine-1-carbonyl)pyridine 1-oxide

[0485] To a solution of tert-butyl 3,3-dimethylpiperazine-1-carboxylate (800 mg, 3.733 mmol, 1.0 equiv) in Py (10 mL) was added 4-carboxypyridine 1-oxide (519 mg, 3.733 mmol, 1.0 equiv) and EDO (1.4 g, 7.466 mmol, 2.0 equiv) at rt. The resulting mixture was stirred for 3 h at rt. The reaction mixture was quenched by water and extracted with EA (30 mL x 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated under vacuum to yield a crude product which was directly purified by flash chromatography (0-100% PE / EA) to afford 4-(4-(tert-butoxycarbonyl)-2,2- dimethylpiperazine-1-carbonyl)pyridine 1-oxide (814 mg, 65.12%) as a white solid. MS (ESI): mass calcd. for C17H25N3O4: 355.18 m / z, found: 336.15 [M+H]+.

[0486] 4-(2,2-dimethylpiperazine-1-carbonyl)pyridine 1-oxide

[0487] To a solution of 4-(4-(tert-butoxycarbonyl)-2,2-dimethylpiperazine-1- carbonyl)pyridine 1-oxide (670 mg, 1.998 mmol, 1.0 equiv) in EA (10 mL), was added 4N HC1 (in EA, 10 mL). The resulting mixture was stirred for 2 h at rt. The product was precipitated by the addition of anhydrous ether. The precipitated solids were collected by filtration to afford 4-(2,2-dimethylpiperazine-1-carbonyl)pyridine 1-oxide (0.4 g, 85.32%) as a white solid. MS (ESI): mass calcd. for C12H17N3O2: 235.13 m / z, found: 236.25 [M+H]+.

[0488] (R)-4-(4-(l-((5-(4-fluorophenoxy)pyridin-2-yl)amino)-1-oxopropan-2-yl)-2,2- dimethylpiperazine-1-carbonyl)pyridine 1-oxide and (S)-4-(4-(l-((5-(4- fluorophenoxy)pyridin-2-yl)amino)-1-oxopropan-2-yl)-2,2-dimethylpiperazine-1- carbonyl)pyridine 1-oxide

[0489] To a solution of 4-(2,2-dimethylpiperazine-1-carbonyl)pyridine 1-oxide (150 mg, 0.638 mmol, 1.0 equiv) in DMF (3 mL) was added 2-bromo-N-[5-(4-fluorophenoxy)pyridin-2- yl]propanamide (216 mg, 0.638mmol, 1.0 equiv) and TEA (193 mg, 1.914 mmol, 3.0 equiv) at rt. The resulting mixture was stirred for 3 h at 60 °C. After cooled to room temperature, the reaction mixture was quenched by water (10 mL) and extracted with EA (20 mL x 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated under vacuum to yield a crude product which was purified by silica gel chromatography (0-100% PE / EA) and Prep-HPLC using a Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm (eluent: 29% to 59% (v / v) CH3CN and H2O, lOmmol / L NH4HCO3+0.05%NH3H2O ) to afford 4-(4-(l-((5-(4-fluorophenoxy)pyridin-2-yl)amino)-1- oxopropan-2-yl)-2,2-dimethylpiperazine-1-carbonyl)pyridine 1-oxide as a white solid. The product was separated by Chiral-Prep-HPLC ( Mobile Phase A: Hex: DCM=3: 1(0.5% 2M NH3-MeOH)— HPLC, Mobile Phase B: EtOH— HPLC; Flow rate: 15 mL / min; Gradient: isocratic 50; Wave Length: 220 / 254 nm) to afford (R)-4-(4-(l-((5-(4-fluorophenoxy)pyridin- 2-yl)amino)- 1 -oxopropan-2-yl)-2,2-dimethylpiperazine- 1 -carbonyl)pyridine 1 -oxide (15.8 mg, first peak) as a white solid. MS (ESI): mass calcd. for C26H28FN5O4: 493.53 m / z, found: 494.05 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 10.21 (s, 1H), 8.19 - 8.26 (m, 2H), 8.12 - 8.19 (m, 2H), 7.53 (dd, J = 9.0, 3.1 Hz, 1H), 7.40 - 7.47 (m, 2H), 7.19 - 7.30 (m, 2H), 7.05 - 7.14 (m, 2H), 3.51 (q, J = 6.9 Hz, 1H), 2.67 - 2.76 (m, 1H), 2.57 - 2.65 (m, 1H), 2.41 - 2.49 (m, 4H), 1.46 (d, J = 3.8 Hz, 6H), 1.18 - 1.26 (m, 3H).19F NMR (376 MHz, DMSO-d6) δ - 119.826. And (S)-4-(4-(l-((5-(4-fluorophenoxy)pyridin-2-yl)amino)-1-oxopropan-2-yl)-2,2- dimethylpiperazine-1-carbonyl)pyridine 1-oxide (25.5 mg, second peak) as a white solid. MS (ESI): mass calcd. for C26H28FN5O4: 493.53 m / z, found: 494.05 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 10.21 (s, 1H), 8.19 - 8.26 (m, 2H), 8.12 - 8.19 (m, 2H), 7.53 (dd, J= 9.0, 3.1 Hz, 1H), 7.40 - 7.47 (m, 2H), 7.19 - 7.30 (m, 2H), 7.05 - 7.14 (m, 2H), 3.51 (q, J = 6.9 Hz, 1H), 2.67 - 2.76 (m, 1H), 2.57 - 2.65 (m, 1H), 2.41 - 2.49 (m, 4H), 1.46 (d, 7 = 3.8 Hz, 6H), 1.18 - 1.26 (m, 3H).19F NMR (376 MHz, DMSO-d6) δ -119.826.

[0490] Example 56: (R)-N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-(4-(6-oxo- 1,6-dihydropyridine- 3-carbonyl)-4,7-diazaspiro[2.5]octan-7-yl)propanamide and Example 57: (S)-N-(5-(4- fluorophenoxy)pyridin-2-yl)-2-(4-(6-oxo-l,6-dihydropyridine-3-carbonyl)-4,7- diazaspiro[2.5]octan-7-yl)propanamide tert-butyl 4-(6-oxo-lH-pyridine-3-carbonyl)-4,7-diazaspiro[2.5]octane-7-carboxylate

[0491] To a solution of tert-butyl 4,7-diazaspiro[2.5]octane-7-carboxylate (1.0 g, 4.710 mmol, 1.0 equiv) in Py (10 mL) was added 6-oxo- l,6-dihydropyridine-3-carboxylic acid (0.66 g, 4.710 mmol, 1.0 equiv) and EDO (1.35 g, 7.065 mmol, 1.5 equiv). The mixture was stirred at room temperature for 2 h. The reaction was quenched by water (10 mL) and extracted with EA (10 mL x 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue obtained was purified by silica gel chromatography (0-10% DCM / MeOH) to afford tert-butyl 4-(6-oxo-l,6- dihydropyridine-3-carbonyl)-4,7-diazaspiro[2.5]octane-7-carboxylate (1.1 g, 68.78%) as a yellow oil. MS (ESI): mass calcd. for C17H23N3O4: 333.16 m / z, found: 334.10 [M+H]+.

[0492] 5-(4,7-diazaspiro[2.5]octane-4-carbonyl)pyridin-2(lH)-one

[0493] To a solution of tert-butyl 4-(6-oxo-lH-pyridine-3-carbonyl)-4,7- diazaspiro[2.5]octane-7-carboxylate (500 mg, 1.500 mmol, 1.0 equiv) in DCM (6 mL) was added TFA (2 mL). The mixture was stirred at room temperature for 2 h. The mixture was concentrated to dryness under reduced pressure to afford 5-(4,7-diazaspiro[2.5]octane-4- carbonyl)pyridin-2(lH)-one (275 mg, 78.71%) as a yellow solid. (MS (ESI): mass calcd. for C12H15N3O2: 233.11 m / z, found: 234.25 [M+H]+.

[0494] (R)-N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-(4-(6-oxo-l,6-dihydropyridine-3-carbonyl)- 4,7-diazaspiro[2.5]octan-7-yl)propanamide and (S)-N-(5-(4-fluorophenoxy)pyridin-2- yl)-2-(4-(6-oxo-l,6-dihydropyridine-3-carbonyl)-4,7-diazaspiro[2.5]oc tan-7- yl)propanamide

[0495] To a solution of 5-(4,7-diazaspiro[2.5]octane-4-carbonyl)pyridin-2(lH)-one (100 mg, 0.429 mmol, 1.0 equiv) in DMF (5 mL) the mixture was added 2-bromo-N-[5-(4- fluorophenoxy)pyridin-2-yl]propanamide (145 mg, 0.429 mmol, 1.0 equiv) and TEA (130 mg, 1.287 mmol, 3.0 equiv). The mixture was stirred for 3 h at 60 °C. After cooled to room temperature, the reaction was quenched by water (20 mL) and extracted with EA (20 mL x 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue obtained was purified by silica gel chromatography (0-20% DCM / MeOH) to afford N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-(4- (6-oxo- l,6-dihydropyridine-3-carbonyl)-4,7-diazaspiro[2.5]octan-7-yl)propanamide as a white solid. The product was separated by Chiral-HPLC (CHIRALPAKIE3; Mobile Phase A: (Hex: DCM=3: l)(0.1%DEA): EtOH=50: 50; Flow rate: ImL / min; Gradient: isocratic ; Injection Volume: 3L mL) to afford (R)-N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-(4-(6-oxo- l,6-dihydropyridine-3-carbonyl)-4,7-diazaspiro[2.5]octan-7-yl)propanamide (8.3 mg, 3.91%) as a white solid. MS (ESI): mass calcd. for C26H26FN5O4: 491.20 m / z, found: 492.05 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 11.78 (s, 1H), 10.21 (s, 1H), 8.10 - 8.18 (m, 2H), 7.60 (d, J = 2.6 Hz, 1H), 7.52 (ddd, J = 9.6, 6.5, 2.8 Hz, 2H), 7.18 - 7.29 (m, 2H), 7.04 - 7.14 (m, 2H), 6.33 (d, J = 9.5 Hz, 1H), 3.50 - 3.92 (m, 2H), 3.45 (d, J = 6.8 Hz, 1H), 2.56 - 2.69 (m, 4H), 1.18 (d, J = 6.9 Hz, 3H), 0.84 (d, J = 17.9 Hz, 4H). And (S)-N-(5-(4- fluorophenoxy)pyridin-2-yl)-2-(4-(6-oxo-l,6-dihydropyridine-3-carbonyl)-4,7- diazaspiro[2.5]octan-7-yl)propanamide (13.1 mg, 6.19%) as a white solid. MS (ESI): mass calcd. for C26H26FN5O4: 491.20 m / z, found: 492.05 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 11.78 (s, 1H), 10.21 (s, 1H), 8.10 - 8.18 (m, 2H), 7.60 (d, J= 2.6 Hz, 1H), 7.52 (ddd, J = 9.6, 6.5, 2.8 Hz, 2H), 7.18 - 7.29 (m, 2H), 7.04 - 7.14 (m, 2H), 6.33 (d, J = 9.5 Hz, 1H), 3.50 - 3.92 (m, 2H), 3.45 (d, J = 6.8 Hz, 1H), 2.56 - 2.69 (m, 4H), 1.18 (d, J = 6.9 Hz, 3H), 0.84 (d,

[0496] J = 17.9 Hz, 4H).

[0497] Example 58: (R)-4-(8-(l-((5-(4-fluorophenoxy)pyridin-2-yl)amino)-1-oxopropan-2-yl)- 5,8-diazaspiro[3.5]nonane-5-carbonyl)pyridine 1-oxide and Example 59: (S)-4-(8-(l-((5- (4-fluorophenoxy)pyridin-2-yl)amino)-1-oxopropan-2-yl)-5,8-diazaspiro[3.5]nonane-5- carbonyl)pyridine 1-oxide

[0498] 4-(8-(tert-butoxycarbonyl)-5,8-diazaspiro[3.5]nonane-5-carbonyl)pyridine 1-oxide

[0499] To a solution of tert-butyl 5,8-diazaspiro[3.5]nonane-8-carboxylate (300 mg, 1.326 mmol, 1.0 equiv) in Pyridine (6 mL) was added isonicotinic acid N-oxide (184 mg, 1.326 mmol, 1 equiv), EDO (381 mg, 1.989 mmol, 1.5 equiv) at rt, the mixture was stirred for 5 h at rt. The reaction was quenched by water (30 mL) and extracted with EA (30 mL x 3). The combined organic extracts were washed with brine (50 mL), dried over anhydrous Na2SO4, and concentrated under vacuum to afford a crude product which was directly purified by flash chromatography (0-80% PE / EA) to afford 4-(8-(tert-butoxycarbonyl)-5,8- diazaspiro[3.5]nonane-5-carbonyl)pyridine 1-oxide (300 mg, 65.14%) as a yellow solid. MS (ESI): mass calcd. for: C18H25N3O4: 347.23 m / z, found: 348.20 [M+H]+.

[0500] 4-(5,8-diazaspiro[3.5]nonane-5-carbonyl)pyridine 1-oxide

[0501] To a solution of 4-(8-(tert-butoxycarbonyl)-5,8-diazaspiro[3.5]nonane-5- carbonyl)pyridine 1-oxide (150 mg, 0.432 mmol, 1.0 equiv) in EA (3 mL) was added HC1 (4 M, in EA, 3 mL) at rt, the mixture was stirred for 2 h at rt . The mixture was concentrated under vacuum to afford 4-(5,8-diazaspiro[3.5]nonane-5-carbonyl)pyridine 1-oxide (100 mg, 93.66%) as a yellow solid. MS (ESI): mass calcd. for: C13H17N3O2: 247.11 m / z, found: 248.25 [M+H]+.

[0502]

[0503] (R)-4-(8-(l-((5-(4-fluorophenoxy)pyridin-2-yl)amino)-1-oxopropan-2-yl)-5,8- diazaspiro[3.5]nonane-5-carbonyl)pyridine 1-oxide and (S)-4-(8-(l-((5-(4- fluorophenoxy)pyridin-2-yl)amino)-1-oxopropan-2-yl)-5,8-diazaspiro[3.5]nonane-5- carbonyl)pyridine 1-oxide

[0504] To a solution of 4-(5,8-diazaspiro[3.5]nonane-5-carbonyl)pyridine 1-oxide (100 mg, 0.404 mmol, 1.0 equiv) in DMA (5 mL) was added 2-bromo-N-(5-(4-fluorophenoxy)pyridin- 2-yl)propanamide (137 mg, 0.404 mmol, 1.0 equiv), TEA (122 mg, 1.212 mmol, 3.0 equiv) at rt. The resulting mixture was stirred for 3 h at 60 °C. After cooled to room temperature, the reaction was quenched by water (20 mL) and extracted with EA (20 mL x 3). The combined organic extracts were washed with brine (20 mL), dried over anhydrous Na2SO4, and concentrated under vacuum. The residue obtained was purified by silica gel chromatography (0-25% DCM / MeOH) and separated by Chiral-HPLC (Column: CHIRAL Amylose-SA, 4.6*150 mml. D.S-5um; Mobile Phase A: Hex: DCM=3: 1 (0.5% 2M NH3-MeOH)-HPLC, Mobile Phase B: EtOH— HPLC; Flow rate: 17 mL / min; Gradient: isocratic 50; Wave Length: 220 / 254 nm) to afford (R)-4-(8-(l-((5-(4-fluorophenoxy)pyridin-2-yl)amino)-1-oxopropan-2- yl)-5,8-diazaspiro[3.5]nonane-5-carbonyl)pyridine 1-oxide (15.4 mg, 7.51%, first peak) as a white solid. MS (ESI): mass calcd. for C27H28FN5O4: 505.11 m / z, found 506.05 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 10.25 (s, 1H), 8.20 - 8.27 (m, 2H), 8.10 - 8.17 (m, 2H), , 7.18

[0505] - 7.29 (m, 2H), 7.09 (ddd, J = 6. , 5.4, 3.0 Hz, 2H), 3.51 (q, J = 6.9 Hz, 1H), 2.75 (s, 2H), 2.35

[0506] - 2.47 (m, 4H), 2.14 - 2.28 (m, 4H), 1.59 - 1.69 (m, 2H), 1.18 (d, J = 6.9 Hz, 3H).19F NMR (282 MHz, DMSO-d6) δ -119.837. And (S)-4-(8-(l-((5-(4-fhiorophenoxy)pyridin-2- yl)amino)-1-oxopropan-2-yl)-5,8-diazaspiro[3.5]nonane-5-carbonyl)pyridine 1-oxide (18.8 mg, 9.17%, second peak) as a white solid. MS (ESI): mass calcd. for C25H23F4N5O4: 505.11 m / z, found 506.05 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 10.25 (s, 1H), 8.20 - 8.27 (m, 2H), 8.10 - 8.17 (m, 2H), 7.44 - 7.52 (m, 3H), 7.18 - 7.29 (m, 2H), 7.04 - 7.14 (m, 2H), 3.51 (q, J = 6.9 Hz, 1H), 2.75 (s, 2H), 2.35 - 2.47 (m, 4H), 2.14 - 2.28 (m, 4H), 1.59 - 1.69 (m, 2H), 1.18 (d, J = 6.9 Hz, 3H).19F NMR (282 MHz, DMSO-d6) δ -119.902. Example 60: (S)-3-chloro-4-(4-(l-((5-(4-fluorophenoxy)pyridin-2-yl)amino)-1- oxopropan-2-yl)-2,2-dimethylpiperazine-1-carbonyl)pyridine 1-oxide and Example 61: (R)-3-chloro-4-(4-(l-((5-(4-fluorophenoxy)pyridin-2-yl)amino)-1-oxopropan-2-yl)-2,2- dimethylpiperazine-1-carbonyl)pyridine 1-oxide

[0507] 4-carboxy-3-chloropyridine 1-oxide

[0508] To a solution of 3 -chloroisonicotinic acid (300 mg, 1.904 mmol, 1.0 equiv) in HO Ac (5 mL) was added 30% H2O2(1 mL) at 0 °C. The resulting mixture was stirred for 4 h at 80 °C. After cooled to room temperature, the mixture was purified by Cl 8 column to afford 4- carboxy-3-chloropyridine 1-oxide (0.3 g, 91.0%) as a white solid. MS (ESI): mass calcd. for C6H4CINO3: 172.99 m / z, found: 174.05 [M+H]+.

[0509] 4-(4-(tert-butoxycarbonyl)-2,2-dimethylpiperazine-1-carbonyl)-3-chloropyridine 1-oxide

[0510] To a solution of 4-carboxy-3-chloropyridine 1-oxide (300 mg, 1.729 mmol, 1.0 equiv) in Py (10 mL) was added tert-butyl 3,3-dimethylpiperazine-1-carboxylate (370 mg, 1.729 mmol, 1.0 equiv), HATU (986 mg, 2.594 mmol, 1.5 equiv) and DIEA (335 mg, 2.594 mmol, 1.5 equiv) at rt. The resulting mixture was stirred for 3 h at rt. The reaction mixture was quenched by water (10 mL) and extracted with EA (20 mL x 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous Na2SO4, and concentrated under vacuum to yield a crude product which was directly purified by flash chromatography (0-100% PE / EA) to afford 4-(4-(tert-butoxycarbonyl)-2,2-dimethylpiperazine-1-carbonyl)-3- chloropyridine 1-oxide (439 mg, 68.70%) as a white solid. MS (ESI): mass calcd. for: C17H24CIN3O4: 369.15 m / z, found: 370.10 [M+H]+.

[0511] 3-chloro-4-(2,2-dimethylpiperazine-1-carbonyl)pyridine 1-oxide

[0512] To a solution of 4-(4-(tert-butoxycarbonyl)-2,2-dimethylpiperazine-1-carbonyl)-3- chloropyridine 1-oxide (400 mg, 1.08 mmol, 1.0 equiv) in EA (5 mL) was added 4N HC1 (in EA, 5 mL) at 0 °C. The resulting mixture was stirred for 3 h at rt. The product was precipitated by the addition of anhydrous ether. The precipitated solids were collected by filtration to afford 3-chloro-4-(2,2-dimethylpiperazine-1-carbonyl)pyridine 1-oxide (233 mg, 80.0%) as a white solid. MS (ESI): mass calcd. for: C12H16CIN3O 269.09 m / z, found: 270.10 [M+H]+.

[0513] (S)-3-chloro-4-(4-(l-((5-(4-fluorophenoxy)pyridin-2-yl)amino)-1-oxopropan-2-yl)-2,2- dimethylpiperazine-1-carbonyl)pyridine 1-oxide and (R)-3-chloro-4-(4-(l-((5-(4- fluorophenoxy)pyridin-2-yl)amino)-1-oxopropan-2-yl)-2,2-dimethylpiperazine-1- carbonyl)pyridine 1-oxide

[0514] To a solution of 3-chloro-4-(2,2-dimethylpiperazine-1-carbonyl)pyridine 1-oxide (100 mg, 0.371 mmol, 1 equiv) in DMA (3 mL) was added 2-bromo-N-(5-(4- fluorophenoxy)pyridin-2-yl)propanamide (126 mg, 0.371 mmol, 1.0 equiv) and TEA (112 mg, 1.113 mmol, 3.0 equiv) at rt. The resulting mixture was stirred for 3 h at 50 °C. After cooled to room temperature, the reaction mixture was quenched by water (10 mL) and extracted with 5:1 DCM / MeOH (20 mL x 3). The combined organic extracts were washed with brine (5 mL), dried over anhydrous Na2SO4, and concentrated under vacuum to yield a crude product which was directly purified by C18 column to afford 3-chloro-4-(4-(l-((5-(4- fluorophenoxy)pyridin-2-yl)amino)- 1 -oxopropan-2-yl)-2,2-dimethylpiperazine- 1 - carbonyl)pyridine 1-oxide as a white solid. The product was separated by Chiral-HPLC (Column: SA 2cm MTBE(0.5% 2M NH3-MeOH): ETOH=70: 30; Mobile Phase A: CHIRALPAK SA 2*25 cm, 5 μm, Mobile Phase B: EtOH-HPLC; Flow rate: MTBE(0.5% 2M NH3-MeOH)— HPLC mL / min; Gradient: isocratic 20; Wave Length: 70 nm) to afford (S)- 3-chloro-4-(4-(l-((5-(4-fluorophenoxy)pyridin-2-yl)amino)-1-oxopropan-2-yl)-2,2- dimethylpiperazine-1-carbonyl)pyridine 1-oxide (9.9 mg) as a white solid. MS (ESI): mass calcd. for: C26H27CIFN5O4: 527.98 m / z, found: 528.15 [M+H]+.1H NMR (300 MHz, DMSO- d6) δ 10.20 (s, 1H), 8.57 (d, J = 1.7 Hz, 1H), 8.23 (dd, J = 6. , 1.7 Hz, 1H), 8.09 - 8.18 (m, 2H), 7.52 (dd, J = 9.1, 3.0 Hz, 1H), 7.42 (d, J = 6.7 Hz, 1H), 7.17 - 7.31 (m, 2H), 7.03 - 7.16 (m, 2H), 3.50 (q, J = 6.8 Hz, 1H), 3.22 - 3.31 (m, 2H), 2.60 - 2.70 (m, 2H), 2.42 - 2.48 (m, 2H), 1.43 - 1.55 (m, 6H), 1.14 - 1.27 (m, 3H). And (R)-3-chloro-4-(4-(l-((5-(4- fluorophenoxy )pyridin-2-yl)amino)-1-oxopropan-2-yl)-2, 2-dimethylpiperazine-1- carbonyl)pyridine 1-oxide (3.7 mg) as a white solid. MS (ESI): mass calcd. for: C26H27CIFN5O4: 527.98 m / z, found: 528.15 [M+H]+.1H NMR (300 MHz, DMSO-d6) δ 10.20 (s, 1H), 8.57 (d, J = 1.7 Hz, 1H), 8.23 (dd, J = 6. , 1.7 Hz, 1H), 8.09 - 8.18 (m, 2H), 7.52 (dd, J = 9.1, 3.0 Hz, 1H), 7.42 (d, J = 6.7 Hz, 1H), 7.17 - 7.31 (m, 2H), 7.03 - 7.16 (m, 2H), 3.50 (q, J= 6.8 Hz, 1H), 3.22 - 3.31 (m, 2H), 2.60 - 2.70 (m, 2H), 2.42 - 2.48 (m, 2H), 1.43 - 1.55 (m, 6H), 1.14 - 1.27 (m, 3H).19F NMR (282 MHz, DMSO-d6) δ -119.83.

[0515] Example 62: (R)-4-(4-(l-((5-(2,4-difluorophenoxy)pyrazin-2-yl)amino)-1-oxopropan-2- yl)-2,2-dimethylpiperazine-1-carbonyl)pyridine 1-oxide and Example 63: (S)-4-(4-(l-((5- (2,4-difluorophenoxy)pyrazin-2-yl)amino)-1-oxopropan-2-yl)-2,2-dimethylpiperazine-1- carbonyl)pyridine 1-oxide

[0516] Synthetic Scheme

[0517] 5-(2,4-difluorophenoxy)pyrazin-2-amine

[0518] To a solution of 5-bromopyrazin-2-amine (3 g, 17.241 mmol, 1.0 equiv) in dioxane (30 mF) was added 2,4-difluorophenol (2.24 g, 17.241 mmol, 1.0 equiv), dimethylglycine (0.71 g, 6.896 mmol, 0.4 equiv), Cui (0.66 g, 3.448 mmol, 0.2 equiv) and CS2CO3(11.24 g, 34.482 mmol, 2.0 equiv) at room temperature. The mixture was stirred at 110 °C for overnight under N2. After cooled to room temperature, the reaction mixture was quenched by addition of water (50 mL). The aqueous layer was extracted with ethyl acetate (100 mL x 3). The combined organic phase was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue obtained was purified by silica gel chromatography (0-60% PE / EA) to afford 5-(2,4-difluorophenoxy)pyrazin-2-amine (2 g, 51.98%) as a yellow solid. MS (ESI): mass calcd for C10H7F2N3O: 223.183 m / z, found: 224.10 [M+H]+.

[0519] 2-bromo-N-(5-(2,4-difluorophenoxy)pyrazin-2-yl)propanamide

[0520] To a solution of 5-(2,4-difluorophenoxy)pyrazin-2-amine (1 g, 4.481 mmol, 1.0 equiv) in DCM (10 mL) was added 2-bromopropanoic acid (0.82 g, 5.377 mmol, 1.2 equiv), DCC (1.11 g, 5.377 mmol, 1.2 equiv) and AgNO3(0.08 g, 0.448 mmol, 0.1 equiv) at room temperature. The mixture was stirred at room temperature for 3 h. After completion of reaction, the reaction mixture was quenched by addition of water (20 mL). The aqueous layer was extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue obtained was purified by silica gel chromatography (0-60% PE / EA) to afford 2-bromo-N-(5-(2,4- difluorophenoxy)pyrazin-2-yl)propanamide (800 mg, 49.85%) as a yellow solid. MS (ESI): mass calcd for C13H10BrF2N3O2: 356.99 m / z, found: 357.95 [M+H]+.

[0521] (R)-4-(4-(l-((5-(2,4-difluorophenoxy)pyrazin-2-yl)amino)-1-oxopropan-2-yl)-2,2- dimethylpiperazine-1-carbonyl)pyridine 1-oxide and (S)-4-(4-(l-((5-(2,4- difluorophenoxy)pyrazin-2-yl)amino)-1-oxopropan-2-yl)-2,2-dimethylpiperazine-1- carbonyl)pyridine 1 -oxide

[0522] To a solution of 2-bromo-N-(5-(2,4-difluorophenoxy)pyrazin-2-yl)propanamide (200 mg, 0.558 mmol, 1.0 equiv) in DMA (5 mL) was added 4-(2,2-dimethylpiperazine- 1- carbonyl)pyridine 1-oxide (131 mg, 0.558 mmol, 1.0 equiv) and TEA (169 mg, 1.67 mmol, 3.0 equiv) at rt. The resulting mixture was stirred for 3 h at 60 °C. After cooled to room temperature, the reaction mixture was quenched by water (10 mL) and extracted with EA (20 mL x 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous Na2SO4, and concentrated under vacuum to yield a crude product which was directly purified by C18 column to afford 4-(4-(l-((5-(2,4-difluorophenoxy)pyrazin-2-yl)amino)-1-oxopropan- 2-yl)-2,2-dimethylpiperazine-1-carbonyl)pyridine 1-oxide as a white solid. The compound was separated by preparative Chiral-HPLC (Column: CHIRALPAK IK, 4.6*150mm, 5μm; Mobile Phase A: Hex: DCM=3: 1(0.5% 2M NH3-MeOH)-HPLC, Mobile Phase B: EtOH-HPLC; Flow rate: 18 mL / min; Gradient: isocratic 50; Wave Length: 220 / 254 nm; RTl(min): 23.918; RT2(min): 33.652; Sample Solvent: EtOH— HPLC) to afford (R)-4-(4-(l-((5-(2,4- difluorophenoxy)pyrazin-2-yl)amino)- 1 -oxopropan-2-yl)-2,2-dimethylpiperazine- 1 - carbonyl)pyridine 1-oxide (22.2 mg) as a white solid. MS (ESI): mass calcd. for C25H26F2N6O4: 512.518 m / z, found: 513.10 [M+H]+.1H NMR (300 MHz, DMSO-d6) δ 10.44 (s, 1H), 8.85 (d, J = 1.4 Hz, 1H), 8.46 (d, J = 1.4 Hz, 1H), 8.17 - 8.27 (m, 2H), 7.38 - 7.56 (m, 4H), 7.11 - 7.24 (m, 1H), 3.54 (q, J = 6.8 Hz, 1H), 3.27 - 3.34 (m, 2H), 2.67 - 2.75 (m, 1H), 2.57 - 2.66 (m, 1H), 2.37 - 3.48 (m, 2H), 1.45 (d, J = 3.0 Hz, 6H), 1.16 - 1.26 (m, 3H).19F NMR (282 MHz, DMSO-d6) δ -113.42, -124.21. And (S)-4-(4-(l-((5-(2,4- difluorophenoxy)pyrazin-2-yl)amino)- 1 -oxopropan-2-yl)-2,2-dimethylpiperazine- 1 - carbonyl)pyridine 1-oxide (42.3 mg) as a white solid. MS (ESI): mass calcd. for C25H26F2N6O4: 512.518 m / z, found: 513.10 [M+H]+.1H NMR (300 MHz, DMSO-d6) δ 10.44 (s, 1H), 8.85 (d, J = 1.4 Hz, 1H), 8.46 (d, J = 1.4 Hz, 1H), 8.17 - 8.27 (m, 2H), 7.38 - 7.56 (m, 4H), 7.11 - 7.24 (m, 1H), 3.54 (q, J = 6.8 Hz, 1H), 3.27 - 3.34 (m, 2H), 2.67 - 2.75 (m, 1H), 2.57 - 2.66 (m, 1H), 2.37 - 3.48 (m, 2H), 1.45 (d, J = 3.0 Hz, 6H), 1.16 - 1.26 (m, 3H).19F NMR (282 MHZ, DMSO-d6) δ -113.42, -124.21.

[0523] Example 64: (R)-N-(5-(2,4-difluorophenoxy)pyrazin-2-yl)-2-(3,3-dimethyl-4-(6-oxo-l,6- dihydropyridine-3-carbonyl)piperazin-1-yl)propanamide and Example 65: (S)-N-(5- (2,4-difluorophenoxy)pyrazin-2-yl)-2-(3,3-dimethyl-4-(6-oxo-l,6-dihydropyridine-3- carbonyl)piperazin- 1 -yl)propanamide

[0524]

[0525] (R)-N-(5-(2,4-difluorophenoxy)pyrazin-2-yl)-2-(3,3-dimethyl-4-(6-oxo-l,6- dihydropyridine-3-carbonyl)piperazin- l-yl)propanamide and (S)-N-(5-(2,4- difluorophenoxy)pyrazin-2-yl)-2-(3,3-dimethyl-4-(6-oxo-l,6-dihydropyridine-3- carbonyl)piperazin- 1 -yl)propanamide

[0526] To a solution of 2-bromo-N-(5-(2,4-difluorophenoxy)pyrazin-2-yl)propanamide (100 mg, 0.279 mmol, 1.0 equiv) in DMA was added 5-(2, 2-dimethylpiperazine-1-carbonyl)pyridin- 2(lH)-one (65 mg, 0.279 mmol, 1.0 equiv) and TEA (113 mg, 1.116 mmol, 4.0 equiv) at room temperature. The reaction mixture was stirred for 3 h at 50 °C. After completion of reaction, the reaction mixture was quenched by addition of water (5 mL). The aqueous layer was extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate filtered and concentrated. The residue obtained was purified by silica gel chromatography (0-20% DCM / MeOH) and Prep-HPLC using a Column: Kinetex EVO C18 Column, 21.2*250 mm, 5μm (eluent: 34% to 64% (v / v) CH3CN and H2O, NH4HCO3+0.1%NH3.H2O) to afford N-(5-(2,4-difluorophenoxy)pyrazin-2-yl)-2- (3,3-dimethyl-4-(6-oxo-l,6-dihydropyridine-3-carbonyl)piperazin-1-yl)propanamide as a white solid. The product was separated by Chiral-Prep-HPLC (CHIRALPAK IF 2*25 cm, 5 μm; Mobile Phase A: MtBE (0.1%DEA)-HPLC, Mobile Phase B: EtOH-HPLC; Flow rate: 15 mL / min; Gradient: isocratic 50; Wave Length: 220 / 254 nm) to afford (R)-N-(5-(2,4- difluorophenoxy)pyrazin-2-yl)-2-(3,3-dimethyl-4-(6-oxo-l,6-dihydropyridine-3- carbonyl)piperazin-1-yl)propanamide (5.6 mg). MS (ESI): mass calcd. for C25H26F2N6O: 512.20 m / z, found: 513.20 [M+H]+,1H NMR (300 MHz, DMSO-d6) δ 11.81 (s, 1H), 10.40 (s, 1H), 8.85 (d, J = 1.4 Hz, 1H), 8.45 (d, J = 1.4 Hz, 1H), 7.56 (d, J = 2.5 Hz, 1H), 7.39 - 7.54 (m, 3H), 7.17 (tdd, J = 9.1, 3.0, 1.6 Hz, 1H), 6.32 (d, J = 9.4 Hz, 1H), 3.52 (t, J = 6.9 Hz, 1H),3.33 - 3.40 (m,2H), 2.67 - 2.78(m,lH), 2.58 - 2.67 (m, 1H), 2.40 (d, J = 2.1 Hz, 2H), 1.40 (d, J = 2.8 Hz, 6H), 1.21 (d, J = 6.8 Hz, 3H).19F NMR (282 MHz, DMSO-d6) δ -113.44, -124.22. And (S)-N-(5-(2,4-difluorophenoxy)pyrazin-2-yl)-2-(3,3-dimethyl-4-(6-oxo-l,6- dihydropyridine-3-carbonyl)piperazin-1-yl)propanamide (9.9 mg). MS (ESI): mass calcd. for C25H26F2N6O: 512.20 m / z, found: 513.20 [M+H]+.1H NMR (300 MHz, DMSO-d6) δ 11.82 (s, 1H), 10.40 (s, 1H), 8.85 (d, J = 1.4 Hz, 1H), 8.45 (d, J = 1.4 Hz, 1H), 7.56 (d, J = 2.6 Hz, 1H), 7.39 - 7.54(m, 3H), 7.11 - 7.24 (m, 1H), 6.32 (d, J = 9.4 Hz, 1H), 3.52 (t, J = 6.9 Hz, 1H), 3.34 - 3.38 (m, 2H), 2.68 - 2.78 (m, 1H), 2.58 - 2.68 (m, 1H), 2.33 - 2.48 (m, 2H), 1.40 (d, J = 2.7 Hz, 6H), 1.21 (d, J = 6.9 Hz, 3H).19F NMR (282 MHz, DMSO-d6) δ -113.43, -124.22.

[0527] Example 66: (R)-4-(4-(l-((5-(4-fluorophenoxy)thiazol-2-yl)amino)-1-oxopropan-2-yl)- 2,2-dimethylpiperazine-1-carbonyl)pyridine 1-oxide and Example 67: (S)-4-(4-(l-((5-(4- fluorophenoxy)thiazol-2-yl)amino)-1-oxopropan-2-yl)-2,2-dimethylpiperazine-1- carbonyl)pyridine 1-oxide

[0528] Synthetic Scheme

[0529] 5-(4-fluorophenoxy)-l,3-thiazol-2-amine

[0530] To a solution of 5-bromothiazol-2-amine (2.0 g, 11.171 mmol, 1.0 equiv) in acetonitrile (30 mL) was added 4-fluorophenol (2.5 g, 22.342 mmol, 2.0 equiv) and CS2CO3(10.9 g, 33.513 mmol, 3.0 equiv) at rt. The resulting mixture was stirred for 2 h at 80 °C under nitrogen atmosphere. After cooled to room temperature, the reaction mixture was quenched by water (50 mL) and extracted with EA (50 mL x 3). The combined organic extracts were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated under vacuum to yield a crude product which was directly purified by silica gel chromatography (0- 60% PE / EA) to afford 5-(4-fluorophenoxy)-l,3-thiazol-2-amine (500 mg, 21.29%) as a yellow solid. MS (ESI): mass calcd. for C9H7FN2OS: 210.2 m / z, found: 211.00 [M+H]+.

[0531] 2-bromo-N-(5-(4-fluorophenoxy)thiazol-2-yl)propanamide

[0532] To a solution of 5-(4-fhiorophenoxy)thiazol-2-amine (470 mg, 2.236 mmol, 1.0 equiv) in CH2CI2(45 mL) was added 2-bromopropanoic acid (684 mg, 4.472 mmol, 2.0 equiv), DCC (692 mg, 3.354 mmol, 1.5 equiv) and AgNO3(57 mg, 0.335 mmol, 0.15 equiv)at rt. The resulting mixture was stirred for 2 h at room temperature. The reaction was quenched by water (10 mL) and extracted with DCM (10 mL x 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue obtained was purified by silica gel chromatography (0-50% PE / EA) to afford 2- bromo-N-[5-(4-fluorophenoxy)-l,3-thiazol-2-yl]propanamide (620 mg, 80.34%) as a yellow solid. MS (ESI): mass calcd. for C12H10BrFN2O2S: 344.1 m / z, found: 345.10 [M+H]+.

[0533] (R)-4-(4-(l-((5-(4-fluorophenoxy)thiazol-2-yl)amino)-1-oxopropan-2-yl)-2,2- dimethylpiperazine-1-carbonyl)pyridine 1-oxide and (S)-4-(4-(l-((5-(4- fluorophenoxy)thiazol-2-yl)amino)-1-oxopropan-2-yl)-2,2-dimethylpiperazine-1- carbonyl)pyridine 1-oxide

[0534] To a solution of 2-bromo-N-[5-(4-fluorophenoxy)-l,3-thiazol-2-yl]propanamide (320 mg, 0.927 mmol, 1.5 equiv) in DMA (5 mL) was added 4-(2,2-dimethylpiperazine-1- carbonyl)pyridine 1-oxide (145 mg, 0.618 mmol, 1.0 equiv), TEA (125 mg, 1.236 mmol, 2.0 equiv) at rt. The resulting mixture was stirred for 2 h at 60 °C. After cooled to room temperature, the reaction mixture was quenched by water (10 mL) and extracted with EA (30 mL x 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated under vacuum to yield a crude product which was directly purified by silica gel column (0-50% PE / EA) & Prep-HPLC (a XBridge Shield RP18 OBD 250 mm x 19 mm x 10 μm column (eluent: 55% to 65% (v / v) MeOH and H2O with 0.05% NH4HCO3) to afford 4-(4-(l-((5-(4-fluorophenoxy)thiazol-2-yl)amino)-1-oxopropan-2-yl)- 2,2-dimethylpiperazine-1-carbonyl)pyridine 1 -oxide as a white solid. The product was separated by Chiral-HPLC (CHIRAL ART Amylose-SA, 5*25 cm, 5 μm column (eluent: 40% to 40%(v / v): EtOH and Hex (0.5% 2M NH3-MeOH)) to afford (R)-4-(4-(l-((5-(4- fluorophenoxy)thiazol-2-yl)amino)- 1 -oxopropan-2-yl)-2,2-dimethylpiperazine- 1 - carbonyl)pyridine 1-oxide (2.2 mg) as a white solid. MS (ESI): mass calcd. for C24H26FN5O4S: 499.17 m / z, found: 500.20 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 11.95 (s, 1H), 8.17 - 8.25 (m, 2H), 7.38 - 7.46 (m, 2H), 7.15 - 7.30 (m, 5H), 3.54 (q, J = 6.9 Hz, 1H), 3.29 (d, J = 5.3 Hz, 2H), 2.69 (dt, J = 10.3, 4.8 Hz, 1H), 2.59 (dt, J = 10.8, 5.2 Hz, 1H), 2.37 - 2.49 (m, 2H), 1.43 (d, J = 4.8 Hz, 6H), 1.26 - 1.18 (m, 3H). And (S)-4-(4-(l-((5-(4- fluorophenoxy)thiazol-2-yl)amino)- 1 -oxopropan-2-yl)-2,2-dimethylpiperazine- 1 - carbonyl)pyridine 1-oxide (2.2 mg) as a white solid. MS (ESI): mass calcd. for C24H26FN5O4S: 499.17 m / z, found: 500.25 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 11.95 (s, 1H), 8.17 - 8.25 (m, 2H), 7.38 - 7.46 (m, 2H), 7.15 - 7.30 (m, 5H), 3.54 (q, J = 6.9 Hz, 1H), 3.29 (d, J = 5.3 Hz, 2H), 2.69 (dt, J = 10.3, 4.8 Hz, 1H), 2.59 (dt, J = 10.8, 5.2 Hz, 1H), 2.37 - 2.49 (m, 2H), 1.43 (d, J = 4.8 Hz, 6H), 1.26 - 1.18 (m, 3H).

[0535] Example 68: (R)-N-(5-(cyclopropylmethoxy)pyridin-2-yl)-2-(3,3-dimethyl-4-(6-oxo-l,6- dihydropyridine-3-carbonyl)piperazin-1-yl)propanamide and Example 69: (S)-N-(5- (cyclopropylmethoxy)pyridin-2-yl)-2-(3,3-dimethyl-4-(6-oxo-l,6-dihydropyridine-3- carbonyl)piperazin- 1 -yl)propanamide

[0536] Synthetic Scheme

[0537] 5- (cyclopropylmethoxy) -2-nitropyridine

[0538] To a solution of 6-nitropyridin-3-ol (600 mg, 4.283 mmol, 1.0 equiv) in DMF (8 mL) was added (bromomethyl)cyclopropane (578 mg, 4.283 mmol, 1.0 equiv) and K2CO3(1.2 g, 8.565 mmol, 2.0 equiv) at room temperature. The mixture was stirred at 80 °C for 3 h. After cooled to room temperature, the reaction was quenched by water (20 mL). The aqueous layer was extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue obtained was purified by silica gel chromatography (0-50% PE / EA) to afford 5-(cyclopropylmethoxy)- 2-nitropyridine (700 mg, 84.17%) as a yellow solid. MS (ESI): mass calcd for C9H10N2O3: 194.19 m / z, found 195.05 [M+H]+.

[0539] 5-(cyclopropylmethoxy)pyridin-2-amine

[0540] To a solution of 5-(cyclopropylmethoxy)-2-nitropyridine (400 mg, 2.060 mmol, 1.0 equiv) in EtOH (20 mL) and H2O (5 mL) was added NH4CI (1.3 g, 24.72 mmol, 12.0 equiv) and Fe (690 mg, 12.36 mmol, 6.0 equiv) at room temperature. The mixture was stirred at 70 °C for 4 h. After cooled to room temperature, the reaction was completed by filtration. The filter cake was rinsed with dichloromethane. The mixture was extracted with dichloromethane (50 mL x 3). The organic phases were combined and washed with saturated brine (20 mL). It was dried over sodium sulfate, filtered with suction, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel chromatography (0-80% PE / EA) to afford 5- (cyclopropylmethoxy)pyridin-2-amine (150 mg, 44.35%) as a yellow solid. MS (ESI): mass calcd for C9H12N2O: 164.20 m / z, found 165. 15[M+H]+.

[0541] 2-bromo-N-(5-(cyclopropylmethoxy)pyridin-2-yl)propanamide

[0542] To a solution of 5-(cyclopropylmethoxy)pyridin-2-amine (135 mg, 0.822 mmol, 1.0 equiv) in DCM (3mL) was added 2-bromopropanoic acid (150 mg, 0.986 mmol, 1.2 equiv), AgNO3(28 mg, 0.16 mmol, 0.2 equiv) and DCC (203 mg, 0.986 mmol, 1.2 equiv) at rt. The mixture was stirred at rt for 3 h. After completion of reaction, the reaction mixture was quenched by addition of water (20 mL). The aqueous layer was extracted with DCM (20 mL x 3). The combined organic phase was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue obtained was purified by silica gel chromatography (0-50% PE / EA) to afford 2-bromo-N-(5-(cyclopropylmethoxy)pyridin-2- yl)propanamide (180 mg, 73.18%) as a yellow solid. MS (ESI): mass calcd for C12H15BrN2O2: 299.168 m / z, found 299.05 [M+H]+.

[0543] (R)-N-(5-(cyclopropylmethoxy)pyridin-2-yl)-2-(3,3-dimethyl-4-(6-oxo-l,6- dihydropyridine-3-carbonyl)piperazin-1-yl)propanamide and (S)-N-(5- (cyclopropylmethoxy)pyridin-2-yl)-2-(3,3-dimethyl-4-(6-oxo-l,6-dihydropyridine-3- carbonyl)piperazin- 1 -yl)propanamide

[0544] To a solution of 5-(2,2-dimethylpiperazine-1-carbonyl)pyridin-2(lH)-one (100 mg, 0.425 mmol, 1.0 equiv) in DMA (3 mL) was added TEA (257 mg, 2.55 mmol, 6.0 equiv) and 2-bromo-N-(5-(cyclopropylmethoxy)pyridin-2-yl)propanamide (127 mg, 0.425 mmol, 1.0 equiv) at rt. The resulting mixture was stirred for 3 h at 60 °C. After cooled to room temperature, the reaction mixture was quenched by water (10 mL) and extracted with EA (20 mL x 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous Na2SO4, and concentrated under vacuum. The residue obtained was purified by silica gel chromatography (0-20% DCM / MeOH) and Prep-HPLC using a Column: XSelect CSH Cl 8 Column, 30*150 mm, 5μm (eluent: 20% to 50% (v / v) CH3CN and H2O, 0.1% FA) to afford 30 mg of N-(5-(cyclopropylmethoxy)pyridin-2-yl)-2-(3,3-dimethyl-4-(6-oxo-l,6- dihydropyridine-3-carbonyl)piperazin-1-yl)propanamide as a white solid. The product was separated by Chiral-Prep-HPLC (Column: CHIRALPAK IA, 2*25 cm, 5 μm; Mobile Phase A: HEX(0.5% 2M NH3-MeOH), Mobile Phase B: IPA; Flow rate: 20 mL / min) to afford (R)-N- (5-(cyclopropylmethoxy)pyridin-2-yl)-2-(3,3-dimethyl-4-(6-oxo-l,6-dihydropyridine-3- carbonyl)piperazin-1-yl)propanamide (8.5 mg, 5.10%, first peak), MS (ESI): mass calcd. for C24H31N5O4453.543 m / z, found 454.25 [M+H]+,1H NMR (300 MHz, DMSO-d6) δ 11.83 (s, 1H), 9.96 (s, 1H), 7.99 - 8.09 (m, 2H), 7.56 (d, J = 2.6 Hz, 1H), 7.38 - 7.50 (m, 2H), 6.32 (d, J = 9.5 Hz, 1H), 3.87 (d, J = 7.0 Hz, 2H), 3.40 - 3.52 (m, 1H), 3.32 - 3.39 (m, 2H), 2.68 - 2.77 (m, 1H), 2.56 - 2.65 (m, 1H), 2.40 (s, 2H), 1.41 (d, J = 1.9 Hz, 6H), 1.23 - 1.28 (m, 1H), 1.14 - 1.22 (m, 3H), 0.52 - 0.64 (m, 2H), 0.27 - 0.38 (m, 2H), and (S)-N-(5- (cyclopropylmethoxy)pyridin-2-yl)-2-(3,3-dimethyl-4-(6-oxo-l,6-dihydropyridine-3- carbonyl)piperazin-1-yl)propanamide (9.9 mg, 5.94%, second peak) as a white solid, MS (ESI): mass calcd. for C24H31N5O4453.543 m / z, found 454.25 [M+H]+,1H NMR (300 MHz, DMSO-d6) δ 11.83 (s, 1H), 9.96 (s, 1H), 7.99 - 8.09 (m, 2H), 7.56 (d, J = 2.6 Hz, 1H), 7.38 - 7.50 (m, 2H), 6.32 (d, J = 9.5 Hz, 1H), 3.87 (d, J = 7.0 Hz, 2H), 3.40 - 3.52 (m, 1H), 3.32 - 3.39 (m, 2H), 2.68 - 2.77 (m, 1H), 2.56 - 2.65 (m, 1H), 2.40 (s, 2H), 1.41 (d, J = 1.9 Hz, 6H), 1.23 - 1.28 (m, 1H), 1.14 - 1.22 (m, 3H), 0.52 - 0.64 (m, 2H), 0.27 - 0.38 (m, 2H).

[0545] Example 70: (R)-2-(3,3-dimethyl-4-(6-oxo-l,6-dihydropyridine-3-carbonyl)piperazin-1- yl)-N-(5-((5-fluoropyridin-2-yl)oxy)pyridin-2-yl)propanamide and Example 71: (S)-2-

[0546] (3,3-dimethyl-4-(6-oxo-l,6-dihydropyridine-3-carbonyl)piperazin-1-yl)-N-(5-((5- fluoropyridin-2-yl)oxy)pyridin-2-yl)propanamide

[0547] Synthetic Scheme

[0548] 5-((5-fluoropyridin-2-yl)oxy)pyridin-2-amine

[0549] To a stirred solution of NaH (1.09 g, 27.243 mmol, 3.0 equiv) in anhydrous DMSO (10 mL) was added 6-aminopyridin-3-ol (2 g, 9.081 mmol, 1.0 equiv). After 15 min, 2,5- difluoropyridine (1.57 g, 13.621 mmol, 1.5 equiv) was added, and the reaction was heated to 110 °C for 90 min. After cooled to room temperature, the reaction was quenched by water (50 mL) and extracted with EA (100 mL x 3). The combined organic extracts were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue obtained was purified by silica gel chromatography (0-100% PE / EA) to afford 5-((5- fhioropyridin-2-yl)oxy)pyridin-2-amine (2 g, 26.68%). MS (ESI): mass calcd. for CioH8FN A): 205.07 m / z, found 206.10 [M+H]+.

[0550] 2-bromo-N-(5-((5-fluoropyridin-2-yl)oxy)pyridin-2-yl)propanamide

[0551] To a stirred solution of 5-((5-fluoropyridin-2-yl)oxy)pyridin-2-amine (660 mg, 3.216 mmol, 1.0 equiv) in DCM was added (R)-2-bromopropanoic acid (590 mg, 3.859 mmol, 1.2 equiv) and DCC (995 mg, 4.824 mmol, 1.5 equiv) followed by catalytic amount of DMAP (39 mg, 0.322 mmol, 0.1 equiv) at room temperature. The reaction mixture was stirred at room temperature for a period of 2.5 h. After completion of reaction, the reaction was quenched by water (10 mL) and extracted with DCM (50 mL x 3). The combined organic extracts were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue obtained was purified by silica gel chromatography (5-25% PE / EA) to afford desired compound 2-bromo-N-(5-((5-fluoropyridin-2-yl)oxy)pyridin-2-yl)propanamide (570 mg, 51.86%) as a light yellow solid. MS (ESI): mass calcd. for C13H11BrFN3O2S: 339.00 m / z, found 339.90 [M+H]+.

[0552]

[0553] (R)-2-(3,3-dimethyl-4-(6-oxo-l,6-dihydropyridine-3-carbonyl)piperazin-1-yl)-N-(5-((5- fluoropyridin-2-yl)oxy)pyridin-2-yl)propanamide and (S)-2-(3,3-dimethyl-4-(6-oxo-l,6- dihydropyridine-3-carbonyl)piperazin-1-yl)-N-(5-((5-fluoropyridin-2-yl)oxy)pyridin-2- yl)propanamide

[0554] To a stirred solution of 2-bromo-N-(5-((5-fluoropyridin-2-yl)oxy)pyridin-2- yl)propanamide (144 mg, 0.425 mmol, 1.0 equiv) in anhydrous DMA (2 mL) was added 5- (2,2-dimethylpiperazine-1-carbonyl)pyridin-2(lH)-one (100 mg, 0.425 mmol, 1.0 equiv) and TEA (258 mg, 2.550 mmol, 6.0 equiv) at room temperature. The reaction mixture was stirred at 60 °C for a period of 3 h. After cooled to room temperature, the reaction was quenched by water (10 mL) and extracted with EA (30 mL x 3). The combined organic extracts were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue obtained was purified by silica gel chromatography (0-25% DCM / MeOH) and Prep-HPLC using a Column: YMC Triart C18 ExRs Column, 20*250mm, 5μm (eluent: 35% to 65% CH3CN and H2O, lOmmol / L NH4HCO3) to afford 2-(3,3-dimethyl-4-(6-oxo-l,6- dihydropyridine-3-carbonyl)piperazin-1-yl)-N-(5-((5-fluoropyridin-2-yl)oxy)pyridin-2- yl)propanamide as a white solid. The product was separated by Chiral-Prep-HPLC (CHIRALPAK IF 2*25 cm, 5 μm; Mobile Phase A: HEX(0.5% 2M NH3-MeOH), Mobile Phase B: IPA; Flow rate: 14 mL / min; Gradient: isocratic 50; Wave Length: 220 / 254 nm) to afford (R)-2-(3,3-dimethyl-4-(6-oxo-l,6-dihydropyridine-3-carbonyl)piperazin-1-yl)-N-(5- ((5-fluoropyridin-2-yl)oxy)pyridin-2-yl)propanamide (19.5 mg, first peak). MS (ESI): mass calcd. for C25H27FN6O4: 494.21 m / z, found: 495.15 [M+H]+,1H NMR (400 MHz, DMSO-d6) 3 11.84 (s, 1H), 10.18 (s, 1H), 8.15 - 8.24 (m, 3H), 7.86 (td, J = 8.5, 3.1 Hz, 1H), 7.62 - 7.71 (m, 1H), 7.57 (d, J = 2.6 Hz, 1H), 7.47 (dd, J = 9.4, 2.6 Hz, 1H), 7.20 (dd, J = 9.0, 3.6 Hz, 1H), 6.32 (d, J = 9.4 Hz, 1H), 3.50 (q, J = 6.9, 6.3 Hz, 1H), 2.70 - 2.77 (m, 1H), 2.63 (d, J = 5.7 Hz, 1H), 2.48 - 2.53 (m, 2H), 2.33 - 2.46 (m, 2H), 1.41 (d, J = 2.9 Hz, 6H), 1.23 (d, J = 6.9 Hz, 3H).19F NMR (376 MHz, DMSO-d6) δ - 135.83, - 135.88, - 136.28. And (S)-2-(3,3- dimethyl-4-(6-oxo-l,6-dihydropyridine-3-carbonyl)piperazin-1-yl)-N-(5-((5-fluoropyridin-2- yl)oxy)pyridin-2-yl)propanamide (19.2 mg, second peak). MS (ESI): mass calcd. for C25H27FN6O4: 494.21 m / z, found: 495.15 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 11.84 (s, 1H), 10.18 (s, 1H), 8.15 - 8.24 (m, 3H), 7.86 (td, J = 8.5, 3.1 Hz, 1H), 7.62 - 7.71 (m,

[0555] 1H), 7.57 (d, J = 2.6 Hz, 1H), 7.47 (dd, J = 9.4, 2.6 Hz, 1H), 7.20 (dd, J = 9.0, 3.6 Hz, 1H), 6.32 (d, J = 9.4 Hz, 1H), 3.50 (q, J = 6.9, 6.3 Hz, 1H), 2.70 - 2.77 (m, 1H), 2.63 (d, J = 5.7 Hz, 1H), 2.48 - 2.53 (m, 2H), 2.33 - 2.46 (m, 2H), 1.41 (d, J = 2.9 Hz, 6H), 1.23 (d, J = 6.9 Hz, 3H).19F NMR (376 MHz, DMSO-d6) δ -135.88.

[0556] Example 72: (R)-2-(3,3-dimethyl-4-(l-methyl-6-oxo-l,6-dihydropyridine-3- carbonyl)piperazin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propanamide and Example 73: (S)-2-(3,3-dimethyl-4-(l-methyl-6-oxo-l,6-dihydropyridine-3- carbonyl)piperazin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propanamide

[0557] (R)-2-(3,3-dimethyl-4-(l-methyl-6-oxo-l,6-dihydropyridine-3-carbonyl)piperazin-1-yl)- N-(5-(4-fluorophenoxy)pyridin-2-yl)propanamide and (S)-2-(3,3-dimethyl-4-(l-methyl- 6-oxo-l,6-dihydropyridine-3-carbonyl)piperazin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2- yl)propanamide

[0558] To a solution of l-methyl-6-oxo-l,6-dihydropyridine-3-carboxylic acid (30 mg, 0.196 mmol, 1.0 equiv) in DMF (2 mL) was added 2-(3,3-dimethylpiperazin-1-yl)-N-(5-(4- fluorophenoxy)pyridin-2-yl)propanamide (73 mg, 0.196 mmol, 1.0 equiv), HATU (71 mg, 0.294 mmol, 1.5 equiv) and DIEA (76 mg, 0.588 mmol, 3.0 equiv). The reaction was stirred at room temperature for 3 h. The mixture was quenched with water (10 mL) extracted with EA (3 x 20 mL). The organic layer were dried and filtered then concentrated to dryness under reduced pressure to provide the crude product. The crude product was purified Cl 8 column then separated by chiral-HPLC (column: CHIRALPAK IA, 2*25 cm, 5 μm column: Mobile Phase A: MtBE(0.5% 2M NH3-MeOH)-HPLC, Mobile Phase B: IPA: DCM=1: 1-HPLC; Flow rate: 20 mL / min) to afford (R)-2-(3,3-dimethyl-4-(l-methyl-6-oxo-l,6-dihydropyridine- 3-carbonyl)piperazin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propanamide (12.7 mg) as a white solid. MS (ESI): mass calcd. for C27H30FN5O4: 507.23 m / z, found: 508.20 [M+H]+.1H NMR (300 MHz, DMSO-d6) δ 10.17 (s, 1H), 8.11 - 8.20 (m, 2H), 7.99 (d, J = 2.5 Hz, 1H), 7.53 (dd, J = 9.0, 3.0 Hz, 1H), 7.46 (dd, J = 9.4, 2.5 Hz, 1H), 7.17 - 7.32 (m, 2H), 7.04 - 7.16 (m, 2H), 6.38 (d, J = 9.3 Hz, 1H), 3.46 - 3.56 (m, 1H), 3.46 (s, 3H), 3.32 (s, 2H), 2.70 - 2.82 (m, 1H), 2.59 - 2.70 (m, 1H), 2.43 (s, 2H), 1.43 (s, 6H), 1.22 (d, J = 6.9 Hz, 3H). And (S)-2- (3,3-dimethyl-4-(l-methyl-6-oxo-l,6-dihydropyridine-3-carbonyl)piperazin-1-yl)-N-(5-(4- fluorophenoxy)pyridin-2-yl)propanamide (16.4 mg) as a white solid. MS (ESI): mass calcd. for C27H30FN5O4: 507.23, found: 508.20 [M+H]+,1H NMR (300 MHz, DMSO-d6) δ 10.17 (s, 1H), 8.11 - 8.21 (m, 2H), 7.99 (d, J = 2.5 Hz, 1H), 7.53 (dd, J = 8.9, 3.1 Hz, 1H), 7.46 (dd, J = 9.3, 2.6 Hz, 1H), 7.17 - 7.31 (m, 2H), 7.03 - 7.16 (m, 2H), 6.38 (d, J = 9.3 Hz, 1H), 3.46 - 3.55 (m, 1H), 3.46 (s, 3H), 3.34 - 3.42 (m, 2H), 2.71 - 2.81 (m, 1H), 2.59 - 2.71 (m, 1H), 2.43 (s, 2H), 1.43 (s, 6H), 1.22 (d, J = 6.8 Hz, 3H).

[0559] Example 74: (S)-N-(5-(2,4-difluorophenoxy)pyrazin-2-yl)-2-(3,3-dimethyl-4-(5-oxo-4,5- dihydropyrazine-2-carbonyl)piperazin-1-yl)propanamide

[0560] Synthetic Scheme

[0561] 5-(2,4-difluorophenoxy)pyrazin-2-amine

[0562] To a stirring solution of 2,4-difluorophenol (18.0 g, 137.930 mmol, 1.2 equiv) in dioxane (200 mL) was added dimethylglycine (1.2 g, 11.494 mmol, 0.1 equiv), 5- bromopyrazin-2-amine (20.0 g, 114.942 mmol, 1.0 equiv), CS2CO3(56.2 g, 172.413 mmol, 1.5 equiv) and Cui (4.4 g, 22.988 mmol, 0.2 equiv) at room temperature. The reaction mixture was stirred at 110 °C for 5h. After cooling to room temperature, the reaction was filtered and the filter cake was washed with EA (200 mL). The filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography (20-40% PE / EA) to afford 5-(2,4- difluorophenoxy)pyrazin-2-amine (20.0 g, 77.83%) as a yellow solid. MS (ESI): mass calcd. for: C10H7F2N3O: 223.05 m / z, found: 224.10 [M+H]+.1H NMR (300 MHz, DMSO-d6) δ 7.92 (d, J = 1.4 Hz, 1H), 7.46 (d, J = 1.4 Hz, 1H), 7.35 - 7.45 (m, 1H), 7.21 - 7.35 (m, 1H), 7.00 - 7.14 (m, 1H), 6.17 (s, 2H).

[0563] T ert-butyl (S)-4- (1 -methoxy- 1 -oxopropan-2-yl)-2,2-dimethylpiperazine- 1 -carboxylate

[0564] To a stirring solution of tert-butyl 2,2-dimethylpiperazine-l -carboxylate (15.0 g, 69.992 mmol, 1.0 equiv) in MeCN (200 mL) was added methyl (R)-2-chloropropanoate (17.2 g, 139.984 mmol, 2.0 equiv) and K2CO3(29.0 g, 209.976 mmol, 3.0 equiv). The reaction stirred overnight at 80 °C. The reaction was subsequently cooled to ambient temperature and concentrated under reduced pressure. Water (100 mL) was added and the contents were extracted with EA (200 mL x 3). The combined organic extracts were washed with water (100 mL x 4), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (5-20% PE / EA) to afford tert-butyl (S)-4-(l-methoxy-1- oxopropan-2-yl)-2,2-dimethylpiperazine-l -carboxylate (15.0 g, 71.34%) as light-yellow oil. MS (ESI): mass calcd. for: C15H28N2O4: 300.20 m / z, found: 300.95 [M+H]+.1H NMR (400 MHz, Methanol-d4) δ 4.09 (q, J = 7.1 Hz, 1H), 3.68 (s, 3H), 3.38 - 3.46 (m, 1H), 3.33 (q, J = 7.1 Hz, 1H), 2.56 - 2.65 (m, 2H), 2.37 - 2.44 (m, 1H), 2.30 (d, J = 11.6 Hz, 1H), 1.44 (s, 9H), 1.36 (d, J = 7.7 Hz, 6H), 1.26 (d, J = 7.1 Hz, 3H).

[0565] (S)-2-(4-(tert-butoxycarbonyl)-3,3-dimethylpiperazin-1-yl)propanoic acid To a stirring solution of tert-butyl (S)-4-(l-methoxy-1-oxopropan-2-yl)-2,2- dimethylpiperazine-1 -carboxylate (15.0 g, 49.934 mmol, 1.0 equiv) in THF (90 mL), MeOH (30 mL) and H2O (30 mL) was added LiOHH2O (3.1 g, 74.901 mmol, 1.5 equiv) at room temperature. After stirring the reaction at room temperature for a period of 4h, the mixture was acidified to a pH = 6 with HC1 (aq., IN). The low boiling point solvent removed under reduced pressure. The residue was extracted with MeOH / DCM=l / 4 (100 mL x 4), dried over anhydrous sodium sulfate, filtered and concentrated to afford (S)-2-(4-(tert-butoxycarbonyl)-3,3- dimethylpiperazin-1-yl)propanoic acid (15.0 g, 94.41%) as light yellow oil. MS (ESI): mass calcd. for : C14H26N2O4: 286.19 m / z, found: 287.25 [M+H]+.

[0566] Tert-butyl (S)-4-(l-((5-(2,4-difluorophenoxy)pyrazin-2-yl)amino)-1-oxopropan-2-yl)-2,2- dimethylpiperazine- 1 -carboxylate

[0567] To a stirring solution of (S)-2-(4-(tert-butoxycarbonyl)-3,3-dimethylpiperazin-1- yl)propanoic acid (15.0 g, 52.379 mmol, 1.0 equiv) in pyridine (150 mL) was added 5-(2,4- difhiorophenoxy)pyrazin-2-amine (15.2 g, 68.093 mmol, 1.3 equiv) and EDO (20.1 g, 104.758 mmol, 2.0 equiv) at room temperature. The reaction mixture was stirred at room temperature for 4h then quenched by the addition of water (100 mL) and extracted with EA (200 mL x 3). The combined organic extracts were washed with water (100 mL x 4), dried over anhydrous sodium sulfate, filtered and concentrated. Purification by silica gel chromatography (5-20% PE / EA) to afforded tert-butyl (S)-4-(l-((5-(2,4-difluorophenoxy)pyrazin-2-yl)amino)-1- oxopropan-2-yl)-2,2-dimethylpiperazine-l -carboxylate (10.0 g, 37.91%, ~90% ee) as yellow oil. MS (ESI): mass calcd. for: C24H31F2N5O4: 491.23 m / z, found: 491.80 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 10.34 (s, 1H), 8.83 (d, J = 1.4 Hz, 1H), 8.45 (d, J = 1.4 Hz, 1H), 7.41 - 7.54 (m, 2H), 7.12 - 7.22 (m, 1H), 3.47 (q, J = 6.8 Hz, 1H), 3.31 - 3.36 (m, 2H), 2.63 (dt, J = 10.9, 5.2 Hz, 1H), 2.51 - 2.56 (m, 1H), 2.31 (s, 2H), 1.39 (s, 9H), 1.33 (d, J = 1.8 Hz, 6H), 1.18 (d, J = 6.9 Hz, 3H). Tert-butyl (S)-4-(l-((5-(2,4-difluorophenoxy)pyrazin-2-yl)amino)-1-oxopropan-2-yl)-2,2- dimethylpiperazine- 1 -carboxylate (hydrochloride)

[0568] To a stirring solution of tert-butyl (S)-4-(l-((5-(2,4-difluorophenoxy)pyrazin-2- yl)amino)-1-oxopropan-2-yl)-2,2-dimethylpiperazine-1-carboxylate (10.0 g, 20.344 mmol, 1.0 equiv) in EA (50 mL) and Et20 (100 mL) was added 4N HC1 (in EA, -15 mL). A precipitate formed which was filtered and washed with ether. The precipitate was dried to afford tert-butyl (S)-4-(l-((5-(2,4-difluorophenoxy)pyrazin-2-yl)amino)-1-oxopropan-2-yl)-2,2- dimethylpiperazine-1 -carboxylate (hydrochloride) (-90% ee). The solid was dissolved with CH3CN (-400 mL) at 90 °C. The solution was allowed to cool to room temperature. The precipitate was filtered and dried under reduced pressure to afford tert-butyl (S)-4-(l-((5-(2,4- difluorophenoxy)pyrazin-2-yl)amino)- 1 -oxopropan-2-yl)-2,2-dimethylpiperazine- 1 - carboxylate (hydrochloride) (8.0 g, >99% ee) as a white solid. MS (ESI): mass calcd. for: C24H31F2N5O4: 491.23 m / z, found: 491.80 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ1H NMR (400 MHz, DMSO-d6) δ 10.51 (s, 1H), 8.82 (s, 1H), 8.50 (d, J = 1.4 Hz, 1H), 7.42 - 7.55 (m, 2H), 7.13 - 7.23 (m, 1H), 3.93 - 4.35 (m, 3H), 3.47 - 3.57 (m, 2H), 2.08 (s, 2H), 1.59 - 1.64 (m, 3H), 1.47 (d, J = 9.1 Hz, 6H), 1.41 (s, 9H).

[0569] (S)-N-(5-(2,4-difluorophenoxy)pyrazin-2-yl)-2-(3,3-dimethylpiperazin-1-yl)propanamide

[0570] (hydrochloride)

[0571] To a stirring solution of tert-butyl (S)-4-(l-((5-(2,4-difluorophenoxy)pyrazin-2- yl)amino)-1-oxopropan-2-yl)-2,2-dimethylpiperazine-1-carboxylate (hydrochloride) (8 g, 15.152 mmol, 1.0 equiv) in MeOH (20 mL) and DCM (60 mL) was added 4N HC1 (in EA, 80 mL). The reaction stirred at room temperature for 2 h and subsequently concentrated under reduced pressure. MeOH (-10 mL) was added to the residue and the mixture was added to Et20 (-200 mL). The solids were filtered and the filter cake was washed with ether and dried under reduced pressure to obtain (S)-N-(5-(2,4-difluorophenoxy)pyrazin-2-yl)-2-(3,3- dimethylpiperazin-1-yl)propanamide (hydrochloride) (6 g, >99% ee). MS (ESI): mass calcd. for: C19H23F2N5O2: 391.18 m / z, found: 392.25 [M+H]+.1H NMR (400 MHz, Methanol-d4) δ 8.87 (s, 1H), 8.30 (s, 1H), 7.33 (td, J = 8.9, 5.5 Hz, 1H), 7.09 - 7.19 (m, 1H), 6.98 - 7.08 (m, 1H), 4.37 (q, J = 6.9 Hz, 1H), 3.82 - 3.90 (m, 1H), 3.69 - 3.72 (m, 2H), 3.59 - 3.65 (m, 3H) , 1.75 (d, J = 6.9 Hz, 3H), 1.65 (d, J = 25.8 Hz, 6H).

[0572] (S)-N-(5-(2,4-difluorophenoxy)pyrazin-2-yl)-2-(4-(5-methoxypyrazine-2-carbonyl)-3,3- dimethylpiperazin- 1 -yl)propanamide

[0573] To a stirring solution of (S)-N-(5-(2,4-difluorophenoxy)pyrazin-2-yl)-2-(3,3- dimethylpiperazin-1-yl)propanamide (hydrochloride) (7.0 g, 16.35 mmol, 1.0 equiv) in DMF (100 mL) was added 5-methoxypyrazine-2-carboxylic acid (3.3 g, 21.25 mmol, 1.3 equiv), HATU (9.3 g, 24.52 mmol, 1.5 equiv) and DIEA (20.0 mL, 114.45 mmol, 7.0 equiv) at rt. The reaction stirred for 5 h at rt. The reaction mixture was quenched with water (100 mL) and extracted with EA (3 x 100 mL). The combined organic extracts were washed with brine (3 x 50 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography (0-20% DCM / MeOH) to afford (S)-N-(5-(2,4- difluorophenoxy)pyrazin-2-yl)-2-(4-(5-methoxypyrazine-2-carbonyl)-3,3-dimethylpiperazin- l-yl)propanamide (5.6 g, 65.1%) as a yellow oil. MS (ESI): mass calcd. for C25H27F2N7O4: 527.21, found: 528.40 [M+H]+.

[0574] (S)-N-(5-(2,4-difluorophenoxy)pyrazin-2-yl)-2-(4-(5-methoxypyrazine-2-carbonyl)-3,3- dimethylpiperazin- 1 -yl)propanamide

[0575] To a solution of (S)-N-(5-(2,4-difluorophenoxy)pyrazin-2-yl)-2-(4-(5- methoxypyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)propanamide (4.0 g, 7.57 mmol, 1.0 equiv) in DMF (80 mL) was added pyridinium hydrobromide (1.2 g, 45.42 mmol, 6.0 equiv) at rt. The resulting mixture was stirred for 12 h at 120 °C. The reaction was subsequently cooled to room temperature and quenched with water (100 mL). The mixture was extracted with EA (3 x 100 mL). The combined organic layers were washed with brine (3 x 100 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by Cl 8 column (eluent: 30% to 60% ACN and H2O (0.01 % FA) to afford (S)-N-(5-(2,4-difluorophenoxy)pyrazin-2- yl)-2-(3,3-dimethyl-4-(5-oxo-4,5-dihydropyrazine-2-carbonyl)piperazin-1-yl)propanamide (2.0 g, 51.3%) as a yellow solid. The solid was dissolved in toluene (~40 mL) at reflux and the resulting solution was allowed to cool to ambient temperature. The precipitate was filtered and dried under reduced pressure to afford 1.6 g of (S)-N-(5-(2,4-difluorophenoxy)pyrazin-2-yl)- 2-(3,3-dimethyl-4-(5-oxo-4,5-dihydropyrazine-2-carbonyl)piperazin- l-yl)propanamide as a yellow solid. MS (ESI): mass calcd. for C24H25F2N7O4: 513.19, found: 514.10 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 12.60 (s, 1H), 10.39 (s, 1H), 8.85 (s, 1H), 8.46 (d, J = 1.5 Hz, 1H), 7.91 (s, 1H), 7.75 (s, 1H), 7.51 - 7.39 (m, 2H), 7.20 - 7.10 (m, 1H), 3.56 - 3.45 (m, 3H), 2.77 - 2.68 (m, 1H), 2.65 - 2.56 (m, 1H), 2.47 - 2.35 (m, 2H), 1.44 - 1.39 (m, 6H), 1.20 (d, J = 6.9 Hz, 3H).

[0576] Example 75: (S)-N-(5-(2,4-difluorophenoxy)pyrazin-2-yl)-2-(4-(4-(2-hydroxyethyl)-5- oxo-4, 5-dihydropyrazine-2-carbonyI)-3,3-dimethyIpiperazin-1-yI)propanamide

[0577]

[0578] Synthesis of methyl 4-(2-((tert-butyldimethylsilyl)oxy)ethyl)-5-oxo-4,5-dihydropyrazine- 2-carboxylate

[0579] To a solution of methyl 5-oxo-4,5-dihydropyrazine-2-carboxylate (10 g, 64.882 mmol, 1.0 equiv) in DMF (100 mL) was added K2CO3(27.1 g, 194.646 mmol, 3.0 equiv) and (2- bromoethoxy)(tert-butyl)dimethylsilane (31.0 g, 129.764 mmol, 2 equiv) at rt. The reaction stirred for 3 h at 80 °C. The reaction was then cooled to room temperature and quenched with water (100 mL). The resulting mixture was extracted with EA (3 x 200 mL). The combined organic layers were washed with brine (3 x 60 mL), dried over anhydrous Na2SO4and concentrated under vacuum. The crude was purified by silica gel column (0-30% PE / EA) to afford methyl 4-(2-((tert-butyldimethylsilyl)oxy)ethyl)-5-oxo-4,5-dihydropyrazine-2- carboxylate (15 g, 73.99%, large polar isomer) as a yellow solid. MS (ESI): mass calcd. for C14H24N2O4Si:312.15, found: 313.10 [M+H]+.1H NMR (300 MHz, DMSO-d6) δ 8.39 (d, J = 1.1 Hz, 1H), 8.02 (d, J = 1.0 Hz, 1H), 4.09 (dd, J = 5.6, 4.5 Hz, 2H), 3.81 (dd, J = 5.6, 4.5 Hz, 2H), 3.78 (s, 3H), 0.76 (s, 9H), -0.11 (s, 6H).

[0580] Synthesis of 4-(2-((tert-butyldimethylsilyl)oxy)ethyl)-5-oxo-4,5-dihydropyrazine-2- carboxylic acid

[0581] To a solution of methyl 4-(2-((tert-butyldimethylsilyl)oxy)ethyl)-5-oxo-4,5- dihydropyrazine-2-carboxylate (10.0 g, 32.006 mmol, 1 equiv) in THF (100 mL), methanol (10 mL) and water (10 mL) was added LiOH (1.15 g, 48.009 mmol, 1.5 equiv) at rt. The resulting mixture was stirred for 1 h at rt then concentrated under vacuum. To the residue was added ice- water and the mixture was acidified to pH 5~6 with 3 N HC1. The precipitate was collected by filtration and washed with H2O (50 mL) to afford 4-(2-((tert-butyldimethylsilyl)oxy)ethyl)-5- oxo-4, 5-dihydropyrazine-2-carboxylic acid (7.5 g, 78.53%) as a yellow solid. MS (ESI): mass calcd. for C13H22N2O4Si: 298.13, found: 299.10 [M+H]+.

[0582] Synthesis of (S)-2-(4-(4-(2-((tert-butyldimethylsilyl)oxy)ethyl)-5-oxo-4,5- dihydropyrazine-2-carbonyI)-3,3-dimethyIpiperazin-1-yI)-N-(5-(2,4- difluorophenoxy)pyrazin-2-yI)propanamide

[0583] To a solution of ((S)-N-(5-(2,4-difluorophenoxy)pyrazin-2-yl)-2-(3,3- dimethylpiperazin-1-yl)propanamide (hydrochloride) (5.0 g, 11.68 mmol, 1.0 equiv) in DMF (80 mL) was added 4-(2-((tert-butyldimethylsilyl)oxy)ethyl)-5-oxo-4,5-dihydropyrazine-2- carboxylic acid (5.2 g, 17.5 mmol, 1.5 equiv), HATU (6.65 g, 17.5 mmol, 1.5 equiv), DIEA (12.2 mL, 70.08 mmol, 6.0 equiv). The resulting mixture was stirred for 2 h at rt. The reaction was subsequently quenched with water (80 mL) and extracted with EA (3 x 100 mL). The combined organic extracts were washed with brine (3 x 50 mL), dried over anhydrous

[0584] Na2SO4and concentrated under vacuum. The crude was purified by silica gel column (0-10% MeOH / DCM) to afford (S)-2-(4-(4-(2-((tert-butyldimethylsilyl)oxy)ethyl)-5-oxo-4,5- dihydropyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)-N-(5-(2,4- difhiorophenoxy)pyrazin-2-yl)propanamide (6 g, 76.9%) as a white solid. MS (ESI): mass calcd. for C32H43F2N?O5Si: 671.30 m / z, found 672.20 [M+H]+.

[0585] Synthesis of (S)-N-(5-(2,4-difluorophenoxy)pyrazin-2-yl)-2-(4-(4-(2-hydroxyethyl)-5-oxo-

[0586] 4,5-dihydropyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)propanamide

[0587] To a solution of (S)-2-(4-(4-(2-((tert-butyldimethylsilyl)oxy)ethyl)-5-oxo-4,5- dihydropyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)-N-(5-(2,4- difluorophenoxy)pyrazin-2-yl)propanamide (6 g, 8.931 mmol, 1 equiv) in THF (100 mL) was added TEA 3HF (5 mL). The resulting mixture was stirred for 1 h at 60 °C. The reaction was then cooled to room temperature. The reaction mixture was diluted with water (60 mL) and extracted with EA (3 x 100 mL). The combined organic extracts were washed with brine (3 x 50 mL), dried over anhydrous Na2SO4and concentrated under vacuum. The crude product was purified by C18 column (eluent: 30% to 65% ACN and H2O) to afford (S)-N-(5-(2,4- difluorophenoxy)pyrazin-2-yl)-2-(4-(4-(2-hydroxyethyl)-5-oxo-4,5-dihydropyrazine-2- carbonyl)-3,3-dimethylpiperazin-1-yl)propanamide (3.2 g, 64.3%) as a white solid. MS (ESI): mass calcd. for C26H29F2N7O5: 557.22 m / z, found 558.10 [M+H]+.1H NMR (300 MHz, DMSO-d6) δ 10.41 (s, 1H), 8.85 (d, J = 1.5 Hz, 1H), 8.46 (d, J = 1.4 Hz, 1H), 7.97 (d, J = 1.1 Hz, 1H), 7.93 (d, J = 1.0 Hz, 1H), 7.55 - 7.39 (m, 2H), 7.24 - 7.11 (m, 1H), 4.96 (t, J = 5.6 Hz, 1H), 4.02 - 3.92 (m, 2H), 3.69 - 3.58 (m, 2H), 3.55 - 3.44 (m, 3H), 2.79 - 2.69 (m, 1H), 2.67 - 2.57 (m, 1H), 2.49 - 2.35 (m, 2H), 1.46 - 1.40 (m, 6H), 1.21 (d, J = 6.9 Hz, 3H).

[0588] Example 76: (2R)-2-[3,3-dimethyI-4-(6-oxo-lH-pyridine-3-carbonyI)piperazin-1-yI]-N- [5-(4-fluorophenoxy)-l,3-thiazoI-2-yI]propanamide and Example 77: (2S)-2-[3,3- dimethyI-4-(6-oxo-lH-pyridine-3-carbonyI)piperazin-1-yI]-N-[5-(4-fluorophenoxy)-l,3- thiazoI-2-yI] propanamide

[0589] Synthesis of 5-(4-fluorophenoxy)-l,3-thiazol-2-amine

[0590] To a stirred mixture of 5-bromo-l,3-thiazol-2-amine (2.0g, 11.171 mmol, 1 equiv) and 4-fluorophenol (2.5 g, 22.342 mmol, 2 equiv) in acetonitrile (20 mL) was added CS2CO3(10.9 g, 33.513 mmol, 3 equiv) in portions at room temperature under air atmosphere. The resulting mixture was stirred for 2 h at 80 °C under nitrogen atmosphere. The resulting mixture was extracted with EtOAc (3 x 10 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:2) to afford 5-(4- fluorophenoxy)- l,3-thiazol-2- amine (500 mg, 21.29 %) as a yellow solid. MS (ESI): mass calcd. for C9H7FN2OS: 210.0 m / z, found: 211.00 [M+H]+.

[0591] 2-bromo-N-[5-(4-fluorophenoxy)-l,3-thiazol-2-yl]propanamide

[0592] To a stirred mixture of 5-(4-fluorophenoxy)-l,3-thiazol-2-amine (470 mg, 2.236 mmol, 1 equiv) and (2R)-2-bromopropanoic acid (684.00 mg, 4.472 mmol, 2 equiv) in CH2CI2(5 mL) were added DCC (691.93 mg, 3.354 mmol, 1.5 equiv) and AgNO3(56.97 mg, 0.335 mmol, 0.15 equiv) in portions at room temperature under air atmosphere. The resulting mixture was stirred for 2 h at room temperature under air atmosphere. The resulting mixture was extracted with CH2CI2(3 x 10 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford 2-bromo-N-[5-(4-fluorophenoxy)-l,3-thiazol-2-yl]propanamide (620 mg, 80.34 %) as a yellow solid. MS (ESI): mass calcd. for C12H10BrFN2O2S: 344.0 m / z, found: 345.0 [M+H]

[0593] 2-[3,3-dimethyI-4-(6-oxo-lH-pyridine-3-carbonyI)piperazin-1-yI]-N-[5-(4- fluorophenoxy)-l,3-thiazoI-2-yI]propanamide

[0594] To a stirred mixture of 2-bromo-N-[5-(4-fluorophenoxy)-l,3-thiazol-2-yl]propanamide (320 mg, 0.927 mmol, 1.5 equiv) and 5-(2,2-dimethylpiperazine-1-carbonyl)-lH-pyridin-2- one (145.41 mg, 0.618 mmol, 1 equiv) in DMA (5 mL) was added TEA (125.08 mg, 1.236 mmol, 2 equiv) in portions at room temperature under air atmosphere. The resulting mixture was stirred for 1.5 h at 60 °C under air atmosphere. The resulting mixture was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (3 x10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE /

[0595] EA (1:4) to afford 2-[3,3-dimethyl-4-(6-oxo-lH-pyridine-3-carbonyl)piperazin-1-yl]-N-[5-(4- fluorophenoxy)-l,3-thiazol-2-yl]propanamide (60 mg, 19.43 %) as a yellow solid. MS (ESI): mass calcd. for C24H26FN5O4S:499.2 m / z, found:500.20 [M+H]+.

[0596] (2R)-2-[3,3-dimethyl-4-(6-oxo-lH-pyridine-3-carbonyl)piperazin-1-yl]-N-[5-(4- fluorophenoxy)-l,3-thiazol-2-yl]propanamide and (2S)-2-[3,3-dimethyI-4-(6-oxo-lH- pyridine-3-carbonyI)piperazin-1-yI]-N-[5-(4-fluorophenoxy)-l,3-thiazoI-2- yl]propanamide

[0597] 2- [3 ,3-dimethyl-4-(6-oxo- 1 H-pyridine-3 -carbonyl)piperazin- 1 -yl] -N - [5-(4- fluorophenoxy)-l,3-thiazol-2-yl]propanamide (30 mg) was purified by chiral-HPLC using a CHIRAL ART Amylose-SA, 5*25 cm, 5 μm column (eluent: 40% (v / v) Hex: DCM=3: 1(0.5% 2M NH -MeOH) and EtOH) to afford (2S)-2-[3,3-dimethyl-4-(6-oxo-lH-pyridine-3- carbonyl)piperazin-1-yl]-N-[5-(4-fluorophenoxy)-l,3-thiazol-2-yl]propanamide (6.4 mg, 21.19 %) as a white solid. MS (ESI): mass calcd. for C24H2eFN5O4S:499.2 m / z, found: 500.20 [M+H]+.1H NMR (400 MHz, Acetonitrile-*) 5 7.55 - 7.65 (m, 1H), 7.47 - 7.55 (m, 1H), 7.13 - 7.21 (m, 4H), 7.06 - 7.13 (m, 1H), 6.37 (d, J = 9.5 Hz, 1H),3.4O - 3.57 (m, 3H), 2.74 - 2.88 (m, 1H), 2.60 - 2.73 (m, 1H), 2.36 - 2.48 (m, 2H), 1.50 (d, J = 4.2 Hz, 6H), 1.31 - 1.32 (m, 3H).19F NMR (376 MHz, CD3CN) 5 -121.32. And (2R)-2-[3,3-dimethyl-4-(6-oxo-lH- pyridine-3-carbonyl)piperazin-1-yl]-N-[5-(4-fluorophenoxy)-l,3-thiazol-2-yl]propanamide (4.8 mg, 15.92 %) as a white solid. MS (ESI): mass calcd. for C24H26FN5O4S: 499.2 m / z, found: 500.25 [M+H]+.1H NMR (400 MHz, Acetonitrile-*) 7.57 - 7.68 (m, 1H), 7.47 - 7.57 (m, 1H), 7.22 - 7.38 (m, 4H), 7.06 - 7.14 (m, 1H), 6.39 (d, J = 9.4, 0.7 Hz, 1H), 3.40 - 3.55 (m, 3H), 2.70 - 2.85 (m, 1H), 2.60 - 2.70 (m, 1H), 2.33 - 2.48 (m, 2H), 1.50 (d, J = 4.3 Hz, 6H), 1.24 - 1.32 (m, 3H).19F NMR (376 MHz, CD3CN) 5 -121.35.

[0598] Example 78: 2-(aminomethyl)-4-{4-[(lR)-1-{[5-(4-fluorophenoxy)pyridin-2- yl]carbamoyl}ethyl]-2,2-dimethylpiperazine-1-carbonyl}pyridin-1-ium-1-olate and Example 79: 2-(aminomethyl)-4-{4-[(lS)-1-{[5-(4-fluorophenoxy)pyridin-2- yl]carbamoyl}ethyl] -2,2-dimethylpiperazine- 1 -carbonyl}pyridin- 1 -ium-1 -olate

[0599] 2-{[(tert-butoxycarbonyl)amino]methyl}pyridine-4-carboxylic acid

[0600] To a solution of methyl 2-{ [(tert-butoxycarbonyl)(methyl)amino]methyl}pyridine-4- carboxylate (260 mg, 0.927 mmol, 1 equiv) in THF / McOH / H2O (4:2:2 mL) was added LiOH (222.14 mg, 9.270 mmol, 10 equiv) at rt. The crude product mixture was used in the next step directly without further purification 2-{ [(tert-butoxycarbonyl)amino]methyl}pyridine-4- carboxylic acid (300 mg, crude). MS (ESI): mass calcd. for C12H16N2O4252.11 m / z, found 253.10 [M+H]+. 2-{[(tert-butoxycarbonyl)amino]methyl}-4-carboxypyridin-1-ium-1-olate

[0601] To a solution of 2-{ [(tert-butoxycarbonyl)amino]methyl}pyridine-4-carboxylic acid (290 mg, 1.150 mmol, 1 equiv) in DCM (5 mL) was added m-CPBA (595.11 mg, 3.450 mmol, 3 equiv) at 0 degrees C .The resulting mixture was stirred for 3h at rt. The reaction mixture was quenched by water and extracted with EA (3*20 mL). The combined organic extracts were washed with brine (10 mL), dried over anhydrous Na2SO4, and concentrated under vacuum to yield a crude product which was directly purified by flash chromatography by C18 to afford product as 2-{ [(tert-butoxycarbonyl)amino]methyl}-4-carboxypyridin-1- ium-1-olate (200 mg, 64.85%) a white solid. MS (ESI): mass calcd. for C12H16N2O5268.11 m / z, found 269.15 [M+H]+.

[0602] 2-{[(tert-butoxycarbonyl)amino]methyl}-4-[4-(l-{[5-(4-fluorophenoxy)pyridin-2-yl] carbamoyl}ethyl)-2,2-dimethylpiperazine-1-carbonyl]pyridin-1-ium-1-olate

[0603] To a solution of 2-{ [(tert-butoxycarbonyl)amino]methyl}-4-carboxypyridin-1-ium-1- olate (190 mg, 0.708 mmol, 1 equiv) in DMF (3mL) was added 2-(3,3-dimethylpiperazin-1- yl)-N-[5-(4-fluorophenoxy) pyridine-2-yl]propanamide (263.78 mg, 0.708 mmol, 1 equiv) and HATU (403.95 mg, 1.062 mmol, 1.5 equiv) and DIEA (183.08 mg, 1.416 mmol, 2 equiv) at rt .The resulting mixture was stirred for 3h at rt. The reaction mixture was quenched by water and extracted with EA (3*20 mL). The combined organic extracts were washed with brine (lOmL), dried over anhydrous Na2SO4, and concentrated under vacuum to yield a crude product which was directly purified by flash chromatography to afford product 2- { [(tert- butoxycarbonyl)amino] methyl } -4- [4-( 1 - { [5-(4-fluorophenoxy)pyridin-2- yl]carbamoyl}ethyl)-2,2-dimethylpiperazine-1-carbonyl] pyridin-1-ium-1-olate (140 mg, 31.74%) as a white solid. MS (ESI): mass calcd. for C32H39FN6O6622.29 m / z, found 623.20 [M+H]+.

[0604] 2-(aminomethyl)-4-{4-[(lR)-1-{[5-(4-fluorophenoxy)pyridin-2-yl]carbamoyl}ethyl]-2,2- dimethylpiperazine-1-carbonyl}pyridin-1-ium-1-olate

[0605] To a solution of 2-{[(tert-butoxycarbonyl)amino]methyl}-4-[4-(l-{[5-(4- fluorophenoxy)pyridin-2-yl] carbamoyl}ethyl)-2,2-dimethylpiperazine-1-carbonyl]pyridin-1- ium- 1-olate (70 mg, 0.112 mmol, 1 equiv) in EA (1 mL) was added hydrochloric acid (in EA) (2 mL) at 0 °C. The resulting mixture was stirred for 2 h at rt. The product was precipitated by the addition of anhydrous ether. The precipitated solids were collected by filtration and washed with anhydrous ether to afford crude product. The crude product was separated by chiral-HPLC using a CHIRALPAK IF Column, 2*25 cm*5 μm column (eluent: 60% (v / v) Hex: DCM=3: 1(0.5% 2M NH3-MeOH) and EtOH) to afford 2-(aminomethyl)-4- {4-[(lR)-1-{[5-(4-fluorophenoxy)pyridin-2-yl]carbamoyl}ethyl]-2,2-dimethylpiperazine-1- carbonyl} pyridine -1-ium-1-olate (4.9 mg, 31.74%) as a white solid. MS (ESI): mass calcd. for C27H31FN6O4522.24 m / z, found: 523.35[M+H]+.1H NMR (300 MHz, DMSO-d6) δ 10.20 (s, 1H), 8.24 (d, .J = 6.5 Hz, 1H), 8.11 - 8.19 (m, 2H), 7.61 (d, J= 2.5 Hz, 1H), 7.49 - 7.57 (m, 1H), 7.29 - 7.37 (m, 1H), 7.19 - 7.28 (m, 2H), 7.09 - 7.14 (m, 2H), 3.79 (s, 2H), 3.43 - 3.55 (m, 1H), 2.67 - 2.77 (m, 2H), 2.59 - 2.64 (m, 2H), 2.45 - 2.50 (m, 2H),1.48 (d, J= 2.4 Hz, 6H), 1.17 - 1.27 (m, 3H).19F NMR (282 MHz, DMSO-d6) δ -119.83. And 2- (aminomethyl)-4- {4- [( 1 S)- 1 - { [5 -(4-fluorophenoxy)pyridin-2-yl]carbamoyl} ethyl] -2,2- dimethylpiperazine-1-carbonyl}pyridin-1-ium-1-olate (4.8 mg, 31.74%) as a white solid. MS (ESI): mass calcd. for C27H31FN6O4522.24 m / z, found: 523.35 [M+H]+. 'HNMR (300 MHz, DMSO-d6) δ 10.20 (s, 1H), 8.24 (d, J = 6.6 Hz, 1H), 8.11 - 8.19 (m, 2H), 7.61 (d, J= 2.5 Hz, 1H), 7.49 - 7.57 (m, 1H), 7.29 - 7.37 (m, 1H), 7.19 - 7.28 (m, 2H), 7.03 - 7.16 (m, 2H), 3.78 (s, 2H), 3.45 - 3.58 (m, 1H), 2.67 - 2.78 (m, 2H), 2.57 - 2.66 (m, 2H), 2.43- 2.52 (m, 2H), 1.48 (d, J= 2.4 Hz, 6H), 1.17 - 1.28 (m, 3H).19F NMR (282 MHz, DMSO-6) δ -119.83. Example 80: 4-{4-[(lR)-1-{[5-(4-fluorophenoxy)pyridin-2-yl]carbamoyl} ethyl ]-2,2- dimethylpiperazine-1-carbonyl}-2-[(methylamino)methyl]pyridin-1-ium-1-olate and Example 81: 4-{4-[(lS)-1-{[5-(4-fluorophenoxy)pyridin-2-yl]carbamoyl} ethyl ]-2,2- dimethylpiperazine- l-carbonyl}-2- [(methylamino)methyl]pyridin- 1 -ium- 1 -olate methyl 2-{[(tert-butoxycarbonyl)amino]methyl}pyridine-4-carboxylate

[0606] To a solution of methyl 2-(aminomethyl)pyridine-4-carboxylate (350 mg, 2.106 mmol, 1 equiv) in DCM (5 mL) was added TEA (639.38 mg, 6.318 mmol, 3 equiv) and BOC2O (919.33 mg, 4.212 mmol, 2 equiv). The mixture was stirred at rt for 3 h. After completion of reaction, the reaction mixture was quenched by addition of water (10 mL). The aqueous layer was extracted with ethyl acetate (50 mL). The combined organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue obtained was purified by silica gel chromatography (0-20% DCM / MeOH) to afford methyl 2- { [(tert-butoxycarbonyl)amino]methyl}pyridine-4-carboxylate (350 mg, 62.40%) as a yellow solid. MS (ESI): mass calcd for C13H18N2O4266.13 m / z, found 267.15 [M+H]+ methyl 2-{[(tert-butoxycarbonyl)(methyl)amino]methyl}pyridine-4-carboxylate

[0607] To a solution of methyl 2-{ [(tert-butoxycarbonyl)amino]methyl}pyridine-4-carboxylate (350 mg, 1.314 mmol, 1 equiv) in DMF (5 mL) was added NaH (78.85 mg, 3.285 mmol, 2.5 equiv) at 0 °C .The resulting mixture was stirred for 0.5h at rt. Then the resulting mixture was added Mel (373.11 mg, 2.628 mmol, 2 equiv) at 0 °C. The resulting mixture was stirred for 4 h at rt. After completion of reaction, the reaction mixture was quenched by addition of water (10 mL). The aqueous layer was extracted with ethyl acetate (2*50 mL). The combined organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue obtained was purified by silica gel chromatography (0-100%) PE / EA to afford methyl 2-{ [(tert-butoxycarbonyl)(methyl)amino]methyl}pyridine-4- carboxylate (270 mg, 73.28%) as a white solid. MS (ESI): mass calcd for C14H20N2O4280.14 m / z, found 281.15 [M+H]+.

[0608] 2-{[(tert-butoxycarbonyl)(methyl)amino]methyl}pyridine-4-carboxylic acid

[0609] To a solution of methyl 2-{ [(tert-butoxycarbonyl)(methyl)amino]methyl}pyridine-4- carboxylate (260 mg, 0.927 mmol, 1 equiv) in THF: MeOH : H2O (2:1:1 mL) was added LiOH (222.14 mg, 9.270 mmol, 10 equiv) at rt .The crude product / resulting mixture was used in the next step directly without further purification to afford 2-{[(tert- butoxycarbonyl)(methyl)amino]methyl}pyridine-4-carboxylic acid (90 mg, 23.58%) as a yellow oil. MS (ESI): mass calcd. for C13H18N2O4266.13 m / z, found 267.05 [M+H]+.

[0610] 2-{[(tert-butoxycarbonyl)(methyl)amino]methyl}-4-carboxypyridin-1-ium-1-olate

[0611] To a solution of methyl 2-(2,2,2-trifluoroethyl)pyridine-4-carboxylate (90 mg, 0.411 mmol, 1 equiv)in DCM (3 mL) was added m-CPBA (207.36 mg, 1.202 mmol, 2 equiv) at 0°C. The resulting mixture was stirred for 3 h at rt. The reaction mixture was quenched by water and extracted with EA (3*20 mL). The combined organic extracts were washed with brine (10 mL), dried over anhydrous Na2SO4, and concentrated under vacuum to yield a crude product which was directly purified by flash chromatography by Cl 8 to afford product as 2- { [(tert-butoxycarbonyl)(methyl)amino]methyl}-4-carboxypyridin-1-ium-1-olate (40 mg, 23.58%) a white solid. MS (ESI): mass calcd. for C13H18N2O5282.12 m / z, found 283.10 [M+H]+.

[0612] 2-{[(tert-butoxycarbonyl)(methyl)amino]methyl}-4-[4-(l-{[5-(4-fluorophenoxy)pyridin- 2-yl] carbamoyl}ethyl)-2,2-dimethylpiperazine-1-carbonyl]pyridin-1-ium-1-olate To a solution of 2-{ [(tert-butoxycarbonyl)(methyl)amino]methyl}pyridine-4-carboxylic acid (35 mg, 0.131 mmol, 1 equiv) in DMF (lOmL) was added 2-(3,3-dimethylpiperazin-1- yl)-N-[5-(4-fluorophenoxy) pyridin-2-yl]propanamide (48.95 mg, 0.131 mmol, 1 equiv) and HATU (99.95 mg, 0.262 mmol, 2 equiv) and DIEA (67.95 mg, 0.524 mmol, 4 equiv) at rt .The resulting mixture was stirred for 3h at rt. The reaction mixture was quenched by water and extracted with EA (3*20 mL).The combined organic extracts were washed with brine (lOmL), dried over anhydrous Na2SO4, and concentrated under vacuum to yield a crude product which was directly purified by flash chromatography(0-20% DCM / MeOH) to afford product 2- { [(tert-butoxycarbonyl)(methyl) amino] methyl } -4- [4-( 1 - { [5- (4- fluorophenoxy)pyridin-2-yl]carbamoyl }ethyl)-2,2-dimethylpiperazine- 1 -carbonyl]pyridin- 1 - ium-1-olate (45 mg, 53.77%) as a white solid. MS (ESI): mass calcd for C33H41FN6O6636.31 m / z, found 637.10 [M+H]+.

[0613] 4-{4-[(lR)-1-{[5-(4-fluorophenoxy)pyridin-2-yl] carbamoyl}ethyl]-2,2- dimethylpiperazine-1-carbonyl}-2-[(methylamino)methyl]pyridin-1-ium-1-olate and 4- {4- [(lS)-1-{[5-(4-fluorophenoxy)pyridin-2-yl] carbamoyl} ethyl ]-2,2-dimethylpiperazine- l-carbonyl}-2-[(methylamino)methyl]pyridin-1-ium-1-olate

[0614] To a solution of 2-{[(tert-butoxycarbonyl)(methyl)amino]methyl}-4-[4-(l-{[5-(4- fluorophenoxy) pyridin-2-yl] carbamoyl } ethyl)-2,2-dimethylpiperazine- 1 -carbonyl]pyridin- 1 - ium- 1-olate (45 mg, 0.071 mmol, 1 equiv) in EA(1 mL), was added hydrochloric acid (4N, in EA) (2 mL) at rt. The resulting mixture was stirred for 2h at rt. The product was precipitated by the addition of anhydrous ether. The precipitated solids were collected by filtration and washed with anhydrous ether to afford crude product. The crude product was separated by chiral-HPLC using a CHIRALPAK IF Column, 2*25 cm*5 μm column (eluent: 50% (v / v) Hex: DCM=3: 1(0.5% 2M NH3-MeOH) and EtOH) to afford 4-{4-[(lR)-1- { [5-(4- fluorophenoxy)pyridin-2-yl]carbamoyl } ethyl] -2,2-dimethylpiperazine- 1 -carbonyl } -2- [(methylamino)methyl]pyridin-1-ium-1-olate (1.9 mg) as a white solid. MS (ESI): mass calcd. for C28H33FN6O4, 536.25 found: 537.25 [M+H]+.1H NMR (300 MHz, DMSO-d6) δ 10.20 (s, 1H), 8.27 (d, J = 6.6 Hz, 1H), 8.11 - 8.20 (m, 2H), 7.48 - 7.58 (m, 2H), 7.30 - 7.38 (m, 1H), 7.17 - 7.30 (m, 2H), 7.04 - 7.16 (m, 2H), 3.75 (s, 2H), 2.68 - 2.78 (m, 1H), 2.58 - 2.65 (m, 1H), 2.42 - 2.50 (m, 4H), 2.26 - 2.33 (m, 3H),1.47 (d, J = 2.4 Hz, 6H), 1.21 (d, J = 6.8 Hz, 3H).19F NMR (282 MHz, DMSO-d6) δ -119.82. And 4-{4-[(lS)-1-{[5-(4- fluorophenoxy)pyridin-2-yl]carbamoyl } ethyl] -2,2-dimethylpiperazine- 1 -carbonyl } -2- [(methylamino)methyl]pyridin-1-ium-1-olate (2.0 mg) as a white solid. MS (ESI): mass calcd. for C28H33FN6O4, 536.25 found: 537.25 [M+H]+.1H NMR (300 MHz, DMSO-d6) δ 10.20 (s, 1H), 8.27 (d, J = 6.6 Hz, 1H), 8.11 - 8.22 (m, 2H), 7.48 - 7.57 (m, 2H), 7.30 - 7.39 (m, 1H), 7.17 - 7.31 (m, 2H), 7.04 - 7.16 (m, 2H), 3.76 (s, 2H), 3.51 (q, J = 6.8 Hz, 1H), 2.67- 2.77 (m, 1H), 2.55 - 2.63 (m, 1H), 2.45 - 2.48(m, 4H), 2.26 - 2.33 (m, 3H), 1.47 (d, J = 2.4 Hz, 6H), 1.21 (d, J = 6.9 Hz, 3H).19F NMR (282 MHz, DMSO-d6) δ -119.82. Example 82: 2-(acetamidomethyl)-4-{4-[(lR)-1-{[5-(4-fluorophenoxy)pyridin-2- yl]carbamoyl}ethyl]-2,2-dimethylpiperazine-1-carbonyl}pyridin-1-ium-1-olate and

[0615] Example 83: 2-(acetamidomethyl)-4-{4-[(lS)-1-{[5-(4-fluorophenoxy)pyridin-2- yl]carbamoyl}ethyl] -2,2-dimethylpiperazine- 1 -carbonyl}pyridin- 1 -ium-1 -olate

[0616] 2-(acetamidomethyl)-4-{4-[(lR)-1-{[5-(4-fluorophenoxy)pyridin-2-yl]carbamoyl}ethyl]- 2,2-dimethylpiperazine- 1 -carbonyl}pyridin- 1 -ium- 1 -olate AND 2-(acetamidomethyl) -4- {4-[(lS)-1-{[5-(4-fluorophenoxy)pyridin-2-yl]carbamoyl}ethyl]-2,2 -dimethylpiperazine- 1 -carbonyl}pyridin- 1 -ium- 1 -olate To a solution of 2-(aminomethyl)-4-[4-(l-{[5-(4-fluorophenoxy)pyridin-2- yl] carbamoyl }ethyl)-2,2-dimethylpiperazine-1-carbonyl]pyridin-1-ium-1-olate (55 mg, 0.105 mmol, 1 equiv) in DCM (1 mL), was added AC2O (0.2 mL) at rt. The resulting mixture was stirred for 4 h at rt. The product was precipitated by the addition of anhydrous ether. The precipitated solids were collected by filtration and washed with anhydrous ether. The crude is separated by chiral-HPLC using a chiral-HPLC using a CHIRALPAK IG, 2*25 cm, 5 μm column (eluent: 60% (v / v) Hex: DCM=3: 1(0.5% 2M NH3-MeOH) and EtOH) to afford 2- (acetamidomethyl)-4- { 4- [( 1 R)- 1 - { [5-(4-fluorophenoxy)pyridin-2-yl] carbamoyl } ethyl] -2,2- dimethylpiperazine-1 -carbonyl }pyridin-1-ium-1-olate (8.3 mg) as a white solid. MS (ESI): mass calcd. for C29H33FN6O5, 564.25 found: 656.30 [M+H]+.1H NMR (300 MHz, DMSO-d6) 5 10.23 (s, 1H), 8.47 (t, 7 = 6.0 Hz, 1H), 8.30 (d, J = 6.6 Hz, 1H), 8.11 - 8.20 (m, 2H), 7.53 (dd, J = 9.0, 3.1 Hz, 1H), 7.38 (dd, J= 6.6, 2.5 Hz, 1H), 7.17 - 7.32 (m, 3H), 7.03 - 7.16 (m, 2H), 4.32 (d, J = 5.9 Hz, 2H), 3.53 (q, J = 6.6 Hz, 1H), 2.56- 2.77 (m, 2H), 2.50 - 2.54 (m, 2H), 2.45 - 2.48(m, 2H), 1.91 (s, 3H), 1.46 (d, J = 3.1 Hz, 6H), 1.21 (d, J = 6.9 Hz, 3H).19F NMR (282 MHz, DMSO-d6) δ -119.83. And 2-(acetamidomethyl)-4-{4-[(lS)-1-{[5-(4- fluorophenoxy)pyridin-2-yl]carbamoyl } ethyl] -2 ,2 -dimethylpiperazine- 1 -carbonyl }pyridin- 1 - ium-1-olate (8.8 mg). MS (ESI): mass calcd. for C29H33FN6O5, 564.25 m / z found: 656.30 [M+H]+.1H NMR (300 MHz, DMSO-d6) δ 10.23 (s, 1H), 8.47 (t, J = 5.9 Hz, 1H), 8.30 (d, J =

[0617] 6.6 Hz, 1H), 8.11 - 8.20 (m, 2H), 7.53 (dd, J = 8.9, 3.1 Hz, 1H), 7.38 (dd, J= 6.6, 2.5 Hz, 1H), 7.17 - 7.32 (m, 3H), 7.04 - 7.16 (m, 2H), 4.32 (d, J = 5.9 Hz, 2H), 3.53 (q, J = 6.7 Hz, 1H), 2.56 - 2.76 (m, 2H), 2.50 - 2.54 (m, 2H), 2.45 - 2.48(m, 2H), 1.91 (s, 3H), 1.46 (d, J =

[0618] 3.7 Hz, 6H), 1.21 (d, J = 6.9 Hz, 3H).19F NMR (282 MHz, DMSO-d6) δ-119.83.

[0619] Example 84: (R)-2-(4-(5-cyano-6-oxo-l,6-dihydropyridine-3-carbonyl)-3,3- dimethylpiperazin- 1 -yl)-N- (5- (4-fluorophenoxy)pyridin-2-yl)propenamide and Example 85: (S)-2-(4-(5-cyano-6-oxo-l,6-dihydropyridine-3-carbonyl)-3,3-dimethylpiperazin-1- yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propanamide Synthetic Scheme methyl 5-cyano-6-methoxynicotinate

[0620] To a solution of methyl 5-bromo-6-methoxypyridine-3-carboxylate (300 mg, 1.219 mmol, 1 equiv) in dimethylformamide (10 mL) the mixture was added zinc cyanide (286.32 mg, 2.438 mmol, 2 equiv) Pd2(dba)3(66.99 mg, 0.073 mmol, 0.06 equiv) dppf (80.82 mg, 0.146 mmol, 0.12 equiv) and Zn (2.39 mg, 0.037 mmol, 0.03 equiv). The mixture was stirred at 100 °C for 2 h under N2. After completion of reaction, the mixture was quenched with water (30 mL) extracted with ethyl acetate (3 x 100 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The residue obtained was purified by silica gel chromatography (0-50% EA / PE) to afford methyl 5-cyano-6-methoxynicotinate (130 mg, 55.48%) as a yellow solid. MS (ESI): mass calcd. for C9H8N2O3: 192.05, found: 193.10 [M+H]+.

[0621] 5-cyano-6-methoxynicotinic acid

[0622] To a solution of methyl 5-cyano-6-methoxypyridine-3-carboxylate (130 mg, 0.676 mmol, 1 equiv) in THF (2 mL) MeOH (1 mL) and H2O (1 mL). The mixture was stirred at room temperature for 2 h. After completion of reaction, the mixture was acidified to pH=3 with (2 N HC1) extracted with ethyl acetate (3 x 100 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated to afford 5-cyano-6- methoxynicotinic acid (102 mg, 84.64%) as a yellow solid. MS (ESI): mass calcd. for C8H6N2O3: 178.04, found: 179.10 [M+H]+.

[0623] 2-(4-(5-cyano-6-methoxynicotinoyl)-3,3-dimethylpiperazin-1-yl)-N-(5-(4- fluorophenoxy)pyridin-2-yl)propanamide

[0624] To a solution of 5-cyano-6-methoxypyridine-3-carboxylic acid (100 mg, 0.561 mmol, 1 equiv) in N,N-dimethylformamide (5 mL) the mixture was added 2-(3,3-dimethylpiperazin- l-yl)-N-[5-(4-fluorophenoxy)pyridin-2-yl]propanamide (209.07 mg, 0.561 mmol, 1.0 equiv), HATU (320.16 mg, 0.842 mmol, 1.5 equiv) then added DIEA (217.65 mg, 1.683 mmol, 3.0 equiv). The mixture was stirred at room temperature for 2 h. After completion of reaction the mixture was quenched with water (10 mL) extracted with ethyl acetate (3 x 10 mL). The combined organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The residue obtained was purified by silica gel chromatography (0-10% DCM / MeOH) to afford 2-(4-(5-cyano-6-methoxynicotinoyl)-3,3-dimethylpiperazin-1-yl)-N- (5-(4-fluorophenoxy)pyridin-2-yl)propanamide (160 mg, 53.52%) as a yellow solid. MS (ESI): mass calcd. for C28H29FN6O4: 532.22, found: 533.05 [M+H]+.

[0625] (R)-2-(4-(5-cyano-6-oxo-l,6-dihydropyridine-3-carbonyl)-3,3-dimethylpiperazin-1-yl)- N-(5-(4-fluorophenoxy)pyridin-2-yl)propanamide and (S)-2-(4-(5-cyano-6-oxo-l,6- dihydropyridine-3-carbonyl)-3,3-dimethylpiperazin-1-yl)-N-(5-(4- fluorophenoxy)pyridin-2-yl)propanamide

[0626] To a solution of 2-[4-(5-cyano-6-methoxypyridine-3-carbonyl)-3,3- dimethylpiperazin-1-yl]-N-[5-(4-fluorophenoxy)pyridin-2-yl]propanamide (100 mg, 0.188 mmol, 1 equiv) in N,N-dimethylformamide(DMF) (2 mL) the mixture was added Pyridine hydrobromide (150.22 mg, 0.940 mmol, 5.0 equiv). The reaction was stirred at 100°C for 3 h. The mixture was concentrated to dryness under reduced pressure to provide the crude product, which was purified by chiral-HPLC using a CHIRALPAK IA, 2*25 cm, 5 μm column (eluent: 40% (v / v) MtBE (0.5% 2M NH3-MeOH) and IPA: DCM=1: 1 to afford (R)- 2-(4-(5-cyano-6-oxo-l,6-dihydropyridine-3-carbonyl)-3,3-dimethylpiperazin-1-yl)-N-(5-(4- fluorophenoxy)pyridin-2-yl)propanamide (13.0 mg, 12.82%) as a white solid. MS (ESI): mass calcd. for C27H27FN6O4: 518.21, found: 519.25 [M+H]+.1H NMR (300 MHz, DMSO- d6) δ 11.98 - 12.70 (br, 1H), 10.18 (s, 1H), 8.11 - 8.20 (m, 3H), 7.93 (d, J = 2.6 Hz, 1H), 7.53 (dd, 7 = 9.0, 3.1 Hz, 1H), 7.17 - 7.31 (m, 2H), 7.02 - 7.16 (m, 2H), 3.50 (q, 7= 6.8 Hz, 1H), 3.32 - 3.42 (m, 2H), 2.69 - 2.81 (m, 1H), 2.57 - 2.69 (m, 1H), 2.35 - 2.50 (m, 2H), 1.42 (d, J = 2.3 Hz, 6H), 1.14 - 1.27 (m, 3H). And (S)-2-(4-(5-cyano-6-oxo-l,6-dihydropyridine-3- carbonyl)-3,3-dimethylpiperazin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propanamide (21.5 mg, 21.91%) as a white solid. MS (ESI): mass calcd. for C27H27FN6O4: 518.21, found: 519.25 [M+H]+.1H NMR (300 MHz, DMSO-d6) δ 11.79 - 12.52 (br, 1H), 10.18 (s, 1H), 8.11

[0627] - 8.20 (m, 3H), 7.93 (d, J = 2.6 Hz, 1H), 7.53 (dd, J = 9.0, 3.1 Hz, 1H), 7.17 - 7.31 (m, 2H), 7.02 - 7.16 (m, 2H), 3.50 (q, 7= 6.8 Hz, 1H), 3.32 - 3.42 (m, 2H), 2.69 - 2.81 (m, 1H), 2.59

[0628] - 2.69 (m, 1H), 2.35 - 2.49 (m, 2H), 1.42 (d, J = 2.3 Hz, 6H), 1.21 (d, J = 6.8 Hz, 3H).

[0629] Example 86: 2-(4-(5-(aminomethyl)-6-oxo-l,6-dihydropyridine-3-carbonyl)-3,3- dimethylpiperazin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propanamide

[0630]

[0631] 2-(4-(5-bromo-6-methoxynicotinoyl)-3,3-dimethylpiperazin-1-yl)-N-(5-(4- fluorophenoxy)pyridin-2-yl)propanamide

[0632] To a solution of 2-(3,3-dimethylpiperazin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2- yl)propanamide (1 g, 2.685 mmol, 1 equiv) in DMF (20 mL) the mixture was added 5- bromo-6-methoxynicotinic acid (623 mg, 2.685 mmol, 1 equiv), HATU (1.83 g, 4.027 mmol, 1.5 equiv), and N,N-diisopropylethylamine (1.39 g, 10.740 mmol, 4 equiv) at rt. The resulting mixture was stirred for 2 hours at rt. The reaction mixture was quenche d by water (10 mL) and extracted with EA (10 mL x 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue obtained was purified by silica gel chromatography (0-10% DCM / MeOH) to give 2- (4-(5-bromo-6-methoxynicotinoyl)-3,3-dimethylpiperazin-1-yl)-N-(5-(4- fluorophenoxy)pyridin-2-yl)propanamide (600 mg, 35.06%) a white solid. MS (ESI): mass calcd. for C27H29BrFN5O4: 585.13, found: 586.20 [M+H]+. tert-butyl ((5-(4-(l-((5-(4-fluorophenoxy)pyridin-2-yl)amino)-1-oxopropan-2-yl)-2,2- dimethylpiperazine-1-carbonyl)-2-methoxypyridin-3-yl)methyl)carbamate

[0633] In a 40-mL round bottom flask, to a solution of 2-(4-(5-bromo-6-methoxynicotinoyl)- 3,3-dimethylpiperazin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propanamide (600 mg, 35.06%) (1 g, 1.705 mmol, 1 equiv) in dioxane (20 mL) and H2O (2 mL) was added tert- butyl N-[(trifluoro-lambda4-boranyl)methyl]carbamate potassium (0.81 g, 3.410 mmol, 2 equiv), Pd(OAc)2(0.04 g, 0.171 mmol, 0.1 equiv), CS2CO3(1.11 g, 3.410 mmol, 2 equiv) and Sphos (0.07 g, 0.171 mmol, 0.1 equiv) at room temprature under. The reaction mixture was stirred at 110 °C for 3 h under N2. After completion of reaction, the reaction was quenched by water (10 mL) and extracted with EA (10 mL x 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue obtained was purified by silica gel chromatography (0-100% EA / PE) to afford tert-butyl ((5-(4-(l-((5-(4-fluorophenoxy)pyridin-2-yl)amino)-1-oxopropan- 2-yl)-2,2-dimethylpiperazine-1-carbonyl)-2-methoxypyridin-3-yl)methyl)carbamate (120 mg, 71.19%). MS (ESI): mass calcd. for C33H41FN6O6: 636.30 m / z. found 637.15 [M+H]+.

[0634] 2-(4-(5-(aminomethyl)-6-methoxynicotinoyl)-3,3-dimethylpiperazin-1-yl)-N-(5-(4- fluorophenoxy)pyridin-2-yl)propanamide

[0635] To a stirred solution of 2-(4-(5-(aminomethyl)-6-methoxynicotinoyl)-3,3- dimethylpiperazin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propanamide (200 mg, 0.314 mmol, 1 equiv) in EA (5 mL) was added HC1 (4 M in EA, 5 mL). The reaction mixture was stirred at room temperature for 1 h. The product was precipitated by the addition of diethyl ether. The product is obtained (120 mg, 71.19%) by filtration and drying. MS (ESI): mass calcd. for C28H33FN6O4: 536.25, m / z, found: 537.15 [M+H]+.

[0636] 2-(4-(5-(aminomethyl)-6-oxo-l,6-dihydropyridine-3-carbonyl)-3,3-dimethylpiperazin-1- yI)-N-(5-(4-fluorophenoxy)pyridin-2-yI)propanamide

[0637] To a solution of 2-(4-(5-(aminomethyl)-6-methoxynicotinoyl)-3,3-dimethylpiperazin-1- yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propanamide (100 mg, 0.186 mmol, 1 equiv) in DMF (5 mL) the mixture was added pyridine hydrobromide (149.10 mg, 0.930 mmol, 5 equiv) . The mixture was stirred at 100°C for 2h. The mixture was concentrated to dryness under reduced pressure to provide the crude product, which was purified by Cl 8 Column (CH3CN & H2O with 10 mmol / L NH4HCO3) to afford 2-(4-(5-(aminomethyl)-6-oxo-l,6- dihydropyridine-3-carbonyl)-3,3-dimethylpiperazin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2- yl)propanamide as a white solid. MS (ESI): mass calcd. for C27H31FN6O4: 522.24, found: 523.15 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 10.17 (s, 1H), 8.12 - 8.19 (m, 2H), 7.44 - 7.57 (m, 3H), 7.19 - 7.32 (m, 2H), 7.05 - 7.15 (m, 2H), 3.44 - 3.54 (...

Claims

We claim:

1. A compound of Formula (la) or (lb):or a pharmaceutical salt thereof; wherein:X is N or CRX;X1, X2, and X3are each independently N or CRX;Rxis independently for each occurrence hydrogen, fluoro, or chloro;Y is C(=O), C(=O)CH2, CH2, or a bond;R1is -OR1aor -CH2R1a; wherein R1ais phenyl, (C1-C6)alkyl, 5- to 6-membered heteroaryl, or (C3-C8)cycloalkyl(C1-C6)alkyl; each of which is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, chloro, (C1- C6)alkyl, (C3C8)cycloalkyl, and (C1-C6)alkoxy;R2is 4-, 5- or 6- membered heterocycloalkyl, 9- or 10-membered bicyclic heterocycloalkyl, 5- or 6- membered heteroaryl, 9- or 10-membered bicyclic heteroaryl, (C3- C8)cycloalkyl, or phenyl; each of which is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, chloro, cyano, hydroxy, (C1-C6)alkyl, (C1-C6)alkenyl, -C(=O)NH2, -NH2, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)hydroxy alkyl, (C1-C6)halohydroxyalkyl, (C1-C6)hydroxyalkoxy, (C1-C6)carboxyalkyl (C1-C6)haloalkoxy, (C3-C8)cycloalkyl, and 4- to 7-membered heterocycloalkyl; wherein (C1- C6)alkyl is optionally substituted with phenyl, 4- to 7-membered heterocycloalkyl, or - NHR2a; or R2is (C1-C6)alkyl;R2ais C(=O)R2b, (C1-C6)alkyl, or (C3-C8)cycloalkyl, wherein (C1-C6)alkyl or (C3- C8)cycloalkyl is optionally substituted with one or more independent instances of halo;R2bis (C1-C6)alkyl;R3and R4are each independently hydrogen, (C1-C6)alkyl, (C1-C6)alkoxyalkyl, or (C1- C6)haloalkyl; or taken together with the carbon atom to which they are attached form a (C3- C6)cycloalkyl;R5is hydrogen, (C1-C6)alkyl, (C1-C6)alkoxyalkyl, or (C1-C6)haloalkyl; or R5taken together with R3or R4forms -(CH2)n-; wherein n is 1, 2, or 3; andR6and R7are independently for each occurrence hydrogen or (C1-C6)alkyl; or R6and R7taken together with the carbon atom to which they are attached form a (C3-C6)cycloalkyl.

2. A compound of Formula (la) or (lb):or a pharmaceutical salt thereof; wherein:X is N or CRX;X1, X2, and X3are each independently N or CRX;Rxis independently for each occurrence hydrogen, fluoro, or chloro;Y is C(=O), C(=O)CH2, CH2, or a bond;R1is -OR1aor -CH2R1a; wherein R1ais phenyl, 5- to 6-membered heteroaryl, or (C3- C8)cycloalkyl(C1-C6)alkyl; each of which is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, chloro, (C1-C6)alkyl, (C3-C8)cycloalkyl, and (C1-C6)alkoxy;R2is 5- or 6- membered heterocycloalkyl, 9- or 10-membered bicyclic heterocycloalkyl 5- or 6- membered heteroaryl, 9- or 10-membered bicyclic heteroaryl, or phenyl; each of which is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, chloro, cyano, hydroxy, (C1-C6)alkyl, (C1- C6)alkenyl, -C(=O)NH2, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, and (C1- C6)haloalkoxy; wherein (C1-C6)alkyl is optionally substituted with phenyl or -NHR2a;R2ais (C3-C8)cycloalkyl, optionally substituted with one or more independent instances of halo;R3and R4are each independently hydrogen, (C1-C6)alkyl, (C1-C6)alkoxyalkyl, or (C1- C6)haloalkyl; or taken together with the carbon atom to which they are attached form a (C3- C6)cycloalkyl;R5is hydrogen, (C1-C6)alkyl, (C1-C6)alkoxyalkyl, or (C1-C6)haloalkyl; or R5taken together with R3or R4forms -(CH2)n-; wherein n is 1, 2, or 3; andR6and R7are independently for each occurrence hydrogen or (C1-C6)alkyl; or R6and R7taken together with the carbon atom to which they are attached form a (C3-C6)cycloalkyl.

3. The compound of claim 1 or 2, wherein the compound is formula (la):

4. The compound of claim 3, wherein X1is N.

5. The compound of claim 3, wherein X1is CH.

6. The compound of any one of claims 3 to 5, wherein X2is CH.

7. The compound of any one of claims 3 to 6, wherein X3is CH.

8. The compound of claim 3, wherein X1is N; X2is CH; and X3is CH.

9. The compound of claim 3, wherein X1is CH; X2is CH; and X3is CH.

10. The compound of claim 1 or 2, wherein the compound is formula (lb):

11. The compound of claim 10, wherein X is CH.

12. The compound of any one of claims 1 to 11, wherein Y is C(=O).

13. The compound of any one of claims 1 to 12, wherein, R1is -OR1a.

14. The compound of any one of claims 1 to 13, wherein R1ais phenyl optionally substituted with one or two instances of fluoro or chloro.

15. The compound of claim 14, wherein R1ais 4-fluorophenyl.

16. The compound of claim 14, wherein R1ais 2,4-difluorophenyl.

17. The compound of claim 14, wherein R1ais 4-chlorophenyl.

18. The compound of any one of claims 1 to 13, wherein R1ais 6-membered heteroaryl optionally substituted with one or two instances of fluoro or chloro.

19. The compound of claim 18, wherein R1ais pyridyl optionally substituted with one or two fluoro or chloro.

20. The compound of claim 17 or 19, wherein R1ais 4-fluoropyridyl.

21. The compound of any one of claims 1 to 13, wherein R1ais (C3-C8)cycloalkyl(C1- C6)alkyl.

22. The compound of any one of claims 1 to 13, wherein R1ais cyclopropylmethyl.

23. The compound of any one of claims 1 to 22, wherein R2is 9- or 10-membered bicyclic heteroaryl optionally substituted with one or more substituents independently selected from the group consisting of fluoro, chloro, cyano, hydroxy, (C1-C6)alkyl, (C1- C6)alkenyl, -C(=O)NH2, -NH2, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)hydroxy alkyl, (C1- C6)halohydroxyalkyl, (C1-C6)hydroxyalkoxy, (C1-C6)carboxyalkyl (C1-C6)haloalkoxy, (C3- C8)cycloalkyl. and 4- to 7-membered heterocycloalkyl; wherein (C1-C6)alkyl is optionally substituted with phenyl, 4- to 7-membered heterocycloalkyl, or -NHR2a.

24. The compound of claim 23, wherein R2is [l,2,4]triazolo[4,3-a]pyridine, [l,2,4]triazolo[l,5-a]pyridine, [l,2,4]triazolo[l,5-a]pyrazine, [l,2,4]triazolo[l,5- a]pyrimidine, [l,2,4]triazolo[4,3-a]pyrimidine, [l,2,4]triazolo[l,5-b]pyridazine, 1H- pyrazolo[3,4-b]pyridine 7-oxide, 3H-imidazo[4,5-b]pyridine 4-oxide, benzo[d]oxazole, 1H- benzo[d]imidazole, benzo [d] thiazole, lH-benzo[d][l,2,3]triazole, [l,2,3]oxadiazolo[4,5- b]pyridine, oxazolo[4,5-b]pyridine, IH-indazole, lH-pyrazolo[3,4-b]pyridine, or oxoisoindolin-1-yl; each of which is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, chloro, cyano, hydroxy, (C1- C6)alkyl, (C1-C6)alkenyl, -C(=O)NH2, -NH2, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1- C6)hydroxyalkyl, (C1-C6)halohydroxyalkyl, (C1-C6)hydroxyalkoxy, (C1-C6)carboxyalkyl (C1- C6)haloalkoxy, (C3-C8)cycloalkyl. and 4- to 7-membered heterocycloalkyl; wherein (C1- C6)alkyl is optionally substituted with phenyl, 4- to 7-membered heterocycloalkyl, or - NHR2a.

25. The compound of claim 22, wherein R2is [l,2,4]triazolo[4,3-a]pyridine, [l,2,4]triazolo[l,5-a]pyridine, [l,2,4]triazolo[l,5-a]pyrazine, [l,2,4]triazolo[l,5- a]pyrimidine, [l,2,4]triazolo[4,3-a]pyrimidine, [l,2,4]triazolo[l,5-b]pyridazine, 1H- pyrazolo[3,4-b]pyridine 7-oxide, 3H-imidazo[4,5-b]pyridine 4-oxide, benzo[d]oxazole, 1H-benzo[d]imidazole, benzo [d] thiazole, lH-benzo[d][l,2,3]triazole, [l,2,3]oxadiazolo[4,5- b]pyridine, oxazolo[4,5-b]pyridine, or IH-indazole, each of which is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, chloro, cyano, hydroxy, (C1-C6)alkyl, (C1-C6)alkenyl, -C(=O)NH2, -NH2, (C1-C6)alkoxy, (C1- C6)haloalkyl, (C1-C6)hydroxyalkyl, (C1-C6)halohydroxyalkyl, (C1-C6)hydroxyalkoxy, (C1- C6)carboxyalkyl (C1-C6)haloalkoxy, (C3-C8)cycloalkyl, and 4- to 7-membered heterocycloalkyl; wherein (C1-C6)alkyl is optionally substituted with phenyl, 4- to 7- membered heterocycloalkyl, or -NHR2a.

26. The compound of any one of claims 1 to 22, wherein R2is 9- or 10-membered bicyclic heterocycloalkyl optionally substituted with one or more substituents independently selected from the group consisting of fluoro, chloro, cyano, hydroxy, (C1-C6)alkyl, (C1- C6)alkenyl, -C(=O)NH2, -NH2, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)hydroxy alkyl, (C1- C6)halohydroxyalkyl, (C1-C6)hydroxyalkoxy, (C1-C6)carboxyalkyl (C1-C6)haloalkoxy, (C3- C8)cycloalkyl. and 4- to 7-membered heterocycloalkyl; wherein (C1-C6)alkyl is optionally substituted with phenyl, 4- to 7-membered heterocycloalkyl, or -NHR2a.

27. The compound of claim 26, wherein R2is 6,7-dihydro-5H-cyclopenta[b]pyridine 1- oxide, 5,6,7,8-tetrahydro-[l,2,4]triazolo[l,5-a]pyridine, 4,5,6,7-tetrahydropyrazolo[l,5- a]pyridine, 4,5,6,7-tetrahydro-[l,2,3]triazolo[l,5-a]pyridine, 5,6,7,8-tetrahydroimidazo[l,2- a]pyridine, 4,5,6,7-tetrahydro-lH-benzo[d]imidazole, 4,5,6,7-tetrahydrobenzo[d]oxazole, 4,5,6,7-tetrahydro-112-benzo[d][l,2,3]triazole, 6,7-dihydro-5H-[l,2,4]triazolo[5,l- b][l,3]oxazine, 4,5,6,7-tetrahydro-2H-benzo[d][l,2,3]triazole, isoindolin-1-one, or 7-oxo-6,7- dihydro-lH-pyrazolo[4,3-d]pyrimidine; each of which is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, chloro, cyano, hydroxy, (C1-C6)alkyl, (C1-C6)alkenyl, -C(=O)NH2, -NH2, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)hydroxy alkyl, (C1-C6)halohydroxyalkyl, (C1-C6)hydroxyalkoxy, (C1-C6)carboxyalkyl (C1-C6)haloalkoxy, (C3-C8)cycloalkyl. and 4- to 7-membered heterocycloalkyl; wherein (C1- C6)alkyl is optionally substituted with phenyl, 4- to 7-membered heterocycloalkyl, or - NHR2a.

28. The compound of claim 27, wherein R2is 6,7-dihydro-5H-cyclopenta[b]pyridine 1- oxide, 5,6,7,8-tetrahydro-[l,2,4]triazolo[l,5-a]pyridine, 5,6,7,8-tetrahydro- [l,2,4]triazolo[l,5-a]pyridine, 4,5,6,7-tetrahydropyrazolo[l,5-a]pyridine, 4,5,6,7-tetrahydro- [l,2,3]triazolo[l,5-a]pyridine, 5,6,7,8-tetrahydroimidazo[l,2-a]pyridine, 4,5,6,7-tetrahydro- lH-benzo[d] imidazole, 4,5,6,7-tetrahydrobenzo[d]oxazole, 4,5,6,7-tetrahydro-lH-benzo[d][l,2,3]triazole, 6,7-dihydro-5H-[l,2,4]triazolo[5,l-b][l,3]oxazine, 4, 5,6,7- tetrahydro-2H-benzo[d][l,2,3]triazole, or isoindolin-1-one, each of which is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, chloro, cyano, hydroxy, (C1-C6)alkyl, (C1-C6)alkenyl, -C(=O)NH2, -NH2, (C1- C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)hydroxy alkyl, (C1-C6)halohydroxyalkyl, (C1- C6)hydroxyalkoxy, (C1-C6)carboxy alkyl (C1-C6)haloalkoxy, (C3-C8)cycloalkyl, and 4- to 7- membered heterocycloalkyl; wherein (C1-C6)alkyl is optionally substituted with phenyl, 4- to 7-membered heterocycloalkyl, or -NHR2a.

29. The compound of any one of claims 1 to 22, wherein R2is pyridin-2(lH)-one, pyridine oxide, pyrimidine oxide, l,5-dihydro-2H-pyrrol-2-one, phenyl, isoindolin-1-one, IH-indazole, tetrahydro-2H-pyran, pyridine, IH-pyrazole, 2-oxo-2,3-dihydro-lH-imidazole, 5 -oxomorpholine, tetrahydropyrimidin-2(lH)-one, piperidin-2-one, pyrimidin-2(lH)-one, pyridazin-3(2H)-one, or pyrazin-2(lH)-one; each of which is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, chloro, cyano, hydroxy, (C1-C6)alkyl, (C1-C6)alkenyl, -C(=O)NH2, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, and (C1-C6)haloalkoxy; wherein (C1-C6)alkyl is optionally substituted with phenyl or -NHR2a.

30. The compound of any one of claims 1 to 22, wherein R2is pyridin-2(lH)-one, pyridine oxide, pyrimidine oxide, l,5-dihydro-2H-pyrrol-2-one, phenyl, isoindolin-1-one, IH-indazole, tetrahydro-2H-pyran, pyridine, IH-pyrazole, 2-oxo-2,3-dihydro-lH-imidazole, or 5-oxomorpholine; each of which is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, chloro, cyano, hydroxy, (C1- C6)alkyl, (C1-C6)alkenyl, -C(=O)NH2, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)hydroxy alkyl, and (C1-C6)haloalkoxy; wherein (C1-C6)alkyl is optionally substituted with phenyl or -NHR2a.

31. The compound of any one of claims 1 to 22, wherein R2is pyridin-2(lH)-one, pyridine oxide, pyrimidine oxide, l,5-dihydro-2H-pyrrol-2-one, phenyl, isoindolin-1-one, IH-indazole, tetrahydro-2H-pyran, pyridine, or IH-pyrazole; each of which is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, chloro, cyano, hydroxy, (C1-C6)alkyl, (C1-C6)alkenyl, -C(=O)NH2, (C1-C6)alkoxy, (C1- C6)haloalkyl, (C1-C6)hydroxy alkyl, and (C1-C6)haloalkoxy; wherein (C1-C6)alkyl is optionally substituted with phenyl or -NHR2a.

32. The compound of claim 29, wherein R2is pyridin-2(lH)-one or pyridine oxide; each of which is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, chloro, cyano, hydroxy, (C1-C6)alkyl, (C1-C6)alkenyl, - C(=O)NH2, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, and (C1-C6)haloalkoxy; wherein (C1-C6)alkyl is optionally substituted with phenyl or -NHR2a.

33. The compound of claim 29, wherein R2is unsubstituted pyridin-2(lH)-one or pyridine oxide.

34. The compound of claim 29, wherein R2is pyrazin-2(lH)-one optionally substituted with (Ci -C6)hydroxy alkyl.

35. The compound of any one of claims 1 to 34, wherein R2ais methyl.

36. The compound of any one of claims 1 to 34, wherein R2ais cyclobutyl optionally substituted with at least one fluoro.

37. The compound of any one of claims 1 to 36, wherein R2bis methyl.

38. The compound of any one of claims 1 to 37, wherein R3and R4are each hydrogen.

39. The compound of any one of claims 1 to 34, wherein R3and R4are each independently (C1-C6)alkyl.

40. The compound of claim 39, wherein R3and R4are each methyl.

41. The compound of any one of claims 1 to 37, wherein one of R3and R4is hydrogen.

42. The compound of claim 41, wherein one of R3and R4is (C1-C6)fluoroalkyl.

43. The compound of claim 42, wherein (C1-C6)fluoroalkyl is trifluoromethyl.

44. The compound of any one of claims 1 to 37, wherein R3and R4taken together with the carbon atom to which they are attached form a (C3-C6)cycloalkyl.

45. The compound of claim 44, wherein R3and R4taken together with the carbon atom to which they are attached form cyclopropyl.

46. The compound of claim 44, wherein R3and R4taken together with the carbon atom to which they are attached form cyclobutyl.

47. The compound of any one of claims 1 to 46, wherein R5is hydrogen.

48. The compound of any one of claims 1 to 43, wherein R5taken together with one of R3or R4forms -(CH2)n-49. The compound of any claim 48, wherein n is 2.

50. The compound of any one of claims 1 to 49, wherein one of R6or R7is hydrogen.

51. The compound of any one of claims 1 to 50, wherein one of R6or R7is (C1-C6)alkyl.

52. The compound of claim 51, wherein one of R6or R7is methyl.

53. The compound of claim 51, wherein one of R6or R7is ethyl.

54. The compound of any one of claims 1 to 49, wherein R6and R7are each hydrogen.

55. The compound of any one of claims 1 to 49, wherein each of R6and R7is (C1-C6)alkyl.

56. The compound of claim 55, wherein each of R6and R7is methyl.

57. The compound of any one of claims 1 to 49, wherein R6and R7taken together with the carbon atom to which they are attached form a (C3-C6)cycloalkyl.

58. The compound of claim 57, wherein R6and R7taken together with the carbon atom to which they are attached form cyclopropyl.

59. A compound having the structure:or a pharmaceutically acceptable salt thereof.

60. A compound having the structure:or a pharmaceutically acceptable salt thereof.

61. A compound having the structure:-126-or a pharmaceutically acceptable salt thereof.

62. A pharmaceutical composition, comprising a compound of any one of claims 1 to 61; and at least one pharmaceutically acceptable excipient.

63. A method of preventing or treating an MRGPRX2-mediated disease or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of the compound of any one of claims 1 to 61.

64. The method of claim 63, wherein the MRGPRX2 -mediated disease or disorder is selected from the group consisting of chronic spontaneous urticaria, prurigo nodularis, irritable bowel syndrome, chronic inducible urticaria, atopic dermatitis, osteoarthritis, rosacea, migraine, pseudo-analphylaxis, mast cell activation syndrome, mastocytosis, pruritus, neurodermatitis, contact urticaria, allergic rhinitis, asthma, acute contact dermatitis, ulcerative colitis, Crohn’s disease, idiopathic chronic cough, rheumatoid arthritis, multiple sclerosis, geographic atrophy, endometriosis, seborrheic dermatitis, psoriasis, chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, neuropathic itch, periodontitis, autism, abdominal aortic aneurysms, deep vein thrombosis, amyotrophic lateral sclerosis, interstitial cystitis, coronary artery disease, cancer, sickle cell disease, obesity, and ulcers.

65. The method of claim 63 or 64, wherein the MRGPRX2-mediated disease or disorder is prevented.

66. The method of claim 63 or 64, wherein the MRGPRX2-mediated disease or disorder is treated.

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